Evidence Report/Technology Assessment 

Number 142 

Testing for BNP and NT-proBNP in the Diagnosis and 

Prognosis of Heart Failure 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0020 

Prepared by: McMaster University Evidence-based Practice Center, Hamilton, ON, Canada

Task Order Leaders: 

Cynthia Balion, Ph.D., F.C.A.C.B. 

Parminder Raina, Ph.D. (EPC Director) 

Authors: 

Cynthia Balion, Ph.D., F.C.A.C.B. 

P. Lina Santaguida, P.T., Ph.D.

Stephen Hill, Ph.D., F.C.A.C.B.

Andrew Worster, M.D., M.Sc. 

Matthew McQueen, M.B.Ch.B. Ph.D., F.C.A.C.B., F.R.C.P.C. 

Mark Oremus, Ph.D. 

Robert S. McKelvie, M.D., Ph.D., F.R.C.P.C. 

Lynda Booker, B.A. 

Joshua Fagbemi, M.Sc. 

Sonja Reichert, B.Sc., M.Sc. 

Parminder Raina, Ph.D. 

AHRQ Publication No. 06-E014 

September 2006
This report is based on research conducted by the McMaster University Evidence-based Practice 

Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-02-0020). The findings and conclusions in this document are 

those of the author(s) who are responsible for its contents; the findings and conclusions do not 

necessarily represent the views of AHRQ. Therefore, no statement in this article should be 

construed as an official position of the Agency for Healthcare Research and Quality or of the 

U.S. Department of Health and Human Services. 

The information in this report is intended to help health care decisionmakers; patients and 

clinicians, health system leaders, and policymakers, make well-informed decisions and thereby 

improve the quality of health care services. This report is not intended to be a substitute for the 

application of clinical judgment. 

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Balion C, Santaguida P, Hill S, Worster A, McQueen M, Oremus M, McKelvie R, Booker L, 

Fagbemi J, Reichert S, Raina P. Testing for BNP and NT-proBNP in the Diagnosis and 

Prognosis of Heart Failure. Evidence Report/Technology Assessment No. 142. (Prepared by the 

McMaster University Evidence-based Practice Center under Contract No. 290-02-0020). AHRQ 

Publication No. 06-E014. Rockville, MD: Agency for Healthcare Research and Quality. 

September 2006. 

Financial Disclosure Statement:

Drs. Hill, McQueen, and Worster have worked on BNP-related projects with Roche 

Diagnostics. Drs. Santaguida, Raina, McKelvie, Balion, and Oremus have no financial interest 

in this field, nor do Mr. Fagbemi, Ms. Booker, or Ms. Reichert. 
iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Beth Collins Sharp, Ph.D., R.N. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Mary P. Nix, M.S., M.T.(ASCP)SBB 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 
iv

Acknowledgments

We are grateful to members of the technical expert panel who were instrumental in developing 

the questions and defining the scope of this review: Dr. Robert Christenson, Dr. John G. 

Cleland, Ms. Carla Herrerias, Dr. Allan Jaffe, Dr. Ijaz Khan, Dr. Theresa McDonagh, Dr. 

Thomas Moyer, Dr. Mark Richards, Dr. Scott Silvers, Dr. Vincenza Snow. 

Our thanks go to Dr. Stephen D. Walter for his statistical consultation as well as to Dr. George 

Heckman for his thoughtful input. We would like to thank the following people who helped with 

the data abstraction for this review: Richard Cleve, Paul Malinowski, Curtis Oleschuk, Rosemary 

Milcz, Christine Mance, Carolyn Archer, Keith Kim, Chi Okonkwo, Dawn Kingston, and Marcia 

James. 

Our editorial staff, Roxanne Cheeseman and Maureen Rice, have provided invaluable input into 

this document. 
v

Structured Abstract 

Objectives: The purpose of this systematic review was to evaluate BNP and NT-proBNP to: (a) 

identify determinants, (b) establish their diagnostic performance in heart failure (HF) patients, (c) 

determine their predictive ability with respect to mortality and other cardiac endpoints, and (d) 

determine their value in monitoring HF treatment. 

Data Sources: MEDLINE®, EMBASE, CINAHL, Cochrane Central and AMED from 1989 to 

February 2005 were searched for primary studies. 

Review Methods: Standard systematic review methodology, including meta-analysis, was 

employed. All study designs were included. Eligibility criteria included English-only studies and 

restricted the number of test methods to maximize generalizability. Outcomes for prognosis were 

limited to mortality and specific cardiac events. Further specific criteria were developed for each 

research question. 

Results: Determinants: There were 103 determinants identified including age, gender, disease, 

treatment, as well as biochemical and physiological measures. Few studies reported independent 

associations and of those that did age, female gender and creatinine levels were positively 

associated with BNP and NT-proBNP. Diagnosis: Pooled sensitivity and specificity values were 

94 and 66 percent for BNP and 92 and 65 percent for NT-proBNP; there was minimal difference 

among settings (emergency, specialized clinics, and primary care). B-type natriuretic peptides 

also added independent diagnostic information above traditional measures for HF. Prognosis: 

Both BNP and NT-proBNP were found to be independent predictors of mortality and other 

cardiac composite endpoints in patients with risk of coronary artery disease (CAD) (risk estimate 

range = 1.10 to 5.40), diagnosed CAD (risk estimate range = 1.50 to 3.00), and diagnosed HF 

patients (risk estimate range = 2.11 to 9.35). With respect to screening, the AUC values (range = 

0.57 to 0.88) suggested poor performance. Monitoring Treatment: Studies showed therapy 

reduced BNP and NT-proBNP, however, relationship to outcome was limited and not consistent. 

Conclusions: Determinants: The importance of the identified determinants for clinical use is 

not clear. Diagnosis: In all settings both BNP and NT-proBNP show good diagnostic properties 

as a rule out test for HF. Prognosis: BNP and NT-proBNP are consistent independent predictors 

of mortality and other cardiac composite endpoints for populations with risk of CAD, diagnosed 

CAD, and diagnosed HF. There is insufficient evidence to determine the value of B-type 

natriuretic peptides for screening of HF. Monitoring Treatment: There is insufficient evidence 

to demonstrate that BNP and NT-proBNP levels show change in response to therapies to manage 

stable chronic HF patients. 

vii

Contents 

Executive Summary...........................................................................................................................1 

Evidence Report...............................................................................................................................7 

Chapter 1. Introduction .....................................................................................................................9 

 B-type Natriuretic Peptides..........................................................................................................9 

 Heart Failure ................................................................................................................................9 

 Determinants of B-type Natriuretic Peptides...............................................................................10 

 Diagnosis of Heart Failure Using B-type Natriuretic Peptides....................................................10 

 Prognostic Utility of B-type Natriuretic Peptides........................................................................10 

 Treatment Monitoring Using B-type Natriuretic Peptides...........................................................11 

 Scope and Purposes of the Systematic Review............................................................................11 

Chapter 2. Methods...........................................................................................................................13 

 Analytic Framework ....................................................................................................................13 

 General Methods..........................................................................................................................14 

 Refinement of the Topic and the Research Questions...........................................................14 

 Search Strategy ......................................................................................................................14 

 Eligibility Criteria ..................................................................................................................14 

 Data Collection and Reliability of Study Selection ...............................................................16 

 Quality Assessment of Included Studies................................................................................16 

 Summarizing our Findings: Descriptive and Analytic Approaches ......................................16 

 Question Specific Methods..........................................................................................................18 

 Population Criteria for Each Question...................................................................................18 

 Intervention for Each Question..............................................................................................19 

 Outcome Criteria for Each Question......................................................................................20 

 Peer Review Process....................................................................................................................20 

Chapter 3. Results .............................................................................................................................21 

 Question 1: What are the determinants of both BNP and NT-proBNP? .....................................22 

Study Characteristics .............................................................................................................22 

Demographic Characteristics.................................................................................................22 

Cardiac Disease......................................................................................................................22 

Non-cardiac Diseases.............................................................................................................23 

Biochemical and Hematological Markers..............................................................................23 

Functional and Physiologic Measure.....................................................................................24 

Hemodynamic, Electrocardiographic and Echocardiographic Measures ..............................24 

Drug Treatment......................................................................................................................25 

 Non-drug Treatment...............................................................................................................25 

Question 2a: What are the clinical performance characteristics of both BNP and NT- 

 proBNP measurement in patients with symptoms suggestive of HF or with known HF? .......25 

 Question 2ai: Emergency Department...................................................................................25 

 Sample and Design Characteristics of Studies...................................................................25 
viii

 Question 2aii: Specialized Clinic or Outpatient Setting........................................................35 

 Sample and Design Characteristics of Studies...................................................................35 

 Question 2aiii: Primary Care ................................................................................................37 

 Sample and Design Characteristics of Studies...................................................................37 

 Question 2aiv: Long Term Care Setting ................................................................................38 

 Question 2av: All Settings Combined ....................................................................................39 

 Meta-Analysis....................................................................................................................39 

 Question 2b: Does measurement of BNP or NT-proBNP add independent diagnostic 

 information to the traditional diagnostic measures of HF in patients with suggestive HF?.....41 

Study Characteristics .............................................................................................................41 

Multivariate Analyses ............................................................................................................41 

Comparison of Estimates of DOR and SROC for Different Tests for HF Based on the 

 Review of Reviews ............................................................................................................42 

B-type Natriuretic Peptides Compared to Other Diagnostic Measures .................................43 

Quality Assessment of Reviews.............................................................................................44 

Question 3a: Do BNP or NT-proBNP levels predict cardiac events in populations at risk 

 of CAD, with diagnosed CAD and HF?...................................................................................44 

 Question 3ai: At risk of CAD.................................................................................................45 

Design and Sample Characteristics of Studies.................................................................45 

CAD Risk Factors............................................................................................................45 

BNP and NT-proBNP Tests and Threshold Values.........................................................45 

Definition of Outcomes....................................................................................................46 

Adjusted Results – Multiple Regression Analysis...........................................................46 

Quality Assessment of Studies.........................................................................................47 

 Question 3aii: With diagnosed CAD......................................................................................47 

 Design and Sample Characteristics of Studies.................................................................47 

 CAD Diagnosis ................................................................................................................48 

 BNP and NT-proBNP Tests and Threshold Values.........................................................48 

 Definition of Outcomes....................................................................................................48

 Adjusted Results – Multiple Regression Analysis...........................................................49 

 Quality Assessment of Studies.........................................................................................50 

 Question 3aiii: With diagnosed HF.......................................................................................50 

 Prognosis Studies Using BNP Levels..............................................................................50 

 Design and Sample Characteristics of Studies.............................................................50 

 HF Diagnosis and Severity ..........................................................................................51 

 BNP and Cut Points .....................................................................................................51 

 Definition of Outcomes................................................................................................52 

 Adjusted Results – Multiple Regression Analysis.......................................................52 

 BNP Studies with Mortality Outcomes........................................................................52 

 BNP Studies with Composite Outcomes .....................................................................53 

 Comparison of NT-proBNP and BNP .........................................................................53 

 Comparison of Studies That Evaluated Baseline and Predischarge Measures............54 

 Quality Assessment of Studies.....................................................................................55 

 Prognosis Studies Using NT-proBNP Levels....................................................................55 

 Study Design and Sample Characteristics of Studies ..................................................55 

 HF Diagnosis and Severity ..........................................................................................56 
ix

 NT-proBNP and Cut Points .........................................................................................56 

 Definition of Outcomes................................................................................................56 

 Adjusted results – Multiple Regression Analysis ........................................................56 

 NT-proBNP Studies With Mortality Outcomes...........................................................57 

 NT-proBNP Studies With Composite Outcomes ........................................................57 

 Quality Assessment of Studies.....................................................................................57 

Question 3b: What are the screening performance characteristics of BNP or NT-proBNP in 

 general asymptomatic populations? ........................................................................................58 

Definition of Screening..........................................................................................................58 

Design and Sample Characteristics........................................................................................58 

Study Outcomes.....................................................................................................................58 

Screening Properties ..............................................................................................................58 

Quality Assessment of Studies...............................................................................................60 

Question 4: Can BNP or NT-proBNP measurement be used to monitor response to 

 therapy? ...................................................................................................................................61 

Sample and Design Characteristics........................................................................................61 

Response to Therapy..............................................................................................................61 

Quality Assessment of Studies...............................................................................................64 

Chapter 4: Discussion .......................................................................................................................113 

 Question 1: What are the determinants of both BNP and NT-proBNP? .....................................113 

Question 2a: What are the clinical performance characteristics of both BNP and NTproBNP measurement in patients with symptoms suggestive of HF or with known HF in 

the four clinical settings of emergency department, specialized clinic or outpatient, 

primary care, and long term care?..........................................................................................114 

 Question 2ai: Emergency Department..................................................................................115 

 Question 2aii: Specialized Clinic or Outpatient Setting ........................................................116 

 Question 2aiii: Primary Care .................................................................................................117 

 Question 2aiv: Long Term Care Settings...............................................................................118 

 Question 2a: All Settings Combined......................................................................................118 

Question 2b: Does measurement of BNP or NT-proBNP add independent diagnostic 

information to the traditional diagnostic measures of HF in patients with 

suggestive HF?.........................................................................................................................120 

Question 3a: Do BNP or NT-proBNP levels predict cardiac events in populations at risk 

 of CAD, with diagnosed CAD and HF?...................................................................................120 

 Question 3ai: At Risk of CAD...............................................................................................120 

 Question 3aii: With Diagnosed CAD ....................................................................................121 

 Question 3aiii: With Diagnosed HF.......................................................................................122 

Methodological Caveats with Interpretation of BNP and NT-proBNP as Predictors of Future 

 Cardiac Events .........................................................................................................................122 

Question 3b: What are the screening performance characteristics of BNP or NT-proBNP in 

 general asymptomatic populations? ........................................................................................125 

Question 4: Can BNP or NT-proBNP measurement be used to monitor response to 

 therapy? ...................................................................................................................................125

Limitations to this Systematic Review ........................................................................................127 

 Comparison of Test Methods.................................................................................................127 
x

Conclusions........................................................................................................................................128 

Determinants................................................................................................................................128 

Diagnostic Properties for HF .......................................................................................................129 

Prognosis......................................................................................................................................129 

Monitoring Treatment..................................................................................................................130 

References..........................................................................................................................................133 

List of Acronyms/Abbreviations........................................................................................................143 

Glossary ............................................................................................................................................145 

Figures 

Figure 1: Analytic Framework..........................................................................................................13 

Figure 2. Flow diagram showing the numbers of articles processed at each level............................21 

Figure 3. Forest plots for BNP in all settings using the lowest cut point provided in each study: 

 a) sensitivity, b) specificity, c) LR+, d) LR-, e) DOR. ................................................................27 

Figure 4. Forest plots for NT-proBNP in all settings using the lowest cut point provided in each 

 study: a) sensitivity, b) specificity, c) LR+, d) LR-, e) DOR. .....................................................30 

Figure 5. Forest plots for BNP in the ED using a cut point of 100 (±5) pg/mL: a) sensitivity, 

 b) specificity, c) LR+, d) LR-, e) DOR........................................................................................33 

Figure 6. Summary ROC curves for a) BNP and b) NT-proBNP from all settings using the 

 lowest cut point provided in each study.......................................................................................40 

Figure 7. Change in BNP or NT-proBNP concentration after treatments .........................................63 

Tables 

Table 1: Details of BNP test characteristics. .....................................................................................15 

Table 2: Details of NT-proBNP test characteristics. .........................................................................15 

Table 3. The effect and association of various biological determinants on BNP and NT-proBNP 

 levels. ...........................................................................................................................................65 

Table 4: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with 

 symptoms suggestive of HF in emergency or urgent care settings..............................................68 

Table 5: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with 

 symptoms suggestive of or with HF in outpatient or specialty clinic settings.............................72 

Table 6: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with 

 symptoms suggestive of HF in primary care settings ..................................................................73 

Table 7: Diagnostic odds ratios for studies that evaluated BNP and NT-proBNP in patients with 

 symptoms suggestive of or with HF across all settings ...............................................................75 

Table 8: Studies that performed multivariate analyses to compare the independent contribution 

 of BNP and NT-proBNP with other diagnostic tests...................................................................78 

Table 9: Characteristics of the systematic reviews of diagnostic tests for HF that were eligible 

 for this review ..............................................................................................................................80 
xi

Table 10: Diagnostic performance estimates of BNP and NT-proBNP compared to other 

 diagnostic tests based on previous systematic reviews................................................................82 

Table 11. Summary of studies in patients with risk of CAD: BNP ...................................................84 

Table 12: Summary of studies in patients with risk of CAD: NT-proBNP.......................................85 

Table 13. Summary of studies in patients with CAD with surgery: BNP .........................................86 

Table 14. Summary of studies in patients with CAD, no surgery: BNP ...........................................87 

Table 15: Summary of studies in patients with CAD not surgery: NT-proBNP ...............................88 

Table 16: Summary of studies in patients with CAD no surgery: NT-proBNP ................................89 

Table 17: Summary of studies in patients with CAD no regression analyses ...................................90 

Table 18. Summary of studies in patients with HF and mortality outcomes: BNP...........................92 

Table 19. Summary of studies in patients with HF and mixed outcomes: BNP................................95 

Table 20. Summary of studies in patients with HF and mortality outcomes: NT-proBNP...............100 

Table 21. Summary of studies in patients with HF and mixed outcomes: NT-proBNP....................102 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population.............106 

Table 23. Evidence table for studies using BNP or NT-proBNP to monitor treatment.....................111 

Table 24. Hypothetical analysis using BNP and NT-proBNP as first line tests and demonstrating 

 the potential for reduction in subsequent requirement for further confirmatory testing for HF..131 

Appendixes 

Appendix A: Search Strings 

Appendix B: Forms 

Appendix C: Evidence Tables 

Appendix D: List of Excluded Studies 

Appendix E: Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/bnp/bnp.pdf. 
1

Executive Summary 

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are promising 

markers for heart failure diagnosis, prognosis, and treatment.1,2 This systematic review addresses 

these four main questions: 

1. What are the determinants of both BNP and NT-proBNP measurement? 

2. With respect to the diagnosis of heart failure: 

a. What are the clinical performance characteristics of both BNP and NT-proBNP 

measurement in patients with symptoms suggestive of heart failure (HF) or with 

known HF 

i. presenting to the emergency department (ED) 

ii. in a specialized clinic or outpatient setting 

iii. presenting to a primary care setting 

iv. presenting in long term care setting 

v. all settings combined 

b. Does measurement of BNP or NT-proBNP add independent diagnostic information to 

the traditional diagnostic measures of HF in patients with symptoms suggestive of 

HF? 

3. Do BNP or NT-proBNP levels predict cardiac events in populations: 

 a. Specific populations 

i. at risk for coronary artery disease (CAD) 

ii. with diagnosed CAD 

iii. with diagnosed HF 

b. What are the screening characteristics of BNP or NT-proBNP in general asymptomatic 

populations? 

4. Can BNP or NT-proBNP measurement be used to monitor response to therapy? 

Methods 

Two search strategies were undertaken, one for the main report and a smaller review of 

reviews for Question 2b. MEDLINE®, EMBASE, CINAHL, Cochrane Central and AMED 

(Allied and Complementary Medicine) were searched from 1989 to February 2005. Hand 

searching was not undertaken. For Question 2b, which compared other diagnostic tests relative to 

BNP and NT-proBNP, a review of reviews was undertaken in MEDLINE® and EMBASE only, 

from January 2000 to September 2005. 

Only English language studies and those that measured BNP in blood by methods 

predominately available for use in clinical laboratories were eligible. There were no restrictions 

on study design. Outcomes for prognosis were restricted to mortality and other cardiac events. 

Standard systematic review methodology was employed for the screening of studies to meet 

eligibility criteria and included two reviewers. Further specific criteria were developed for each 

research question. Both qualitative and quantitative (meta-analysis) summary of the results were 

undertaken. 
2

Results and Discussion 

The search yielded 4338 citations, from which 1733 proceeded to full text screening. After 

the final eligibility screening, data were abstracted from a total of 144 studies. 

What Are the Determinants of Both BNP and NT-proBNP? 

A total of 72 studies showed a relationship between B-type natriuretic peptides and a 

determinant. These determinants have the potential to affect accurate diagnosis, prognosis and 

the ability to monitor treatment effectively. 

For demographic determinants, age was the most frequently reported determinant and in 13 

of 15 studies was positively correlated with both BNP and NT-proBNP.3-15 Few functional 

measures were evaluated. Of these weight,8

 but not BMI,9,10 showed a negative relationship with 

B-type natriuretic peptides and these two studies had no,9

 or very few,10 patients who were 

obese. 

 In general, evidence available on 21 cardiac diseases was associated with an increase in 

the B-type natriuretic peptides. However, there were differences among diseases within the broad 

category of cardiac ischemia. The evidence available on 11 non-cardiac diseases and B-type 

natriuretic peptide levels was mixed; the non-cardiac causes of dyspnea,16-18 diabetic 

nephropathy,15 and stroke8

 were all associated with higher levels of B-type natriuretic peptides. 

There were 29 biochemical and hematological markers where an association with the B-type 

natriuretic peptides was made. Markers of myocardial damage, including Tn-I,3,19,20 TnT,8,14,16,21-26 myoglobin,21 and CK-MB,21,27-29 were mostly positively associated with B-type 

natriuretic peptide levels. There were 23 measures from 14 studies reported for heart function.4,8-

12,14,15,29-34 Most of the hemodynamic, electrocardiographic and echocardiographic measures 

were compared to BNP and a few were compared to NT-proBNP. Both positive and negative 

associations were found. There were 14 studies, including nine different drug treatments, with 

data on the effect of drug therapy.31,35-47 All showed a decrease in, or no effect on, B-type 

natriuretic peptide levels. 

What Are the Clinical Performance Characteristics of Both BNP and 

NT-proBNP Measurement in Patients with Symptoms Suggestive of 

HF or with Known HF? 

 There were a total of 27 studies eligible for evaluation of the clinical performance of BNP and 

NT-proBNP and not all of these reported performance characteristics or were suitable for metaanalysis. We meta-analyzed studies within specific settings and also across all study settings 

where sufficient data were available to calculate sensitivity, specificity, positive likelihood ratio 

(LR+) and negative likelihood ratio (LR-), diagnostic odds ratio (DOR) and summary ROC 

curves. Since there is no guideline for meta-analyzing studies that present results with single and 

multiple cut points the lowest cut point was chosen in studies with multiple cut points to 

maximize sensitivity. Summary estimates for studies within setting and across all settings were 

calculated. 
3

Presenting to emergency department. Fourteen articles7,16-18,48-57 were selected for data 

abstraction. The 12 studies evaluating BNP utilized several cut point values ranging from 50 to 

400 pg/mL and reported sensitivities from 60 to 100 percent, specificities from 27 to 99 percent, 

and areas under the curve (AUC) of 0.67 to 0.99. In addition, the LR+ ranged from 0.69 to 70 

and the LR- from 0 to 0.44. DOR values ranged from 13 to 1635 and based on the metaanalysis of eight studies the summary estimate was 81 (95 percent CI: 29 to 219). 

The three studies evaluating NT-proBNP utilized values ranging from 254 to 4567 pg/mL 

and reported sensitivities from 74 to 98 percent, specificities from 47 to 93 percent, and AUC 

values of 0.89 to 0.96. The LR+ ranged from 1.85 to 13.43 and the LR- from 0.03 to 0.29. DOR 

values ranged from 17 to 291 with a summary estimate of 60 (95 percent CI: 9 to 407). 

Most studies of the studies scored high on the Quality Assessment of Diagnostic Accuracy 

Studies (QUADAS) items indicating lack of bias. 

Specialized clinic or outpatient setting. There were a total of six studies eligible for review 

in specialized clinics,11,58-62 though diagnostic performance data could be abstracted in only 

three. All studies evaluated BNP except two58,60 which compared both BNP and NT-proBNP. 

These two studies evaluated BNP using the same method, had similar cut points (135 and 142 

pg/mL) and gave similar sensitivities (72 and 73 percent), specificities (73 and 77 percent), AUC 

(0.79 and 0.83), LR+ (2.7 and 3.17) and LR- (0.38 and 0.35), respectively. 

Although different methods and cut points were used for NT-proBNP measurement, the 

diagnostic performance data were similar to each other and to the BNP data. The cut points were 

695 and 4127 pg/mL, with corresponding sensitivities of 85 and 70 percent, specificities of 73 

and 77 percent, AUC of 0.82 and 0.79, LR+ of 3.19 and 2.59 and LR- of 0.2 and 0.41. 

Methodological quality was high on the QUADAS for these studies. 

Primary care setting. There were a total of seven papers34,63-68 from this setting and data 

could be abstracted from only five. Two studies evaluated BNP with cut points ranging from 10 

to 115 pg/mL and reported sensitivities from 66 to 92 percent, specificities from 18 to 88 

percent, AUC from 0.70 to 0.88, LR+ from 1.12 to 5.7, and LR- from 0 to 0.27. Meta-analysis 

gave a summary DOR of 2 (95 percent CI: 1 to 6). 

The three studies evaluating NT-proBNP with cut points from 67 to 338 pg/mL and reported 

sensitivities from 67 to 100 percent, specificities from 18 to 84 percent, AUC from 0.70 to 0.93, 

LR+ from 1.22 to 5.7, and LR- from 0 to 0.27. Meta-analysis gave a summary DOR 17 (95 

percent CI: 9 to 32). 

These studies generally rated well on the QUADAS. 

Long term care setting. There were no studies with patients with symptoms suggestive of 

HF or with known HF presenting in long term care settings. 

All settings. From the all settings combined, 15 studies had sufficient data for meta-analysis. 

The cut points across all settings ranged from 10 to 200 pg/mL (mean = 95 pg/mL) for BNP and 

125 to 1691 pg/mL (mean = 642 pg/mL) for NT-proBNP. Sensitivities for BNP and NT-proBNP 

ranged from 50 to 99 percent and 83 to 99 percent, respectively. Specificities for BNP and NTproBNP ranged from 19 to 97 percent and 46 to 89 percent, respectively. 

We observed significant heterogeneity when the data were meta-analyzed and the sources 

were subsequently explored. The Moses-Littenberg regression model was not significant 

indicating that cut point was not a factor in explaining heterogeneity. The meta-analysis 

indicated the diagnostic parameters remain similar even when results from all settings are 

combined. The summary estimate of sensitivity was high for both BNP (94 percent; 95 percent 

CI: 32 to 97) and NT-proBNP (92 percent; 95 percent CI: 87 to 97), whereas the summary 
4

estimate for specificity was low for BNP (66 percent; 95 percent CI: 52 to 79) and NT-proBNP 

(65 percent; 95 percent CI: 51 to 78). The LR- summary estimates for BNP (0.10; 95 percent CI: 

0.05 to 0.22) and NT-proBNP (0.14; 95 percent CI: 0.09 to 0.23) were much better than the 

summary estimates for LR+ for both BNP (2.92; 95 percent CI: 2.09 to 4.09) and NT-proBNP 

(2.67; 95 percent CI: 1.98 to 3.59). 

 The summary ROC curves for BNP and NT-proBNP both tended to curve strongly towards 

the upper left hand corner, signifying high accuracy. Furthermore, the AUC values were 0.86 for 

both BNP and NT-proBNP, suggesting that regardless of the clinical setting, the cut point 

chosen, or the test used, measurement of B-type natriuretic peptides is useful in the diagnosis of 

HF. 

 Further analysis of heterogeneity was possible to do in six studies from the ED setting that 

measured BNP by one method with a cut point of 100 (± 5) pg/mL. Even with this uniformity, 

specificity remained wide (28 to 94 percent). Given that the inclusion and exclusion criteria were 

not the same in these studies, and are themselves possible determinants of BNP, this 

heterogeneity is not unexpected. 

Overall, there is not clear evidence to suggest the superiority of either BNP or NT-proBNP 

when all settings are considered. 

Does Measurement of BNP or NT-proBNP Add Independent 

Diagnostic Information to the Traditional Diagnostic Measures of HF 

in Patients with Suggestive HF? 

We first examined the subset of primary papers from Question 2a that performed multivariate 

logistic regression analysis to determine whether or not BNP or NT-proBNP measurement 

provided independent information in the diagnosis of HF. Odds ratios for the B-type natriuretic 

peptides ranged from 9 to 220 and were generally as high as or higher than, other diagnostic 

variables. This suggests that measurement of the B-type natriuretic peptide does provide 

information independent from the traditional diagnostic measures. 

Secondly, we examined existing systematic reviews of the diagnosis of HF. These reviews 

considered many diagnostic tests for HF, both alone and in combination. The DOR ranged from 

11 to 569 for BNP and 15 to 230 for NT-proBNP. 

These data suggest measurement of the BNP or NT-proBNP are as good as, or better than 

traditional diagnostic measures for ruling out HF. 

Do BNP or NT-proBNP Levels Predict Cardiac Events in Populations 

at Risk of CAD, with Diagnosed CAD and HF? 

There were 108 studies eligible for evaluating the ability of BNP or NT-proBNP levels to 

predict cardiac events. Both B-type natriuretic peptides were found to be independent predictors 

of mortality and other cardiac composite endpoints in patients, but few evaluated NT-proBNP 

and even fewer evaluated both. Thus there is limited evidence to suggest that either of these Btype natriuretic peptides is a better prognostic marker of mortality or cardiac events than the 

other. 

At risk of CAD. The prognostic value of BNP or NT-proBNP for mortality and cardiac 

events was examined in 12 studies4,9,9,10,15,24,69-74 of individuals with risk factors for CAD. These 
5

studies differed in terms of the age and gender of their participants, methods of diagnosing risk 

factors for CAD, lengths of follow up, and outcomes. Multiple regression analyses consistently 

showed that the level of BNP or NT-proBNP was positively associated (adjusted measures of 

risk 1.10 to 5.40) with the outcome. 

With diagnosed CAD. The 38 studies3,8,13,14,19-22,27-29,33,75-100 evaluating CAD patients varied 

with respect to the age and gender of participants, sample size, length of follow up, and 

outcomes. However, consistent positive associations were found between the level of BNP or 

NT-proBNP and the outcome of interest. For BNP the range of risk estimate is 2.00 to 3.00 and 

for NT-proBNP it is 1.50 to 3.00. For both these B-type natriuretic peptides, the small number 

of studies prevents any differential prediction in persons with or without prior cardiac related 

surgery. 

With diagnosed HF. There were 58 studies eligible for evaluating BNP or NT-proBNP 

levels in predicting cardiac events in HF patients. The majority of the 38 

studies12,23,25,30,32,36,41,48,101-130 found baseline BNP levels to be independent predictors of 

mortality across various cut points and six studies evaluated both BNP and NT-proBNP tests. 

The adjusted hazard ratio (HR) showed a 2.5 to a 7.2 fold increase relative to those subjects with 

lower levels of BNP. Baseline BNP values were independent predictors of composite outcomes 

with HR estimates from 1.7 to 3.2. Studies comparing baseline and predischarge BNP levels 

suggest differences in the prediction of mortality. More research is required to establish the 

relative contribution of these two measurements of BNP. Primarily single studies evaluated the 

combined use of baseline BNP levels with other markers of cardiac dysfunction (e.g., troponin I 

and T, or percent VO2 max) as predictors of mortality and composite outcomes. Although the 

findings may suggest that the combined markers increase the ability to predict future outcomes, 

more research is needed to establish their relative benefit. 

The majority of the 18 NT-proBNP studies26,35,41,103,112,125,126,128,131-140 found this marker to be 

a significant independent predictor of death or composite endpoints at various cut points. The 

adjusted risk estimates varied from 2.17 to 9.35 for mortality outcomes, and 2.11 to 5.96 for 

cardiac composite outcomes. 

What Are the Screening Performance Characteristics of the BNP or 

NT-proBNP in General Asymptomatic Populations? 

A screening test was defined as being used to detect preclinical cardiac dysfunction, systolic 

or diastolic, in the general population. There were eight studies5,74,122,141-145 in populations 

without established or overt disease; two studies had no sensitivity or specificity data.74,122 BNP 

generally shows poor screening test characteristics for both the detection of moderate to severe 

LVSD and of diastolic dysfunction. It is even less accurate for the detection of milder degrees of 

systolic dysfunction. There was a single NT-proBNP study145 and it showed the screening 

highest for those with LVEF > 40, and over 70 years of age. 

Can BNP or NT-proBNP Measurement Be Used To Monitor Response 

to Therapy? 

There were 18 studies meeting the eligibility criteria.31,37-47,110,146-150 The studies included 

chronic HF patients with at least three B-type natriuretic peptide measurements over time. Only 
6

half these studies reported the change in BNP or NT-proBNP and related the change to other 

outcomes including cardiac function, exercise capacity, symptoms or clinical events. 

A number of these studies demonstrated a relationship between the change in BNP or NTproBNP and either mortality, morbidity or other clinical parameters. Although promising, the 

findings have not been uniform and the majority of studies were of poor methodological quality; 

overall this suggests limited evidence that BNP or NT-proBNP may be useful to monitor therapy 

in HF patients. 

Conclusions 

Determinants 

Numerous factors have been found to be associated with the levels of B-type natriuretic 

peptides. However, the value of these associations for clinical use is not clear and future research 

should explore these associations, particularly as a function of HF severity. 

Diagnostic Properties for HF 

In all settings (ED, specialized clinics, and primary care) both BNP and NT-proBNP have 

high sensitivity and lower specificity. This would suggest that these measurements could serve 

as a test for ruling out cardiac dysfunction. Measurement of B-type natriuretic peptide levels 

adds independent information relative to traditional diagnostic measures for this condition. Large 

multicentre trials (especially in ED with complex clinical patients) that allow for multivariate 

analyses to evaluate variables that contribute to low specificity should be undertaken in the 

future. 

Prognosis 

BNP and NT-proBNP have been shown to be independent predictors of mortality and other 

cardiac composite endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed 

HF. There were few studies which evaluated B-type natriuretic peptides in populations without 

known heart failure. All but a single study suggest these are not sufficiently accurate to be an 

effective screening test for unrecognized left ventricular dysfunction. Future research should 

explore the relative merits of B-type natriuretic peptides compared to and combined with other 

markers of cardiac dysfunction to predict future outcomes. 

Monitoring Treatment 

There is insufficient evidence to demonstrate that BNP and NT-proBNP levels show change 

in response to therapies to manage stable chronic HF patient. Future research could include large 

randomized trials to show whether therapy guided by changes in B-type natriuretic peptides 

affect outcome. 
 EVIDENCE REPORT

9

Chapter 1. Introduction 

B-type Natriuretic Peptides 

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have emerged as 

promising markers for heart failure (HF) diagnosis, prognosis, and treatment. BNP is produced 

from heart muscle cells, mainly in the left ventricular myocardium but also in the atrial 

myocardium, as a pro-hormone and released into the cardiovascular system in response to 

ventricular dilation and pressure overload. Regulation of BNP is at the level of gene expression; 

there is no storage of BNP in cardiomyocytes. The pro-hormone (proBNP1-108) is split inside the 

myocyte by the protease furin and secreted as the physiologically active C-terminal fragment 

BNP77-108 (BNP1-32 or BNP) and the inactive NT-proBNP1-76 fragment. BNP exhibits several 

physiologic functions including vasodilation, promotion of natriuresis and diuresis, inhibition of 

the sympathetic nervous system and several hormone systems such as the renin-angiotensinaldosterone system, as well as inhibitory and beneficial effects on the physiological mechanisms 

associated with the cardiovascular system.151 BNP has a half-life of 22 minutes,152 whereas NTproBNP has a longer half-life estimated to be 1 to 2 hours.153 The major clearance mechanisms 

for BNP are endocytosis through the natriuretic peptide receptor C and by enzymatic degradation 

by neutral endopeptidase, while for NT-proBNP it is through the reticuloendothelial system and 

renal clearance. For more information on the biochemistry and physiology of B-type natriuretic 

peptides the reader is referred to recent reviews on this subject.154,155 In this report BNP and NTproBNP will be referred to as the B-type natriuretic peptides unless it is pertinent to refer to one 

of these specifically. 

Heart Failure 

 Heart failure is a complex clinical syndrome that occurs when there is alteration in the 

function or structure of the heart that reduces its capability to supply adequate blood flow 

throughout the body. It is an important clinical problem with significant morbidity, mortality, 

and socioeconomic impact. Approximately 5 million patients in the United States of America 

have HF, and a first time diagnosis will occur in over 550,000 patients annually.156 The 

prevalence is 1.8 percent but rises to 10 percent after age 75. Heart failure is the leading cause 

of hospitalization in people over 65 years. The natural history of HF is poor, and within 5 years 

of diagnosis 60 percent of men and 49 percent of women will die of the disease. 

Given that HF is a complex clinical syndrome, diagnosis relies on clinical judgments with 

respect to generic symptoms reflecting cardiac problems. The clinical symptoms in the early 

stages of HF are non-specific and although a key symptom is dyspnea, it may be difficult to 

identify the cause. Similar symptoms are found in the elderly or obese patients with respiratory 

disease,157 and syndromes associated with edema and fatigue. Imaging diagnostics such as chest 

x-rays, echocardiography, radionuclide angiogram (RNA), magnetic resonance imaging (MRI) 

and computed tomography (CT) are used as objective criteria to diagnosis and monitor patients. 

Several guidelines for diagnosis and management of HF have been produced including those 

from the American College of Cardiology/American Heart Association,156 the Canadian 

Cardiology Society,158 the European Society of Cardiology, 159 and the modified Framingham 
10

Clinical Criteria for Heart Failure160. Early diagnosis of HF and prompt treatment (e.g., 

angiotensin-converting enzyme (ACE) inhibitors , diuretics, and beta blockers) leads to a better 

prognosis and quality of life.161 

Determinants of B-type Natriuretic Peptides 

As B-type natriuretic peptides are involved in several physiological processes their 

concentrations will be influenced by factors that affect these processes. Increasing age is 

associated with a decline in cardiac function and endocrine diseases such as hyperthyroidism 

increase blood pressure. Drugs such as ACE inhibitors that affect the renin-angiotensinaldosterone system, or that reduce the effects of catecholamines such as beta blockers, as well as 

those like diuretics that increase fluid loss, will alter the level of B-type natriuretic peptides. 

These are just a few examples of variables that may be important when interpreting B-type 

natriuretic peptide levels. Analytical factors such as sample collection procedure, test method, 

interference and sample stability can also falsely alter concentrations.155 Given the potential 

importance of B-type natriuretic peptides there was interest in gathering the evidence on 

determinants that are associated with changes in B-type natriuretic peptide levels.162 These 

determinants have the potential to confound the accurate interpretation related to diagnosis, 

prognosis and the ability to monitor treatment effectively.151

Diagnosis of Heart Failure Using B-type Natriuretic Peptides 

Evaluation of the diagnostic properties of the B-type natriuretic peptides are important if they 

are to be fully understand both in terms of both strengths and weaknesses for use in HF. The 

quality of any biochemical test is dependent upon the biological properties of the analyte, the test 

method used, the diagnostic threshold chosen and the skill and knowledge of those interpreting 

the test result. The characteristics of the population that presents for testing, including the 

prevalence and severity of the disease, are also important. This is particularly true in situations 

where the severity of the disease affects the magnitude of the test response, such as in HF. The 

diagnostic characteristics of a test, including sensitivity, specificity, negative and positive 

likelihood ratio, are likely to vary by the setting where patients present for care. The acuity of 

symptoms in patients who are evaluated in an emergency department setting, for instance, are 

likely to be quite different than those who are seen in primary care settings or in a specialized 

clinic. Furthermore, when interpreting the results of a diagnostic test, it is important to know 

whether or not the information obtained is independent from, and of added value to, information 

obtained by other tests. 

Prognostic Utility of B-type Natriuretic Peptides 

There are high rates of mortality and acute decomposition events requiring hospitalization in 

HF patients. This demonstrates the need for a good prognostic indicator so that treatments can be 

optimized. Identification of patients who may be at higher risk for readmission could result in 

these patients being treated more aggressively. B-type natriuretic peptides could be used to more 

quickly identify patients who are at higher risk for developing cardiovascular events. Again, as 

for HF patients, these at risk patients may benefit from accelerated therapy. It is not clear, 
11

however, whether or not B-type natriuretic peptides measurements provide an added benefit to 

current methods of assessment of patients who may be at high risk for cardiovascular events. 

Several studies have reported that elevated B-type natriuretic peptide levels are inversely 

related to the prognosis in patients with coronary artery disease (CAD), HF and possibly other 

subgroups. Higher levels of B-type natriuretic peptides, or levels that do not decrease despite an 

intervention, suggest a poorer prognosis overall.163 The ability of the B-type natriuretic peptides 

tests to function as a prognostic marker for subsequent cardiac events is important to consider. 

As a prognostic marker B-type natriuretic peptides could have great value in identifying subjects 

by level of risk for subsequent cardiac events and in identifying those most amenable to 

interventions for arresting further progression to more serious disease. 

The use of B-type natriuretic peptides as a screening test could assist in reducing morbidity 

associated with subsequent heart dysfunction development. However, its use would also have to 

take into consideration the efficacy and acceptability of the current therapies for HF, and the 

degree to which the natural history of the disease is understood. 

 Treatment Monitoring Using B-type Natriuretic Peptides 

Therapeutic strategies range from drugs to invasive and costly methods such as cardioverterdefibrillators and heart transplantation. The pace and type of therapy given is, for the most part, 

clinically guided. It would be of benefit to have more objective guides to monitor therapy. Btype natriuretic peptides may be helpful in this regard as they have been shown to predict 

morbidity and mortality in HF patients. 

There has been some evidence that suggests the potential usefulness of sequential BNP or 

NT-proBNP measurements in monitoring patients with HF.148,149 B-type natriuretic 

concentrations decrease when patients with HF are treated, and lower BNP concentrations are 

associated with fewer cardiovascular events. It remains unclear, however, both if monitoring 

BNP levels can reduce those levels more quickly by prompting the use of more aggressive 

therapy and, what the target levels should be. It might be possible to improve current drug 

therapy by tailoring it to the patient if clearer measures of the effect of the therapy were known. 

Some patients may benefit from dosages higher than the guidelines indicate, or conversely, lower 

doses may be sufficient in other patients thereby reducing the risk of side effects. Moreover, it is 

not clear if the utility of the B-type natriuretic peptides measurement varies with the type of 

intervention used to manage HF. It was therefore of interest to search the literature for 

information on the utility of sequential BNP or NT-proBNP measurements in monitoring 

treatment in stable HF patients. 
12

Scope and Purposes of the Systematic Review 

This systematic review addresses 4 main questions as follows: 

1. What are the determinants of both BNP and NT-proBNP measurement? 

2. With respect to the diagnosis of heart failure: 

a. What are the clinical performance characteristics of both BNP and NT-proBNP 

measurement in patients with symptoms suggestive of heart failure (HF) or with 

known HF 

i. presenting to the emergency department (ED) 

ii. in a specialized clinic or outpatient setting 

iii. presenting to a primary care setting 

iv. presenting in long term care setting 

v. all settings combined 

b. Does measurement of BNP or NT-proBNP add independent diagnostic information to 

the traditional diagnostic measures of HF in patients with symptoms suggestive of 

HF? 

3. Do BNP or NT-proBNP levels predict cardiac events in populations: 

 a. Specific populations 

i. at risk for coronary artery disease (CAD) 

ii. with diagnosed CAD 

iii. with diagnosed HF 

b. What are the screening characteristics of BNP or NT-proBNP in general asymptomatic 

populations? 

4. Can BNP or NT-proBNP measurement be used to monitor response to therapy? 

This systematic review will serve to identify both the strength of the evidence and gaps in 

existing research to facilitate future research priorities. 
13

Chapter 2. Methods 

Analytic Framework 

An analytic framework is a schematic representation of the strategy for organizing topics for 

review and guiding literature searches. Figure 1 illustrates the inter-relationship among the 

questions being asked in this systematic review. The key areas addressed were diagnosis of heart 

failure (HF) using B-type natriuretic peptide tests, the prognostic value of B-type natriuretic 

peptide levels, and guiding treatment of HF patients using B-type natriuretic peptide 

measurements. The B-type natriuretic peptides included BNP and NT-proBNP and in the figure 

they are illustrated as the central component for the key areas. Four settings were chosen to 

evaluate the diagnostic ability of B-type natriuretic peptides for HF. They included the 

emergency department, primary care, outpatient clinics and long term care. Patients with 

coronary artery disease (CAD) risk factors, diagnosed CAD or HF were chosen to evaluate 

whether B-type natriuretic peptides levels are useful prognostic indicators. In addition the 

general population was used to determine whether B-type natriuretic peptides could be used for 

screening. Monitoring of B-type natriuretic peptides with respect to outcome was used to assess 

the effect of therapy in patients with HF. Furthermore, determinants that affect B-type natriuretic 

peptide levels independent of HF were extracted for each of the key areas, but not shown as part 

of the analytic framework. 

Figure 1: Analytic Framework 

Diagnosis of 

heart failure 

Prognosis

e.g., mortality, composite 

endpoints, myocardial 

infarction, rehospitalization 

Therapies for heart failure 

e.g., medications, surgeries, medical 

devices, lifestyle

Other diagnostic 

tests for heart failure 

e.g., chest x-ray, 

echocardiography, 

MRI, CT, cardiac 

catherization 

With diagnosed 

CAD

At risk of CAD 

Emergency 

Department 

Primary 

Care 

Outpatient 

Clinic 

Long-Term 

Care 

Screening 

With diagnosed 

Heart failure 

BNP and NTproBNP
14

 The methodological chapter has been divided into two sections: (1) General Methods and (2) 

Question Specific Methods. The first section will describe methods that were general in nature 

and were applicable to almost all of the research questions in this review. The second section 

will describe the specific methodological decisions that were relevant to each research question. 

General Methods 

 

Refinement of the Topic and the Research Questions 

The first step during the topic assessment and refinement process was to organize a 

teleconference with partner organizations. The Task Order Officer (TOO) invited topic experts 

and the McMaster multidisciplinary research team to define the magnitude of the topic to be 

addressed and to refine/clarify the preliminary research questions for this evidence report. An 

international Technical Expert Panel (TEP) was assembled to provide high-level content 

expertise on this topic (Appendix E) and to participate in conference calls on an as-needed basis 

throughout the data refinement and extraction phase. 

Search Strategy 

Two search strategies were undertaken, one for the main report (Appendix A) and a second 

one for the review of reviews (Appendix A) for Question 2b. The bibliographic databases 

searched included MEDLINE®, EMBASE, CINAHL, Cochrane Central and AMED (Allied and 

Complementary Medicine) from 1989 to February 2005. Hand searching was not undertaken for 

this systematic review. 

For Question 2b, which compared other diagnostic tests relative to BNP and NT-proBNP, a 

review of reviews was undertaken in MEDLINE® and EMBASE from January 2000 to 

September 2005. The start date of 2000 was chosen in order to identify only the most recent 

reviews. 

Eligibility Criteria 

 

A list of eligibility criteria was developed in Systematic Review Software (SRS) for the 

purposes of this systematic review. Details of the eligibility criteria can be found in Appendix B. 

Publication 

Criteria for publication inclusion. Language: Only English language studies were eligible. 

The number of non-English studies that were excluded equaled approximately 6 percent of all 

possible citations (268/4342). Publication Date: 1989 to February 2005. Our search started in 

1989, as this was the first year an assay for BNP was reported. 

Criteria for publication exclusion. Narrative and systematic reviews (except for Question 

2b), editorials, letters, comments, opinions, abstracts and unpublished studies were excluded. 
15

Assay method 

Measurement of BNP or NT-proBNP. This systematic review included only those studies that 

measured BNP by methods that were available commercially for diagnostic use in a clinical 

setting up to February 2005 (Table 1). However, for NT-proBNP methods, three methods were 

included that were not commercially available for use in clinical settings for the purposes of 

diagnosis (see Table 2). One of these methods was the early generation assay to the Roche NTproBNP method (ELISA method). The other two methods (Biomedica and Christchurch) were 

included because of their frequent use and because comparison studies have been done with the 

Roche NT-proBNP method.147,164 The purpose of these restrictions was to ensure that results 

from this systematic review were not unduly affected by the test method used. The goal was to 

reduce the variability and thus uncertainty in the analysis of our results and for them to be 

directly applicable for clinical use (since these will be the methods clinical laboratories will use). 

One limitation with this approach is the possible exclusion of studies with important information 

not available in any of the included studies. Also, the strength of some findings may be 

weakened due to a smaller number of studies reporting similar findings but using different test 

methods. Tables 1 and 2 provide the details of the assays used in this review to measure BNP or 

NT-proBNP. 

Table 1: Details of BNP test characteristics. 

Table 

row # Company Name Test / Instrument Name Date Available 

1 Shionogi & Co. Ltd, Osaka, Japan Shionoira-IRMA 1993 

2 Biosite, Inc., San Diego, CA, United States Triage® B-Type Natriuretic 

Peptide (BNP) Nov. 2002 

3 Bayer Diagnostics Corporation, Tarrytown, NY, United 

States 

ADVIA Centaur® B-Type 

Natriuretic Peptide (BNP) June 2003 

4 Beckman Coulter Inc, Fullerton CA, United States Access Oct 2003 

5 Abbott Laboratories. Abbott Park, IL, United States Abbott AxSYM ® B-Type 

Natriuretic Peptide (BNP) Feb 2004 

Table 2: Details of NT-proBNP test characteristics. 

Table 

row # Company Name / Reference Test / Instrument Name Date Available 

6 

Christchurch, New Zealand referenced to: Hunt PJ, 

Richards AM, Nicholls MG, Yandle TG, Doughty RN, 

Espiner EA. Immunoreactive aminoterminal probrain 

natriuretic peptide (NT-proBNP): A new marker for 

cardiac impairment. Clin Endocrinol 1997; 47:287-296 

NT-proBNP 1997 

7 

Roche Diagnostics GmbH, Tutzing, Germany, referenced 

to: Karl J, Borgya A, Gallusser A, Huber E, Krueger K, 

Rollinger W, Schenk J. Development of a novel, Nterminal-proBNP (NT-proBNP) assay with a low detection 

limit. Scand J Clin Lab Invest Suppl. 1999; 230:177-81 

NT-proBNP 1999 

8 Biomedica, Vienna, Austria NT-proBNP ELISA 2001a

9 Roche Diagnostics Corporation, Indianapolis, IN, United 

States Elecsys

® 

NT-proBNP 

Immunoassay 

Nov. 2002 

10 Dade Behring, Inc., Newark, DE, United States Dimension

® 

NT-proBNP 

(PBNP) July 2004 

a. For research purposes only. 
16

Number of measurements of BNP or NT-proBNP. For Question 4, BNP or NT-proBNP was 

to be measured at a minimum of 3 time points. This restriction was not applied to any other 

question in this review. 

Population 

Criteria for population inclusion. Any population including any subjects aged greater than or 

equal to 18 years of age. 

Criteria for population exclusion. All studies conducted on animals or on human samples 

other than blood (e.g., urine) or cell cultures were excluded from this review. 

Study designs 

Criteria for study designs inclusion. All study designs (randomized controlled trials (RCTs), 

observational, case control, cohort studies) for primary data were included. In addition, 

systematic reviews were included to address Question 2b. 

Data Collection and Reliability of Study Selection 

 

A team of trained research assistants evaluated the title, abstract and full text screening. 

Standardized forms and a guide explaining the criteria were developed. Two reviewers were 

required to achieve consensus on the identification, selection, validity and abstraction of articles 

and information. Disagreements that were not resolved by consensus were settled by one or 

more members of the local expert team. 

Quality Assessment of Included Studies 

To assess the quality of primary studies we utilized standardized rating scales with 

acceptable reliability and validity. The specific scale to be used was dependent on the study 

design and the research question. The Quality Assessment of Diagnostic Accuracy Studies 

(QUADAS)165 was selected to evaluate studies chosen for the research question addressing 

diagnostic accuracy of the BNP or NT-proBNP test. The QUADAS was developed specifically 

to take into account biases unique to the design of diagnostic studies. Quality items were 

considered individually rather than as a composite score as recommended by the developers of 

this tool.166 The Jadad scale was used for studies that were RCTs.167 For non-randomized study 

designs the only two criteria selected for evaluation were consecutive sampling and blinding to 

the outcome.168 For quality assessment of systematic reviews, the Screening and Test Evaluation 

Program (STEP) checklist was used.169 Appendix B shows the instruments used to evaluate 

quality. 

Summarizing Our Findings: Descriptive and Analytic Approaches 

Both descriptive and quantitative approaches were used to summarize study characteristics 

and outcomes. Multiple publications on the same study cohort were grouped together and treated 

as a single study for statistical analysis. Standardized summary tables explicating important 

study population and BNP or NT-proBNP test characteristics, as well as study results, were 

created. Results for BNP and NT-proBNP measurements were reported using the units pg/mL. 
17

Conversions were made to pg/mL, using the factor 1 pmol/L = 3.46 pg/mL for BNP and 1 

pmol/L = 8.457 pg/mL for NT-proBNP. 

Meta-analysis was only carried out for Question 2a. Meta-analysis for the remaining 

questions was not considered for several reasons including lack of data, too few studies and 

significant clinical heterogeneity. Quality scores were not used for weighting data in any of the 

analyses; rather, the inverse of the variance was used to weight studies. 

For each primary study included in Question 2a, we calculated the following measures of test 

results accuracy: sensitivities, specificities, likelihood ratios (positive LR+ and negative LR-) and 

diagnostic odds ratios (DOR). For those papers where the actual numbers of true and false 

positive and negative results (TP, FP, TN, FN) were presented, or where enough information was 

given to allow us to calculate and estimate these numbers, we recalculated the sensitivities, 

specificities and calculated the LR+, LR- and DOR with the accompanying 95 percent 

confidence intervals (CI). 

 These measures were calculated across different cut points and by study setting (emergency, 

outpatient, primary care and long term care settings) for BNP and NT-proBNP separately. 

Overall estimates of the diagnostic accuracy of the test were obtained by pooling the 

sensitivities, specificities and LRs obtained from each primary study. These different analyses 

were assessed for publication bias (graphical as well as statistical). We used sensitivity analysis 

to examine the influence of one study at a time and Galbraith plots for assessing heterogeneity 

across studies. 

Our initial analyses considered the level of heterogeneity across the individual studies that 

were included in the meta-analysis. The Cochrane’s Q test was used as a measure of 

heterogeneity in all the meta-analyses and the I2

 as a measure of inconsistency. We observed 

some heterogeneity in many of our meta-analyses and as a result, analyses using the random 

effects models were selected. Subgroup analysis and stratification were carried out to further 

explore the causes. As a part of these, meta-regression methods were employed to study the 

effects of a few covariates on the respective diagnostic test measures. Due to the number of 

studies available, we were only able to carry out univariate meta-regressions in most cases. We 

also assessed the correlation between sensitivities and specificities. However, no significant 

correlations were observed. All statistical analyses were carried out using Stata/SE 8.0 for 

Windows (Stata Corporation) and Meta Package. 

Pooled estimates were also calculated for DORs and summary receiver operator 

characteristic (SROC) curves were created in our analyses to assess the effect of different cut 

points. A DOR is a simple measure used when combining sensitivities and specificities from 

different studies. It is easy to calculate and less sensitive to diagnostic thresholds.170 The DOR 

makes use of the sensitivity and specificity pair by comparing the odds of one to the other. It 

compares the odds of positive test results in the trial participants with the outcome of interest, to 

the odds for positive test results for those without the outcome of interest (Equation 1). 

Equation 1: DOR 

(1 ) /( )

/(1 )

specificity specificity

sensitivity sensitivity DOR − − =

The standard error of the log DOR is approximately given by: 1/TP + 1/FN + 1/TN + 1/FP 
18

Where TP is true positive, FP is false positive, TN is true negative and FN is false negative. 

Appropriate adjustments are made in cases of zero counts. 

An alternative formulation of the DOR is given in Equation 2: 

Equation 2: Alternative calculation for DOR. 

−

+

= −

− = LR

LR

( sensitivity)/(specificity)

sensitivity/( specificity)

1

1 DOR

Where the LRs are the positive and negative likelihood ratios. 

Using this definition, a DOR is a measure of the spread between the two LRs. The SROC 

curve mimics the receiver operator characteristic (ROC) curve and is a way to measure the 

diagnostic accuracy across different studies. It is based on logit transformation of the data, which 

plots D, the difference between the logit of the true-positive rates (TPR, sensitivity) and the logit 

of the false-positive rates(FPR, 1 - specificity) on the y axis against theirsum S on the x axis i.e., 

D = logit TPR – logit FPR against S = logit TPR + logit FPR. The y axis (D) is equivalent to the 

log (DOR), and the x axis(S) is a way to measure how the test characteristics vary with respect 

to the thresholds of the diagnostic tests. A regression equation (D = + ß * S) derived from the 

SROC curve analysis can be used to assessthe heterogeneity among study results.171. It is 

possible to get spurious SROC plots based on regression analysis when individual studies have 

homogeneity in their results since regression analysis with small variations in both the 

independent and dependent variables can result in misleading results. 

Question Specific Methods 

Population Criteria for Each Question 

Question 1: criteria for population inclusion. All studies that were eligible for Questions 2, 

3 and 4 were considered for Question 1. For Question 1, all determinants associated with B-type 

natriuretic peptides were abstracted except for the well-known relationship to systolic HF or 

severity of HF, and echocardiographic parameters associated with systolic dysfunction. Both 

categorical determinants (e.g., gender, disease status, drug therapy) and determinants with 

continuous scale (e.g., creatinine, weight, left ventricular mass) were included, however, 

determinants were excluded if the continuous scale was categorized into a categorical variable 

(i.e., above and below a cut point value). Drug therapy data were included if the therapy was 

compared to baseline or a placebo group. Data on all determinants that were analyzed using 

univariate or multivariate regression approaches were abstracted; however, if both analyses were 

available, the multivariate took primacy in the results. If data were given for multiple time points 

the admission time was chosen unless otherwise specified in the evidence tables (Evidence Table 

1, Appendix C). Although these restrictions decreased the number of abstractable pieces of data, 

it also reduced the classification error. 

Question 2a: criteria for population inclusion. A study was also eligible if it considered 

one of the following symptoms or signs as a marker for HF: anginal pain, anginal syndrome, 

ankle swelling, bilateral leg edema, breathlessness, cardiac dysfunction, cardiac insufficiency, 

cardiomegaly on chest x-ray, diastolic distensibility, diastolic dysfunction, diastolic dysfunction 
19

on cardiac catheterization, diastolic stiffness, dyspnea, ejection fraction (EF), elevated jugular 

venous pressure, fatigue, fluid retention, hepatomegaly, left ventricular (LV) relaxation, filling, 

LV systolic function (or dysfunction), nocturnal cough, orthopnea, palpitation, paroxysmal 

nocturnal dyspnea, peripheral edema, pleural effusion, pulmonary congestion, pulmonary rales, 

tachycardia (heart rate ≥ 120 beats/min), third heart sound, ventricular dysfunction, weight loss. 

Question 2a: criteria for population exclusion. For emergency of primary care settings 

only, studies were excluded if the population had subjects with known HF, and samples that only 

included subjects with any of the following: heart transplantation, obesity clinic patients, 

hypertrophic cardiomyopathy, mitral valve regurgitation patients. Inpatient hospital or 

community settings were excluded. 

Question 2b: criteria for population inclusion. Primary studies with traditional diagnostic 

tests of HF included the following: chest x-ray, echocardiography, myocardial radionuclide 

angiogram (MRNA), dobutamine echo, cardiac catheter, magnetic resonance imaging (MRI), 

computerized tomography (CT), and pulmonary/vascular measures. 

Question 3a: criteria for population inclusion. All patients with: i) at risk of CAD; ii) with 

diagnosed CAD; iii) with diagnosed HF. The citation was required to use at least one of the 

following terms to indicate HF: i) HF; ii) congestive HF; iii) New York Heart Association 

(NYHA) criteria, NYHA functional class, American College of Cardiology (ACC), American 

Heart Association (AHA), Canadian Cardiovascular Society (CCS), Modified Framingham 

Clinical Criteria for diagnosis of Heart Failure, and European Study Group on Diastolic Heart 

Failure; iv) cardiac dysfunction. 

Question 3a: criteria for population exclusion. Studies were excluded if the population 

had any of the following health conditions: heart transplant, stenosis, renal disease, pulmonary 

embolism, cardiomyopathy, tumour, amyloid, leukemia, atrial fibrillation after pacemaker 

implant, respiratory disease, pulmonary hypertension, ischemic stroke, sepsis, perimyocarditis, 

intensive care unit patients. 

Question 3b: criteria for population inclusion. General populations with no known cardiac 

dysfunction. 

Question 4: criteria for population inclusion. Studies evaluating treatments for HF had to 

have identified the subjects using one of the following criteria: ACC / AHA, NYHA, CCS, 

Modified Framingham Clinical Criteria for the Diagnosis of Heart Failure, European Study 

Group on Diastolic Heart Failure. 

Question 4: criteria for population exclusion. Studies were excluded if the patients’ HF 

was not stable. 

Intervention for Each Question 

Selection of interventions was not relevant for research Questions 1, 2 and 3. 

Question 4: criteria for intervention inclusion. Treatments for HF could include any of the 

following: 

• Medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor 

blocker therapy; beta blockers; cardiac glycosides; diuretics; nitrates; spironolactone 
20

• Surgeries, Procedures and Medical Devices: balloon valvuloplasty catheter; enhanced 

counterpulsation; heart valve replacement surgery; automatic implantable cardiac 

defibrillator; cardiac resynchronization therapy; intra-aortic balloon pump insertion; 

prosthetic heart valve; ventricular assist device; valvuloplasty (balloon or surgical). 

• Healthy Lifestyles: Exercise; maintain a healthy weight; eat a healthy diet; control blood 

pressure; control blood cholesterol; prevent and manage diabetes mellitus; quit smoking; 

manage stress. 

Outcome Criteria for Each Question 

 

Question 2a and 2b outcomes criteria for outcomes inclusion. Any measure of the degree 

or presence of HF was accepted, including: clinical diagnosis, left ventricular ejection fraction 

(LVEF), change in NYHA class, left ventricular end-diastolic pressure, left ventricular enddiastolic dimension, left ventricular end-systolic dimension, end-diastolic thicknesses of the 

inter-ventricular septum. 

Question 3a and 3b outcomes criteria for outcomes inclusion. Admission to hospital for 

any of the following outcomes: angina requiring a minimum 24 hour hospitalization (acute 

coronary syndrome), angiographic percutaneous coronary interventions (including terms 

angioplasty, bypass surgery, coronary artery bypass graft, cardiac revascularization, 

percutaneous transluminal coronary angioplasty, stent), atrial fibrillation (arrhythmias), 

cerebrovascular event (e.g., stroke), composite endpoint, congestive heart failure (CHF), isolated 

diastolic ventricular dysfunction, mortality (all cause), myocardial infarction (MI). 

Question 4 outcomes. criteria for outcomes inclusion. No a priori outcomes were 

identified for inclusion. 

Criteria for outcomes exclusion. Non-cardiac events 

Peer Review Process 

A list of potential peer reviewers was assembled at the outset of the study from a number of 

sources including our technical expert panel (TEP), our partners, the McMaster research team, 

and the AHRQ. During the course of the project, additional names were added to this list by the 

McMaster Center and AHRQ. Thirteen content experts have reviewed this report (see Appendix 

E) and their comments and suggestions have been incorporated where possible. 

21

Chapter 3. Results 

The search yielded 4338 citations in total. From these 1733 citations proceeded to full text 

screening. Criteria for each specific research question were applied to these 1733 citations that 

yielded 4 subsets of papers to be further screened: one for each of the research questions (Figure 

2). A total of 264 citations (6 percent) were eliminated because of non-English language of 

publication (6 percent) at the title and abstract phase. The final number of eligible papers varied 

as a function of the specific research question. A total of 30 studies were eligible for Question 2; 

the results of the review of reviews for Question 2b are detailed later in the results. For question 

3, a total of 150 citations were eligible, and from these 110 are evaluated for this report. Forty of 

the citations for Question 3 reflected very specialized populations that did not necessarily reflect 

cardiac dysfunction. Finally for Question 4, a total of 18 studies were abstracted and evaluated. 

The results of the systematic review are presented in this chapter according to the four 

research questions: determinants, diagnostic performance, prognosis and monitoring of 

treatment. 

Figure 2. Flow diagram showing the numbers of articles processed at each level 

Title and abstract screen 4338 

Full text screen 1733

Screen for relevance to separate review questions 

635

Question 1 

Include 72

Question 2: Include 27 

2ai: ER: 14, 2aii: Clinic 6 

2aiii: Primary care 7

Question 3: Include 116 

3ai CAD: 12, 3aii: 38 

3aiii HF: 58, 3b: 8

Question 4 

Include 18

Exclude: Does not evaluate BNP...................... 955 

Exclude: Population is not human adults.............857 

Exclude: Not a full report of a primary study.........529 

Exclude: Not English language.........................264

Exclude: Not full report of a primary study........................................... 434 

Exclude: Does not evaluate adult, human blood.................................. 174 

Exclude: BNP or NT-proBNP test method is not an included one..............430 

Exclude: Case series or report with <11 subjects.....................................54 

Exclude: Natriuretic peptide used as treatment.........................................6

Question 2b 

Include 9
22

 Question 1: What Are the Determinants of Both BNP and 

NT-proBNP? 

Study Characteristics 

There were 144 studies included for all the clinical questions in this systematic review 

(Appendix C - Reference List of Included Articles). Of these, 72 studies showed a relationship 

between B-type natriuretic peptides and a biological determinant. In general, most determinants 

showed a positive association with B-type natriuretic peptides in this review. The determinants 

were categorized according to type of measurement (i.e., demographic, biochemical or 

physiological), disease and treatment. The determinant was considered to show a significant 

effect on B-type natriuretic peptide levels if the p-value was less than 0.05. Table 3 lists the 

details of the associations found and is presented according to the determinant category, effect 

(increase, none, and decrease) and test type (BNP and NT-proBNP). 

Demographic Characteristics 

Age was the most frequently reported determinant and in 13 of 15 studies was positively 

correlated with both BNP and NT-proBNP.3-15 There were two studies that did not show a 

relationship with age,31,34 but these studies had the smallest number of patients (n = 21 and 36, 

respectively) as compared to the other studies (range = 85 to 6809). One study reported no 

difference between African Americans and Caucasians.49 The association of B-type natriuretic 

peptides with gender was examined in 11 studies, with an almost equal number reporting either a 

higher level (n=5), or no difference in males (n = 6). There were no obvious similarities among 

studies with respect to observed association and patient population. However, larger studies were 

more likely than smaller studies to report a higher B-type natriuretic peptide level in females 

compared to males. Two studies looked at current smoking and reported no association.8,85

Cardiac Disease 

In general, all cardiac diseases (n = 21) were associated with an increase in the B-type 

natriuretic peptides. These included diastolic dysfunction,5,11,16,33,34,65 cardiac decompensation,26

acute right HF,57 and cardiac pulmonary edema (CPE).57 Acute right HF without cardiac 

pulmonary decompensation was not related to BNP concentration. Cardiac decompensation, 

however, was related to an increase in NT-proBNP. Patients with CPE had higher levels of BNP 

than patients with obstructive lung disease. Patients with diastolic dysfunction had elevated Btype natriuretic peptide levels but not as elevated as patients with systolic dysfunction.11,16,172 

There were differences among diseases within the broad category of cardiac ischemia. 

Patients with acute coronary syndrome (ACS) had elevated NT-proBNP levels,85 but there was 

no difference between patients with and without ischemic heart disease unless the patients had 

cardiovascular risk factors.4,116 Acute myocardial infarction (MI)4,8,29 or historical MI14,85 were 

associated with increased levels of B-type natriuretic peptides. Stable angina was not associated 

with a difference in B-type natriuretic peptides in one study4

 that included hypertensive patients, 

but was positively associated in patients with Non ST-elevation myocardial infarction (NSTEMI) 

ACS.57 Patients with left anterior descending (LAD) coronary artery lesions had elevated BNP 

and those with proximal lesions had higher levels than those with mid-lesions.95 Multi-vessel 
23

disease was associated with higher NT-proBNP levels.85 Also NT-proBNP levels were positively 

associated with patients who had previous revascularization.8

 There was no difference between 

patients with dilated cardiomyopathy and old MI.124 Arrhythmia65 was associated with elevated 

levels of B-type natriuretic peptides; however, there was no difference between atrial fibrillation 

and sinus rhythm115 valvular disease65 and all severities of aortic stenosis6 were positively 

associated with B-type natriuretic peptides levels. 

Non-cardiac Diseases 

The effect of non-cardiac diseases (n = 11) on B-type natriuretic peptide levels was mixed. 

Non-cardiac causes of dyspnea,16-18 diabetic nephropathy,15 and stroke8 were all associated with 

higher levels of B-type natriuretic peptides. Lung disease compared to HF,56 or HF plus lung 

disease,65 had lower BNP and NT-proBNP levels respectively. Diabetic retinopathy15 and 

cerebrovascular disease (including stroke and transient ischemic attack)4,8 did not show 

association with B-type natriuretic peptide levels. For diabetes, one study showed a positive 

association with NT-proBNP8

 but in three studies4,14,85 there was no association. Four of five 

studies that evaluated hypertension8,10,34,89 showed a positive association with B-type natriuretic 

peptides. The one study85 that did not show a difference used a statistical test for the difference in 

medians whereas the other studies used mean difference tests or regression analysis. Duration of 

hypertension was also not associated with BNP levels.10 There was no difference in NT-proBNP 

levels between patients with peripheral vascular disease as compared to patients without risk 

factors for cardiovascular disease (CVD).4 Two studies reported hyperlipidemia as a 

determinant. One of these studies showed an inverse relationship with NT-proBNP levels85 using 

the Wilcoxon rank sum test, whereas the other study showed no relationship8 using multiple 

linear regression analysis. 

Biochemical and Hematological Markers 

There were 29 biochemical and hematological markers where an association with the B-type 

natriuretic peptides was made. Markers of myocardial damage, including Tn-I,3,19,20 TnT,8,14,16,21-26 myoglobin,21 and CK-MB,21,27-29 were mostly positively associated with B-type 

natriuretic peptide levels. One study did not show a statistically significant correlation with CKMB.27 This study included only ST-segment elevation myocardial infarction (STEMI) patients, 

whereas the other studies excluded STEMI patients, or included MI patients admitted to the 

coronary care unit. No significant association was found in one study with Tn-I.20 This study 

included only NSTEMI and unstable angina patients in contrast to the other studies that included 

STEMI and ACS patients. Total creatine kinase showed no significant association with BNP but 

this may be because no patients in this study had elevated levels of this marker.26 Furthermore, 

the cardiac hormones ANP,12,13,25,84 NT-proANP,13,20,41,74,84,144,144 and second messenger 

cGMP,12,84 were positively associated with B-type natriuretic peptide levels. However, relaxin, 

also a cardiac hormone, showed no association with NT-proBNP.136 Several markers of 

inflammation including C-reactive protein,8,14,21 interleukin-6,22 the ST2 receptor protein90 and 

osteoprotegerin98 were positively associated with B-type natriuretic peptide levels. The 

association with lymphocytes was patient group specific.105 There was no statistically significant 

association between BNP and lymphocytes observed in the patient group with hypertensive heart 

disease, mitral stenosis, atrial fibrillation and hypertrophic cardiomyopathy, but a negative 

association was observed in a group composed of patients with ischemic heart disease, dilated 
24

cardiomyopathy aortic stenosis, aortic regurgitation and mitral regurgitation. There was a mixed 

association with markers of the renin-angiotensin-aldosterone system (RAAS). Plasma renin 

activity106 was inversely associated with BNP, whereas andromedullin84 and aldosterone106

showed no significant relationship with NT-proBNP and BNP, respectively. The ACE genotype 

DD,81 endothelin-1,106 big endothelin-1,41,106 epinephrine84 and norepinephrine12,25,39,41,84,106 were 

all positively associated with the B-type natriuretic peptides. Creatinine, an indirect marker of 

renal function, increased in five of eight studies with increasing levels of B-type natriuretic 

peptides.8,9,13,29,34,36,76,100 The reason why two studies29,34 did not show a correlation with 

creatinine is unknown; however, these two studies had the smallest sample size (n = 64 and 36, 

respectively) compared to the other studies (n = 84 to 6809). There was also no significant 

relationship observed between total protein9

 and BNP. Fasting glucose15 and HbA1c9,15 tests for 

diabetes showed no significant relationship with B-type natriuretic peptides, but random 

glucose135 was positively associated with BNP. Cholesterol,9,15 a marker of HF, showed no 

significant relationship with BNP or NT-proBNP. However, hemoglobin,15 a marker of anemia, 

was negatively associated with NT-proBNP. 

Functional and Physiologic Measure 

Two measures of renal function, glomerular filtration rate15 and creatinine clearance,122

showed an inverse relationship with B-type natriuretic peptides. Weight,8 but not BMI,9,10

showed a negative relationship with B-type natriuretic peptides. Exercise testing also showed 

that a decrease in physical endurance was related to higher B-type natriuretic peptide levels.116

Two studies which evaluated BMI as a determinant had no,9

 or very few,10 patients who were 

obese. 

Hemodynamic, Electrocardiographic and Echocardiographic 

Measures 

 

There were 23 measures from 14 studies reported for heart function.4,8-12,14,15,29-34 Most of the 

hemodynamic, electrocardiographic and echocardiographic measures were compared to BNP and 

a few were compared to NT-proBNP. Nine were positively associated with the B-type 

natriuretic peptides whereas eight showed no association. I-123 – metaiodobenzylquanidine 

(MIBG) activity,30 was negatively associated with B-type natriuretic peptides. Deceleration time 

of early mitral inflow was also negatively associated with BNP (the lower the deceleration time, 

the higher the plasma BNP).32 Heart rate and systolic blood pressure were the only two 

measurements that showed discrepant effects on B-type natriuretic levels. Heart rate was 

associated with both an increase8,12,31 and no change9,34 in B-type natriuretic peptides. Of the two 

studies that did not show an association, one included only hypertensive patients34 and in the 

other, the association was in elderly subjects ( > 80 years).9

 Systolic blood pressure was either 

positively4,15 associated with NT-proBNP, or showed no association with BNP.10,31 In one of 

these studies31 the association changed to positive after the patients were treated with a beta 

blocker. 
25

Drug Treatment 

There were 14 studies, including nine different drug treatments, with data on the effect of 

drug treatment.31,35-47 The effect of these drugs was a decrease or no effect on B-type natriuretic 

peptide levels. Studies involving therapy with amiodarone,37 atenolol,41 enalapril40,42 and 

valsartan39,43,45,46 all showed a decrease in B-type natriuretic peptides. Studies that assessed Btype natriuretic peptide levels after therapy with perindopril47 or metoprolol44 showed no 

difference compared to baseline. There was no dose dependent change in B-type natriuretic 

peptide levels with lisinopril36 or furosemide.36 The effect of carvedilol therapy on B-type 

natriuretic peptide levels, compared to baseline or a placebo group, showed either a 

decrease,31,36,47 or no change.35,44 There were two studies38,44 that treated patients with beta 

blockers but did not differentiate between the two drugs (carvedilol or metoprolol). One study 

reported a decrease in NT-proBNP concentration38 whereas the other study reported no change in 

BNP concentration44 after treatment. 

Non-drug Treatment 

There was only one study in this group of papers that reported a non-drug therapy. In this 

study the concentration of BNP decreased after implantation of a left ventricular device.150

Question 2a: What Are the Clinical Performance 

Characteristics of Both BNP and NT-proBNP Measurement in 

Patients with Symptoms Suggestive of HF or with Known 

HF? 

Question 2ai: Emergency Department 

Sample and Design Characteristics of Studies 

Fourteen articles met all of the inclusion criteria and were selected for data abstraction.7,16-

18,48-57 Of the 14 selected studies, four were from the Breathing Not Properly Multinational 

Study.18 The data from the sub-studies49,51,54 were excluded from the meta- analyses. This study 

and seven others examined only BNP.17,48,50,52,55-57 Two other studies examined only NTproBNP, 16,53 and one study examined variations of both BNP and NT-proBNP.7

 The included 

studies were published over a period of four years (2001 – 2004) with the majority published in 

2002 and 2004 (Table 4). The patients enrolled in all studies presented to emergency 

departments with shortness of breath and were over 18 years of age. One study57 limited 

enrolment to patients over 65 years of age while another16 limited enrolment to patients between 

44 and 88 years of age. 

Diagnosis of HF in studies. All studies except two52,53 selected for data abstraction 

employed a cohort design and a reference standard agreed upon by consensus of at least two 

physicians (mostly cardiologists). Two studies based the diagnosis on the opinion of a single 

cardiologist48,52 and the third only stated that the definitive diagnosis was based on the 
26

Framingham criteria and echocardiography results.53 The adjudicating physicians each arrived at 

a diagnosis of HF based on their interpretation of all available clinical data, often including 

echocardiography results. The Boston Criteria were employed in the diagnosis in one study52

and the Framingham criteria in three studies,18,53,55 one of which also applied the National Health 

and Nutrition Examination Survey (NHANES).18

Diagnostic properties. Table 4 presents the results to answer the question “What are the 

clinical performance characteristics of both BNP and NT-proBNP measurement in patients with 

symptoms suggestive of HF or with known HF presenting to an emergency department?” 

The 12 studies evaluating BNP utilized several cut point values ranging from 50 to 400 

pg/mL and reported sensitivities from 60 percent to 100 percent, specificities from 27 to 99 

percent, and areas under the curve (AUC) of 0.67 to 0.99.7,17,18,48-52,54-57 In addition, the reported 

positive likelihood ratio (LR+) ranged from 0.69 to 70 and the negative likelihood ratio (LR-) 

ranged from 0.00 to 0.44 (Table 4). The three studies evaluating NT-proBNP utilized several 

values ranging from 254 to 4567 pg/mL and reported sensitivities from 74 percent to 98.6 

percent, specificities from 47 to 93 percent, and AUC values of 0.89 to 0.96. It was possible to 

do meta-analysis on eight studies for BNP7,17,18,48,52,55-57 and three studies for NT-proBNP.7,16,53

To maximize sensitivity the lowest cut point was used if multiple cut point data were given. The 

data are summarized in Table 7 and Figures 3 and 4. The sensitivities of the BNP studies were 

similar with a summary sensitivity of 97 percent and a CI of 96 to 98 percent. In contrast, the 

specificity data was very heterogeneous with a summary estimate of 70 percent and a CI ranging 

from 56 to 85 percent (see Appendix C, Table 13-15 for results of tests for heterogeneity with 

regards to setting). The corresponding likelihood ratios (LRs) showed that the LR- (0.06, 95 

percent CI: 0.03 to 0.10) was better than the LR+ (3.63, 95 percent CI: 2.49 to 5.31) in terms of 

diagnostic value. The diagnostic odds ratio (DOR) for BNP ranged from 13 to 1635 with a 

summary estimate of 81 (95 percent CI: 29 to 219). With the exception of the pooled sensitivity 

estimates (Figure 3a) for BNP in the ED, all other combined estimates (for specificity, LR+, LR-, 

and DOR) had positive tests for heterogeneity; as such our confidence in these pooled estimates 

is decreased. 

For NT-proBNP the summary estimates were similar to BNP in that the sensitivity (95 

percent, 95 percent CI: 90 to 101) was much higher than the specificity (72 percent, 95 percent 

CI: 53 to 90). The LR- (0.07, 95 percent CI: 0.02 to 0.27) was also better than the LR+ (3.35, 95 

percent CI: 1.75 to 6.41). The DOR from these three studies assessing NT-proBNP ranged from 

17 to 291 with a summary estimate of 60 (94 percent CI: 9 to 407). All pooled estimates of NTproBNP diagnostic accuracy measures were significant for heterogeneity for ED studies. 

There were six studies that provided diagnostic information at a BNP cut point of 100 (±5) 

pg/mL.7,17,18,55-57 The meta-analysis on these studies shows a similar pattern to that described for 

varying cut points (Figure 5); with the exception of LR-, all other diagnostic pooled estimates 

were positive for heterogeneity. The sensitivity summary estimation is 95 percent (95 percent 

CI: 91 to 96) with a lower and broader specificity summary estimation (67 percent, 95 percent 

CI: 53 to 80). The LR+ was 3.4 (95 percent CI: 2.14 to 5.42) and the LR- was 0.11 (95 percent 

CI: 0.08 to 0.15), which is higher than the lowest cut point summary estimate. The overall DOR 

for this group of studies was reduced to 38 but the 95 percent CI was tighter (17 to 85) compared 

to the lowest cut point summary estimate. 

 
27

Figure 3. Forest plots for BNP in all settings using the lowest cut point provided in each study: a) sensitivity, 

b) specificity, c) LR+, d) LR-, e) DOR. 

3a. Summary Sensitivity, Random Effects 

3b. Summary Specificity, Random Effects 
28

3c. Summary LR+, Random Effects 

3d. Summary LR-, Random Effects 
29

3e. Summary Diagnostic Odds Ratio, Random Effects 
30

Figure 4. Forest plots for NT-proBNP in all settings using the lowest cut point provided in each study: a) 

sensitivity, b) specificity, c) LR+, d) LR-, e) DOR. 

4a. Summary Sensitivity, Random Effects 

4b. Summary Specificity, Random Effects 
31

4c. Summary LR+, Random Effects 

4d. Summary LR-, Random Effects 
32

4e. Summary Diagnostic Odds Ratio, Random Effects 
33

Figure 5. Forest plots for BNP in the ED using a cut point of 100 (±5) pg/mL: a) sensitivity, b) specificity, c) 

LR+, d) LR-, e) DOR. 

5a. Summary Sensitivity, Random Effects 

5b. Summary Specificity, Random Effects 
34

5c. Summary LR+, Random Effects 

5d. Summary LR-, Random Effects 
35

5e. Summary Diagnostic Odds Ratio, Random Effects 

Quality assessment of studies. Results from the application of the QUADAS Question 14, 

quality assessment tool are as follows (see also Appendix C Evidence Figures, Figure 1): one 

(9.1 percent) of the studies clearly addressed the issue of disease progression bias (QUADAS 

Question 4); the reference standard was independent of the index test result (QUADAS Question 

7) in 10 (90.9 percent) of the studies; the reference standard was described in sufficient detail 

(QUADAS Question 9) in seven (63.6 percent) of the studies; interpretation of the peptide 

marker (BNP or NT-proBNP) measurement was clearly without knowledge of the reference test 

results (QUADAS Question 10) in one (9.1 percent) of the studies; interpretation of the reference 

test results was clearly without knowledge of the B-type natriuretic peptide marker results 

(QUADAS Question 11) in seven (63.6 percent) of the studies; none (100 percent) of the studies 

stated whether or not the clinical data was available when the B-type natriuretic peptide test 

results were interpreted as would be the case when the test is used in practice (QUADAS 

Question 12); one (9.1 percent) of the studies reported uninterpretable or intermediate test results 

(QUADAS Question 13) and; withdrawals were not explained in two (18.2 percent) of the 

studies (QUADAS Question 14). Overall, the quality of these studies was good. 

Question 2aii: Specialized Clinic or Outpatient Setting 

Sample and Design Characteristics of Studies 

There were a total of six papers eligible for review published between 1997 and 2004.11,58-62

All studies evaluated BNP with the exception of two58,60 which compared both BNP and NTproBNP. The studies were conducted in Austria, Japan, Portugal and USA. Two studies were 

based on patients referred to a HF clinic11,59 and the remaining, to outpatient settings.58,60-62 All 

studies provided evaluation on BNP and two compared BNP and NT-proBNP.58,60 Three of these 

papers provided data on sensitivity, specificity, and ROC curves for BNP or NT-proBNP 11,58,60. 
36

Three of these papers did not provide ROC characteristics or sensitivity or specificity data; 

instead, only correlation data for BNP or NT-proBNP with different variables of cardiac 

structure, function and symptoms were provided. 

Diagnosis of HF in studies. Three studies58,60,62 used echocardiography as the reference 

standard, one study used echocardiography plus clinical criteria11 and two studies59,61 used the 

NYHA classification. 

Diagnostic properties. Hammerer-Lercher et al.60 directly compared the diagnostic values 

of NT-proBNP with BNP in 57 patients with stable chronic HF. In the analysis of normal 

(echocardiographic ejection fraction (EF) ≤ to 48 percent or radionuclide angiographic EF ≤ to 

55 percent) versus impaired (echocardiographic EF < 48 percent or radionuclide angiographic EF 

< 55 percent) LVEF the AUC for BNP was 0.75 (SE ± 0.06), and for NT-proBNP was 0.67 (SE 

± 0.07) (Table 5). In the analysis of LVEF less than 40 percent versus greater than or equal to 40 

percent, the AUC for BNP was 0.83 (SE ± 0.06), and for NT-proBNP was 0.79 (SE ± 0.07). 

Positive and negative LRs were 3.17 and 0.35, respectively for BNP and 2.59 and 0.41, 

respectively for NT-proBNP. NT-proBNP did not differ significantly from BNP in either of the 

analyses. The optimal discriminator values were 142 pg/mL for BNP, and 4127 pg/mL for NTproBNP for the detection of LVEF less than 40 percent compared to greater than or equal to 40 

percent. For these discriminators the sensitivity was 73 percent for BNP, and 70 percent for NTproBNP. The specificities were 77 percent for BNP, and 73 percent for NT-proBNP. 

Bettencourt et al.11 studied 100 patients with symptoms suggestive of HF referred to a HF 

clinic. These patients had suspected or not previously investigated HF. Since healthy controls 

were included in this study, this suggested the potential for spectrum bias, although it was not 

clear if the control data was used in the estimates of diagnostic accuracy. For a cut point value of 

39.7 pg/mL, the positive predictive value was 95.5 percent. For the diagnosis of HF regardless 

of LVEF, the AUC was 0.92 (95 percent CI: 0.86 to 0.99; p < 0.0001). The accuracy of BNP for 

the detection of systolic dysfunction was slightly less with an AUC of 0.78 (95 percent CI: 0.69 

to 0.88; p < 0.0001). The BNP performance for detection of diastolic dysfunction expressed by 

the AUC was 0.89 (95 percent CI: 0.78 to1.00; p < 0.0001) for the patients without systolic 

dysfunction. Multiple regression analysis demonstrated that age, left ventricular mass index, and 

LVEF were independently associated with BNP. 

Seino et al.58 compared BNP and NT-proBNP relative to LVEF less than 40 percent and less 

than 50 percent in patients with HF. Their data indicate that detection of LVEF less than 50 

percent was slightly greater for NT-proBNP than BNP (AUC 0.820 and 0.794, respectively). The 

reverse was true for LVEF less than 40 percent, with BNP having slightly greater AUC (0.770) 

compared to NT-proBNP (0.754). The optimum cut point values were determined to be 135 

pg/mL for BNP and 695 pg/mL for NT-proBNP. There were four papers11,59,61,62 that 

examined the relationship between BNP only and other HF variables but did not provide any 

data about the sensitivity, specificity or accuracy of these measurements. In general, it was 

demonstrated that BNP was related to cardiac function measured either as LVEF62 or left 

ventricular end diastolic pressure.61 One study59 examined 41 HF patients and found BNP was 

related to the NYHA class. 

There was only one study58 that contained sufficient information to conduct meta-analysis by 

clinic setting alone. Therefore, no overall estimates for the individual clinic setting are possible. 

However, this one study was used to conduct meta-analysis for all sites combined (Figure 3 and 

4). The results of this analysis are described elsewhere. 
37

Quality assessment of studies. Results from the application of the QUADAS Question 14 

quality assessment tool are as follows (see also Appendix C Evidence Figures - Figure 2): three 

(50.0 percent) of the studies clearly addressed the issue of spectrum bias(QUADAS Question 1); 

the selection criteria were only described in four (66.7 percent) of the studies (QUADAS 

Question 2) and in remaining two (33.3 percent) of the studies it was difficult to assess the 

selection criteria; four (66.7 percent) of the studies described if the reference standard was likely 

to correctly classify the HF (QUADAS Question 3); three (50 percent) of the studies clearly 

described the issue of disease progression (QUADAS Question 4); the reference standard was 

described in sufficient detail (QUADAS Question 9) in five (83.3 percent) of the studies; 

interpretation of the peptide marker (BNP or NT-proBNP) measurement was clearly made 

without knowledge of the reference test results (QUADAS Question 10) in five (83.3 percent) of 

the studies; interpretation of the reference test results was clearly made without knowledge of the 

B-type natriuretic peptide marker results (QUADAS Question 11) in all of the studies; five (83.3 

percent) of the studies stated whether or not the clinical data was available when the B-type 

natriuretic peptide test results were interpreted as would be the case when the test is used in 

practice (QUADAS Question 12); one (16.7 percent) of the studies reported uninterpretable or 

intermediate test results (QUADAS Question 13); and withdrawals were explained in five (83.3 

percent) of the studies (QUADAS Question 14). Overall, the quality of these studies was good.

Question 2aiii: Primary Care 

 

Sample and Design Characteristics of Studies 

There were seven papers eligible for review that selected patients from a primary care 

setting. Five of these studies were cross-sectional in design34,65-68 and one was a RCT64. There 

was one study that selected patients randomly and identified a high risk cohort group.63 

Two of the studies restricted their recruitment by age; one to 40 years of age and above,64 and 

one to more than 45 years of age.63 One study presented data stratified by gender.65 The RCT64

examined the effect of BNP measurement on diagnostic accuracy in primary care. All patients 

had BNP measured, but the groups were randomized as to whether or not the primary care 

physician received the results. Nevertheless, this paper is useful because the BNP concentrations 

can be compared against the reference standard of HF (expert diagnosis) in both arms of the 

study. 

Two studies34,67 either did not provide estimates of the diagnostic performance of the BNP 

test, or presented the data in a manner such that these diagnostic characteristics could not be 

calculated. 

Diagnosis of HF in studies. Four studies used evaluation of left ventricular systolic function 

by echocardiogram as the reference standard for HF.63,65,67,68 Three used LVEF of less than or 

equal to 40 percent,63,67,68 one used LVEF less than or equal to 45 percent,65 and one34 did not 

state the reference cut point. Another study used x-ray or echocardiogram with evidence of 

pulmonary edema or cardiomegaly as the reference cut point.66 The European Society of 

Cardiology criteria were used as the reference standard for the RCT study.64 

Diagnostic properties. Table 6 presents the results to answer the question, “What are the 

clinical performance characteristics of both BNP and NT-proBNP measurement in patients with 

symptoms suggestive of HF or with known HF presenting to a primary care physician?” Three 

papers evaluated only BNP,34,66,67 three evaluated only NT-proBNP,64,65,68 and one evaluated 
38

both.63 Two of seven failed to indicate the cut point for BNP or NT-proBNP used. Two studies 

presented data for more than one cut point.65,66 The range in cut points were 10 to 115 pg/mL for 

BNP and 67 to 338 pg/mL for NT-proBNP. Where possible, sensitivities, specificities, and LRs, 

either reported or calculated, are presented. Area under the ROC curve is presented when 

reported. Sensitivity ranged from 66 to 92 percent for BNP and 80 to 100 percent for NTproBNP. Specificity ranged from 18 to 88 percent for BNP and 18 to 84 percent for NT-proBNP. 

For BNP, LR+ ranged from 1.12 to 6.71 and LR- ranged from 0.022 to 0.75. For NT-proBNP the 

LR+ ranged from 1.22 to 5.7 and the LR- ranged from 0 to 0.27. 

Meta-analysis was done on two studies63,66 for BNP and three studies for NT-proBNP.63-65 To 

maximize sensitivity the lowest cut point was used if data for multiple cut points were given. The 

data for the meta-analysis are summarized in Table 7 and the results presented in Figures 3 and 

4. Since there were few studies available, the accompanying pooled summary statistics must be 

interpreted with caution. However, looking at the three studies for NT-proBNP the DOR 

summary estimate was 17 (95 percent CI: 9 to 32) whereas it was only 2 (95 percent CI: 1 to 6) 

for BNP. Furthermore, in the Hobbs study63where both BNP and NT-proBNP were measured, 

the DOR was about eight times higher (2 and 17 for BNP and NT-proBNP, respectively). Tests 

for heterogeneity were not significant for either of the B-type natriuretic peptides for the pooled 

LR- or DOR. 

Quality assessment of studies. Results from the application of the QUADAS Question 14 

quality assessment tool are as follows (see also Appendix C Evidence Figures - Figure 3): six 

(85.7 percent) of the studies clearly addressed the issue of spectrum bias(QUADAS Question 1); 

the selection criteria were only described in six (85.7 percent) of the studies (QUADAS Question 

2); all of the studies described if the reference standard was likely to classify the HF properly 

(QUADAS Question 3); five (71.4 percent) of the studies clearly described the issue of disease 

progression (QUADAS Question 4); the reference standard was described in sufficient detail 

(QUADAS Question 9) in six (85.7 percent) of the studies; interpretation of the peptide marker 

(BNP or NT-proBNP) measurement was clearly without knowledge of the reference test results 

(QUADAS Question 10) in all of the studies; interpretation of the reference test results was 

clearly without knowledge of the B-type natriuretic peptide marker results (QUADAS Question 

11) in all of the studies; six (85.7 percent) of the studies stated whether or not the clinical data 

was available when the B-type natriuretic peptide test results were interpreted as would be the 

case when the test is used in practice (QUADAS Question 12); five (71.4 percent) studies 

reported uninterpretable or intermediate test results (QUADAS Question 13) and; withdrawals 

were explained in five (71.4 percent) studies (QUADAS Question 14). Overall, the quality of 

these studies was good. 

Question 2aiv: Long Term Care Setting 

 No papers were identified in the screening process that examined the question “What are the 

clinical performance characteristics of both BNP and NT-proBNP measurement in patients with 

symptoms suggestive of HF or with known HF presenting in long term care settings?” 
39

Question 2av: All Settings Combined 

 

Meta-Analysis 

We chose studies for meta-analysis from Questions 2ai, 2aii and 2aiii where sufficient 

information was presented to allow calculation of sensitivity, specificity, LRs and DOR for as 

many diagnostic cut points as were presented (Table 7). Using this information, we developed 

summary estimates of these parameters (Figures 3, 4 and 5) as well as summary receiver operator 

characteristic (SROC) curves (Figure 6). In the pooling these data, we observed significant 

heterogeneity. As a result, we tried to explore the sources of the heterogeneity using metaregressions and stratifications. We evaluated potential sources of heterogeneity for B-type 

natriuretics by stratifying groups according to the following factors: a) study setting (clinic, 

emergency department, and primary care), b) study design (cross-sectional, prospective cohort, 

randomized trials, and diagnostic types), c) sample size (greater than or equal to 500 and less 

than 500), d) comparison to reference standard (LVEF, compared to other signs and symptoms, 

and HF defined by clinical criteria), and e) cut points (exactly 100 pg/mL, greater than 100 

pg/mL, and less than 100 pg/mL). Across the 5 different metrics of diagnostic accuracy 

(sensitivity, specificity, LR+, LR-, DOR), many of these were observed to be positive for 

heterogeneity, suggesting that no single factor helped to explain the variation between studies 

(Appendix C, Tables 13-26 detail the results of the heterogeneity tests by factors). The small 

number of studies within each of the various categories was also a limiting factor in exploring 

the relative contribution of these covariates to the observed heterogeneity. 

We also used the Moses-Littenberg regression model to develop a summary ROC curve and 

test for the presence of a threshold effect. Using both weighted and unweighted regressions, the 

slope parameter was small and not statistically significant (BNP p = 0.4183, NT-proBNP p = 

0.3430), thus indicating the lack of a threshold effect. These data show that despite the various 

cut points and patient cohorts studied there was fairly high concordance among the studies. 

Figure 6 presents the summary ROC curves for BNP and NT-proBNP. In both cases the 

curve tends strongly towards the upper left hand corner. The cut points ranged from 10 to 200 

pg/mL (mean = 95 pg/mL) for BNP and 125 to 1691 pg/mL (mean = 642 pg/mL) for NTproBNP. Sensitivities for BNP and NT-proBNP ranged from 50 to 99 percent and 83 to 99 

percent, respectively. Specificities for BNP and NT-proBNP ranged from 19 to 97 percent and 

46 to 89 percent, respectively. The areas under the curves, however, are 0.86 for both BNP and 

NT-proBNP, suggesting that regardless of the clinical setting, the cut point chosen, or the test 

used, measurement of B-type natriuretic peptides are useful in the diagnosis of HF. The standard 

error (SE) for the BNP AUC was slightly higher than for the NT-proBNP AUC (0.068 compared 

to 0.034, respectively). There are two noted outliers in the BNP SROC with respect to sensitivity 

that can account for this. One is from the clinic setting58 and the other is from the primary care 

setting.63 Although there were two studies from the primary care setting in the SROC, the study 

that appeared as an outlier selected patients who were at high risk for HF (prevalence = 7.5 

percent) compared to the other study which selected patients suspected of having HF (prevalence 

= 32 percent).66 
40

Figure 6. Summary ROC curves for a) BNP and b) NT-proBNP from all settings using the lowest cut point 

provided in each study. 

6a. Summary-ROC curves for BNP

The lines on this graph represent the best-fit curve and 95 percent CIs around it. Each number on the graph indicates the various 

cut point in pg/mL

200 

110 

80 

94 

135 

115 

50

100

69 

80

10 Symmetric SROC

AUC= 0.8623 

SE(AUC)= 0.0679 

Q*= 0.7930 

SE(Q*)= 0.06581 
41

6b. Summary ROC curves for NT-proBNP

The lines on this graph represent the best-fit curve and 95 percent CIs around it. Each number on the graph indicates the various 

cut point in pg/mL. 

Question 2b: Does Measurement of BNP or NT-proBNP Add 

Independent Diagnostic Information to the Traditional 

Diagnostic Measures of HF in Patients with Suggestive HF? 

Study Characteristics 

To address this question, data were abstracted from studies included in Question 2a. These 

included evaluation of multivariate analysis to quantify the independent contribution of the Btype natriuretic peptides for the diagnosis of HF. 

For the review of reviews a total of 145 reviews were evaluated for relevance by examining 

the titles and abstracts and 13 reviews were retrieved for full text screening.151,163,173-183 One 

additional review was obtained by the local expert panel,184 bringing the total to fourteen. 

However, only nine reviews met our inclusion criteria for data abstraction. 

Multivariate Analyses 

It is recognized that clinicians request more than a single test, which are typically not 

independent of each other. Thus, methods that adjust for multiple tests such as, multivariate 

1691 

1184 

211 695 

254

125

388 

Symmetric SROC

AUC= 0.8634 

SE(AUC)= 0.0340 

Q*= 0.7940 

SE(Q*)= 0.0331 
42

regression analysis, may assist in evaluating the independence of all the tests used within the 

same study. These analyses also provide estimates of the independent ability to “predict” the 

probability of the disease of interest while controlling for other tests. Limitations of multivariate 

analyses include sample sizes and the number of variables included in the model.185

Studies from Questions 2ai, 2aii and 2iii that performed multiple linear regression or multiple 

logistic regression to assess the value of B-type natriuretic peptides for the diagnosis of HF were 

brought forward into Question 2b. Nine papers from 2ai (emergency department) met this 

requirement. Eight of these studies used BNP17,18,49,51,54-57 and one used NT-proBNP53 for HF 

diagnosis. Four of the BNP studies were from the Breathing Not Properly Cohort.18,49,51,54 There 

were no studies from 2aii (specialized or outpatient clinic) or 2aiii (primary care) with 

multivariate analysis data. 

The diagnostic measures considered in this section included: clinical signs and symptoms 

(dyspnea, edema, rales, orthopnea, increased jugular venous pressure (JVP), S3 heart sound and 

murmurs); other objective diagnostic measures (chest X-ray echocardiography, myocardial 

radionuclide angiogram, cardiac catheterization, MRI, CT scan); and composite scoring systems 

(NHANES score, Framingham score, NYHA class, and clinical judgment). In eight studies the 

NHANES and Framingham composite scoring systems and LVEF less than 40 percent were used 

as the reference standard to establish the diagnosis of HF.17,18,51,53-57

Two papers49,54 used clinical judgment as a composite measure, five18,51,53,56,57 used edema, 

four17,18,53,55 used increased JVP, four18,53,55,57 used rales, three17,53,56 used orthopnea, and two 

used gallops or murmurs53,56 as variables in the regression analysis. X-ray measures included 

four papers on pulmonary venous hypertension,18,55,56,186 three papers on cardiomegaly,51,53,55 and 

two on x-ray edema.17,51 Seven of the papers report the results of multiple logistic regression as 

odds ratios (ORs) or exponential β, two use chi square, and one used diagnostic accuracy. 

Table 8 presents the results of the data abstraction for this section. In cases where the results 

are expressed as ORs with 95 percent CI, BNP appears to add significant information to the 

diagnosis of HF that is independent of other diagnostic measures. The ORs associated with BNP 

ranged from 12.3 (95 percent CI: 7.4 to 20.4) to 221 (95 percent CI: 24.6 to 1983.1), and were 

usually larger than the other diagnostic measures in the study. The single paper reporting the 

results of NT-proBNP53 gave an OR of 8.9 (95 percent CI: 3.9 to 20.5) 

Those publications that reported the results as chi-square or diagnostic accuracy, also suggest 

that BNP measurement adds significant information to the diagnosis. This suggests that BNP and 

NT-proBNP measurement can add independent diagnostic information beyond that which is 

available from the traditional diagnostic measures. 

Comparison of Estimates of DOR and SROC for Different Tests for HF 

Based on the Review of Reviews 

Review characteristics. A total of 14 reviews evaluated some aspect of tests used for HF. 

Table 9 describes the characteristics of these reviews. Of these 14, nine151,173,174,177,179,181-184

contained information that was useful and pertinent to this review. Five studies were excluded 

from further analysis. Three163,176,178 were systematic reviews, but did not examine the diagnosis 

of heart failure. The remaining two175,180 were not systematic reviews. 

Two reviews174,184 considered patients in all settings, one182 considered only emergency 

department patients, one177 primary care only, one183 considered both primary care and 

emergency department patients, and three151,173,179 did not specifically state a clinical setting. 
43

One review181 selected studies “on the basis of quality and relevance to primary care”. Three 

reviews182-184 have examined the value of BNP and NT-proBNP measurement in the diagnosis of 

HF compared to other diagnostic measures. One review 174 examined BNP alone, and one151

examined BNP and “related peptides” alone. One review177 examined the 12-lead 

electrocardiogram (ECG) only, and one181examined the clinical exam, x-ray and ECG. Neither of 

these studies provided a comparison to B-type natriuretic peptides, but both present useful 

supporting evidence for the discussion. 

The National Health Service Quality Improvement Scotland Technology Assessment Report 

#6183 examined the role of B-type natriuretic peptide measurement and ECG in primary care. 

They concluded that BNP or NT-proBNP is superior to machine-read ECGs, but equivalent to an 

accurate physician-interpreted ECG in deciding which patients to refer to echocardiography. A 

systematic review of the 12-lead ECG for the evaluation of suspected HF177 concludes that this is 

an inadequate tool to screen for those patients that require echocardiography. 

Doust et al.184 prepared a systematic review for the National Institute for Clinical Studies in 

Melbourne Australia. The results of this review are difficult to interpret because no pooled 

estimates of the data are presented. Nevertheless, they conclude that most signs and symptoms 

lack both the sensitivity and specificity required for the diagnosis of HF. Tachycardia at rest, 

elevated JVP, displaced apex beat, and added heart sounds are the most specific. A normal ECG 

will rule out HF, but may require specialist interpretation. An abnormal chest x-ray is useful only 

when accompanied by an abnormal ECG. They further conclude that B-type natriuretic peptide 

measurement is the most valuable tool in ruling out HF, because of its high negative predictive 

value. 

Wang et al.182 reviewed papers that assessed the diagnosis of HF in patients presenting to the 

ED with dyspnea. The features that increased the probability of HF were S3 gallop, chest x-ray 

showing pulmonary venous congestion and an ECG showing atrial fibrillation. Those that 

decreased the probability were an absence of rales, a normal response to the Valsalva maneuver, 

absence of cardiomegaly or edema on x-ray and a normal ECG. A serum BNP less than 100 

pg/mL proved to be the most useful tool in ruling out HF (LR- .011, 95 percent CI: 0.07 to 0.16). 

Table 10 outlines the diagnostic tests examined and the performance characteristics in each 

of the reviews. To compare the performance of diagnostic tests between reviews, we chose to use 

the DOR. This performance characteristic is the single most useful measure of diagnostic 

performance and the most easily comparable between studies and reviews, partly because it is 

relatively insensitive to the decision threshold chosen in each study. In cases where the DOR was 

not presented, we estimated the DOR from the sensitivity and specificity or positive and negative 

LR. 

Three reviews151,173,174 considered only BNP or NT-proBNP without comparison to other 

tests. In these studies the DOR or the estimated DOR for BNP ranged from 31 to 569. The single 

review that examined NT-proBNP has an estimated DOR of 230. BNP and NT-proBNP were 

compared to other diagnostic tests in three other reviews.182-184 In these reviews the DOR for 

BNP ranged from 10 to 498, and the single review comparing NT-proBNP to other tests had a 

DOR of 14. 

B-type Natriuretic Peptides Compared to Other Diagnostic Measures 

In our assessment of the primary research studies of the diagnostic properties of BNP and 

NT-proBNP, we looked for papers that compared the B-type natriuretic peptides against a 

number of reference measures. Therefore, in our examination of reviews, we also looked for 
44

studies that measured the independent contribution of these peptides against these reference 

measures. No reviews compared the diagnostic performance characteristics of BNP or NTproBNP against myocardial radionuclide angiography, cardiac catheterization, MRI, or CT scan. 

Three reviews182-184 compared BNP to abnormal ECG and one177 examined ECG 

abnormalities alone. The estimated DOR ranged from 3 to 223 whereas the DOR for BNP in the 

same studies ranged from 10 to 498. The DOR for an abnormal ECG exceeded the DOR for BNP 

in only one case183 (12.4 vs. 10.4), but the 95 percent CIs were overlapping. Similarly the DOR 

for NT-proBNP was similar to that for an abnormal ECG (14.9 vs. 12.4). One systematic 

review181 describes an abnormal ECG as having a high sensitivity but poor specificity and useful 

for confirmation of diagnosis only but no numerical values were provided. 

Two parameters of the chest x-ray (evidence of pulmonary venous hypertension and evidence 

of cardiomegaly), had diagnostic importance and were examined in three studies.181,182,184 The 

estimated DOR for these two tests were 3 to 28 for pulmonary venous hypertension and 2 to 10 

for cardiomegaly. Again this is less than the DOR of BNP in the same studies. 

Any abnormality in the clinical exam, history of paroxysmal nocturnal dyspnea, S3 gallop, 

and increased JVP were the components of the clinical exam that had diagnostic usefulness. 

Three reviews182-184 compared these parameters to BNP. In all cases the estimated DOR for these 

tests was less than the estimated DOR for BNP. 

Quality Assessment of Reviews 

The quality of the reviews was assessed by the STEP Questionnaire.169 The quality of 

reviews varied from good to poor. Three reviews173,182,183 were obviously of higher quality than 

the rest. These reviews clearly stated the main question, the clinical population and the main 

comparators. Inclusion and exclusion criteria were plainly stated and it is unlikely that relevant 

studies were missed. Assessments were made by at least two reviewers and the results were 

presented clearly. Meta-analysis was performed where appropriate. Two reviews177,184 were of 

good quality, but the results were presented in a less clear manner. Five further 

reviews151,174,175,180,181 were of lesser quality. 

Question 3a: Do BNP or NT-proBNP Levels Predict Cardiac 

Events in Populations at Risk of CAD, with Diagnosed CAD 

and HF? 

 A total of 150 studies were eligible for evaluating the prognostic ability of BNP or NTproBNP levels in HF patients to predict cardiac events of interest for this review. For the 

purposes of this review we have limited the findings to four major groups and these include, 

people at risk of CAD, those diagnosed CAD or HF, and general populations for screening. A 

small group (n = 40) of studies included populations in ICU, with pulmonary embolism, stroke, 

or renal failure; the data from these specialized groups will not be presented here. 
45

Question 3ai: At risk of CAD 

 

Design and Sample Characteristics of Studies 

The prognostic value of BNP or NT-proBNP was examined in 12 studies of people with risk 

factors for CAD, ten were prospective cohorts,9,10,15,24,69-74 one was a RCT,4 and one was crosssectional.6

 Sample sizes ranged from 1119 to 3346.74 Most study participants were between 50 

and 75 years of age, although eight studies included patients over 50 years.6,10,15,24,69,71,73,74 Four 

studies included participants under 75 years of age.9,10,24,71 The widest age range, (19 to 105 

years) was from an Irish study71 in an emergency room. In one study,70 only the mean age of 

participants was reported so it was not possible to assess the age range of the sample. The 

percentage of males in the studies ranged from 21 percent9 to 96 percent.69 Follow up averaged 8 

to 9 years in two studies15,70 and 8 to 12 days in another.71 Excluding the cross-sectional study,6

and another study for which the follow up time was reported as “until discharge,”72 follow up 

time ranged from approximately 1 to 5 years.4,9,10,24,69,73,74

CAD Risk Factors 

Study participants were recruited in an emergency room or when admitted to a cardiac care 

unit. CAD risk factors included diabetes,15,69,70,74 suspicion of cardiac dysfunction,69 ACS or 

chest pain,24 suspected heart disease,9,71,74 cardiac arrest with cardiac cause,72 hypertension,4,10,74

prior MI,74 aortic stenosis or aortic valve replacement,6

 left atrial enlargement or left ventricular 

hypertrophy,74 significant heart disease upon admission, or a cardiac event within 90 days of 

admission.73

CAD risk factors were assessed using a mixture of electrocardiography, chest x-ray, clinical 

examination, LVEF, or NYHA classification criteria. Diabetes was assessed by clinical criteria 

such as persistent macroalbuminuria ( > 300 mg/24 hours) in at least two out of three consecutive 

24-hour urine collections, with the presence of diabetic retinopathy and the absence of other 

kidney or urinary tract disease. Hypertension was defined as systolic blood pressure greater than 

or equal to 140 mmHg or diastolic blood pressure greater than or equal to 90 mmHg. 

BNP and NT-proBNP Tests and Threshold Values 

BNP was measured using the Triage BNP method in two studies,69,71 and the ShionoriaIRMA method in four studies.9,10,72,74 NT-proBNP was measured using the Elecsys method in 

six studies.4,6,15,24,70,73

BNP or NT-proBNP cut point values were not uniform; six studies6,9,24,69,71,73 reported 

multiple and six6,24,70,71,73,74 reported single cut points. Cut points were chosen based on median 

or percentile levels of fasting plasma NT-proBNP4,70 or plasma BNP,9,74 mean BNP,10 ROC 

curves,6,72,73 information from the test package insert,71 or miscellaneous external sources.15 In 

two studies, the selection of cut points was arbitrary or unexplained.24,69
46

Definition of Outcomes 

Death was a primary outcome in 10 studies,4,9,10,15,24,69-71,73,74 although in four 4,10,70,73 it was 

part of a composite outcome including other cardiovascular events (e.g., non-fatal MI). Death 

was limited to cardiovascular events in four studies4,10,70,73 and included all-cause mortality in six 

studies.9,15,24,69,71,74 Deaths were ascertained using public records (e.g., death certificates) in four 

studies,15,24,69,73 while in three there was mention of “clinical assessment” of cardiovascular 

outcomes (including death).4,10,74 Assessment of death was not described in three studies.9,24,71

The two studies with non-death outcomes were the only studies that enrolled patients with 

prior surgeries. In the first study,72 27 to 40 percent of patients had an intra-aortic balloon 

counterpulsation or a coronary revascularization. The outcomes ranged from survival to hospital 

discharge. In the second study,6

 12 percent of patients had coronary artery bypass graft (CABG) 

and 9 percent had percutaneous coronary intervention. The outcome was the severity of aortic 

stenosis. Outcomes other than death were measured by clinical tests such as the mean 

transvalvular pressure gradient6

 or LVEF.73

Four studies had secondary outcomes, including non-cardiac causes of death69 and 

cardiovascular mortality plus hospitalization for HF.70 One study74 had three secondary 

outcomes: MI, heart disease, and atrial fibrillation. The fourth study72 had four secondary 

outcomes: return of spontaneous circulation, hospital admission, 24-hour survival, and favorable 

neurologic outcome after discharge. 

Adjusted Results – Multiple Regression Analysis 

Eleven of the 12 studies (Neilson et al.73 excepted) featured regression analysis to examine 

the association between levels of BNP or NT-proBNP and the outcome of interest. In two of the 

11 studies, one BNP69 and one NT-proBNP,6 the reported regression results consisted only of pvalues or chi-square test statistics. See Tables 11 and 12 for summary results for all 12 studies. 

BNP was treated as a categorical variable in four studies,9,71,72,74 with the categories based on 

the cut points discussed above. Higher levels of BNP were consistently found to be positively 

associated with all-cause mortality or the occurrence of cardiac events (e.g., HF).9,71,74 The 

adjusted measures of association (OR or hazard ratio (HR)) ranged from 1.10 to 4.26 and did not 

appear to differ by outcome in two studies (point estimates < 2.00 in both studies).9,74 In one 

mortality study,71 though, the estimated OR for BNP ( ≥ 700 pg/mL versus < 700 pg/mL) was 

found to be much larger at 4.26. 

In the final study where BNP was treated as categorical,72 the outcome was survival to 

hospital discharge. For the study participants, some of whom had prior surgery, all of the 

adjusted, estimated ORs were less than 1.00. Since the ORs decreased as the level of BNP 

increased, higher levels of BNP were negatively associated with survival. 

The results of the study10 where BNP was treated as a continuous variable showed that higher 

values of BNP were positively associated with the occurrence of cardiovascular events (adjusted 

risk ratio (RR) = 1.02; 95 percent CI: 1.01 to 1.02). 

NT-proBNP was also treated as a categorical variable in four studies.4,15,24,70 Again, the 

categories were based on the cut points discussed above. Higher levels of NT-proBNP were 

consistently found to be positively associated with composite endpoints that included both 

cardiovascular mortality and other cardiac events such as non-fatal MI.4,70 Positive associations 

were also found between levels of NT-proBNP and all-cause mortality.15,24 The adjusted 
47

measures of association (RR or HR) ranged from 1.85 to 5.40, with a concentration between 2.8 

and 3.6. 

In 10 of the studies, all of the adjusted measures of association (i.e., OR, HR, RR) were 

statistically significant at the 5 percent level. In the other two studies,9,24 all of the measures 

except for three were also statistically significant at the 5 percent level. 

Several variables were included in many of the regression models as covariates, including 

age, gender, blood pressure, cholesterol level, left ventricular mass or function, and smoking. 

Quality Assessment of Studies 

Selection and information bias are two common threats to the internal validity of 

observational studies. One method of minimizing selection bias is to evaluate all patients who 

present at the research site between a certain set of fixed dates. Patients who meet the inclusion 

criteria are then entered into the study. This method of enrollment – often called ‘consecutive 

enrollment’ – helps to prevent a conscious or unconscious bias from affecting the selection of 

patients into the study. The bias would occur if, for example, patients with multiple risk factors 

for CAD, or with higher risk factors for CAD, were the only persons selected for the study. In 

the 12 studies of persons with risk factors for CAD, the authors of only four studies15,24,71,73

explicitly wrote that patients were enrolled consecutively. The other eight studies contained no 

mention of consecutive enrollment. The authors of future studies should be explicit about the 

order of patient enrollment so as to allow readers to assess study quality. 

Information bias occurs when study subjects are misclassified on their exposure or disease 

status. Misclassification can occur due to random chance (e.g., inaccurate measures of BNP or 

NT-proBNP), or because the persons who take study measurements have knowledge of a 

subject’s exposure and disease status. For example, knowing that subjects have very high levels 

of BNP or NT-proBNP could trigger additional clinical investigations that lead to what would 

have otherwise been unmade diagnoses or treatments. This could inflate the association between 

BNP or NT-proBNP and the outcome of interest. Blinding is one way to avoid the problem. In 

the 12 studies involving persons at risk for CAD, the authors of five publications4,6,70,73,74

reported that blinding had occurred and the authors of seven studies did not mention anything 

about blinding. Again, authors should be explicit about what they do (blinding, no blinding) so 

as to facilitate the assessment of study quality. 

The absence of information about consecutive enrollment or blinding makes the presence of 

bias impossible to rule out for a majority of the studies. The same absence of information 

prevents the extent of any bias from being ascertained. 

Question 3aii: With diagnosed CAD 

 

Design and Sample Characteristics of Studies 

Thirty-eight studies examined the association between BNP or NT-proBNP and outcomes 

such as mortality or re-infarction in persons with CAD. Twenty-eight of the studies were 

prospective cohorts,3,13,19-22,29,33,75-94 nine were RCTs,8,14,27,28,95-99 and one was cross-sectional.100 

Sample sizes ranged from a low of 1494 to a high of 7800.8,97 The mean age of study participants 

was clustered around 55 and 65 years, with a range of approximately 40 to 70 years. The widest 

age range spanned 54 years and was observed in two studies (21 to 75 years,27 and 26 to 80 
48

years80). The percentage of males in 31 of the studies ranged from a low of 45 percent3 to a high 

of 100 percent.91 The percentage was not reported in five studies.20,22,78,83,94 Lengths of follow 

up varied greatly between the studies. The mean, median, or maximum follow up was up to and 

including 6 months in 12 studies,3,21,27,28,76,86,87,90,92,93,96,99 7 to 12 months in eight 

studies,8,33,77,78,83,91,95,97 13 to 24 months in eight studies,14,20,29,75,84,85,89,94 and more than 24 

months in eight studies.13,22,79-82,88,98 Follow up time was not reported in two studies.19,100 The 

shortest follow up time was 72 hours99 and the longest was 4.9 years.88

CAD Diagnosis 

Study participants were recruited after admission to hospital for a CAD related event. CAD 

related events included MI (16 studies),3,13,27,29,33,77,78,80,82,84,85,88,91,92,95,100 angina (10 

studies),8,20,76,77,82,85,92,95-97 ischemia (five studies),22,81,90,96,100 chest pain (three studies),21,77,86

stenosis (three studies),19,79,85 LVD (one study),98 ACSs (one study),3 cardiac arrest (one study),99

and hypertension (one study).89 More than one CAD event was involved in several studies. 

CAD was diagnosed with a plethora of clinical tests such as electrocardiography, ST 

elevation, development of left bundle blockade, rises in creatinine kinase levels, T-wave 

inversion, and blood pressure. In some studies,14,28,83,87 persons were enrolled on the basis of 

whether test results exceeded a certain threshold value (e.g., ST elevation ≥ 1 mm). In other 

studies, persons were enrolled if they were undergoing percutaneous transluminal coronary 

angioplasty (PTCA)75 or CABG.91,93,94,99

BNP and NT-proBNP Tests and Threshold Values 

BNP was measured using the Triage method in nine studies,3,19,28,29,77,78,83,95,96 the ShionoriaIRMA method in seven studies,13,33,79,88,90,93,94 and the ADVIA Centaur method in one study.27 

NT-proBNP was measured using either the Elecsys system in 13 studies8,14,21,22,75,76,85-87,92,97,99,100

or by a variety of other methods in seven studies.20,80-82,84,89,98

BNP or NT-proBNP cut points were not uniform. Twenty-four of the studies3,13,19-21,27-29,75,77-

79,81-83,87-90,93,95,96,98,100 reported a single cut point and six8,76,86,91,92,97 reported multiple cut points. 

Another six studies reported a single cut point, but the analyses were stratified by disease,33,84,85

gender,22 BNP versus NT-proBNP,80 or time period during follow up.14 The cut points were 

based on the medians or quartiles of measured BNP or NT-proBNP in the study 

participants,8,13,14,19,22,75,76,78,80-82,85-87,89,95,97,98,100 ROC curves,3,21,27,29,33,79,84,88,91,92 previously 

published literature,20,28,77,83,90,96 or regression analysis93Cut points were not reported in two 

studies.94,99

Definition of Outcomes 

Primary outcomes were death in 32 studies,3,8,13,14,19-22,27-29,75-77,80-90,92,94-98,100 non-fatal MI in 

15 studies,8,14,21,22,75,77,80,83,85,86,92,95-98 HF or cardiogenic shock in 10 studies,28,33,78,80,83,87,89,90,92,100

re-infarction in four studies,19,28,29,100 repeat hospitalizations for ACS in five studies,28,80,91,95,96

angina in three studies,29,79,94 ischemia in two studies,33,87 miscellaneous cardiovascular 

complications (e.g., arrhythmia, cardiogenic shock) in two studies,91,92 BNP or NT-proBNP 

levels in two studies,93,99 and LVD in one study.33 Twenty-five studies8,14,19,21,22,28,29,33,75,77,80,83,85-

87,89-92,94-98,100 included more than one outcome or had a composite outcome that was formed by 

aggregating two or more single outcomes. The outcomes were ascertained using clinical 
49

definitions (e.g., LVEF < 35 percent) in 20 studies.3,8,21,29,33,75,77-79,83,84,87,89-92,97-100 In the other 18 

studies,13,14,19,20,22,27,28,76,80-82,85,86,88,93-96 the authors simply named the outcomes without 

specifying how they were assessed. This lack of specification was often the case with mortality: 

authors did not describe their method (e.g., review of death certificates) of determining whether 

and why a participant died. 

Nine studies had secondary outcomes, including death,33,88,97 coronary HF or cardiogenic 

shock,78 recurrent MI,90 poor myocardial perfusion or failed ST segment resolution,27 recurrent 

ischemic events and severe HF,76 stroke,98 and thrombosis in MI.3

Adjusted Results – Multiple Regression Analysis 

Thirty-three of the studies used regression analysis to examine the association between levels 

of BNP or NT-proBNP and the outcome of interest. Multiple regression was used in 31 of the 

studies3,8,13,14,19-22,27,28,33,75-78,80-90,93,96-98,100 and simple regression was used in two of the 

studies.79,94 Logistic regression was the sole approach in 17 studies.3,8,19-21,27,28,33,76-

78,84,86,87,90,96,100 Logistic regression was also employed with Cox regression in two studies75,97

and with linear regression in two studies.14,89 Cox regression was utilized alone in ten 

studies.13,22,79-83,85,88,98 Regression analysis was not used in five studies.29,91,92,95,99 The studies 

were stratified according to type of B-type natriuretic peptide (BNP or NT-proBNP). Further 

stratification was done according to whether patients received prior cardiac related surgery 

(yes/no) and whether the outcome was mortality or non-fatal event (e.g., MI). For BNP, 

measures of association (OR, HR, etc.) ranged from 1.60 to 16.30 in studies of prior surgery 

patients and mortality3,28,77,96 (Table 13). The measures of association were concentrated in the 

range of 1.60 to 2.96 and they were statistically significant at the 5 percent level in three of the 

four studies.3,28,77 In two studies of prior surgery patients and non-fatal outcomes, point 

estimates of the measures of association were 3.928 and 41.1279 (Table 14). Both estimates were 

statistically significant at the 5 percent level. 

The predictive ability of BNP was found to be 2.53 (HR)13 or 7.20 (OR)27 in two mortality 

studies of patients with no prior cardiac related surgery. Three studies33,78,83 were conducted to 

examine non-fatal outcomes in patients with no prior surgery and the measures of association 

ranged from 1.01 to 3.03 (Table 14). The measures of association in all five studies were 

statistically significant at the 5 percent level. 

Turning to NT-proBNP, the measures of association spanned from 1.33 to 6.63 in six 

mortality studies of patients with prior cardiac related surgeries, with most measures 

concentrated in the range of 1.33 to 3.42.8,21,75,76,80,82 All of the measures were statistically 

significant at the 5 percent level in five studies. In the sixth study,76 only one of three ORs was 

significant at 5 percent. Studies8,21,80 of non-fatal outcomes in patients with prior surgery 

yielded measures of association that ranged from 1.01 to 3.51. However, the measures were 

statistically significant at the 5 percent level in only one study (Table 15).80

In studies of NT-proBNP as a predictor of mortality in persons who did not have a prior 

cardiac related surgery, the measures of association ranged from 1.01 to 19.70, with a 

concentration in the range of 1.50 to 4.80. The measures were all statistically significant at the 5 

percent level in four studies,20,22,81,84 two of the three measures were significant in one study,97

and none were significant in two studies.87,98 In the case of non-fatal outcomes in persons who 

did not have a prior surgery, measures of association ranged from 0.64 to 5.90 and the 

concentration was between 1.30 and 5.50. The measures were all significant in two studies,84,86
50

three measures of 13 were significant in three studies,85,87,97 and none were significant in two 

studies (Table 16).22,98

In one89 of the two studies where linear regression was used as an analytic tool, NT-proBNP 

was found to be a predictor (p = 0.03) of left ventricular systolic volume after MI. However, the 

authors did not quantify the relationship by providing an estimated regression coefficient. In the 

other study, several variables were found to predict baseline levels of, and rates of change in, 

NT-proBNP.14 These variables were age, gender, diabetes, previous MI, cTnT level greater than 

or equal to 0.01 μg/L, calculated creatinine clearance less than 73 ml/min, C-reactive protein 

greater than 10 mg/l, ST-segment depression, and use of diuretics or nitrates on admission to 

hospital (Table 17). 

Table 17 shows the studies for which no regression results were reported (even though the 

authors claimed to have conducted regression analyses) as well as the studies for which no 

regression analyses were performed. 

Several variables were included in many of the regression models as covariates, including 

age, gender, biological markers (e.g., heart rate, blood pressure, baseline creatine kinase, LVEF), 

and disease history (e.g., history of MI, hypertension, diabetes). 

Quality Assessment of Studies 

The authors of 11 studies3,20,21,33,75,77,79,82,84,91,92 indicated that participants were consecutively 

enrolled in their research. The authors of the remaining 28 studies did not report whether or not 

enrolment was consecutive. For blinding, reporting was only slightly better as the authors of 14 

studies3,8,13,19,21,28,29,78,81,87,92,95,97,99 reported that outcomes were assessed in a blinded fashion, 

while the authors of the remaining 25 studies did not mention blinding in their published 

manuscripts. The lack of reporting in both areas meant that it was impossible to rule out the 

presence of selection or information bias in a majority of the studies. 

Question 3aiii: With diagnosed HF 

Thirty-eight publications evaluated BNP levels and 14 evaluated NT-proBNP and the 

association with cardiac events in patients with HF. The predictive value of BNP and NTproBNP are presented separately with respect to the ability to predict future outcomes of interest. 

Six publications evaluated both BNP and NT-proBNP.41,103,112,125,126,128 The findings from these 

studies are presented in the BNP section only. 

Prognosis Studies Using BNP Levels 

Design and Sample Characteristics of Studies. All the studies evaluating BNP levels were 

prospective cohort designs with the exception of three publications based on the ValHeFT106,110

including a sub-study41which were randomized trials. The evaluation of the VaLHeFT cohort 

included both arms of the trial in the evaluations. In addition to the ValHeFT publications, an 

additional two publications reported on the same study cohort125,128 with different follow up 

periods. Twelve studies12,23,104,105,107,111,113,118-120,124,129 recruited patients that were admitted as 

hospital inpatients for acute episodes; three studies contained patients recruited from both 

emergency and inpatients,102 and outpatient clinics and inpatients combined.25,117 Twenty 

studies30,36,41,101,103,106,108-110,112,115,116,121-123,125-128,130 indicated that patients were recruited from 
51

primary care, general population, specialty clinics and outpatient settings (see Tables 18 and 19). 

Three studies recruited patients with HF from emergency departments.32,48,114

Sample sizes ranged from a low of 3332 subjects to a high of 4300 subjects.106,110 The mean 

sample size for all 36 studies was 327 (± 829) and the median was 102. The mean age of study 

participants was clustered around 65 years, with the widest range of 68 years113 ranging from 17 

to 85 years. The percentage of males in 32 of the studies ranged from a low of 44 percent111 to a 

high of 100 percent.48,119 The percentage was not reported in four studies.101,106,110,122 One 

cohort102 based on the REDHOT study had a high proportion of African Americans (63.4 

percent). 

Lengths of follow up varied greatly between the studies, with the shortest time being 30 

days119 and the longest being 92 months.126 For studies with short term follow up, the period 

varied from 30 days119 to 90 days32,48,102 and six months.107,109,111,114,124 For the remaining studies 

the mean or median follow up was 7 to 12 months,118,130 13 to 24 

months,12,23,30,101,103,105,115,116,125,129 25 to 48 months,25,36,41,104,113,117,120,121,123 and greater than 48 

months.126,127 Several other studies did not report median or mean follow up times but rather end 

points of 12 months,112 18 months,108 36 months,110,128 and 60 months122 or did not specify.106 

HF Diagnosis and Severity. The diagnosis of HF was established in a number of ways, but 

predominately confirmed using echocardiography, carried out as part of the study, or obtained 

from previous medical records. The exceptions were three studies that used 

ventriculography41,121,187 and eight that used clinical evaluation (signs and 

symptoms).102,103,105,108,114,122,126,188 All but two studies48,107 reported some rating of the NYHA 

classification for all the subjects or a subgroup. 

The majority of studies included subjects across all levels of the NYHA classification I-IV. 

The exceptions were eight studies23,32,108,109,119,120,123,124 that restricted subjects to levels III-IV 

and one that possibly restricted to level IV.107 A single study121 enrolled subjects with level I and 

II; three other studies36,127,130 had predominately level I and II with less than 10 percent of 

subjects with level III, and none at level IV. Three studies48,114,122 did not specify the NYHA 

classification of their subjects. 

LVEF was not reported in seven studies102,104,105,111,114,122,127. Mean LVEF percentages were 

reported in 22 studies and varied between 50 percent,115 40 to 49 percent,32,129 30 to 39 

percent,12,23,36,107,113,118,119,123,123,126,130 and 20 to 29 percent.25,108,109,112,117,120,125,128 Seven studies 

reported a threshold LVEF of less than 45 percent,48,101,106,110,121 less than 40 percent,124 and less 

than 30 percent.30

BNP and Cut Points. BNP was measured using the Triage method in 11 studies48,107-

109,111,112,114,119,125,128,189 and by Shionoria-IRMA method in the remaining 25 studies (see Tables 

18 and 19). Four studies112,125,126,128 also measured NT-proBNP using the Biomedica method. 

Results are described in the NT-proBNP section of this report.

The rationale for selecting the BNP cut points differed and as such, the values varied 

significantly (Table 18 and 19). Sixteen studies12,30,32,36,101,106,110,117-121,123,124,126,130 selected the 

mean or median values as the cut point for categorizing high and low BNP groups . Eight 

studies23,108,114,120,125,128,129,190 selected values based on ROC. Five studies categorized the sample 

BNP values into two levels,127 three levels,107,109 four levels,119 and five levels.122 Six 

studies104,105,111-113,115 did not specify a threshold as they used the BNP values as a continuous 

variable in their statistical analyses. Three studies used other rationale for threshold selection 

including: previous literature reference,48 75th percentile value,116 and an unspecified internal 

analysis.102
52

Definition of Outcomes. All studies with the exception of one,48 had a primary outcome of 

mortality or a composite endpoint. These endpoints typically included death, other cardiac 

events, readmission or worsening HF. There were 21 studies12,23,30,32,36,102,104,106,109,112,114,117,119-

123,125-127,130 that evaluated either all-cause mortality, cardiac related mortality or both. There 

were 25 studies23,25,101-103,105-108,110-120,123,124,126,128,129 that evaluated composite endpoints that 

included a mixture of fatal and non-fatal cardiac events. One study116 evaluated the performance 

of BNP relative to the Heart Failure Survival Score. Most authors did not specify how the 

outcomes of death were verified or subsequent events (such as other events or re-admission to 

hospital) were evaluated. 

Adjusted Results – Multiple Regression Analysis. Twenty-nine studies undertook Cox 

proportional hazards regression analyses and five studies undertook logistic regression analyses 

to evaluate the relationship between BNP levels and various outcomes (Table 18 and 19). For 

the studies using Cox regression analyses, three studies32,111,115 presented only univariate 

analyses, 10 studies101,105,110,112,113,122-124,126,127 presented only the results from multivariate 

analyses, and the remaining 16 studies12,23,30,36,104,106-109,117,118,120,121,125,129,130 undertook both 

univariate and multivariate computations. Four studies undertook multivariate logistic 

regression25,48,102,116 and one study119 univariate logistic regression, to evaluate the strength of the 

association between levels of BNP and the outcomes of interest. A single study114 reported 

unadjusted RRs and another study121 undertook an unspecified type of linear regression.

BNP Studies with Mortality Outcomes. Table 18 details the 21 studies with the outcomes 

of all-cause mortality, cardiac mortality and sudden death. The results are expressed as both 

univariate and multivariate HR,12,23,30,36,104,106,109,113,117,122,123,127 Chi square statistic and 

probabilities values,12,32,102,120,125,126,130 beta values,102,130 and unadjusted RR.114 One study 

measured, but did not report, findings specific to mortality.119 Some studies102,123,125reported the 

estimates of risk based on the log of the BNP levels, which makes interpretation of the 

magnitude somewhat limited. In general, there were 11 studies12,23,30,36,106,109,113,123,125,127,130 that 

found baseline BNP levels to be significant predictors for mortality related outcomes after 

adjustment in multivariate models. For those studies that presented adjusted HR, the risk 

estimates varied from 2.48 (95 percent CI: 2.13 to 2.88)106 to 7.2 (95 percent CI: 1.6 to 32.1),30

with the majority point estimates clustering around 2.5 to 3.0. It should be noted that despite the 

differing cut points, ( > 97 pg/mL,106 > 172 pg/mL,30 > 230 pg/mL,114 > 260.4 pg/mL,36 > 700 

pg/mL,32 1000 pg/mL,109 > 346 pg/mL,127), the multivariate models found baseline BNP to be a 

significant predictor of mortality outcomes. All these regression models used a variety of 

variables within their models, which makes comparisons across studies challenging. 

Six of the studies evaluating mortality recruited decompensated HF patients,12,23,102,112

emergency department patients,32,114 or mixed patients.114 Five of these studies reported 46 to 

100 percent of patients in NYHA class III and IV suggesting relatively severe HF patients. 

Although all studies reported that BNP was a significant predictor of mortality, only one 

study23provided an estimate of the HR; the multivariate model included a variable of troponin T 

and baseline BNP. The log BNP had a HR = 3.11 (95 percent CI: 1.61 to 6.01, p = 0.0005). 

One study reported unadjusted RR for HF death for baseline BNP greater than 230 pg/mL vs. 

less than 230 pg/mL: RR = 24.1 (95 percent CI: 6.3.5 to 491.1); for the outcome of cardiac death 

unadjusted baseline BNP greater than 230 pg/mL vs. less than 230 pg/mL: RR = 37.9 (95 percent 

CI: 5.7.5 to 755.8). The widely varying CI suggests instability with the estimate; therefore, 

results must be interpreted with caution. 
53

There were six studies that found BNP levels to be not significant predictors of mortality 

based on univariate analyses alone,32,126 or on multivariate analyses;30,104,117,122 one study123

found sudden unexpected death to be significant but not HF death. One of these studies32 had a 

small sample size (n = 33) and 73 percent of patients were NYHA level IV. No clear trend from 

these studies can account for the non-significance. 

BNP Studies with Composite Outcomes. Table 19 details the 27 studies with composite 

outcomes which included death in all but four publications.111,113,118,128 The results are expressed 

as both univariate and multivariate HR,23,25,106,110,115,117 chi square and probabilities 

values,113,119,121,124,128,129,191 and unadjusted RR.114 Some studies23,102,118,119,123,128,129 reported the 

estimates of risk based on log BNP levels, which makes comparison with studies not using log 

values difficult. 

In general, there were 9 studies12,30,36,106,109,123,125,127,130 that found baseline BNP levels to be 

significant predictors for composite outcomes after adjustment in multivariate models. Two 

studies105,111 with only univariate analyses showed baseline BNP levels to be not significant 

predictors and three studies (multivariate estimates106,117 and univariate estimate115) showed only 

marginal significance. 

For those studies that presented adjusted risk estimates for baseline BNP, the values varied 

from HR = 1.66 (95 percent CI: 1.36 to 2.04, p less than 0.0001)110 to RR = 3.23 (95 percent CI: 

1.32 to 7.94, p = 0.01)25, with the majority point estimates clustering around 2.0. Three 

studies23,108,123 included estimates of HR that combined levels of troponin I, troponin T and 

LVEF with baseline BNP. One study114 reported unadjusted RR for HF events that varied from 

baseline BNP greater than 230 pg/mL vs. less than 230 pg/mL: RR = 15.5 (95 percent CI : 6.2 to 

43.7) to BNP greater than 480 pg/mL vs. less than 230 pg/mL: RR = 8.2 (95 percent CI: 4.7 to 

14.3). 

Comparison of NT-proBNP and BNP. Six studies41,103,112,125,126,192 evaluated both BNP 

and NT-proBNP levels within the same group of subjects. Van Beneden et al.126 compared a 

small number of subjects who had mild to moderate HF (NYHA I-II) with severe HF patients 

(NYHA level IIII-IV). Their univariate analysis showed that NT-proBNP was a significant 

predictor of mortality. However, no association between BNP and mortality was observed using 

either assay method. Two studies evaluated both B-type natriuretic peptides in predominately 

NYHA level II patients (approximately 78 percent). One study103 found log BNP levels 

significant in predicting worsening HF in both univariate and multivariate analyses while NTproBNP was significant only in the univariate model. In contrast, a second study,41 with mild to 

moderate HF subjects, found that BNP and NT-proBNP levels differed in their ability to predict 

4-year mortality with respect to whether baseline levels, or measurement taken at last follow up, 

were considered. In this study, BNP was significant in the univariate analysis for baseline and 

significant for last follow up in the multivariate analysis; NT-proBNP was not significant at 

baseline in the univariate analysis but significant for the multivariate analysis that included last 

follow up NT-proBNP level. The findings of this study41 would suggest that measures of either 

BNP or NT-proBNP may be independent predictors of mortality, but the sample size for this 

study was relatively small (n = 100).

Two other studies (based on three publications)112,125,128 from the same research team 

evaluated BNP and NT-proBNP. With respect to predicting event free survival at 1 year in an 

ambulatory group of patients, one study112 found both BNP and NT-proBNP were significant 

predictors at 1 year in univariate analysis. The subsequent multivariate analysis found four of the 

nine variables to be significant and included BNP, N-ANP, RAAS antagonists, and Living with 
54

Heart Failure questionnaire. From the same research group, but in a different study cohort, 

Berger et al.,125 using univariate analysis, found the log transformation of both B-type natriuretic 

peptides to be significant predictors of pump failure death; however, only the log of NT-proBNP 

was significant in multivariate analyses. A sub-analysis, which excluded patients with atrial 

fibrillation, showed that BNP was the best independent predictor of sudden death. Their findings 

suggest that the magnitude of the prognostic prediction is dependent on the specific mode of 

death and the specific form of the natriuretic peptide. A re-analysis of this same cohort of 

subjects was undertaken in a third study.128 The sample was classified according to severity 

levels based on LVEF and NYHA classification; a multivariate analysis was undertaken to see 

which factors predicted combined death and urgent heart transplant (for each of the 3 years of 

follow up). For Group A (NYHA I-II, LVEF ≤ 20 percent) log BNP was significant in both year 

2 and 3. For Group B (NYHA I-II, LVEF < 20 percent, or, NYHA III-IV, LVEF ≤ 20 percent) 

only the log BNP was a significant predictor for year 1, but only log NT-proBNP was significant 

for years 2 and 3. For Group C (NYHA III-IV, LVEF < 20 percent) both log BNP and log NTproBNP were significant for year 1; only log NT-proBNP was a significant predictor for years 2 

and 3. These results would suggest that the strength of prediction for the B-type natriuretic 

peptides is also dependent on the year of follow up and less so on the severity of the HF. 

Overall, of the six studies evaluating both BNP and NT-proBNP, only two studies found both 

BNP and NT-proBNP to be independent predictors of mortality. In one study128 year of follow 

up and group stratification, and in a second study41 the timing of the B-type natriuretic peptide 

measurement, similarly altered the predictive ability. No clear pattern emerges to suggest 

superiority of one type of B-type natiruetic peptide relative to the other in these head to head 

studies. 

Comparison of Studies That Evaluated Baseline and Predischarge Measures. 

All studies with the exception of seven publications36,41,107,111,118,119,124 evaluated only 

baseline BNP levels. One of these studies36 evaluated outpatients and measured BNP levels at 

two time points with an interval of 8 to 12 months. Another study evaluated patients BNP and 

NT-proBNP levels at successive follow up intervals over a 4-year period.41 Three107,119,124 of 

these studies had severe HF patients (NYHA III-IV) and approximately LVEF less than 40 

percent; a fourth study111 had 88 percent of subjects at NYHA level III and IV (LVEF not 

reported). Logeart et al.,107 which had the largest sample size of all these seven studies, found 

the univariate HR for each 100 pg/mL increase of BNP to be slightly larger for predischarge 

BNP levels (HR = 1.22, 95 percent CI: 1.15 to 1.30, p = 0.0001) than baseline BNP levels (HR = 

1.06, 95 percent CI: 1.03 to 1.10, p = 0.0001) for the composite outcome (death and 

readmission). In addition, they demonstrated a gradient of increasing risk from the first quartile 

(0 to 130) to the last quartile (660 to 1725) with the latter having the largest HR risk estimate 

(HR = 13.77). Similarly, the adjusted HR in this study showed increasing risk for poor outcome 

with increasing predischarge ranges, with the highest threshold ( > 700 pg/mL) having a HR = 

15.2, (95 percent CI: 8.5 to 27). Hamada et al.124 found predischarge BNP levels to be the only 

significant (p = 0.0086) predictor of re-hospitalization within 1 year in a multivariate analysis 

that included baseline admission BNP levels. Cheng et al.119 undertook only univariate logistic 

regression and found admission BNP and discharge BNP to both be significant for the composite 

endpoint and 30 day readmission; however, the small sample in this study size did not permit a 

true multivariate analysis. Given the likely strong correlation between admission and discharge 

BNP levels, it would be important to use multivariate analyses to adjust for strong correlations 

between these two measures of BNP. Similarly, Bettencourt et al.111 in a univariate analysis did 
55

not find median levels of either admission BNP ( > 541 pg/mL) or discharge BNP ( > 321 

pg/mL) to be significant predictors of their composite endpoint (death or readmission). 

Cheng et al.119 and a second study118 specifically recruited for new onset or first episode of 

HF. However, Tamura et al.118 measured BNP at discharge only and found the discharge log 

BNP to have the largest risk (HR = 2.656, p = 0.015) relative to the other variables significant in 

the model (NYHA class, LVEF, and left ventricular mass index) for predicting cardiac events. 

A single study36 evaluated patients in an outpatient clinic (sample was 93 percent NYHA 

level I-II) and measured BNP levels at initial visit and second time-point (8 to12 months later), 

as well as the change in BNP levels (per 100 pg/mL) and any BNP level increase (versus 

decrease) during follow up. However, they did not include discharge BNP as a unique variable 

in subsequent univariate or multivariate models. In this study, the change in BNP (HR = 1.34, 95 

percent CI: 1.10 to 1.63) and change in NYHA class (HR = 6.68, 95 percent CI: 2.23 to 19.12) 

were the only significant variables in the multivariate model.

Kaplan Meier Survival Analyses. Twenty-seven studies12,23,30,32,36,41,101,103-105,108-118,120-

123,129,130 reported results from Kaplan Meier survival analyses using various cut points that were 

based primarily on median/mean or best values from ROC curves. All studies that undertook 

Kaplan Meier analysis, regardless of the outcome or cut point, found significant differences 

between the two groups. 

Quality Assessment of Studies. For this research question, which evaluated prognosis, the 

eligible studies were based predominately on prospective cohort designs. As such, selection 

biases attributed to non-consecutive enrolment, and misclassification bias attributed to blinding, 

were chosen as the main criteria for methodological quality evaluation. Thirteen 

studies30,104,105,107,108,112-114,118,120,121,129,130 selected patients in a consecutive manner. The 

remaining studies did not specify, and likely did not employ, this strategy to minimize bias as 

convenience samples were generally selected. 

Attempts were made to evaluate the potential for misclassification bias through lack of 

blinding of clinicians who evaluated subjects or those who ascertained the endpoints. Blinding of 

the clinicians to the BNP level was undertaken in only four studies23,36,102,115 and this minimized 

the potential for clinicians to systematically provide differential treatments or request additional 

tests. Blinding to NT-proBNP levels was not undertaken in any study; however, three 

studies113,120,193 indicated that the outcome was judged by researchers external to the clinical 

setting and had some potential to minimize ascertainment bias. 

Prognosis Studies Using NT-proBNP Levels 

Study Design and Sample Characteristics of Studies. For those studies evaluating NTproBNP, four were RCTs41,136,138,140 and the remaining 14 were prospective cohort 

studies.26,35,103,112,125,126,128,131-135,137,139 Six of these studies evaluated both NT-proBNP and 

BNP41,103,112,125,126,128. Two publications were based on the same COPERNICUS study35,140 and 

an additional two publications reported on the same study cohort125,128 with different follow up 

periods.

Only four studies26,135,136,139 recruited patients that were admitted to hospital for acute 

episodes. The remaining 14 studies35,41,103,112,125,126,128,131-134,137,138,140 indicated that patients were 

recruited from primary care or specialty clinics and outpatient settings (see Tables 20 and 21). 

Sample sizes ranged from a low of 48131 to a high of 2320 subjects.133 The mean sample size 

for all 18 studies was 378 (± 596) and the median was 121. The mean age of study participants 
56

clustered around 65 years but varied from 51 to 78 years; the widest age range spanned 64 years 

(40 to 104 years).133

Lengths of follow up varied greatly between the studies and the shortest time was 6 

months139 while the longest time was 92 months126. The mean or median follow up time varied 

from 7 to 12 months,135,136 13 to 24 months,103,134 25 to 48 months,35,128,131,194 and greater than 48 

months.126 Several studies specified only endpoints of 6 months,139 12 months,112,133,137 17/18 

months,26,138 24 months,140 and 48 months41 (Tables 19 and 20). 

HF Diagnosis and Severity. The diagnosis of HF was established in a number of ways, and 

these included echocardiography (carried out as part of the study or obtained from previous 

medical records) in six studies,35,112,125,132,133,140 ventriculography in four studies,41,134,137,138

clinical evaluation (signs and symptoms or NYHA classification) in six studies,103,126,131,135,136,139

and other methods in one study.26 All studies used the NYHA classification, with the exception 

of one study135 which used the Killip method, and three studies35,133,140 which did not report any 

rating. 

With respect to severity of HF, the majority of studies included subjects across all levels of 

the NYHA classification. The exception to this was one study139 that restricted subjects to levels 

III-IV. A single study112 enrolled subjects with predominately level II. Three studies35,133,140 did 

not specify the NYHA classification of their subjects. A single study135 used the Killup method 

of classification, and these patients varied from levels II to IV. 

LVEF was not reported in four studies on admission.26,135,136,139 Four studies35,132,137,138

reported a threshold LVEF of less than 45 percent, five studies112,125,126,128,134 less than 35 

percent, and five studies41,103,131,133,140 less than 25 percent. 

NT-proBNP and Cut Points. NT-proBNP was measured in nine studies using the Elecsys 

method , six studies used the Biomedica method,41,103,112,125,126,128 two used the Roche ELISA 

method, 135,137 and one study used the Christchurch method138 (Tables 20 and 21). Six of these 

studies evaluated both NT-proBNP and BNP.41,103,112,125,126,128

From the two publications based on the COPERNICUS study, one of the reports35 stated that 

a newly developed NT-proBNP Roche ELISA method was used and that samples would 

subsequently be retested using the Elecsys method. The re-analysis was published the same year 

but does not reference the previous report. Since this is the same cohort, we assume that the 

assay met our eligibility criteria but was not adequately reported. 

Definition of Outcomes. Ten of these reports examined mortality as a discrete end 

point.35,41,125,126,131,133,134,136,138,140 Nine studies103,112,128,134-137,139,140 reported composite end point 

of death or worsening HF. The remaining studies evaluated the ability to predict 

recommendation of heart transplantation,132 worsening HF alone,138 and in one case no estimate 

of risk was provided.26

Adjusted results – Multiple Regression Analysis. One26 study examined stratification with 

troponin level and presented no relative measure of risk such as a HR. However, it did make the 

limited statement that there were fewer events when NT-proBNP levels were below rather than 

above the median admission level (1357 pg/mL, p < 0.01). 

Eleven studies undertook Cox proportional hazard regressions analyses and six studies 

undertook logistic regression analyses to evaluate the relationship between BNP levels and the 

relationship to the various outcomes. For the studies using Cox proportional hazard regression 

analyses, two studies112,138 presented only multivariate estimates and the remaining studies 

undertook both univariate and multivariate computations. Six studies undertook multivariate 
57

logistic regression126,132,133,135-137 to evaluate the strength of the association between levels of 

BNP and the outcomes of interest. A single study26 did not report estimates of risk. 

NT-proBNP Studies With Mortality Outcomes. Eleven 

studies35,41,112,125,126,131,133,134,136,138,140 evaluated mortality outcomes and these are detailed in 

Table 20. The results are expressed as both univariate and multivariate HR,35,131,140 chi square 

statistic,41,112,126,134 OR,133,134,136or not specified.138 Some studies41,126,131,133 reported the estimates 

of risk based on the log NT-proBNP levels. In general, all studies that undertook univariate or 

both univariate and multivariate analyses found NT-proBNP to be a significant predictor of 

mortality. One study135 found multivariate estimate on a subsample with HF to be significant 

(OR = 5.30, 95 percent CI: 1.4 to 168.9, p = 0.026) but the CI was wide. For those studies that 

presented adjusted HR, the risk estimates varied from HR = 2.17 (NT-proBNP > 1767 pg/mL) 

(95 percent CI: 1.33 to 3.54, p < 0.02)140 to HR = 9.35 (log NT-proBNP) (95 percent CI: 2.42 to 

36.10, p = 0.001). These estimates encompass baseline, discharge and change of NT-proBNP 

levels. 

NT-proBNP Studies With Composite Outcomes. Table 21 details the ten studies with the 

composite end points, which included death as a component of the outcome. The results are 

expressed as both univariate and multivariate HR,139,140 chi square statistic,103,112,128,134,137 OR,134-

136 or not specified.195 One study128 reported the estimates of risk based on the log NT-proBNP 

levels. 

In general, there were seven studies112,128,134-137,140 that found baseline, discharge or change 

levels of NT-proBNP levels to be significant predictors for composite outcomes after adjustment 

in multivariate models. Two studies103,139 showed marginal or no statistical significance. All 

these regression models used a variety of variables within their models, which makes 

comparisons across studies challenging. 

For those studies that presented adjusted risk estimates for NT-proBNP, the values varied 

from HR = 2.11 (95 percent CI: 1.54 to 2.90, p < 0.0001) for NT-proBNP greater than 1767 

pg/mL,140 to HR = 5.96 (95 percent CI: 3.23 to 11.01) for change in NT-proBNP vs. decrease 

greater than 30 percent or increase greater than 30 percent. 

Quality Assessment of Studies. As with the BNP studies, potential for selection bias 

(attributed to non-consecutive enrolment) and misclassification bias (attributed to blinding) were 

chosen as the main criteria for methodological quality evaluation. Eight studies26,112,132-135,137,139

selected patients in a consecutive manner. The remaining studies did not specify and likely did 

not employ this strategy to minimize bias, as convenience samples were generally selected. 

Blinding of the clinicians or the investigators to the NT-proBNP levels with respect to the 

outcomes was undertaken in only three studies132,136,139 suggesting some potential for 

ascertainment bias for of the outcome.
58

Question 3b: What Are the Screening Performance 

Characteristics of BNP or NT-proBNP in General 

Asymptomatic Populations? 

Definition of Screening 

A screening test can be used in defined populations who need not believe that they are at risk 

of a disease or that they are already affected by it or by its complications. It may also be used in 

clinical practice in individuals who do not have established or overt disease, but who may have 

one or more risk factors for the disease. In this review, a screening test was defined as being 

used to detect preclinical cardiac dysfunction, systolic or diastolic, in general asymptomatic 

population. 

Design and Sample Characteristics 

There were eight studies5,74,122,141-145 identified in populations apparently without established 

or overt disease (or heart failure). Two studies had no sensitivity or specificity data.74,122 Six 

studies had relevant data,5,141-145 two were cross-sectional141,143 and four were prospective cohort 

studies.5,142,144,145 The age of the population included in these six studies ranged between 40 and 

84. All but one study145 evaluated BNP. 

Study Outcomes 

Although, these studies using BNP and NT-proBNP for screening focused primarily on LVD, 

there were differences in the specific outcomes with respect to the type and level of severity. 

One study5 evaluated preclinical ventricular dysfunction, both diastolic and systolic components, 

(EF at < 40 percent); similarly, another study141 evaluated left ventricular systolic dysfunction 

alone (EF at < 40 percent). One study143 evaluated asymptomatic systolic (EF < 55 percent) and 

diastolic dysfunction (diastolic dominant pulmonary vein flow with EF of > 55 percent). 

Other studies broadened the types of dysfunction. One study142 evaluated cardiac dysfunction 

(defined as left ventricular systolic and diastolic, unknown LVD, and valvular dysfunction), 

while another study144 used three outcomes that included left ventricular mass, EF of less than 50 

percent and moderate to severe LVSD (EF < 40 percent). The sole study145 evaluating NTproBNP evaluated the outcomes of LVSD, mortality, chronic heart failure admissions, and other 

cardiac admissions. 

Screening Properties 

To ensure comparability of the test characteristics, the sensitivity, specificity, LR+ and LR-, 

and AUC are included (Table 22), either as listed in the original publications or 

calculated141,142,145 from the available data. Comments on the performance of the index test are 

based on a LR+ greater than 10 or LR- less than 0.1 and AUC greater than 0.8 providing 

convincing evidence for accuracy. Moderate to strong evidence for accuracy is provided by a 

LR+ greater than 5 or LR- less than 0.2 and AUC 0.70 to 0.80. Poor evidence for accuracy 

comes from LR+ less than 5, LR- greater than 0.2 and AUC less than 0.70.168
59

The study by Redfield et al.5 showed the AUC for detection of LVEF less than 50 percent or 

mild diastolic dysfunction were consistently less than 0.70, so the authors then confined the use 

of BNP to detecting an EF less than 40 percent or moderate to severe diastolic dysfunction. This 

study explored a variety of factors with respect to screening properties including systolic versus 

diastolic dysfunction within these categories: age over 65 years, gender, and high-risk groups. 

For the diastolic category alone, the subgroup of moderate to severe dysfunction had some or all 

diagnostic properties assessed. The prevalence rates varied significantly within these sub 

groupings, with the lowest values in the general population and women with systolic 

dysfunction, and the greatest rates for the population with diastolic dysfunction of moderate to 

severe levels (Table 22). The corresponding diagnostic estimates of accuracy reflected moderate 

strength at best for LR+ (7.4) for two of the thirty subgroups they evaluated; similarly, the LRreflected poor accuracy. With the exception of systolic dysfunction in high-risk men, the AUC 

was generally in the moderate range. In general, within the systolic and diastolic groups there 

were no differences due to gender and age. Overall this would suggest poor detection 

characteristics for BNP as a screening test. The low prevalence of preclinical systolic 

dysfunction and the observed specificity would result in a large number of screened people 

requiring an echocardiogram and nearly all of them would be negative. Using a higher cut point, 

for example one based on the upper normal value, would result in fewer confirmatory 

echocardiograms but would miss 30 percent or more of people with preclinical systolic 

dysfunction. 

These results are similar to those of Vasan et al.144 which showed the test characteristics of 

BNP are limited at each of the three discriminatory levels; this study only reported AUC as a 

metric of accuracy. Overall, the AUC for BNP was less than 0.75 for elevated LSVD and left 

ventricular mass in both genders. This estimate exceeded 0.80 in high-risk women, but this was 

based on a very small sample size and the confidence interval was wide suggesting caution in 

interpretation. When maximizing the sums of sensitivity and specificity the cut point for women 

is BNP 27 pg/mL for LV mass greater than 90th percentile, it is 34 pg/mL for any LVSD and is 

also 34 pg/mL for moderate to severe LVSD ( < 40 percent). For LV mass this gives a 

sensitivity of 26 percent, specificity 86 percent, LR+ 1.82, LR- 0.86. For any LVSD it gives a 

sensitivity of 26 percent, specificity 89 percent, LR+ 2.49, LR- 0.82, and for moderate to severe 

LVSD ( < 40 percent) the sensitivity is 80 percent, specificity 90 percent, LR+ 7.67, LR- 0.22 

(Table 22). The performance of the test improved in women but not in men when select highrisk subgroups were targeted. Discriminatory limits that were based on a high specificity (95 

percent) give better positive predictive values and LR, yet identified less than one third of the 

participants who had elevated LV mass or LVSD. Both these studies5,144 highlight the need for 

different BNP levels for women. 

In the study by Hedberg et al.141 a BNP greater than 28 pg/mL gave the highest specificity at 

a sensitivity greater than 95 percent in detecting LVSD, but the highest accuracy was found with 

a concentration greater than 73 pg/mL in a random sample of subjects 75 years of age. Both of 

these values produce negative predictive values of 98 to 99 percent but the routine predictive 

value for BNP greater than 28 pg/mL is 13 percent (95 percent CI: 9 to 19) and for BNP greater 

than 73 pg/mL it is 34 percent (95 percent CI: 24 to 47), and the latter cut point will miss more 

individuals with preclinical systolic dysfunction. The combination of ECG and BNP greater than 

28 pg/mL and BNP less than 28 pg/mL found LVSD in less than 1 percent of the study 

population irrespective of the BNP concentrations, leading to the conclusion that the BNP had 
60

screening value in addition to the ECG, but only in those with abnormal ECG’s. Overall, the 

AUC for either cut point of greater than 731 or greater than 28 show the same AUC (0.88). 

The screening test characteristics for BNP for systolic and/or diastolic dysfunction are also 

poor in one study142 in which a BNP value of 20 pg/mL was pre-selected. The overall negative 

predictive value was 57 percent (95 percent CI: 48 to 65) and the accuracy of BNP did not 

change with higher cut points but these produced decreasing sensitivity and negative predictive 

value. The AUC were not estimated, but the LRs indicate poor evidence for accuracy. Another 

study143 of patients with stable CAD and a pre-selected BNP cut point of 100 pg/mL had all of 

the participants undergo an extensive examination and an exercise stress treadmill test to ensure 

no overt symptoms of HF. The test characteristics for BNP were poor for systolic dysfunction 

with a 38 percent sensitivity, 80 percent specificity, LR+ 1.9 (95 percent CI: 1.2 to 2.9), LR- 0.8 

(95 percent CI: 0.60 to 1.00) and AUC 0.59 (95 percent CI: 0.49 to 0.69). They were also poor 

for diastolic dysfunction with a 55 percent sensitivity, 85 percent specificity, LR+ 3.8 (95 

percent CI: 2.4 to 5.9), LR- 0.8 (95 percent CI: 0.4 to 0.8 and AUC 0.79 (95 percent CI: 0.71 to 

0.87). 

Only one study145 used NT-proBNP as the index test and accuracy was evaluated with 

respect to LVEF levels, European Society Cardiology (ESC) criteria for HF and further stratified 

by age over 70 years, and high risk medical history. The subgroup classified by ESC criteria, 

LVEF less than 40 percent, and age over 70 years, showed very strong evidence for accuracy 

(LR+ 10.71, LR- 0.10, AUC 94); values for a similar group (without the age restriction) showed 

moderately high values (Table 22). This suggests that for these groups there is some potential 

benefit for screening for LVSD. Using the Cox proportional hazard model, Log NT-proBNP 

(HR = 5.70), and male gender (HR = 3.10) were shown to be significant independent predictors 

of mortality in patients that were followed up for a median of 805 days. Log NT-proBNP (HR = 

13.83), male gender (HR = 2.71) and dyspnea (HR = 1.45) were significant independent 

predictors of admission for heart failure. Finally, log NT-proBNP (HR = 3.69), abnormal ECG 

(HR = 2.56) and history of ischemic heart disease (HR = 1.9) were independent predictors of 

other cardiac admissions, eliminating LVEF from all prognostic models. 

Quality Assessment of Studies 

BNP was the index test in five5,141-144 of the accepted studies and NT-proBNP in the sixth 

one.145 In all six echocardiography was a reference test. The subjects were either randomly 

selected from the community,5,141 were part of another prospective community cohort,144,145 or 

cross-sectional study.141,143 In the selected studies subjects may have had risk factors for HF, 

such as stable CAD, but none had overt or symptomatic HF. The patient samples were 

consecutively or randomly selected, the index and reference tests were clearly described, the 

index test was not available to those making the clinical diagnosis, the study populations were 

not classified by disease state, and appropriate descriptions were given as to the steps taken to 

ensure that the subjects did not have overt cardiac dysfunction. 
61

Question 4: Can BNP or NT-proBNP Measurement Be Used 

To Monitor Response to Therapy? 

 

Sample and Design Characteristics 

There were 18 studies meeting the eligibility criteria to be included in this section.31,37-

47,110,146-150 In brief, the included studies enrolled chronic HF patients with at least three B-type 

natriuretic peptide measurements over time. The LVEF was reported as less than 25 percent,41,150

≤ 35 percent,149 ≤ 40 percent,39,42,43,43-47,110,147,148 less than 45 percent,37,38 less than 50 percent;31

it was not reported in two studies.40,146 A total of nine of these papers reported the change in 

BNP or NT-proBNP and related the change to other outcomes including cardiac function, 

exercise capacity, symptoms or clinical events.31,37,38,41,44,110,148-150 The other nine studies 

reported changes in BNP or NT-proBNP and also may have reported the changes in other 

variables; however, there was no determination in these studies of the relationship between 

change in the B-type natriuretic peptide and change in these other variables.39,43,45-47,146,147,196,197

Five39,43,45,46,110 of the 18 papers that reported findings, examined in different ways, data from a 

recently published large randomized clinical trial (Val-HeFT). Two other studies also used the 

same database147,148, but one of these was a comparison of two different NT-proBNP methods.147

Although all these studies described collection of at least three B-type natriuretic peptide 

measurements, there were only ten studies that provided values for each of the time points.31,37-

41,44,146,147,149

Response to Therapy 

In the studies where change in BNP or NT-proBNP was related to other clinical findings, it 

was found that the B-type natriuretic peptide was related to at least one other variable in seven of 

the nine studies (Table 23). A study by Murdoch et al. was the first to evaluate whether plasma 

BNP would be useful to tailor therapy in patients with chronic stable HF (BNP guided group).149 

They randomized 20 patients to receive optimization ACE inhibitor therapy based on serial 

plasma BNP measures or clinical assessment with up-titration of ACE inhibitor to the target 

levels used in clinical trials, over the 8 week course of the study. They found only the BNP 

driven approach was associated with greater reductions in plasma BNP concentration throughout 

the course of the study and that there was a significantly greater suppression when compared to 

the clinical assessment group after 4 weeks of therapy (p = 0.03), but not at 8 weeks (p = 0.73) 

(Figure 7D). Although there was a decrease in BNP observed, there were no significant changes 

observed in haemodynamics within either group; however, heart rate was significantly different 

between groups (p = 0.02). 

Troughton et al. examined whether titration of treatment to reduce plasma NT-proBNP 

concentrations in systolic HF patients (NT-proBNP guided group) would be superior to clinically 

based treatment.148 There were 69 NYHA class II-IV HF patients with LVEF less than 40 

percent recruited into the study, with a median follow up of 9.5 months. Although the mean NTproBNP concentrations decreased to 668 pg/mL below baseline in the NT-proBNP guided group, 

compared with 25 pg/mL in the clinical group, this difference was not significant (p = 0.16) 

(Figure 7D). The BNP guided group had fewer cardiovascular events (death, hospital admission, 

or HF decompensation) compared to the clinical group (19 versus 54; p = 0.02). Changes in left 
62

ventricular function, quality-of-life score, 6 minute walk test, blood pressure, renal function, and 

adverse events were similar in both groups. 

Three additional studies have demonstrated that changes in BNP or NT-proBNP 

concentrations relate to changes in mortality and morbidity.37,41,110 Two of these three papers had 

study sizes of less than 100 patients.37,41 The third study110 was part of a large clinical trial and 

the BNP was measured at baseline in 4305 NYHA class II-IV HF patients (Val-HeFT). Follow 

up measurements were made at 4, 12, and 24 months after randomization. They found the 

baseline BNP predicted all-cause mortality and first morbid events. The study results 

demonstrated at study end that the group taking valsartan (the study drug) had a decline in BNP 

(decreased by 21 ± 5 pg/mL) compared to the placebo group (increased by 23 ±5 pg/mL). 

Patients with the greatest percent decrease in BNP from baseline to 4 months had the lowest, 

whereas patients with the greatest percent increase in BNP had the highest all-cause mortality 

and first morbid events. 

In six of the papers, change in NT-proBNP or BNP was related to change in cardiac function, 

functional capacity or quality-of-life.31,37,38,44,148,149 In three of these papers, despite changes in 

BNP or NT-proBNP, there was no relationship to changes in these other variables.37,148,149 The 

two exceptions were blood pressure (p = 0.015)148 and heart rate (p = 0.02).149 One of these 

studies demonstrated changes in left ventricular end diastolic dimension and end systolic 

dimension, but no change in BNP concentrations.44 This study also found a significant 

difference in BNP change in patients with HF of non-ischemic etiology in both early and late 

phases (p < 0.05), but not in those of ischemic etiology. In this study all the patients were 

receiving beta blocker therapy. 

There were two studies31,38 demonstrating that the changes in BNP or NT-proBNP were 

related to changes in cardiac function. Patients with ischemic heart disease treated with 

metoprolol showed significant differences at 12 weeks and 1 year from baseline for LVEF (32 

percent and 38 percent, respectively, p < 0.01), symptom questionnaire score (3.9 and 3.6, p < 

0.01) and 6 minute walk test (1310 and 1269 feet respectively, p < 0.05).38 In the other study, 

patients with idiopathic dilated cardiomyopathy treated with carvedilol demonstrated significant 

differences in all parameters measured.31 These parameters included NYHA (r = 0.50, p < 

0.0001), systolic blood pressure (r = 0.31, p = 0.014), heart rate (r = 0.43, p = 0.0007), LVEDD 

(r = 0.84, p < 0.0001), LVESD (r = 0.84, p < 0.0001), LVEF (r = -0.60, p < 0.0001), and LV 

mass index (r = 0.66, p < 0.0001). 

There were nine papers that examined the response of BNP or NT-proBNP to different types 

of HF therapy.39,40,42,43,45-47,146,150 In four of these studies BNP or NT-proBNP changes were 

related to changes in HF therapy.40,42,146,150 These studies demonstrated that the B-type natriuretic 

peptide concentration varied in response to the intensity of drug therapy40,42,146,150 or the use of 

various types of left ventricular assist devices.150 The other studies 39,45-47 demonstrated that HF 

patients receiving active therapy had a greater reduction in B-type natriuretic peptide 

concentration than those not taking the therapy. However, none of these studies examined 

whether BNP or NT-proBNP were related to change in drug dose. 
63

Figure 7. Change in BNP or NT-proBNP concentration after treatments 

Change in BNP or NT-proBNP concentration after treatment with A) an antiarrythmic (amiodarone), 

B) an angiotensin converting enzyme inhibitor (enalapril) and an angiotensin receptor blocker 

(valsartan), C) beta-blockers (atenolol, carvediolol, metoprolol), and D) heart failure therapy that is 

clinically or BNP guided. The dashed line in each figure indicates no change from baseline. 
64

 Figure 7 is a compilation of all studies with abstractable data showing percent change from 

baseline in BNP31,37,39,40,44,149 or NT-proBNP38,41,147 concentration with time and drug therapy. 

There were four studies, which treated patients with beta blockers,31,38,41,44 and all showed a 

decrease in BNP or NT-proBNP with time. The metoprolol and carvedilol treated patients31,38,44

were very similar in their changes to BNP or NT-proBNP levels over time in contrast to the 

atenolol treated patients.41 The one study with the antiarrhythmic amiodarone showed a rate of 

change similar to the beta blocker group.37 Valsartan treated patients had lower BNP values from 

baseline at 4 months after treatment but exhibited a slight increase over time.39 The ACE 

inhibitor enalapril showed a greater rate of change and greatest overall change from baseline 

compared to all treatments.40 The high dose treatment group showed a similar change in BNP as 

those in the low dose treatment group up to 12 weeks but there was a large departure at 24 weeks 

(75 percent versus 54 percent, respectively). Of these nine studies, only four included a placebo 

group.31,37,39,41 In two of these studies, the placebo groups37,41 showed no significant change 

from baseline at any time point. 

In the valsartan therapy study,39 all time points levels in the placebo group were higher than 

the treated group and increased with time. The carvedilol therapy study with a placebo group31

provided data at baseline and end of study only. Both the placebo and carvedilol treated groups 

had significantly lower BNP levels at six months compared to baseline and were not significantly 

different from each other over time (p = 0.18). 

There were two studies which assessed change in BNP149 and NT-proBNP147 in patients 

guided by the B-type natriuretic peptide level compared to patients following a clinically driven 

protocol (Table 23). Both studies demonstrated that the B-type natriuretic peptide guided therapy 

groups sustained faster and lower concentrations. The study that did not use any beta blocker 

therapy showed the smallest change overall, particularly in the clinically guided treatment 

group.147 Overall, Figure 7 shows that drug treatment decreases B-type natriuretic peptide levels 

in a time-dependent mode indicating that BNP or NT-proBNP might be reasonably good markers 

for monitoring the effect of treatment of chronic HF patients. 

Quality Assessment of Studies 

Of the 18 studies, 12 were RCTs. The quality of these 12 studies were evaluated using the 

Jadad scale167. Two studies147,148 scored 4, one study41 scored 3. The remaining studies39,40,43-

47,110,149 scored less than 3, indicating poor quality. 
65

Table 3. The effect and association of various biological determinants on BNP and NT-proBNP levels.* 

Increase None Decrease

Determinant 

BNP NT-proBNP BNP NT-proBNP BNP NT-proBNP 

Demographic Characteristics 

African-American 1 

Age 8 4 2 

Female 2 3 2 4 

Smoker, current 2 

Cardiac Disease 

Acute coronary syndrome 1 

Acute right heart failure (no CPE group) 1 

Angina, stable 1 1 

Aortic stenosis 3 

Arrhythmia 1 

Atrial fibrillation 1 

Cardiac decompensation 1 

Cardiogenic pulmonary edema (CPE) 1 

Diastolic dysfunction 3 1 2a 1a

Dilated cardiomyopathy 1 

Hypertension, with diastolic dysfunction 2 

Ischemic heart disease 1 1 

LAD culprit lesion 1 

LAD lesion, proximal vs mid 1 

Left ventricular mass 1 

Multi-vessel disease 1 

Myocardial infarction 1 2 

Myocardial infarction, history 2 

Previous CHF 1 

Revascularization 1 

Valvular disease 1 

Non–cardiac Disease 

Diabetes 1 3 

Diabetic nephropathy 1 

Diabetic retinopathy 1 

Dyspnea, non-cardiac 2 1 

Hyperlipidemia 1 1 

Hypertension 2 3 1 

Hypertension, duration 1 

Lung disease 1b 1c

Peripheral vascular disease 1 

Stroke 1 

Stroke and TIA 1 
66

Table 3. The effect and association of various biological determinants on BNP and NT-proBNP levels.* 

Increase None Decrease

Determinant 

BNP NT-proBNP BNP NT-proBNP BNP NT-proBNP 

Biochemical and Hematological Markers 

ACE genotype DD 1 

Adrenomedullin 1 

Aldosterone 1 

ANP 3 1 

Big endothelin-1 2 

cGMP 1 1 

Cholesterol 1 1 

Creatinine kinase 1 

Creatinine kinase-MB 2 1 1 

C-reactive protein 3 

Creatinine 2 3 2 

Endothelin-1 1 

Epinephrine 1 

Glucose, random 1 

Glucose, fasting 1 

HbA1c 1 1 

Hemoglobin 1 

Interleukin-6 1 

Lymphocytes 1 1 

Myoglobin 1 

Norepinephrine 5 1 

NT-proANP 5 2 

Osteoprotegerin 1 

Plasma renin activity 1 

Relaxin 1 

ST2, soluble receptor 1 

Total protein 1 

Troponin-I 3 1 

Troponin-T 2 9 

Functional and Physiologic Measures 

Activities of daily living score 1 

BMI 2 

Creatinine clearance 1 

Exercise 1d

Glomerular filtration rate 2 

Weight 1 

Hemodynamic, echocardiographic and electrocardiographic measures 

Blood pressure 3 

Blood pressure, systolic 2 2 
67

Table 3. The effect and association of various biological determinants on BNP and NT-proBNP levels.* 

Increase None Decrease

Determinant 

BNP NT-proBNP BNP NT-proBNP BNP NT-proBNP 

Cardiac index 1 

E/A ratio 2 

Fibrosis 1 

Fractional shortening 2 

Heart rate 2 1 2 

Left ventricular diastolic dimension 1 

Left ventricular end-systolic diameter 1 

Left ventricular mass index 6 

Left ventricular relative wall thickness 1 

MIBG activity 1 

Mid-wall left ventricular fractional shortening 1 

PCWP 1 

Perfusion defect size 1 

Pulmonary arterial pressure 1 

Pulse pressure 1 

Restrictive filling pattern of deceleration time 1 

Right atrial pressure 1 

ST-segment depression 2 

Telesystolic volume 1 

Drug treatment 

Amiodarone 2 

Atenolol 1 

Beta-blockers 1 1 

Carvedilol 2 1 2 

Enalapril 3 

Furosemide, dosage 1 

Lisinopril, dosage 1 

Metoprolol 1 

Perindopril 1 

Valsartan 4 

Treatment – Nondrug 

Left ventricular assist device 1 

Abbreviations: ACE=angiotensin converting enzyme; ANP=atrial natriuretic peptide; BMI=body mass index; E/A=early to 

late(atrial) echocardiographic phases of ventricular filling; cGMP=cyclic guanosine mononucleotide phosphate; CHF=congestive 

heart failure; CPE=cardiogenic pulmonary edema; HbA1c=hemoglobin A1c; LAD=left anterior descending coronary artery; 

MIBG=123I-etaiodobenzylguanidine; PCWP=pulmocapillary wedge pressure; TIA=transient ischemic attack 

* Study details for the determinants in alphabetical order including sample size, method, type, statistical method and values 

can be found in Evidence Table 1 in Appendix C. 

** The numbers given for each determinant refer to the number of associations abstracted from the studies according to effect

and type of B-type natriuretic peptide. a

 = Compared to systolic dysfunction; b = Compared to CHF; c = CHF and CHF + lung disease; d = Increased physical activity
68 

Table 4: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in emcare settings 

Report Study Design Study Population n Age** % Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

110 96* 91* 170 82 94 

Barcarse48 2004 Prospective Cohort Convenience sample VA with SOB 98 65 y 100% 58 1 Cardiologist review clinical BNP(2) 300 70 99 

>254 98.6 46.7 >423 95.7 73.3 >592 94.3 73.3 >761 91.4 73.3 >973 91.4 93.3 

BayesGenis16

2004 

Prospective 

Cohort 

SOB 

NYHA III or IV 

89 

71 y 

54% 

83 2 Cardiologists review clinical NT- ProBNP (9) 

>1099 90 93.3 

80 98 92 

100 94 94 115 90 96 120 90 96 

Dao56

2001 

Crosssectional SOB 250 63 y 94% 39 2 Cardiologists review clinical BNP(2) 

150 87 97 

Jose53

2003 

Crosssectional SOB of > 6 m 119 54 y 66% 61 NR Framingham Echo NT- ProBNP (8) 1691 97 89 

≥50 95 37.9 

≥100 90 55.2 ≥150 92.5 62.1 

SOB 

Male 

69 

74 y 

100% 

58 2 Cardiologists review clinical BNP(2) 

≥200 90 72.4 

≥50 100 37.3 

≥100 94.3 54.9 ≥150 91.4 58.8 

SOB 

Female 

86 

78 y 

0% 

41 2 Cardiologists review clinical BNP(2) 

≥200 88.6 62.7 

SOB 

Age ≥ 76 y 

NR NR NR 

NR 2 Cardiologists review clinical BNP(2) NR NR NR 

Knudsen50

2004 Diagnostic 

SOB 

Age < 76 y 

NR NR NR 

NR 2 Cardiologists review clinical BNP(2) NR NR NR 
69 

Table 4: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in emcare settings (continued) 

Report Study Design Study Population n Age** % Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

≥100 90 75 ≥200 80 87 ≥300 71 90 

Knudsen51

2004 

Crosssectional SOB 880 64 y 55% 51 2 Cardiologists review clinical BNP(2) 

≥400 64 92 

1184 87 71 2030 83 82 2906 80 87 3721 74 90 

NTProBNP 

(9) 

4567 92 68 

69 97 44 

104 97 49 208 94 70 277 83 78 

Lainchbury7

2003 Diagnostic SOB 

205 

70 y 

 49% 

34 2 Cardiologists review clinical 

BNP(2) 

346 77 84 

80 97 27 

100 96 31 150 93 45 200 93 56 250 91 68 300 88 87 

Logeart17

2002 

Crosssectional SOB 163 67 y 67% 71 

2 Cardiologists 

and 

1 

Pneumologist 

review 

clinical BNP(2) 

400 79 93 

≥50 97 62 ≥80 93 74 

≥100 90 76 ≥125 87 79 

Maisel18

2002 

Crosssectional SOB 1586 64 y 56% 47 2 Cardiologists review clinical BNP(2) 

≥150 85 83 
70 

Table 4: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in emcare settings (continued) 

Report Study Design Study Population n Age** % Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

≥100 90.4 72.9 ≥200 81.4 85.1 ≥300 72.5 88.6 

SOB 

1586 

64 y 

56% 

47 2 Cardiologists review clinical BNP(2) 

≥400 62.7 91.1 

≥100 86 82 ≥200 77 91 ≥300 69 94 

SOB 

18-69 y 

NR NR NR 

NR 2 Cardiologists review clinical BNP(2) 

≥400 60 95 

≥100 94 53 ≥200 85 72 ≥300 75 77 

SOB 

70-105 y 

NR NR NR 

NR 2 Cardiologists review clinical BNP(2) 

≥400 65 83 

≥100 92 76 ≥200 83 88 ≥300 73 90 

SOB 

Male 

883 

NR 

100% 

48 2 Cardiologists review clinical BNP(2) 

≥400 64 93 

≥100 88 59 ≥200 78 82 ≥300 72 87 

SOB 

Female 

703 

NR 0% 

46 2 Cardiologists review clinical BNP(2) 

≥400 61 89 

≥100 93 69 ≥200 82 82 ≥300 72 86 

SOB 

White race 

773 

NR NR 

50 2 Cardiologists review clinical BNP(2) 

≥400 60 90 

≥100 87 76 ≥200 81 88 ≥300 74 91 

Maisel49

2004 

Prospective 

Cohort 

SOB 

Black race 

715 

NR NR 

44 2 Cardiologists review clinical BNP(2) 

≥400 66 93 
71 

Table 4: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in emcare settings (continued) 

Report Study Design Study Population n Age** % Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

McCullough5 4

2002 

Diagnostic SOB 

1538 

64 y 

56% 

47 2 Cardiologists review clinical BNP(2) ≥100 90 73 

94 98 86 

105 94 86 135 90 90 195 85 94 

Morrison55

2002 

Crosssectional SOB 

321 

NR NR 42 2 Cardiologists review clinical BNP(2) 

240 79 96 

≥100 90 59 ≥150 85 71 ≥200 82 84 ≥250 78 90 ≥300 72 92 ≥350 67 92 

Ray57

2004 

Crosssectional 

SOB 

> 65 y 

Respiration 

measures cutoffs

308 

80 y 

49% 45.7 

2 of: 

Cardiologist 

Pulmonologist

GM Internist 

Geriatrician 

ED Physician

clinical BNP(2) 

≥400 60 95 

Villacorta52

2002 

Crosssectional SOB 70 72 y 47% 51 1 Cardiologist review clinical BNP(2) 200 100 97 

Abbreviations: ACS=acute coronary syndrome, AU ROC=area under the receiver operator characteristics curve, ED=emergency department, LR- =ne=positive likelihood ratio, NR=not reported, Sens% =sensitivity(%), SOB=shortness of breath, Spec% =specificity, uLL=unadjusted log likelihood

Administration., y=years. 

• estimated from ROC curve ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide ** Mean age if given in report
72 

Table 5: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with Hspecialty clinic settings 

Report Study design Study population n Age** % Male Prevalence % Reference test Reference standard Index Test^ Index cut point (pg/mL) Sens % Spec % 

HF BNP(1) NR NR NR 

Systolic HF BNP(1) NR NR NR 

Bettencourt11 2000 Cross- sectional Suspected HF 100 69 y 54% 100 Clinical by 2 Internists and 1 Cardiologist Diastolic HF BNP(1) NR NR NR 

impaired (< 48% BNP(1) 142 NR NR 

by 3D echo and 

<55% by RNV) 

NTproBNP(8) 4127 NR NR 

BNP(1) 142 0.73 0.77 

Hammerer60

2001 

Crosssectional Stable chronic HF 57 45-80 y NR 100 LVEF resting LVEF 

<40% NT- proBNP(8) 4127 0.70 0.73 

Lee59

2002 

Prospective 

cohort HF 

41 

23-85 y

70% 

100 Change in NYHA Class none (correlation) BNP(1) NR NR NR 

Maeda61

1998 

Crosssectional LVD (LVEF <50%) 72 61 y 74% 100 LVEDP NR BNP(1) NR NR NR 

< 40% BNP(1) NR NR NR < 50% BNP(1) 135 72.3 73.2 < 40% NT- proBNP(9) NR NR NR 

Seino58 2003 Cross- sectional Chronic HF and Controls 105 64 y 80% 100 LVEF 

< 50% NT- proBNP(9) 695 85.4 73.2 

LVEDD > 56mm BNP(1) NR NR NR 

LVESD ≥ 40mm BNP(1) NR NR NR 

LVEF < 50% BNP(1) NR NR NR 

Yamada62

1997 

Crosssectional various cardiovascul ar diseases 122 71 y 66% NR 

IVS < 11mm BNP(1) NR NR NR 

Abbreviations: AU ROC=area under the receiver operating characteristics curve, HF=heart failure, IVS=Interventricular septum,LR+=positive likelih

likelihood ratio, LVD=left ventricular dysfunction, LVEDD= left ventricular ejection diastolic dysfunction, LVEDP=left ventricular end-diastolic pre

ejection fraction, LVESD= left ventricular ejection systolic dysfunction, NR=not reported, NYHA=New York Heart Association, SE=standard error, s

spec=specificity, RNV=radionuclide ventriculography. y= years. ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 

** Mean age if given in report 
73 

Table 6: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in p

Report Study Design Study Population n Age**% Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

Alehagen67

2002 

Crosssectional 65-82 years Symptoms of HF 415 72 y 52% 48 Clinical and Echo LVEF < 40% BNP(1) NR NR NR 

Bettencourt34

1999 

Crosssectional Community HT and normal controls 47 65 y 47% 33 Doppler Echo LV diastolic dysfunction BNP(1) NR NR NR 

Gustafsson68

2003 

Crosssectional Dyspnea referred for echo 367 69 y 46% 10 Doppler Echo LVEF < 40 % NT- proBNP (9) 125 97 46 

General population 307 >45 y NR 1 80 88 

HF diagnosis 103 >45 y NR 20 71 52 

On diuretics 

87 

>45 y 

NR 

8 86 65 

High risk of HF 

133 

>45 y 

NR 

8 

BNP(1) >115 

50 67 

General population 

307 

>45 y 

NR 

1 80 73 

HF diagnosis 

103 

>45 y 

NR 

20 100 18 

On diuretics 

87 

>45 y 

NR 

8 86 40 

Hobbs63

2004 Diagnostic 

High risk of HF 

133 

>45 y 

NR 

8 

LVSD by 

Doppler 

Echo 

LVEF < 40% 

NTproBNP

(9) 

>338 

100 46 

Table 6: Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in primary car
74 

Report Study Design Study Population n Age** % Male Prevalence % Reference test Reference standard Index test^ Index cut point (pg/mL) Sens % Spec % 

>10 92 18 

>17.9 88 34 

Landray66 2000 Cross- sectional Suspected HF 126 74 y 54% 32 X-Ray or Echo LVSD LVEF NR BNP(1) >76 66 87 

Dyspnea 

Male 

176 

> 50 y 

100% 

27 93 96 67 

Dyspnea 

Female 

169 

> 50 y 

0% 

20 143 94 69 

Dyspnea 

Male 

176 

> 50 y 

100% 

27 76 100 60 

Dyspnea 

Female 

169 

> 50 y 

0% 

20 67 100 27 

Dyspnea 

Male 

176 

> 50 y 

100% 

27 152 89 79 

Nielsen65

2004 

Crosssectional 

Dyspnea 

Female 

169 

> 50 y 

0% 

20 

HF 

ESC HF 

definition 

LSVD by 

Echo 

NTproBNP

(9) 

219 91 84 

Wright64

2003 RCT Dyspnea and/or edema 305 72 y 35% 25 HF ESC definition of HF NT- proBNP (6) 211 90 63 

Abbreviations: AU ROC=area under the receiver operator characteristics curve, Clin=clinical, Dx= diagnosis, ESC=European Society of Cardiology 

failure, HT=hypertension, LVEF=left ventricular ejection fraction, LVSD=left ventricular systolic dysfunction, LR+=positive likelihood ratio, LR-=nLV=left ventricular, NR=not reported, RCT=randomized controlled trial, Sens%=sensitivity (%), Spec%=specificity(%), y=years. • Estimated from the ROC curve ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 

** Mean age, if given in report 
75 

Table 7: Diagnostic odds ratios for studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with 

Sensitivity Specificity Diagn

Report Setting Test^ Cut point (pg/mL) Lower 

95% CI 

Upper 

95% CI

Lower 

95% CI 

Upper 

95% CI 

BNP(1) 135 0.723 0.613 0.800 0.731 0.614 0.822 7 

Seino58

2004 Clinic NTproBNP(9) 695 0.857 0.777 0.911 0.731 0.614 0.822 16 

110 0.958 0.830 0.980 0.940 0.830 0.970 360 170 0.842 0.726 0.914 0.928 0.809 0.975 69 

Barcarse48 2004 ED BNP(2) 

300 0.701 0.573 0.809 0.976 0.876 0.995 96 

80 0.979 0.927 0.994 0.921 0.869 0.954 558 

100 0.912 0.839 0.954 0.941 0.892 0.968 167 115 0.896 0.820 0.943 0.960 0.917 0.981 213 120 0.869 0.820 0.943 0.960 0.917 0.981 213 

Dao56

2001 ED BNP(2) 

150 0.875 0.794 0.927 0.970 0.930 0.987 231 

80 0.969 0.920 0.988 0.270 0.165 0.410 12 

100 0.960 0.908 0.983 0.282 0.173 0.425 10 150 0.930 0.868 0.964 0.458 0.325 0.597 11 200 0.930 0.868 0.964 0.562 0.422 0.693 17 250 0.913 0.847 0.952 0.687 0.546 0.800 23 

Logeart17

2002 ED BNP(2) 

300 0.878 0.806 0.926 0.875 0.753 951.000 50 

50 0.970 0.955 0.980 0.620 0.586 0.652 54 80 0.930 0.909 0.946 0.739 0.709 0.768 38 

100 0.901 0.876 0.920 0.760 0.730 0.787 27 125 0.869 0.843 0.891 0.890 0.761 0.816 25 

Maisel18

2002 ED BNP(2) 

150 0.849 0.822 0.873 0.830 0.803 0.854 28 
76 

Table 7: Diagnostic odds ratios for studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with (continued) 

Sensitivity Specificity Diagn

Report Setting Test^ Cut point (pg/mL) Lower 

95% CI 

Upper 

95% CI

Lower 

95% CI 

Upper 

95% CI 

94 0.977 0.936 0.992 0.855 0.798 0.898 258 

105 0.940 0.866 0.969 0.855 0.798 0.898 93 135 0.903 0.841 0.942 0.898 0.846 0.934 82 195 0.850 0.780 0.901 0.941 0.897 0.966 91 

Morrison55

2002 ED BNP(2) 

540 0.791 0.714 0.851 0.962 0.924 0.981 97 

100 0.900 0.840 0.939 0.592 0.517 0.664 13 150 0.851 0.783 0.900 0.712 0.639 0.775 14 200 0.822 0.751 0.876 0.838 0.775 0.886 24 250 0.780 0.704 0.840 0.898 0.843 0.935 31 300 0.732 0.644 0.790 0.922 0.871 0.953 31 

Ray57

2004 ED BNP(2) 

350 0.673 0.592 0.745 0.922 0.871 0.953 24 

Villacorta52

2002 ED BNP(2) 200 0.99 0.88 1.00 0.96 0.83 0.99 1635 

69 .971 .901 .992 .437 .356 .521 26 

104 .971 .901 .992 .511 .427 .594 36 208 .942 .862 .977 .703 .621 .774 39 277 .828 .723 .899 .777 .700 .839 17 

BNP(2) 

346 .771 .660 .854 .837 .765 .889 17 

1184 .871 .773 .930 .711 .629 .780 17 2030 .828 .723 .899 .822 .749 .877 22 2875 .800 .691 .877 .866 .799 .914 26 

Lainchbury7

2003 ED 

NTproBNP(9)

3721 .742 .629 .830 .903 .842 .942 27 

254 0.986 0.925 0.997 0.467 0.248 0.698 62 423 0.958 0.884 0.985 0.600 0.357 0.801 35 592 0.944 0.865 0.978 0.800 0.855 0.929 68 972 0.902 0.812 0.952 0.933 0.701 0.988 130 

Bayes-Genis16

2004 ED NT- proBNP(9)

1099 0.917 0.830 0.916 0.933 0.702 0.988 154 
77 

Table 7: Diagnostic odds ratios for studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with (continued) 

Sensitivity Specificity Diagn

Report Setting Test^ Cut point (pg/mL) Lower 

95% CI 

Upper 

95% CI

Lower 

95% CI 

Upper 

95% CI 

Jose 53

2003 ED NT- proBNP(8) 1691 0.972 0.905 0.992 0.891 0.769 0.952 291 

10 0.925 0.801 0.974 0.186 0.118 0.281 3 

17.9 0.875 0.738 0.945 0.348 0.256 0.454 4 

Landray66 2000 Primary Care BNP(1) 

76 0.675 0.520 0.799 0.872 0.785 0.927 14 

BNP(1) 115 0.500 0.237 0.763 0.667 0.579 0.744 2 

Hobbs63

2004 Primary Care NTproBNP(9) 338 0.952 0.667 0.995 0.463 0.378 0.551 17 

Gustafsson68

2003 Primary Care NT- proBNP(9) 125 0.969 0.846 0.994 0.458 0.405 0.511 27 

Wright64

2003 Primary Care NT- proBNP(6) 211 0.831 0.732 0.898 0.771 0.713 0.821 17 

Abbreviations: HF=heart failure, ED=emergency department, CI=confidence interval ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
78 

Table 8: Studies that performed multivariate analyses to compare the independent contribution of BNP and NT-proBNP with ottests. 

Report Outcome criteria Description of model Variable Response type Value 

Heart size Chi Square 31.9 

Murmurs Chi Square 19.2 

Pulmonary venous hypertension Chi Square 11.9 

Pedal edema Chi Square 10.0 

Orthopnea Chi Square 6.4 

Dao56

2001 HF - Framingham Criteria multivariate analysis 

BNP Chi Square 95.2 

Rales OR 1.8 

Increased JVP OR 2.9 

Cardiomegaly OR 3.1 

Ankle edema OR 6.5 

Orthopnea OR 8.8 

S-3 gallup OR 11.3 

Jose53

2003 HF- Framingham & echo logistic regression 

NT-proBNP OR 8.9 

Rales OR 1.6 

Lower extremity edema OR 2.3 

Cardiomegaly OR 2.3 

Cephalization OR 6.4 

Interstitial edema OR 7.0 

Knudsen51 2004 HF @ 30 days - Framingham & NHANES final multivariate model 

BNP > 100 OR 12.3 

Increased JVP OR 3.5 

Orthopnea OR 4.0 

X-ray edema OR 9.0 

BNP 80 to 300 OR 5.4 

Logeart17 2002 HF - Framingham criteria logistic regression 

BNP > 300 OR 221.0 
79 

Table 8: Studies that performed multivariate analyses to compare the independent contribution of BNP and NT-proBNP with ottests. (continued) 

Report Outcome criteria Description of model Variable Response type Value 

Increased JVP OR 1.9 

Rales OR 2.2 

Edema OR 2.9 

Cephalization of vessels OR 10.7 

Maisel18 2002 HF - NHANES & Framingham multiple logistic 

regression 

BNP > 100 OR 29.6 

Maisel Clinical Judgment >50% sure Exp Beta 9.73 

49

2004 HF- expert review of medical record simultaneous logistic regression Log BNP Exp Beta 12.02 

Clinical Judgment Diagnostic accuracy 74% 

BNP > 100 Diagnostic 

accuracy 

81.20% 

McCullough54 2002 HF - Framingham & NHANES logistic regression 

Both Diagnostic 

accuracy 

81.50% 

Rales chi square 4.3 

Pulmonary venous hypertension chi square 6.4 

Increased JVP chi square 12.9 

Chest X-ray enlarged heart chi square 33.0 

Morrison55 2002 HF - Framingham, hospital course, echo, nuclear medicine 

EF, cardiac catheter 

multivariate 

analysis 

BNP chi square 119.6 

Rales OR 3.1 

Lower extremity edema OR 4.6 

Ray57 2004 cardiopulmonary edema - expert Dx using Framingham forward logistic regression BNP > 250 OR 24.4 

Abbreviations: CI=confidence interval, Dx=diagnosis, EF=ejection fraction, HF=heart failure, JVP=jugular venous distension, NR=Not reported, O
80 

Table 9: Characteristics of the systematic reviews of diagnostic tests for HF that were eligible for this review 

Report Description Number of papers reviewed Results reported Includ

rev

Ahmed180

2003 

Review of heart failure evaluation and management guidelines: relevance to elderly. Recommendations of expert panel. 

 N

Cardarelli174

2003 

Systematic Review. Randomized double blinded & well designed cohort studies. Included reference standard. Tests evaluated in complete spectrum of patients 

4 

No pooling, Results from papers 

presented. AUC, sens, spec, 

LR+, PPV, NPV 

Y

Clerico151

2004 

Systematic review. Studies to evaluate Dx accuracy & prognostic relevance of NPs. Critical comparison of "gold standard" 

9 

No pooling, Results from papers 

presented. AUC, sens, spec, 

PPV, NPV 

Y

Craig183

2005 

Systematic review. Diagnosis of HF in primary care & emergency - BNP, NT-proBNP, ECG 

BNP 23 

NT-proBNP 8 

ECG 12 

Pooled sens, spec, DOR (95% 

CI) Y

Doust184

2002 

Systematic review. Diagnosis of HF – signs, symptoms, investigations 

Diagnosis & exam – 7 

Increased JVP – 8 

CXR for pulmonary HR – 3

CXR for cardiomegaly – 5

Abnormal ECG – 10 

NT-proBNP - 2 

No pooling, sens, spec. LR Y

Doust173

2004 

Systematic review. Papers that evaluated NP against reference standard and results reported so that 2x2 table could be constructed. 

20 Pooled DOR (95% CI), SROC, AUC Y

Doust163

2005 

Systematic review. BNP & cardiac outcome prediction in patients with HF N

Jortani176

2004 

Review of biomarkers of HF and strategies for developing new biomarkers. Not stated N

Khunti177

2004 

Systematic review of 12 lead ECG in DX of HF. Studies of patients referred from primary care 4 No pooling - sens, spec, SROC Y

McGowan179

2003 

Systematic Review. Accuracy of echcocardiography vs radionuclide or contrast vetriculography 

25 correlation coefficients Y
81 

Table 9: Characteristics of the systematic reviews of diagnostic tests for HF that were eligible for this review. (continued) 

Report Description Number of papers reviewed Results reported Includ

rev

Thomas178

2004 

Review of diastolic heart failure - prevalence, criteria, morbidity, mortality N

van der Sloot175

2003 Review of important papers published in 2002 1 

No - th

includ

review 

Khunti181

2000 

Systematic review. Dx of heart failure in primary care - signs, symptoms, investigations. Not stated narrative Y

Wang182

2005 

Systematic review. Dx of heart failure in dyspneic patients in ED - signs, symptoms, CXR, ECG, BNP 

22 Pooled sens, spec, LR (95%CI). Y

Abbreviations: AUC=area under the curve, CI=confidence interval, CXR=chest x-ray, DOR=diagnostic odds ratio, Dx= diagnosis, ECG=electrocardio

department, HF=heart failure, LR+=positive likelihood ratio, NP=,NPV=negative predictive value, PPV=positive predictive value, sens=sensitivity, sp

SROC=summary receiver operating characteristic. 
82 

Table 10: Diagnostic performance estimates of BNP and NT-proBNP compared to other diagnostic tests based on previous sys

Report Included Studies Results Reported Clinical Exam Nocturnal Dyspnea S-3 Gallop Increased JVP CXR +ve for PVC CM on CXR Abnormal ECG BNP 

Cardarell174

2003 

4 studies, OP 

and Urgent 

Care, BNP vs 

ref standard to 

DX HF 

Max 

estimate 

from 

studies 

evaluated 

BNP @ 80 pg/mL 

sens 0.98, spec 

0.92, LR+ 12.3, 

AUC 0.98, 

Est. DOR 569

Clerico151

2004 

9 studies 

diagnostic 

accuracy vs 

"gold standard" 

Max 

estimate 

from 

studies 

evaluated 

BNP @ 28.9 

pg/mL sens 0.94, 

spec 0.77, AUC 

0.91(0.90 - 0.93) 

Est. DOR 53

Craig183

2005 

BNP 23 

studies, NTproBNP 8 

studies, ECG 

12 studies Dx 

of HF in 

Primary Care 

and 

Emergency 

pooled 

estimates 

(95% CI) 

for LVSD - 

cardiologist read, 

sens 0.90 (0.88-

0.92), spec 0.58 

(0.56-0.60), DOR 

12.41 (7.09-

21.71), machine 

read sens 0.83 

(0.74-0.91), spec 

0.21 (0.17-0.25), 

DOR 1.41 (0.46-

4.34)

For LVSD - sens 0.88 (0.84-0.91), 

spec 0.62 (0.60-

0.63), DOR 

10.74 (6.51-

17.72)

Doust184

2002 All Settings 

Max 

estimate 

from 

studies 

evaluated 

sens 

0.68, 

spec 

0.76, 

LR+ 2.6, 

LR- 0.4 

Est. 

DOR 7

sens 0.17, 

spec, 

0.98, LR+ 

8.3, LR0.8 

Est. DOR 

10

sens 

0.64, 

spec 

0.60, 

LR+ 

1.6, LR0.6 

Est. 

DOR 3

sens 

0.90, 

spec 

0.15 

Est. 

DOR 2

sens 0.98, spec 

0.82, LR+3.2, 

LR- 0.2 

Est. DOR 223

sens 1.00, spec 

0.99, LR+ 6.0, 

LR - 0.13 

Est. DOR 498

Doust173

2004 

25 studies 

BNP vs LVEF 

or Clinical 

Criteria, 

General 

Practice and 

Hospital 

pooled 

estimates 

(95% CI) 

BNP @ 15 pg/mL 

vs LVEF <40 

DOR 11.6 (8.4 - 

16.1) AUC 0.83, 

vs Clinical 

Criteria DOR 

30.9(27.0-35.4) 
83 

Table 10: Diagnostic performance estimates of BNP and NT-proBNP compared to other diagnostic tests based on previous sys(continued)

Report Included Studies Results Reported Clinical Exam Nocturnal Dyspnea S-3 Gallop Increased JVP CXR +ve for PVC CM on CXR Abnormal ECG BNP 

Khunti181

2000 Primary Care narrative 

70% 

accurate 

in Dx of 

dyspnea

sens 

0.37 

sens 

0.51 

high sens, poor 

spec, used for 

confirmation of 

DX only 

Khunti177

2004 

4 studies 12 

Lead ECG vs 

Echo 

sens 0.94, spec 

0.65, AUC 0.84 

(0.33-1.00) 

Est. DOR 30

McGowan179

2003 

25 studies 

accuracy of 

echo vs 

radionuclide or 

contrast 

ventriculo 

correlation 

coefficients, 

max and 

min from 

studies 

evaluated 

Wang182

2004 

22 studies Dx 

of HF in 

patients with 

dyspnea in ED 

pooled 

estmates 

(95% CI) 

sens 

0.61, 

spec 

0.86, 

LR+ 4.4 

(1.8-

10.0), 

LR- 0.45 

(0.28-

0.73) 

Est 

DOR 10

sens 0.4, 

spec 0.84, 

LR+ 2.6 

(1.5-4.5), 

LR- 0.70 

(0.54-

0.91) 

Est. DOR 

4

sens 

0.13, 

spec 

0.99, 

LR+ 11 

(4.9-

25.00, 

LR0.88 

(0.83-

0.94) 

Est. 

DOR 15

sens 0.39, spec 0.92, 

LR + 5.1 

(3.2-7.9), 

LR0.66(0.57-

0.77) 

Est. DOR 

8

sens 

0.54, 

spec 

0.96, 

LR+ 

12.0 

(6.8-

21.0), 

LR0.48 

(0.28-

0.83) 

Est. 

DOR 

28

sens 

0.74, 

spec 

0.78, 

LR+ 3.3 

(2.4-4.7), 

LR- 0.33 

(0.23-

0.48) 

Est. 

DOR 10

sens 0.50, spec 

0.78, 

LR+ 2.2 (1.6-3.1), 

LR- 0.64 (0.47-

0.88) 

Est. DOR 3

BNP @100 sens 

0.93, spec 0.66, 

LR+ 2.7 (2.0-

3.9), LR- 0.11 

(0.07-0.16) 

Est. DOR 23

Abbreviations: AUC=area under the curve, CI=confidence interval, CM=cardiomyopathy, CXR=chest x-ray, CM=, Dx=diagnosis, ECG=electrocardi

department, Est.DOR=estimated diagnostic odds ratio, HF=heart failure, JVP=jugular venous pressure, LR-=negative likelihood ratio, LR+=positive 

ventricular ejection fraction, LVSD=left ventricular systolic dysfunction, OP=outpatient, PVC=, sens=sensitivity, spec=specificity. 
84 

Table 11. Summary of studies in patients with risk of CAD: BNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Bhalla692004 USA 

n: 482 Age: 52 y 

Clinical suspicion of cardiac dysfunction 

BNP(2) 120 All-cause mortality uLR 

Kellett712004 Ireland 

n: 646 Age: 73.7 y 

Admitted for acute medical emergencies 

BNP(2) 700 In-hospital mortality aOR 

Nagao722004 Japan 

n: 401 Age range: 61.5 – 65.4 y 

Cardiac arrest BNP(1) 100 Survival to hospital 

discharge 

aOR 0.13 

Suzuki102002 Japan 

n: 229 Age: 66 y 

Hypertensive BNP(1) 68 Cardiovascular 

events (including death) 

uRR aRR 

Ueda92003 Japan 

n: 111 Age: 85.5 y 

Electrocardiographic abnormalities, stroke, or IHD 

BNP(1) 100 1) Cardiac event 

2) Death 

1) u2) u

Wang742004 USA 

n: 3,346 Age: 59 y 

Not reported in article 

BNP(1) 20.0 (men) 

23.3 (women) 

Death aHR 

Abbreviations: aHR=adjusted hazards ratio, aOR=adjusted odds ratio, aRR=adjusted risk ratio, CAD=Coronary artery disease, IHD=ischemic heart di

hazards ratio, uLR=unadjusted likelihood ratio, uRR=unadjusted risk ratio, y=years ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
85 

Table 12: Summary of studies in patients with risk of CAD: NT-proBNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Gaede702005 Denmark 

n: 160 Age: 55.1 y Diabetes NT-proBNP(9) 33.5 Mortality 

Jernberg242002 Sweden 

n: 775 Age range: 55 – 77 y Chest pain NT-proBNP(9) ≤ 112, 113-400, 401- 1653, ≥ 1654 Death 

Nielsen732004 Denmark 

n: 2,224 Age range: 40 – 75 y LVEF > 0.55 NT-proBNP(9) 368.00 – 2,114.25 Major adverse card

events 

Olsen42004 USA, Denmark, Nor. 

n: 183 Age range: 66 – 70 y LV hypertrophy NT-proBNP(9) 184 Composite endpoin

including death 

Tarnow152005 Denmark 

n: 386 Age range: 41.0 – 42.5 y 

Diabetic nephropathy NT-proBNP(9) 125 All-cause mortality 

Weber62004 Germany 

n: 209 Age: 60 y 

Degenerative aortic stenosis NT-proBNP(9) 550 Severity of aortic stenosis 

Abbreviations: aHR=adjusted hazards ratio, CAD=coronary artery disease, LV=left ventricular, LVEF=left ventricular ejection fraction, Nor= Norway

ratio, uRR=unadjusted risk ratio, y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
86 

Table 13. Summary of studies in patients with CAD with surgery: BNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Grabowski3

2004 Poland 

n: 126 Age: 58.8 y 

Myocardial infarction, acute coronary syndrome 

BNP(2) 100 pg/mL All-cause mortality 

Jiang77

2004 China, Saudi Arabia 

n: 949 Age: 52.5 y 

Chest pain, angina, acute myocardial infarction 

BNP(2) 80 pg/mL Mortality 

Morrow28

2003 USA 

n: 1,676 Age range: 60 – 69 y 

Miscellaneous electrocardiographic and laboratory data 

BNP(2) 80 pg/mL Mortality 

Takase79

2004 Japan 

n: 77 Age: 67 y Angina BNP1) 68 pg/mL Recurrence of angi

attacks 

Wiviott96

2004 USA 

n: 1,865 Age range: 60.2 –  64.5 y 

Angina, eligibility for PCI, ischemia BNP(2) 80 pg/mL 

Combined outcomedeath, myocardial infarction 

Abbreviations: aOR=adjusted odds ratio, CAD=coronary artery disease, PCI = percutaneous coronary intervention, uHR=unadjusted hazards ratio, uO

y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
87 

Table 14. Summary of studies in patients with CAD, no surgery: BNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Bettencourt33

2000 Portugal 

n: 101 Age: 58.3 y 

Acute myocardial infarction BNP(1) 93.8 – 380.5 pg/mL Left ventricular dysfunction 

Mega272004 USA 

n: 438 Age range: 21-75 y 

ST segment elevation myocardial infarction BNP(3) 80 pg/mL Mortality 

Omland131996 Scandanavia 

n: 131 Age: 67.8 y Unspecified BNP(1) 115.22 pg/mL Mortality 

Sabatine83

2002 USA 

n: 450 Age: not reported in the article 

Non-ST elevation acute coronary syndromes 

BNP(2) 80 pg/mL Composite: death, M

CHF 

Wylie78

2004 USA 

n: 1,124 Age: NR 

Ischemic discomfort, documented coronary artery disease 

BNP(2) 80 pg/mL Development of CHF or cardiogenic shock 

Abbreviations: aHR=adjusted hazards ratio, aOR=adjusted odds ratio, CAD=coronary artery disease, CHF = congestive heart failure, MI = myocardiareported, uOR=unadjusted odds ratio, y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide.
88 

Table 15: Summary of studies in patients with CAD not surgery: NT-proBNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome Result 

Bazzino212004 Argentina 

n: 1,483 Mean age: 66+/- 12 y 

Resting chest pain 

NT-proBNP(9) 586 pg/mL Mortality aOR = 3.42 

de Winter752004 Netherlands 

n: 1,172 Age range: 60 – 68 y PTCA NT-proBNP(9) 456 pg/mL Death uOR = 13.47 

Galvani76

2004 Italy 

n: 1,726 Age range: 59 – 65 y Angina NT-proBNP(9) 

≤ 107 pg/mL, 108-353 pg/mL, 354-1357 pg/mL, ≥1358 pg/mL 

Mortality at 30 days aOR range: 1

3.91 

James8

2003 Sweden 

n: 6,809 Mean age: 65 +/- 11 y Angina NT-proBNP(9) 

≤ 237 pg/mL, 238-668 pg/mL, 669-1869 pg/mL, ≥1870 pg/mL 

Mortality 

Mortality (1 yeaOR range = 3.2 

Omland822002 Sweden 

n: 609 Age range: 62 – 69 y 

Clinical diagnosis not specified 

NT-proBNP(7) 4,609 pg/mL All-cause mortality uRR = 3.9 aRR = 2.1 

Richards80

2003 New Zealand 

n: 666 Age: 62.4 y 

Myocardial infarction 

NT-proBNP(6) 1,370 pg/mL Mortality aRR = 6.63 

Abbreviations: aOR=adjusted odds ratio, aRR=adjusted risk ratio, CAD=coronary artery disease, PTCA = percutaneous transluminal coronary angiop

 uOR=unadjusted odds ratio, uRR=unadjusted risk ratio, y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide.
89 

Table 16: Summary of studies in patients with CAD no surgery: NT-proBNP 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Heeschen862004 Germany, NZ 

n: 1,791 Mean age: 59.9–64.1 y Chest pain NT-proBNP(9) 246 pg/mL Mortality or myocar

infarction 

James97

2004 Europe, USA 

n: 1,381 Age: 65 y Angina, ST-depression NT-proBNP(9) <237, 237-669, 670- 1869, >1869 pg/mL Mortality 

Jarai20

2005 Austria 

n: 120 Age: 63 y 

Angina, myocardial ischemia NT-proBNP(8 ) 2,791 pg/mL Cardiovascular mortality 

Jernberg22

2003 Sweden 

n: 2,019 Age range: 40-84 y Myocardial ischemia NT-proBNP(9) 535 pg/mL (men) 672 pg/mL (women) Mortality 

Latini87

2004 Italy 

n: 724 Age: 31.9 y 

Persistent ST-segment elevation NT-proBNP(9) 

0-818 pg/mL 819-2012 pg/mL > 2012 pg/mL 

All-cause mortality 

Palmer81

2003 New Zealand 

n: 978 Age: 62.1 y Cardiac ischemia NT-proBNP(6 ) 186 pg/mL Mortality 

Richards84

1998 New Zealand 

n: 156 Age: 64 y 

Acute myocardial infarction NT-proBNP(6) 254 pg/mL 1,032 pg/mL All-cause mortality 

Schnabel85

2005 Germany 

n: 904 Age range: 60.7– 62 y 

Acute coronary syndrome NT-proBNP(9) 

<160.8, 160.8-538.1, 538.2-1356.0, >1356.0 pg/mL 

Cardiovascular eve

Ueland98

2004 U.K. 

n: 249 Age range: 63– 72 y 

Left ventricular dysfunction, heart failure 

NT-proBNP(7) 10,537 pg/mL All-cause mortality 

Abbreviations: aHR=adjusted hazards ratio, aOR=adjusted odds ratio, aRR=adjusted risk ratio, CAD=coronary artery disease, SS = statistically signifi

uOR=unadjusted odds ratio, uRR=unadjusted risk ratio, y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
90 

Table 17: Summary of studies in patients with CAD no regression analyses 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Dokainish19

2005 USA 

n: 895 Mean age: 57.3–60.6 y 

Coronary artery disease BNP(2) 80 Death or Re-infarct

Hutfless91

2004 USA 

n: 98 Age: 63 y 

Coronary artery disease (multiple clinical diagnoses) 

BNP(2 ) 

120 280 385 

Intra- and postoperative cardiac events 

Julier99

2003 Switzerland 

n: 72 Age: 63.5 y Cardiac arrest NT-proBNP(9) None 

postoperative cardiovascular and renal adverse even

Kerbaul92

2004 France 

n: 60 Age range: 67–68 y 

Myocardial infarction, angina, peripheral arteriosclerosis 

NT-proBNP(9) 397, 430, 491 Cardiovascular complications 

Lindahl14

2005 Sweden 

n: 961 Age: 67 y Chest pain, ischemia NT-proBNP(9) 529 Mortality 

Panteghini29

2003 Italy 

n: 92 Age: 52.5 y 

Acute myocardial infarction BNP (2) 83 All cause mortality 

Richards89

2002 New Zealand 

n: 747 Age: 63.6 y 

Antecedent hypertension NT-proBNP(6 ) 1,015 Mortality 

Sadanandan95

2004 USA 

n: 276 Age: 61–67 y 

Unstable angina, myocardial infarction BNP(2) 80 Mortality 

Shimpo90

2004 USA 

n: 810 Age: 58 y Ischemic discomfort BNP(1) 80 Mortality 

Song93

2004 Japan 

n: 40 Age range: 66.7–71.6 y 

New York Heart Association BNP(1) 450 1) Pleural effusion 2) Atrial fibrillation 
91 

Table 17: Summary of studies in patients with CAD no regression analyses. (continued) 

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Suzuki882004 Japan 

n: 145 Age: 64.7–66.7 y 

Acute myocardial infarction BNP(1) 180 Cardiac related mortality 

Watanabe942003 Japan 

n: 14 Age: NR 

Elective CABG with cardiopulmonary bypass 

BNP(1) None 1) Death 2) Angina 

Zeller100

2004 France 

n: 101 Age: 69 y Myocardial infarction NT-proBNP(9) 1150 

Death, recurrent myocardial infarctioheart failure 

Abbreviations: CABG=coronary artery bypass graft, CAD=coronary artery disease, NR = not reported, y=years. ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
92 

Table 18. Summary of studies in patients with HF and mortality outcomes: BNP 

Report N Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Akioka322000 Japan 

 n:33 Age: 71 y 

Chronic HF with decompensation. NYHA III-IV Mean LVEF 41% 

BNP(1) > 700 pg/mL 

1) Cardiac mortality, baseline BNP 2) Cardiac mortality, deceleration time <120 and Baseline BNP > 700 pg/mL 

1) uChi Sq. = 2.2) uChi Sq. = 5.

Alehagen1272004 Sweden 

n:458 Age: 73 y 

Clinical evaluation NYHA I-III LVEF < 40% 

BNP(1) 173 - 346 pg/mL > 346 pg/mL 

Cardiovascular mortality: 1) BNP 173-346 pg/mL 2) BNP >346 pg/mL All cause mortality: 3) BNP 173-346 pg/mL 4) BNP >346 pg/mL 

1) HR = 1.58 2) HR = 3.38 3) HR = 0.99 4) HR = 1.90 

Berger125

2005 Austria 

 n:452 Age: 54 y 

Clinical evaluation NYHA I -IV LVEF < 35% 

BNP(2) > 130 pg/mL 

Pump failure death 1) BNP 2) Log BNP 3) Log BNP 

1) aChi Sq. = 7·2) uChi Sq. = 333) aChi Sq. = 10

Bettencourt130

2000 Portugal 

n:139 Age: 69 y 

Clinical examination NYHA I-III Mean LVEF = 33.5% 

BNP(1) > 274 pg/mL All cause mortality uBeta = 0.001 aBeta = 0.0001 

Bettencourt36

2004 Portugal 

 n:84 Age: 69 y 

Clinical examination NYHA I –III Mean LVEF 31.2% 

BNP(1) 

1) > 260.4 pg/mL 2) Increase vs decrease BNP 3) Per increase of 100 pg/mL 

Mortality 

1) uHR = 2.96 2) uHR = 2.64 3) uHR = 1.28  aHR = 1.34 

Cheng1192001 USA 

 n:72 Age: 68 y 

Framingham criteria NYHA III-IV LVEF < 50% 

BNP(2) 

430 pg/mL 840 pg/mL 1090 pg/ml 1220 pg/mL 

Death in hospital or death within 30 days after initial discharge 

Mortality outcom

Harrison114

2002 USA 

n:325 (41% with HF) Age: 65 y 

At ED with dyspnea Previous Echocardiogram NYHA NR LVEF NR 

BNP(2) >230 pg/mL vs. </=230 pg/mL 1) HF death 2) Cardiac death 1) uRR = 24 2) uRR = 37 

Imamura1172001 Japan 

n:171 Age: 63 y 

Clinical evaluation NYHA II-IV Mean LVEF 27% 

BNP(1) <160 pg/mL Cardiac mortality u HR = 1 aHR = NS 
93 

Table 18. Summary of studies in patients with HF and mortality outcomes: BNP (continued) 

Report N Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Ishii129

2002 Japan 

 n:98 Age: 69 y 

Worsening HF Admission to CCU Echocardiography NYHA (mean) 3.5 Mean LVEF 42% 

BNP(1) > 440 pg/mL Cardiac death uChi Sq.= 6.66 aChi Sq. = 4.45 

Ishii232003 Japan 

n:100 Age: 68 y 

Hospitalized for worsening HF NYHA III-IV Mean LVEF 36% in 12% of patients 

BNP(1) > 160 pg/mL Cardiac death uHR = 5.66 aHR = 3.11 

Kyuma30

2004 Japan 

n:158 Age: 64 y 

HF Symptoms NHYA I-IV LVEF NR 

BNP(1) >172 pg/mL 

1) Cardiac death due to pump failure 2) Cardiac mortality 

1) uHR = 1.001  aHR = 1.001 2) uHR = 7.2 

Latini106

2004 Italy 

 n: 4300 Age: NR 

Stable but symptomatic HF NYHA I-IV LVEF < 40% 

BNP(1) 

1) > 97 pg/mL 2) Change >/= 10 pg/mL 

Mortality 

1) uHR = 2.47  aHR = 2.48 2) aHR = 1.012 

Maeda120

2000 Japan 

n:102 Age: 63 y 

Hospitalized for HF NYHA III-IV Mean LVEF 23% 

BNP(1) > 170 pg/mL > 240 pg/mL 

Cardiac death for BNP: 1) baseline 2) 3 m post treatment 3) baseline 4) 3 m post treatment 

1) uChi Sq. = 5.2) uChi Sq. = 403) aChi Sq.= 2.64) aChi Sq. = 29

Maisel1022004 USA 

 n:464 Age: Mean 64 y 

Clinical evaluation NYHA (I-IV) LVEF NR BNP > 100pg/mL 

BNP(2) > 200 pg/mL Mortality aExp(Beta) = 4.

Tsutamoto12

1997 Japan 

n:85 Age: 60 y 

Hospitalized with chronic HF NYHA II-IV LVEF < 45% 

BNP(1) > 73 pg/mL Cardiac mortality 

uChi Sq. = 60.8aChi Sq. = 19.6aHR = 1.003 

Tsutamoto121

1999 Japan 

n:290 Age: 59 y 

Clinical evaluation NYHA I-II LVEF < 45% 

BNP(1) > 56 pg/mL Cardiac mortality 

aHR = 1.004 uChi Sq. = 100.aChi Sq. = 59.2
94 

Table 18. Summary of studies in patients with HF and mortality outcomes: BNP (continued) 

Report N Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Van Beneden1262004 Belgium 

n:117 Age: 67 y in severe HF 

Clinical evaluation NYHA I-IV Mean LVEF Mild /moderate = 29.4% Severe = 20.8% 

BNP(1) Severe HF and BNP > 8,457 pg/mL Mortality in severe HF IRMA uLL Chi S

van der Meer104

2004 Netherlands 

 n:74 Age range: 26-90 y 

European Society for Cardiology criteria NYHA II - IV LVEF NR 

BNP(1) Mean BNP 109.9 pg/mL All cause mortality uHR =1.006 aHR = Not signi

Vrtovec109

2003 New Zealand 

 n:241 Age: 67 y 

Clinical evaluation NYHA III-IV Mean LVEF = 26% BNP >400 pg/mL 

BNP(2) 

i) 400-700 pg/mL ii) 701-1000 pg/mL iii) >1000 pg/mL iv) >1000 pg/mL 

1) All cause mortality 2) Cardiac death 3) Pump failure death 4) Sudden cardiac death 

Unadjusted: 1) i) p = 0.0003, 0.0001, iv) aHR 2) i) p = 0.0004, 0.0003, iv) aHR 3) i) p = 0.0003, 0.0001, iv) aHR 4) All cut points 

Wallén122

1997 Sweden 

n:541 Age: 85 y 

Clinical evaluation and heart volume NYHA NR LVEF NR 

BNP(1) 39.8 -3816.4 pg/mL 

All cause mortality: 1) total population 2) CV disorder 3) no CV disorder 

1) aHR = 1.259 2) aHR = 1.240 3) aHR = 1.382 

Watanabe123

2005 Japan 

 n:417 Age: 64 y 

Framingham criteria NYHA III-IV LVEF < 50% 

BNP(1) > 132 pg/mL BNP and EF < 38% Sudden death aHR = 3.46 

Abbreviations: aChi sq.=adjusted chi square, aHR=adjusted hazards ratio, CCU=cardiac care unit, CV = cardiovascular, ED=emergency department, E

HF=heart failure, IRMA=immunoradiometric assay, LVEF=left ventricular ejection fraction, , , NR=not reported, NYHA=New York Heart Associatio

square, uHR=unadjusted hazards ratio, uHR=unadjusted hazards ratio, uLL = unadjusted log likelihood, uRR=unadjusted risk ratio, y=years. 

** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
95 

Table 19. Summary of studies in patients with HF and mixed outcomes: BNP 

Report N Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Anand110

2003 USA 

n:4300 Age: NR 

Stable, symptomatic HF NHYA I-IV LVEF =/< 40% 

BNP(1) 

1) > 97 pg/mL 2): % change 3rd vs 1st quartile 3) % change 4th vs 1st quartile 

All cause mortality and first morbid event 

1) 2) 3) 

Barcarse48

2004 USA 

n:98 Age: 64 y 

Cardiologist review of medical record (58% HF) Echocardiogram LVEF <= 45% 

BNP(2) > 100 pg/mL 

Cardiac death, readmission and ED visit within 90 days 

NR 

Berger128

2003 Austria 

n:452 Age: 54 y 

Clinical evaluation NYHA I -IV LVEF NR 

BNP(2) > 130 pg/mL 

Death or urgent heart transplantation 1) Mild HF 2 yr 2) Mild HF 3 yr 3) Moderate HF 3 y 4) All Subjects 

1) 2) 3) 4) 

Bertinchant252005 France 

n:63 Age: 54 y 

Acute and chronic Clinical evaluation only NYHA I-IV LVEF < 45% 

BNP(1) > 254 pg/mL Worsening HF and cardiac death uC

aR

Bettencourt111

2002 Portugal 

n:50 Age: 71 y 

Hospitalized with decompensated heart failure Clinical evaluation only NYHA II-IV LVEF NR 

BNP(2) 

1) > 541 pg/mL 2) Increased BNP during hospital stay 3) DIscharge BNP > 321 pg/mL 

Cardiovascular death or hospital re-admission 

1) 2) 3) 

Cheng1192001 USA 

n:72 Age: 68 y 

New-onset HF by Framingham criteria or previously documented HF NYHA III-IV LVEF < 50% 

BNP(2) 

i) Mean admission ii) Mean discharge iii) % change in BNP 

1) Hospital readmission for HF within 30 days 

2) Death or readmission 

1 

 

1  1 2 

 

2  2 

de Groote1012004 France 

n:407 Age: 57 y 

HF patients referred to cardiology department NYHA III in 26% patients LVEF <= 45% 

BNP(1) > 109 pg/mL Cardiac event-free survival aH
96 

Table 19. Summary of studies in patients with HF and mixed outcomes: BNP (continued) 

Report 

N 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Dias115

2001 USA 

n:46 Age: 70 y 

European Society of Cardiology criteria NYHA NR EF > 40% 

BNP(1) NR 

Death or hospitalization from cardiac cause 1) Atrial fibrillation group 2) Sinus rhythm group 

1) 2) 

Hamada124

2005 Japan 

n:52 Age: 64 y 

Chronic HF hospitalized for decompensation Clinical evaluation NYHA III-IV LVEF <40 

BNP(1) 

> 230 pg/mL i) Baseline BNP ii) Baseline BNP/(deceleration time)2 

iii) Discharge BNP iv) Discharge BNP/(deceleration time)2

Re-hospitalization for acute decompensation of HF or cardiac death 

i) ii) iii) iv) 

Harrison114

2002 USA 

n:325 Age: 65 y 

To ED with dyspnea (41% HF) Previous echocardiogram resultsNYHA NR LVEF NR 

BNP(2) i) > 230 pg/mL ii) > 480 pg/mL 1) HF event or HF death 2) Cardiac event or death for HF, ischemia, infarction 1) 

2) 

Horwich108

2003 USA 

n:238 Age: 52 y 

Referred for cardiac transplantation Clinical evaluation only NYHA class III-IV LVEF 0.25 

BNP(2) 

1) BNP < 485 pg/mL and Tropinin I < 0.04 ng/mL 2) BNP < 485 pg/mL and Tropinin I > 0.04 ng/mL 3) BNP > 485 pg/mL and Tropinin I < 0.04 ng/mL 4) BNP > 485 pg/mL and Tropinin I > 0.04 ng/mL 

All cause mortality or urgent cardiac transplantation 

1) 2) 3) 4) 

Hulsmann112

2002 Austria 

n:96 Age: 57 y 

Clinic patients with HF based on LVEF function NYHA I-IV Mean LVEF 26% 

BNP(2) 

NR Mean BNP 2051.7 pg/mL in patients with death or worsening HF 

Death or worsening heart failure aC

Imamura1172001 Japan 

n:171 Age: 63 y 

Clinical evaluation NYHA II-IV LVEF 27% 

BNP(1) > 160 pg/mL Hospitalization and death for worsening HF uR

aR

Ishii129

2002 

n:98 Age: 69 y 

In CCU for worsening HF Echocardiography BNP(1) >440 pg/mL Cardiac or Readmission for worsening chronic HF uC

aC
97 

Table 19. Summary of studies in patients with HF and mixed outcomes: BNP (continued) 

Report 

N 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Japan NYHA mean 3.5 

Mean LVEF = 42% 

or MI 

Ishii232003 Japan 

n:100 Age: 68 y 

Hospitalized for worsening HF Clinical evaluation NYHA III-IV LVEF 36% in 12% of patients 

BNP(1) 

1) 10 fold increase 2) >160 pg/mL with increase in cTnT 3) ) >160 pg/mL 

Cardiac events including death 

1) 2) 3) 

Koglin116

2001 Germany 

n:78 Age: 51 y 

Chronic HF NHYA I-IV LVEF 36% 

BNP(1) i) > 107.5 pg/mL ii) per 100 pg/mL change 1) Changes in limitations of physical activity 2) Clinical event 1 

2 

Latini106

2004 Italy 

n:4300 Age: NR 

Stable but symptomatic HF NYHA I-IV LVEF < 40% 

BNP(1) 1) > 97 pg/mL 2) Change = 10 pg/mL Mortality and morbidity 1) 

2) 

Logeart107

2004 France 

n:223 Age: 70 y 

Framingham criteria NYHA class IV LVEF 34.7 

BNP(2) 

Predischarge: 1) 100 pg/mL increase 2) > 700 pg/mL 3) Mean at 1 month 4) Mean at 6 months 5) >350 pg/mL 6) 50-700 pg/mL 7) >700 pg/mL 8) Mean at 6 months 

Combined death or first readmission for HF 

1) 2) 3) 4) 5) 6) 7) 8) 

Maeda120

2000 Japan 

n:102 Age: 64 y 

Hospitalized with HF Echocardiography NYHA III-IV LVEF 23% 

BNP(1) 

i) Pretreatment ii) 3 months post treatment iii) > 170 pg/mL 

1) Mortality 2) Mortality or cardiac morbidity 

1      2  
98 

Table 19. Summary of studies in patients with HF and mixed outcomes: BNP (continued) 

Report 

N 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Maisel1022004 USA 

n:464 Age: 64 y 

Clinical evaluation only NYHA I-IV LVEF NR BNP > 100pg/mL 

BNP(2) > 200 pg/mL Cardiac mortality or events aE

2.

Sakatani105

2004 Japan 

n:80 Age: 72 y 

Clinical evaluation only Hospitalized HF patients NYHA I-IV LVEF NR 

BNP(1) Mean 402 pg/mL Cardiac death or rehospitalization aO

Tsutsui1132002 Japan 

n:84 Age: 63 y 

HF with DCM or ischemic cardiomyopathy Echocardiogram NYHA II-IV LVEF < 45% 

BNP(1) 

NR Mean 334 pg/mL 

Cardiac death or hospitalization for worsening HF, MI or fatal arrhythmia 

uCaC

Tamura118

2001 Japan 

n:48 Age: 78 y 

First episode of HF Clinical evaluation NYHA I-IV Mean LVEF 38.1% to 49.2% 

BNP(1) Predischarge > 132 pg/mL Cardiac event aH

Tsutamoto121

1999 Japan 

n:290 Age: 59 y 

Early-stage HF NYHA I-II LVEF < 45% 

BNP(1) > 56 pg/mL CV hospitalization or CV mortality uC

aC

Van Beneden1262004 Belgium 

In severe HF group: n:47 Age: 67 y 

Clinical evaluation only NYHA III-IV in severe HF group LVEF severe HF = 20.8% 

BNP(1) NR Mortality uL

Watanabe123

2005 Japan 

n:417 Age: 64 y 

Framingham criteria Clinical evaluation and echocardiography NYHA III-IV LVEF < 50% 

BNP(1) Log BNP >=2.12 and low ejection fraction (<=38%) HF mortality or HF hospitalization aH

Abbreviations: aChi sq.=adjusted Chi square, aex(beta)=adjusted ex(beta), aHR=adjusted hazards ratio, aOR=adjusted odds ratio, aRR=CCU=coronary care unit HF=heart failure, DCM=dilated cardiomyopathy, ED=emergency department, EF=ejection fraction, LVEF=left ventricular eMI=myocardial infarction, NR=not reported, NS=not significant, NYHA=New York Heart Association, uChi sq.=unadjusted Chi square, uHR=unuLL=unadjusted log likelihood, uOR=unadjusted odds ratio, uRR=unadjusted risk ratio, y=years. 
99 

** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
100 

Table 20. Summary of studies in patients with HF and mortality outcomes: NT-proBNP

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Berger125

2005 

Austria 

n:452 

Age: 54 y 

Clinical evaluation 

NYHA I -IV 

LVEF < 35% 

NTproBNP(8) Log N-BNP Pump failure death uC

Gardner134

2003 

Scotland 

n:142 

Age: 50 y 

Advanced HF 

Clinical evaluation

NYHA II-IV 

LVEF < 35% 

NTproBNP(9) >1490 pg/mL 1) All cause mortality (2) All cause mortality or urgent transplantation 1) 

aC2) aC

Hartmann35

2004 

Germany 

n:1048 

Age: 62 y 

Chronic severe HF 

NYHA NR 

Mean LVEF 20.4%

NTproBNP(9) 1) 84.6 pg/mL increase 2) median 2727 pg/mL All cause mortality 1) 

2) 

Hartmann140

2004 

Germany 

n:1011 

Age: 62 y 

Chronic severe HF 

Clinical evaluation

NYHA NR 

Mean LVEF 20.4% 

NTproBNP(9) > 1767 pg/ml 

1) All cause mortality 2) All cause mortality or hospitalization for HF 3) All-cause mortality or protocol specified CV hospitalization 

1) aR2)  3) 

Kirk133

2004 

Denmark 

n:2230 (161 

with HF) 

Age: 78 y 

(with HF) 

European Society 

of Cardiology 

criteria 

NYHA NR 

Mean LVEF 45.3%

NTproBNP(9) ln(NT-proBNP) All cause mortality aO

Richards138

2001 

New Zealand 

n:297 

Age: NR 

Chronic stable HF

Clinical evaluation

NYHA II-IV 

LVEF < 45% 

NTproBNP(6) continuous variable 

1) All cause mortality or worsening HF 2) Admission with acute coronary syndrome 

1) 2) 

Rossig131

2004 

Germany 

n:48 

Age: 57 y 

Clinical evaluation

NYHA II-IV 

LVEF 25% 

NTproBNP(9) 

Baseline Log NT-proBNP per log (pro-BNP) 1) Baseline LogNT-proBNP 2) with NYHA class 3) with serum creatinine: 4) with blood pressure 5) with blood pressure and apoptosis 

All-cause mortality 

1) 2) 3) 4) 5) 

Rothenburger1 32

2004 

Germany 

n:550 

Age: 54 y 

Clinical evaluation 

NYHA II-IV 

Mean LVEF 32% 

NTproBNP(9) > 1000 pg/mL Prediction ability for selection of cardiac transplant uO
101 

Table 20. Summary of studies in patients with HF and mortality outcomes: NT-proBNP. (continued)

Report n Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Stanek41

2001 

Austria 

n:91 

Age: 51 y 

Clinical evaluation

NYHA II-IV 

LVEF < 25% 

NTproBNP(8) Log NT-proBNP Cardiac mortality aC

Taniguchi26

2004 

Japan 

n:71 

Age: 68 y 

Acute 

decompensated HF 

Clinical evaluation 

NYHA I-IV 

LVEF NR 

NTproBNP(9) cardiac decompensation 1.050 pg/ml cardiac events 2,000 pg/ml Sudden death, HF death, rehospitalization for HF, adverse cardiac events NR 

VAN 

BENEDEN126

2004 

Belgium 

n:117 

Age: 64 y 

Clinical evaluation

NYHA I-IV 

Mean LVEF in 

severe HF 20.8% 

NTproBNP(8) continuous variable All cause mortality or urgent heart transplant LL 

Abbreviations: aChi sq.=adjusted Chi square, aHR=adjusted hazards ratio, aOR=adjusted odds ratio, aRR=adjusted risk ratio, CV=cardiovascular, ECHF=heart failure, LL=log likelihood, LVEF=left ventricular ejection fraction, NR=not reported, NS=not significant, NYHA=New York Heart Associa

hazards, uChi sq.=unadjusted Chi square, uHR=unadjusted hazards ratio, uOR=unadjusted odds ratio, uRR=unadjusted risk ratio, y=years. 

** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
102 

Table 21. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Report 

n 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Berger128

2003 

Austria 

n:452 

Age: 54 y 

Clinical evaluation 

NYHA I -IV 

LVEF NR 

NT-proBNP( 8 )

continous variable 

Baseline Log NTproBNP 

Death or urgent heart transplant 

1) Mild HF 2) Moderate HF at 2 y 3) Moderate HF at 3 y 4) All subjects at 1 y 5) All subjects at 2 y 6) All subjects at 3 y 

1) aCh2) aCh3) aCh4) aCh5) aCh6) aCh

Bettencourt139

2004 

Portugal 

n:156 

Age: 73 y 

Decompensated HF 

European Society of 

Cardiology criteria or 

Framingham criteria 

NYHA III-IV 

LVEF NR 

NT-proBNP(9)

i) Baseline per 1000 pg/mL increase ii) Discharge per 1000 pg/mL increase iii Decrease > 30% iv) Decrease > 30% or increase > 30% 

1) Death or hospital re-admission

2) Death 

1 i) uH1 ii) uH1 iii) uaHR = 1 iv) uaHR = 2 iii) aiv)aHR 

Fisher136

2003 

UK 

n:87 

Age: 75 y 

Hospitalized for HF 

Clinical evaluation 

NYHA II-IV 

LVEF not reported 

NT-proBNP(9)

Predischarge 

NTproBNP 

> 2994 pg/mL 

1) Death or readmission with HF

2) Death 

1) aO2) aO

Gardner134

2003 

Scotland 

n:142 

Age: 50.4 y 

Advanced HF 

NYHA II-IV 

LVEF < 35% 

NT-proBNP(9) >1490 pg/mL 

1) All cause mortality 

2) All cause mortality or urgent 

transplantation 

1) uOaChi S2) uOaChi S
103 

Table 21. Summary of studies in patients with HF and mixed outcomes: NT-proBNP (continued) 

Report 

n 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Gwechenberg

er103

2004 

Austria 

n:100 

Age: 51 y 

Stable HF 

Clinical examination

NYHA II-IV 

LVEF <=25% 

NT-proBNP(8)

NR 

LogNT-proBNP Worsening HF uChi S

aChi S

Hartmann140

2004 

Germany 

n:1011 

Age: 62.7 y 

Chronic severe HF 

Clinical evaluation 

NYHA NR 

Mean LVEF 20.4% 

NT-proBNP(9) > 1767 pg/mL 

1) All cause mortality 

2) Death or hospitalized for HF 

3) Death or hospitalized for CV 

as specified in protocol 

1) uRR aRR = 2) uRR aRR = 3) uRR 

Hartmann35

2004 

Germany 

n:1048 

Age: 62 y 

Chronic severe HF 

NYHA NR 

Clinical evaluation 

Mean LVEF 20.4% 

NT-proBNP(9)

NR 

specified as above 

and below median

(1) all cause mortality (2) all cause mortality or hospitalization for HF (3) all cause mortality or CV hospitalisation (4) all cause mortality or hospitalisation for any reason 

1) RR 2) RR 3) RR 4) RR 

Hulsmann112

2002 

Austria 

n:96 

Age: 57 y 

Documented HF 

NYHA I-III 

Mean LVEF 26 

NT-proBNP(8) continuous variable Death or worsening HF aChi 

O'Brien135

2003 

UK 

n:96 

Age: 74 y 

In CCU 

Clinical evaluation. 

Killip class II-IV 

LVEF NR 

NT-proBNP(7)

continuous variable

1) Baseline NTproBNP 

2) Predischarge 

NT-proBNP 

Combined endpoint of death, HF 

readmission, and worsening HF

1) aO2) aO

Van 

Beneden126

2004 

Belgium 

For severe HF 

group: 

n:47 

Age: 67 y 

Clinical evaluation 

NYHA III-IV in 

severe HF group 

LVEF severe HF = 

20.8% 

NT-proBNP(8)

For severe HF: NBNP 

12,863 pg/mL 

Mortality uLL = 
104 

Table 21. Summary of studies in patients with HF and mixed outcomes: NT-proBNP (continued) 

Report 

n 

Age** Diagnosis Method^ Cut point (pg/mL) Outcome 

Zugck137

2002 

Germany 

n:408 

Age: 55 y 

Chronic HF 

Clinical evaluation 

NYHA I-IV 

LVEF < 45% 

NT-proBNP(7) continuous variable Cardiac death or hospital admission for worsening HF uChi S

aChi S

Abbreviations: aChi sq.=adjusted Chi square, aHR=adjusted hazards ratio, aRR=adjusted risk ratio, aOR=adjusted odds ratio, CCU=cardiac care unit, 

HF=heart failure, LVEF=left ventricular ejection fraction, NR=not reported, NS=not significant, NYHA=New York Heart Association, uChi sq.=una

uHR=unadjusted hazards ratio, uLL=unadjusted log likelihood, uOR=unadjusted odds ratio, uRR=unadjusted risk ratio, y=years. 

** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
105 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population. 

Report 

n 

Age** 

% Male 

Study 

population Reference Standard 

Prevalence

% 

Index test^ 

Index cut 

point 

(pg/mL) 

Sens 

% 

Unknown LVD 29 BNP(2) 20 79 Only systolic dysfunction 13 BNP(2) 20 80 Only diastolic dysfunction 38 BNP(2) 20 75 

Atisha142

2004 

USA 

202 

65 y 

96% 

VA hospital 

admission with 

heart disease 

symptoms 

Systolic and diastolic dysfunction 5 BNP(2) 20 100 

Sys. Dys., EF< 55% 16 BNP(2) >100 38 Sys. Dys.,EF< 55% for age < 65 y NR BNP(2) NR NR Sys. Dys.,EF< 55% for age 65 to 75 y NR BNP(2) NR NR Sys. Dys.,EF< 55% for age >75 y NR BNP(2) NR NR Diastolic dominant pulmonary vein flow with EF >55% 13 BNP(2) >100 55 Diastolic dominant pulmonary vein flow with EF >55% for age < 65 y NR BNP(2) NR NR Diastolic dominant pulmonary vein flow with EF >55% for age 65-75 y NR BNP(2) NR NR Diastolic dominant pulmonary vein flow with EF >55% for age >75 y NR BNP(2) NR NR Sys. Dys., EF< 45% NR BNP(2) >100 65 Sys. Dys., EF< 55% 16 BNP(2) >30 60 Diastolic dominant pulmonary vein flow with EF >55% 13 BNP(2) >30 90 

BibbinsDomingo1 43

2003 

USA 

293 

69 y 

92% 

Stable coronary 

disease with no 

HF 

Sys. Dys., EF< 45% NR BNP(2) >30 76 
106 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population (continued). 

Report 

n 

Age** 

% Male 

Study 

populatio

n 

Reference Standard Prevalence % Index test^ Index cut point (pg/mL) Sens % 

LVEF < 50 % 11.5 NT- proBNP(7) 351 70 LVEF < 45 % 8.6 NT- proBNP(7) 366 74 LVEF < 40 % 5.6 NT- proBNP(7) 414 76 LVEF < 35 % 3.1 NT- proBNP(7) 850 76 ESC criteria for HF and LVEF < 50 % 7.3 NT- proBNP(7) 616 65 ESC criteria for HF and LVEF < 40 % 1.9 NT- proBNP(7) 902 92 ESC criteria for HF and LVEF < 50 % , Age > 70 y 12.2 NT- proBNP(7) 902 64 ESC criteria for HF and LVEF < 40 %, Age > 70 y 3.7 NT- proBNP(7) 1937 91 ESC criteria for HF and LVEF < 50 %, High risk 

medical history 13.8 NT- proBNP(7) 615 68 

Groenning 145

2004 

Denmark 

672 

50 -90 y 

43% 

Recruited 

from 

General 

Practitione

rs 

ESC criteria for HF and LVEF < 40 %, High risk 

medical history 3.7 NT- proBNP(7) 902 89 

LVEF < 40% 6.9 BNP(1) >73l 79 LVEF < 40% 6.9 BNP(1) >28 93 

Hedberg14 1

2004 

Sweden 

407 

75 y 

49.6% 

Random 

sample of 

75 year 

olds LVEF < 40% in pop with major ECG abnormalities NR BNP(1) NR 96 

Redfield5 2042 Random EF ≤ 40% BNP(2) 25.9 62 
107 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population (continued). 

Report 

n 

Age** 

% Male 

Study 

populatio

n 

Reference Standard Prevalence % Index test^ Index cut point (pg/mL) Sens % 

Sys. Dys. in population 1.1 BNP(2) 54.5 90 Sys. Dys., EF ≤ 40% in >65 y 2.0 BNP(2) 75.3 80 Sys. Dys., EF ≤ 40% in men 1.9 BNP(2) 54.5 88 Sys. Dys., EF ≤ 40% in women 0.3 BNP(2) 98.5 67 Sys. Dys., EF ≤ 40% in high-risk men 5.3 BNP(2) 66.3 85 Sys. Dys., EF ≤ 40% in high-risk women 0.6 BNP(2) 128.8 50 Sys. Dys., EF ≤ 40% in population 1.1 BNP(2) NR* 65 Sys. Dys., EF ≤ 40% in >65 y 2.0 BNP(2) NR* 67 Sys. Dys. in men 1.9 BNP(2) NR* 71 Sys. Dys., EF ≤ 40% in women 0.3 BNP(2) NR* 33 Sys. Dys., EF ≤ 40% in high-risk men 5.3 BNP(2) NR* 80 Sys. Dys., EF ≤ 40% in high-risk women 0.6 BNP(2) NR* 0 Dia. Dys. in population 6.9 BNP(2) 36.4 75 Dia. Dys. in > 65 y 12.3 BNP(2) 58.0 67 Dia. Dys. in men 6.7 BNP(2) 20.6 81 Dia. Dys. in women 7.1 BNP(2) 53.1 71 Dia. Dys. in high-risk men 15.9 BNP(2) 113.6 52 Dia. Dys. in high-risk women 17.5 BNP(2) 124.3 41 Mod to sev Dia. Dys. in population 6.9 BNP(2) 36.4 75 Mod to sev Dia. Dys., EF ≤ 40% in >65 y 12.3 BNP(2) 58.0 67 Mod to sev Dia. Dys., EF ≤ 40% in men 6.7 BNP(2) 20.6 81 Mod to sev Dia. Dys., EF ≤ 40% in women 7.1 BNP(2) 53.1 71 Mod to sev Dia. Dys., EF ≤ 40% in high-risk men 15.9 BNP(2) 113.6 52 Mod to sev Dia Dys, EF ≤ 40% in high-risk women 17.5 BNP(2) 124.3 41 

2004 

USA 

62 y 

48% 

sample of 

residents 

older than 

44 y 

Mod to sev Dia. Dys., EF ≤ 40% population 6.9 BNP(2) NR* 41 
108 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population (continued). 

Report 

n 

Age** 

% Male 

Study 

populatio

n 

Reference Standard Prevalence % Index test^ Index cut point (pg/mL) Sens % 

Mod to sev Dia. Dys., EF ≤ 40% in >65 y 12.3 BNP(2) NR* 47 Mod to sev Dia. Dys. in men 6.7 BNP(2) NR* 44 Mod to sev Dia. Dys., EF ≤ 40% in women 7.1 BNP(2) NR* 39 Mod to sev Dia. Dys., EF ≤ 40% in high-risk men 15.9 BNP(2) NR* 58 Mod to sev Dia Dys, EF ≤ 40% in high-risk women 17.5 BNP(2) NR* 56 All subjects male, Elevated LV mass 76 BNP(1) NR NR All subjects male, Any LVSD NR BNP(1) NR NR All subjects male, Moderate to severe LVSD NR BNP(1) NR NR All subjects female, Elevated LV mass 84 BNP(1) NR NR All subjects female, Any LVSD NR BNP(1) NR NR All subjects female, Moderate to severe LVSD NR BNP(1) NR NR Age >= 60 y male, Elevated LV mass 69 BNP(1) NR NR Age >= 60 y male, Any LVSD NR BNP(1) NR NR Age >= 60 y male, Mod to sev LVSD NR BNP(1) NR NR Age >= 60 y female, Elevated LV mass 80 BNP(1) NR NR Age >= 60 y female, Any LVSD NR BNP(1) NR NR Age >= 60 y female, Mod to sev LVSD NR BNP(1) NR NR Hypertensive subjects male, Elevated LV mass 73 BNP(1) NR NR Hypertensive subjects male, Any LVSD NR BNP(1) NR NR Hypertensive subjects male, Mod to sev LVSD NR BNP(1) NR NR Hypertensive subjects female, Elevated LV mass 80 BNP(1) NR NR Hypertensive subjects female, Any LVSD NR BNP(1) NR NR Hypertensive subjects female, Mod to sev LVSD NR BNP(1) NR NR 

Vasan144

2002 

USA 

3177 

(from 

3532) 

58 (+10) 

y 

42% 

Participant

s in 

prospectiv

e cohort 

study with 

no HF 

Prevalent CVD male, Elevated LV mass 70 BNP(1) NR NR 
109 

Table 22. Summary of studies evaluating BNP and NT-proBNP in the general population (continued). 

Report 

n 

Age** 

% Male 

Study 

populatio

n 

Reference Standard Prevalence % Index test^ Index cut point (pg/mL) Sens % 

Prevalent CVD male, Any LVSD NR BNP(1) NR NR Prevalent CVD male, Mod to sev LVSD NR BNP(1) NR NR Prevalent CVD female, elevated LV mass 78 BNP(1) NR NR Prevalent CVD female, Any LVSD NR BNP(1) NR NR Prevalent CVD female, Mod to sev LVSD NR BNP(1) NR NR >=2 high risk features male, Elevated LV mass 70 BNP(1) NR NR >=2 high risk features male, Any LVSD NR BNP(1) NR NR >=2 high risk features male, Mod to sev LVSD NR BNP(1) NR NR >=2 high risk features female, Elevated LV mass 79 BNP(1) NR NR >=2 high risk features female, Any LVSD NR BNP(1) NR NR >=2 high risk features female, Mod to sev LVSD NR BNP(1) NR NR 

Abbreviations: AUC=area under the curve, , CVD=cardiovascular disease, Dia Dys=diastolic dysfunction, EF=ejection fraction, ESC=European Socifailure, LV=left ventricular, LVD=left ventricular dysfunction, LVSD=left ventricular systolic dysfunction, LVEF=left ventricular ejection fraction, L

ratio, LR- = negative likelihood ratio, Mod=moderate, NR=not reported, sens=sensitivity, Sev=severe, spec=specificity, Sys Dys=systolic dysfunctionAdministration, y=years * Based on age and sex specific upper normal values ** Mean age if given in report ^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
110 

Table 23. Evidence table for studies using BNP or NT-proBNP to monitor treatment. 

Report Population n Treatment Dosing Time (weeks) Concentration change Variable 

B

Anand110

2003 

Stable symptomatic heart failure patients who were undergoing prescribed heart failure therapy, LVEF <40%, and LVIDd/BSA >= 2.9 cm/m2

4305 

Prescribed heart failure therapy 

 24 

At 4 months patients with the greatest decrease (< 51 pg/mL) or greatest increase (>= 19 pg/mL) has the highest mortality risk. Similar findings were observed at 12 months. 

BNP incrgroup (23 decrease(21 +/-5). 

Fung382003 

5 with ischemic cardiomyopathy and 10 with hypertensive heart disease; treated with furosemide 

24 Metoprolol 

4-week titration period at weekly intervals from 6.25 to 50 mg twice daily. 

52 998 to 406 pg/mL 

At 12 wea significbaseline +/- 2.8 % respectivquestionn3.6 +/- 1.minute wyear the and 1269 LVEF at negativel(r = -0.52p < 0.001

Fung382003 

11 with ischemic cardiomyopathy and 16 with hypertensive heart disease; all but one treated with furosemide 

49 Metoprolol or Carvedilol as above 52 913 to 381 pg/mL (p = 0.003) 

LVEF - B0.047), 10.001), 50.001) 

Fung382003 

6 with ischemic cardiomyopathy and 6 with hypertensive heart disease; all but one treated with furosemide 

25 Carvedilol 

4-week titration period at weekly intervals from 3.125 to 25 mg twice daily. 

52 846 to 381 pg/mL 

LVEF at negativel(r = -0.52p < 0.001
111 

Table 23. Evidence table for studies using BNP or NT-proBNP to monitor treatment. (continued) 

Report Population n Treatment Dosing Time (weeks) Concentration change Variable 

B

Kawai31

2001 

Patients with idiopathic dilated cardiomyopathy but no underlying systemic hypertension, manifest vulvular disease, congentital malformation of the heart and vessels, and intrinsic pulmonary or renal disease 

21 Carvedilol titrated to full dosage 24 

A significant difference from baseline at 6 months (69 +/-92 pg/mL vs 127 +/-113 pg/mL, p <0.0166), but not at 2 months (100 +/- 111 pg/mL). P value over time = 0.014 and 0.18 vs control. 

Pooled drespectiv0.0001), (0.31, 0.00.0007), LVESD (0.6, <0.0(0.66, <0also calcmonths a

Murdoch149

1999 

Well-compensated chronic heart failure patients receiving stable treatment included ACEi for at least 3 months prior to the study 

20 

ACEi (captopril = 4, enalapril = 9, lisinopril = 3,trandolapril = 2, perinodopril = 1, quinapril = 1) Losartan in some cases. 

BNP group - higher ACEi dosage if BNP not below 50 pg/mL at clinic visit. Losartan at 25 to 50 mg if BNP remained elevated despite maximum ACEi dosage. Clinical 

group - increased dosing as per suggested by clinical trial data. Clinician at discretion to add Losartan.

8 

BNP vs c(p = 0.17mean PAoutput (p = 0.50), sresistancvascular heart rate pressure 

Shiga372003 

Compensated heart failure - NYHA class II to IV; treatead with diuretics, ACEi or AT1-blocker 

46 Amiodarone 

Loading dose: 400 mg daily for 14 days or 800 mg daily for 7 days. Maintenance dosage: 100 to 200 mg daily (mean dose +/-SE 168 +/- 6 mg daily at month 6). 

24 303 +/- 48 to 180 +/- 30 pg/mL (p<0.001) 

Mean heventricula= 0.315), 0.243), cthyroid st0.189) Follow-up the survivfor BNP < BNP > 10
112 

Table 23. Evidence table for studies using BNP or NT-proBNP to monitor treatment. (continued) 

Report Population n Treatment Dosing Time (weeks) Concentration change Variable 

B

Stanek41

2001 

Heart failure patients with LVEF <25% and treated with digitalis and enalapril 

91 Atenolol 

50 to 100 mg/day, mean dosage 89 mg/day or placebo 

24 

At 6, 12 and 24 months the change from baseline was p < 0.01 for all. 

Mortality with basepmol/L cobelow thi0.0004). 

Troughton148

2000 

Impaired left-ventricular systolic dysfunction (LVEF <40%), NYHA II - IV and treated with ACE inhibitors, loop diuretic with or without digoxin 

69 

Enalapril, furosemide, digoxin, spironolactone, metolazone, isorbide mononitrate, felodipine 

BNP group - titration with medications to achieve an NTproBNP concentration < 1691 pg/L. Clinical group - titration with 

medications according to an objective score (heart failure score <2).

38 

BNP group mean change 668 pg/L below baseline by 6 months compared to only 25 pg/L in the clinical group. 

BNP vs cmonths (pressure creatinine 0.32), clin(decreastest, qualof the stuevents in to the clin0.7 vs 0.2 Events indeath, hooutpatien

Yoshizawa44

2004 

NYHA class II to IV, LVEF <40%. Excluded patients with baseline heart rate <50 bpm, systolic BP <90 mm Hg, contradictions to betablockers such as obstructive pulmonary disease and renal dysfunction. Therapy included digitalis glycosides (59%), diuretics (77%), and ACE inhibitors or angiotensin receptor antagonists (95%). 

78 Metoprolol 

Metoprolol (n = - 5 mg/day titrated to target dose of 80 mg/day over 12 weeks. Carvedilol (n = 58) - 2.5 mg/day titrated to target dose of 20 mg/day over 12 weeks. 

4 

(early 

phase) 16 

to 48 (late 

phase) 

No change from baseline (290 +/- 384 pg/mL) at the early phase (234 +/-284 pg/mL) or late phase (177 +/-256 pg/mL) for either beta-blocker. However, patients in the 0 to 25th percentile in the early phase had increased levels (n = 22, 51 +/-37 vs 37 +/-17 pg/mL, p < 0.05) whereas patients in the 75th to 100th percentile had decreased levels (n = 21, 562 +/-385 vs 815 +/-454 pg/mL, p < 0.05). 

BNP in nshowed a both the 0.05), buin the isc

Abbreviations: BP=blood pressure, LVEDD=left ventricular ejection LVEF=left ventricular ejection fraction, LVESD=left ventricular end-systolic d

York Heart Association, PAP=pulmonary artery pressure, PAWP=pulmonary artery wedge pressure, RAP=right atrial pressure, SE=standard error. 
113

Chapter 4: Discussion 

Question 1: What Are the Determinants of Both BNP and NTproBNP? 

 Factors associated with changes in B-type natriuretic levels were extracted from all studies 

used to answer Questions 2, 3 and 4 of this review. The identification of determinants is 

important, as they are potential confounders to accurate diagnosis of heart failure (HF), 

prediction of cardiac events, and the ability to monitor therapy in patients with HF. The 

identification of determinants is also useful for the purpose of defining reference intervals and 

for interpreting unanticipated, patient specific, BNP or NT-proBNP values. Furthermore, they 

can be used to gain an increased understanding of the physiology and pathophysiology of BNP 

and NT-proBNP as well as to identify aspects which have been well investigated and to identify 

gaps where further research is needed. It is also important, for effective design and interpretation 

of future research, to know what the determinants for BNP and NT-proBNP are. 

The determinants found in this systematic review were clinical or biological parameters such 

as age, gender, diseases, and treatments. There were no data available on factors that affect the 

analytical test method for BNP or NT-proBNP. Much of this data is not published in journals, 

but is instead largely in the grey literature, most commonly in the literature supplied by the 

diagnostic company when applying for FDA approval to market their test method. One recent 

review, however, does present an overview of analytical determinants.198

The impact of age and gender on B-type natriuretic peptide levels has been reported 

extensively in the literature and this systematic review has clearly shown that increasing age is 

positively associated with increased B-type natriuretic peptide levels. In the populations 

evaluated in this systematic review, the female gender did not consistently show higher levels of 

B-type natriuretic peptides compared to the male gender. In healthy populations B-type 

natriuretic concentrations are significantly higher in females compared to males, but it appears 

that these differences are attenuated with disease processes, at least in the studies included for 

this systematic review. 

The relationships of the B-type natriuretic peptides with various diseases and measures are 

listed in Table 3. For the most part, all cardiac diseases showed an increase in B-type natriuretic 

peptides. Stable angina and ischemic heart disease showed a positive effect only when other 

cardiovascular risk factors were also present. Furthermore, B-type natriuretic peptides were 

positively associated with many biochemical markers of inflammation such as C-reactive protein 

(CRP), interleukin-6, ST2 soluble receptor and osteoprotegerin, supporting their role as potential 

risk markers for cardiovascular disease (CVD). The most frequently reported non-cardiac 

determinants were non-cardiac dyspnea, hypertension and diabetes. The B-type natriuretic 

peptides were elevated in both non-cardiac dyspnea and hypertension. For diabetes, three of four 

studies reported no association. However, other diabetes related determinants including 

creatinine levels, decrease in glomerular filtration rate, and nephropathy, were positively 

associated with B-type natriuretic peptides. From this it is rational to extrapolate that B-type 

natriuretic peptides could be a marker of diabetes complications. 
114

There were few studies5,8-10,14,34,199 in this systematic review that looked at the independent 

association of B-type natriuretic peptide with any determinant using multivariate models. Of 

these studies, only two included HF severity using left ventricular ejection fraction (LVEF) as a 

continuous variable in the model.5,11 There were three determinants (age, gender and creatinine 

level) which appeared more than twice among the studies that performed multivariate analysis. 

All studies included age as a variable and all except one study found age to be independently 

associated with B-type natriuretic peptides. The reason this one study34 did not find this 

association is probably due to its very small sample size (n = 36). There was also no association 

with creatinine levels seen in this study. However, the level of creatinine was positively and 

independently associated with BNP9

 and NT-proBNP8 in two other studies. Female gender was 

associated with increased BNP5 and NT-proBNP8,14 in three studies, and no increase in one study 

that contained a high proportion of females (79 percent).9

 

Even though determinants, such as age, gender and creatinine levels, may be found to be 

independently associated with B-type natriuretic peptide levels, it is not clear how clinically 

important it would be to adjust for them. The identification of determinants found in this 

systematic review does not imply either their causal association with, or their importance in 

regards to, altered BNP or NT-proBNP concentration. Rather, they offer a basis towards a better 

understanding of variance in BNP and NT-proBNP levels. 

These determinants reflect what is reported in studies central to our clinical research 

questions but may have different effects in other studies. The magnitude or consistency of the 

determinant’s association with the B-type natriuretic peptides will dictate how it is used. In 

addition, their use may vary depending on the situation in which they are used, from 

epidemiological studies and large clinical cohorts to specific clinical settings and individual 

patient care. Consideration of these variables is made in the context of the individual’s disease 

state and treatment. A statistically significant effect may not translate to a clinically significant 

effect. Also, the populations where an effect has been shown may range from a small 

homogenous population to a large heterogeneous population and that effect may not be 

applicable to an individual. Specifically, in relation to this systematic review, these determinants 

may be used to explain variation among studies. 

Question 2a: What Are the Clinical Performance 

Characteristics of Both BNP and NT-proBNP Measurement in 

Patients with Symptoms Suggestive of HF or with Known HF 

in the Four Clinical Settings of Emergency Department, 

Specialized Clinic or Outpatient, Primary Care, and Long 

Term Care? 

One objective of this systematic review was to focus on studies that enrolled patients with 

clinical symptoms of HF as the presenting complaint regardless of comorbidity in order to 

generate a clinically applicable summary with maximum generalizability. With the exception of 

HF referred to specialized clinics, this review excluded all studies in which a diagnosis of any 

disease or medical condition (e.g., heart transplant) was an inclusion criterion for enrolment. To 

this end, and compared to previous systematic reviews, we screened a greater number of primary 
115

studies and evaluated the diagnostic performance of BNP and NT-proBNP as a function of 

clinical setting. 

The diagnosis of HF is challenging. It is typically based on the clinical history, physical 

examination, electrocardiogram (ECG), chest x-ray, and assessment of left ventricular function.54

Diagnosis by consensus decisions of cardiologists based on interpretation of these clinical data 

will reveal that many patients with symptoms of HF do not have the disease.200 This can be 

explained in part by the fact that some of these patients may have comorbidities that could 

account for their symptoms.173 Conversely, not all patients with left ventricular dysfunction 

(LVD) have symptomatic HF.201-203 The concern is that cardiac function can be interpreted as 

normal in the presence of a normal systolic function if an assessment of diastolic function is not 

also included. Diagnostic imaging methods best suited for evaluation of diastolic function 

(doppler echocardiography, M-mode echocardiography, multiple gated acquisition scan, cardiac 

catheterization) were not used in the majority of studies evaluated in this review. Diagnostic 

tests other than those specified above were used as reference standards and this is problematic. 

Therefore, the misinterpretation of normal systolic function as indicating the absence of HF 

could result in misclassification by the reference test. Given that the levels of B-type natriuretic 

peptide markers are reported to rise in the presence of myocardial wall stress resulting from 

systolic and/or diastolic dysfunction, this misclassification can result in a false negative 

interpretation of the corresponding B-type natriuretic peptide measurement. 

The high pooled diagnostic odds ratios (DORs) and high sensitivities reported in this review 

indicate that these B-type natriuretic peptide markers have diagnostic value. However, there is 

no consensus on the optimum cut point for clinical application. Doust et al.173 found, as we did 

in this review, that there is variation in the estimates of diagnostic accuracy between studies, and 

that this does not seem to be accounted for by differences in the clinical setting or the type of test 

used. This is explained, in part, by misclassification bias, which can underestimate the 

diagnostic accuracy of the B-type natriuretic peptides and subsequently yield a falsely elevated 

cut point. 

 Raymond et al.204 also reported problems in determining a cut point for the diagnosis of HF. 

They concluded that in the determination and application of a cut point, an adjustment should be 

made at least for the independent effects of age and gender. Hence, the changes in BNP and NTproBNP are not specific to HF; a conclusion that has also been supported by the results of 

Question 1 in this review. This means that elevated peptide markers do not confirm HF as a 

cause of the patient’s symptoms. These markers, however, do appear to be sensitive to HF. 

In summary, patients who present with symptoms of HF who are found to have a normal 

BNP or NT-proBNP are highly unlikely to have HF as a cause of their symptoms. These patients 

require further investigation of their condition to determine the reason for increased B-type 

natriuretic peptide levels. 

Question 2ai: Emergency Department 

With regards to emergency department (ED) settings, the findings are consistent with 

suggesting that BNP and NT-proBNP tests may be useful in ruling out cardiac dysfunction. In 

general, all studies enrolled patients with shortness of breath, which is typical of ED settings. 

Although, a variety of different cut points were evaluated, in all studies the sensitivity was 

reported as greater than 90 percent, however specificity varied widely from 27 to 91 percent. A 

similar pattern of high sensitivity and widely ranging specificity was observed for NT-proBNP. 
116

Although a cut point cannot unequivocally rule in HF, according to Doust,173 BNP values less 

than 51.75 pg/ can be used to exclude the disease in patients in whom it is suspected. This is 

lower than most of the cut points reported in this systematic review. There have been fewer 

studies evaluating the diagnostic performance of NT-proBNP than BNP. Januzzi et al.205 report 

an age-independent cut point of NT-proBNP to rule out acute HF of 300 pg/mL (95 percent CI: 

241 to 369) demonstrating a sensitivity of 99 percent, specificity of 60 percent, and a negative 

predictive value of 98 percent. However, their pooled analysis was not based on a systematic 

review, but rather on three selected clinical trials without any specific a priori inclusion criteria. 

Our review revealed that a study by Jose employing a cut point of 200 pg/mL had the highest 

sensitivity (97.2 percent) and DOR (291).53 

In the studies reviewed, there was minimal insight into the diagnostic utility of B-type 

natriuretic peptides in complex cases where there is uncertainty in diagnosis. It is these cases that 

present a greater diagnostic challenge where it would be particularly valuable to have a test that 

could increase the certainty for HF. Based on the findings of our systematic review, the most 

likely use of B-type natriuretic peptides in the ED setting would be to identify which patients 

require further investigation to determine the cause of their symptoms. Patients with normal 

peptide levels will most likely have a condition other than HF as a cause of their symptoms, 

while those with elevated levels will likely need confirmatory testing for the disease.173 One 

study17considered cases with inconclusive BNP values (80 to 300 pg/mL) and found BNP to be a 

poor predictor of the final diagnosis using multivariate regression analysis (OR 1.85, 95 percent 

CI: 0.4 to 7.8, p = 0.4). Overall, the quality of the studies in the ED setting was high. Except for 

the problem with misclassification bias, the literature was very consistent and the external 

validity was good. Future research should ideally include multicentre studies enrolling patients 

with symptoms of HF and employing definitive diagnostic imaging as the objective determinant 

of the presence or absence of the disease. Given large enough study populations, subgroup 

analyses will identify confounding variables and their impact on B-type natriuretic peptide 

levels. 

Question 2aii: Specialized Clinic or Outpatient Setting 

With regards to specialized clinics and outpatient settings, BNP and NT-proBNP levels 

correlate with cardiac function as well as symptoms. However, there are some important 

limitations to all of these studies. They have generally had relatively small sample sizes and 

have exclusively been single centre studies. The wide range of cut points for both BNP and NTproBNP was also apparent in this setting as it was in other settings. It should be recognized that a 

rather select group of patients has been evaluated in these studies. These are patients referred for 

symptoms suggestive of HF or are patients with stable chronic HF. As sensitivity, specificity 

and the AUC for the ROC curves are dependent on the patient population studied, it is difficult to 

generalize these results to the broader population and to those within specialized clinics. A 

single study60 that compared BNP with NT-proBNP in stable HF patients found no difference in 

the performance characteristics of these two markers. 

Based on the limited number of studies in clinical or outpatient settings, the B-type 

natriuretic peptides are not useful to rule in HF. The low specificity of the test precludes it from 

being used in this way. In some situations within specialized clinics the high sensitivity of these 

peptides may be useful in ruling out HF as a cause of the symptoms. In both cases, however, 

supplementary investigations may be required to guide clinical management of the patient. 
117

Measurement of the natriuretic peptides does not reduce the need for these additional 

investigations. Overall, these studies had high internal validity as they scored well on the 

QUADAS items. The results of these studies are very encouraging, but further studies are 

required to better define the role of BNP and NT-proBNP in diagnosing HF in a specialized 

clinic or outpatient setting. 

Question 2aiii: Primary Care 

 With regards to the primary care setting, the findings of this review do not differ from those 

in the ED and clinic settings. One of the dilemmas facing physicians is how to appropriately 

manage patients who present with suspected HF. BNP and NT-proBNP tests are less expensive 

and are probably easier to obtain in primary care situations than echocardiography and thus offer 

the possibility of use as a first line diagnostic test. Echocardiography will be needed in the 

confirmation of the diagnosis and for staging and prognosis. BNP or NT-proBNP measurement 

might aid the physician in distinguishing between those patients who can be safely discharged 

and those who should be sent to specialist clinics or physicians for further work up and 

confirmation. 

Of the few studies included in the meta-analysis, only one study63 stood out as being different 

from the others. In this study, a random sampling of patients over 45 years old was selected 

(using computerized practice registers) from 16 random primary care practices in England. The 

sample was stratified by age and socioeconomic status. Four cohorts were identified: general 

population, patients labelled as having HF (may not be confirmed), patients prescribed diuretics, 

and those at high risk for HF (history of previous myocardial infarction (MI), angina, 

hypertension, or diabetes). The high-risk cohort group from this study was compared to the other 

cohorts which were selected based on a family practitioner’s suspicion that the patient may have 

HF. The data from the high risk cohort shows a lower prevalence of HF and poorer diagnostic 

performance of the B-type natriuretic peptides (Figures 3, 4). Furthermore, the large difference in 

the DOR between BNP and NT-proBNP measurements in this study suggests either the cut 

point(s) chosen were not comparable or that the NT-proBNP test has a higher diagnostic 

accuracy. 

Table 24 presents the results of a hypothetical analysis designed to answer who can be safely 

discharged and who should be referred on. Following the example set in the paper by Redfield et 

al.,5

 we calculated the following: (1) the portion of the population that would test positive if BNP 

or NT-proBNP were used as a first line diagnostic test, (2) the portion of those positive tests that 

would subsequently be confirmed as negative, (3) the portion that would test negative and not be 

further followed, and (4) the portion of subjects with a positive outcome that would be missed. 

Two studies using BNP,5,66 three using NT-proBNP,64,68,145 and one using both,63 could be 

analyzed in this way (Table 24). Using this two-step approach would mean that 13 to 63 percent 

of the population would be referred for an ECG. In all cases (except one,64 which used a high 

NT-proBNP cut point of 245 pg/mL), 60 to 90 percent of these positive tests would be 

subsequently confirmed negative by echocardiography. Ten to 40 percent of those with a positive 

B-type natriuretic peptide test result would be confirmed positive by echocardiography. The 

portion of the general primary care population with a false negative result that would be missed 

using this approach is less than 4 percent. Negative likelihood ratios (LR-) (Table 6) ranged from 

0 (highly useful) to 0.27 (marginally useful). These two pieces of information suggest that B-
118

type natriuretic peptides measurement is useful for ruling out HF. Because of the poor specificity 

of the test, a positive result does not necessarily rule in HF. 

One randomized controlled trial (RCT)64 examined the effect of NT-proBNP measurement 

on the diagnosis of HF in a primary care situation. Patients in the study group had their NTproBNP results sent to their general practitioner along with an interpretive comment, whereas 

those in the control group had their NT-proBNP results withheld. The ability of physicians to 

accurately diagnose HF was compared between the two groups. The diagnostic accuracy was 

significantly increased when the NT-proBNP was available to the physician, with the greatest 

improvement being in the ability to rule out HF. They conclude that NT-proBNP measurement 

adds value over and above the current diagnostic strategies available to primary care physicians. 

One paper,206 published after the close of the literature search for this systematic review, 

describes the results of a multicentre trial to assess the diagnostic accuracy of BNP, NT-proBNP 

and ECG in 306 primary care patients referred for investigation of suspected HF. They report a 

high sensitivity for NT-proBNP (0.98 at 125 pg/mL) and a somewhat lower sensitivity for BNP 

(0.87 at 65 pg/mL). Negative likelihood ratios were 0.05 and 0.23 respectively. These authors’ 

conclusions are similar to those in our systematic review, which is that B-type natriuretic 

peptides are useful to rule out HF as a cause of the symptoms, but not useful as a rule in tool. In 

primary care situations, B-type natriuretic peptide measurements may aid in the diagnosis of HF. 

Results below the diagnostic cut point can reliably rule out the diagnosis. Results above the cut 

point identify patients who require additional investigations to determine the cause of their 

symptoms. 

Question 2aiv: Long Term Care Settings 

This review did not find any relevant papers to address this question. Patients in long term 

care settings are likely to be older and have more comorbidities than the general population. This 

places them at higher risk for the development of HF. This is an area that requires further 

investigation to assess the utility of BNP or NT-proBNP as a diagnostic marker of HF. 

Question 2a: All Settings Combined 

The diagnostic ability of BNP and NT-proBNP was examined by setting in Question 2ai 

through 2aiii. Further investigations were performed to assess the diagnostic performance of 

BNP or NT-proBNP, irrespective of the clinical setting. 

In each of the clinical settings, measurement of the B-type natriuretic peptides was shown to 

be of value in the diagnosis of HF. Patients who are found to have a BNP or NT-proBNP below 

the diagnostic cut point are unlikely to have HF as a cause of their symptoms. 

In the ED setting there were enough papers to justify combining them to determine pooled 

estimates of the diagnostic characteristics. This was not the case for either the specialized clinic 

or primary care settings and therefore we combined all studies together. Since there is no 

guideline for pooling studies that present results with single and multiple cut points the choice 

was made to select the lowest one in studies with multiple cut points. The lowest cut point 

corresponds to the highest sensitivity and is therefore the best test characteristic to rule out HF. 

We also examined the special case of BNP using the cut point of 100 (±5) pg/mL. This was the 
119

single most common cut point amongst the studies in this review. It is also the cut point 

suggested by manufacturers of the common commercial assays. 

The meta-analysis indicated the diagnostic parameters remain similar even when results from 

all settings are combined. The pooled sensitivity was high (94 percent for BNP and 92 percent 

for NT-proBNP) and the pooled specificity was low (66 percent for BNP and 65 percent for NTproBNP). In the absence of clearly demonstrated superiority of either BNP or NT-proBNP, the 

choice of analyte will likely depend on factors such as local expertise and availability of 

analytical instruments. 

The largest difference among studies in all settings was seen with specificity. There are 

number of factors that could explain the heterogeneity including test type (BNP or NT-proBNP), 

test method, setting, study population, study design, study sample size, and reference test (from 

LVEF measurement alone to clinical classification with all available patients results). 

Multivariate analysis did not show a difference with respect to study design, sample size or 

reference test. There were too few studies in the subgroups of test type or test method to perform 

a sub-group analysis. 

The determinants for BNP and NT-proBNP were not often considered in the diagnostic 

papers. The effect of determinants such as age, obesity, other diseases (e.g., hypertension, 

diabetes, renal failure) or drugs (e.g., beta blockers, diuretics, angiotensin converting enzyme 

(ACE) inhibitor) on B-type natriuretic levels is important to consider and is the only reason we 

could find that could explain the wide variation in specificity among the studies. 

Further analyses to examine the issue of heterogeneity was possible using six studies that 

used the BNP Biosite test with a cut point of 100 pg/mL (±5 pg/mL). The average study sample 

size was 472 (range 163 to 1586). Five of the six studies were cross-sectional in design and one 

was a diagnostic study design. All studies used a clinical diagnosis of HF for the reference test. 

However, even with this high level of homogeneity among the studies there was still a wide 

range in specificities (28 to 94 percent) (Figure 5). The sensitivities were much higher and tighter 

ranging from 90 to 97 percent. The only explanation to account for these diagnostic parameters 

appears to lie in the heterogeneity of the study populations. 

The average age range was 63 to 80 years and the percentage of males ranged from 49 to 94 

percent. All six studies included patients with dyspnea, two studies had no exclusion criteria,7,57

and the other four had various exclusion criteria. Three studies18,55,56 excluded patients with 

cardiac tamponade, MI and trauma. Additional exclusion criteria for these studies were renal 

failure,18 unstable angina,18,55 and acute coronary syndrome (ACS).56 The sixth study17 excluded 

patients with acute MI, trauma, recent surgery and treatments started 2 hours before arrival to the 

ED (mechanical ventilation, diuretics, nitrates, or inotropic agents). Since many of these included 

and excluded parameters are factors that affect the BNP concentration, it is not surprising that 

there is a wide variation in the specificity of the test. 

The specificity of the BNP is higher (76, 86 and 94 percent) 18,55,56 in those studies that 

excluded patients that were very likely to have elevated BNP levels compared to those that did 

not (28, 51 and 59 percent).7,17,57 The false positive (FP) rate in the three studies with the highest 

specificity ranged from 3.6 to 12.7 percent compared to a much higher FP rate (20.2 to 32.2 

percent) in the three studies with the lowest specificity. If further exclusion criteria are employed 

in studies assessing HF in the ED such as chronic obstructive pulmonary disease (COPD) there 

could be a further reduction in the FP rate. 

The number of misclassified patients who would be ruled out with a B-type natriuretic 

peptide test but who would actually have HF is low. The overall mean false negative (FN) rate 
120

for ED studies including BNP and NT-proBNP tests was 1.9 percent (range = 0.7 to 4.6 percent, 

n = 11) using a variety of cut points (10 to 200 pg/mL for BNP and 125 to 1691 pg/mL for NTproBNP). The FN rate is similar even if limited to studies using the Triage BNP method using 

100 (± 5) pg/mL as the cut point (mean = 2.9 percent, range = 1.0 to 4.6 percent, n = 6). Based 

on this data, the FN rate would only be expected to go lower if the patient selection was more 

specific. 

 Question 2b: Does Measurement of BNP or NT-proBNP add 

Independent Diagnostic Information to the Traditional 

Diagnostic Measures of HF in Patients with Suggestive HF? 

We examined the subset of primary papers that performed multivariate logistic regression 

analysis to determine whether or not BNP or NT-proBNP measurement provided independent 

information in the diagnosis of HF. Odds ratios for the B-type natriuretic peptides ranged from 9 

to 220 and were usually as high as, or higher than, other diagnostic variables. The conclusion 

from this analysis is that measurement of the B-type natriuretic peptides does indeed provide 

information independent from the traditional diagnostic measures. 

Secondly, we examined existing systematic reviews of the diagnosis of HF. These reviews 

considered many diagnostic tests for HF, both alone and in combination. The DORs, actual and 

estimated, ranged from 10 to 569 for BNP and 14 to 230 for NT-proBNP. 

These two lines of evidence both point to the conclusion that the measurement of the B-type 

natriuretic peptides is as good as, or better than, the traditional diagnostic measures for ruling out 

cardiac dysfunction. For these purposes, BNP and NT-proBNP appear to be of equivalent value. 

The information provided by the BNP or NT-proBNP tests is independent of that provided by the 

other measures. 

A recent systematic review compared the ECG to BNP and found no difference in diagnostic 

accuracy for LVSD.207 The echocardiogram is a better diagnostic test for HF; however, there 

were no systematic reviews identified which either evaluated the echocardiogram for HF or that 

compared BNP to the echocardiogram. If there is difficulty obtaining an echocardiogram or, if 

reducing costs is an issue, the B-type natriuretic test is a sensitive test to rule out HF. The caveat 

is that there will be FP cases that will need further workup. 

Question 3a: Do BNP or NT-proBNP Levels Predict Cardiac 

Events in Populations at Risk of CAD, with Diagnosed CAD 

and HF? 

Across the three different cardiac groups evaluated for Question 3a, both BNP and NTproBNP have predictive value with respect to the outcomes of mortality or composite cardiac 

endpoints. The discussion is summarized according to each of these cardiac groups. In general, 

there were fewer studies evaluating NT-proBNP than BNP and even less comparing both these. 
121

Question 3ai: At Risk of CAD 

There were 12 studies that examined whether BNP or NT-proBNP had prognostic value for 

mortality or the occurrence of cardiac events in persons with risk factors for coronary artery 

disease (CAD). The 12 studies differed from one another in terms of the age and gender of the 

participants, the methods of diagnosing risk factors for CAD, the length of follow up, and the 

outcomes. 

Despite these differences, the results of the multiple regression analyses consistently showed 

that the level of BNP or NT-proBNP was positively associated with the outcome, which was 

usually mortality. The adjusted measures of association in cases where BNP or NT-proBNP was 

treated as categorical were in the relatively tight range of 1.10 to 5.40. Although point estimates 

of the measures of association appeared to be larger for NT-proBNP than for BNP, the 

heterogeneity of the studies allowed for only tenuous comparisons between the two forms of 

peptide. There was no firm evidence to suggest that NT-proBNP was a better prognostic marker 

of mortality or cardiac events than BNP. Due to study heterogeneity, a meta-analysis was not 

conducted to summarize the data. 

In conclusion, the overall consistency of the studies’ results suggests that BNP and NTproBNP do have prognostic value for persons who present with risk factors for CAD. This 

agrees with the conclusion of Doust et al.163 Future research should compare the relative merits 

of BNP and NT-proBNP, as well as focus on how this prognostic information can be applied for 

patient care. 

Question 3aii: With Diagnosed CAD 

Overall, the 38 studies evaluating CAD patients varied from one another with respect to the 

age and gender of participants, sample size, length of follow up, and outcomes. Despite the 

heterogeneity, consistent positive associations were found between the level of BNP or NTproBNP and the outcome of interest (mortality or otherwise). This suggests that BNP and NTproBNP do have some predictive value with respect to these outcomes. However, given the 

diversity of the studies – a fact that precluded the use of a meta-analysis to summarize the data 

and the potential for selection or information bias, a single, global predictive effect for either 

peptide cannot be estimated from the available data. 

If BNP and NT-proBNP are taken separately, then the approximate general effects appear to 

be in the range of an odds or hazard ratio of 2.00 to 3.00 for BNP and 1.50 to 3.00 for NTproBNP (excluding studies with extreme results3,79,84). However, in the case of both peptides, 

the small number of studies does not allow for a determination of whether outcomes are 

predicted differently in persons with or without prior cardiac related surgery. Nor can a 

judgment be made about whether one of the peptides is a better predictor of mortality or nonfatal outcomes. In fact, there is no evidence at this time to suggest that BNP or NT-proBNP are 

different from one another in predicting outcomes such as mortality or re-infarction in persons 

with CAD. 
122

Question 3aiii: With Diagnosed HF 

The majority of the 38 studies evaluated in this review found baseline BNP levels to be an 

independent predictor of mortality outcomes across various cut points. When calculated, the 

adjusted HR varied from a 2.5 to a 7.2 fold increase relative to those subjects with lower BNP 

levels. Similarly, baseline BNP values were independent predictors of composite outcomes with 

HR estimates varing from 1.7 to 3.2. Some studies compared baseline and predischarge BNP 

levels and the findings would suggest differences in the ability to predict subsequent mortality; 

more research is required to establish the relative contribution between these two measurements 

of BNP. Several studies evaluated the combined use of baseline BNP levels with other markers 

of cardiac dysfunction (e.g., troponin I and T, percent VO2 max, or EF) as predictors of 

mortality and composite outcomes. The studies evaluating these markers were primarily single 

studies. Although the findings may suggest that the combined markers increase the ability to 

predict future outcomes, more research is needed to establish the relative benefit of these 

combined parameters. Similar to BNP levels, the majority of the 18 studies showed that NTproBNP was a significant independent predictor of death or composite endpoints. The estimates 

of adjusted risk estimates varied from 2.17 to 9.35 for mortality outcomes, and 2.11 to 5.96 for 

cardiac composite outcomes. Similar to BNP, NT-proBNP was shown to be a significant 

predictor of outcomes at various cut points. Overall, the quality of studies was limited 

suggesting the potential for selection and particularly, misclassification bias in the majority of 

studies. 

There was some interest in evaluating the evidence with respect to potential differences in the 

predictive ability of BNP and NT-proBNP for future cardiac events in HF patients. These two 

B-type natriuretic peptides are different molecules with different half-lives and blood 

concentrations and so there are some plausible physiological reasons to consider potential 

differences in performance as a clinical test. As such, there is currently some controversy about 

whether poor kidney function is a confounder for the interpretation of NT-proBNP levels. In 

addition, since the concentration of NT-proBNP is higher than BNP it has the potential to have 

greater (or finer) sensitivity. With respect to prognosis, few studies overall evaluated NTproBNP and even fewer evaluated both types within the same study (n = 6). Within these six 

studies at least one of these B-type natriuretic peptides was a significant predictor of the 

outcome. Only two studies found both BNP and NT-proBNP to be independent predictors of 

mortality and the ability to predict varied with the year of follow up and the timing of the 

measurement. In general, the sample sizes within these studies were small and this may have 

been a factor in the multivariate analyses. No clear pattern emerges to suggest superiority of one 

type of B-type natriuretic peptide relative to the other in these head to head studies. Further 

research aimed at exploring potential differences in the prognostic abilities of these tests is 

required. 

Methodological Caveats with Interpretation of BNP and NT-proBNP as 

Predictors of Future Cardiac Events 

Much of the variation in the strength of BNP and NT-proBNP as a predictor of mortality and 

composite endpoints can be attributed to several key factors including: (1) differing HF 

populations with respect to severity, (2) the study settings, (3) differing BNP cut points, and (4) 
123

differing parameters included in multivariate regression models. Many studies had small sample 

sizes and the outcomes were relatively rare in some severity groups; small sample sizes reduce 

the validity of undertaking multivariate analyses. There were also a number of important 

potential confounders identified in Question 1 of this review that was not controlled for in many 

studies. In particular, most studies did not control for treatment interventions as a confounder. 

For example, ACE inhibitors, which are commonly used in the management of HF patients, are 

suspected to affect HF prognosis. The mechanism of influence of some of these commonly used 

drugs on B-type natriuretic peptide levels is poorly understood in the literature. In general, the 

types of drug therapies and their doses were not controlled for or well described in many studies. 

Similarly, the majority of studies employed prospective cohort research designs and as such 

subjects were not randomized; this decreases confidence that differences between groups within 

these studies did not exist with respect to treatment interventions. Moreover, standard treatment 

varied between studies, which may serve as an important source of heterogeneity. Although 

drugs are an important intervention within this population, other treatments had the potential to 

influence prognosis estimates. For example, several studies performed catheterization 

procedures after admission and evaluation of B-type natriuretic peptide levels and as such, the 

estimates of prognosis would be influenced by these if not controlled for in the analysis. Thus, 

future research should attempt to control for and evaluate the influence of various treatments for 

HF on B-type natriuretic peptide levels. 

Other diseases that HF subjects had were also not consistently controlled for in many studies. 

An overriding aim of most studies was to determine the independent contribution of B-type 

natriuretic peptide levels relative to other hemodynamic markers. Diseases such as diabetes or 

renal dysfunction, which affect both the B-type natriuretic peptide levels and prognosis 

estimates, were not always included in regression models. 

Many studies did not specify the time the B-type natriuretic peptide measurements were 

taken, although the majority did so at some point in the admission process. Whether sampling of 

B-type natriuretic peptide levels occurred before or after acute interventions (in emergency for 

example) was not always specified. For baseline measures of B-type natriuretic peptide, it is not 

known if time dependent changes in B-type natriuretic peptide levels can improve or worsen 

prognosis estimates. In the case of longer-term studies, B-type natriuretic peptide levels may 

change due to worsening HF and influence the strength of the prediction estimate. The ValHeft 

studies106,208 would suggest that the changes in BNP levels are related to prognosis as well. 

Whether baseline measures are sufficient in longer-term studies may be a concern for future 

research in this area. Conversely, it may be difficult to determine the best timing or interval for 

BNP measurement during the clinical course of HF. Consensus on best timing is required, 

particularly for those that maintain that serial measurements improve the ability of BNP or NTproBNP to serve as a predictor of outcomes.36

Diagnosis of HF is another important source of heterogeneity within the studies evaluated in 

this systematic review. Specifically, classification of HF severity (disconnect between clinical 

presentation and hemodynamic function of the heart) is problematic; in part this is due to the 

differing classification systems and reference tests used to establish diagnosis. Accepted 

classification systems currently used to assist in determining the severity and functional status of 

patients serve to broadly classify HF groups and are limited in their precision. Alternative 

classifications have been recently proposed 209 for acute HF syndrome, dividing patients into 

three clinical groups: worsening chronic HF associated with reduced or preserved LVEF, (70 

percent of all admissions); de novo HF, (25 percent of all admissions); and advanced HF (i.e., 
124

refractory to HF) with severe LV systolic dysfunction, associated with a continually worsening 

low output state (5 percent of admissions). These authors acknowledge that it may be difficult to 

classify patients at time of hospital presentation, but may be more useful in classifying patients in 

hospital or post discharge. Similar to problems with admission for HF, variations in discharge 

criteria for HF patients following an acute episode107 are also an important source of 

heterogeneity for the prognosis estimates. Thus, not only is the diagnosis of HF potentially 

inconsistent and inaccurate, but also, the clinical impressions of “sufficient circulatory 

stabilization” may be inconsistent between studies in addition to being inaccurate.107 Greater 

uniformity in criteria for discharge would also assist in understanding the role of BNP levels in 

predicting future outcomes. 

Variation between studies in the types of HF patients or HF subgroups that were excluded 

was also evident and a rationale was frequently not provided. This variation in exclusion criteria 

may have had the potential to influence prognosis. For example, one study124 excluded patients 

with a degree of mitral regurgitation, as this might influence a hemodynamic parameter 

(transmitral flow). The aim of that study was to evaluate how well transmitral flow as well as 

BNP levels predicted mortality; this exclusion likely influenced prognosis and limited 

comparison of results with other studies. Differentiation between subgroups of HF patients (for 

example those with and without preserved systolic function) were not always evaluated within 

studies; demonstrating that there were no differences between subgroups rather than assuming 

this would have been preferred. The problem in defining some subgroups is further compounded 

by the lack of consensus on features to classify patients (for example, the exact percent EF to 

classify those with or without preserved left ventricular systolic function is not currently 

established). 

Unbiased verification of the outcomes was limited in the studies in this review, as most 

assessors were not blinded. Some studies did attempt to have adjudicators of outcome that were 

external to those managing the patients (who were blind to BNP or NT-proBNP levels). 

However, there are some additional challenges in determining some of the outcomes, such as 

sudden death or sudden cardiac events and whether these are “witnessed” or not; consensus on 

what constitutes sudden is not yet established. For subjects who were admitted to acute care 

hospitals some medications would be stopped, new ones introduced, and doses of existing 

maintenance drugs altered as a strategy to manage the acute episode. It has been suggested that 

often patients with the worse conditions receive less therapy because they can tolerate only lower 

doses (for example ACE inhibitor).112 Thus, hospitalized patients, particularly those with 

increasing severity of HF, may have worse outcomes because of the use or contraindications of 

medications (beta blockers versus ACE inhibitor for example) rather than their BNP levels. 

Study setting was also another important source of heterogeneity amongst studies influencing 

the magnitude of predictive estimates of risk. Most patients were either recruited at admission to 

acute care hospital, to ED or outpatient clinics. Those admitted to acute care centers were 

typically in a decompensated state and required rapid and intense interventions to stabilize 

conditions. For those enrolled in studies from outpatient and emergency settings, subjects that 

were subsequently hospitalized (versus those that were not) were not always stratified in the 

analyses; as such differential bias was a concern. It was not always clear if those studies that 

admitted patients with high acuity also had increased severity of HF relative to those patients that 

were not hospitalized or were recruited in outpatient settings or ED. Disentangling the 

relationships between study setting, patient acuity (decompensated versus stable), and severity of 

HF should be an important consideration in future research evaluating prognosis. Exploration of 
125

these factors will account for the heterogeneity of the estimated risk levels and the varying 

thresholds that were observed in this systematic review. 

Many studies in this systematic review were aimed at establishing the relative strength and 

independent contribution of BNP or NT-proBNP levels in predicting the outcomes of interest. 

Moreover, the literature reflected interest in establishing the relative merit of B-type natriuretic 

peptides in combination with other parameters such as troponin T and I, percent VO2max, 

percent lymphocytes and in particular hemodynamic factors. Since HF is complex and HF 

mortality is not only caused by mechanical dysfunction of the heart but also by arrhythmic 

disturbances,116 it is likely that consideration of a wide variety of factors (rather than a single 

hemodynamic parameter) may improve their diagnostic and prognostic ability. 

Question 3b: What Are the Screening Performance 

Characteristics of BNP or NT-proBNP in General 

Asymptomatic Populations? 

In general, a test is considered important to utilize as a screening tool if the burden of 

suffering is high, the test itself is accurate and if early detection of the disease with the test is an 

effective intervention such that mortality/morbidity is reduced for those that were screened. 

In the studies that used BNP as the index test, adequate screening characteristics were not 

observed, and this is true even for the detection of moderate to severe LVSD. It is even less 

accurate for detection of milder degrees of systolic dysfunction, which is more common in the 

general population. BNP is also quite poor for the detection of diastolic dysfunction. One 

requirement for screening is that there is evidence that early detection and intervention reduces 

morbidity and mortality. This evidence cannot be provided for BNP since it fails to detect those 

with milder degrees of systolic dysfunction who are known to be at increased risk. A single study 

using NT-proBNP as the index test with Danish patients recruited from general practices showed 

some promise for select subgroups of patients. There is also a need for more screening studies 

using NT-proBNP before any conclusions can be reached. 

Question 4: Can BNP or NT-proBNP Measurement Be Used 

To Monitor Response to Therapy? 

The findings from these studies suggest that BNP or NT-proBNP may be useful to monitor 

therapy in HF patients. A number of these studies demonstrated a relationship between the 

change in BNP or NT-proBNP and either mortality, morbidity or other clinical parameters such 

as left ventricular function. However, the findings have not been uniform as some of the studies 

do not show a relationship and therefore would not support the suggestion that BNP or NTproBNP could be used to monitor a response to treatment. There are a number of limitations to 

the studies undertaken to date. Aside from one large study of over 4000 patients that was part of 

a clinical trial, the studies have been small with patient enrolment in most cases being less than 

100 individuals. In some cases the studies have been single blinded and some were retrospective 

observational studies. Only two of the studies have altered therapies in response to the change in 

BNP or NT-proBNP and then assessed the outcome in a group treated by natriuretic peptides 

guided therapy compared to usual clinical management. For many of the studies patients were 
126

not being treated with beta blocker therapy, and the effect of this form of therapy on BNP or NTproBNP concentrations has been observed to be variable. Thus the results from these studies 

should be considered as pilot data, they provide the rational for larger studies of hormone-guided 

treatment including the use of beta blocker therapy. These larger studies would more reliably 

answer the question of whether BNP or NT-proBNP measurement can be used to monitor a 

response to therapy for HF patients. Four large studies are ongoing and include the United 

Kingdom Natriuretic Peptide Study (UKNPS), BNP-Assisted Treatment To Lessen Serial 

Cardiovascular Readmissions and Death (BATTLE-SCARRED), Rapid Assessment of Bedside 

BNP in Treatment of Heart Failure (RABBIT) and Suivi du Traitement dans l-innsuffisAnce 

caRdiaque Systolique (STARS) or treatment monitoring of systolic cardiac insufficiency.210 The 

STARS trial in an abstract has reported preliminary findings on 220 patients showing HF events 

(death or hospitalizations) were reduced and delayed in the BNP guided therapy group compared 

to the clinically guided therapy group (p = 0.001, median follow up time was 15 months).211 

Monitoring therapy with BNP or NT-proBNP requires serial measurements. Therefore 

knowledge of their biological variation is needed to know when a change in concentration 

signals a change in the pathophysiological process of the disease. Several studies have looked at 

the within day, day to day and week to week variation of these peptides in healthy individuals 

and patients with stable chronic HF.212-216 The biological variation for individuals (CVI) was 

found to increase with time between measurements for both BNP and NT-proBNP. The withinday day variation was 8.4 percent and 8.6 percent, the day-to-day was 25 percent and 20 percent 

and the week-to-week variation was 44 percent and 35 percent, for BNP and NT-proBNP, 

respectively.212 There is also a slight increase in BNP and NT-proBNP from morning to early 

afternoon (approximately, 10 percent and 20 percent, respectively).212

Other studies looked at only week to week variation but found similar results for healthy 

individuals and patients with stable chronic HF.213,215,216 There was also no difference between 

assay methods (BNP methods included Abbott, Bayer and Biosite while only the Roche method 

was used for NT-proBNP). Ultimately, the parameter that is used to monitor serial measurements 

is the reference change value (RCV) and includes both the analytical variation (CVA) and 

individual variation (CVI). At a 95 percent CI the formula is: RCV = 1.96 x 21/2 (CVA

2

 + 

CVI

2

)

1/2.217 The RCV values calculated for these studies212,213,215,216 showed that the RCV for 

BNP was slightly higher than for NT-proBNP (about 120 percent and 100 percent, respectively), 

but very similar among methods and between healthy and stable HF patients. These large RCV’s 

indicate that a substantial change (about double or half) in serial measurements is required to 

indicate a significant change in concentration. 

There is therefore a need to know if there are relevant and easily modifiable determinants 

that can be reduced such that the CVI, since this is by far the largest component to the RCV 

(CVA’s are less than 25 percent of CVI’s). Standardized protocols (e.g., time of day, exercise, 

fluid intake) or taking replicate samples may help to reduce the RCV. Interestingly, the Melzi 

d’Eril study214 found a much lower CVI using the NT-proBNP method (9.1 percent). Although 

data analysis in this study was done using log-transformed data this would not account for the 

value being almost 75 percent lower. Although collection time could be a factor (since there is 

some diurnal variation), the collection times varied among studies. This observation merits 

further investigation since a lower CVI would make monitoring of B-type natriuretic peptides 

more feasible. Since BNP is a hormone that is highly responsive to hemodynamic change this 

likely explains why biological variation is high. 
127

The reduction in B-type natriuretic peptide concentration is variable among treated HF 

patients and rarely does it fall back into the normal reference range. Most treatment studies in 

this review reported decreases of about 40 percent and none exceeded 80 percent for any 

medication or B-type natriuretic peptide. Considering the large CVI for both BNP (44 percent) 

and NT-proBNP (35 percent) this poses a major limitation for their use in monitoring therapy. 

However, there is good evidence, as described in Question 3 of this review that the risk of 

adverse events increases with higher concentrations of B-type natriuretic peptides. In view of 

this, and the association of decreasing B-type natriuretic peptide concentration with drug therapy, 

B-type natriuretic peptides show promise for use in optimizing therapy in a more objective way 

then querying symptoms. An analogy of B-type natriuretic peptide measurement in HF may be 

that of HbA1c in diabetes. The goal of therapy would be to stabilize the B-type natriuretic 

peptide levels and readjust therapy when significant changes occur. The results of the larger 

trials will provide more information on how the B-type natriuretic peptides can be used and 

possible target levels. 

Limitations to this Systematic Review 

The studies selected for this systematic review are English-language only. The budget and 

timelines available were a limiting factor to obtaining, translating, and abstracting non-English 

trials. In addition, we did not undertake to collect additional unpublished studies or to provide 

results/data that were not presented in the published articles. Although contact with the original 

authors of the studies (to supplement the missing information from the included publications) 

could have compensated for many of the reporting challenges we encountered, this strategy was 

not feasible given the timeline of this systematic review. Our experience at the McMaster 

University Evidence-based Practice Center suggests that the majority of authors do not respond 

in a timely fashion, if at all. Additionally, efforts were not made to contact industry for 

unpublished studies. Not contacting authors of eligible studies for additional data and not 

attempting to locate unpublished studies (either by other authors/ experts or by industry) may 

introduce publication bias in this systematic review. 

Another possible limitation to this systematic review was the restriction of the BNP and NTproBNP methods to a subset; our rationale was to reduce heterogeneity amongst studies to assay. 

Also, we wished to maximize external validity of the findings of this study by selecting 

predominately assays that are widely available for use in clinical laboratories. Lastly, we limited 

the collection of determinants to only studies included for research Questions 2, 3, and 4 due to 

issues of feasibility and relevance. 

Comparison of Test Methods 

Although this systematic review did not address the question of method differences it is 

important to note that differences do exist even among the methods selected for this review. All 

BNP methods included for this systematic review can be traced back to the original BNP method 

produced by Shionogi & Company in 1993. However, they vary in assay design and type of 

antibody (recognition to different epitopes) which results in quantitative measurement 

differences both systematically and randomly. Similarly, differences among the NT-proBNP 

methods include antibodies recognizing different epitopes and assay design. A systematic 
128

difference refers to a consistent difference between methods, independent of test sample or 

concentration, which can be applied without condition. However, there are also random 

differences between methods that cannot be clearly described and can vary with test sample and 

concentration. As a consequence these differences demonstrate a lack of standardization among 

B-type natriuretic peptide methods. 

For example, the Triage BNP assay when compared to the Shionoria assay gives consistently 

higher values and the magnitude of difference increases with both concentration and severity of 

HF.218,219 One study found that at 100 pg/mL using the Triage system, there was a bias of -26 

pg/mL, -10 pg/mL and +7 pg/mL compared to the ADVIA Centaur and Access, and AxSYM 

assays, respectively.220 

Comparisons among NT-proBNP methods show considerably higher values for the Roche 

Diagnostics method versus the Biomedica method.164,218 In a healthy population the difference is 

about 20 fold but decreases with severity of HF.164 Similarly, the Christchurch method also 

produces lower values compared to the Roche Diagnostics method but not of the same 

magnitude (about 20 percent lower).147 The bias between the early generation of the Roche assay 

(manual) and the present assay (Elecsys) is 2.7 fold.221

A review of the issues that need to be addressed regarding standardization have been 

presented in the publication “Quality specifications for B-type natriuretic peptide assays”.198

Consideration of these quality specifications and action to fulfill them will improve the 

comparability between assay methods. This will result in reduced heterogeneity among clinical 

studies especially with respect to cut point. 

Conclusions 

The volume of literature that has been published on B-type natriuretic peptides in such a 

short period of time exceeds that of any other biomarker. The rate of publication is 

unprecedented and as such many publications did not fall within the timeline established for this 

systematic review. However, the number of studies included in this review exceeds those in other 

reviews published on B-type natriuretic peptides as well as including a wider range of questions 

and interpretations. 

In this systematic review we were cognizant that the setting, test type, and method were 

important considerations when evaluating the applicability of B-type natriuretic peptides. 

Therefore, this review, in contrast to the few that have been published so far, established these 

criteria at the outset and groups studies accordingly. 

Determinants 

Numerous determinants have been found to be associated with the B-type natriuretic 

peptides. However, the value of these associations for clinical use is not clear. 

Future recommendations 

• Further studies are required to assess the independent association of B-type natriuretic 

peptides with determinants, particularly as a function of HF severity. 
129

• There is a need to design clinical studies to assess the magnitude of the effect 

determinants have on the diagnostic, prognostic and monitoring treatment roles of the Btype natriuretic peptides. 

Diagnostic Properties for HF 

In all settings (ED, clinics, and primary care) both BNP and NT-proBNP have high 

sensitivity and lower specificity, suggesting these measurements could play a role in ruling out 

cardiac dysfunction. In addition, the measurement of B-type natriuretic peptide levels adds 

independent information to traditional diagnostic measures for ruling out cardiac dysfunction. 

Future recommendations 

• Future research is required to explore the variation in optimum cut points for clinical 

applications. In particular, the potential influence of clinical determinants and population 

subgroups should be evaluated with respect to these optimum cut points for ruling out the 

presence of disease. 

• The reporting of diagnostic metrics requires standardization to enable consistent 

comparisons. Ideally, all studies could report diagnostic characteristics based on a 

common sensitivity, specificity, likelihood value or cut point. 

• Further studies are needed to evaluate the diagnostic value of B-type natriuretic peptides 

in diastolic HF. 

• Large multicentre studies with sufficient sample size are needed to allow for adequate 

multivariate analysis to understand the variables that account for low specificity. 

• Further studies evaluating NT-proBNP in all settings are needed to more clearly establish 

its role for diagnosis. 

• There is a need to evaluate the B-type natriuretic peptides in long term care settings as 

this has been identified as a significant gap in the literature. 

• Future research should increase the number of studies evaluating both NT-proBNP and 

BNP within the same study to compare their relative merits. 

• Further studies are needed that are designed to compare B-type natriuretic peptides with 

other diagnostic tests, particularly echocardiography. 

• Future studies should address the subset of patients who present to the ED with complex 

clinical pictures or atypical clinical findings. 

Prognosis 

BNP and NT-proBNP are consistent independent predictors of mortality and other cardiac 

composite endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed HF. 

There is insufficient evidence to make any conclusion as to the value of B-type natriuretic 

peptides for screening for HF. 

Future recommendations 

• Future research should compare the relative merits of BNP and NT-proBNP, as well as 

focus on whether there are differences in prognostic value for persons with HF. 
130

• Conduct studies in acutely ill HF patients and compare predictive abilities of Bnatriuretic type peptides at baseline relative to predischarge levels. 

• Compare the relative merits of BNP and NT-proBNP, as well as focus on whether there 

are differences in prognostic value for persons with and without prior cardiac surgery in 

populations who are at risk for CAD or who have CAD. 

• Future research should explore the relative merits of B-type natriuretic peptides 

compared to and combined with other markers of cardiac dysfunction to predict future 

outcomes. 

• Large multicentre studies with sufficient sample size are needed to allow for adequate 

multivariate analysis and adjustment of determinants. 

• As more studies become available that can be grouped together, meta-analysis of these 

would be useful to provide information on the overall predictive effect of B-type 

natriuretic peptides for cardiac events. 

Monitoring Treatment 

 

There is insufficient evidence to demonstrate that BNP or NT-proBNP levels show change in 

response to therapies to manage stable chronic HF patients. 

Future recommendations 

• There is a need for large randomized trials to show whether therapy guided by increases 

and decreases in B-type natriuretic peptides affect outcome. 

• Studies should be conducted to assess optimal timing for B-type natriuretic peptide 

testing for serial monitoring in stable chronic HF patients. 

• Further research is needed to investigate if there are determinants of the biological 

variation that can be controlled for.
131

Table 24. Hypothetical analysis using BNP and NT-proBNP as first line tests and demonstrating the potential for reduction in sfor further confirmatory testing for HF* 

Report Population Prevalence % Index test^ % of population with positive test % of positive tests subsequently confirmed negative % of population wit

negative test 

primary care general 

population 1.6 13 90 87 

primary care Clinical Dx 

of HF 20.3 53 72 74 

primary care, on 

diuretics 33.3 39 82 61 

Hobbs63

2004 

primary care, high risk 

HF 7.5 

BNP(1) 

34 89 66 

Redfield5

2004 

> 45 yrs, random 

sample of pop'n 1.9 BNP(2) 24 96 76 

Groenning1452004 

primary care recruit 

from GP, 50 -90 y, 

exclude nursing homes 

5.6 NT-proBNP(7) 35 87 65 

Gustafsson682003 

primary care with 

dyspnea referred for 

echo 

8.9 NT proBNP(9) 63 78 37 

primary care general 

population 1.6 28 95 72 

primary care Clinincal 

Dx of HF 20.3 85 76 15 

primary care, on 

diuretics 33.3 62 88.8 38 

Hobbs63

2004 

primary care, high risk 

HF 7.5 

NT-proBNP(9)

57 86 43 

Wright64

2003 

> 40 y, Present to GP 

with dyspnea/edema 25 NT-proBNP(6) 47 28 53 

Abbreviations: Dx=diagnosis, GP=general practitioner, HF=heart failure, y=years. * Based on Redfield et al.5).

^ Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide. 
133

References 

1. Silver MA, Maisel A, Yancy CW, et al. BNP 

Consensus Panel 2004: A clinical approach for the 

diagnostic, prognostic, screening, treatment monitoring, 

and therapeutic roles of natriuretic peptides in 

cardiovascular diseases. [Review] [153 refs]. Congest 

Heart Fail 2004 Sep;10(5 Suppl 3):1-30. 

2. Rademaker MT, Richards AM. Cardiac 

natriuretic peptides for cardiac health. [Review] [105 refs]. 

Clin Sci (Colch ) 2005 Jan;108(1):23-36. 

3. Grabowski M, Filipiak KJ, Karpinski G, et al. 

Serum B-type natriuretic peptide levels on admission 

predict not only short-term death but also angiographic 

success of procedure in patients with acute ST-elevation 

myocardial infarction treated with primary angioplasty. 

Am Heart J 2004 Oct;148(4):655-62. 

4. Olsen MH, Wachtell K, Tuxen C, et al. Nterminal pro-brain natriuretic peptide predicts 

cardiovascular events in patients with hypertension and left 

ventricular hypertrophy: a LIFE study. J Hypertens 2004 

Aug;22(8):1597-604. 

5. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. 

Plasma brain natriuretic peptide to detect preclinical 

ventricular systolic or diastolic dysfunction: a communitybased study. Circulation 2004 Jun 29;109(25):3176-81. 

6. Weber M, Arnold R, Rau M, et al. Relation of 

N-terminal pro-B-type natriuretic peptide to severity of 

valvular aortic stenosis. Am J Cardiol 2004 Sep 

15;94(6):740-5. 

7. Lainchbury JG, Campbell E, Frampton CM, et al. 

Brain natriuretic peptide and n-terminal brain natriuretic 

peptide in the diagnosis of heart failure in patients with 

acute shortness of breath. J Am Coll Cardiol 2003 Aug 

20;42(4):728-35. 

8. James SK, Lindahl B, Siegbahn A, et al. Nterminal pro-brain natriuretic peptide and other risk 

markers for the separate prediction of mortality and 

subsequent myocardial infarction in patients with unstable 

coronary artery disease: a Global Utilization of Strategies 

To Open occluded arteries (GUSTO)-IV substudy. 

Circulation 2003 Jul 22;108(3):275-81. 

9. Ueda R, Yokouchi M, Suzuki T, et al. Prognostic 

value of high plasma brain natriuretic peptide 

concentrations in very elderly persons. Am J Med 2003 

Mar;114(4):266-70. 

10. Suzuki M, Hamada M, Yamamoto K, et al. Brain 

natriuretic peptide as a risk marker for incident 

hypertensive cardiovascular events. Hypertens Res 2002 

Sep;25(5):669-76. 

11. Bettencourt P, Ferreira A, Dias P, et al. 

Evaluation of brain natriuretic peptide in the diagnosis of 

heart failure. Cardiology 2000;93(1-2):19-25. 

12. Tsutamoto T, Wada A, Maeda K, et al. 

Attenuation of compensation of endogenous cardiac 

natriuretic peptide system in chronic heart failure: 

prognostic role of plasma brain natriuretic peptide 

concentration in patients with chronic symptomatic left 

ventricular dysfunction. Circulation 1997 Jul 

15;96(2):509-16. 

13. Omland T, Aakvaag A, Bonarjee VV, et al. 

Plasma brain natriuretic peptide as an indicator of left 

ventricular systolic function and long-term survival after 

acute myocardial infarction. Comparison with plasma atrial 

natriuretic peptide and N-terminal proatrial natriuretic 

peptide. Circulation 1996 Jun 1;93(11):1963-9. 

14. Lindahl B, Lindback J, Jernberg T, et al. Serial 

analyses of N-terminal pro-B-type natriuretic peptide in 

patients with non-ST-segment elevation acute coronary 

syndromes A Fragmin and fast Revascularisation during 

InStability in coronary artery disease (FRISC)-II substudy. 

J Am Coll Cardiol 2005 Feb 15;45(4):533-41. 

15. Tarnow L, Hildebrandt P, Hansen BV, et al. 

Plasma N-terminal pro-brain natriuretic peptide as an 

independent predictor of mortality in diabetic nephropathy. 

Diabetologia 2005 Jan;48(1):149-55. 

16. Bayes-Genis A, Santalo-Bel M, Zapico-Muniz E, 

et al. N-terminal probrain natriuretic peptide (NT-proBNP) 

in the emergency diagnosis and in-hospital monitoring of 

patients with dyspnoea and ventricular dysfunction. Eur J 

Heart Fail 2004 Mar 15;6(3):301-8. 

17. Logeart D, Saudubray C, Beyne P, et al. 

Comparative value of Doppler echocardiography and Btype natriuretic peptide assay in the etiologic diagnosis of 

acute dyspnea. J Am Coll Cardiol 2002 Nov 

20;40(10):1794-800. 

18. Maisel AS, Krishnaswamy P, Nowak RM, et al. 

Rapid measurement of B-type natriuretic peptide in the 

emergency diagnosis of heart failure.summary for patients 

in J Fam Pract. 2002 Oct;51(10):816; PMID: 12401145]. 

N Engl J Med 2002 Jul 18;347(3):161-7. 

19. Dokainish H, Pillai M, Murphy SA, et al. 

Prognostic implications of elevated troponin in patients 

with suspected acute coronary syndrome but no critical 

epicardial coronary disease: a TACTICS-TIMI-18 

substudy. J Am Coll Cardiol 2005 Jan 4;45(1):19-24. 

20. Jarai R, Iordanova N, Jarai R, et al. Risk 

assessment in patients with unstable angina/non-STelevation myocardial infarction and normal N-terminal probrain natriuretic peptide levels by N-terminal pro-atrial 

natriuretic peptide. Eur Heart J 2005 Feb;26(3):250-6. 

21. Bazzino O, Fuselli JJ, Botto F, et al. Relative 

value of N-terminal probrain natriuretic peptide, TIMI risk 

score, ACC/AHA prognostic classification and other risk 
134

markers in patients with non-ST-elevation acute coronary 

syndromes. Eur Heart J 2004 May;25(10):859-66. 

22. Jernberg T, Lindahl B, Siegbahn A, et al. Nterminal pro-brain natriuretic peptide in relation to 

inflammation, myocardial necrosis, and the effect of an 

invasive strategy in unstable coronary artery disease. J 

Am Coll Cardiol 2003 Dec 3;42(11):1909-16. 

23. Ishii J, Cui W, Kitagawa F, et al. Prognostic 

value of combination of cardiac troponin T and B-type 

natriuretic peptide after initiation of treatment in patients 

with chronic heart failure. Clin Chem 2003 

Dec;49(12):2020-6. 

24. Jernberg T, Stridsberg M, Venge P, et al. Nterminal pro brain natriuretic peptide on admission for early 

risk stratification of patients with chest pain and no STsegment elevation. J Am Coll Cardiol 2002 Aug 

7;40(3):437-45. 

25. Bertinchant JP, Combes N, Polge A, et al. 

Prognostic value of cardiac troponin T in patients with both 

acute and chronic stable congestive heart failure: 

comparison with atrial natriuretic peptide, brain natriuretic 

peptide and plasma norepinephrine. Clin Chim Acta 2005 

Feb;352(1-2):143-53. 

26. Taniguchi R, Sato Y, Yamada T, et al. 

Combined measurements of cardiac troponin T and Nterminal pro-brain natriuretic peptide in patients with heart 

failure. Circ J 2004 Dec;68(12):1160-4. 

27. Mega JL, Morrow DA, de Lemos JA, et al. Btype natriuretic peptide at presentation and prognosis in 

patients with ST-segment elevation myocardial infarction: 

an ENTIRE-TIMI-23 substudy. J Am Coll Cardiol 2004 

Jul 21;44(2):335-9. 

28. Morrow DA, de Lemos JA, Sabatine MS, et al. 

Evaluation of B-type natriuretic peptide for risk assessment 

in unstable angina/non-ST-elevation myocardial infarction: 

B-type natriuretic peptide and prognosis in TACTICSTIMI 18.[erratum appears in J Am Coll Cardiol. 2003 May 

21;41(10):1852]. J Am Coll Cardiol 2003 Apr 

16;41(8):1264-72. 

29. Panteghini M, Cuccia C, Bonetti G, et al. Rapid 

determination of brain natriuretic peptide in patients with 

acute myocardial infarction. Clin Chem Lab Med 2003 

Feb;41(2):164-8. 

30. Kyuma M, Nakata T, Hashimoto A, et al. 

Incremental prognostic implications of brain natriuretic 

peptide, cardiac sympathetic nerve innervation, and 

noncardiac disorders in patients with heart failure. J Nucl 

Med 2004 Feb;45(2):155-63. 

31. Kawai K, Hata K, Takaoka H, et al. Plasma brain 

natriuretic peptide as a novel therapeutic indicator in 

idiopathic dilated cardiomyopathy during beta-blocker 

therapy: a potential of hormone-guided treatment. Am 

Heart J 2001 Jun;141(6):925-32. 

32. Akioka K, Takeuchi K, Yanagi S, et al. 

Prognostic value of Doppler transmittal flow patterns and 

cardiac natriuretic peptides in patients with chronic 

congestive heart failure admitted for episodes of acute 

decompensation. Heart Vessels 2000;15(2):53-60. 

33. Bettencourt P, Ferreira A, Pardal-Oliveira N, et 

al. Clinical significance of brain natriuretic peptide in 

patients with postmyocardial infarction. Clin Cardiol 2000 

Dec;23(12):921-7. 

34. Bettencourt P, Ferreira A, Sousa T, et al. Brain 

natriuretic peptide as a marker of cardiac involvement in 

hypertension. Int J Cardiol 1999 May 15;69(2):169-77. 

35. Hartmann F, Packer M, Coats AJ, et al. NTproBNP in severe chronic heart failure: rationale, design 

and preliminary results of the COPERNICUS NT-proBNP 

substudy. Eur J Heart Fail 2004 Mar 15;6(3):343-50. 

36. Bettencourt P, Frioes F, Azevedo A, et al. 

Prognostic information provided by serial measurements of 

brain natriuretic peptide in heart failure. Int J Cardiol 2004 

Jan;93(1):45-8. 

37. Shiga T, Hosaka F, Wakaumi M, et al. 

Amiodarone decreases plasma brain natriuretic peptide 

level in patients with heart failure and ventricular 

tachyarrhythmia. Cardiovasc Drugs Ther 2003 

Jul;17(4):325-33. 

38. Fung JW, Yu CM, Yip G, et al. Effect of beta 

blockade (carvedilol or metoprolol) on activation of the 

renin-angiotensin-aldosterone system and natriuretic 

peptides in chronic heart failure. Am J Cardiol 2003 Aug 

15;92(4):406-10. 

39. Latini R, Masson S, Anand I, et al. Effects of 

valsartan on circulating brain natriuretic peptide and 

norepinephrine in symptomatic chronic heart failure: the 

Valsartan Heart Failure Trial (Val-HeFT). Circulation 

2002 Nov 5;106(19):2454-8. 

40. Yoshimura M, Mizuno Y, Nakayama M, et al. 

B-type natriuretic peptide as a marker of the effects of 

enalapril in patients with heart failure. Am J Med 2002 Jun 

15;112(9):716-20. 

41. Stanek B, Frey B, Hulsmann M, et al. Prognostic 

evaluation of neurohumoral plasma levels before and 

during beta-blocker therapy in advanced left ventricular 

dysfunction. J Am Coll Cardiol 2001 Aug;38(2):436-42. 

42. Brunner-La Rocca HP, Weilenmann D, Kiowski 

W, et al. Within-patient comparison of effects of different 

dosages of enalapril on functional capacity and 

neurohormone levels in patients with chronic heart failure. 

Am Heart J 1999 Oct;138(4 Pt 1):654-62. 

43. Baruch L, Glazer RD, Aknay N, et al. Morbidity, 

mortality, physiologic and functional parameters in elderly 

and non-elderly patients in the Valsartan Heart Failure Trial 

(Val-HeFT). Am Heart J 2004 Dec;148(6):951-7. 

44. Yoshizawa A, Yoshikawa T, Nakamura I, et al. 

Brain natriuretic peptide response is heterogeneous during 
135

beta-blocker therapy for congestive heart failure. J Card 

Fail 2004 Aug;10(4):310-5. 

45. Krum H, Carson P, Farsang C, et al. Effect of 

valsartan added to background ACE inhibitor therapy in 

patients with heart failure: Results from Val-HeFT. Eur J 

Heart Fail 2004;6(7):937-45. 

46. Maggioni AP, Anand I, Gottlieb SO, et al. 

Effects of valsartan on morbidity and mortality in patients 

with heart failure not receiving angiotensin-converting 

enzyme inhibitors. J Am Coll Cardiol 2002;40(8):1414-21. 

47. Sliwa K, Norton GR, Kone N, et al. Impact of 

initiating carvedilol before angiotensin-converting enzyme 

inhibitor therapy on cardiac function in newly diagnosed 

heart failure. J Am Coll Cardiol 2004;44(9):1825-30. 

 48. Barcarse E, Kazanegra R, Chen A, et 

al. Combination of B-type natriuretic peptide levels and 

non-invasive hemodynamic parameters in diagnosing 

congestive heart failure in the emergency department. 

Congest Heart Fail 2004 Jul;10(4):171-6. 

49. Maisel AS, Clopton P, Krishnaswamy P, et al. 

Impact of age, race, and sex on the ability of B-type 

natriuretic peptide to aid in the emergency diagnosis of 

heart failure: results from the Breathing Not Properly 

(BNP) multinational study. Am Heart J 2004 

Jun;147(6):1078-84. 

50. Knudsen CW, Riis JS, Finsen AV, et al. 

Diagnostic value of a rapid test for B-type natriuretic 

peptide in patients presenting with acute dyspnoe: effect of 

age and gender. Eur J Heart Fail 2004 Jan;6(1):55-62. 

51. Knudsen CW, Omland T, Clopton P, et al. 

Diagnostic value of B-Type natriuretic peptide and chest 

radiographic findings in patients with acute dyspnea. Am J 

Med 2004 Mar 15;116(6):363-8. 

52. Villacorta H, Duarte A, Duarte NM, et al. The 

role of B-type natriuretic peptide in the diagnosis of 

congestive heart failure in patients presenting to an 

emergency department with dyspnea. Arq Bras Cardiol 

2002;79(6):569-72. 

53. Jose JV, Gupta SN, Selvakumar D. Utility of Nterminal pro-brain natriuretic peptide for the diagnosis of 

heart failure. Indian Heart J 2003 Jan;55(1):35-9. 

54. McCullough PA, Nowak RM, McCord J, et al. 

B-type natriuretic peptide and clinical judgment in 

emergency diagnosis of heart failure: analysis from 

Breathing Not Properly (BNP) Multinational Study. 

Circulation 2002 Jul 23;106(4):416-22. 

55. Morrison LK, Harrison A, Krishnaswamy P, et 

al. Utility of a rapid B-natriuretic peptide assay in 

differentiating congestive heart failure from lung disease in 

patients presenting with dyspnea. J Am Coll Cardiol 2002 

Jan 16;39(2):202-9. 

56. Dao Q, Krishnaswamy P, Kazanegra R, et al. 

Utility of B-type natriuretic peptide in the diagnosis of 

congestive heart failure in an urgent-care setting. J Am 

Coll Cardiol 2001 Feb;37(2):379-85. 

57. Ray P, Arthaud M, Lefort Y, et al. Usefulness of 

B-type natriuretic peptide in elderly patients with acute 

dyspnea. Intensive Care Med 2004 Dec;30(12):2230-6. 

58. Seino Y, Ogawa A, Yamashita T, et al. 

Application of NT-proBNP and BNP measurements in 

cardiac care: a more discerning marker for the detection 

and evaluation of heart failure. Eur J Heart Fail 2004 Mar 

15;6(3):295-300. 

59. Lee SC, Stevens TL, Sandberg SM, et al. The 

potential of brain natriuretic peptide as a biomarker for 

New York Heart Association class during the outpatient 

treatment of heart failure. J Card Fail 2002 Jun;8(3):149-

54. 

60. Hammerer-Lercher A, Neubauer E, Muller S, et 

al. Head-to-head comparison of N-terminal pro-brain 

natriuretic peptide, brain natriuretic peptide and N-terminal 

pro-atrial natriuretic peptide in diagnosing left ventricular 

dysfunction. Clin Chim Acta 2001 Aug 20;310(2):193-7. 

61. Maeda K, Tsutamoto T, Wada A, et al. Plasma 

brain natriuretic peptide as a biochemical marker of high 

left ventricular end-diastolic pressure in patients with 

symptomatic left ventricular dysfunction. Am Heart J 1998 

May;135(5 Pt 1):825-32. 

62. Yamada Y, Goto J, Yokota M, et al. Brain 

natriuretic peptide is a sensitive indicator of impaired leftventricular function in elderly patients with cardiovascular 

disease. Cardiology 1997 Sep;88(5):401-7. 

63. Hobbs FD, Davis RC, Roalfe AK, et al. 

Reliability of N-terminal proBNP assay in diagnosis of left 

ventricular systolic dysfunction within representative and 

high risk populations. Heart 2004 Aug;90(8):866-70. 

64. Wright SP, Doughty RN, Pearl A, et al. Plasma 

amino-terminal pro-brain natriuretic peptide and accuracy 

of heart-failure diagnosis in primary care: a randomized, 

controlled trial. J Am Coll Cardiol 2003 Nov;42(10):1793-

800. 

65. Nielsen LS, Svanegaard J, Klitgaard NA, et al. 

N-terminal pro-brain natriuretic peptide for discriminating 

between cardiac and non-cardiac dyspnoea. Eur J Heart 

Fail 2004 Jan;6(1):63-70. 

66. Landray MJ, Lehman R, Arnold I. Measuring 

brain natriuretic peptide in suspected left ventricular 

systolic dysfunction in general practice: cross-sectional 

study. BMJ 2000 Apr 8;320(7240):985-6. 

67. Alehagen U, Eriksson H, Nylander E, et al. 

Heart failure in the elderly: Characteristics of a Swedish 

primary health care population. Heartdrug 2002;2(5):211-

20. 

68. Gustafsson F, Badskjaer J, Hansen FS, et al. 

Value of N-terminal proBNP in the diagnosis of left 

ventricular systolic dysfunction in primary care patients 

referred for echocardiography. Heartdrug 2003;3(3):141-6. 
136

69. Bhalla MA, Chiang A, Epshteyn VA, et al. 

Prognostic role of B-type natriuretic peptide levels in 

patients with type 2 diabetes mellitus. J Am Coll Cardiol 

2004 Sep 1;44(5):1047-52. 

70. Gaede P, Hildebrandt P, Hess G, et al. Plasma Nterminal pro-brain natriuretic peptide as a major risk 

marker for cardiovascular disease in patients with type 2 

diabetes and microalbuminuria. Diabetologia 

2005;48(1):156-63. 

71. Kellett J. Prediction of in-hospital mortality by 

brain natriuretic peptide levels and other independent 

variables in acutely ill patients with suspected heart 

disease. Can J Cardiol 2004 May 15;20(7):686-90. 

72. Nagao K, Hayashi N, Kanmatsuse K, et al. Btype natriuretic peptide as a marker of resuscitation in 

patients with cardiac arrest outside the hospital. Circ J 

2004 May;68(5):477-82. 

73. Wendelboe Nielsen O, Kirk V, Bay M, et al. 

Value of N-terminal pro brain natriuretic peptide in the 

elderly: data from the prospective Copenhagen Hospital 

Heart Failure study (CHHF). Eur J Heart Fail 2004 Mar 

15;6(3):275-9. 

74. Wang TJ, Larson MG, Levy D, et al. Plasma 

natriuretic peptide levels and the risk of cardiovascular 

events and death. N Engl J Med 2004 Feb 12;350(7):655-

63. 

75. de Winter RJ, Stroobants A, Koch KT, et al. 

Plasma N-terminal pro-B-type natriuretic peptide for 

prediction of death or nonfatal myocardial infarction 

following percutaneous coronary intervention. Am J 

Cardiol 2004 Dec 15;94(12):1481-5. 

76. Galvani M, Ottani F, Oltrona L, et al. N-terminal 

pro-brain natriuretic peptide on admission has prognostic 

value across the whole spectrum of acute coronary 

syndromes. Circulation 2004 Jul 13;110(2):128-34. 

77. Jiang CY, Li N, Wang JA. Use of B-type 

natriuretic peptide in evaluation of early percutaneous 

coronary intervention in patients with acute coronary 

syndrome. Chin Med J 2004 Aug;117(8):1130-4. 

78. Wylie JV, Murphy SA, Morrow DA, et al. 

Validated risk score predicts the development of congestive 

heart failure after presentation with unstable angina or nonST-elevation myocardial infarction: results from OPUSTIMI 16 and TACTICS-TIMI 18. Am Heart J 2004 

Jul;148(1):173-80. 

79. Takase H, Toriyama T, Sugiura T, et al. Brain 

natriuretic peptide in the prediction of recurrence of angina 

pectoris. Eur J Clin Invest 2004 Feb;34(2):79-84. 

80. Richards AM, Nicholls MG, Espiner EA, et al. 

B-type natriuretic peptides and ejection fraction for 

prognosis after myocardial infarction. Circulation 2003 Jun 

10;107(22):2786-92. 

81. Palmer BR, Pilbrow AP, Yandle TG, et al. 

Angiotensin-converting enzyme gene polymorphism 

interacts with left ventricular ejection fraction and brain 

natriuretic peptide levels to predict mortality after 

myocardial infarction. J Am Coll Cardiol 2003 Mar 

5;41(5):729-36. 

82. Omland T, Persson A, Ng L, et al. N-terminal 

pro-B-type natriuretic peptide and long-term mortality in 

acute coronary syndromes. Circulation 2002 Dec 

3;106(23):2913-8. 

83. Sabatine MS, Morrow DA, de Lemos JA, et al. 

Multimarker approach to risk stratification in non-ST 

elevation acute coronary syndromes: simultaneous 

assessment of troponin I, C-reactive protein, and B-type 

natriuretic peptide. Circulation 2002 Apr 16;105(15):1760-

3. 

84. Richards AM, Nicholls MG, Yandle TG, et al. 

Plasma N-terminal pro-brain natriuretic peptide and 

adrenomedullin: new neurohormonal predictors of left 

ventricular function and prognosis after myocardial 

infarction. Circulation 1998 May;97(19):1921-9. 

85. Schnabel R, Rupprecht HJ, Lackner KJ, et al. 

Analysis of N-terminal-pro-brain natriuretic peptide and Creactive protein for risk stratification in stable and unstable 

coronary artery disease: results from the AtheroGene study. 

Eur Heart J 2005 Feb;26(3):241-9. 

86. Heeschen C, Hamm CW, Mitrovic V, et al. Nterminal pro-B-type natriuretic peptide levels for dynamic 

risk stratification of patients with acute coronary 

syndromes. Circulation 2004 Nov 16;110(20):3206-12. 

87. Latini R, Maggioni AP, Peri G, et al. Prognostic 

significance of the long pentraxin PTX3 in acute 

myocardial infarction. Circulation 2004 Oct;110(16):2349-

54. 

88. Suzuki S, Yoshimura M, Nakayama M, et al. 

Plasma level of B-type natriuretic peptide as a prognostic 

marker after acute myocardial infarction: a long-term 

follow-up analysis. Circulation 2004 Sep 14;110(11):1387-

91. 

89. Richards AM, Nicholls MG, Troughton RW, et 

al. Antecedent hypertension and heart failure after 

myocardial infarction. J Am Coll Cardiol 

2002;39(7):1182-8. 

90. Shimpo M, Morrow DA, Weinberg EO, et al. 

Serum Levels of the Interleukin-1 Receptor Family 

Member ST2 Predict Mortality and Clinical Outcome in 

Acute Myocardial Infarction. Circulation 

2004;109(18):2186-90. 

91. Hutfless R, Kazanegra R, Madani M, et al. 

Utility of B-type natriuretic peptide in predicting 

postoperative complications and outcomes in patients 

undergoing heart surgery. J Am Coll Cardiol 2004 

May;43(10):1873-9. 

92. Kerbaul F, Collart F, Giorgi R, et al. Increased 

plasma levels of pro-brain natriuretic peptide in patients 

with cardiovascular complications following off-pump 
137

coronary artery surgery. Intensive Care Med 2004 

Sep;30(9):1799-806. 

93. Song MH, Kobayashi Y, Michi H. Clinical 

implication of atrial and brain natriuretic Peptide in 

coronary artery bypass grafting. Asian Cardiovasc Thorac 

Ann 2004 Mar;12(1):41-6. 

94. Watanabe M, Egi K, Hasegawa S, et al. 

Significance of serum atrial and brain natriuretic peptide 

release after coronary artery bypass grafting. SURG 

2003;33(9):671-3. 

95. Sadanandan S, Cannon CP, Chekuri K, et al. 

Association of elevated B-type natriuretic peptide levels 

with angiographic findings among patients with unstable 

angina and non-ST-segment elevation myocardial 

infarction. J Am Coll Cardiol 2004 Aug 4;44(3):564-8. 

96. Wiviott SD, Cannon CP, Morrow DA, et al. 

Differential expression of cardiac biomarkers by gender in 

patients with unstable angina/non-ST-elevation myocardial 

infarction: a TACTICS-TIMI 18 (Treat Angina with 

Aggrastat and determine Cost of Therapy with an Invasive 

or Conservative Strategy-Thrombolysis In Myocardial 

Infarction 18) substudy. Circulation 2004 Feb 

10;109(5):580-6. 

97. James S. Coagulation, inflammation and 

myocardial dysfunction in unstable coronary artery disease 

and the influence of glycoprotein IIb/IIIa inhibition and low 

molecular weight heparin. Ups J Med Sci 2004;109(2):71-

122. 

98. Ueland T, Jemtland R, Godang K, et al. 

Prognostic value of osteoprotegerin in heart failure after 

acute myocardial infarction. J Am Coll Cardiol 

2004;44(10):1970-6. 

99. Julier K, Da Silva R, Garcia C, et al. 

Preconditioning by sevoflurane decreases biochemical 

markers for myocardial and renal dysfunction in coronary 

artery bypass graft surgery: A double-blinded, placebocontrolled, multicenter study. Anesthesiology 

2003;98(6):1315-27. 

100. Zeller M, Cottin Y, Laurent Y, et al. N-terminal 

pro-brain natriuretic peptide levels in patients with non-STelevation myocardial infarction. Cardiology 

2004;102(1):37-40. 

101. de Groote P, Dagorn J, Soudan B, et al. B-type 

natriuretic peptide and peak exercise oxygen consumption 

provide independent information for risk stratification in 

patients with stable congestive heart failure.[see comment]. 

J Am Coll Cardiol 2004 May 5;43(9):1584-9. 

102. Maisel A, Hollander JE, Guss D, et al. Primary 

results of the Rapid Emergency Department Heart Failure 

Outpatient Trial (REDHOT). A multicenter study of B-type 

natriuretic peptide levels, emergency department decision 

making, and outcomes in patients presenting with shortness 

of breath. J Am Coll Cardiol 2004 Sep 15;44(6):1328-33. 

103. Gwechenberger M, Hulsmann M, Berger R, et al. 

Interleukin-6 and B-type natriuretic peptide are 

independent predictors for worsening of heart failure in 

patients with progressive congestive heart failure. J Heart 

Lung Transplant 2004 Jul;23(7):839-44. 

104. van der MP, Voors AA, Lipsic E, et al. 

Prognostic value of plasma erythropoietin on mortality in 

patients with chronic heart failure. J Am Coll Cardiol 2004 

Jul 7;44(1):63-7. 

105. Sakatani T, Hadase M, Kawasaki T, et al. 

Usefulness of the percentage of plasma lymphocytes as a 

prognostic marker in patients with congestive heart failure. 

Jpn Heart J 2004 Mar;45(2):275-84. 

106. Latini R, Masson S, Anand I, et al. The 

comparative prognostic value of plasma neurohormones at 

baseline in patients with heart failure enrolled in Val-HeFT. 

Eur Heart J 2004 Feb;25(4):292-9. 

107. Logeart D, Thabut G, Jourdain P, et al. 

Predischarge B-type natriuretic peptide assay for 

identifying patients at high risk of re-admission after 

decompensated heart failure. J Am Coll Cardiol 2004 Feb 

18;43(4):635-41. 

108. Horwich TB, Patel J, MacLellan WR, et al. 

Cardiac troponin I is associated with impaired 

hemodynamics, progressive left ventricular dysfunction, 

and increased mortality rates in advanced heart failure. 

Circulation 2003 Aug;108(7):833-8. 

109. Vrtovec B, Delgado R, Zewail A, et al. 

Prolonged QTc interval and high B-type natriuretic peptide 

levels together predict mortality in patients with advanced 

heart failure. Circulation 2003 Apr 8;107(13):1764-9. 

110. Anand IS, Fisher LD, Chiang YT, et al. Changes 

in brain natriuretic peptide and norepinephrine over time 

and mortality and morbidity in the Valsartan Heart Failure 

Trial (Val-HeFT). Circulation 2003 Mar 11;107(9):1278-

83. 

111. Bettencourt P, Ferreira S, Azevedo A, et al. 

Preliminary data on the potential usefulness of B-type 

natriuretic peptide levels in predicting outcome after 

hospital discharge in patients with heart failure. Am J Med 

2002 Aug 15;113(3):215-9. 

112. Hulsmann M, Berger R, Sturm B, et al. 

Prediction of outcome by neurohumoral activation, the sixminute walk test and the Minnesota Living with Heart 

Failure Questionnaire in an outpatient cohort with 

congestive heart failure. Eur Heart J 2002 Jun;23(11):886-

91. 

113. Tsutsui T, Tsutamoto T, Wada A, et al. Plasma 

oxidized low-density lipoprotein as a prognostic predictor 

in patients with chronic congestive heart failure. J Am Coll 

Cardiol 2002 Mar 20;39(6):957-62. 

114. Harrison A, Morrison LK, Krishnaswamy P, et 

al. B-type natriuretic peptide predicts future cardiac events 
138

in patients presenting to the emergency department with 

dyspnea. Ann Emerg Med 2002 Feb;39(2):131-8. 

115. Dias P, Rodrigues RA, Queiros MC, et al. 

Prognosis in patients with heart failure and preserved left 

ventricular systolic function. Rev Port Cardiol 2001 

Dec;20(12):1223-32. 

116. Koglin J, Pehlivanli S, Schwaiblmair M, et al. 

Role of brain natriuretic peptide in risk stratification of 

patients with congestive heart failure. J Am Coll Cardiol 

2001 Dec;38(7):1934-41. 

117. Imamura Y, Fukuyama T, Mochizuki T, et al. 

Prognostic value of iodine-123-metaiodobenzylguanidine 

imaging and cardiac natriuretic peptide levels in patients 

with left ventricular dysfunction resulting from 

cardiomyopathy. Jpn Circ J 2001 Mar;65(3):155-60. 

118. Tamura K, Takahashi N, Nakatani Y, et al. 

Prognostic impact of plasma brain natriuretic peptide for 

cardiac events in elderly patients with congestive heart 

failure. Gerontology 2001 Jan;47(1):46-51. 

119. Cheng V, Kazanagra R, Garcia A, et al. A rapid 

bedside test for B-type peptide predicts treatment outcomes 

in patients admitted for decompensated heart failure: a pilot 

study. J Am Coll Cardiol 2001 Feb;37(2):386-91. 

120. Maeda K, Tsutamoto T, Wada A, et al. High 

levels of plasma brain natriuretic peptide and interleukin-6 

after optimized treatment for heart failure are independent 

risk factors for morbidity and mortality in patients with 

congestive heart failure. J Am Coll Cardiol 2000 Nov 

1;36(5):1587-93. 

121. Tsutamoto T, Wada A, Maeda K, et al. Plasma 

brain natriuretic peptide level as a biochemical marker of 

morbidity and mortality in patients with asymptomatic or 

minimally symptomatic left ventricular dysfunction. 

Comparison with plasma angiotensin II and endothelin-1. 

Eur Heart J 1999 Dec;20(24):1799-807. 

122. Wallen T, Landahl S, Hedner T, et al. Brain 

natriuretic peptide predicts mortality in the elderly. Heart 

1997 Mar;77(3):264-7. 

123. Watanabe J, Shiba N, Shinozaki T, et al. 

Prognostic value of plasma brain natriuretic peptide 

combined with left ventricular dimensions in predicting 

sudden death of patients with chronic heart failure. J Card 

Fail 2005 Feb;11(1):50-5. 

124. Hamada Y, Tanaka N, Murata K, et al. 

Significance of predischarge BNP on one-year outcome in 

decompensated heart failure-comparative study with echoDoppler indexes. J Card Fail 2005 Feb;11(1):43-9. 

125. Berger R, Huelsmann M, Strecker K, et al. 

Neurohormonal risk stratification for sudden death and 

death owing to progressive heart failure in chronic heart 

failure. Eur J Clin Invest 2005 Jan;35(1):24-31. 

126. Van Beneden R, Gurne O, Selvais PL, et al. 

Superiority of big endothelin-1 and endothelin-1 over 

natriuretic peptides in predicting survival in severe 

congestive heart failure: a 7-year follow-up study. J Card 

Fail 2004 Dec;10(6):490-5. 

127. Alehagen U, Dahlstrom U, Lindahl TL. Elevated 

D-dimer level is an independent risk factor for 

cardiovascular death in out-patients with symptoms 

compatible with heart failure. Thromb Haemost 2004 

Dec;92(6):1250-8. 

128. Berger R, Strecker K, Huelsmann M, et al. 

Prognostic power of neurohumoral parameters in chronic 

heart failure depends on clinical stage and observation 

period. J Heart Lung Transplant 2003 Sep;22(9):1037-45. 

129. Ishii J, Nomura M, Nakamura Y, et al. Risk 

stratification using a combination of cardiac troponin T and 

brain natriuretic peptide in patients hospitalized for 

worsening chronic heart failure. Am J Cardiol 2002 Mar 

15;89(6):691-5. 

130. Bettencourt P, Ferreira A, Dias P, et al. 

Predictors of prognosis in patients with stable mild to 

moderate heart failure. J Card Fail 2000 Dec;6(4):306-13. 

131. Rossig L, Fichtlscherer S, Heeschen C, et al. The 

pro-apoptotic serum activity is an independent mortality 

predictor of patients with heart failure. Eur Heart J 2004 

Sep;25(18):1620-5. 

132. Rothenburger M, Wichter T, Schmid C, et al. 

Aminoterminal pro type B natriuretic peptide as a 

predictive and prognostic marker in patients with chronic 

heart failure. J Heart Lung Transplant 2004 

Oct;23(10):1189-97. 

133. Kirk V, Bay M, Parner J, et al. N-terminal 

proBNP and mortality in hospitalised patients with heart 

failure and preserved vs. reduced systolic function: data 

from the prospective Copenhagen Hospital Heart Failure 

Study (CHHF). Eur J Heart Fail 2004 Mar 15;6(3):335-41. 

134. Gardner RS, Ozalp F, Murday AJ, et al. Nterminal pro-brain natriuretic peptide. A new gold standard 

in predicting mortality in patients with advanced heart 

failure. Eur Heart J 2003 Oct;24(19):1735-43. 

135. O'Brien RJ, Squire IB, Demme B, et al. Predischarge, but not admission, levels of NT-proBNP predict 

adverse prognosis following acute LVF. Eur J Heart Fail 

2003 Aug;5(4):499-506. 

136. Fisher C, Berry C, Blue L, et al. N-terminal pro 

B type natriuretic peptide, but not the new putative cardiac 

hormone relaxin, predicts prognosis in patients with 

chronic heart failure. Heart 2003 Aug;89(8):879-81. 

137. Zugck C, Haunstetter A, Kruger C, et al. Impact 

of beta-blocker treatment on the prognostic value of 

currently used risk predictors in congestive heart failure. J 

Am Coll Cardiol 2002 May 15;39(10):1615-22. 

138. Richards AM, Doughty R, Nicholls MG, et al. 

Plasma N-terminal pro-brain natriuretic peptide and 

adrenomedullin: prognostic utility and prediction of benefit 

from carvedilol in chronic ischemic left ventricular 
139

dysfunction. Australia-New Zealand Heart Failure Group. 

J Am Coll Cardiol 2001 Jun 1;37(7):1781-7. 

139. Bettencourt P, Azevedo A, Pimenta J, et al. Nterminal-pro-brain natriuretic peptide predicts outcome 

after hospital discharge in heart failure patients. 

Circulation 2004 Oct 12;110(15):2168-74. 

140. Hartmann F, Packer M, Coats AJ, et al. 

Prognostic impact of plasma N-terminal pro-brain 

natriuretic peptide in severe chronic congestive heart 

failure: a substudy of the Carvedilol Prospective 

Randomized Cumulative Survival (COPERNICUS) trial. 

Circulation 2004 Sep 28;110(13):1780-6. 

141. Hedberg P, Lonnberg I, Jonason T, et al. 

Electrocardiogram and B-type natriuretic peptide as 

screening tools for left ventricular systolic dysfunction in a 

population-based sample of 75-year-old men and women. 

Am Heart J 2004 Sep;148(3):524-9. 

142. Atisha D, Bhalla MA, Morrison LK, et al. A 

prospective study in search of an optimal B-natriuretic 

peptide level to screen patients for cardiac dysfunction. 

Am Heart J 2004 Sep;148(3):518-23. 

143. Bibbins-Domingo K, Ansari M, Schiller NB, et 

al. Is B-type natriuretic peptide a useful screening test for 

systolic or diastolic dysfunction in patients with coronary 

disease? Data from the Heart and Soul Study. Am J Med 

2004 Apr 15;116(8):509-16. 

144. Vasan RS, Benjamin EJ, Larson MG, et al. 

Plasma natriuretic peptides for community screening for 

left ventricular hypertrophy and systolic dysfunction: the 

Framingham heart study. JAMA 2002 Sep 

11;288(10):1252-9. 

145. Groenning BA, Raymond I, Hildebrandt PR, et 

al. Diagnostic and prognostic evaluation of left ventricular 

systolic heart failure by plasma N-terminal pro-brain 

natriuretic peptide concentrations in a large sample of the 

general population. Heart 2004 Mar;90(3):297-303. 

146. Konishi H, Nishio S, Tsutamoto T, et al. Serum 

carvedilol concentration and its relation to change in 

plasma brain natriuretic peptide level in the treatment of 

heart failure: a preliminary study. Int J Clin Pharmacol 

Ther 2003 Dec;41(12):578-86. 

147. Troughton RW, Frampton CM, Yandle TG, et al. 

Plasma amino-terminal B-type natriuretic peptide measured 

by Elecsys 2010 assay in a trial of hormone-guided 

treatment for heart failure. Clin Chem 2003 

Jul;49(7):1212-5. 

148. Troughton RW, Frampton CM, Yandle TG, et al. 

Treatment of heart failure guided by plasma aminoterminal 

brain natriuretic peptide (N-BNP) concentrations. Lancet 

2000 Apr 1;355(9210):1126-30. 

149. Murdoch DR, McDonagh TA, Byrne J, et al. 

Titration of vasodilator therapy in chronic heart failure 

according to plasma brain natriuretic peptide concentration: 

randomized comparison of the hemodynamic and 

neuroendocrine effects of tailored versus empirical therapy. 

Am Heart J 1999 Dec;138(6 Pt 1):1126-32. 

150. Thompson LO, Skrabal CA, Loebe M, et al. 

Plasma neurohormone levels correlate with left ventricular 

functional and morphological improvement in LVAD 

patients. J Surg Res 2005 Jan;123(1):25-32. 

151. Clerico A, Emdin M. Diagnostic accuracy and 

prognostic relevance of the measurement of cardiac 

natriuretic peptides: a review. [Review] [151 refs]. Clin 

Chem 2004 Jan;50(1):33-50. 

152. Holmes SJ, Espiner EA, Richards AM, et al. 

Renal, endocrine, and hemodynamic effects of human brain 

natriuretic peptide in normal man. J Clin Endocrinol Metab 

1993 Jan;76(1):91-6. 

153. Mair J, Friedl W, Thomas S, et al. Natriuretic 

peptides in assessment of left-ventricular dysfunction. 

[Review] [21 refs]. Scand J Clin Lab Invest Suppl 

1999;230:132-42. 

154. Hall C. Essential biochemistry and physiology of 

(NT-pro)BNP. [Review] [25 refs]. Eur J Heart Fail 2004 

Mar 15;6(3):257-60. 

155. McGrath MF, de Bold ML, de Bold AJ. The 

endocrine function of the heart. [Review] [118 refs]. 

Trends in Endocrinology & Metabolism 16(10):469-77, 

2005 Dec; 

156. Hunt SA, Abraham WT, Chin MH, et al. 

ACC/AHA 2005 guideline update for the diagnosis and 

management of chronic heart failure in the adult: A report 

of the American College of Cardiology/American Heart 

Association Task Force on practice guidelines (writing 

committee to update the 2001 guidelines for the evaluation 

and management of heart failure). J Am Coll Cardiol 

2005;46(6):e1-e82 

157. Mair J, Friedl W, Thomas S, et al. Natriuretic 

peptides in assessment of left-ventricular dysfunction. 

[Review] [21 refs]. Scandinavian Journal of Clinical and 

Laboratory Investigation Supplement 230:132-42, 1999; 

158. Liu P, Arnold JM, Belenkie I, et al. The 2002/3 

Canadian Cardiovascular Society consensus guideline 

update for the diagnosis and management of heart failure. 

Can J Cardiol 2003;19(4):347-56. 

159. Remme WJ, Swedberg K, European Society of 

Cardiology. Comprehensive guidelines for the diagnosis 

and treatment of chronic heart failure. Task force for the 

diagnosis and treatment of chronic heart failure of the 

European Society of Cardiology. Eur J Heart Fail 

2002;4(1):11-22. 

160. Ho KK, Pinsky JL, Kannel WB, et al. The 

epidemiology of heart failure: the Framingham Study. J 

Am Coll Cardiol 1993;22(4:Suppl:A):Suppl-13A 

 161. McKelvie R. Heart failure.[update in 

Clin Evid. 2002 Dec;(8):60-81; PMID: 12603873]. 

[Review] [59 refs]. Clinical Evidence (7):57-78, 2002 Jun; 
140

162. McKie PM, Burnett JC, Jr. B-type natriuretic 

peptide as a biomarker beyond heart failure: speculations 

and opportunities. [Review] [67 refs]. Mayo Clinic 

Proceedings 80(8):1029-36, 2005 Aug; 

163. Doust JA, Pietrzak E, Dobson A, et al. How well 

does B-type natriuretic peptide predict death and cardiac 

events in patients with heart failure: systematic review. 

[Review] [9 refs]. BMJ 2005 Mar;330(7492):625 

164. Mueller T, Gegenhuber A, Poelz W, et al. 

Comparison of the Biomedica NT-proBNP enzyme 

immunoassay and the Roche NT-proBNP 

chemiluminescence immunoassay: implications for the 

prediction of symptomatic and asymptomatic structural 

heart disease. Clin Chem 2003 Jun;49(6 Pt 1):976-9. 

165. Whiting P, Rutjes A, Reitsma J, et al. The 

development of QUADAS: a tool for the quality 

assessment of studies of diagnostic accuracy included in 

systematic reviews. BMC Medical Research Methodology 

2003;3(1):25 

166. Whiting P, Rutjes AW, Dinnes J, et al. A 

systematic review finds that diagnostic reviews fail to 

incorporate quality despite available tools. [Review] [116 

refs]. J Clin Epidemiol 2005 Jan;58(1):1-12. 

167. Jadad AR, Moore RA, Carroll D, et al. Assessing 

the quality of reports of randomized clinical trials: is 

blinding necessary? Control Clin Trials 1996 Feb;17(1):1-

12. 

168. Altman DG, Altman DG. Systematic reviews of 

evaluations of prognostic variables. BMJ 2001 Jul 

28;323(7306):224-8. 

169. Patrick Bossuyt, Les Irwig Paul Glasziou. 

Diagnostic Test Appraisal Form. Screening and Test 

Evaluation Program (STEP). Internet. 

http://www.health.usyd.edu.au/step/about/appraisal.htm

170. Deeks JJ, Deeks JJ. Systematic reviews in health 

care: Systematic reviews of evaluations of diagnostic and 

screening tests.. [Review] [24 refs]. BMJ 2001 Jul 

21;323(7305):157-62. 

171. Littenberg B, Moses LE, Littenberg B, et al. 

Estimating diagnostic accuracy from multiple conflicting 

reports: a new meta-analytic method. Med Decis Making 

1993 Oct;13(4):313-21. 

172. Nakayama T, Soma M, Mizutani Y, et al. A 

novel missense mutation of exon 3 in the type A human 

natriuretic peptide receptor gene: possible association with 

essential hypertension. Hypertens Res 2002 

May;25(3):395-401. 

173. Doust JA, Glasziou PP, Pietrzak E, et al. A 

systematic review of the diagnostic accuracy of natriuretic 

peptides for heart failure. [Review] [41 refs]. Arch Intern 

Med 2004 Oct 11;164(18):1978-84. 

174. Cardarelli R, Lumicao TG, Jr. B-type natriuretic 

peptide: a review of its diagnostic, prognostic, and 

therapeutic monitoring value in heart failure for primary 

care physicians. [Review] [21 refs]. J Am Board Fam Pract 

2003 Jul;16(4):327-33. 

175. van der Sloot JA. New developments in the 

management of heart failure: a review of the literature in 

2002. [Review] [7 refs]. Neth J Med 2003 May;61(5 

Suppl):19-27. 

176. Jortani SA, Prabhu SD, Valdes R, Jr., et al. 

Strategies for developing biomarkers of heart failure. 

[Review] [120 refs]. Clin Chem 2004;50(2):265-78. 

177. Khunti K, Squire I, Abrams KR, et al. Accuracy 

of a 12-lead electrocardiogram in screening patients with 

suspected heart failure for open access echocardiography: a 

systematic review and meta-analysis. [Review] [36 refs]. 

Eur J Heart Fail 2004 Aug;6(5):571-6. 

178. Thomas MD, Fox KF, Coats AJ, et al. The 

epidemiological enigma of heart failure with preserved 

systolic function. [Review] [109 refs]. Eur J Heart Fail 

2004 Mar 1;6(2):125-36. 

179. McGowan JH, Cleland JG. Reliability of 

reporting left ventricular systolic function by 

echocardiography: a systematic review of 3 methods. 

[Review] [82 refs]. Am Heart J 2003 Sep;146(3):388-97. 

180. Ahmed A. American College of 

Cardiology/American Heart Association Chronic Heart 

Failure Evaluation and Management guidelines: relevance 

to the geriatric practice. J Am Geriatr Soc 2003 

Jan;51(1):123-6. 

181. Khunti K, Baker R, Grimshaw G. Diagnosis of 

patients with chronic heart failure in primary care: 

usefulness of history, examination, and investigations. 

[Review] [75 refs]. Br J Gen Pract 2000 Jan;50(450):50-4. 

182. Wang CS, FitzGerald JM, Schulzer M, et al. 

Does this dyspneic patient in the emergency department 

have congestive heart failure?. [Review] [70 refs]. JAMA 

2005 Oct;294(15):1944-56. 

183. Craig J et al. The use of B-type natriuretic 

peptides (BNP and NT-proBNP) investigation of patients 

with suspected heart failure. report 

2005http://www.nhshealthquality.org/nhsqis/files/bnp_final

_report.pdf. 2005. 

184. Doust JA, Saunders S, Pirozzo S et al. The 

diagnosis and recognition of congestive cardiac failure. 

The Centre for Evidence Based Practice at the Universtiy 

of Queensland; 2002. 

185. Fischer JE, Bachmann LM, Jaeschke R. A 

readers' guide to the interpretation of diagnostic test 

properties: clinical example of sepsis. [Review] [23 refs]. 

Intensive Care Medicine 29(7):1043-51, 2003 Jul; 

186. Missouris CG, Varma C, Ward D, et al. Cardiac 

peptides and plasma renin activity in acute dilated 

cardiomyopathy. Eur J Heart Fail 2001 Jan;3(1):109-11. 

187. Inoue M, Kanda T, Arai M, et al. Impaired 

expression of brain natriuretic peptide gene in diabetic rats 
141

with myocardial infarction. Exp Clin Endocrinol Diabetes 

1998;106(6):484-8. 

188. Yoshinari K, Yaoita H, Maehara K, et al. 

Different therapeutic responses to treadmill exercise of 

heart failure due to ischemia and infarction in rats. 

Cardiovasc Res 2005 Feb 1;65(2):457-68. 

189. Mueller C. Rapid measurement of B-type 

natriuretic peptides reduced time to discharge and treatment 

costs in patients with acute dyspnea. ACP J Club 2005 

Jan;142(1):A14-A15 

190. Mantone J. The need for speed. Rapid blood tests 

have quickened the diagnostic process, and even faster 

products are on the way. Mod Healthc 2004 Aug 

9;34(32):30-1. 

191. Clerico A, Emdin M. Endocrine paradox in heart 

failure: resistance to biological effects of cardiac natriuretic 

hormones. Clin Chem 2004 Dec;50(12):2465-7. 

192. Scharhag J, Urhausen A, Herrmann M, et al. No 

difference in N-terminal pro-brain natriuretic peptide (NTproBNP) concentrations between endurance athletes with 

athlete's heart and healthy untrained controls. Heart 2004 

Sep;90(9):1055-6. 

193. Publication Committee for the VMAC 

Investigators (Vasodilatation in the Management of Acute 

CHF). Intravenous nesiritide vs nitroglycerin for treatment 

of decompensated congestive heart failure: a randomized 

controlled trial.[erratum appears in JAMA 2002 Aug 

7;288(5):577]. JAMA 2002 Mar 27;287(12):1531-40. 

194. Iqbal R, Rizvi SA, Akbay C, et al. Chiral 

separations in microemulsion electrokinetic 

chromatography. Use of micelle polymers and 

microemulsion polymers. J Chromatogr 2004 Jul 23;A.. 

1043(2):291-302. 

195. Nagai T, Imamura M, Inukai T, et al. Brain 

natriuretic polypeptide in type 2 NIDDM patients with 

albuminuria. J 2001;32(3-4):169-80. 

196. Puddy VF, Amirmansour C, Williams AF, et al. 

Plasma brain natriuretic peptide as a predictor of 

haemodynamically significant patent ductus arteriosus in 

preterm infants. Clin Sci (Colch ) 2002 Jul;103(1):75-7. 

197. Richards M. Outpatient management of heart 

failure. [Review] [44 refs]. Heart Fail Rev 2003 

Oct;8(4):345-8. 

198. Apple FS, Panteghini M, Ravkilde J, et al. 

Quality specifications for B-type natriuretic peptide assays. 

Clinical Chemistry 51(3):486-93, 2005 Mar; 

199. Bibbins-Domingo K, Ansari M, Schiller NB, et 

al. B-type natriuretic peptide and ischemia in patients with 

stable coronary disease: data from the Heart and Soul 

study. Circulation 2003 Dec 16;108(24):2987-92. 

200. Cowie MR, Struthers AD, Wood DA, et al. 

Value of natriuretic peptides in assessment of patients with 

possible new heart failure in primary care. Lancet 1997 

Nov 8;350(9088):1349-53. 

201. Morgan S, Smith H, Simpson I, et al. Prevalence 

and clinical characteristics of left ventricular dysfunction 

among elderly patients in general practice setting: cross 

sectional survey. BMJ 1999 Feb 6;318(7180):368-72. 

202. McDonagh TA, Morrison CE, Lawrence A, et al. 

Symptomatic and asymptomatic left-ventricular systolic 

dysfunction in an urban population. Lancet 1997 Sep 

20;350(9081):829-33. 

 203. Mosterd A, Hoes AW, de Bruyne MC, 

et al. Prevalence of heart failure and left ventricular 

dysfunction in the general population; The Rotterdam 

Study. Eur Heart J 1999 Mar;20(6):447-55. 

204. Raymond I, Groenning BA, Hildebrandt PR, et 

al. The influence of age, sex and other variables on the 

plasma level of N-terminal pro brain natriuretic peptide in a 

large sample of the general population. Heart 2003 

Jul;89(7):745-51. 

205. Januzzi JL, van Kimmenade R, Lainchbury J, 

Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, Pinto 

YM, and Richards M. NT-proBNP testing for diagnosis and 

short-term prognosis in acute destabilized heart failure: an 

international pooled analysis of 1256 patients The 

International Collaborative of NT-proBNP Study. Eur 

Heart J. 2005; 2005 Nov 17; [Epub ahead of print] 

206. Zaphiriou A, Robb S, Murray-Thomas T, et al. 

The diagnostic accuracy of plasma BNP and NTproBNP in 

patients referred from primary care with suspected heart 

failure: results of the UK natriuretic peptide study. 

European Journal of Heart Failure 7(4):537-41, 2005 Jun; 

207. Davenport C, Cheng EYL, Kwok YTT, et al. 

Assessing the diagnostic test accuracy of natriuretic 

peptides and ECG in the diagnosis of left ventricular 

systolic dysfunction: A systematic review and metaanalysis. Br J Gen Pract 2006;56(522):48-56. 

208. Shimizu Y, Uematsu M, Nagaya N, et al. 

Myocardial velocity gradient reflects the severity of 

myocardial damage regardless of the presence or absence 

of mitral regurgitation. J Am Soc Echocardiogr 2003 

Mar;16(3):246-53. 

209. Gheorghiade M, Zannad F, Sopko G, et al. Acute 

heart failure syndromes: current state and framework for 

future research. Circulation 112(25):3958-68, 2005 Dec 

20; 

210. Cowie MR, Jourdain P, Maisel A, et al. Clinical 

applications of B-type natriuretic peptide (BNP) testing. 

[Review] [68 refs]. Eur Heart J 2003 Oct;24(19):1710-8. 

211. Jourdain P, Funck F, Gueffet P, et al. Benefit of 

BNP plasma levels for optimizing therapy: the Systolic 

Heart Failure Treatment Supported by BNP Multicenter 

Randomised Trial (STARS-BNP). J Am Coll Cardiol 

2005;45(Supp A):1001-151. 
142

212. Bruins S, Fokkema MR, Romer JW, et al. High 

intraindividual variation of B-type natriuretic peptide 

(BNP) and amino-terminal proBNP in patients with stable 

chronic heart failure. Clin Chem 2004 Nov;50(11):2052-8. 

213. Wu AH, Smith A, Wieczorek S, et al. Biological 

variation for N-terminal pro- and B-type natriuretic 

peptides and implications for therapeutic monitoring of 

patients with congestive heart failure. Am J Cardiol 2003 

Sep 1;92(5):628-31. 

214. Melzi dG, Tagnochetti T, Nauti A, et al. 

Biological variation of N-terminal pro-brain natriuretic 

peptide in healthy individuals. Clin Chem 

2003;49(9):1554-5. 

215. Jones GRD B L S H-G. Clin Biochem Rev, 

editor. 70. 2002; 40th Annual Scientific Conference of the 

AACB, Adelaide: Clin Biochem Rev; 2002. 

216. Pagani F, Stefini F, Panteghini M. Biological 

variation in serum concentrations of N-terminal pro-brain 

natriuretic peptide (NT-proBNP). [Abstract]. Clin Chem 

2003;49(Suppl 6):A34 

217. Fraser GC. Biological variation: from principles 

to practice. Washington: AACC press; 2001. 

218. Hammerer-Lercher A, Ludwig W, Falkensammer 

G, et al. Natriuretic peptides as markers of mild forms of 

left ventricular dysfunction: effects of assays on diagnostic 

performance of markers. Clin Chem 2004 Jul;50(7):1174-

83. 

219. Fischer Y, Filzmaier K, Stiegler H, et al. 

Evaluation of a new, rapid bedside test for quantitative 

determination of B-type natriuretic peptide. Clin Chem 

2001 Mar;47(3):591-4. 

220. Rawlins ML, Owen WE, Roberts WL. 

Performance characteristics of four automated natriuretic 

peptide assays. American Journal of Clinical Pathology 

123(3):439-45, 2005 Mar; 

221. Nielsen OW, Kirk V, Bay M, et al. Value of Nterminal pro brain natriuretic peptide in the elderly: Data 

from the prospective Copenhagen Hospital Heart Failure 

study (CHHF). Eur J Heart Fail 2004;6(3):275-9. 
143

List of Acronyms/Abbreviations 

ACC American College of Cardiology 

ACE Angiotensin Coverting Enzyme 

ACID Automatic Implantable Cardiac Defibrillator 

ACS Acute Coronary Syndrome 

AF Atrial Fibrillation 

AHA American Heart Association 

AHRQ Agency for Healthcare Research Quality 

AMED Allied and Complementary Medicine 

ANP A-Type Natriuretic Peptide 

AR Aortic Regurgitation 

AS Aortic Stenosis 

AUC Area Under the (plasma time) Curve 

BMI Body Mass Index 

BNP B-Type Natriuretic Peptide 

CAD Coronary Artery Disease 

CAGB Coronary Artery Bypass Graft 

CHF Congestive Heart Failure 

CCS Canadian Cardiovascular Society 

cGMP Cyclic guanosine mononucleotide phosphate 

CI Confidence Interval 

CPE Cardiogenic pulmonary edema 

CRP C-reactive protein 

CRT Cardiac Resynchronization Therapy 

CT Computerized Tomography 

CVD Cardiovascular Disease 

DOR Diagnostic Odds Ratio 

E/A Early to late(atrial) echocardiographic phases of ventricular filling 

ECG Electrocardiogram 

ECP Enhanced Counterpulsation 

ED Emergency Department 

EF Ejection Fraction 

ELISA Enzyme Linked ImmunoSorbent Assay 

FDA Food and Drug Administration 

FN False Negative 

FPR False-Positive Rates 

HbA1c Hemoglobin A1c 

HF Heart Failure 

HR Hazard Ratio 

IABP Intra-Aortic Balloon Pump 

IHD Idiopathic Heart Disease 

JVP Jugular Venous Pressure 

LAD Left Anterior Descending 

LR Likelihood Ratio 
144

LR- Negative Likelihood Ratio 

LR+ Positive Likelihood Ratio 

LV Left Ventricular 

LVD Left Ventricular Dysfunction 

LVEDD Left Ventricular End Diastolic Diameter 

LVEF Left Ventricular Ejection Fraction 

LVESD Left Ventricular End Systolic Dimension 

LVSD Left Ventricular Systolic Dysfunction 

MIBG 123I-metaiodobenzylguanidine

MI Myocardial Infarction 

MRI Magnetic Resonance Imaging 

MRNA Myocardial Radionuclide Angiogram 

MS Mitral Stenosis 

NHANES National Health and Nutrition Examination Survey 

NPV Negative Predictive Value 

NSTEMI Non ST-Elevation Myocardial Infarction 

NT-proBNP N-Terminal proBNP 

NYHA New York Heart Association 

PCI Percutaneous Coronary Interventions 

PTCA Percutaneous Transluminal Coronary Angioplasty 

PCWP Pulmocapillary wedge pressure 

QoL Quality of Life 

QUADS Quality Assessment of Diagnostic Accuracy Studies 

RCT Randomized Controlled Trial 

RNA Radionuclide Angiogram 

ROC Receiver Operator Characteristic 

RR Relative Risk 

SROC Summary Receiver Operator Characteristic 

SRS Systematic Review Software 

STEMI ST-Elevation Myocardial Infarction

TEP Technical Expert Panel 

TIA Transient ischemic attack 

TN True Negative 

TOO Task Order Officer 

TP True Positive 

TPR True-Positive Rates 

UKNPS United Kingdom Natriuretic Peptide Study 

VAD Ventricular Assist Device
145
145

Glossary 

Statistical/Methodological Terms Defined

ANOVA. Analysis of Variance. A test of the statistical significance of the differences among 

the mean scores of two or more groups on one or more variables 

Backward selection logistic regression. See stepwise regression (variables are removed one at a 

time) 

Chi-square χ2 test. Any statistical hypothesis test in which the test statistic has a chi-square 

distribution if the null hypothesis is true. For example, it is used to compute the probability that 

there is no significant difference between the expected frequency of an occurrence with the 

observed frequency of that occurrence. 

Cochranes’s Q test. A test for statistical heterogeneity between studies, calculated as the sum of 

the squared differences between each study’s effect estimate and the overall effect estimate, 

weighted for the information provided by the study. Under the null hypothesis, it follows a chisquared distribution with degrees of freedom equal to the total number of studies less one 

Correlation Coefficient. The correlation coefficient measures the strength of a linear 

relationship between two variables. Commonly designated as r, its values range from -1 to +1, 

indicating a strong negative relationship to a strong positive relationship with 0 (zero) as neutral 

Cox Regression Model. A regression technique that allows adjustment for known differences in 

baseline characteristics between experimental and control groups as applied to survival data 

Diagnostic Odds Ratio. This is a useful measure when combining studies in a systematic 

review. The DOR describes the odds of positive test results in participants with disease 

compared with the odds of positive test results in those without disease. A single diagnostic odds 

ratio corresponds to a set of sensitivities and specificities depicted by a receiver operating 

characteristic curve 

Fisher’s exact test. A test which can be used to determine if there are nonrandom associations 

between two categorical variables. It is an alternative to the Chi-square test. The test is based on 

exact probabilities from a specific distribution. The Chi-square test relies on a large sample 

approximation. Therefore, Fisher’s test may be used in situations where a large sample 

approximation is inappropriate 

Forest Plots. A graphical display tool that presents individual studies (black squares) with 

confidence interval lines through them, stacked upon each other, and summarized in a pooled 

effect estimate (black diamond) 

Forward logistic regression. See stepwise regression. (variables are added one at a time) 

Hazard Ratio. The weighted relative risk over the entire period of the study 
146

Kaplan Meier Survival Analysis. Often shown as a curve that starts at 100% of the study 

population and shows the percentage of the population still surviving (or free of disease or some 

other outcome) at successive times for as long as information is available. Synonymous with 

Survival Curve 

Kruskal Wallis. This is a non-parametric test for assessing differences between the medians of 

two or more samples to determine if the samples have come from different populations. It is 

useful for situations where the ANOVA normality assumptions may not apply. 

Likelihood ratio. This statistic incorporates both the sensitivity and specificity of the test and 

provides a direct estimate of how much a test result will change the odds of having a disease. 

The likelihood ratio for a positive result (LR+) tells you how much the odds of the disease 

increase when a test is positive. The likelihood ratio for a negative result (LR-) tells you how 

much the odds of the disease decrease when a test is negative

Logistic regression. A term used for a regression analysis in which the dependent or target 

variable is dichotomous. 

Multiple linear mixed effects. These fit linear relationships between dependent and independent 

variables using mixed-effects models. Mixed effects models provide a powerful and flexible tool 

for the analysis of balanced and unbalanced grouped data in the presence of fixed and random 

effects. 

Multiple linear regression. This aim of this analysis is to find a linear relationship between one 

dependent variable, and multiple independent variables 

Multiple logistic regression. An extension of logistic regression to accommodate a dependent 

variable with more than 2 levels or categories (i.e. polytomous or multinomial variable)

Negative predictive value. The probability that the patient will not have the disease when 

restricted to all patients who test negative 

Odds Ratio. This term differs from risk in that it involves two probabilities instead of just one 

and these are expressed in terms of a ratio. Specifically, odds are the ratio of the probability of an 

event occurring to the probability of the event not occurring 

Pearson product-moment correlation coefficient. It is one example of a correlation 

coefficient. It is a measure of the linear association between two variables that have been 

measured on interval or ratio scales. It is calculated by dividing the covariance of the two 

variables by the product of their standard deviations 

Positive Predictive Value. The probability that the patient has the disease when restricted to 

those patients who test positive 
147

Relative Risk. A measure of the number of outcome events in the treatment group vs. the 

number in the control group. An RR = 1 indicates that the outcome rate is the same in both 

groups, i.e. the treatment group is no better or worse than the control group. An RR < 1 indicates 

that the event rate is less in the treatment group and an RR > 1 indicates that the event rate is 

more in the treatment group. The further that the RR is from 1, the greater the difference in 

event rates between the treatment and control 

ROC. Receiver Operating Characteristic Curves. Used as a measure to assess the accuracy of 

diagnostic tests. They display the relationship between sensitivity (true positive rate) and 1-

specificity (false positive rate) across all possible threshold values that define the positivity of a 

disease or condition. Summary measures i.e., the area under the curve (AUC) can explain the 

capacity of a test to discriminate a diseased from a non-diseased subject. An ROC curve for a 

perfect test has an area under the curve = 1.0 while a test that performs no better than by chance 

has an area under the curve of only 0.5 

Sensitivity. The probability that the test is positive when given to a group of patients with the 

disease. A large sensitivity means that a negative test can rule out the disease 

Simple (univariate) linear regression. This analysis aims to find a linear relationship between 

a response variable and a possible predictor variable by the method of least squares (the most 

common method of defining a straight line through a set of points on a scatterplot) 

Simultaneous logistic regression. See multiple logistic regression. 

Spearman’s rank correlation coefficient. The nonparametric equivalent to the standard 

correlation coefficient (an expression of the relationship between two variables with one another) 

Specificity. The probability that the test will be negative among patients who do not have the 

disease. A large specificity means that a positive test can rule in the disease 

Standard Error (SE). The standard deviation of an estimate of a population parameter (thus, 

the standard error of the mean is the standard deviation of the estimate of the population mean 

value) 

Stepwise Regression. Related to multiple regression analysis, but differs in that variables are 

entered into or removed from computational analysis one at a time to determine how much is 

“gained” or “lost” by each variable 

Wilcoxon Mann-Whitney Test. This test does not require the assumption that the differences 

between the two samples are normally distributed. It is one of the most powerful of the nonparametric tests for comparing two populations. The t-test for independent samples (between 

groups), would be the comparable parametric test 
A-1 

Appendix A: Search terms for Peptides review 

Main Review

MEDLINE® February 2005 

natriuretic peptide, brain/ 

2. bnp.mp. [mp=title, original title, abstract, name of substance word, subject 

heading word] 

3. nt-probnp.mp. 

4. brain-type natriuretic peptide.mp. 

5. bnp1-32.mp. 

6. bnp-32.mp. 

7. bnp77-108.mp. 

8. probnp.mp. 

9. nt-probnp1-76.mp. 

10. natriuretic factor-32.mp. 

11. natriuretic peptide type-b.mp. 

12. type-b natriuretic peptide.mp. 

13. ventricular natriuretic peptide.mp. 

14. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 

15. 14 

16. limit 15 to yr=1989 – 2005 

EMBASE 2005 Week 08 

1 Brain Natriuretic Peptide/ct, ec, an, dv [Clinical Trial, Endogenous 

Compound, Drug Analysis, Drug Development] (2172) 

2 bnp.tw. (1838) 

3 nt-probnp.tw. (150) 

4 brain-type natriuretic peptide.tw. (9) 

5 bnp 1-32.tw. (4) 

6 bnp1-32.tw. (1) 

7 bnp-32.tw. (44) 

8 bnp77-108.tw. (0) 

9 bnp 77-108.tw. (2) 

10 probnp.tw. (195) 

11 nt-probnp1-76.tw. (0) 

12 nt-probnp 1-76.tw. (1) 

13 natriuretic factor-32.tw. (0) 

14 natriuretic peptide type-b.tw. (3) 

15 type-b natriuretic peptide.tw. (16) 

16 ventricular natriuretic peptide.tw. (24) 

17 or/1-16 (2895) 
A-2 

18 limit 17 to yr=1989-2005 (2881) 

19 from 18 keep 1-1000 (1000) 

CINAHL February 2005 Week 3 

 

1 exp Peptides/an, me, bl, ph, st, df, du, ur [Analysis, Metabolism, Blood, 

Physiology, Standards, Deficiency, Diagnostic Use, Urine] (657) 

2 nt-probnp.tw. (3) 

3 brain-type natriuretic peptide.tw. (1) 

4 bnp 1-32.tw. (0) 

5 bnp-32.tw. (0) 

6 bnp77-108.tw. (0) 

7 probnp.tw. (3) 

8 nt-probnp1-76.tw. (0) 

9 natriuretic factor-32.tw. (0) 

10 natriuretic peptide type-b.tw. (0) 

11 type-b natriuretic peptide.tw. (0) 

12 ventricular natriuretic peptide.tw. (0) 

13 or/1-12 (659) 

14 limit 13 to yr=1989-2005 (654) 

15 from 14 keep 1-654 (654) 

AMED February 2005 

1 exp peptides/ (142) 

2 bnp.tw. (2) 

3 nt-probnp.tw. (0) 

4 brain-type natriuretic peptide.tw. (0) 

5 bnp 1-32.tw. (0) 

6 bnp-32.tw. (0) 

7 bnp77-108.tw. (0) 

8 probnp.tw. (0) 

9 nt-probnp1-76.tw. (0) 

10 natriuretic factor-32.tw. (0) 

11 natriuretic peptide type-b.tw. (0) 

12 type-b natriuretic peptide.tw. (0) 

13 ventricular natriuretic peptide.tw. (0) 

14 or/1-13 (143) 

15 limit 14 to yr=1989-2005 (143) 

16 from 15 keep 1-143 (143) 
A-3 

Cochrane 2005 CDSR, ACP Journal Club, DARE 

1 [Natriuretic Peptide, Brain/me, bi, bl, se, du [Metabolism, Biosynthesis, 

Blood, Secretion, Diagnostic Use]] (0) 

2 bnp.mp. [mp=ti, ab, tx, kw, ct] (10) 

3 nt-probnp.mp. [mp=ti, ab, tx, kw, ct] (0) 

4 brain-type natriuretic peptide.tw. (0) 

5 bnp1-32.tw. (0) 

6 bnp-32.tw. (0) 

7 bnp77-108.tw. (0) 

8 probnp.tw. (0) 

9 nt-probnp1-76.tw. (0) 

10 natriuretic factor-32.tw. (0) 

11 natriuretic peptide type-b.tw. (0) 

12 type-b natriuretic peptide.tw. (0) 

13 ventricular natriuretic peptide.tw. (0) 

14 or/1-13 (10) 

15 limit 14 to yr=1989-2005 [Limit not valid in: DARE; records were retained] 

(10) 

17 from 15 keep 1-10 (10) 

Review of Reviews

EMBASE 2005 Week 45 

1 meta-analysis.sh,pt. or meta-analy:.tw. or metaanaly:.tw. (23869) 

2 ((systematic: or quantitativ:) adj (review: or overview:)).tw. (7475) 

3 (chochrane or medline or cinahl or embase or scisearch or psychinfo or 

psycinfo or psychlit or psyclit or (national and library)).tw. (12680) 

4 ((handsearch: or search:) and (cochrane or medline or cinahl or embase or 

scisearch or psychinfo or psychlit or psyclit or (national and library) or (hand: or 

manual: or electronic: or bibliograph: or database:))).tw. (18474) 

5 ((review or guideline).pt. or consensus.ti. or guideline:.ti. or literature.ti. or 

overview.ti. or review.ti.) and (3 and 4) (6533) 

6 ((synthesis or overview or review or survey) and (systematic or critical or 

methodologic or quantitative or qualitative or literature or evidence or evidencebased)).ti. (21933) 

7 1 or 2 or 3 or 4 or 5 or 6 (62142) 

8 heart failure.mp. [mp=title, abstract, subject headings, heading word, drug 

trade name, original title, device manufacturer, drug manufacturer name] (43809) 

9 exp heart failure/ (54121) 
A-4 

10 8 or 9 (58713) 

11 7 and 10 (1802) 

12 diagnosis/ (1735) 

13 diagnos:.ti. (75557) 

14 12 or 13 (77064) 

15 11 and 14 (27) 

16 15 (27) 

17 limit 16 to (english language and yr="2000 - 2005") (17) 

18 from 17 keep 1-10 (10) 

Ovid MEDLINE(R) October 2005 Week 4 

1 meta-analysis.sh,pt. or meta-analy:.tw. or metaanaly:.tw. (17167) 

2 ((systematic: or quantitativ:) adj (review: or overview:)).tw. (7963) 

3 (chochrane or medline or cinahl or embase or scisearch or psychinfo or 

psycinfo or psychlit or psyclit or (national and library)).tw. (15249) 

4 ((handsearch: or search:) and (cochrane or medline or cinahl or embase or 

scisearch or psychinfo or psychlit or psyclit or (national and library) or (hand: or 

manual: or electronic: or bibliograph: or database:))).tw. (22660) 

5 ((review or guideline).pt. or consensus.ti. or guideline:.ti. or literature.ti. or 

overview.ti. or review.ti.) and (3 and 4) (9900) 

6 ((synthesis or overview or review or survey) and (systematic or critical or 

methodologic or quantitative or qualitative or literature or evidence or evidencebased)).ti. (22940) 

7 1 or 2 or 3 or 4 or 5 or 6 (59490) 

8 heart failure.mp. [mp=title, original title, abstract, name of substance word, 

subject heading word] (32938) 

9 exp heart failure/ (23361) 

10 8 or 9 (35572) 

11 7 and 10 (683) 

12 diagnos:.ti,ab. (402579) 

13 diagnosis/ (1065) 

14 12 or 13 (403061) 

15 11 and 14 (121) 

16 15 (121) 

17 limit 16 to (english language and yr="2000 - 2005") (81) 

18 [from 17 keep 1-159] (0) 

19 from 17 keep 1-81 (81) 
B-1 

Appendix B: LEVEL 1 – TITLE & ABSTRACT SCREENING 

1. Does citation evaluate BNP in any way? (using any related term: BNP, NT-proBNP, 

proBNP, BNP77-108, nt-proBNP1-76, brain type natriuretic peptide, natriuretic factor, 

natriuretic peptide type-b, type-b natriuretic peptide, ventricular natriuretic peptide Btype) 

No

Yes

Unsure

Clear Selection

Submit Data
B-2 

LEVEL 2 - LANGUAGE 

1. Is this article published in English? 

YES

NO (specify 

language)

UNSURE

Clear Selection

Save to finish later Submit Data
B-3 

LEVEL 3 – FULL-TEXT SCREENING 

YES NO 

 (STOP 

 NOW)

UNSURE 

(continue)

1. This report is published in English.

Clear

2. The publication date is 1989 or later. Clear

3. This report describes a primary study. (contains original data and is not an editorial, letter, 

comment, opinion, thesis, abstact only, or conference proceeding)

Clear

4. Samples evaluated include separately analyzed: serum or plasma or whole blood of 

adult (>/= 18 yr) humans (not cultured cells or urine).

Clear

 

5. Test method is one of the following: 

For BNP

- Abbott laboratories - AxSYM 

- Bayer Healthcare - ADVIA Centaur 

- Beckman Couldter - Access or Access (Biosite) 

- Biosite Diagnostics - Triage 

- Shionogi & Co. Ltd.- No instrument, Shionoria-IRMA (manual assay) 

For NT-proBNP

- Biomedica Grupe - No instrument, EIA (manual assay) 

- Dade Behring - Dimension 

- Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular 

- Manual method referencing: Karl J, Borgya A, Gallusser A, et al. Development of a novel, Nterminal-proBNP (NT-proBNP) assay with a low detection limit. Scand J Clin Lab Invest Suppl 

1999; 230:177-81

- New Zealand (Christchurch) - No instrument, manual assay (Author may be Mark Richards)

Clear

YES (STOP 

NOW)

NO 

(continue)

UNSURE 

(continue)

6. This is a case report or a case series with </= 10 

subjects.

Clear

7. This is a report of a trial of effectiveness of Nesiritide 

(Natrecor) or any natriuretic peptide?

Clear

 

8. Report examines any aspect of health status of subjects who had BNP or NT-proBNP level measured. Examples of aspects of health status include: 

cardiac events

cardiac testing

blood pressure

blood levels of substances other than BNP

chest x-ray

etc

YES

NO (STOP NOW)

UNSURE

9. Is a diagnosis of Heart Failure or a marker for Heart Failure an outcome?

(they must have used one of these terms for Heart Failure, Congestive Heart Failure, HF, CHF, NYHA criteria, NYHA functional class, 

cardiac dysfunction) or analyzed one of the following markers for HF:

Anginal pain
B-4 

Anginal syndrome

Ankle swelling

Bilateral leg edema

Breathlessness

Cardiac dysfunction

Cardiac insufficiency

Cardiomegaly on chest x-ray

Diastolic distensibility

Diastolic dysfunction

Diastolic dysfunction on cardiac catheterization

Diastolic stiffness

Dyspnea

EF

Elevated jugular venous pressure

Fatigue

Fluid retention 

Hepatomegaly 

Left Ventricular (LV) relaxation, filling

Left Ventricular (LV) systolic function (or dysfunction)

Nocturnal cough

Orthopnea

Palpitation

Paroxysmal nocturnal dyspnea

Peripheral edema

Pleural effusion

Pulmonary congestion

Pulmonary rales

Tachycardia (heart rate >/= 120 beats/min

Third heart sound

Ventricular dysfunction

Weight loss 

YES

NO

UNSURE

10. Was one of the following tests performed? Chest X-ray 

Echocardiography 

Myocardial radionuclide angiogram (MRNA) 

Dobutamine echo 

Cardiac catheter

MRI

CT

pulmonary / vascular measures

YES

NO

UNSURE

11. Were either of the two previous questions answered with a 'NO'?

YES

NO

12. Are cardiac events presented as outcomes? (see list below) CARIOVASCULAR EVENTS

Admission to hospital for any of the relevant outcomes below: 

 

Angina requiring a minimum 24 hour hospitalization (Acute Coronary Syndrome) Angiographic percutaneous coronary interventions (PCI) including terms: Angioplasty 
B-5 

 Bypass surgery 

 CABG (Coronary Artery Bypass Graft) 

 Cardiac revascularization 

 PCTA ( Percutaneous Transluminal Coronary Angioplasty) 

 Stent 

Atrial fibrillation (arrhythmias) 

Cerebrovascular event (e.g. Stroke) 

Composite endpoint 

Congestive heart failure (CHF) 

Isolated diastolic ventricular dysfunction 

Mortality (all cause) Myocardial infarction (MI) 

YES

NO

UNSURE

13. Do subjects who had BNP or NT-proBNP measured have a diagnosis of heart failure? (stable heart failure) By Criteria of: 

American College of Cardiology (ACC) / American Heart Association (AHA)

New York Heart Association (NYHA)

Canadian Cardiovascular Society (CCS)

Modified Framingham Clinical Criteria for the Diagnosis of Heart Failure

European Study Group on Diastolic Heart Failure

YES

NO

UNSURE

14. 

Are subjects who have BNP or NT-proBNP measured being evaluated for the effect of a treatment (medication, lifestyle 

intervention, surgery or therapy) intended to improve symptoms of heart failure?

Treatments

Medications:

Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin Receptor Blocker Therapy 

Beta Blockers 

Cardiac Glycosides 

Diuretics 

Nitrates 

Spironolactone 

Surgeries, Procedures and Medical Devices:

Balloon Valvuloplasty Catheter 

Enhanced Counterpulsation (ECP) 

Heart Valve Replacement Surgery 

Intra-Aortic Balloon Pump (IABP) Insertion 

Prosthetic Heart Valve 

Ventricular Assist Device(VAD) 

Valvuloplasty (Balloon or Surgical)

 

Healthy Lifestyles:

Exercise 

Maintain A Healthy Weight 

Eat A Healthy Diet 

Control Blood Pressure 
B-6 

Control Blood Cholesterol 

Prevent And Manage Diabetes Mellitus 

Quit Smoking 

Manage Stress 

YES

NO

UNSURE

15. Were either of the two previous questions answered with a 'NO"?

YES

NO
B-7 

LEVEL 5 – Q1 SCREENING 

1. Is a biological or analytical determinant described? 

YES

NO

Paper should be excluded 

overall

Save to finish later Submit Data
B-8 

LEVEL 6 – Q2a SCREENING 

1. Is BNP evaluated as a marker of heart failure (or synonyms)?

YES - HF as defined by criteria of NYHA, ACC/AHA, CCS, 

Modified Framingham Clinical Criteria for the Diagnosis of HF, 

European Study Group on Diastolic HF 

Compared to Left ventricular ejection fraction , (Left) ventricular 

dysfunction, Cardiac dysfunction, Reduced left ventricular function

Compared to other signs or symptoms of HF

NO

2. Is the population an included one? (i.e. not heart transplant, renal disease patients) 

NO

YES

3. Has paper been excluded by either of the two previous questions? 

YES

NO

4. What is the setting of the study? (Use of text box not required)
B-9 

Emergency Department

Specialized clinic or outpatient setting (cardiovascular)

Primary care physician

Long-term care setting

Other

Save to finish later Submit Data
B-10 

LEVEL 7 – Q2b SCREENING 

1. Does the paper report results of multiple linear regression or multiple logistic 

regression of variables that can be used in the diagnosis of HF? 

YES

NO

Clear Selection

Save to finish later Submit Data
B-11 

LEVEL 8 – Q3 SCREENING 

1. Does this report present data which uses BNP or NT-ProBNP to predict one or more cardiac 

events? (Use of text box is not required)

NO

YES - CAD

YES - RISK FOR CAD

YES - SCREEN

YES - HF

YES - OTHER
B-12 

LEVEL 9 – Q4 SCREENING 

1. 

Does study include separately analyzed (for BNP or NT-proBNP and other outcomes) subjects with Heart 

Failure diagnosed by the criteria of one of the following: (it is not required to use text boxes)

American College of Cardiology (ACC) / American Heart Association (AHA) 

New York Heart Association (NYHA) 

Canadian Cardiovascular Society (CCS) 

Modified Framingham Clinical Criteria for the Diagnosis of Heart Failure 

European Study Group on Diastolic Heart Failure

Yes

No

2. At what timepoints were reported BNP measures taken?

Baseline only

Baseline plus one other

Multiple timepoints (more than 

two)

Other
B-13 

LEVEL 10 – Q1 DATA 

1. What population type by inclusion criteria was the determinant assessed in?

Enlarge Shrink

2. What population type by exclusion criteria was the determinant assessed in?

Enlarge Shrink

1 2 3 4 5

3. 

Determinant 

name (use 

checkbox to 

indicate 

determinant)

4. 

Determinant 

category 

(PF; PV; DC; 

DN; TN; TD; 

AP; AI)

 

5. Effect of 

determinant 

(inc; dec; 

none)

6. Briefly 

describe 

effect

 

Question 4. 
B-14 

Determinant category Code 

Physiologic-Fixed PF 

Physiologic-Variable PV 

Disease-Cardiac DC 

Disease - Noncardiac DN 

Treatment - Nondrug TN 

Treatment - Drug TD 

Analytical - Processing AP 

Analytical - Interference AI 

Question 5. 

Effect of Determinant Code 

Increase Inc 

Decrease Dec 

No effect None 
B-15 

LEVEL 11 – Q2a DATA 

1. Number of subjects 

Enlarge Shrink

2. Prevalence 

Enlarge Shrink

3. Description of study population 

Enlarge Shrink

4. Reference test 

Enlarge Shrink

5. Reference decision point 

Enlarge Shrink

6. Index test 

Enlarge Shrink

7. Index decision point 

Enlarge Shrink
B-16 

Outcome positive Outcome 

negative

8. Test positive

 

9. Test 

negative

10. Sensitivity 

Enlarge Shrink

11. Specificity 

Enlarge Shrink

12. Accuracy 

Enlarge Shrink

13. Likelihood Ratio +ve 

Enlarge Shrink

14. Likelihood Ratio -ve 
B-17 

Enlarge Shrink

15. Area under ROC 

Enlarge Shrink

Save to finish later Submit Data
B-18 

LEVEL 13 – Q3 DATA 

1. PC Risk factors (CAD/Other) 

Enlarge Shrink

2. Number of subjects (control/treatment) 

Enlarge Shrink

3. Diagnosis criteria 

Enlarge Shrink

4. Unit /BNP threshold 

Enlarge Shrink

5. Primary outcomes 

Enlarge Shrink

6. Secondary outcomes 

Enlarge Shrink

7. Ascertainment outcome 

Enlarge Shrink

8. Number of events 
B-19 

Enlarge Shrink

9. Follow-up (average time) 

Enlarge Shrink

10. Analysis / model (adjusted / unadjusted) 

Enlarge Shrink

11. Variables (multivariate) 

Enlarge Shrink

12. Risk estimate (RR or OR or HR)(CI) 

Enlarge Shrink

13. Other measures of association 

(means/proportions) 

Enlarge Shrink

14. Quality assessment score 

Enlarge Shrink

15. COMMENTS 
B-20 

Enlarge Shrink

16. Were subjects a consecutive cohort? 

YES

NO

OTHER

17. Was blinding reported? 

YES

Not Reported

18. Prior surgery? 

Enlarge Shrink

Save to finish later Submit Data

Bottom of Form
B-21 

LEVEL 14 – Q4 DATA 

1. Patient population 

Enlarge Shrink

2. Which treatment(s) are being monitored by BNP or NT-proBNP. 

Enlarge Shrink

3. What outcomes are being correlated to BNP or NT-proBNP? 
B-22 

CV death

Hospital admission for heart failure

QOL questionnaire score

Blood pressure

LEV change

All-cause Mortality

Cardiac volumes (or dimensions)

Pulmonary capillary wedge pressure

Cardiac output

Right atrial pressure

Other hemodynamic outcome

Exercise test results

6 minute wald test distance

NYHA class

Other
B-23 

4. Describe the effect of the treatment. 
B-24 

CV death

Hospital admission for heart failure

Correlation between BNP and other parameter

Blood pressure

LEV change

All-cause mortality

Cardiac volumes (or dimensions)

Pulmonary capillary wedge pressure

Cardiac output

Right atrial pressure

Other hemodynamic outcome

Exercise test results

6 minute wald test distance

NYHA class

Other
B-25 

Save to finish later Submit Data
B-26 

LEVEL 15 – GENERAL DATA 

1. What is first author's surname?

Enlarge Shrink

2. In what country was study carried out? (If not stated clearly, in what country did authors 

usually work?) 

Enlarge Shrink

3. What is the study name (cohort identifier)? (enter none, if one does not exist)

Enlarge Shrink

4. What is the sample size? (Choose the number of subjects originally included in the trial, for all 

conditions)

Enlarge Shrink

5. What is the mean age of subjects? (Provide whatever information is available)
B-27 

All subjects mean age

Condition 1 mean age

Condition 2 mean age

All subjects age range

Condition 1 age range

Condition 2 age range

Condition 3 mean age

Condition 3 age range

Condition 4 mean age

Condition 4 age range

Not stated

6. What is the % male subjects in the entire population?
B-28 

Enlarge Shrink

7. What test method was used to measure BNP or NT-proBNP?

[BNP] Abbott Labs - AxSYM

[BNP] Bayer Healthcare - ADVIA Centaur

[BNP] Beckman Coulter - Access or Access (Biosite)

[BNP] Biosite Diagnostics - Triage

[BNP] Shionogi & Co. Ltd - No instrument, Shionoria-IRMA (manual assay)

[NT-proBNP] Biomedica Grupe - No instrument, EIA (manual assay)

[NT-proBNP] Dade Behring - Dimension

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular

[NT-proBNP] Manual method referencing - Carl J., Borgya A., Gallusser A. et al. 

Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection 

limit. Scand J Clin Lab Invest Suppl 1999; 230:177-81

[NT-proBNP] New Zealand (Christchurch) - no instrument, manual assay 

None of the above

8. Name the funding source for the trial?

Funding support

Supplies

Direct involvement (analysis, authorship etc)

Unstated

9. What is the study design?

Diagnostic
B-29 

Randomized trial

Non-randomized 

trial

Prospective cohort 

Retrospective cohort

Case-control

Time series

Before-after

Cross-sectional

Other (specify)

Not reported

Save to finish later Submit Data
B-30 

Critical Appraisal of Systematic Reviews 

Are the results of the study valid? (Internal Validity) 

1. Did the systematic review address a focused clinical question? 

What is best? Where do I find the information?

The main question being addressed should be clearly 

stated. The clinical population, the diagnostic test, and 

relevant comparators. 

The Title, Abstract or final paragraph of the Introduction

should clearly state the question. If you still cannot 

ascertain what the focused question is after reading these 

sections, search for another paper!

This paper: Yes  No  Unclear  

Comment: 

2. Were the criteria used to select articles for inclusion appropriate? 

What is best? Where do I find the information?

The inclusion or exclusion of studies in a systematic 

review should be clearly defined a priori. The eligibility 

criteria used should specify the patients, tests and 

compartors. In many cases the type of study design will 

also be a key component of the eligibility criteria. 

The Methods section should describe in detail the 

inclusion and exclusion criteria. Normally, this will include 

the study design.

This paper: Yes  No  Unclear  

Comment: 

3. Is it unlikely that important, relevant studies were missed? 

What is best? Where do I find the information?

The starting point for a comprehensive search for all 

relevant studies is the major bibliographic databases 

(e.g., Medline, EMBASE, etc) but should also include a 

search of reference lists from relevant studies, use of 

Science Citation Index, and contact with experts, 

particularly to inquire about unpublished studies. The 

search should not be limited to English language only. 

The search strategy should include both MESH terms and 

text words. 

The Methods section should describe the search strategy, 

including the terms used, in some detail. The Results 

section will outline the number of titles and abstracts 

reviewed, the number of full-text studies retrieved, and the 

number of studies excluded together with the reasons for 

exclusion. This information may be presented in a figure or 

flow chart. 

This paper: Yes  No  Unclear  

Comment: 

4. Were the included studies sufficiently valid for the type of question asked? 

What is best? Where do I find the information?

The article should describe how the quality of each study 

was assessed using predetermined quality criteria 

appropriate to the type of clinical question (e.g., 

consecutive patients, blinding of tests and reference 

standards, and completeness of verification). 

The Methods section should describe the assessment of 

quality and the criteria used. The Results section should 

provide information on the quality of the individual studies. 
B-31 

This paper: Yes  No  Unclear  

Comment: 

5. Were assessments of studies reproducible? 

What is best? Where do I find the information?

The studies should be assessed independently by at least 

2 reviewers and the procedure to deal with disagreement 

should be provided. 

Methods section should describe the how the 

assessments was done and by whom. 

This paper: Yes  No  Unclear  

Comment: 

6. Were the results similar from study to study? 

What is best? Where do I find the information?

The results of the different studies may be similar or 

homogeneous. The authors may estimate whether there 

is statistically significant heterogeneity. Possible reasons 

for the heterogeneity (population characteristics or study 

methods) should be explored. 

The Results section should state whether the results are 

heterogeneous and discuss possible reasons. The SROC 

should illustrate the heterogeneity due to differences in 

threshold (spread along the SROC line), discrimination 

(spread around the SROC line) and the extent to which the 

SROC varies by population characteristics or study quality.

This paper: Yes  No  Unclear  

Comment: 

What were the results? 

How are the results presented? 
B-32 

A systematic review provides a summary of the data from the results of a number of individual studies. If the results of 

the individual studies are similar, a statistical method (called meta-analysis) is used to combine the results from the 

individual studies and an overall summary estimate is calculated. The meta-analysis gives weighted values to each of 

the individual studies according to their size. Results are traditionally displayed in a figure, like the one below, called a 

SROC plot. 

The SROC plot depicted above represents a meta-analysis of 5 studies that assessed the accuracy of the whispered 

voice test. 

Exploring heterogeneity 

Heterogeneity can be assessed using the “eyeball” test or more formally with statistical tests, such as the Cochran Q 

test. With the “eyeball” test one looks for scatter of the studies compared to the summary ROC . In the example above 

note that the solid line is the SROC and the points are well placed along this indicating little heterogeneity. 

Note: The level of significance for Cochran Q is often set at 0.1 due to the low power of the test to detect heterogeneity. 

1-Specificity

0.0 0.2 0.4 0.6 0.8 1.0

Sensitivity 0.0

0.2

0.4

0.6

0.8

1.0
B-33 

RCT QUALITY ASSESSMENT 

Systematic Review of Sport and Recreational Injury Prevention Strategies

Reference ID/RM # _________ Date of Review ___________

 Reviewer_________ 

Q1. Was the study described as randomized? 

A trial reporting that it is “randomized” is to receive one point. 

Yes 1 

No 0 

Q2. If randomized, was the randomization appropriate? 

Trials describing an appropriate method of randomization (table of random 

numbers, computer generated) receive an additional point. However, if the report 

describes the trial as randomized and uses an inappropriate method of 

randomization (date of birth, hospital numbers) a point is deducted. 

If no information on randomization is given, no point is given or deducted (i.e. “0”). 

Yes 1 

No -1 

 

Randomization = ___ / 2 

Q3. Was the study described as double-blind? 

A trial reporting that it is “double blind”, it is to receive one point. 

Yes 1 

No 0 

Q4. If double-blind, was the blinding appropriate? 

Trials that describe an appropriate method of double blinding (identical placebo, 

active placebo) are to receive an additional point. However, if the report describes 

the trial as double blind and uses an inappropriate method (comparison of tablets 

versus injection with no double dummy), a point is deducted. 

If no information on blinding is given, no point is given or deducted (i.e. “0”). 

 

Yes 1 

No -1 

Double-blind = ___ / 2 

Q5. Was there a description of withdrawals and drop-outs? 

A trial reporting the number and reasons for withdrawals are to receive one point. If 

there is no statement, no point is given. 

Yes 1 
B-34 

No 0 

Withdrawals and drop-outs = ___ / 1 

 

Total = ___ / 5 

Poor Quality < 3 
B-35 

QUADAS Quality Screening 

From: 

Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J: The development of 

QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in 

systematic reviews. BMC Med Res Methodol 2003, 3:25-. 

Users' guide to QUADAS

1. Was the spectrum of patients representative of the patients who will receive 

the test in practice? 

a. What is meant by this item

Differences in demographic and clinical features between populations may 

produce measures of diagnostic accuracy that vary considerably, this is known 

as spectrum bias. It refers more to the generalisability of results than to the 

possibility that the study may produce biased results. Reported estimates of 

diagnostic accuracy may have limited clinical applicability (generalisability) if the 

spectrum of tested patients is not similar to the patients in whom the test will be 

used in practice. The spectrum of patients refers not only to the severity of the 

underlying target condition, but also to demographic features and to the presence 

of differential diagnosis and/or co-morbidity. It is therefore important that 

diagnostic test evaluations include an appropriate spectrum of patients for the 

test under investigation and also that a clear description is provided of the 

population actually included in the study. 

b. Situations in which this item does not apply

This item is relevant to all studies of diagnostic accuracy and should always be 

included in the quality assessment tool. 

c. How to score this item
B-36 

Studies should score "yes" for this item if you believe, based on the information 

reported or obtained from the study's authors, that the spectrum of patients 

included in the study was representative of those in whom the test will be used in 

practice. The judgement should be based on both the method of recruitment and 

the characteristics of those recruited. Studies which recruit a group of healthy 

controls and a group known to have the target disorder will be coded as "no" on 

this item in nearly all circumstances. Reviewers should pre-specify in the protocol 

of the review what spectrum of patients would be acceptable taking factors such 

as disease prevalence and severity, age, and sex, into account. If you think that 

the population studied does not fit into what you specified as acceptable, the item 

should be scored as "no". If there is insufficient information available to make a 

judgement then it should be scored as "unclear". 

2. Were selection criteria clearly described? 

a. What is meant by this item

This refers to whether studies have provided a clear definition of the criteria used 

as in- and exclusion criteria for entry into the study. 

b. Situations in which this item does not apply

This item is relevant to all studies of diagnostic accuracy and should always be 

included in the quality assessment tool. 

c. How to score this item

If you think that all relevant information regarding how participants were selected 

for inclusion in the study has been provided then this item should be scored as 

"yes". If study selection criteria are not clearly reported then this item should be 

scored as "no". In situations where selection criteria are partially reported and 

you feel that you do not have enough information to score this item as "yes", then 

it should be scored as "unclear". 
B-37 

3. Is the reference standard likely to correctly classify the target condition? 

a. What is meant by this item

The reference standard is the method used to determine the presence or 

absence of the target condition. To assess the diagnostic accuracy of the index 

test its results are compared with the results of the reference standard; 

subsequently indicators of diagnostic accuracy can be calculated. The reference 

standard is therefore an important determinant of the diagnostic accuracy of a 

test. Estimates of test performance are based on the assumption that the index 

test is being compared to a reference standard which is 100% sensitive and 

specific. If there are any disagreements between the reference standard and the 

index test then it is assumed that the index test is incorrect. Thus, from a 

theoretical point of view the choice of an appropriate reference standard is very 

important. 

b. Situations in which this item does not apply

This item is relevant to all studies of diagnostic accuracy and should always be 

included in the quality assessment tool. 

c. How to score this item

If you believe that the reference standard is likely to correctly classify the target 

condition or is the best method available, then this item should be scored "yes". 

Making a judgement as to the accuracy of the reference standard may not be 

straightforward. You may need experience of the topic area to know whether a 

test is an appropriate reference standard, or if a combination of tests are used 

you may have to consider carefully whether these were appropriate. If you do not 

think that the reference standard was likely to have correctly classified the target 

condition then this item should be scored as "no". If there is insufficient 

information to make a judgement then this should be scored as "unclear". 
B-38 

4. Is the time period between reference standard and index test short enough to 

be reasonably sure that the target condition did not change between the two 

tests? 

a. What is meant by this item

Ideally the results of the index test and the reference standard are collected on 

the same patients at the same time. If this is not possible and a delay occurs, 

misclassification due to spontaneous recovery or to progression to a more 

advanced stage of disease may occur. This is known as disease progression 

bias. The length of the time period which may cause such bias will vary between 

conditions. For example a delay of a few days is unlikely to be a problem for 

chronic conditions, however, for many infectious diseases a delay between 

performance of index and reference standard of only a few days may be 

important. This type of bias may occur in chronic conditions in which the 

reference standard involves clinical follow-up of several years. 

b. Situations in which this item does not apply

This item is likely to apply in most situations. 

c. How to score this item

When to score this item as "yes" is related to the target condition. For conditions 

that progress rapidly even a delay of several days may be important. For such 

conditions this item should be scored "yes" if the delay between the performance 

of the index and reference standard is very short, a matter of hours or days. 

However, for chronic conditions disease status is unlikely to change in a week, or 

a month, or even longer. In such conditions longer delays between performance 

of the index and reference standard may be scored as "yes". You will have to 

make judgements regarding what is considered "short enough". You should think 

about this before starting work on a review, and define what you consider to be 
B-39 

"short enough" for the specific topic area that you are reviewing. If you think the 

time period between the performance of the index test and the reference 

standard was sufficiently long that disease status may have changed between 

the performance of the two tests then this item should be scored as "no". If 

insufficient information is provided this should be scored as "unclear". 

5. Did the whole sample or a random selection of the sample, receive verification 

using a reference standard? 

a. What is meant by this item

Partial verification bias (also known as work-up bias, (primary) selection bias, or 

sequential ordering bias) occurs when not all of the study group receive 

confirmation of the diagnosis by the reference standard. If the results of the index 

test influence the decision to perform the reference standard then biased 

estimates of test performance may arise. If patients are randomly selected to 

receive the reference standard the overall diagnostic performance of the test is, 

in theory, unchanged. In most cases however, this selection is not random, 

possibly leading to biased estimates of the overall diagnostic accuracy. 

b. Situations in which this item does not apply

Partial verification bias generally only occurs in diagnostic cohort studies in which 

patients are tested by the index test prior to the reference standard. In situations 

where the reference standard is assessed before the index test, you should firstly 

decide whether there is a possibility that verification bias could occur, and if not 

how to score this item. This may depend on how quality will be incorporated in 

the review. There are two options: either to score this item as 'yes', or to remove 

it from the quality assessment tool. 

c. How to score this item
B-40 

If it is clear from the study that all patients, or a random selection of patients, who 

received the index test went on to receive verification of their disease status 

using a reference standard then this item should be scored as "yes". This item 

should be scored as yes even if the reference standard was not the same for all 

patients. If some of the patients who received the index test did not receive 

verification of their true disease state, and the selection of patients to receive the 

reference standard was not random, then this item should be scored as "no". If 

this information is not reported by the study then it should be scored as "unclear". 

6. Did patients receive the same reference standard regardless of the index test 

result? 

a. What is meant by this item

Differential verification bias occurs when some of the index test results are 

verified by a different reference standard. This is especially a problem if these 

reference standards differ in their definition of the target condition, for example 

histopathology of the appendix and natural history for the detection of 

appendicitis. This usually occurs when patients testing positive on the index test 

receive a more accurate, often invasive, reference standard than those with a 

negative test result. The link (correlation) between a particular (negative) test 

result and being verified by a less accurate reference standard will affect 

measures of test accuracy in a similar way as for partial verification, but less 

seriously. 

b. Situations in which this item does not apply

Differential verification bias is possible in all types of diagnostic accuracy studies. 

c. How to score this item

If it is clear that patients received verification of their true disease status using the 

same reference standard then this item should be scored as "yes". If some 
B-41 

patients received verification using a different reference standard this item should 

be scored as "no". If this information is not reported by the study then it should be 

scored as "unclear". 

7. Was the reference standard independent of the index test (i.e. the index test 

did not form part of the reference standard)? 

a. What is meant by this item

When the result of the index test is used in establishing the final diagnosis, 

incorporation bias may occur. This incorporation will probably increase the 

amount of agreement between index test results and the outcome of the 

reference standard, and hence overestimate the various measures of diagnostic 

accuracy. It is important to note that knowledge of the results of the index test 

alone does not automatically mean that these results are incorporated in the 

reference standard. For example, a study investigating MRI for the diagnosis of 

multiple sclerosis could have a reference standard composed of clinical followup, CSF analysis and MRI. In this case the index test forms part of the reference 

standard. If the same study used a reference standard of clinical follow-up and 

the results of the MRI were known when the clinical diagnosis was made but 

were not specifically included as part of the reference then the index test does 

not form part of the reference standard. 

b. Situations in which this item does not apply

This item will only apply when a composite reference standard is used to verify 

disease status. In such cases it is essential that a full definition of how disease 

status is verified and which tests form part of the reference standard are 

provided. For studies in which a single reference standard is used this item will 

not be relevant and should either be scored as yes or be removed from the 

quality assessment tool. 
B-42 

c. How to score this item

If it is clear from the study that the index test did not form part of the reference 

standard then this item should be scored as "yes". If it appears that the index test 

formed part of the reference standard then this item should be scored as "no". If 

this information is not reported by the study then it should be scored as "unclear". 

8. Was the execution of the index test described in sufficient detail to permit 

replication of the test? 

9. Was the execution of the reference standard described in sufficient detail to 

permit its replication? 

a. What is meant by these items

A sufficient description of the execution of index test and the reference standard 

is important for two reasons. Firstly, variation in measures of diagnostic accuracy 

can sometimes be traced back to differences in the execution of index test or 

reference standard. Secondly, a clear and detailed description (or citations) is 

needed to implement a certain test in another setting. If tests are executed in 

different ways then this would be expected to impact on test performance. The 

extent to which this would be expected to affect results would depend on the type 

of test being investigated. 

b. Situations in which these items do not apply

These items are likely to apply in most situations. 

c. How to score these items

If the study reports sufficient details or citations to permit replication of the index 

test and reference standard then these items should be scored as "yes". In other 

cases these items should be scored as "no". In situations where details of test 
B-43 

performance are partially reported and you feel that you do not have enough 

information to score this item as "yes", then it should be scored as "unclear". 

10. Were the index test results interpreted without knowledge of the results of the 

reference standard? 

11. Were the reference standard results interpreted without knowledge of the 

results of the index test? 

a. What is meant by these items

This item is similar to "blinding" in intervention studies. Interpretation of the 

results of the index test may be influenced by knowledge of the results of the 

reference standard, and vice versa. This is known as review bias, and may lead 

to inflated measures of diagnostic accuracy. The extent to which this may affect 

test results will be related to the degree of subjectiveness in the interpretation of 

the test result. The more subjective the interpretation the more likely that the 

interpreter can be influenced by the results of the reference standard in 

interpreting the index test and vice versa. It is therefore important to consider the 

topic area that you are reviewing and to determine whether the interpretation of 

the index test or reference standard could be influenced by knowledge of the 

results of the other test. 

b. Situations in which these items do not apply

If, in the topic area that you are reviewing, the index test is always performed first 

then interpretation of the results of the index test will usually be without 

knowledge of the results of the reference standard. Similarly, if the reference 

standard is always performed first (for example, in a diagnostic case-control 

study) then the results of the reference standard will be interpreted without 

knowledge of the index test. However, if test results can be interpreted at later 

date, after both the index test and reference standard have been completed, then 
B-44 

it is still important for a study to provide a description of whether the interpretation 

of each test was performed blind to the results of the other test. In situations 

where one form of review bias does not apply there are two possibilities: either 

score the relevant item as "yes" or remove this item from the list. If tests are 

entirely objective in their interpretation then test interpretation is not susceptible 

to review bias. In such situations review bias may not be a problem and these 

items can be omitted from the quality assessment tool. Another situation in which 

this form of bias may not apply is when tests results are interpreted in an 

independent laboratory. In such situations it is unlikely that the person 

interpreting the test results will have knowledge of the results of the other test 

(either index test or reference standard). 

c. How to score these items

If the study clearly states that the test results (index or reference standard) were 

interpreted blind to the results of the other test then these items should be scored 

as "yes". If this does not appear to be the case they should be scored as "no". If 

this information is not reported by the study then it should be scored as "unclear". 

12. Were the same clinical data available when test results were interpreted as 

would be available when the test is used in practice? 

a. What is meant by this item

The availability of clinical data during interpretation of test results may affect 

estimates of test performance. In this context clinical data is defined broadly to 

include any information relating to the patient obtained by direct observation such 

as age, sex and symptoms. The knowledge of such factors can influence the 

diagnostic test result if the test involves an interpretative component. If clinical 

data will be available when the test is interpreted in practice then this should also 

be available when the test is evaluated. If however, the index test is intended to 

replace other clinical tests then clinical data should not be available, or should be 
B-45 

available for all index tests. It is therefore important to determine what 

information will be available when test results are interpreted in practice before 

assessing studies for this item. 

b. Situations in which this item does not apply

If the interpretation of the index test is fully automated and involves no 

interpretation then this item may not be relevant and can be omitted from the 

quality assessment tool. 

c. How to score this item

If clinical data would normally be available when the test is interpreted in practice 

and similar data were available when interpreting the index test in the study then 

this item should be scored as "yes". Similarly, if clinical data would not be 

available in practice and these data were not available when the index test 

results were interpreted then this item should be scored as "yes". If this is not the 

case then this item should be scored as "no". If this information is not reported by 

the study then it should be scored as "unclear". 

13. Were uninterpretable/ intermediate test results reported? 

a. What is meant by this item

A diagnostic test can produce an uninterpretable/indeterminate/intermediate 

result with varying frequency depending on the test. These problems are often 

not reported in diagnostic accuracy studies with the uninterpretable results simply 

removed from the analysis. This may lead to the biased assessment of the test 

characteristics. Whether bias will arise depends on the possible correlation 

between uninterpretable test results and the true disease status. If 

uninterpretable results occur randomly and are not related to the true disease 

status of the individual then, in theory, these should not have any effect on test 

performance. Whatever the cause of uninterpretable results it is important that 
B-46 

these are reported so that the impact of these results on test performance can be 

determined. 

b. Situations in which this item does not apply

This item is relevant to all studies of diagnostic accuracy and should always be 

included in the quality assessment tool. 

c. How to score this item

If it is clear that all test results, including 

uninterpretable/indeterminate/intermediate are reported then this item should be 

scored as "yes". If you think that such results occurred but have not been 

reported then this item should be scored as "no". If it is not clear whether all 

study results have been reported then this item should be scored as "unclear". 

14. Were withdrawals from the study explained? 

a. What is meant by this item

This occurs when patients withdraw from the study before the results of either or 

both of the index test and reference standard are known. If patients lost to followup differ systematically from those who remain, for whatever reason, then 

estimates of test performance may be biased. 

b. Situations in which this item does not apply

This item is relevant to all studies of diagnostic accuracy and should always be 

included in the quality assessment tool. 

c. How to score this item

If it is clear what happened to all patients who entered the study, for example if a 

flow diagram of study participants is reported, then this item should be scored as 
B-47 

"yes". If it appears that some of the participants who entered the study did not 

complete the study, i.e. did not receive both the index test and reference 

standard, and these patients were not accounted for then this item should be 

scored as "no". If it is not clear whether all patients who entered the study were 

accounted for then this item should be scored as "unclear". 
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Palmer, 2003 ACE genotype DD increase NT-proBNP -ChrSchnabel, 2005 ACS No ACS increase NT-proBNP - EleUeda, 2003 Activities of daily living score increase BNP - ShionogiRay, 2004

Acute right heart failure (no CPE group) No acute right HF (no CPE group) none

BNP - Triage

Richards, 1998 Adrenomedullin increase NT-proBNP - ChMaisel, 2004a African-American Caucasian none BNP - TriageBettencourt, 2000a Age increase BNP - ShionogiGrabowski, 2004 Age increase BNP - TriageJames, 2003 Age increase NT-proBNP - EleLainchbury, 2003 Age increase NT-proBNP -ChrLindahl, 2005 Age increase NT-proBNP - EleOlsen, 2004 Age increase NT-proBNP - EleOmland, 1996 Age increase BNP - ShionogiRedfield, 2004 Age increase BNP - TriageRedfield, 2004 Age increase BNP - TriageSuzuki, 2002 Age increase BNP - ShionogiTsutamoto, 1997 Age increase BNP - ShionogiUeda, 2003 Age increase BNP - ShionogiTarnow, 2005 Age (DN) increase NT-proBNP - Ele

C-1
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Latini, 2004a Aldosterone none BNP - ShionogiShiga, 2003 Amiodarone No Amiodarone decrease BNP - ShionogiShiga, 2003 Amiodarone Baseline decrease BNP - ShionogiJames, 2003 Angina, stable increase NT-proBNP - EleOlsen, 2004 Angina, stable without CV risk none NT-proBNP - EleBertinchant, 2005 ANP increase BNP - ShionogiOmland, 1996 ANP increase BNP - ShionogiRichards, 1998 ANP increase NT-proBNP - ChTsutamoto, 1997 ANP increase BNP - ShionogiWeber, 2004 Aortic stenosis, mild Normal LVF increase NT-proBNP - EleWeber, 2004 Aortic stenosis, moderate Normal LVF increase NT-proBNP - EleWeber, 2004 Aortic stenosis, severe Normal LVF increase NT-proBNP - EleNielsen, L.S., 2004 Arrhythmia Non-cardiac dyspnoea increase NT-proBNP - RoStanek, 2001 Atenolol Baseline decrease BNP - ShionogiDias, 2001 Atrial fibrillation Sinus Rhythym none BNP - ShionogiFung, 2003 Beta-blocker (carvedilol, metoprolol) Baseline decrease NT-proBNP - RoYoshizawa, 2004

Beta-blocker (carvedilol, metoprolol) Baseline none

BNP - Shionogi

Latini, 2004a Big endothelin-1 increase BNP - ShionogiStanek, 2001 Big endothelin-1 increase BNP - ShionogiBettencourt, 1999 Blood pressure (hypertension group) none BNP - ShionogiTsutamoto, 1997 Blood pressure none BNP - ShionogiUeda, 2003 Blood pressure none BNP - ShionogiKawai, 2001 Blood pressure, systolic Baseline none BNP - ShionogiOlsen, 2004 Blood pressure, systolic increase NT-proBNP - EleSuzuki, 2002 Blood pressure, systolic none BNP - Shionogi

C-2
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Tarnow, 2005 Blood pressure, systolic (DN) increase NT-proBNP - EleSuzuki, 2002 BMI none BNP - ShionogiUeda, 2003 BMI none BNP - ShionogiTaniguchi, 2004 Cardiac decompensation No cardiac decompensation increase NT-proBNP - RoTsutamoto, 1997 Cardiac index none BNP - ShionogiRay, 2004

Cardiogenic pulmonary edema (CPE) Obstructive lung disease increase

BNP - Triage

Bettencourt, 2004 Carvedilol No beta-blocker decrease BNP - ShionogiHartmann, 2004a Carvedilol Placebo none NT-proBNP - RoKawai, 2001 Carvedilol No carvedilol none BNP - ShionogiSliwa, 2004 Carvedilol Perindopril decrease NT-proBNP - Ro

Sliwa, 2004 Carvedilol Baseline decrease NT-proBNP - RoYoshizawa, 2004 Carvedilol Baseline none BNP - Shionogi

Sliwa, 2004 Carvedilol + Perindopril (6 months 

later)

Perindopril + Carvedilol (6 months later)

decrease

NT-proBNP - Ro

Olsen, 2004 Cerebrovascular disease (stroke or 

TIA)

without CV risk none NT-proBNP - Ele

Richards, 1998 cGMP increase NT-proBNP - Ch

Tsutamoto, 1997 cGMP increase BNP - ShionogiTarnow, 2005 Cholesterol none NT-proBNP - EleUeda, 2003 Cholesterol none BNP - ShionogiBazzino, 2004 C-reactive protein increase NT-proBNP - E17James, 2003 C-reactive protein increase NT-proBNP - EleLindahl, 2005 C-reactive protein increase NT-proBNP - EleBettencourt, 2004 Creatinine increase BNP - ShionogiBettencourt, 1999 Creatinine (hypertension group) none BNP - ShionogiGalvani, 2004 Creatinine increase NT-proBNP - Ele

C-3
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

James, 2003 Creatinine increase NT-proBNP - EleOmland, 1996 Creatinine increase BNP - ShionogiPanteghini, 2003 Creatinine none BNP - TriageUeda, 2003 Creatinine increase BNP - ShionogiZeller, 2004 Creatinine increase NT-proBNP - EleWallen, 1997 Creatinine clearance none BNP - ShionogiTaniguchi, 2004 Creatinine kinase none NT-proBNP - RoBazzino, 2004 Creatinine kinase, CK-MB increase NT-proBNP - E17Mega, 2004 Creatinine kinase, CK-MB none BNP - CentaurMorrow, 2003 Creatinine kinase, CK-MB increase BNP - TriagePanteghini, 2003 Creatinine kinase, CK-MB increase BNP - Triage

Determinant Name Control or comparison group for categorical 

assocations

Effect M

James, 2003 Diabetes increase NT-proBNP - EleLindahl, 2005 Diabetes No diabetes none NT-proBNP - EleOlsen, 2004 Diabetes without CV risk none NT-proBNP - EleSchnabel, 2005 Diabetes No diabetes none NT-proBNP - EleTarnow, 2005 Diabetic nephropathy Normoalbuminuric increase NT-proBNP - EleTarnow, 2005 Diabetic retinopathy none NT-proBNP - EleSuzuki, 2002 Diastolic blood pressure none BNP - ShionogiBayes-Genis, 2004 Diastolic failure Systolic LV dysfunction decrease NT-proBNP - EleBettencourt, 2000c Diastolic failure Systolic dysfunction decrease BNP - Shionogi

C-4
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Bettencourt, 2000c Diastolic failure Normal ventricular function increase BNP - ShionogiBettencourt, 2000a Diastolic failure Systolic heart failure decrease BNP - ShionogiBettencourt, 1999 Diastolic failure (hypertension group) increase BNP - ShionogiNielsen, L.S., 2004 Diastolic failure Non-cardiac dyspnoea increase NT-proBNP - RoRedfield, 2004 Diastolic failure increase BNP - TriageHamada, 2005 Dilated cardiomyopathy Old myocardial infarction none BNP - ShionogiBayes-Genis, 2004 Dyspnoea, non-cardiac Control increase NT-proBNP - EleLogeart, 2002 Dyspnoea, non-cardiac Control increase BNP - TriageMaisel, 2002. Dyspnoea, non-cardiac No CHF increase BNP - TriageMorrison, 2002 Dyspnoea, non-cardiac CHF decrease BNP - TriageAkioka, 2000 E/A ratio none BNP - ShionogiSuzuki, 2002 E/A ratio none BNP - ShionogiYoshimura, 2002 Enalapril Baseline decrease BNP - ShionogiYoshimura, 2002 Enalapril (15-mg) Enalapril (5-mg) decrease BNP - ShionogiBrunner-La Rocca, 1999

Enalapril (40-mg) Enalapril (10-mg) decrease BNP - Shionogi

Taniguchi, 2004 End-diastolic dimension none NT-proBNP - RoLatini, 2004a Endothelin-1 increase BNP - ShionogiRichards, 1998 Epinephrine increase NT-proBNP - ChKoglin, 2001 Exercise decrease BNP - ShionogiJames, 2003 Female increase NT-proBNP - EleLindahl, 2005 Female Male increase NT-proBNP - EleMaisel, 2004a Female Male none BNP - TriageOlsen, 2004 Female Male none NT-proBNP - EleRedfield, 2004 Female Male increase BNP - TriageSchnabel, 2005 Female Male increase NT-proBNP - EleUeda, 2003 Female Male none BNP - ShionogiWeber, 2004 Female Male none NT-proBNP - EleWiviott, 2004 Female Male increase BNP - TriageNielsen, O.W.,2004 Female (>74) Male (>74) none NT-proBNP - EleNielsen, O.W.,2004 Female (40-59) Male (40-59) none NT-proBNP - Ele

C-5
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Nielsen, O.W.,2004 Female (60-74) Male (60-74) none NT-proBNP - EleTarnow, 2005 Female (DN) Male none NT-proBNP - EleKawai, 2001 Fibrosis Baseline none BNP - ShionogiBettencourt, 1999 Fractional shortening (hypertension group) none BNP - ShionogiBettencourt, 2004 Furosemide, dosage none BNP - ShionogiTarnow, 2005 Glomerular filtration rate (ND) decrease NT-proBNP - EleTarnow, 2005 Glomerular filtration rate (No DN) decrease NT-proBNP - EleTarnow, 2005 Glucose, fasting none NT-proBNP - EleO'Brien, 2003 Glucose, random increase NT-proBNP - RoTarnow, 2005 HbA1c none NT-proBNP - EleUeda, 2003 HbA1c none BNP - ShionogiBettencourt, 1999 Heart rate none BNP - ShionogiJames, 2003 Heart rate increase NT-proBNP - EleKawai, 2001 Heart rate Baseline increase BNP - ShionogiTsutamoto, 1997 Heart rate increase BNP - ShionogiUeda, 2003 Heart rate none BNP - ShionogiTarnow, 2005 Hemoglobin (DN) decrease NT-proBNP - EleSchnabel, 2005 Hyperlipidemia No hyperlipidemia decrease NT-proBNP - EleJames, 2003 Hyperlipidemia 

(hypercholesterolemia)

none NT-proBNP - Ele

James, 2003 Hypertension increase NT-proBNP - EleSchnabel, 2005 Hypertension No hypertension none NT-proBNP - EleSuzuki, 2002 Hypertension, duration none BNP - ShionogiSuzuki, 2002 Hypertension, left ventricular 

hypertrophy

Normotensive increase BNP - Shionogi

Suzuki, 2002 Hypertension, normal left ventricular 

mass

Normotensive increase BNP - Shionogi

Bettencourt, 1999 Hypertension, with diastolic 

dysfunction

Hypertension, without diastolic dysfunction increase BNP - Shionogi

C-6
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Bettencourt, 1999 Hypertension, with diastolic 

dysfunction

Control & hypertension without diastolic dysfunction increase BNP - Shionogi

Bettencourt, 1999 Hypertension, without diastolic 

dysfunction

Control increase BNP - Shionogi

Richards, 2002 Hypertensive (MI) Normotensive (MI) increase NT-proBNP - ChRichards, 2002 Hypertensive (OMI) Normotensive (OMI) increase NT-proBNP - ChJernberg, 2003 Interleukin-6 increase NT-proBNP - Ele

Koglin, 2001 Ischemic heart disease Nonischemic heart disease none BNP - ShionogiOlsen, 2004 Ischemic heart disease without CV risk increase NT-proBNP - EleSadanandan, 2004 LAD culprit lesion nonLAD culprit lesion increase BNP - TriageSadanandan, 2004 LAD lesion, proximal vs mid Mid LAD lesion increase BNP - TriageThompson, 2005 Left ventricular assist device

Baseline decrease

BNP - Triage

Kawai, 2001 Left ventricular diastolic dimension Baseline increase BNP - ShionogiKawai, 2001 Left ventricular end-systolic diameter Baseline increase BNP - ShionogiBettencourt, 2000c Left ventricular mass index increase BNP - ShionogiBettencourt, 2000a Left ventricular mass index increase BNP - ShionogiBettencourt, 1999 Left ventricular mass index (hypertension group) increase BNP - ShionogiBettencourt, 1999 Left ventricular mass index increase BNP - ShionogiKawai, 2001 Left ventricular mass index Baseline increase BNP - ShionogiSuzuki, 2002 Left ventricular mass index increase BNP - ShionogiSuzuki, 2002 Left ventricular relative wall thickness none BNP - ShionogiBettencourt, 2004 Lisinopril, dosage decrease BNP - ShionogiDao, 2001 Lung disease CHF decrease BNP - TriageNielsen, L.S., 2004 Lung disease CHF and CHF + lung disease decrease NT-proBNP - RoSakatani, 2004 Lymphocytes (HHD, MS, AF, HC) none BNP - ShionogiSakatani, 2004 Lymphocytes (IHD, DC, AS, AR, MR) decrease BNP - ShionogiYoshizawa, 2004 Metoprolol Baseline none BNP - Shionogi

Kyuma, 2004 MIBG activity decrease BNP - Shionogi

C-7
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Suzuki, 2002 Mid-wall left ventricular fractional 

shortening

none BNP - Shionogi

Schnabel, 2005 Multi-vessel disease No multi-vessel disease

increase

NT-proBNP - Ele

James, 2003 Myocardial infarction increase NT-proBNP - EleOlsen, 2004 Myocardial infarction without CV risk increase NT-proBNP - ElePanteghini, 2003 Myocardial infarction increase BNP - TriageLindahl, 2005 Myocardial infarction, history No previous MI increase NT-proBNP - EleSchnabel, 2005 Myocardial infarction, history No myocardial infarction, history increase NT-proBNP - EleBazzino, 2004 Myoglobin increase NT-proBNP - E17Bertinchant, 2005 Norepinephrine increase BNP - ShionogiLatini, 2004a Norepinephrine increase BNP - ShionogiLatini, 2002 Norepinephrine increase BNP - ShionogiRichards, 1998 Norepinephrine increase NT-proBNP - ChStanek, 2001 Norepinephrine increase BNP - ShionogiTsutamoto, 1997 Norepinephrine increase BNP - ShionogiJarai, 2005 NT-proANP increase NT-proBNP - BioOmland, 1996 NT-proANP increase BNP - ShionogiRichards, 1998 NT-proANP increase NT-proBNP - ChStanek, 2001 NT-proANP increase BNP - ShionogiWang, 2004 NT-proANP increase BNP - ShionogiVasan, 2002 NT-proANP (females) increase BNP - ShionogiVasan, 2002 NT-proANP (males) increase BNP - Shionogi

C-8
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Ueland, 2004 Osteoprotegerin increase NT-proBNP - Ro

Tsutamoto, 1997 PCWP increase BNP - ShionogiPanteghini, 2003 Perfusion defect size increase BNP - TriageSliwa, 2004 Perindopril Baseline none NT-proBNP - RoOlsen, 2004 Peripheral vascular disease without CV risk none NT-proBNP - EleLatini, 2004a Plasma renin activity decrease BNP - ShionogiLindahl, 2005 Previous CHF No previous CHF increase NT-proBNP - EleTsutamoto, 1997 Pulmonary arterial pressure increase BNP - ShionogiSuzuki, 2002 Pulse pressure increase BNP - ShionogiFisher, 2003 Relaxin none NT-proBNP - RoAkioka, 2000 Restrictive filling pattern of 

deceleration time (DcT)

decrease BNP - Shionogi

James, 2003 Revascularization increase NT-proBNP - EleTsutamoto, 1997 Right atrial pressure increase BNP - ShionogiSchnabel, 2005 Smoker, current Non-smoker none NT-proBNP - EleJames, 2003 Smoking, current none NT-proBNP - EleShimpo, 2004 ST2, soluble receptor none BNP - Shionogi

James, 2003 Stroke increase NT-proBNP - EleLindahl, 2005 ST-segment depression No ST-segment depression increase NT-proBNP - EleJames, 2003 ST-segment depression > 5mm increase NT-proBNP - ElePanteghini, 2003 Telesystolic volume none BNP - TriageUeda, 2003 Total protein none BNP - ShionogiGrabowski, 2004 Troponin-I increase BNP - Triage

C-9
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study Determinant Name Control or comparison group for categorical 

assocations

Effect M

Jarai, 2005 Troponin-I none NT-proBNP - BioDokainish, 2005 Troponin-I (CAD) Tn-I negative (CAD) increase BNP - TriageDokainish, 2005 Troponin-I (No CAD) Tn-I negative (No CAD) increase BNP - TriageBayes-Genis, 2004 Troponin-T increase NT-proBNP - EleBazzino, 2004 Troponin-T increase NT-proBNP - E17Bertinchant, 2005 Troponin-T increase BNP - ShionogiIshii, 2003 Troponin-T increase BNP - ShionogiJames, 2003 Troponin-T increase NT-proBNP - EleJernberg, 2003 Troponin-T increase NT-proBNP - EleJernberg, 2002 Troponin-T increase NT-proBNP - EleLindahl, 2005 Troponin-T increase NT-proBNP - EleTaniguchi, 2004 Troponin-T (> 0.01 ng/mL) Troponin-T (< 0.01 ng/mL) increase NT-proBNP - Ro

Krum, 2004 Valsartan Placebo decrease BNP - ShionogiLatini, 2002 Valsartan Placebo decrease BNP - ShionogiMaggioni, 2002

Valsartan Placebo decrease

BNP - Shionogi

Krum, 2004 Valsartan (ACEi < median) Placebo (ACEi < median) decrease BNP - ShionogiKrum, 2004 Valsartan (ACEi > median) Placebo (ACEi > median) decrease BNP - ShionogiBaruch, 2004 Valsartan (age < 65 y) Placebo (age < 65 y) decrease BNP - ShionogiBaruch, 2004 Valsartan (age > 65 y) Placebo (age > 65 y) decrease BNP - Shionogi

Krum, 2004 Valsartan (no ACEi) Placebo (no ACEi) decrease BNP - ShionogiNielsen, L.S., 2004 Valvular disease Non-cardiac dyspnoea increase NT-proBNP - RoJames, 2003 Weight decrease NT-proBNP - Ele

C-10
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Palmer, 2003 196 522 28.6 +/-21.7 24.2 +/-13.8 pmol/L Chi-square 0.007Schnabel, 2005 904 542.0 

(161.43/1355.50)

192.0 

(88.67/487.90)

pg/mL Wilcoxon rank sum <0.001

Ueda, 2003 111 pg/mL Univariate / Multivariate 0.0001/0.

002

Ray, 2004 52 115 125 (75 to 752) 59 (41 to 88) pg/mL Mann-Whitney Richards, 1998 100 pmol/L Pearson product moment <0.001 Maisel, 2004a 715 773 pg/mL Kruskal-Wallis and MannWhitney 

U tests

<0.001

Bettencourt, 2000a 85 pg/mL Multiple regression 0.173 Grabowski, 2004 126 pg/mL Spearman correlation 

coefficient

0.01 

James, 2003 6809 ng/L Multiple linear regression Lainchbury, 2003 205 pmol/L Pearson's correlation 

coefficient

<0.01

Lindahl, 2005 1352 / 

999

ng/L not clear / Multiple linear 

mixed effects

<0.001 / 

<0.05

Olsen, 2004 183 pmol/L correlation, not specified <0.001 Omland, 1996 131 pmol/L Linear regression analysis <0.001 Redfield, 2004 726 pg/mL Least squares regression 

(controlled for diastolic dysfunction)

0.0003

Redfield, 2004 2042 pg/mL Least squares regression 

(controlled for EF)

0.0007

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0001/0.

0210

Tsutamoto, 1997 85 pg/mL Linear regression analysis <0.0001 Ueda, 2003 111 pg/mL Univariate / Multivariate 0.001/0.0

5

Tarnow, 2005 198 ng/L na <0.0001 

C-11
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Latini, 2004a 4223 pg/mL Spearman's coefficient ns Shiga, 2003 42 18 180 +/-30 282 +/-71 pg/mL Mann-Whitney <0.001Shiga, 2003 37 41 333 +/-107 146 +/-40 pg/mL Mann-Whitney <0.05James, 2003 3181 ng/L Multiple linear regression Olsen, 2004 15 123 29.7 +/- 136 19.8 +/- 62.0 pmol/L Unpaired Student's t-test nsBertinchant, 2005 63 ug/L Spearman rank correlation <0.0001 Omland, 1996 131 pmol/L Linear regression analysis <0.001 Richards, 1998 100 pmol/L Pearson product moment <0.001 Tsutamoto, 1997 85 pg/mL Linear regression analysis <0.0001 Weber, 2004 26 32 612 +/- 151 140 +/- 27 pg/mL Kruskal Wallis <0.001Weber, 2004 29 32 1441 +/- 32 140 +/- 27 pg/mL Kruskal Wallis <0.001Weber, 2004 91 32 2579 +/- 13 140 +/- 27 pg/mL Kruskal Wallis <0.001Nielsen, L.S., 2004 10 264 pmol/L t -test <0.001

Stanek, 2001 51 fmol/L ANOVA <0.01Dias, 2001 14 32 175.9 +/-39.5 215.3 +/-57.5 pg/mL na 0.98Fung, 2003 43 43 - 37.0 +/-14.5 pmol/L Student's t -test 0.015

Yoshizawa, 2004

84 84 290 +/-384 177 +/-256 pg/mL t-test ns

Latini, 2004a 2312 pg/mL Spearman's coefficient <0.001 Stanek, 2001 100 fmol/L Spearman rank-correlation 

coefficient

0.0001 

Bettencourt, 1999 36 pg/mL Multiple linear regression 0.445 Tsutamoto, 1997 85 pg/mL Linear regression analysis 0.044 Ueda, 2003 111 pg/mL Univariate / Multivariate 0.99 Kawai, 2001 21 pg/mL Linear regression 0.28 Olsen, 2004 183 pmol/L regression, method not 

specified

<0.001 

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.1199 

C-12
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Tarnow, 2005 198 ng/L regression, method not 

specified

<0.0001 

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0002/0.

0530

Ueda, 2003 111 pg/mL Univariate 0.47 Taniguchi, 2004 45 26 7233 +/-2369 1303 +/-291 pg/mL na <0.05Tsutamoto, 1997 85 pg/mL Linear regression analysis ns Ray, 2004 141 167 611 (370 to 709) 56 (48 to 97) pg/mL Mann-Whitney <0.001Bettencourt, 2004 57 27 pg/mL 0.02Hartmann, 2004a 815 unknown unknown 261.5 233.6 pmol/L not given nsKawai, 2001 21 9 pg/mL Repeated-measures analysis 

of variance

0.18

Sliwa, 2004 27 30 -80 pg/mL t-test <0.01Sliwa, 2004 27 27 -125 pg/mL t-test <0.0005

Yoshizawa, 2004 58 58 -44 pg/mL t-test nsSliwa, 2004

27 30 -75 pg/mL t-test <0.01

Olsen, 2004 19 123 28.5 +/- 36 19.8 +/- 62.0 pmol/L Unpaired Student's t-test nsRichards, 1998 100 pmol/L Pearson product moment <0.001 Tsutamoto, 1997 85 pg/mL Linear regression analysis 0.0002 Tarnow, 2005 386 ng/L na nsUeda, 2003 111 pg/mL Univariate / Multivariate 0.72 Bazzino, 2004 1483 pg/mL Spearman correlation 

coefficient

0.01 

James, 2003 6809 ng/L Multiple linear regression Lindahl, 2005 1352 / 

999

787 (696 to 890) 358 (327 to 

390)

ng/L Mann-Whitney / Multiple 

linear mixed effects

< 0.001 / 

0.05

Bettencourt, 2004 84 pg/mL Spearman 0.01 Bettencourt, 1999 36 pg/mL Multiple linear regression 0.939 Galvani, 2004 1756 ng/L Spearman correlation 

coefficient

0.01 

C-13
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

James, 2003 6809 ng/L Multiple linear regression na Omland, 1996 131 pmol/L Linear regression analysis <0.01 Panteghini, 2003 64 pg/mL Standard Linear regression 0.21 Ueda, 2003 111 pg/mL Univariate / Multivariate 0.02/0.00

2

Zeller, 2004 101 pmol/L Logistic regression <0.01 Wallen, 1997 200 pg/mL na 0.126 Taniguchi, 2004 71 pg/mL na nsBazzino, 2004 1483 pg/mL Spearman correlation 

coefficient

<0.001 

Mega, 2004 436 pg/mL Spearman correlation 

coefficient

0.19 

Morrow, 2003 1676 pg/mL Spearman correlation <0.001 Panteghini, 2003 64 pg/mL Standard Linear regression 0.002 

n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

James, 2003 1420 ng/L Multiple linear regression 

Lindahl, 2005 1352 / 

999

447 (366 to 546) 474 (438 to 

512)

ng/L Mann-Whitney / Multiple 

linear mixed effects

0.60 / ns

Olsen, 2004 20 123 21 +/- 67 19.8 +/- 62.0 pmol/L Unpaired Student's t-test nsSchnabel, 2005 904 204 700 351.8 

(107.35/875.00)

231.5 

(101.00/691.90

)

pg/mL Wilcoxon rank sum ns

Tarnow, 2005 198 188 110 (5 to 79640) 27 (5 to 455) ng/L t-test <0.0001Tarnow, 2005 320 66 ng/L t-test nsSuzuki, 2002 185 pg/mL Univariate/multivariate 0.0558 Bayes-Genis, 2004 28 33 848 +/-297 1118 +/-199 pmol/L Mann-Whitney 0.054Bettencourt, 2000c 31 36 168.0 +/-110.5 339.1 +/-249.9 pg/mL t-test 0.001

C-14
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Bettencourt, 2000c 36 33 339.1 +/-249.9 68.3 +/- 72.6 pg/mL t-test <0.001Bettencourt, 2000a 17 55 137.2 +/- 364.1 362 +/- 536.4 pg/mL Chi-square <0.03Bettencourt, 1999 36 pg/mL Multiple linear regression 0.027 Nielsen, L.S., 2004 32 264 pmol/L t -test <0.001

Redfield, 2004 726 pg/mL Pearson' correlation 

coefficient

<0.0001 

Hamada, 2005 21 31 784 +/-682 688 +/-487 pg/mL Chi-square nsBayes-Genis, 2004 15 86 50 +/-15 9 +/-3 pmol/L Mann-Whitney <0.05Logeart, 2002 48 30 187 +/-158 44 +/-39 pg/mL t-test <0.05Maisel, 2002. 72 770 346 +/-390 110 +/-225 pg/mL t-test <0.001Morrison, 2002 85 135 61 +/-92 759 +/-799 pg/mL t-test <0.001Akioka, 2000 33 pg/mL Linear regression nsSuzuki, 2002 185 pg/mL Univariate/multivariate 0.7956 Yoshimura, 2002 24 24 pg/mL t-test 0.01Yoshimura, 2002 12 12 78 +/-58 139 +/-61 pg/mL t-test 0.05Brunner-La Rocca, 1999

45 45 192 152 pg/mL <0.005

Taniguchi, 2004 71 pg/mL na nsLatini, 2004a 1929 pg/mL Spearman's coefficient <0.001 Richards, 1998 100 pmol/L Pearson product moment <0.01 Koglin, 2001 78 pg/mL Logistic regression <0.0001 James, 2003 2597 ng/L Multiple linear regression Lindahl, 2005 1352 / 

999

606 (529 to 693) 426 (391 to 

463)

ng/L Mann-Whitney / Multiple 

linear mixed effects

<0.001 / 

<0.05

Maisel, 2004a 703 883 pg/mL Kruskal-Wallis and MannWhitney 

U tests

0.756

Olsen, 2004 183 pmol/L nsRedfield, 2004 1058 984 pg/mL Multivariate models <0.0001Schnabel, 2005 208 696 354.5 

(148.4/1288.0)

231.5 

(94.66/662.30)

pg/mL Wilcoxon rank sum <0.001

Ueda, 2003 88 23 pg/mL Univariate / Multivariate 0.98 Weber, 2004 95 114 1852 1221.0 pg/mL Mann-Whitney 0.59Wiviott, 2004 638 1227 68.4 +/-4.5 46.1 +/-2.4 ng/mL Student t test <0.0001Nielsen, O.W.,2004 85 23 pmol/L t-test 0.74Nielsen, O.W.,2004 89 75 pmol/L t-test 0.59

C-15
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Nielsen, O.W.,2004 60 49 pmol/L t-testTarnow, 2005 150 236 ng/L t-test 0.28Kawai, 2001 21 pg/mL Linear regression 0.25 Bettencourt, 1999 36 pg/mL Multiple linear regression 0.551 Bettencourt, 2004 84 pg/mL Spearman 0.48 Tarnow, 2005 198 ng/L na <0.0001 Tarnow, 2005 188 ng/L na 0.002 Tarnow, 2005 386 ng/L na nsO'Brien, 2003 96 fmol/L Pearson product moment 

correlation coefficient

0.011 

Tarnow, 2005 386 ng/L na nsUeda, 2003 111 pg/mL Univariate / Multivariate 0.87 Bettencourt, 1999 36 pg/mL Multiple linear regression 0.825 James, 2003 6809 ng/L Multiple linear regression Kawai, 2001 21 pg/mL Linear regression 0.012 Tsutamoto, 1997 85 pg/mL Linear regression analysis <0.0001 Ueda, 2003 111 pg/mL Univariate / Multivariate 0.46 Tarnow, 2005 198 ng/L na <0.0001 Schnabel, 2005 904 645 259 214.5 

(95.61/670.05)

361.5 

(137.13/1011.7

5)

pg/mL Wilcoxon rank sum <0.001

James, 2003 1995 ng/L Multiple linear regression James, 2003 3515 ng/L Multiple linear regression Schnabel, 2005 904 695 209 261.8 

(103.75/261.8)

213.8 

(96.39/662.30)

pg/mL Wilcoxon rank sum test ns

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0015/.1

795

Suzuki, 2002 89 44 57.3 +/-55.4 19.5 +/-24.0 pg/mL One-way ANOVA 0.01Suzuki, 2002 96 44 29.7 +/-28.3 19.5 +/-24.0 pg/mL One-way ANOVA 0.05Bettencourt, 1999 12 24 pg/mL t-test 0.001

C-16
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Bettencourt, 1999 36 11 61.16 +/-45.38 31.27 +/-18.10 pg/mL t-test 0.001Bettencourt, 1999 24 11 pg/mL t-test 0.0003Richards, 2002 436 657 192 +/-175 160 +/-150 pmol/L Chi-square 0.034Richards, 2002 436 657 111 +/-134 76 +/-80 pmol/L Chi-square <0.001Jernberg, 2003 2019 ng/L not found <0.001 Koglin, 2001 24 54 150.6 +/-25.7 158.9 +/-22.2 pg/mL na nsOlsen, 2004 26 123 67.3 +/- 118 19.8 +/- 62.0 pmol/L Unpaired Student's t-test < 0.05Sadanandan, 2004 88 188 40 24.0 pg/mL Wilcoxon rank-sum test 0.005Sadanandan, 2004 83 6 41 10.0 pg/mL Wilcoxon rank-sum test 0.03Thompson, 2005

19 221.1 +/-124.2 754.1 +/-261.1 pg/mL t-test

<0.0001

Kawai, 2001 21 pg/mL Linear regression <0.001 Kawai, 2001 21 pg/mL Linear regression <0.001 Bettencourt, 2000c pg/mL Pearson's correlation 0.008 Bettencourt, 2000a 85 pg/mL Multiple regression <0.001 Bettencourt, 1999 36 pg/mL Multiple linear regression 0.041 Bettencourt, 1999 47 pg/mL Pearson's correlation 

coefficient

<0.001 

Kawai, 2001 21 pg/mL Linear regression 0.012 Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0001/0.

0095

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0159/0.

4925

Bettencourt, 2004 84 pg/mL Spearman <0.001 Dao, 2001 56 94 86 +/- 39 1076 +/- 138 pg/mL t-test <0.001Nielsen, L.S., 2004 136 81 2.19 +/- 0.97 4.39 +/- 1.31 pmol/L t -test <0.001

Sakatani, 2004 30 pg/mL Linear regression 0.393 Sakatani, 2004 40 pg/mL Linear regression 0.011 Yoshizawa, 2004 26 26 -27 pg/mL t-test nsKyuma, 2004 158 pg/mL Linear regression <0.0001 

C-17
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Suzuki, 2002 185 pg/mL Univariate/multivariate 0.1014 Schnabel, 2005

904 393 511 290.4 (127.6/873.2)

181.8 

(86.91/659.6)

pg/mL Wilcoxon rand sum

<0.001

James, 2003 2067 ng/L Multiple linear regression Olsen, 2004 16 123 112.5 +/- 131 19.8 +/- 62.0 pmol/L Unpaired Student's t-test < 0.01Panteghini, 2003 64 28 119.5 (5-730) 6 (5-48) pg/mL Standard Linear regression < 0.0001Lindahl, 2005 1352 / 

999

651 (569 to 744) 414 (381 to 

451)

ng/L Mann-Whitney / Multiple 

linear mixed effects

< 0.001 / 

0.05

Schnabel, 2005 904 301.5 (135.0/714.8) 218.5 

(90.38/727.95)

pg/mL Wilcoxon rand sum 0.03

Bazzino, 2004 1483 pg/mL Spearman correlation 

coefficient

0.01 

Bertinchant, 2005 63 ug/L Spearman rank correlation <0.0001 Latini, 2004a 4284 pg/mL Spearman's coefficient <0.001 Latini, 2002 4284 pg/mL na <0.001 Richards, 1998 100 pmol/L Pearson product moment <0.001 Stanek, 2001 100 fmol/L Spearman rank-correlation 

coefficient

<0.05 

Tsutamoto, 1997 85 pg/mL Linear regression analysis <0.0001 Jarai, 2005 120 nmol/L Spearman rank correlation <0.0001 Omland, 1996 131 pmol/L Linear regression analysis <0.001 Richards, 1998 100 pmol/L Pearson product moment <0.001 Stanek, 2001 100 fmol/L Spearman rank-correlation 

coefficient

0.0001 

Wang, 2004 3346 pg/mL Spearman's coefficient <0.001 Vasan, 2002 1707 pg/mL Spearman correlation 

coefficient

<0.001 

Vasan, 2002 1470 pg/mL Spearman correlation 

coefficient

<0.001 

C-18
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Ueland, 2004 234 pmol/L na <0.0001 Tsutamoto, 1997 85 pg/mL Linear regression analysis 0.47 Panteghini, 2003 64 pg/mL Standard Linear regression 0.001 Sliwa, 2004 30 30 -45 pg/mL t-test ns

Olsen, 2004 5 123 33.3 +/- 98 19.8 +/- 62.0 pmol/L Unpaired Student's t-test nsLatini, 2004a 4274 pg/mL Spearman's coefficient <0.001 Lindahl, 2005 1352 / 

999

784 (552 to 1113) 460 (427 to 

495)

ng/L Mann-Whitney 0.004

Tsutamoto, 1997 85 pg/mL Linear regression analysis <0.0001 Suzuki, 2002 185 pg/mL Univariate/multivariate 0.0007/0.

0176

Fisher, 2003 87 pg/mL NA nsAkioka, 2000 33 pg/mL Linear regression 0.003 James, 2003 1035 ng/L Multiple linear regression Tsutamoto, 1997 85 pg/mL Linear regression analysis 0.31 Schnabel, 2005 592 312 252.9 

(88.31/758.25)

243.6 

(100.7/767.85)

pg/mL Wilcoxon rank sum ns

James, 2003 1536 ng/L Multiple linear regression 

Shimpo, 2004 448 pg/mL Spearman's coefficient 0.15 James, 2003 153 ng/L Multiple linear regression Lindahl, 2005 1352 / 

999

651 (587 to 723) 350 (318 to 

385)

ng/L Mann-Whitney / Multiple 

linear mixed effects

< 0.001 / 

0.05

James, 2003 6809 ng/L Multiple linear regression Panteghini, 2003 64 pg/mL Standard Linear regression 0.083 Ueda, 2003 111 pg/mL Univariate / Multivariate 0.06/0.69 Grabowski, 2004 126 pg/mL Spearman <0.0001 

C-19
Evidence Table 1. Effect of clinical determinants on BNP and NT-proBNP listed by study

Study n Determinant 

n

Control or 

comparsi

on group 

n

Determinant 

Concentration

Control or 

comparison 

group 

concentration

Units Statistical Method p 

Jarai, 2005 120 nmol/L Spearman rank correlation 0.246 Dokainish, 2005 454 252 38 (8/81) 16 (3/39) pg/mL Student t test <0.0001Dokainish, 2005 29 65 19 (3/57) 15 (0/37) pg/mL Student t test <0.0001Bayes-Genis, 2004 175 pmol/L Spearman's rank correlation <0.0001 Bazzino, 2004 1483 pg/mL Spearman correlation 

coefficient

0.01 

Bertinchant, 2005 63 ug/L Spearman rank correlation 0.002 Ishii, 2003 100 ng/L Linear regression <0.05 James, 2003 6809 ng/L Multiple linear regression Jernberg, 2003 2019 ng/L not found <0.001 Jernberg, 2002 ng/L Spearman rank-correlation 

coefficient

0.01 

Lindahl, 2005 1352 / 

999

797 (719 to 883) 293 (267 to 

321)

ng/L Mann-Whitney / Multiple 

linear mixed effects

< 0.001 / 

0.05

Taniguchi, 2004 20 51 13260 +/-5035 1847 +/-311 pg/mL na <0.001Krum, 2004 1532 1502 -21.56 27.2

pg/mL

Least squares mean change <0.00001

Latini, 2002 1940 1979 (-)21 (+)23 pg/mL Least squares mean <0.0001Maggioni, 2002

123 pg/mL Least squares mean change 0.005

Krum, 2004 1024

pg/mL

Least squares mean change 0.00006

Krum, 2004 1278

pg/mL

Least squares mean change 0.00003

Baruch, 2004 2112 -36.4 pg/mL Placebo-subtracted leastsquares mean difference <0.001Baruch, 2004 1807 -51.4 pg/mL Placebo-subtracted leastsquares mean difference <0.001Krum, 2004 169

pg/mL

Least squares mean change 0.05

Nielsen, L.S., 2004 12 264 pmol/L t -test <0.001

James, 2003 6809 ng/L Multiple linear regression 

C-20
C - 21 

Evidence Table 2. Summary of studies in patients with risk of CAD: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/U

Bhalla 2004 USA 

Cohort: N/A Age: Condition 1 mean age = 52 +/- 20 years (referred group) Condition 2 mean age =  61 +/- 12 years (not referred group) % Male: 96 

482 Followup: 1) Condition 1 (referred group) :827 +/- 384 days2) Condition 2 (nonreferred group): 864 +/- 207 days

Subjects were either referred by physicians or nurse practitioner for echocardiography for clinical suspicion of cardiac dysfunction (referred group) or randomly selected and recruited from the diabetic clinic (not referred group). In this group of patients, there was no suspicion of cardiac dysfunction, no referrals to cardiologists, and no previous records of echocardiography with abnormalities of LV function (systolic or diastolic). 

1) Cardiac mortality 2) All-cause mortality 

NR/NR 1) Unadjusted: initial 

BNP = mortality (referred group) 2) Adjusted (nonreferred) 3) Other variables used in regression analyses, but not statistically significant (p<0.05), were gender, type of diabetes, LV function, and ejection fraction. 

Biosite Diagnostics Triage Cut-off poin20, 40, 60, 100, 120 pg/ml 
C - 22 

Evidence Table 2. Summary of studies in patients with risk of CAD: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/U

Kellett 2004 Ireland 

Cohort: N/A Age: mean age = 73.7 +/- 11.9 (range 19-105) years % Male: 57 

646 Followup: 1) Until discharge 8.3 +/- 6.9 days 2) Until death in hospital 12.2 +/- 9.9 days 

Patients with suspected heart disease who were admitted for acute medical emergencies. Cardiac function was assessed by clinical exam, ECG, and chest Xray. 

In-hospital mortality 

Yes/NR Mortality = systolic 

blood pressure </= 90 mmHg, hemoglobin level </= 100 g/l, white blood cell count > 13000, being unwell before the current illness, BNP >/= 700 pg/ml 

Biosite Diagnostics Triage 700 pg/ml (200 pg/ml increments from 0 to 1pg/ml then >/=1200 pg/ml) 

Suzuki 2002 Japan 

Cohort: N/A Age: mean age = 66 +/- 11 years % Male: 50 

229 Followup: 34.6 months 

Hypertensive persons (systolic blood pressure >/= 140 mmHg or diastolic blood pressure >/= 90 mmHg). 

Cardiovascular events (angina pectoris, myocardial infarction, arrhythmia, stroke, cardiovascular death, sudden death) 

NR/NR Univariate and 

multivariate analysis: age; systolic blood pressure; diastolic blood pressure; pulse pressure; left ventricular mass index ; left ventricular relative wall thickness; mid-wall left ventricular fractional shortening ; E/A ratio; ANP; BNP 

Shionogi & Co. Ltd - NinstrumentShionoriaIRMA (manassay) Cut-off poin68pg/ml 
C - 23 

Evidence Table 2. Summary of studies in patients with risk of CAD: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/U

Ueda 2003 Japan 

Cohort: N/A Age: mean age = 85.5 +/- 5.2 years % Male: 21 

111 Followup: 2 years 

Electrocardiographic abnormalities (presence of left bundle branch block, major Q waves according to the Minnesota code [Q111-Q128]; ST-J depression of 1mm or more or negative T waves in leads II, V2 to V6, AVL, and AVF; voltage criteria for left ventricular hypertrophy; or arrhythmias). Also, patients who had a clinical history of stroke or ischemic heart disease (without hospitalization). 

1) Cardiac event 2) Death 

NR/NR Cox regression: 

plasma BNP = cardiac events, total mortality. Linear regression: plasma BNP = age, sex, body mass index, blood pressure, heart rate, serum total protein, serum creatinine, hemoglobin A1C, serum total cholesterol, ADL score. 

Shionogi & Co. Ltd - NinstrumentShionoriaIRMA (manassay) 1) Cut-off point # 1: > pg/ml (KapMeier) 2) Cut-off point # 2: >100 pg/ml (Cox regression) 
C - 24 

Evidence Table 2. Summary of studies in patients with risk of CAD: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/U

Wang 2004 USA 

Cohort: Framingham Offspring Study Age: Condition 1 mean age = 59 +/- 10 years Condition 2 mean age =  58 +/- 10 years % Male: 47 

3346 Followup: 5.2 years 

Readers are referred to another publication on the Framingham Study to obtain information on diagnostic criteria for cardiovascular events. 

1) Death 2) Major cardiovascular events (myocardial infarction, coronary insufficiency,death from coronary heart disease, heart failure, stroke) 

NR/Yes Cox proportional 

hazards model 

Shionogi & Co. Ltd - NinstrumentShionoriaIRMA (manassay) 1) 20.0 pg/(men) 2) 23.3 pg/(women) 
C - 25 

Evidence Table 2. Summary of studies in patients with risk of CAD: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/U

Nagao 2004 Japan 

Cohort: N/A Age: Condition 1 mean age = 61.5 +/- 12.9 years Condition 2 mean age =  63.4 +/- 10.2 years Condition 3age range =  64.9 +/- 13.4 years Condition 4 age range =  65.4 +/- 10.6 years % Male: 80 

401 Followup: Until discharge (specific length of time not provided) 

Cardiac arrest prior to the arrival of emergency, with presumed cardiac origin of the arrest according to the Utstein Style. 

Survival to hospital discharge 

NR/NR Survival to hospital 

discharge = cardiac arrest, age, gender, CPR, call-response interval, initial cardiac rhythm, ROSC 

Shionogi & Co. Ltd - NinstrumentShionoriaIRMA (manassay) 1) Cut-off point: 100 pg/ml. 2) Analysis based on quartiles of BNP: 2.0-3pg/ml (condition 133.9-152.0 pg/ml (condition 2152.1-392.pg/ml (condition 3392.1-2620pg/ml (condition 4

Abbreviations: N/A=not applicable, NR=not reported, ADL=activities of daily living, LV=left ventricular, ECG=electrocardiograph, E/A=ea

natriuretic peptide, IRMA=immunoradiometric assay, SD=standard deviation, CPR=cardiopulmonary resuscitation, ROSC=return of spon
C - 26 

Evidence Table 3: Summary of studies in patients with risk of CAD: NT-proBNP 

Author Sample Characteristics Sample Size/ Followup Diagnosis criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method/

Gaede 2005 Denmark 

Cohort: Steno-2 study Age: mean age = 55.1 % Male: 74 

160 Followup: 7.8 years 

Diabetic patients between 40-65 years of age. 

Combined mortality endpoint for cardiovascular disease: cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, percutaneous coronary interventions, coronary artery bypass graft, vascular surgery, amputations 

NR/Yes Model 1: CVD = 

diabetes duration, CVD, sex, age Model 2: CVD = diabetes duration, CVD, sex, age, systolic blood pressure, diastolic blood pressure, HbA1c, fasting serum levels of total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, urinary AER 

Roche DiagnostiElecsys 1Elecsys 2E170 or Modular Cut-off po33.5 pg/m

Jernberg 2002 Sweden 

Cohort: N/A Age: Condition 1 mean age 55 (range 48-64) years Condition 2 mean age 70 (range 59-76) years Condition 3 mean age 75 (range 68-80) years Condition 4 mean age 77 (range 70-83) years 

775 Followup: Median 40 months (range 35 to 47 months) 

History of chest pain or other symptoms suggestive of an acute coronary syndrome. 

Death Yes/NR Model 1: death = 

age, diabetes, ECG changes, elevated cTnT, Pcreatinine Model 2: death = BNP, age, diabetes, ECG changes, elevated cTnT, P-creatinine

Roche DiagnostiElecsys 1Elecsys 2E170 or Modular Condition 112 ng/l; condition 113-400 ncondition 401-1653 condition 1654 ng/l 
C - 27 

Evidence Table 3: Summary of studies in patients with risk of CAD: NT-proBNP 

Author Sample Characteristics Sample Size/ Followup Diagnosis criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method/

% Male: 60 

Olsen 2004 USA, Denmark, Norway 

Cohort: Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study Age: Condition 1 mean age 66 +/- 7 years Condition 2 mean age 70 +/- 6 years % Male: 64 

183 Followup: 60 +/- 5 months (range 54 to 68 months) 

Electrocardiographic LV hypertrophy by the Cornell voltage-duration product or the Sokolow-Lyon voltage criterion 

Composite endpoint: cardiovascular death, fatal/non-fatal myocardial infarction, fatal/non-fatal stroke 

NR/Yes Composite 

endpoint = NTproBNP, NTproANP, cardiovascular risk, LV midwall fractional shortening, body weight, smoking, age, LV mass 

Roche DiagnostiElecsys 1Elecsys 2E170 or Modular Cut-off po21.8 pmo
C - 28 

Evidence Table 3: Summary of studies in patients with risk of CAD: NT-proBNP 

Author Sample Characteristics Sample Size/ Followup Diagnosis criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method/

Tarnow 2005 Denmark 

Cohort: N/A Age: Condition 1 (nephropathy) mean age 41 +/- 9.5 years Condition 2 (normoalbuminuria) mean age 42.5 +/-9.9 years % Male: 61 

386 Followup: 9.3 years (range 0 to 9.5 years) 

Diabetic nephropathy: persistent macroalbuminuria (>300 mg 24 h) in at least two out of three consecutive 24-h urine collections, in the presence of diabetic retinopathy and the absence of other kidney or urinary tract disease were recruited 

All-cause mortality Yes/NR Mortality = BNP, 

smoking, antihypertensive medication, systolic blood pressure, serum cholesterol 

Roche DiagnostiElecsys 1Elecsys 2E170 or Modular Cut-off po125 pg/l 

Weber 2004 Germany 

Cohort: N/A Age: 60 (range 46-75) years % Male: 55 

209 Followup: N/A (crosssectional) 

Degenerative aortic stenosis >/= 12 months. Aortic stenotic severity was assessed by the mean transvalvular pressure gradient obtained echocardiographically. 

Severity of aortic stenosis 

NR/Yes Severity of aortic 

stenosis = NTproBNP, NYHA class, left ventricular mass index, body mass index, ejection fraction (data in published report provided only for NT-proBNP and NYHA class) 

Roche DiagnostiElecsys 1Elecsys 2E170 or Modular Cut-off po550 pg/m
C - 29 

Evidence Table 3: Summary of studies in patients with risk of CAD: NT-proBNP 

Author Sample Characteristics Sample Size/ Followup Diagnosis criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method/

Nielsen 2004 Denmark 

Cohort: Copenhagen Hospital Heart Failure Study Age: age range 40-75 years % Male: not reported 

2224 Followup: 1 year 

No obvious heart disease: sinus rhythm, LV ejection fraction > 0.55, no valvular heart disease or dilated or congenital heart disease at referral 

Major adverse cardiac events (MACEs): as LV ejection fraction < 0.35, valvular heart disease, pulmonary congestion on the chest X-ray at the time of admission or development of one of the following incidents during a 90 day follow up period: symptoms of heart failure, myocardial infarction, valvular disease, sudden death or cardiac death. 

Yes/Yes N/A Roche 

DiagnostiElecsys 1Elecsys 2E170 or Modular Cut-off po40-59 yea43.5 pmo74 years pmol/l; >/years = 2pmol/l 

Abbreviations: NR=not reported, N/A=not applicable, CVD=cardiovascular disease, HDL=high density lipoprotein, LDL=low density lipop

excretion rate, ECG=electrocardiograph, cTnT=cardiac tropinin T, LV=left ventricular, CV=cardiovascular, NYHA=New York Heart Asso
C - 30 

Evidence Table 4. Summary of studies in patients with CAD with surgery: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method

Grabowski 2004 Poland 

Mean age: 58.8 +/- 10.7 % Male: 45% 

126 Followup: 42 days 

Admission with acute STEMI, Clinical symptoms of 

ACS, or ST elevation 

>= 1 mm on at least 2 ECG at admission.

All-cause mortality 

Yes/Yes Simple and 

stepwise multiple logistic regression 

Biosite DiagnostTriage Thresholpg/mL 

Jiang 2004 China, Saudi Arabia 

Condition 1 - mean age: 52.8 +/- 9.8 Condition 2 - mean age: 51.8 +/- 9.9 % Male: 83% 

949 completed followup (960 enrolled) Followup: 1 and 6 months 

Current chest pain and unstable angina developed within 24 hours of admission. Patients with acute MI and at least 2 of the following: a) persistent chest pain over 20 minutes, b) elevation of ST segment in at least 2 related leads or developed a branch bundle blockade, c) new abnormal regional wall movement on Echocardiogram, d) elevation of biomarker of myocardium. 

1) Mortality (1 and 6 months)2) Heart failure3) Acute MI 4) ACS 5) Death (all cause/ 6 months) 6) Acute MI (newly developed) 

Yes/NR 1x1 variable 

comparisons using chisquare test Multiple logistic Regression (forward selection) 

Biosite DiagnostTriage Thresholpg/mL 
C - 31 

Evidence Table 4. Summary of studies in patients with CAD with surgery: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method

Wiviott 2004 USA 

TACTICSTIMI 18 Condition 1 mean age  60.2 Condition 2 mean age  64.5, % Male: 66% 

1,865 Followup: 6 months 

Accelerated or prolonged angina, eligibility for PCI, and the presence of at least 1 objective marker of ischemia. 

Combined incidence of death, myocardial infarction (MI), and rehospitalization for acute coronary syndrome (ACS) 

NR/NR Multiple logistic 

regression controlling for differences between genders 

Biosite DiagnostTriage Thresholmg/dl 

Morrow 2003 USA 

Condition 1 - mean age: 60 Condition 2 - mean age: 69 % Male: 62.7% 

1,676 Followup: 6 months 

The index diagnosis was established by the investigator based on local electrocardiographic and laboratory data. 

1) All cause death 2) New or recurrent MI 3) Rehospitalization for acute coronary syndrome (ACS) 4) New or worsening congested heart failure 

NR/Yes Simple logistic 

regression 

Biosite DiagnostTriage BNP dichotom80 pg/ml on previoliterature
C - 32 

Evidence Table 4. Summary of studies in patients with CAD with surgery: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BN

Method

Takase 2004 Japan 

Mean age: 67+/- 1, % Male: 70% 

77 Followup: 25.9 ± 1.4 months 

Positive results on an exercise myocardial singlephoton-emission computed tomography scan using 99m technetiumsestamibi, 99m technetiumtetrofosmin, or 201 thallium-chloride, and had an angiographically significant coronary stenosis (75% stenosis of coronary artery). 

Recurrence of anginal attacks. 

Yes/NR Simple Cox 

proportional hazards 

Shionogi Ltd - No instrumeShionoria(manual Thresholpg/ml 

Abbreviations: STEMI=ST-elevation myocardial infarction, ACS=acute coronary syndrome, ECG=electrocardiograph, UnAdj=unadjusted

ratio, MI=myocardial infarction, PCI=percutaneous coronary intervention, TIMI=thrombolysis in myocardial infarction, NR=not reported 
C - 33 

Evidence Table 5. Summary of studies in patients with CAD no surgery: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units 

Mega 2004 USA 

Age range: 21-75 years % Male: 77 

438 Followup: 30 days from angioplasty 

ST segment elevation myocardial infarction 

Mortality NR/NR Fisher's exact 

test and Chi Square test for simple comparisons between variables. Logistic regression 

Bayer Healthcare - ADVICentaur Threshold: 80 pg/mL 

Omland 1996 Scandanavia 

Mean age: 67.8 % Male: 74.8 

131 Followup: Median = 1293 days 

Unspecified Mortality NR/Yes Simple and 

multiple Cox proportional hazards regression 

Shionogi & Co. Ltd - No instrument, ShionoriaIRMA (manual assay) Threshold: 115.22 pg/mL 
C - 34 

Evidence Table 5. Summary of studies in patients with CAD no surgery: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units 

Wylie 2004 USA 

No data reported in the publication - readers are referred to another reference. 

1124 Followup: periods at 30 days, 10 months 

Ischemic discomfort at rest lasting >/= 5 minutes and associated with >/=1 of these features: new ST segment deviation >/= 0.5 mm, Twave inversion >/= 3 mm in 3 leads or left bundle branch block, positive cardiac markers, or documented coronary artery disease. 

Development of CHF or cardiogenic shock 

NR/Yes Backward 

selection logistic regression 

Biosite Diagnostics – Triage Threshold: 80 pg/mL 
C - 35 

Evidence Table 5. Summary of studies in patients with CAD no surgery: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units 

Sabatine 2002 USA 

No data reported in the publication - readers are referred to another reference. 

450 patients from OPUSTIMI-16 trial 1635 patients from TACTICS-TIMI 18 trial (as part of validation cohort) Followup: periods at 6 months, 10 months 

Non-ST elevation acute coronary syndromes (OPUS-TIMI16) 

1) All cause mortality 2) Non-fatal MI 3) Development of congestive heart failure 4) Composite of 1-3 

NR/NR Multiple Cox 

proportional hazards regression 

Biosite Diagnostics – Triage Threshold: 80 pg/mL 
C - 36 

Evidence Table 5. Summary of studies in patients with CAD no surgery: BNP 

Author Sample Characteristics Sample Size/ Followup Diagnostic Criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units 

Bettencourt 2000 Portugal 

Mean age: 58.3 +/- 12.6 % Male: 84.2 

101 Followup: 12 months 

Admission to cardiac unit with acute myocardial infarction as defined by the presence of typical cardiac ischemic symptoms, presence of ischemic changes on ECG in two or more leads, and peak elevation of plasma creatinine kinase to at least level twice of normal. 

1) Left ventricular dysfunction 2) Heart failure 3) Ischemia event 

Yes/NR Likelihood ratiobased forward 

stepwise logistic regression analysis 

Shionogi & Co. Ltd - No instrument, ShionoriaIRMA (manual assay) Threshold values: 142.3 pg/mL for systolic dysfunction; 93.8 pg/mL for isolated diastolic dysfunction or systolic dysfunction; 259.1 pg/mL for heart failure; 380.5 pg/mL for death. 

Abbreviations: NR=not reported ADVIA= CHF=congestive heart failure, IRMA= immuno radiometric assay, OPUS=Orbofib

Unstable Coronary Syndromes, TIMI= thrombolysis in myocardial infarction, MI=myocardial infarction, ECG=electrocardiog
C - 37 

Evidence Table 6: Summary of studies in patients with CAD not surgery: BNP 

Study 

Sample 

Characteristi

cs 

Sample 

Size 

/Followup 

Diagnostic 

criteria Outcomes

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units Measu

de Winter 2004 Netherlands 

Condition 1 - mean age: 68 +/- 10 years Condition 2 - mean age: 60 +/- 11 years % Male: 70 

1172 Followup: 12 to 14 months 

Consecutive patients undergoing PTCA 

1) Death 2) Myocardial infarction 

Yes/NR Simple logisitic 

regression (highest quartile as decision threshold for increased NT proBNP), Stepwise multiple logistic regression, Cox survival analysis 

Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: 456 pg/mL 

Mortality infarctionratio = 7.0interval 3Mortality: = 13.47 (4Myocardiunadjuste(0.77-8.34Event-freodds ratio 

Galvani 2004 Italy 

Condition 1 - mean age: 59 +/- 11 years Condition 2 - mean age: 65 +/- 11 years % Male: 71 

1726 Followup: 30 days 

Rest anginal pain lasting more than 10 minutes and occurring within 24 hours of admission to coronary care unit (angina was associated with ischemic ECG changes) 

Mortality at 30 days 

NR/NR Simple and 

multiple logistic regression for 30 day mortality 

Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Threshold: Modular/Quartiles: </= 107 pg/mL, 108–353 pg/mL, 354–1357 pg/mL, >/= 1358 pg/mL 

First quarcategory 30 day m2nd quartUnadjuste(1.15-7.52Adjusted (0.79-2.243rd QuartUnadjuste(2.19-12.9Adjusted (1.00-3.584th quartiUnadjuste(4.90-26.8Adjusted (1.51-10.
C - 38 

Evidence Table 6: Summary of studies in patients with CAD not surgery: BNP 

Study 

Sample 

Characteristi

cs 

Sample 

Size 

/Followup 

Diagnostic 

criteria Outcomes

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units Measu

Bazzino 2004 Argentina 

Mean age: 66+/- 12 years % Male: 63.6 

1483 Followup: From hospital admission to 180 days or death (which came first) 

Resting chest pain within 24 hours of admission to coronary care unit 

1) Combined endpoint of mortality or or non-fatal MI. 2) All cause mortality (in hospital and 180 day). 3) New non-fatal myocardial infarction (MI). 

Yes/Yes Stepwise multiple 

logistic regression 

Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: 586 pg/mL 

For 180 dstrongest predictor cardiac mcategoricadjusted (1.95-5.98After forwregressioremained For 180 dodds ratio For 180 dmyocardiodds ratio For in-hosadjusted (1.31–2.2

James 2003 Sweden 

Mean age: 65 +/- 11 years % Male: 61.9 

6809 Followup:1) 30 days 2) 12 months 

One or more episodes of angina lasting >/= 5 minutes, within 24 hours of admission, and either a positive cardiac troponin test or >/= 0.5 mm of ST-segment depression. 

1) Myocardial Infarction 2) Mortality: 30 day and 12 month 

NR/Yes Multiple logistic 

regression 

Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: Quartiles: <= 237 pg/mL, 238–668 pg/mL, 669–1869 pg/mL, >1869 pg/mL 

For the ouinfarction confidencquartiles of 1.00, ththe adjust(depicted statistical5% level. For mortaadjusted from appr(depicted odds ratiosignifican
C - 39 

Evidence Table 6: Summary of studies in patients with CAD not surgery: BNP 

Study 

Sample 

Characteristi

cs 

Sample 

Size 

/Followup 

Diagnostic 

criteria Outcomes

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units Measu

Richards 2003 New Zealand 

Mean age: 62.4 +/- 10.4 (range 26-80) years % Male: 78.2 

666 Followup:3 years (mean) 

Myocardial infarction: ischemic change (including ST elevation or depression or dynamic T-wave changes; i.e., includes STelevation, non–ST elevation, Qwave, and non–Q-wave infarcts) in 2 or more ECG leads and peak elevation of plasma creatinine kinase to at least twice the upper limit of normal. 

1) Mortality2) Readmission to hospital with heart failure 3) New Myocardial Infarction 4) All recurrent acute coronary syndromes (ACS) 

NR/NR Stepwise Cox 

proportional hazards regression 

[NT-proBNP] New 

Zealand (Christchurch) - no instrument, manual assay

Threshold: 1370 pg/mL 

Death: ad6.63 (3.72between fraction < ratio = 3.2Death or rate ratio Reinfarcti= 3.51 (1.between fraction < ratio = 3.8Death, hereinfarctio= 2.27 (1.between fraction < ratio = 1.5Death, hecoronary rate ratio interactioand ejectadjusted (1.17-2.10
C - 40 

Evidence Table 6: Summary of studies in patients with CAD not surgery: BNP 

Study 

Sample 

Characteristi

cs 

Sample 

Size 

/Followup 

Diagnostic 

criteria Outcomes

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis/Model BNP Method/Units Measu

Omland 2002 Sweden 

Condition 1 - mean age: 62 Condition 2 - mean age: 69 % Male (NTproBNP <=545 pmol/L): 73 % Male (NTproBNP <545 pmol/L): 70 

609 Followup:Median: 51 months (range 19-72 months) 

Clinical diagnosis not specified 

All-cause mortality 

Yes/NR Multiple Cox 

proportional hazards regression 

Manual method referencing - Carl J., Borgya A., Gallusser A. et al. Development of a novel, N-terminalproBNP (NTproBNP) assay with a low detection limit. Scand J Clin Lab Invest Suppl 1999; 230:177-81 Threshold: 4609 pg/mL 

Unadjuste(2.4-6.5) Adjusted 3.9) (after and eject= 2.4 [1.1

Abbreviations: PTCA= NR=not reported, ECG=electrocardiogram, MI=myocardial infarction, PCTA=percutaneous transluminal coronary 
C - 41 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Squire 2004 U.K. 

Mean age: 65 (range 32-95) years % Male: 75 

403 Followup: Median = 462 (range 5-764) days 

AMI was defined as presentation with at least two of three standard criteria, i.e. appropriate symptoms, acute ECG changes of infarction (ST elevation, new left bundle branch block) and a rise in creatine kinase to at least twice the upper limit of normal, i.e. > 400 international units/(200 nmol) in 0.1 mol/l phosphate buffer, and the tracer purified on reversed-phase HPLC. Acute MI pateints who presented with 2 or 3 criteria (i.e. appropriate symptoms, acute ECG changes [ST elevation, new left bundle branch block]) and a rise in creatine kinase to at least twice the upper limit of normal, i.e. >400 international units/l. 

1) Mortality <30 days 2) Mortality > 30 days 

Yes/NR ANOVA, Cox 

proportional hazards (multiple), logisitic regression (multiple), Kaplan-Meier curves 

Manual mreferencinJ., Borgya Gallusser Developmnovel, N-tproBNP (NproBNP) awith a low detection Scand J CInvest Sup1999; 230Thresholdpg/mL 
C - 42 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Jernberg 2003 Sweden 

Age range: 40-84 years % Male: Not reported 

2019 Followup:</= 2 years 

Myocardial ischemia had to be verified by an electrocardiogram (STsegment depression =>0.10 mV or T-wave inversion =>0.10 mV) or by raised biochemical markers. 

1) Mortality 2) Myocaridal infarction 

NR/NR Multiple 

logistic regression and multiple Cox proportional hazards 

Roche DiagnosticElecsys 1Elecsys 2E170 or MThresholdpg/mL (me672 pg/mL (women) 

Palmer 2003 New Zealand 

Mean age: 62.1 years % Male: 78 

978 Followup: Median = 2.4 (range 2-2119) days 

The presence of typical cardiac ischemic symptoms, ischemic change on the electrocardiogram in two or more contiguous leads, and peak elevation of plasma creatine kinase to at least twice normal (400 U/l). All patients were troponin T positive. 

Mortality postmyocardial infarction 

NR/Yes Multiple Cox 

proportional hazards 

New Zeala(Christchuno instrummanual asThresholdpg/mL 
C - 43 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Richards 1998 New Zealand 

Mean age: 64 +/- 10 years % Male: 74 

Control: 35 normal subjects not matched for age. Treatment: 121 patients with acute myocardial infarction. Followup: 24 months 

Acute myocardial infarction was defined by the presence of typical cardiac ischemic symptoms, the presence of ischemic changes on the ECG in two or more ECG leads, and peak elevation of plasma creatine kinase to at least twice normal (400 U/L). 

1) All-cause mortality 2) Left ventricular ejection 

Yes/NR Multiple 

logistic regression 

New Zeala(Christchuno instrummanual asThresholdpg/mL for 1032 pg/mleft ventricfailure 

Darbar 1996 USA 

Mean age: 63.0 years % Male: 70.7 

75 Followup: Median: 19.7 (range 14-31) months 

Patients were assessed by clinical, echocardiographic, and neurohormonal methods to identify left ventricular dysfunction. 

1) Cardiovascular death 2) Development of symptomatic heart failure 

NR/Yes Stepwise 

logistic regression 

New Zeala(Christchuno instrummanual asThresholdpg/mL 
C - 44 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Jarai 2005 Austria 

Mean age: 63 +/- 13 years % Male: Not reported 

120 Followup: 2 years 

Typical angina symptoms within the last 24 hours and signs of myocardial ischaemia in the 12 lead ECG (ST-depression of 0.1 mV in two continuous leads, T-wave inversion or both with concomitantly elevated TnI [>0.15 ng/mL] levels were diagnosed as non-STelevation myocardial infarction). Patients without TnI elevations were diagnosed with unstable angina. 

Cardiovacular death 

Yes/NR Multiple 

logistic regression 

Biomedica - No instruEIA (manuassay) Thresholdpg/mL (upor normal 

Latini 2004 Italy 

Mean age: 31.9 % Male: 69 

724 Followup: 3 months 

Clinical persistent STsegment elevation, maximal CK value exceeding 2X upper limit of reference range during the first hours after the index event. 

1) All-cause mortality 2) Episodes of heart failure 3) Cardio residual ischemia 4) Combined death and heart failure 

NR/Yes Multiple 

logistic regression 

Roche DiagnosticElecsys 1Elecsys 2E170 or MThresholdpg/mL 
C - 45 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

James 2004 Europe, North America 

Mean age: 65 % Male: 62 

1381 Followup: 12 months 

1 or more episodes of angina > 5 min and STdepression > 5mm or Troponin or I test elevation. 

1) Mortality at 12 months 2) Myocardial infarction 3) Death or MI 

NR/Yes Multiple 

logistic regression 

Roche DiagnosticElecsys 1Elecsys 2E170 or MThresholdQuartiles: pg/mL, 23pg/mL, 66pg/mL, anpg/mL 
C - 46 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Ueland 2004 U.K. 

Condition 1 - mean age: 63 +/- 8 years (osteoprotegerin<2.1) Condition 2 - mean age: 67 +/- 10 years (OPG<3.0) Condition 3 - mean age: 69 +/- 10 years (OPG<4.1) Condition 4 - mean age: 72 +/- 11 years (OPG>4.1) % Male: 70.2 

Control: 15 age and gender matched healthy controls Treatment: 234 patients with acute myocardial infarction complicated by heart failure Followup: Median 2.7 years 

Left ventricular dysfunction (i.e., left ventricular ejection fraction [LVEF] <35% or a left ventricular end-diastolic dimension >65 mm) and/or HF during the acute phase as suggested by one or more of the following: treatment with diuretic or intravenous vasodilator therapy for HF, pulmonary rales, third heart sound, persistent sinus tachycardia (=/> 100 beats/min), or radiographic evidence of pulmonary congestion. 

1) Non-fatal myocardial infarction 2) Cardiovascular death 3) Total mortality death 

NR/NR Simple Cox 

proportional hazards 

Manual mreferencinJ., Borgya Gallusser Developmnovel, N-tproBNP (NproBNP) awith a low detection Scand J CInvest Sup1999; 230Thresholdpg/mL 
C - 47 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Schnabel 2005 Germany 

Condition 1 - mean age: 60.7 +/- 9.7 years Condition 2 - mean age: 62 +/- 11.2 years % Male: 77 

904 Followup: Median 2 years (maximum 3.7 years) 

Under coronary angiography: at least one stenosis >30% diagnosed in a major coronary artery, unstable angina classified by Braunwald classification (class B or C), acute myocardial infarction (STsegment elevation in at least two corresponding leads plus troponin elevation - LVEF was determined by LV-angiography and off-line analysis according to the area–length method). 

Cardiovascular events 

NR/NR Multiple Cox 

proportional hazards 

Roche DiagnosticElecsys 1Elecsys 2E170 or MThresholdpatients wstable angquartile 1 pg/ml) quartile 2 192.0 pg/mquartile 3 487.9 pg/mquartile 4 pg/ml) Hazard raaccording quartiles obaseline NproBNP in patients wquartile 1 pg/ml) quartile 2 538.1 pg/mquartile 3 1356.0 pgquartile 4 pg/ml) 
C - 48 

Evidence Table 7: Summary of studies in patients with CAD no surgery: NT-proBNP 

Author Sample Characteristics Sample Size /Followup Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP M

/Un

Heeschen 2004 Germany, New Zealand 

Condition 1 - mean age: 59.9 +/- 10.9 years Condition 2 - mean age: 64.1 +/- 10.8 years % Male: 67% 

1791 Followup: 30 days 

Chest pain at rest or accelerating chest pain within the previous 24 hours. All patients had evidence of coronary artery disease as described in another article. 

1) Mortality 2) Myocardial infarction 

NR/NR Multiple 

logistic regression 

Roche DiagnosticElecsys 1Elecsys 2E170 or MThresholdpg/mL 

Abbreviations: LVEF=left ventricular ejection fraction, AMI=acute myocardial infarction, ECG=electrocardiogram, HPLC=high pressure 

MI=myocardial infarction, NR=not reported, HF=heart failure 
C - 49 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Dokainish 2005 USA 

Condition 1 - mean age: 57.3 +/- 11.6 years Condition 2 - mean age: 60.6 +/- 13.3 years % Male: 57 

895 Followup: NR 

Angiographic CAD if >/= 50% stenosis in coronary artery 

Death or Re-infarction NR/Yes Chi-square, 

Fisher exact test, t-test, Wilcoxon rank-sum, KruskalWallis 

[BNP] BiosDiagnostics Triage Threshold: 80 pg/mL 

Lindahl 2005 Sweden 

Mean age: 67 years % Male: 71 

961 Followup: 2 years if randomized to invasive vs noninvasive surgery 6 months if randomized to daltperin vs placebo 

Non-ST-segment elevation. Both chest pain and signs of ischemia (ST-segment depression =>0.10 mV or T-wave inversion =>.10 mV or raised biochemical markers. 

1) Changes in NT-proBNP after 5 serial measures expressed as  a) median values  b) mean rate of change  per visit Outcomes for the FRISC-II trial2) mortality 3) MI 

NR/NR Multiple 

linear and logistic regression 

[NT-proBNRoche Diagnostics Elecsys 10Elecsys 20E170 or MoThreshold: Baseline NproBNP me= 529 pg/mmonths me238 pg/mL 
C - 50 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Panteghini 2003 Italy 

All subjects mean age  52.5 years All subjects age range  33-78, 89% 

Controls: 28 agematched apparently healthy laboratory workers Treatment: 64 acute myocardial infarction patients Followup: 13 months median (range 4 to 23 months) 

Made by cardiologist 

1) All cause mortality 2) Unstable angina or recurrrent MI 

NR/Yes Linear 

regression, KaplanMeier survival curve 

[BNP] BiosDiagnostics Triage Threshold: 83 pg/ml 

Richards 2002 New Zealand 

Mean age: 63.6 years % Male: 72.6 

747 Followup: 2 year mean (up to 1000 days) 

Patients were categorized as having antecedent hypertension if this diagnosis was known by the patient to have been made by their family physician or after specialist referral, if the acute admission note indicated a history of hypertension and/or they were receiving antihypertensive medication. 

1) Mortality 2) Pre-discharge heart failure 3) Re-admission for heart failure

NR/NR Multiple Cox 

proportional hazards or logistic regression 

NT-proBNP Threshold: pg/mL 
C - 51 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Sadanandan 2004 USA 

Condition 1 - mean age: 61 years Condition 2 - mean age: 67 years % Male: 65% 

276 Followup: 6 months 

Subjects from TACTICS-TIMI-18 trial. All patients had unstable angina, non-ST elevated myocardial infarction (UA/NSTEMI), and cardiac cathertization within 4-48 hrs and revascularization. 

Composite endpoint of death, non-fatal re-infarction, and repeat hospitalization for ACS (P) 

NR/Yes Chi square 

test 

[BNP] BiosDiagnostics Triage Threshold: 80 pg/mL 

Shimpo 2004 USA 

Mean age: 58 years % Male: 79.2 

810 Followup: 30 days 

Episode of ischemic discomfort of at least 30 minutes within 6 hours or 12 hours and exhibited at least 0.1-mV STsegment elevation in 2 contiguous ECG leads. 

1) Congestive heart faliure 2) Mortality 30 day 3) Mortality 

NR/NR Multiple 

logistic regression 

[BNP] Shio& Co. Ltd - instrument, Shionoria-I(manual asThreshold: 80 pg/ml 

Suzuki 2004 Japan 

Condition 1 - mean age: 64.7 +/- 11.1 years Condition 2 - mean age: 66.7 +/- 7.9 years % Male: 73% 

145 Followup: 58.6 month mean (range 1-158 months) 

The diagnosis of AMI was made from clinical symptoms, including chest pain,ECG changes including ST elevation and ST depression, and an elevation of serum creatine kinase-MB isoenzyme to more than twice the normal upper level. 

Cardiac related mortality NR/NR Cox 

proportional hazards regression 

[BNP] Shio& Co. Ltd - instrument, Shionoria-I(manual asThreshold: 180 pg/ml 
C - 52 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Zeller 2004 France 

Mean age: 69 (range 55-77) Years % Male: 69 

101 Followup: NR 

All patients with a diagnosis of MI exceeding the decision limit increase in troponin I (10.1 ng/ml) associated with either typical ischemic symptoms or ECG signs (STsegment depression or negative T waves). 

1) Death or recurrent MI 2) Death or recurrent MI or heart failure 

NR/NR Multiple 

logistic regression 

[NT-proBNRoche Diagnostics Elecsys 10Elecsys 20E170 or MoThreshold: proBNP 13pmol/L 
C - 53 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Hutfless 2004 USA 

Mean age: 63 +/- 9.1 years % Male: 100 

98 Followup: NR 

CAD included: 1) Myocardial infarction within 6 weeks preoperatively n=7.2) CHF NYHA functional class III or IV n=9. 3) Insulindependent diabetes mellitus n=10. 4) Past cerebrovascular accident n=10. 5) Chronic renal insufficiency n=7. 6) Previous percutaneous transluminal coronary angioplasty/stent n=19. 7) Previous thoracotomy n=9. All male patients undergoing heart surgery at the VA hospital were eligible for inclusion

Clinical end points included: 1) intraoperative and postoperative cardiac events: significant STsegment change, significant arrhythmia, new Q-wave, or cardiac enzyme elevation; 2) ventilator dependence >48 h postoperatively; 3)intensive care unit stay longer than 5 days postoperatively; 4) hospital stay longer than 10 days postoperatively; 5) emergency reintubation other than for reoperation; 6)cardiothoracic reoperation within 2 weeks of initial surgery;7) readmission within 30 days for cardiac reasons; 8) requirement for intra-aortic balloon pump (IABP); 9) mortality within 30 days and within 1 year postoperatively; and 10) postoperative requirement for epinephrine, lidocaine, and/or pressor doses of dopamine. 

Yes/NR None [BNP] Bios

Diagnostics Triage Threshold: cut-points: 120 pg/ml 280 pg/ml 385 pg/ml 

Julier 2003 Switzerland 

Mean age: 63.5 years % Male: 81.9 

72 Followup: 72 hours 

Scheduled for elective CABG surgery on CPB circuit with cardiac arrest. 

NT-proBNP levels in treated vs. placebo patients postoperative cardiovascular and renal adverse events. 

NR/Yes None [NT-proBN

Roche Diagnostics Elecsys 10Elecsys 20E170 or MoThreshold: 
C - 54 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Kerbaul 2004 France 

Condition 1 - mean age: 68 +/- 10 years Condition 2 - mean age: 67+/- 9 years % Male: 80% 

60 Followup: Without complications: 2.6 +/- 0.9 days With complications: 6.9 +/- 3.8 days 

1) Recent MI: acute coronary syndrome with or without ST modification or and with Tropinin I level modifications occurring within 6 weeks of the operation. 2) Unstable angina: associated with acute coronary sybdrome w/out modification in Tropinin I. 3) Peripheral arteriosclerosis: history of claudication or peripheral vascular surgery. patients undergoing elective OPCAB who were free of active preoperative infection and inflammation 

1) Cardiovascular complications (myocardial infarction, cardiogenic shock, arrhythmias, 

CHF, and death occurring after the fourth postoperative hour) Abnormal post-operative cardiovascular course: ICU: (a) systolic arterial pressure < 90 mmHg with low cardiac output (cardiac index <2 l min^-1 m^-2) and signs of hypoperfusion such as oliguria; (b) need for catecholamines for cardiovascular support (dobutamine >5 ug kg^-1 min^-1 or any amount of epinephrine or norepinephrine >6 h); (c) postoperative myocardial infarction defined as a maximal creatine kinase MB fraction level >100 IU l^-1 associated electrocardiographic modifications and segmental hypokinesia at the echocardiography; (d) CHF defined by fluid retention and persistent chest infiltration; (e) atrial fibrillation >15 min with hemodynamic instability requiring electrical or pharmacological cardioversion; (f) ventricular fibrillation or tachycardia requiring electrical cardioversion; (f) operative mortality occurring within 30 days of the operation. 

Yes/Yes Unadjusted 

regression:BNP = preoperative left ventricular ejection fraction BNP = NYHA status 

[NT-proBNRoche Diagnostics Elecsys 10Elecsys 20

E170 or MoThreshold: minutes aftintroduction anesthesia before surg> 397 pg/mT1: 10 minuafter the ensurgery --> pg/ml. T2: 4 hours the end of surgery --> pg/ml. (Various measures oproBNP ovtime) 
C - 55 

Evidence Table 8: Summary of studies in patients with CAD no regression analyses 

Author 

Sample 

Characteristi

cs 

Sample 

Size/Follow

up 

Diagnostic criteria Outcomes 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis/M

odel 

BNP 

Method/U

Song 2004 Japan 

Condition 1 - mean age: 66.7+/- 9.3 years (onpump CABG) Condition 2 - mean age: 71.6 +/- 7.4 (off-pump CABG) % Male: 72.5% 

40 Followup: 1 month 

New York Heart Association 

BNP levels Correlations between BNP and sample characteristics in both surgery groups. 

NR/NR Simple and 

multiple regression:BNP = CAB + pleural effusion BNP = CAB + atrial fibrillation 

[BNP] Shio& Co. Ltd - instrument, Shionoria-I(manual asThreshold: pg/ml 

Watanabe 2003 Japan 

Not Reported 14 

Followup: 20 months 

Undergoing elective CABG with cardiopulmonary bypass (CPB) 

1) Clincal status: death, requiring intra-aortic balloon pump (IABP) support for left ventricular dysfunction, angina, graft failure, heart disease, cardiac scintingraphy, occlusion or critical stenosis of bypass grafts or progression of native coronary stenosis). 2) Presence of angina, NYHA class, positive cardiac scintigraphy, occlusion or critical stenosis of bypass grafts. 

NR/NR Simple 

linear regression:BNP = clinical status 

[BNP] Shio& Co. Ltd - instrument, Shionoria-I(manual asThreshold: 

Abbreviations: CAD=cardiovascular artery disease, MI=myocardial infarction, NR=not reported, ECG=electrocardiogram, AMI=acute myOR=odds ratio, CI=confidence interval, CHF=congestive heart disease, NYHA=New York Heart Association, ACS=acute coronary syndartery bypass graft 
C - 56 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Maisel 2004 USA 

•Cohort: REDHOT •Age: Mean, 64 •Age: Range, 51 - 76 •% Male: 54% 

464 Followup: 30 and 90 days 

•REDHOT cohort enrolled only If had BNP > 100pg/mL NYHA (I-IV): 3.0% level I, 29% level II, 46% level III, 22.6% level IV. 45 % Level III •Clinical evaluation only. •LVEF Not Reported

Mortality NR/Yes Multivariate 

logistic regression 

[BNP] Biosite Diagnostics – Threshold:200 (chosen retrospectivelon internal an

van der Meer 2004 Netherlands 

•Cohort: NA •Age: Range, 26 to 90 •% Male: 80% 

74 Followup: Deceased: mean 621 days (range 16 to 1,728 days) Survivors: mean 1100 days (range 844 to 1,934 days) and a median of 987 days (37 months) 

•Stable mild to moderate CHF patients admitted to clinic (NYHA II - IV): 37% level II,32% level III, 31% level IV•Based on standard criteria from European Society for Cardiology (including echocardiography) and standard criteria (NYHA) •Used in regression analyses as a continuous variable to predict all cause mortality 

All cause mortality 

Yes/No Uni and 

multivariate Cox backward Wald regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold:No threshold speMean BNP 1013.5 pmol/L [Conversion 3pg/mL +/- 46.
C - 57 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Latini 2004 Italy 

•Cohort: Val-HeFT •Age: Mean, No info •%Male: No info 

4300 Followup: Not Specified (23 months outcomes are discussed in the results but not clear if this is total followup time) 

•ValHeFT cohort: stable but symptomatic HF (NYHA I-IV) •LVEF < 40% and LV internal diameter in diastole adjusted for body surface area (LVIDd/BSA) of =>2.9 cm/m2. •LVEF < 40% 

Mortality NR/No Uni and 

multivariate Cox proportional hazard regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold:97 (median samp

Kyuma 2004 Japan 

•Cohort: N.A. •Age: Mean, 64+/-13, •% Male: 69.6% 

158 Followup: 16 months +/-9 months 

•NHYA (I-IV): 12% level I, 49% level 2, 25% level III, 14% level IV •Presence of symptoms, 2D echocardiogram, IMIGB scintography•Pr34 % had </= 30% LVEF 

Cardiac death due to pump failure 

Yes/No Uni and 

mulitvariate Cox proportional hazards regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: >1pg/mL (mediasample) 
C - 58 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Bettencourt 2004 Portugal 

•Cohort: N.A. •Age: Mean, 69.4+/-9.3 •% Male: 71.4% 

84 Followup: Median 1190 days (interquartile range 863–1572). 40 months 

•Patients referred to a HF clinic and then followed on an outpatient basis. Note that those who did not survive to second scheduled measurement were excluded from the study. (NYHA I -III): 11.9% level I, 81% level II, 7% level III.•Clinical examination including ECG, chest X-ray, spirometry, echocardiogram, serum biochemical analyses. •Mean LVEF 31.2% +/- 12.0 

Mortality NR/Yes Uni and 

multivariate Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: 26pg/mL (mediasample); also compared subwhose BNP leincreased verthose that decfollowing treat

Ishii 2003 Japan 

•Cohort: N.A. •Age: Mean, 68 + 11 •% Male: 56% 

100 Followup: Mean 391 days (range 16-884) 13 months 

•Patients admitted to hospital for worsening CHF (NYHA III-IV): 54% level III and 46% level IV •Cardiologists not directly involved in the study determined if pateients met exclusion criteria. 2D Echocardiogram and venous blood samples were used to detrmine severity.•12% of patients had mean LVEF 36% 

Cardiac death (death from worsening CHF, fatal MI or sudden death) 

NR/Yes Uni and 

multivariate Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold:160 (based on RObest sensitivit[Conversion 1pg/mL] 
C - 59 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Vrtovec 2003 New Zealand 

•Cohort: N.A. •Age: Mean, 67+/-14, •% Male: 59% 

241 Followup: 6 months 

•Patients referred with heart failure to single centre (Patients with BNP >400 pg/mL who had been NYHA class III-IV for at least 2 months before evaluation) (NYHA III-IV): 74% level III, 26% level IV. •Clinical evaluation and ECG. •Mean LVEF = 26% +/- 9% 

All cause mortality 

NR/No Uni and 

multivariate Cox proportional hazard regression 

[BNP] Biosite Diagnostics - Threshold: Thcategories (<7pg/ml, 701-10pg/mL, > 1000 
C - 60 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Ishii 2002 Japan 

•Cohort: N.A. •Age: Mean, All subjects, 69+/- 9 •Age: Mean, Condition 1: 71+/-10 •Age: Mean, Condition 2: 68+/-10 •Age Range, All subjects, 22-88 •% Male: 52% 

98 Followup: Mean 451 +- 98 days (range 13 to 667 days) 15 months 

•Patients were admitted to a coronary care unit due to worsening CHF. (NYHA mean 3.5 +/- 0.6) •2D echocardiography read by experts blinded to the study. •Mean LVEF = 42% +/- 17 

1) Cardiac death (death from worsening chronic heart failure, fatal myocardial infarction, or sudden death) 

Yes/No (but endpoints judged by independent researchers) 

Uni and multivariate Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: BNpg/ml (based analysis) 

Harrison 2002 USA 

•Cohort: N.A. •Age: Mean, 65 •Age: Range, 29-83 •% Male: 95% 

325 Followup: Mean followup time=682.2 +- 55.0 days 23 months 

A convenience sample presenting with dyspnea to the emergency department (41% CHF) Diagnosis: Echocardiogram results from previous records was used to establish CHF. LVEF not reported 

Mortality (any cardiac, noncardiac, and CHF) 

No/Yes Unadjusted 

Relative Risks

[BNP] Biosite Diagnostics - Threshold: 48based on ROpg/mL (providfalse negative 

Stanek 2001 Austria 

Subjects with HF (LVEF < 25%) from a substudy of subjects from RCT evaluating those on atenolol versus placebo. (NYHA II-IV): 78% level II, 13% level III, 2% level IV. 

SS = 91 Followup: 4 years 

Radionuclide ventriculography and clinical evaluation 

Cardiac mortality 

NR/No Uni and 

mulitvariate Cox proportional hazards regression 

[NT-proBNP] Biomedica GrNo instrumen(manual assaThreshold: 30fmol/ml N-BNavailable plaslevel). 
C - 61 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Imamura 2001 Japan 

•Cohort: Ehime MIBG Heart Failure (EMIHEF Study) •Age: Mean, All subjects, 63 +/- 11 •Age: Mean, Condition 1: 64 +/- 11 (Event free) •Age: Mean, Condition 2: 65 +/- 12 (Cardiac death) •Age: Mean, Condition 3: 61 +/- 14 ( hospitalization) •% Male: 73% 

171 Followup: 27+/- 8 months 

•Ehime MIBG Heart Failure Study (EMIHEF) randomized trial. (NYHA II-IV): 54% level II, 18% level III, 3% level IV. •Clinical evaluation, including NYHA, IMIBG images, Chest x-ray, 2D echocardiography •Mean LVEF 27%+/-10% 

Cardiac mortality, defined as death from progressive CHF or sudden cardiac death 

NR/No Uni and 

multivariate Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: <1pg/ml (mean osample) 

Cheng 2001 USA 

•Cohort: N.A. •Age: Mean, 68 +/- 1.6 •Age: Range, 28 - 110 •% Male: 100% 

72 Followup: 30 days 

•Convenience sample of veterans (NYHA III-IV) : mean level 3.64 +/- 0.07. •New-onset CHF: confirmed by at least one cardiologist using standard Framingham criteria or exacerbation of previously documented CHF, NYHA class. •LVEF < 50% (mean LVEF 37% +/-2%) 

1) Death in hospital or death within 30 days after initial discharge 

NR/No Univariate 

logistic regression 

[BNP] Biosite Diagnostics - Threshold: Meadmission andischarge levfour categoriethreshold (430 840 pg/mL, 10pg/ml, 1220 p
C - 62 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Akioka 2000 Japan 

•Cohort: N.A. •Age: Mean, 71 +/- 15 •% Male: 57% 

33 Followup: 3 months 

•Patients with chronic CHF admitted to the ER for episodes of acute decompensation. (NYHA III-IV): 23% level III, 73% level IV. •Clinical evaluation, chest X-ray, and 2D echocardiography. •Mean LVEF 41% +/- 13% 

Cardiac mortality 

NR/No Univariate Cox 

proportional hazards regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: > 7pg/ml (median 

Bettencourt 2000 Portugal 

•Cohort: N. A. •Age: Mean, 69.6 +/- 9.3 •% Male: 59% 

139 Followup: 541.4+-346.5 days. 11.5 months 

•Patients with mild to moderate heart failure who were referred to an outpatient HF clinic. (NYHA I-III): 11.5% level I, 82.7% level II, 5.8% level III. •Clinical examination, echocardiography, and doppler •Mean LVEF = 33.5% +/-13.2%. 

All cause mortality 

Yes/No Uni and 

multivariate Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: 27(median of sa
C - 63 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Maeda 2000 Japan 

•Cohort: N.A. •Age: Mean, 63.6 +/- 1.5 •% Male: 64% 

102 Followup: Mean: 807 days (+/- 42.3) Range: 120-1568 days (27 months) 

•Patients hospitalized with chronic severe. (NYHA III-IV): 56% level III, 44% level IV. •Echocardiography at admission and 3 months. •Mean LVEF 23% +/- 0.9% 

1) Cardiac death (worsening CHF, lethal MI, sudden death) or survival 

Yes/No (but judged independently by researchers) 

Uni and multivariate Cox proportional hazards regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: 17(median from or 240 pg/ml (ROC curve) 

Tsutamoto 1999 Japan 

•Cohort: N.A. •Age: Mean, 59 + 0.7 •Age: Range,18-82 •% Male: 76.6% 

290 Followup: Mean = 502 days (range 31-1,619 days) in patients with an outcome Mean = 1,071 days (range 31-2,541 days) for event-free patients. 36 months 

•Consecutive earlystage HF patients who subsequently underwent cardiac catheterization. (NYHA I-II):32% level I, 68% level II.•Clinical evaluation and LVEF demonstrated by ventriculography with contrast medium. •LVEF < 45% 

Cardiac mortality 

Yes/No Linear 

regression Uni and multivariate Cox proportional hazards regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: 56 (median of totsample) 
C - 64 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Tsutamoto 1997 Japan 

•Cohort: N.A. •Age: Mean, 60 •Age: Range, 22 - 84 •% Male: 72% 

85 Followup: > 1 year (mean 24 months) 

•Chronic CHF pateints admitted to hospital. (NYHA IIIV): 54% level II, 21% level III, 25% level IV. •LVEF of <45% determined with ventriculography with radionuclide or contrast medium, and laboratory tests.•LVEF < 45% (Mean LVEF = 31.1% +/-1.1% 

Cardiac mortality 

NR/No Uni and 

multivariate Cox proportional hazard regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: 73 (median plasmconcentration

Wallén 1997 Sweden 

•Cohort: 70 year old people in Gothenburg Sweden •Age: Mean, 85 •% Male: No info. 

541  Followup: 60 months 

•Sample from longitudinal study of those born in 1901 -02 in Swedish city; the current study followed 85 year olds for 5 years. Not all patients had CHF.•Clinical evaluation and heart volume. •Not Reported 

All cause mortality 

NR/No Multivariate 

Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: Diinto quintiles: - 11.3 fmol/mL pg/mL], Q5 = 1103.0 fmol/m[212.8 pg/mL pg/mL] 
C - 65 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Watanabe 2005 Japan 

•Cohort: CHART •Age: Mean, 64 •% Male: 69.4% 

417 Followup: mean 26 months 

•Hospital based cohort from the CHART study who represented CHF in real clinical situations as they had both impaired or preserved systolic dysfuntion. (NYHA III-IV): 19.3% had level III/IV. •Framingham criteria for HF, echocardiography and clinical evalution. •LVEF < 50% (mean LVEF 38% +/- 12%)

Mortality (due to exacerbation of HF) Sudden death (without unexpected worsening of HF) Mortality (all cause) Combined HF events (HF mortality of hospitalization due to exacerbation of HF) 

NR/No Multivariate 

Cox regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: Lo>=2.12 (medibased on sam

Berger 2005 Austria 

 452 

Followup: mean 592 days +/- 387 days 20 months 

•Ambulatory patients recruited from a HF centre.(NYHA I -IV): 12% level I, 34% l3vel II, 33% level III, 21% level IV. •Clinical evaluation and LVEF (method not specified). •LVEF < 35% (Mean 20% +/- 7%) 

Sudden death and heart failure death 

NR/No Uni and 

multivariate Cox proportional hazard regression 

[BNP] Biosite Diagnostics - Threshold: log2.11 (approxim130 pg/mL anon ROC curve analysis (to discriminate bpatients who succumbed to death and surThresholds foN-BNP, logN-were not repoused inmultivaanalyses. 
C - 66 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Van Beneden 2004 Belgium 

•Cohort: N.A. •Age: Mean, 58 +/- 6 (Controls) •Age: Mean, Condition 1: 62 +/- 7 (Mild to moderate CHF) •Age: Mean, Condition 2: 67 +/- 8 (Severe CHF), •% Male: 84% 

117 Followup: Severe CHF group survivors mean 81 +/- 15 months (range 60-91 months) Mild to moderate CHF group survivors mean 92 +/- 3 months (range 87–96) 

•Three groups: Patients with mild to moderate CHF, severe CHF, and 30 healthy age and sex matched controls. (NYHA I-IV) •Clinical evaluation only. •Mean LVEF Mild /moderate group = 29.4% +/- 4%, mean LVEF severe CHF = 20.8% +/- 6%. 

All cause mortality Cardiovascular mortality Urgent heart transplant 

NR/No Multivariate 

Cox regression analysis 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: Mevalues of BNPBNP, LogBNPLogN-BNP (vnot reported) used only if significant. OlogN-BNP waas it had the hstatisitical significance. values for milmoderate CHBNP = 491 fm[4152.3 pg/mLsevere CHF N1,521 fmol/mL pg/mL] 
C - 67 

Evidence Table 9. Summary of studies in patients with HF and mortality outcomes: BNP 

Study Sample Characteristics Sample Size/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutive 

Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

thresho

Alehagen 2004 Sweden 

•Cohort: N.A. •Age: Mean, 73 +/- 6 •Age: Range, 65 - 87 •% Male: 52% 

458 Followup: 5.5 years median (range 242-2,222 days) all patients 3.8 years median nonsurvivors (range 242-2,156 days) 5.7 years median survivors (range 1,883-2,222 days) 68 months 

•Patients referred to primary care with signs and symptoms attributed to HF. (NYHA I-III): 46% level I, 43% level II, 10% level III. •Cardiologist performed clinical evaluation, echocardiography. •Not reported but in multivariate analysis used LVEF < 40% as variable 

All cause mortality and cardiovascular mortality 

NR/No Mutlivariate 

Cox proportional hazard regression 

[BNP] ShionoCo. Ltd - No instrument, SIRMA (manuaThreshold: Twlevels: 50-100 and >100 pmo[Conversion 1346 pg/mL anpg/mL] 

Abbreviations: NYHA=New York Heart Association, LVEF=left ventricular ejection fraction, NR=not reported, HF=heart failure 
C - 68 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

de Groote 2004 France 

•Cohort: N/A, •Age: Mean, 57 +/- 11, •% Male: No info. 

407 Followup: median followup period of 787 days 26 months 

•CHF patients referred to cardiology department (26% had NYHA III) •[Angiography, Echocardiography, Cardiopulmonary exercise test, 24 h halter monitoring] •LVEF <= 45% 

1) Cardiac mortality (defined as cardiac related death or urgent cardiac transplantation 2) Cardiac eventfree (defined as cardiac-related death or cardiac transplantation) 

NR/No Multivariate 

Cox proportional hazard analyses 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 10pg/ml (median level of group

Barcarse 2004 USA 

•Cohort: N/A •Age: Mean, 64.6 +/- 1.2 •% Male:100% 

98 Followup: 90 day end point 

•Convenience sample presenting to urgent care centre or emergency department (58% CHF) •Cardiologist blinded to the hemodynamic parameters reviewed the patient's medical record; Echocardiogram for every patient •Subgroup LVEF <= 45% to distinguish those with systolic dysfunction 

1) Sensitivity and specificity predicting death or re-admission when BNP and Cardiac index elevated 2) Severity of CHF (include death, re-admission, and emergency visit within 90 days) 

NR/No Multivariate 

logistic regression 

[BNP] Biosite Diagnostics - Triage Threshold: 10pg/ml (Based literature) 
C - 69 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Maisel 2004 USA 

•Cohort: REDHOT •Age: Mean, 64 •Age: Range, 51 - 76 •% Male: 54% 

464 Followup: 30 and 90 days 

•REDHOT cohort enrolled only If had BNP > 100pg/mL NYHA (I-IV): 3.0% level I, 29% level II, 46% level III, 22.6% level IV. 45 % Level III •Clinical evaluation only.•LVEF Not Reported 

Cardiac events (mortality, or cardiac related admission, or emergency room visit) 

NR/Yes Multivariate 

Logistic Regression 

[BNP] Biosite Diagnostics - Triage Threshold: 20pg/ml (chosen retrospectivelbased on inteanalysis) 

Gwechenberger 2003 Austria 

Cohort: NA Age: Condition 1 mean 52.47+/- 9.69 Condition 2 mean 50.52+/- 11.0 % Male: 89% 

SS = 100 Followup: mean 378 days (range 4 to 999 days) 13 months 

Stable CHF (NYHA IIIV), 78% level II, 20% level III, 2% level IV Clinical Examination LVEF <=25% 

Worsening Myocardial Failure (WHF) defined as any of the following: (1) Hospitalized for WHF; (2) need for IV therapy; (3) need for urgent CTx; or (4) death from pump failure as a consequence of WHF 

NO (Clinical 

Trial)/ NO 

Uni and Multivariate Cox proportional hazards regression 

[NT-proBNP] Biomedica Gr- No instrumeEIA (manual assay) Threshold: 27fmol/L (Media
C - 70 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Sakatani 2004 Japan 

•Cohort: N.A. •Age: Mean, All subjects, 72 +/- 12 •Age: Mean, Condition 1: 74 +/- 10 •Age: Mean, Condition 2: 71 +/- 12 •Age: Range, All subjects, 33-91 •% Male: 49% 

80 Followup: 17 =/-9 months 

•CHF patients admitted to hospital (NYHA IIV):6% level 1, 43% level 2, 43% level III, 8% level IV •Clinical evaluation only.•Not reported 

Cardiac event (i.e. death or rehospitalization)

Yes/No Multivariate 

Cox proportional hazard regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: No threshold specified. MeBNP in cardiaevent group 4+/-168 pg/ml; mean BNP in non-cardiac event group 1+/-51 pg/ml. 

Latini 2004 Italy 

•Cohort: ValHeFT •Age: Mean, No info •%Male: No info 

4300 Followup: Not Specified (23 months outcomes are discussed in the results but not clear if this is total followup time) 

•ValHeFT cohort: stable but symptomatic HF (NYHA I-IV) •LVEF < 40% and LV internal diameter in diastole adjusted for body surface area (LVIDd/BSA) of =>2.9 cm/m2. •LVEF < 40% 

Combined mortality and morbidity (morbidity defined as cardiac arrest with resuscitation, hospitalization for HF or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalization) 

NR/No Uni and 

multivariate Cox proportional hazard regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 97 pg/mL (median of sa
C - 71 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Logeart 2004 France 

•Cohort: N.A. •Age: Mean, Condition 1: 69.4+/- 14.4 (Derivation study) •Age: Mean, Condition 2: 70.9 +/- 13.3 (Validation study) •% Male: 60.5 % 

223 (114 finally included (derivation study) and 109 from another centre included in validation study) Followup: 1 month and 6 months for 51/105 patients either dead or readmitted; mean time from discharge to first event was 72 +/- 48 days 

•Patients presenting to two hospitals (NYHA class IV) •The diagnosis of decompensated CHF was confirmed by two senior cardiologists using the generally accepted Framingham criteria and corroborative information including the hospital course and results of further cardiac tests. •Derivation group: LVEF 37.5% +/-14.9; Validation group 31.8% +/- 14.5 

Combined death or first readmission for CHF 

Yes/No Uni and 

multivariate Cox proportional hazards regression 

[BNP] Biosite Diagnostics - Triage Threshold: Categorized i3 predischarglevel categori(<350 ng/L, 3700 ng/L, >70ng/L). [Conversion <350 pg/mL, 350-700 pg/m>700 pg/mL] 
C - 72 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Ishii 2003 Japan 

•Cohort: N.A. •Age: Mean, 68 + 11 •% Male: 56% 

100 Followup: Mean 391 days (range 16-884) 13 months 

•Patients admitted to hospital for worsening CHF (NYHA III-IV): 54% level III and 46% level IV •Cardiologists not directly involved in the study determined if patients met exclusion criteria. 2D Echocardiogram and venous blood samples were used to determine severity. •12% of patients had mean LVEF 36% 

Cardiac events (death from worsening CHF, fatal MI or sudden death) and re-admission for worsening CHF or MI 

NR/Yes Uni and 

multivariate Cox regression

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 16ng/L (based oROC with bessensitivity). [Conversion 1pg/mL] 
C - 73 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Horwich 2003 USA 

•Cohort: N.A. •Age: Mean, 52+/-13 •% Male: 71% 

238 Followup: 18 months 

•Patients with advanced heart failure referred for cardiac transplantation to a single centre (NYHA class III-IV): 50% were level IV. •Clinical evaluation only•Mean LVEF 0.25 +/- 0.09 

All cause mortality or urgent cardiac transplantation. 

Yes/No Univariate and 

multivariate Cox regression

[BNP] Biosite Diagnostics - Triage Threshold: <4pg/ml (based ROC curve; Bnot considereindependent oTroponin I levels). 

Anand 2003 USA 

•Cohort: Valsartan Heart Failure Trial (ValHeFT) •Age: Mean, No info. •% Male: No info. 

4300 Followup: mean followup 2-3 years (at 4 months, year, and 2 years) 32 months 

•ValHeFT cohort: stable but symptomatic HF (NHYA I-IV) •Patients with stable, symptomatic HF who were undergoing prescribed HF therapy and had left ventricular ejection fraction (LVEF) =/< 40% and P7 •LVEF < 40% 

All cause mortality and first morbid event (death, sudden death with resuscitation, hospitalization for HF, or intravenous inotropic or vasodilator therapy for at least 4 hours) 

NR/No Multivariate 

Cox proportional hazard model [% change, quartile changes after 4 months] 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 97 pg/mL median (no range specified). Alsevaluated usiquartiles < 41pg/mL, 41-pg/mL, 97- 238pg/mL, >2pg/mL). 
C - 74 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Bettencourt 2002 Portugal 

•Cohort: N.A. •Age: Mean, 71+/-44 •% Male: 44% 

50 Followup: 6 months (time from discharge to first event ranged from 4 to 153 days (mean, 53 days)) 

•Patients admitted with decompensated heart failure to hospital (NYHA II-IV): 12% level II, 54% level III, 35% level IV. •Clinical evaluation only•Not reported 

Death or hospital re-admission for cardiovascular causes 

NR/No Univariate Cox 

regression 

[BNP] Biosite Diagnostics - Triage Threshold: No threshold specified. Admission median levels 541 pg/mL, discharge median level 321 pg/ml, anthese that decreased by discharge. 
C - 75 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Hulsmann 2002 Austria 

•Cohort: N.A. •Age: Mean, 57 +/- 8 •% Male: 82% 

96 Followup: 1 year 

•Patients treated in clinic with documented HF based on LVEF function. Subjects were excluded from analysis if they underwent elective heart transplant. (NYHA I-III): 35% level I, 30% level II, 29% level III, 6% level IV. •HF based on LVEF level •Mean LVEF 26+/- 10%. 

Death or worsening heart failure (decompensation, needing I.V. support and malignant arrhythmia) 

Yes/No Multivariate 

Cox proportional hazard regression 

[BNP] Biosite Diagnostics - Triage Threshold: No thresholds specified for Band proBNP. Mean BNP: 1+/- 264 fmol/m[629.7 pg/mL] patients no events and 6+/- 423 fmol/m[2380 pg/mL] patients who either died or developed worsening hefailure within year. Mean proBNP 325 198 fmol/ml [913.4 pg/mL] patients with nevents and 5+/- 275 fmol/mpatients who either died or developed worsening HF
C - 76 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Tsutsui 2002 Japan 

•Cohort: N.A. •Age: Mean, All subjects 63 +/- 1.5 •Age: Mean, Condition 1: 58.9 +/- 3.1 •Age: Range, All subjects, 17-85 •Age: Range, Condition 1: 17-79 •% Male: 75% (subjects), 78% (controls) 

84 + 18 ControlsFollowup: Survivors > 589 days (mean 780 +/- 15.6 days (range 589 to 984 days)). 26 months 

•Patients with CHF with DCM or ischemic cardiomyopathy, LVEF < 45% (NYHA II-IV). •Serum blood tests and Echocardiogram • Mean LVEF = 30.7% +/- 1.0 

Cardiac death (worsening CHF, lethal MI or sudden death) or hospitalization for worsening CHF, MI or fatal arrhythmia 

Yes/No Multivariate 

Cox proportional hazards regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold not specified. Meall patients 33+/- 42 pg/mL. 

Ishii 2002 Japan 

•Cohort: N.A. •Age: Mean, All subjects, 69+/- 9 •Age: Mean, Condition 1: 71+/-10 •Age: Mean, Condition 2: 68+/-10 •Age Range, All subjects, 22-88 •% Male: 52% 

98 Followup: Mean 451 +- 98 days (range 13 to 667 days) 15 months

•Patients were admitted to a coronary care unit due to worsening CHF. (NYHA mean 3.5 +/- 0.6) •2D echocardiography read by experts blinded to the study. •Mean LVEF = 42% +/- 17 

1) Cardiac death (death from worsening chronic heart failure, fatal myocardial infarction, or sudden death); 2) Readmission for worsening chronic heart failure or myocardial infarction. 

Yes/No 

(but 

endpoints 

judged by 

independent 

researchers)

Uni and multivariate Cox regression

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: >4pg/mL (based ROC) 
C - 77 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Harrison 2002 USA 

•Cohort: N.A. •Age: Mean, 65 •Age: Range, 29-83 •% Male: 95% 

325 Followup: Mean followup time=682.2 +- 55.0 days 23 months 

A convenience sample presenting with dyspnea to the emergency department (41% CHF) Diagnosis: Echocardiogram results from previous records was used to establish CHF. LVEF not reported

Hospital admissions (any cardiac and CHF), 3) repeat ED visits for CHF. 

No/Yes Unadjusted 

Relative Risks 

[BNP] Biosite Diagnostics - Triage Threshold: 48pg/mL based ROC; 230 pg/(provided few false negative values) 

Dias 2001 USA 

•Cohort: N.A. •Age: Mean, 70.4+/-1.2 •% Male: 45.7% 

46 Followup: 6 months 

•A convenience sample presenting with dyspnea to the emergency department (41% CHF)•Echocardiogram results from previous records was used to establish CHF. •Not Reported 

Death or hospitalization from cardiac cause 

NR/Yes Unadjusted 

relative risks 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: >4pg/mL based ROC curve of sample; 230 pg/mL (providfew false negative valu
C - 78 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Koglin 2001 Germany 

•Cohort: N.A. •Age: Mean, 51 +/- 9 •Age: Range, 24 - 65, •% Male: 88% 

78 Followup: Median 398 days (range 248-493). 13 months 

•Patients with chronic CHF who were referred to a heart failure outpatient clinic; subjects were included after optimization of medical therapy. (NHYA I-IV): 12.8% level I, 42.3% level II, 33.3% level III, 11.5% level IV.•Clinical history and examination, ECG, echocardiogram, laboratory results cardiopulmonary exercise test. •Mean LVEF 36% +/-15 at admission 

Changes in degree of cardiovascular disability: improvement, stabilization, deterioration (includes death) 

NR/No Logistic 

regression and Cox proportional hazard regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 10pg/ml (based 75th percentiland BNP cha(increase by 1pg/ml). 
C - 79 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Imamura 2001 Japan 

•Cohort: Ehime MIBG Heart Failure (EMIHEF Study) •Age: Mean, All subjects, 63 +/- 11 •Age: Mean, Condition 1: 64 +/- 11 (Event free) •Age: Mean, Condition 2: 65 +/- 12 (Cardiac death) •Age: Mean, Condition 3: 61 +/- 14 ( hospitalization) •% Male: 73% 

171 Followup: 27+/- 8 months 

•Ehime MIBG Heart Failure Study (EMIHEF) randomized trial. (NYHA II-IV): 54% level II, 18% level III, 3% level IV. •Clinical evaluation, including NYHA, I-MIBG images, Chest x-ray, 2D echocardiography •Mean LVEF 27%+/-10% 

Progressive CHF, (combined cardiac death and CHF requiring hospitalization) 

NR/No Uni and 

multivariate Cox regression

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: > pg/mL ((baseon mean of sample) 
C - 80 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Tamura 2001 Japan 

•Cohort: N.A. •Age: Mean, All subjects, 78 +/- 1 •Age: Mean, Condition 1: 81 +/- 2 (Cardiac event) •Age: Mean, Condition 2: 77 +/- 1 (No cardiac event) •Age: Range, All subjects, 67-92 •% Male: 48% 

48 Followup: 10.8+-1.1 months (range: 1-25 months) 

•Patients aged >=65 admitted to hospital with their first episode of CHF (NYHA I-IV): 23% level I, 33% level II, 8% level III, 38% level IV. •Clinical evaluation, 2D echocardiography, radionuclide angiography and laboratory tests. •mean LVEF varied from 38.1% +/- 5.0 ((sample with cardiac events) and 49.2% +/-2.4 (groups with noncardiac events) 

Cardiac event (readmission because of worsening CHF, angina pectoris or acute myocardial infarction or death from CHF or sudden cardiac death) 

Yes/No Uni and 

multivariate Cox regression

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 13pg/ml (median based on sample) 

Cheng 2001 USA 

•Cohort: N.A. •Age: Mean, 68 +/- 1.6 •Age: Range, 28 - 110 •% Male: 100% 

72 Followup: 30 days 

•Convenience sample of veterans (NYHA III-IV) : mean level 3.64 +/- 0.07. •New-onset CHF: confirmed by at least one cardiologist using standard Framingham criteria or exacerbation of previously documented CHF, NYHA class. •LVEF < 50% (mean LVEF 37% +/-2%) 

1) readmission to the hospital facility for CHF within 30 days of initial discharge 2) All events (combined into a single dichotomous outcome (occurrence of death or readmission vs. no occurrence of either event)). 

NR/No Univariate 

logistic regression 

[BNP] Biosite Diagnostics - Triage Threshold: Meadmission andischarge levand four categories of threshold (430 pg/mL, 840 pg/mL, 1090 pg/mL, 1220 pg/mL) 
C - 81 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Maeda 2000 Japan 

•Cohort: N.A. •Age: Mean, 63.6 +/- 1.5 •% Male: 64% 

102 Followup: Mean: 807 days (+/- 42.3) Range: 120-1568 days (27 months) 

•Patients hospitalized with chronic severe. (NYHA III-IV): 56% level III, 44% level IV. •Echocardiography at admission and 3 months. •Mean LVEF 23% +/- 0.9% 

Hospitalization for worsening CHF or MI 

Yes/No (but 

judged 

independentl

y by 

researchers)

Uni and multivariate Cox proportional hazards regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: >1pg/mL (mediafrom sample) 240 pg/ml (froROC) 

Tsutamoto 1999 Japan 

•Cohort: N.A. •Age: Mean, 59 + 0.7 •Age: Range,18-82 •% Male: 76.6% 

290 Followup: Mean = 502 days (range 31-1,619 days) in patients with an outcomeMean = 1,071 days (range 31-2,541 days) for event-free patients. 36 months 

•Consecutive earlystage HF patients who subsequently underwent cardiac catheterization. (NYHA I-II):32% level I, 68% level II. •Clinical evaluation and LVEF demonstrated by ventriculography with contrast medium. •LVEF < 45% 

Morbidity (hospitalization) or mortality due to cardiovascular causes 

Yes/No Linear 

regression Uni and multivariate Cox proportional hazards regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: 56 pg/mL (mediatotal sample) 
C - 82 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Watanabe 2005 Japan 

•Cohort: CHART •Age: Mean, 64 •% Male: 69.4% 

417 Followup: mean 26 months 

•Hospital based cohort from the CHART study who represented CHF in real clinical situations as they had both impaired or preserved systolic dysfunction. (NYHA III-IV): 19.3% had level III/IV. •Framingham criteria for HF, echocardiography and clinical evaluation.•LVEF < 50% (mean LVEF 38% +/- 12%) 

Combined HF events (HF mortality of hospitalization due to exacerbation of HF) 

NR/No Multivariate 

Cox regression

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: LoBNP >=2.12 (median baseon sample) 

Hamada 2005 Japan 

•Cohort: N.A. •Age: Mean, Condition 1: 67 +/- 9 (old MI) •Age: Mean, Condition 2: 60 +/- 17 years (dilated cardiomyopathy) •% Male: 63% 

52 Followup: 1 year (5.9 +/- 3.7 months) 

•Patients with chronic CHF admitted for acute emergency decompensation. (NYHA III-IV) •Clinical evaluation, chest X-ray, and echocardiography. •LVEF <40 

Rehospitalization for acute decompensation of CHF or cardiac death 

NR/No Multivariate 

Cox proportional hazards regression 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: > 2pg/ml (median pre-discharge BNP level) 
C - 83 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Bertinchant 2005 France 

•Cohort: N.A. •Age: Median, 54 +/- 7.2 •% Male: 87% 

63 Followup: median 22 months (range 1-45), median event-free survival time for all CHF patients was 33.8 months

•Acute and chronic CHF patients referred to the cardiology department. Those that were acute (n=19) required urgent hospital admission because of cardiac decompensation. All patients had been symptomatic withinthe previous 12 months. (NYHA I-IV): 36.6 levels I/II, 49.2 level III, 14.3 level IV. •Clinical evaluation only.•LVEF < 45% (mean 24% +/- 9.7%) 

Worsening CHF and cardiac death 

NR/No Uni and 

multivariate Logistic Cox regression analysis 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: > 2ng/l (optimal threshold from ROC analysis[Conversion 2pg/mL] 
C - 84 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Van Beneden 2004 Belgium 

•Cohort: N.A. •Age: Mean, 58 +/- 6 (Controls) •Age: Mean, Condition 1: 62 +/- 7 (Mild to moderate CHF) •Age: Mean, Condition 2: 67 +/- 8 (Severe CHF), •% Male: 84% 

117 Followup: Severe CHF group survivors mean 81 +/- 15 months (range 60-91 months) Mild to moderate CHF group survivors mean 92 +/- 3 months (range 87–96) 

•Three groups: Patients with mild to moderate CHF, severe CHF, and 30 healthy age and sex matched controls. (NYHA I-IV) •Clinical evaluation only.•Mean LVEF Mild /moderate group = 29.4% +/- 4%, mean LVEF severe CHF = 20.8% +/- 6%. 

Urgent heart transplant 

NR/No Multivariate 

Cox regression analysis 

[BNP] Shiono& Co. Ltd - No instrument, Shionoria-IRM(manual assaThreshold: Median valueBNP, N-BNP, LogBNP, and LogN-BNP (values not reported) werused only if significant. OlogN-BNP waused as it had the highest statisitical significance. Mean values mild to moderCHF N-BNP = 491 fmol/mL [4152.3 pg/mLand sever CHN-BNP = 1,52fmol/mL [8,45pg/mL] 
C - 85 

Evidence Table 10. Summary of studies in patients with HF and mixed outcomes: BNP 

Study 

Sample 

Characteristic

s 

Sample Size 

/Followup Diagnostic criteria Outcomes 

Quality: 

Consecutiv

e Cohort / 

Outcome 

Blinding 

Analysis 

/Model 

BNP metho

/Unit thresh

Berger 2003 Austria 

•Cohort: N.A. •Age: Mean, 54 +/- 10 •% Male: 87% 

452 Followup: followed up at 1, 2, and 3 years. 36 months 

•Ambulatory patients recruited from a HF centre.(NYHA I -IV): 12% level I, 34% l3vel II, 33% level III, 21% level IV. •Clinical evaluation and LVEF (method not specified •Not specified 

Death or urgent heart transplantation 

NR/NR Multivariate 

Cox proportional hazard regression 

[BNP] Biosite Diagnostics - Triage/EvaluaBNP and N-BThreshold: logBNP 2.11 (approximated 130 pg/mL) awas based on the highest sensitivity from ROC curve analysis (to discriminate between patiewho succumbto sudden deaand survivorsThresholds foBNP, N-BNP, logN-bnp wernot reported buse dinmultivariatanalyses. 

Abbreviations: NA=not applicable, NR=not reported, HF=heart failure, CHF=congestive heart failure, LVEF=left ventricular ejection fractiHeart Association, MI=myocardial infarction, ECG=electrocardiograph 
C - 86 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Rossig 2004 Germany 

Cohort: NA Age: mean 57 +/- 1 % Male: 77% 

48 Followup: Minimum followup of 30 months (median followup for survivors 1254 days). 42 months 

Outpatient HF clinic (NYHA class II-IV): 42% level II, 44% level III, 14% level IV. Clinical evaluation and previous medical history. Mean LVEF 25% +/- 1% 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: continuous variable (pg/mL) 

No/No All-cause 

mortality 

Uni and multivariable Cox Proportional Hazard Regression 
C - 87 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Rothenburger 2004 Germany 

Cohort: NA Age: Condition 1 mean age 55 +/- 11 Age: Condition 2 mean age 57 +/- 8 % Male: 75% 

550 Followup: 2 yrs 

Recruited to interdisciplinary Heart Failure Program (NYHA II-IV): Dilative Cardiomyopathy mean NYHA 2 +/- 1, CAD mean NYHA 3 +/- 1. Clinical, Echocardiography, ECG. Dilative Cardiomyopathy mean LVEF 32% +/- 13% CAD LVEF 31% +/- 11%. 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: > 1000 ng/mL 

Yes/Yes Prediction ability 

for selection of cardiac transplant by cardiologists blinded to NTproBNP levels 

Multivariate Cox Logistic Regression 

Hartmann 2004 Germany 

Cohort: COPERNICUS Age: Mean 62.5 +/- 11.0 % Male: 81% 

1048 Followup: 29 months 

European patients with chronic severe HR enrolled in a Multicenter RCT (Copernicus) one treatment arm on carvedilol (NYHA not reported). Clinical evaluation, LVEF. Mean LVEF 20.4% +/- 3.6% 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: specified as above and below median (value not reported) (pmol/L) 

No/No (1) all cause 

mortality (2) all cause mortality or heart failure hospitalisation (3) all cause mortality or hospitalisation for cardiovascular reasons (4) all cause mortality or hospitalisation for any reason 

Univariate Cox proportional hazards regression 
C - 88 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Kirk 2004 Denmark 

Cohort: CHHF (Copenhagen Hospital Heart Failure Study) Age: Condition 1 mean 73.0 years (no HF)Age: Condition 2 mean 78.0 years (HF) % Male: 41% 

2230 Followup: 1 year

Patients admitted to general city hospital with HF (NYHA classification not reported) (Total sample contained subjects subsequently determined to not have HF). European Society of Cardiology criteria (clinical and echocardiography). mean LVEF HF group: 45.3% +/- 1.1% 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: continuous variable (pmol/L)

Yes/No 

(Physician 

blinded to 

NT-proBNP 

levels) 

All cause mortality 

Multivariate logistic regression 

Gardner 2003 Scotland 

Cohort: NA Age: mean 50.4+/-10.5 % Male: 82.4% 

142 Followup: median time 374 days range (1-660 days)13 months 

Patients with advanced CHF referred for consideration of heart transplant surgery (NYHA II-IV): 14.8% level II, 66.2% l3v3l III, 19% level IV. Clinical evaluation and radionuclide ventriculography. Mean LVEF = 14.9% +/- 7.1%; LVEF < 35% 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: >1490 pg/mL (median of sample) 

Yes/No 1) All cause 

mortality, (2) death from worsening HF, 3) Hospitalisation for CHF or Coronary syndromes 

Uni and multivariate Cox proportional hazards analysis 
C - 89 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Stanek 2001 Austria 

Cohort: NA Age: Condition 1 mean 51+/-11 years (Atenolol) Age: Condition 2 mean 52+/-10 years (Placebo) % Male: 97% 

91 Followup: 4 years 

Subjects with HF (LVEF < 25%) from a substudy of subjects from RCT evaluating those on atenolol versus placebo. (NYHA II-IV): 78% level II, 13% level III, 2% level IV. Radionuclide ventriculography and clinical evaluation. LVEF < 25% (mean 17% ) 

[NT-proBNP] Biomedica Grupe - No instrument, EIA (manual assay) Threshold: continuous variable (fol/mL) 

No (clinical 

trial)/No 

Cardiac mortality Uni and 

mulitvariate Cox proportional hazards regression 
C - 90 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Richards 2001 New Zealand 

Cohort NA: Age: Not reported % Male: Not reported 

297 Followup: 18 months 

Substudy of patients with chronic stable randomized to receive Atenolol or placebo. (NYHA II-IV). 30% level I at randomization, but 43% had been previously in level IV. Radionuclide ventriculography and clinical evaluation. LVEF < 45% (mean LVEF 29%) 

[NT-proBNP] New Zealand (Christchurch) - no instrument, manual assay Threshold: continuous variable (pmol/L) 

No(subset of 

clinical 

trial)/No 

1) All-cause mortality 2) Death from worsening HF3) Episodes of worsening HF (defined as deterioration requiring an increase in nonstudy anti-HF treatments, an increase in NYHA functional class, hospital admission for worsening symptoms of HF or nonsudden death from progressive HF)4) Hospital admission for worsening HF and hospital admission for acute coronary syndromes 

Multivariate Cox proportional hazards analysis 
C - 91 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Taniguchi 2004 Japan 

Cohort : NA Age: mean 68.4 +/- 1.4 % Male: 52% 

71 Followup: 17 months 

Patients hospitalized for acute HF (decompensated) (NYHA I-IV): 14% level I , 31% level II, 31% level III, 24% level IV. Clinical evaluation and roentgenographically apparent pulmonary eodema. LVEF Not reported 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: cardiac decompensation 1.050 pg/ml; cardiac events 2,000 pg/ml (based on ROC analysis) 

Yes/No Sudden death, 

CHF death, rehospitalization for CHF, adverse cardiac events (sudden death without apparent ischemia, death from CHF, or rehospitalisation for cardiac decompensation with pulmonary oedema) 

Kaplan Meier’s and ROC curves only 
C - 92 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

Hartmann 2004 Germany 

Cohort: COPERNICUS Age: mean 62.7 +/- 10.9 % Male: 81% 

1011 Followup: 24 months 

European patients with chronic severe HF enrolled in a Multicenter RCT (Copernicus) one treatment arm on carvedilol (NYHA not reported). Clinical evaluation, LVEF. Mean LVEF 20.4% +/- 3.6% 

[NT-proBNP] Roche Diagnostics - Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: > 1767 pg/ml (median) 

No/No 1) All cause 

mortality 2) death or hospitalized for HF 3) death or hospitalized for CV reasons specified in protocol 4) death or hospitalization for any reason 

Uni and multivariate Cox proportional hazards regression 

Berger 2005 Austria 

Cohort: none Age: mean 54 +/- 10 % Male: 87% 

452 Followup: mean 592 days +/- 387 days 20 months 

Ambulatory patients recruited from a HF centre. (NYHA I -IV): 12% level I, 34% l3vel II, 33% level III, 21% level IV. Clinical evaluation and LVEF (method not specified). LVEF < 35% (Mean 20% +/- 7%) 

[BNP] Biosite Diagnostics - Triage [NT-proBNP] Biomedica Grupe - No instrument, EIA (manual assay) Threshold: continous variable (pg/mL) 

No/No Sudden death 

and heart failure death 

Uni and multivariate Cox proportional hazard regression 
C - 93 

Evidence Table 11. Summary of studies in patients with HF and mortality outcomes: NT-proBNP 

Study 

Sample 

characteristi

cs 

Sample size 

/Followup Diagnostic criteria BNP method /Unit threshold

Quality 

Consecuti

ve cohort 

/Outcome 

blinding 

Outcomes Analysis / model 

VAN BENEDEN 2004 Belgium 

Cohort: none Age: All mean 58 +/- 6 years (Controls)Age: Condition 1 mean 62 +/- 7 years (Mild to moderate CHF)Age: Condition 2 mean 67 +/- 8 years (Severe CHF % Male: 84% 

117 Followup: Severe CHF group survivors mean 81 +/- 15 months (range 60-91 months) Mild to moderate CHF group survivors mean 92 +/- 3 months (range 87–96) 

Three groups: Patients with mild to moderate CHF, severe CHF, and 30 healthy age and sex matched controls. (NYHA I-IV). Clinical evaluation only. Mean LVEF Mild /moderate group = 29.4% +/- 4%, mean LVEF severe CHF = 20.8% +/- 6%. 

[BNP] Shionogi & Co. Ltd - No instrument, Shionoria-IRMA (manual assay)[NTproBNP] Biomedica Grupe - No instrument, EIA (manual assay) Threshold: continous variable (pg/mL) 

No/No All cause 

mortality Cardiovascular mortalityUrgent heart transplant 

Multivariate Cox regression analysis 

Abbreviations: HF=heart failure, LVEF=left ventricular ejection fraction, HR=hazards ratio, CI=confidence interval, NA=not applicable, NY

Association, RIA=radioimmunoassay, CHF=congestive heart failure, ROC=receiver operator characteristic, CAD=coronary artery diseas
C - 94 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Gwechenberger 2004 Austria 

Cohort: NA Age: Condition 1 mean 52.47+/- 9.69/ Condition 2 mean 50.52+/- 11.0 % Male: 89% 

100 Followup: mean 378 days (range 4 to 999 days) 13 mon 

Stable CHF (NYHA IIIV), 78% level II, 20% level III, 2% level IV. Clinical examination. LVEF <=25% 

[NT-proBNP] Biomedica Grupe - No instrument, EIA (manual assay) Threshold: not specified for NTproBNP (fmol/L) 

No/No Worsening 

Myocardial Failure (WHF)defined as any of the following: (1) Hospitalised for WHF; (2) need for IV therapy; (3) need for urgent CTx; or (4) death from pump failure as a consequence of WHF 

Uni and Multivariate Cox proportional hazards regression 

WorseLog NT0.049 WorseLogNTpredicWorseLogBNWorseLogBN

Hartmann 2004 Germany 

Cohort: COPERNICUS Age: Mean 62.5 +/- 11.0 % Male: 81% 

1048 Followup: 29 months 

European patients with chronic severe HR enrolled in a Multicentre RCT (Copernicus) one treatment arm on carvedilol (NYHA not reported). Clinical evaluation, LVEF. Mean LVEF 20.4% +/- 3.6% 

[NT-proBNP] Roche Diagnostics -Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: specified as above and below median (value not reported) (pmol/L) 

No/No (1) all cause 

mortality (2) all cause mortality or heart failure hospitalisation (3) all cause mortality or hospitalisation for cardiovascular reasons (4) all cause mortality or hospitalisation for any reason

Univariate Cox proportional hazards regression 

Not re
C - 95 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Gardner 2003 Scotland 

Cohort: NA Age: mean 50.4+/-10.5 % Male: 82.4% 

142 Followup: median time 374 days range (1-660 days)13 months 

Patients with advanced CHF referred for consideration of heart transplant surgery (NYHA II-IV): 14.8% level II, 66.2% l3v3l III, 19% level IV. Clinical evaluation and radionuclide ventriculography. Mean LVEF = 14.9% +/- 7.1%; LVEF < 35% 

[NT-proBNP] Roche Diagnostics -Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: >1490 pg/mL (median of sample) 

Yes/No 1) All cause 

mortality, (2) death from worsening HF, 3) Hospitalisation for CHF or Coronary syndromes 

Uni and multivariate Cox proportional hazards analysis 

All cauproBNCI, 1.6All cautranspproBNCI, 2.2All cauproBNp = 0.0All cautransp1490 p

O'Brien 2003 UK 

Cohort: NA Age: mean 74 % Male: 56% 

96 Followup: median 350 days (2-762) 11.6 months

Patients admitted to coronary care unit with dianosis of acute left ventricular failure. (Killp class II-IV): 39% level II, 55% level III, 6% level IV. Clinical evalation. LVEF not reported 

[NT-proBNP] Manual method referencing * Threshold: continuous variable (fmol/mL) 

Yes/No Combined 

endpoint of death, HF readmission, and worsening HF in an outpatient setting. 

Univariate and multivariate analyses (type not specified) 

CombWhole OR = 0.185. CombSubseproBN168.9]

Fisher 2003 UK 

Cohort: NA Age: mean 75 % Male: 58.6% 

87 Followup: mean 12 months 

Patients admitted on an emergency basis with CHF caused by left ventricular systolic dysfunction (NYHA IIIV): 24% level II, 32% level III, 44% level IV. Clinical evaluation. LVEF not reported 

[NT-proBNP] Roche Diagnostics -Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: > 2994 pg/mL (median in 

No (clinical 

trial)/Yes 

Death or readmission with HF 

Uni and multivariate regression analysis (type not specified) 

Death MultivaproBNDeathproBN
C - 96 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

sample) 

Hulsmann 2002 Austria 

Cohort: NA Age: mean age 57 +/- 8 % Male: 82% 

96 Followup: 1 year 

Patients treated in clinic with documented HF based on LVEF function. Subjects were excluded from analysis if they underwent elective cTx. (NYHA I-III): 35% level I, 30% level II, 29% level III, 6% level IV. HF based on LVEF level. Mean LVEF 26+/- 10%. 

[BNP] Biosite Diagnostics -Triage [NBNP] Biomedica Threshold: continuous variable (fmol/mL) 

Yes/No Death or 

worsening heart failure (decompensation, needing I.V. support and malignant arrhythmia) 

Multivariate Cox proportional hazard regression 

Death Baseli0·01DeMultiva= 58, p 
C - 97 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Zugck 2002 Germany 

Cohort: NA Age: mean 55 +/11 % Male: 84% 

408 Followup: 1 year 

Ambulatory chronic CHF patients being treated with ACE inhibitor or angiotensin type 1 receptor antagonist. Subjects divided into 2 groups: those treated with Betablockers and those not treated with bblockers. (NYHA I-IV). 15% level I, 41% level II, 42% level III, 2% level IV, and mean NYHA level 2.3 +/- 0.7. Clinical evaluation, Radionuclide ventriculography. LVEF < 45%. Mean LVEF = 22% +/- 10%

[NT-proBNP] Manual method referencing * Threshold: continuous variable (pmol/L) 

Yes/No Cardiac death 

or hospital admission for worsening HF or hospital admission with IV inotropic, diuretic, or mechanical support. 

Uni and multivariate Cox regression analysis 

Combpatien= 0.00treated blockeMultivaChi Sqonly foblocke
C - 98 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Bettencourt 2004 Portugal 

Cohort: NA Age: mean 73 +/- 11  % Male: 47% 

156 Followup: 6 months 

Patients admitted due to decompensated heart failure (NYHA III-IV): 33% level III, 67% level IV. Clinical diagnosis using European Society of Cardiology criteria or Framingham criteria for HF. LVEF not reported on admission 

[NT-proBNP] Roche Diagnostics -Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: continuous variable but categorized into 1000 pg/mL and relative change of 30% 

Yes/No Death or 

hospital readmission 

Uni and multivariate Cox proportional hazard regression 

Compo~ Univ(per 101.012, ~Univa(per 101.018, ~Univa(vs deeither 1.23- 3‘Univa(vs de30% Hp NR ~ Mult(vs deineithe1.14 - ~ Mult(vs deHR = 5NR DeathproBNchang[95% CDeathproBNincrea1.36–9
C - 99 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Hartmann 2004 Germany 

Cohort: COPERNICUS Age: mean 62.7 +/- 10.9 % Male: 81% 

1011 Followup: 24 months 

European patients with chronic severe HR enrolled in a Multicentre RCT (Copernicus) one treatment arm on carvedilol (NYHA not reported). Clinical evaluation, LVEF. Mean LVEF 20.4% +/- 3.6% 

[NT-proBNP] Roche Diagnostics -Elecsys 1010, Elecsys 2010, E170 or Modular Threshold: > 1767 pg/ml (median) 

No/No 1) All cause 

mortality 2) death or hospitalized for HF 3) death or hospitalized for CV reasons specified in protocol 4) death or hospitalization for any reason

Uni and multivariate Cox proportional hazards regression 

All cauproBNCI, 1.7 mortalfailure1767 p3.4], pprotocUnivarRR = 20.0001 All cauproBN[95% Ccause HF: Mpg/mL 2.90], 
C - 100 

Evidence Table 12. Summary of studies in patients with HF and mixed outcomes: NT-proBNP 

Study Sample characteristics Sample size /Followup Diagnostic criteria 

NT-proBNP 

method 

/Unit 

threshold 

Quality 

Consecutive 

cohort 

/Outcome 

blinding 

Outcomes Analysis /model 

Berger 2003 Austria 

Cohort: none Age: mean 54 +/- 10 % Male: 87% 

452 Followup: 1, 2, and 3 years. 36 months 

Ambulatory patients recruited from a HF centre.(NYHA I -IV): 12% level I, 34% l3vel II, 33% level III, 21% level IV. Clinical evaluation and LVEF (method not specified). LVEF not specified 

[BNP] Biosite Diagnostics -Triage[NTproBNP] Biomedica Grupe - No instrument, EIA (manual assay) Threshold: continous variable (pg/mL) 

No/No death, urgent 

heart transplantation

Multivariate Cox proportional hazard regression 

For coMultivaA):Bas5, p < 0.005MBaseli< 0.00ALL Ssignific(Group significMODEBNP 2 LogNT0.0001 ALL SproBNLog NT005; L11, p < 

* Carl J., Borgya A., Gallusser A. et al. Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit. Scand 1999; 230:177-81 Abbreviations: LVEF=left ventricular ejection fraction, NYHA=New York Heart Association, HF=heart failure, CHF=congestive heart failu

CV=cardiovascular, NR=not reported, NA=not applicable
C - 101 

Evidence Table 13: Tests for heterogeneity due to STUDY SETTINGS for BNP using the lowest cut point 

provided in each study (Figures 3 a-e). 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Clinic (n=1) NA NA NA 

ED (n=8) 8.55 0.286 18.2% 

Primary Care (n=2) 9.03 0.003 88.9% 

Overall (n=11) 47.77 0.000 79.1% 

SPECIFICITY 

Clinic NA NA NA 

ED 335.03 0.000 97.9% 

Primary Care 66.25 0.000 98.5% 

Overall 508.63 0.000 98.0% 

LR + 

Clinic NA NA NA 

ED 149.64 0.000 95.3% 

Primary Care 0.64 0.425 0.0% 

Overall 238.47 0.000 95.8% 

LR - 

Clinic NA NA NA 

ED 22.36 0.002 68.7% 

Primary Care 0.83 0.362 0.0% 

Overall 108.45 0.00 90.8% 

DOR 

Clinic NA NA NA 

ED 48.55 0.00 85.6% 

Primary Care 0.13 0.713 0.0% 

Overall 99.80 0.00 90.0% 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio, NA = not able calculate because not enough studies
C - 102 

Evidence Table 14: Tests for heterogeneity due to STUDY SETTINGS for BNP using the lowest cut point 

provided in each study (Figures 4a-e). 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Clinic (n=1) NA NA NA 

ED (n=3) 6.86 0.032 70.8% 

Primary Care (n=3) 6.17 0.046 67.6% 

Overall (n=7) 24.15 0.000 75.2% 

SPECIFICITY 

Clinic NA NA NA 

ED 15.99 0.000 87.5% 

Primary Care 75.63 0.000 97.4% 

Overall 121.61 0.000 95.1% 

LR + 

Clinic NA NA NA 

ED 10.64 0.005 81.2% 

Primary Care 25.22 0.000 92.1% 

Overall 49.51 0.000 87.9% 

LR - 

Clinic NA NA NA 

ED 7.31 0.026 72.6% 

Primary Care 1.61 0.447 0.0% 

Overall 11.55 0.073 48.1% 

DOR 

Clinic NA NA NA 

ED 9.51 0.009 79.0% 

Primary Care 0.20 0.904 0.0% 

Overall 11.81 0.066 49.2% 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio, NA = not able calculate because not enough studies 
C - 103 

Evidence Table 15: Tests for heterogeneity due to STUDY SETTINGS for BNP in the ED using a cut point of 

100 pg/mL (Figures 5a-e). 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

ED (n=6) 14.24 0.014 64.9% 

SPECIFICITY 

ED 203.58 0.000 97.5% 

LR + 

ED 152.93 0.000 96.7% 

LR - 

ED 9.16 0.103 45.4% 

DOR 

ED 33.56 0.00 85.1% 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio 
C - 104 

Evidence Table 16: Tests for heterogeneity due to STUDY DESIGN for BNP using the lowest cut point 

provided in each study. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Cross sectional (n=8) 35.68 0.000 80.4% 

Diagnostic (n=2) 11.93 0.001 91.6% 

Prospective Cohort (n=1) NA NA NA 

Overall (n=11) 47.77 0.000 79.1% 

SPECIFICITY 

Cross sectional 424.00 0.000 98.3% 

Diagnostic 14.94 0.00 93.37% 

Prospective Cohort NA NA NA 

Overall 508.63 0.000 98.1% 

LR + 

Cross sectional 219.52 0.000 96.8% 

Diagnostic 0.16 0.689 0.0% 

Prospective Cohort NA NA NA 

Overall 238.47 0.000 95.8% 

LR - 

Cross sectional 78.89 0.00 91.2% 

Diagnostic 9.93 0.002 89.9% 

Prospective Cohort NA NA NA 

Overall 108.45 0.00 90.8% 

DOR 

Cross sectional 76.71 0.000 90.9% 

Diagnostic 6.78 0.009 85.3% 

Prospective Cohort NA NA NA 

Overall 99.80 0.00 90.0% 

Abbreviations: DOR = diagnostic odds ratio, LR- = negative likelihood ratio, LR+ = positive likelihood ratio, NA = not 

able calculate because not enough studies 
C - 105 

Evidence Table 17: Tests for heterogeneity due to STUDY DESIGN for NT-proBNP using the lowest cut point 

provided in each study. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Cross sectional (n=3) 8.51 0.014 80.4% 

Diagnostic (n=2) 0.76 0.382 0.0% 

Prospective Cohort (n=1) NA NA NA 

Randomized Trial (n=1) NA NA NA 

Overall (n=7) 24.15 0.000 75.2% 

SPECIFICITY 

Cross-sectional 72.43 0.000 97.2% 

Diagnostic 17.79 0.000 94.4% 

Prospective Cohort NA NA NA 

Randomized trial NA NA NA 

Overall 121.61 0.000 95.1% 

LR + 

Cross-sectional 219.52 0.000 96.8% 

Diagnostic 0.16 0.689 0.0% 

Prospective Cohort NA NA NA 

Randomized Trial NA NA NA 

Overall 49.53 0.000 87.9% 

LR - 

Cross-sectional 7.56 0.023 73.5% 

Diagnostic 0.19 0.667 0.0% 

Prospective Cohort NA NA NA 

Randomized Trial NA NA NA 

Overall 11.58 0.072 48.2% 

DOR 

Cross-sectional 9.84 0.007 79.7% 

Diagnostic 0.00 0.955 0.0% 

Prospective Cohort NA NA NA 

Randomized Trial NA NA NA 

Overall 11.80 0.066 49.2% 

Abbreviations: DOR = diagnostic odds ratio, LR- = negative likelihood ratio, LR+ = positive likelihood ratio, NA = not 

able calculate because not enough studies 
C - 106 

Table 18: Tests for heterogeneity due to STUDY DESIGN for BNP in the ED using a cut point of 100 pg/mL. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Cross sectional (n=5) 9.89 0.042 59.5% 

Diagnostic (n=1) NA NA NA 

SPECIFICITY 

Cross sectional 159.97 0.000 97.5% 

Diagnostic NA NA NA 

LR + 

Cross sectional 139.89 0.000 97.1% 

Diagnostic NA NA NA 

LR - 

Cross sectional 7.90 0.095 49.4% 

Diagnostic NA NA NA 

DOR 

Cross sectional 33.51 0.000 88.1% 

Diagnostic NA NA NA 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio, NA = not able calculate because not enough studies: 
C - 107 

Table 19: Tests for heterogeneity due to CUT POINT near or exactly 100 pg/mL BNP. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Exactly 100pg/mL (n=1) NA NA NA 

Greater than 100 pg/mL (n=4) 32.52 0.000 90.8% 

Less than 100 pg/mL (n=6) 1.52 0.911 0.0% 

Overall (n=11) 47.77 0.000 79.1% 

SPECIFICITY 

Exactly 100pg/mL NA NA NA 

Greater than 100 pg/mL 41.19 0.000 92.7% 

Less than 100 pg/mL 400.57 0.000 98.8% 

Overall 508.63 0.000 98.0% 

LR + 

Exactly 100pg/mL NA NA NA 

Greater than 100 pg/mL 19.28 0.000 84.4% 

Less than 100 pg/mL 212.84 0.000 97.7% 

Overall 238.47 0.000 95.8% 

LR - 

Exactly 100pg/mL NA NA NA 

Greater than 100 pg/mL 19.50 0.006 69.5% 

Less than 100 pg/mL 16.41 0.006 69.5% 

Overall 108.45 0.00 90.8% 

DOR 

Exactly 100pg/mL NA NA NA 

Greater than 100 pg/mL 31.23 0.000 88.8% 

Less than 100 pg/mL 41.56 0.000 88.0% 

Overall 99.80 0.00 90.0% 

Abbreviations: DOR = diagnostic odds ratio, LR- = negative likelihood ratio, LR+ = positive likelihood ratio, NA = not 

able calculate because not enough studies: 
C - 108 

Table 20: Tests for heterogeneity due to CUT POINT exactly or greater than 100 pg/mL BNP studies in ED. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Exactly 100pg/mL (n=4) 9.28 0.026 67.7% 

Greater than 100 pg/mL (n=2) 0.81 0.369 0.0% 

Overall (n=6) 14.24 0.14 64.9% 

SPECIFICITY 

Exactly 100pg/mL 154.28 0.000 98.1% 

Greater than 100 pg/mL 48.26 0.000 97.9% 

Overall 203.58 0.000 97.5% 

LR + 

Exactly 100pg/mL 117.42 0.000 97.4% 

Greater than 100 pg/mL 34.94 0.000 97.1% 

Overall 152.93 0.000 96.7% 

LR - 

Exactly 100pg/mL 4.89 0.180 38.6% 

Greater than 100 pg/mL 0.08 0.777 0.0% 

Overall 9.16 0.103 45.4% 

DOR 

Exactly 100pg/mL 25.55 0.000 88.3% 

Greater than 100 pg/mL 1.29 0.255 22.7% 

Overall 33.56 0.00 85.1% 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio 
C - 109 

Table 21: Heterogeneity for SAMPLE SIZE for the lowest cut point provided in each BNP study. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Large [n>=500] (n=1) NA NA NA 

Small [n<500] (n=10) 46.55 0.000 80.7% 

Overall (n=11) 47.77 0.000 79.1% 

SPECIFICITY 

Large [n>=500] NA NA NA 

Small [n<500] 463.31 0.000 98.1% 

Overall 508.63 0.000 98.0% 

LR + 

Large [n>=500] NA NA NA 

Small [n<500] 191.11 0.000 95.3% 

Overall 238.47 0.000 95.8% 

LR - 

Large [n>=500] NA NA NA 

Small [n<500] 63.49 0.000 85.8% 

Overall 108.45 0.00 90.8% 

DOR 

Large [n>=500] NA NA NA 

Small [n<500] 83.41 0.000 89.2% 

Overall 99.80 0.00 90.0% 

Abbreviations: DOR = diagnostic odds ratio, LR- = negative likelihood ratio, LR+ = positive likelihood ratio, NA = not 

able calculate because not enough studies 
C - 110 

Table 22: Heterogeneity for SAMPLE SIZE for the lowest cut point provided in each NT-proBNP study. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Small [n<500] (n= 7) 24.11 0.0000 75.2% 

SPECIFICITY 

Small [n<500] 121.61 0.000 95.1% 

LR + 

Small [n<500] 49.53 0.000 87.9% 

LR - 

Small [n<500] 11.58 0.072 48.2% 

DOR 

Small [n<500] 11.80 0.066 49.2% 

Abbreviations: DOR = diagnostic odds ratio, LR- = negative likelihood ratio, LR+ = positive likelihood ratio 
C - 111 

Table 23: Heterogeneity for SAMPLE SIZE for ED with a BNP cut point near 100 pg/mL. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Large [n≥500] (n=1) NA NA NA 

Small [n<500] (n=5) 5.12 0.275 21.9% 

SPECIFICITY 

Large [n≥500] NA NA NA 

Small [n<500] 102.66 0.000 96.7% 

LR + 

Large [n≥500] NA NA NA 

Small [n<500] 152.93 0.000 96.7% 

LR - 

Large [n≥500] NA NA NA 

Small [n<500] 7.91 0.095 49.4% 

DOR 

Large [n≥500] NT NT NT 

Small [n<500] NT NT NT 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, LR- = negative likelihood ratio, LR+ = 

positive likelihood ratio, NA = not able calculate because not enough studies 
C - 112 

Table 24: Tests for heterogeneity due to REFERENCE used to diagnose HF for BNP using the lowest cut 

point provided in each study.

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Compared to LVEF (n=5) 15.21 0.004 73.7% 

Compared to SS (n=4) 0.50 0.919 0.0% 

HF to Clinical Scales (n=2) 26.02 0.00 96.2% 

Overall (n=11) 47.77 0.000 79.1% 

SPECIFICITY 

Compared to LVEF 206.99 0.000 98.1% 

Compared to SS 216.40 0.00 98.6% 

HF to Clinical Scales 4.44 0.035 77.5% 

Overall 508.63 0.000 98.0% 

LR + 

Compared to LVEF 53.03 0.000 92.5% 

Compared to SS 87.43 0.000 96.6% 

HF to Clinical Scales 11.16 0.001 91.0% 

Overall 238.47 0.000 95.8% 

LR - 

Compared to LVEF 24.44 0.000 83.6% 

Compared to SS 4.10 0.251 26.9% 

HF to Clinical Scales 19.95 0.000 95.0% 

Overall 108.45 0.00 90.8% 

DOR 

Compared to LVEF 53.03 0.000 92.5% 

Compared to SS 87.43 0.000 96.6% 

HF to Clinical Scales 11.16 0.001 91.0% 

Overall 99.80 0.00 90.0% 

Abbreviations: DOR = diagnostic odds ratio, HF = heart failure, LR- = negative likelihood ratio, LR+ = positive 

likelihood ratio, LVEF = left ventricular ejection fraction, SS = suggestive symptoms 
C - 113 

Table 25: Tests for heterogeneity due to REFERENCE used to diagnose HF for NT-proBNP using the lowest 

cut point provided in each study. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Compared to LVEF (n=5) 15.88 0.003 74.8% 

HF to Clinical Scales (n=2) 7.96 0.005 87.4% 

Overall (n=7) 24.15 0.000 75.2% 

SPECIFICITY 

Compared to LVEF 85.52 0.000 95.3% 

HF to Clinical Scales 5.13 0.024 80.5% 

Overall 121.61 0.000 95.1% 

LR + 

Compared to LVEF 33.13 0.000 88.1% 

HF to Clinical Scales 4.92 0.0227 79.7% 

Overall 49.53 0.000 87.9% 

LR - 

Compared to LVEF 4.85 0.303 17.6% 

HF to Clinical Scales 6.69 0.010 85.1% 

Overall 11.58 0.072 48.2% 

DOR 

Compared to LVEF 1.44 0.837 0.0% 

HF to Clinical Scales 9.84 0.002 89.8% 

Overall 11.80 0.066 49.2% 

Abbreviations: DOR = diagnostic odds ratio, HF = heart failure, LR- = negative likelihood ratio, LR+ = positive 

likelihood ratio, LVEF = left ventricular ejection fraction 
C - 114 

Table 26: Tests for heterogeneity due to REFERENCE used to diagnose HF for BNP in the ED using a cut 

point of 100 pg/mL. 

Study Setting Heterogeneity 

Statistic (Q-test) Probability I-Squared 

SENSITIVITY 

Compared to LVEF (n=2) 4.36 0.037 77.1% 

Compared to SS (n=3) 8.68 0.013 77.0% 

HF to Clinical Scales (n=1) NA NA NA 

Overall (n=6) 14.24 0.014 64.9% 

SPECIFICITY 

Compared to LVEF 2.04 0.1530 51.0% 

Compared to SS 124.18 0.000 98.4% 

HF to Clinical Scales NA NA NA 

Overall 203.58 0.000 97.5% 

LR + 

Compared to LVEF 0.65 0.420 0.0% 

Compared to SS 111.88 0.000 98.2% 

HF to Clinical Scales NA NA NA 

Overall 152.93 0.000 96.7% 

LR - 

Compared to LVEF 2.15 0.143 53.4% 

Compared to SS 3.79 0.151 47.2% 

HF to Clinical Scales NA NA NA 

Overall 9.16 0.103 45.4% 

DOR 

Compared to LVEF 1.51 0.219 33.8% 

Compared to SS 19.69 0.000 89.8% 

HF to Clinical Scales NA NA NA 

Overall 33.56 0.000 85.1% 

Abbreviations: DOR = diagnostic odds ratio, ED = emergency department, HF = heart failure, LR- = negative 

likelihood ratio, LR+ = positive likelihood ratio, LVEF = left ventricular ejection fraction, NA = not able calculate 

because not enough studies, SS = suggestive symptoms 
C - 115 

Evidence Figure 1. QUADAS results for question 2ai papers 

0% 20% 40% 60% 80% 100%

Q1Q2Q3Q4Q5Q6Q7Q8Q9

Q10Q11Q12Q13Q14

Rating1 (Yes)Rating2 (No)Rating3 (Uncertain)
C - 116 

Evidence Figure 2. QUADAS results for question 2aii papers 

0% 20% 40% 60% 80% 100%

Q1Q2Q3Q4Q5Q6Q7Q8Q9

Q10Q11Q12Q13Q14

Rating1 (Yes)Rating2 (No)Rating3 (Uncertain)
C - 117 

Evidence Figure 3. QUADAS results for question 2aiii papers 

0% 20% 40% 60% 80% 100%

Q1Q2Q3Q4Q5Q6Q7Q8Q9

Q10Q11Q12Q13Q14

Rating1 (Yes)Rating2 (No)Rating3 (Uncertain)
C - 118 

Evidence Figure 4. QUADAS results for all question 2 papers 

0% 20% 40% 60% 80% 100%

Q1Q2Q3Q4Q5Q6Q7Q8Q9

Q10Q11Q12Q13Q14

Rating1 (Yes)Rating2 (No)Rating3 (Uncertain)
C - 119 

Reference List of Included Articles for Appendix C 

Akioka K, Takeuchi K, Yanagi S, et al. Prognostic value of Doppler transmittal flow patterns and cardiac natriur

patients with chronic congestive heart failure admitted for episodes of acute decompensation. Heart Vess

Alehagen U, Dahlstrom U, Lindahl TL, et al. Elevated D-dimer level is an independent risk factor for cardiovasc

patients with symptoms compatible with heart failure. Thromb Haemost 2004 Dec;92(6):1250-8. 

Alehagen U, Eriksson H, Nylander E, et al. Heart failure in the elderly: Characteristics of a Swedish primary hea

Heartdrug 2002;2(5):211-20. 

Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and m

morbidity in the Valsartan Heart Failure Trial (Val-HeFT).[see comment]. Circulation 2003 Mar 11;107(

Atisha D, Bhalla MA, Morrison LK, et al. A prospective study in search of an optimal B-natriuretic peptide leve

for cardiac dysfunction. Am Heart J 2004 Sep;148(3):518-23. 

Barcarse E, Kazanegra R, Chen A, et al. Combination of B-type natriuretic peptide levels and non-invasive hem

in diagnosing congestive heart failure in the emergency department. Congest Heart Fail 2004 Jul;10(4):1

Bayes-Genis A, Santalo-Bel M, Zapico-Muniz E, et al. N-terminal probrain natriuretic peptide (NT-proBNP) in 

diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction. Eur J Heart 

15;6(3):301-8. 

Bazzino O, Fuselli JJ, Botto F, et al. Relative value of N-terminal probrain natriuretic peptide, TIMI risk score, A

classification and other risk markers in patients with non-ST-elevation acute coronary syndromes.[see com

2004 May;25(10):859-66. 

Berger R, Huelsmann M, Strecker K, et al. Neurohormonal risk stratification for sudden death and death owing 

failure in chronic heart failure. Eur J Clin Invest 2005 Jan;35(1):24-31. 
C - 120 

Berger R, Strecker K, Huelsmann M, et al. Prognostic power of neurohumoral parameters in chronic heart failur

stage and observation period. J Heart Lung Transplant 2003 Sep;22(9):1037-45. 

Bertinchant JP, Combes N, Polge A, et al. Prognostic value of cardiac troponin T in patients with both acute and 

congestive heart failure: comparison with atrial natriuretic peptide, brain natriuretic peptide and plasma nChim Acta 2005 Feb;352(1-2):143-53. 

Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal-pro-brain natriuretic peptide predicts outcome after hosp

failure patients. Circulation 2004 Oct 12;110(15):2168-74. 

Bettencourt P, Ferreira A, Dias P, et al. Evaluation of brain natriuretic peptide in the diagnosis of heart failure.[s

Cardiology 2000;93(1-2):19-25. 

Bettencourt P, Ferreira A, Dias P, et al. Predictors of prognosis in patients with stable mild to moderate heart fai

2000 Dec;6(4):306-13. 

Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients w

infarction. Clin Cardiol 2000 Dec;23(12):921-7. 

Bettencourt P, Ferreira A, Sousa T, et al. Brain natriuretic peptide as a marker of cardiac involvement in hyperte

1999 May 15;69(2):169-77. 

Bettencourt P, Ferreira S, Azevedo A, et al. Preliminary data on the potential usefulness of B-type natriuretic pe

predicting outcome after hospital discharge in patients with heart failure. Am J Med 2002 Aug 15;113(3)

Bettencourt P, Frioes F, Azevedo A, et al. Prognostic information provided by serial measurements of brain natr

heart failure. Int J Cardiol 2004 Jan;93(1):45-8. 

Bhalla MA, Chiang A, Epshteyn VA, et al. Prognostic role of B-type natriuretic peptide levels in patients with ty

mellitus. J Am Coll Cardiol 2004 Sep 1;44(5):1047-52. 

Bibbins-Domingo K, Ansari M, Schiller NB, et al. Is B-type natriuretic peptide a useful screening test for systol

dysfunction in patients with coronary disease? Data from the Heart and Soul Study.[see comment]. Am J 

15;116(8):509-16. 
C - 121 

Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in p

decompensated heart failure: a pilot study. J Am Coll Cardiol 2001 Feb;37(2):386-91. 

Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive 

urgent-care setting. J Am Coll Cardiol 2001 Feb;37(2):379-85. 

de Groote P, Dagorn J, Soudan B, et al. B-type natriuretic peptide and peak exercise oxygen consumption provid

information for risk stratification in patients with stable congestive heart failure.[see comment]. J Am Co

5;43(9):1584-9. 

de Winter RJ, Stroobants A, Koch KT, et al. Plasma N-terminal pro-B-type natriuretic peptide for prediction of 

myocardial infarction following percutaneous coronary intervention. Am J Cardiol 2004 Dec 15;94(12):

Dias P, Rodrigues RA, Queiros MC, et al. Prognosis in patients with heart failure and preserved left ventricular 

Rev Port Cardiol 2001 Dec;20(12):1223-32. 

Dokainish H, Pillai M, Murphy SA, et al. Prognostic implications of elevated troponin in patients with suspected 

syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol 24. 

Fisher C, Berry C, Blue L, et al. N-terminal pro B type natriuretic peptide, but not the new putative cardiac horm

prognosis in patients with chronic heart failure. Heart 2003 Aug;89(8):879-81. 

Fung JW, Yu CM, Yip G, et al. Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-ang

system and natriuretic peptides in chronic heart failure. Am J Cardiol 2003 Aug 15;92(4):406-10. 

Gaede P, Hildebrandt P, Hess G, et al. Plasma N-terminal pro-brain natriuretic peptide as a major risk marker fo

disease in patients with type 2 diabetes and microalbuminuria. Diabetologia 2005;48(1):156-63. 

Galvani M, Ottani F, Oltrona L, et al. N-terminal pro-brain natriuretic peptide on admission has prognostic value 

spectrum of acute coronary syndromes. Circulation 2004 Jul 13;110(2):128-34. 

Gardner RS, Ozalp F, Murday AJ, et al. N-terminal pro-brain natriuretic peptide. A new gold standard in predict

patients with advanced heart failure. Eur Heart J 2003 Oct;24(19):1735-43. 
C - 122 

Grabowski M, Filipiak KJ, Karpinski G, et al. Serum B-type natriuretic peptide levels on admission predict not o

but also angiographic success of procedure in patients with acute ST-elevation myocardial infarction trea

angioplasty. Am Heart J 2004 Oct;148(4):655-62. 

Groenning BA, Raymond I, Hildebrandt PR, et al. Diagnostic and prognostic evaluation of left ventricular systo

plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general populationMar;90(3):297-303. 

Gustafsson F, Badskjaer J, Hansen FS, et al. Value of N-terminal proBNP in the diagnosis of left ventricular sys

primary care patients referred for echocardiography. Heartdrug 2003;3(3):141-6. 

Gwechenberger M, Hulsmann M, Berger R, et al. Interleukin-6 and B-type natriuretic peptide are independent p

worsening of heart failure in patients with progressive congestive heart failure. J Heart Lung Transplant 44. 

Hamada Y, Tanaka N, Murata K, et al. Significance of predischarge BNP on one-year outcome in decompensate

comparative study with echo-Doppler indexes. J Card Fail 2005 Feb;11(1):43-9. 

Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic 

natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction2001 Aug 20;310(2):193-7. 

Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in pa

the emergency department with dyspnea. Ann Emerg Med 2002 Feb;39(2):131-8. 

Hartmann F, Packer M, Coats AJ, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in 

congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COP

Circulation 2004 Sep 28;110(13):1780-6. 

Hartmann F, Packer M, Coats AJ, et al. NT-proBNP in severe chronic heart failure: rationale, design and prelim

COPERNICUS NT-proBNP substudy. Eur J Heart Fail 2004 Mar 15;6(3):343-50. 

Hedberg P, Lonnberg I, Jonason T, et al. Electrocardiogram and B-type natriuretic peptide as screening tools for 

systolic dysfunction in a population-based sample of 75-year-old men and women. Am Heart J 2004 Sep
C - 123 

Heeschen C, Hamm CW, Mitrovic V, et al. N-terminal pro-B-type natriuretic peptide levels for dynamic risk str

with acute coronary syndromes. Circulation 2004 Nov 16;110(20):3206-12. 

Hobbs FD, Davis RC, Roalfe AK, et al. Reliability of N-terminal proBNP assay in diagnosis of left ventricular s

within representative and high risk populations. Heart 2004 Aug;90(8):866-70. 

Horwich TB, Patel J, MacLellan WR, et al. Cardiac troponin I is associated with impaired hemodynamics, progr

dysfunction, and increased mortality rates in advanced heart failure. Circulation 2003 Aug;108(7):833-8

Hulsmann M, Berger R, Sturm B, et al. Prediction of outcome by neurohumoral activation, the six-minute walk 

Minnesota Living with Heart Failure Questionnaire in an outpatient cohort with congestive heart failure. Jun;23(11):886-91. 

Hutfless R, Kazanegra R, Madani M, et al. Utility of B-type natriuretic peptide in predicting postoperative comp

outcomes in patients undergoing heart surgery. J Am Coll Cardiol 2004 May;43(10):1873-9. 

Imamura Y, Fukuyama T, Mochizuki T, et al. Prognostic value of iodine-123-metaiodobenzylguanidine imaging 

natriuretic peptide levels in patients with left ventricular dysfunction resulting from cardiomyopathy. Jpn Mar;65(3):155-60. 

Ishii J, Cui W, Kitagawa F, et al. Prognostic value of combination of cardiac troponin T and B-type natriuretic p

of treatment in patients with chronic heart failure. Clin Chem 2003 Dec;49(12):2020-6. 

Ishii J, Nomura M, Nakamura Y, et al. Risk stratification using a combination of cardiac troponin T and brain na

patients hospitalized for worsening chronic heart failure. Am J Cardiol 2002 Mar 15;89(6):691-5. 

James S, James S. Coagulation, inflammation and myocardial dysfunction in unstable coronary artery disease an

glycoprotein IIb/IIIa inhibition and low molecular weight heparin. Ups J Med Sci 2004;109(2):71-122. 

James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the s

mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Globa

Strategies To Open occluded arteries (GUSTO)-IV substudy.[see comment]. Circulation 2003 Jul 22;108
C - 124 

Jarai R, Iordanova N, Jarai R, et al. Risk assessment in patients with unstable angina/non-ST-elevation myocard

normal N-terminal pro-brain natriuretic peptide levels by N-terminal pro-atrial natriuretic peptide. Eur H

Feb;26(3):250-6. 

Jernberg T, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide in relation to inflammation, m

and the effect of an invasive strategy in unstable coronary artery disease.[see comment]. J Am Coll Card3;42(11):1909-16. 

Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk str

with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002 Aug 7;40(3):437-45. 

Jiang CY, Li N, Wang JA, et al. Use of B-type natriuretic peptide in evaluation of early percutaneous coronary i

patients with acute coronary syndrome. Chin Med J 2004 Aug;117(8):1130-4. 

Jose JV, Gupta SN, Selvakumar D. Utility of N-terminal pro-brain natriuretic peptide for the diagnosis of heart f

2003 Jan;55(1):35-9. 

Jose JV, Gupta SN, Selvakumar D. Utility of N-terminal pro-brain natriuretic peptide for the diagnosis of heart f

2003 Jan;55(1):35-9. 

Jose JV, Gupta SN, Selvakumar D. Utility of N-terminal pro-brain natriuretic peptide for the diagnosis of heart f

2003 Jan;55(1):35-9. 

Julier K, Da Silva R, Garcia C, et al. Preconditioning by sevoflurane decreases biochemical markers for myocar

dysfunction in coronary artery bypass graft surgery: A double-blinded, placebo-controlled, multicenter st2003;98(6):1315-27. 

Kawai K, Hata K, Takaoka H, et al. Plasma brain natriuretic peptide as a novel therapeutic indicator in idiopathi

cardiomyopathy during beta-blocker therapy: a potential of hormone-guided treatment. Am Heart J 2001 

Kellett J, Kellett J. Prediction of in-hospital mortality by brain natriuretic peptide levels and other independent va

patients with suspected heart disease.[see comment]. Can J Cardiol 2004 May 15;20(7):686-90. 

Kerbaul F, Collart F, Giorgi R, et al. Increased plasma levels of pro-brain natriuretic peptide in patients with car

complications following off-pump coronary artery surgery. Intensive Care Med 2004 Sep;30(9):1799-80
C - 125 

Kirk V, Bay M, Parner J, et al. N-terminal proBNP and mortality in hospitalised patients with heart failure and p

systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF). Eur J He15;6(3):335-41. 

Knudsen CW, Omland T, Clopton P, et al. Diagnostic value of B-Type natriuretic peptide and chest radiographi

with acute dyspnea.[see comment]. Am J Med 2004 Mar 15;116(6):363-8. 

Knudsen CW, Riis JS, Finsen AV, et al. Diagnostic value of a rapid test for B-type natriuretic peptide in patients 

acute dyspnoe: effect of age and gender. Eur J Heart Fail 2004 Jan;6(1):55-62. 

Koglin J, Pehlivanli S, Schwaiblmair M, et al. Role of brain natriuretic peptide in risk stratification of patients w

failure. J Am Coll Cardiol 2001 Dec;38(7):1934-41. 

Kyuma M, Nakata T, Hashimoto A, et al. Incremental prognostic implications of brain natriuretic peptide, cardi

innervation, and noncardiac disorders in patients with heart failure. J Nucl Med 2004 Feb;45(2):155-63. 

Lainchbury JG, Campbell E, Frampton CM, et al. Brain natriuretic peptide and n-terminal brain natriuretic pepti

heart failure in patients with acute shortness of breath. J Am Coll Cardiol 2003 Aug 20;42(4):728-35. 

Landray MJ, Lehman R, Arnold I, et al. Measuring brain natriuretic peptide in suspected left ventricular systolic 

general practice: cross-sectional study.[see comment]. BMJ 2000 Apr 8;320(7240):985-6. 

Latini R, Maggioni AP, Peri G, et al. Prognostic significance of the long pentraxin PTX3 in acute myocardial in

2004 Oct;110(16):2349-54. 

Latini R, Masson S, Anand I, et al. The comparative prognostic value of plasma neurohormones at baseline in pa

failure enrolled in Val-HeFT.[see comment]. Eur Heart J 2004 Feb;25(4):292-9. 

Lee SC, Stevens TL, Sandberg SM, et al. The potential of brain natriuretic peptide as a biomarker for New York 

class during the outpatient treatment of heart failure. J Card Fail 2002 Jun;8(3):149-54. 

Lindahl B, Lindback J, Jernberg T, et al. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients 

elevation acute coronary syndromes A Fragmin and fast Revascularisation during InStability in coronary 

(FRISC)-II substudy. J Am Coll Cardiol 2005 Feb 15;45(4):533-41. 
C - 126 

Logeart D, Saudubray C, Beyne P, et al. Comparative value of Doppler echocardiography and B-type natriuretic 

etiologic diagnosis of acute dyspnea.[see comment]. J Am Coll Cardiol 2002 Nov 20;40(10):1794-800. 

Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at h

admission after decompensated heart failure. J Am Coll Cardiol 2004 Feb 18;43(4):635-41. 

Maeda K, Tsutamoto T, Wada A, et al. Plasma brain natriuretic peptide as a biochemical marker of high left ven

pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998 May;135(5 Pt 1):82

Maeda K, Tsutamoto T, Wada A, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after op

heart failure are independent risk factors for morbidity and mortality in patients with congestive heart fail

Cardiol 2000 Nov 1;36(5):1587-93. 

Maisel A, Hollander JE, Guss D, et al. Primary results of the Rapid Emergency Department Heart Failure Outpa

(REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision ma

patients presenting with shortness of breath.[see comment]. J Am Coll Cardiol 2004 Sep 15;44(6):1328-3

Maisel AS, Clopton P, Krishnaswamy P, et al. Impact of age, race, and sex on the ability of B-type natriuretic pe

emergency diagnosis of heart failure: results from the Breathing Not Properly (BNP) multinational study. Jun;147(6):1078-84. 

Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergen

failure.[see comment][summary for patients in J Fam Pract. 2002 Oct;51(10):816; PMID: 12401145]. N 18;347(3):161-7. 

McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency di

failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002 Jul 23;106(4

Mega JL, Morrow DA, de Lemos JA, et al. B-type natriuretic peptide at presentation and prognosis in patients w

elevation myocardial infarction: an ENTIRE-TIMI-23 substudy. J Am Coll Cardiol 2004 Jul 21;44(2):33

Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid B-natriuretic peptide assay in differentiating 

failure from lung disease in patients presenting with dyspnea.[see comment]. J Am Coll Cardiol 2002 Jan 
C - 127 

Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in un

ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18.[see appears in J Am Coll Cardiol. 2003 May 21;41(10):1852]. J Am Coll Cardiol 2003 Apr 16;41(8):1264-7

Murdoch DR, McDonagh TA, Byrne J, et al. Titration of vasodilator therapy in chronic heart failure according t

natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effecempirical therapy.[see comment]. Am Heart J 1999 Dec;138(6 Pt 1):1126-32. 

Nagao K, Hayashi N, Kanmatsuse K, et al. B-type natriuretic peptide as a marker of resuscitation in patients wit

outside the hospital. Circ J 2004 May;68(5):477-82. 

Nielsen LS, Svanegaard J, Klitgaard NA, et al. N-terminal pro-brain natriuretic peptide for discriminating betwe

cardiac dyspnoea. Eur J Heart Fail 2004 Jan;6(1):63-70. 

O'Brien RJ, Squire IB, Demme B, et al. Pre-discharge, but not admission, levels of NT-proBNP predict adverse 

acute LVF. Eur J Heart Fail 2003 Aug;5(4):499-506. 

Olsen MH, Wachtell K, Tuxen C, et al. N-terminal pro-brain natriuretic peptide predicts cardiovascular events in 

hypertension and left ventricular hypertrophy: a LIFE study. J Hypertens 2004 Aug;22(8):1597-604. 

Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular sy

long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide anproatrial natriuretic peptide.[see comment]. Circulation 1996 Jun 1;93(11):1963-9. 

Omland T, Persson A, Ng L, et al. N-terminal pro-B-type natriuretic peptide and long-term mortality in acute co

syndromes.[see comment]. Circulation 2002 Dec 3;106(23):2913-8. 

Palmer BR, Pilbrow AP, Yandle TG, et al. Angiotensin-converting enzyme gene polymorphism interacts with le

fraction and brain natriuretic peptide levels to predict mortality after myocardial infarction.[see comment2003 Mar 5;41(5):729-36. 

Panteghini M, Cuccia C, Bonetti G, et al. Rapid determination of brain natriuretic peptide in patients with acute 

infarction. Clin Chem Lab Med 2003 Feb;41(2):164-8. 
C - 128 

Ray P, Arthaud M, Lefort Y, et al. Usefulness of B-type natriuretic peptide in elderly patients with acute dyspne

Med 2004 Dec;30(12):2230-6. 

Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide to detect preclinical ventricula

dysfunction: a community-based study. Circulation 2004 Jun 29;109(25):3176-81. 

Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedul

and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New 

Group. J Am Coll Cardiol 2001 Jun 1;37(7):1781-7. 

Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis aft

infarction.[see comment]. Circulation 2003 Jun 10;107(22):2786-92. 

Richards AM, Nicholls MG, Troughton RW, et al. Antecedent hypertension and heart failure after myocardial in

Cardiol 2002;39(7):1182-8. 

Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedu

neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulati

May;97(19):1921-9. 

Rossig L, Fichtlscherer S, Heeschen C, et al. The pro-apoptotic serum activity is an independent mortality predic

heart failure. Eur Heart J 2004 Sep;25(18):1620-5. 

Rothenburger M, Wichter T, Schmid C, et al. Aminoterminal pro type B natriuretic peptide as a predictive and p

patients with chronic heart failure. J Heart Lung Transplant 2004 Oct;23(10):1189-97. 

Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation a

syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Ci16;105(15):1760-3. 

Sadanandan S, Cannon CP, Chekuri K, et al. Association of elevated B-type natriuretic peptide levels with angio

among patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Ca

4;44(3):564-8. 
C - 129 

Sakatani T, Hadase M, Kawasaki T, et al. Usefulness of the percentage of plasma lymphocytes as a prognostic m

congestive heart failure. Jpn Heart J 2004 Mar;45(2):275-84. 

Schnabel R, Rupprecht HJ, Lackner KJ, et al. Analysis of N-terminal-pro-brain natriuretic peptide and C-reactiv

stratification in stable and unstable coronary artery disease: results from the AtheroGene study. Eur HearFeb;26(3):241-9. 

Seino Y, Ogawa A, Yamashita T, et al. Application of NT-proBNP and BNP measurements in cardiac care: a m

for the detection and evaluation of heart failure. Eur J Heart Fail 2004 Mar 15;6(3):295-300. 

Shiga T, Hosaka F, Wakaumi M, et al. Amiodarone decreases plasma brain natriuretic peptide level in patients w

ventricular tachyarrhythmia. Cardiovasc Drugs Ther 2003 Jul;17(4):325-33. 

Shimpo M, Morrow DA, Weinberg EO, et al. Serum Levels of the Interleukin-1 Receptor Family Member ST2 P

Clinical Outcome in Acute Myocardial Infarction. Circulation 2004;109(18):2186-90. 

Song MH, Kobayashi Y, Michi H, et al. Clinical implication of atrial and brain natriuretic Peptide in coronary ar

Asian Cardiovasc Thorac Ann 2004 Mar;12(1):41-6. 

Stanek B, Frey B, Hulsmann M, et al. Prognostic evaluation of neurohumoral plasma levels before and during b

advanced left ventricular dysfunction. J Am Coll Cardiol 2001 Aug;38(2):436-42. 

Suzuki M, Hamada M, Yamamoto K, et al. Brain natriuretic peptide as a risk marker for incident hypertensive c

Hypertens Res 2002 Sep;25(5):669-76. 

Suzuki S, Yoshimura M, Nakayama M, et al. Plasma level of B-type natriuretic peptide as a prognostic marker a

infarction: a long-term follow-up analysis. Circulation 2004 Sep 14;110(11):1387-91. 

Takase H, Toriyama T, Sugiura T, et al. Brain natriuretic peptide in the prediction of recurrence of angina pecto

2004 Feb;34(2):79-84. 

Tamura K, Takahashi N, Nakatani Y, et al. Prognostic impact of plasma brain natriuretic peptide for cardiac eve

with congestive heart failure. Gerontology 2001 Jan;47(1):46-51. 
C - 130 

Taniguchi R, Sato Y, Yamada T, et al. Combined measurements of cardiac troponin T and N-terminal pro-brain 

patients with heart failure. Circ J 2004 Dec;68(12):1160-4. 

Tarnow L, Hildebrandt P, Hansen BV, et al. Plasma N-terminal pro-brain natriuretic peptide as an independent p

in diabetic nephropathy. Diabetologia 2005 Jan;48(1):149-55. 

Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided by plasma aminoterminal br

(N-BNP) concentrations.[see comment]. Lancet 2000 Apr 1;355(9210):1126-30. 

Tsutamoto T, Wada A, Maeda K, et al. Plasma brain natriuretic peptide level as a biochemical marker of morbid

patients with asymptomatic or minimally symptomatic left ventricular dysfunction. Comparison with plas

endothelin-1. Eur Heart J 1999 Dec;20(24):1799-807. 

Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide s

heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symventricular dysfunction.[see comment]. Circulation 1997 Jul 15;96(2):509-16. 

Tsutsui T, Tsutamoto T, Wada A, et al. Plasma oxidized low-density lipoprotein as a prognostic predictor in pat

congestive heart failure. J Am Coll Cardiol 2002 Mar 20;39(6):957-62. 

Ueda R, Yokouchi M, Suzuki T, et al. Prognostic value of high plasma brain natriuretic peptide concentrations i

persons.[see comment]. Am J Med 2003 Mar;114(4):266-70. 

Ueland T, Jemtland R, Godang K, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardi

Coll Cardiol 2004;44(10):1970-6. 

Van Beneden R, Gurne O, Selvais PL, et al. Superiority of big endothelin-1 and endothelin-1 over natriuretic pe

survival in severe congestive heart failure: a 7-year follow-up study. J Card Fail 2004 Dec;10(6):490-5. 

van der MP, Voors AA, Lipsic E, et al. Prognostic value of plasma erythropoietin on mortality in patients with c

Am Coll Cardiol 2004 Jul 7;44(1):63-7. 

Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricu

systolic dysfunction: the Framingham heart study. JAMA 2002 Sep 11;288(10):1252-9. 
C - 131 

Villacorta H, Duarte A, Duarte NM, et al. The role of B-type natriuretic peptide in the diagnosis of congestive h

presenting to an emergency department with dyspnea. Arq Bras Cardiol 2002;79(6):569-72. 

Vrtovec B, Delgado R, Zewail A, et al. Prolonged QTc interval and high B-type natriuretic peptide levels togeth

patients with advanced heart failure.[see comment]. Circulation 2003 Apr 8;107(13):1764-9. 

Wallen T, Landahl S, Hedner T, et al. Brain natriuretic peptide predicts mortality in the elderly. Heart 1997 MaWang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and 

N Engl J Med 2004 Feb 12;350(7):655-63. 

Watanabe J, Shiba N, Shinozaki T, et al. Prognostic value of plasma brain natriuretic peptide combined with left 

dimensions in predicting sudden death of patients with chronic heart failure. J Card Fail 2005 Feb;11(1):

Watanabe M, Egi K, Hasegawa S, et al. Significance of serum atrial and brain natriuretic peptide release after co

grafting. SURG 2003;33(9):671-3. 

Weber M, Arnold R, Rau M, et al. Relation of N-terminal pro-B-type natriuretic peptide to severity of valvular a

Cardiol 2004 Sep 15;94(6):740-5. 

Wendelboe Nielsen O, Kirk V, Bay M, et al. Value of N-terminal pro brain natriuretic peptide in the elderly: dat

prospective Copenhagen Hospital Heart Failure study (CHHF). Eur J Heart Fail 2004 Mar 15;6(3):275-9

Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients 

angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and dTherapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy.Circulation 2004 Feb 10;109(5):580-6. 

Wright SP, Doughty RN, Pearl A, et al. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of hea

primary care: a randomized, controlled trial. J Am Coll Cardiol 2003 Nov;42(10):1793-800. 

Wylie JV, Murphy SA, Morrow DA, et al. Validated risk score predicts the development of congestive heart fail

with unstable angina or non-ST-elevation myocardial infarction: results from OPUS-TIMI 16 and TACTIHeart J 2004 Jul;148(1):173-80. 
C - 132 

Yamada Y, Goto J, Yokota M, et al. Brain natriuretic peptide is a sensitive indicator of impaired left-ventricular 

patients with cardiovascular disease. Cardiology 1997 Sep;88(5):401-7. 

Yoshizawa A, Yoshikawa T, Nakamura I, et al. Brain natriuretic peptide response is heterogeneous during beta-

congestive heart failure. J Card Fail 2004 Aug;10(4):310-5. 

Zeller M, Cottin Y, Laurent Y, et al. N-terminal pro-brain natriuretic peptide levels in patients with non-ST-elev

infarction. Cardiology 2004;102(1):37-40. 

Zugck C, Haunstetter A, Kruger C, et al. Impact of beta-blocker treatment on the prognostic value of currently u

congestive heart failure. J Am Coll Cardiol 2002 May 15;39(10):1615-22. 
D-1 

Appendix D: Excluded Studies 

Abdulla H, H.M. The natriuretic peptides: universal volume controllers. Medical Hypotheses 2001; 

56(4):451-453. 

Excluded because not a report of a primary study 

Abe S, Okura Y, Hoyano M, Kazama R, Watanabe S, Ozawa T et al. Plasma concentrations of cytokines 

and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous 

immunoglobulin and percutaneous cardiopulmonary support. Circulation Journal 2004; 68(12):1223-1226. 

Excluded because this is a case report or series with 10 subjects 

Abraham WT. Physiology and therapeutic implications of natriuretic peptides in heart failure. Heart Failure 

1996; 12(2):55-72. 

Excluded because not a report of a primary study 

Abraham WT. Natriuretic peptides in heart failure. Prevention & Management of Congestive Heart Failure 

1998; 4(2):23-33. 

Excluded because not a report of a primary study 

Abraham W, Lowes B, Ferguson D, Odom J, Kim J, Robertson A et al. Systemic hemodynamic, 

neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients 

with hemodynamically decompensated heart failure. Journal of Cardiac Failure 1998; 4(1):37-44. 

Excluded because adult blood not measured 

Adams Jr KF. Are angiotensin-converting enzyme inhibitors and beta-blockers making an impact on the 

epidemiology of heart failure? Current Cardiology Reports 2004; 6(3):162-168. 

Excluded because not a report of a primary study 

Adams J. Markers to define ischemia: Are they ready for prime time use in patients with acute coronary 

syndromes? Current Cardiology Reports 2004; 6(4):253-258. 

Excluded because not a report of a primary study 

Afzal A, Brawner C, and Keteyian SJ. Exercise training in heart failure. Progress in Cardiovascular 

Diseases 1998; 41(3):175-190. 

Excluded because not a report of a primary study 

Aggarwal A, D.M. Neurohormonal assessment of cardiac function. Coronary Artery Disease 2002; 

13(8):415-419. 

Excluded because not a report of a primary study 

Aghababian R, G.C. Acutely decompensated heart failure: Opportunities to improve care and outcomes in 

the emergency department. Reviews in Cardiovascular Medicine 2002; 3(SUPPL. 4):S1-S2. 

Excluded because not a report of a primary study 

Akaji K, Tatsumi T, Yoshida M, Kimura T, Fujiwara Y, and Kiso Y. Synthesis of cystine-peptide by a new 

disulphide bond-forming reaction using the silyl chloride-sulphoxide system. Journal of the Chemical 

Society - Series Chemical Communications 1991;(pp 167-168):167-168. 

Excluded because adult blood not measured 

Akaji K, Tatsumi T, Yoshida M, Kimura T, Fujiwara Y, and Kiso Y. Disulfide bond formation using the silyl 

chloride-sulfoxide system for the synthesis of a cystine peptide. Journal of the American Chemical Society 

1992; 114(11):4137-4143. 

Excluded because adult blood not measured 
D-2 

Akama H, B.P. The kidney in heart failure: Vasodilator-natriuretic systems. Nephrology 1997; 3(4):297-

308. 

Excluded because not a report of a primary study 

Akashi Y, Musha H, Nakazawa K, Miyake F, Akashi Y, Musha H et al. Plasma brain natriuretic peptide in 

takotsubo cardiomyopathy. Qjm 2004; 97(9):599-607. 

Excluded because this is a case report or series with 10 subjects 

Akashi Y, Nakazawa K, Sakakibara M, Miyake F, Sasaka K, Akashi YJ et al. Reversible left ventricular 

dysfunction "takotsubo" cardiomyopathy related to catecholamine cardiotoxicity. Journal of 

Electrocardiology 2002; 35(4):351-356. 

Excluded because not a report of a primary study 

Akashi Y, Tejima T, Sakurada H, Matsuda H, Suzuki K, Kawasaki K et al. Left ventricular rupture 

associated with takotsubo cardiomyopathy. Mayo Clinic Proceedings 2004; 79(6):821-824. 

Excluded because this is a case report or series with 10 subjects 

Akazawa H, I. Too much Csx/Nkx2-5 is as bad as too little? Journal of Molecular & Cellular Cardiology 

2003; 35(3):227-229. 

Excluded because not a report of a primary study 

Akiba T, Tachibana K, Togashi K, Hiroe M, Marumo F, Akiba T et al. Plasma human brain natriuretic 

peptide in chronic renal failure. Clinical Nephrology 1995; 44 Suppl 1:S61-S64. 

Excluded because BNP assay method is not an included one 

Ala-Kopsala M, Magga J, Peuhkurinen K, Leipala J, Ruskoaho H, Leppaluoto J et al. Molecular 

heterogeneity has a major impact on the measurement of circulating N-terminal fragments of A- and Btype natriuretic peptides. Clinical Chemistry 2004; 50(9):1576-1588. 

Excluded because BNP assay method is not an included one 

Alehagen U, Lindstedt G, Eriksson H, Dahlstrom U, Alehagen ULGEHaDU. Utility of the amino-terminal 

fragment of pro-brain natriuretic peptide in plasma for the evaluation of cardiac dysfunction in elderly 

patients in primary health care. Clinical Chemistry 2003; 49(8):1337-1346. 

Excluded because BNP assay method is not an included one 

Almenar L, Hervas I, Martinez-Dolz L, Rueda J, Arnau M, Osa A et al. The value of brain natriuretic 

peptide for the diagnosis of heart transplant rejection. Transplantation Proceedings 2002; 34(1):174-175. 

Excluded because not a report of a primary study 

Altemose G, Gritsus V, Jeevanandam V, Goldman B, Margulies K, Altemose G et al. Altered myocardial 

phenotype after mechanical support in human beings with advanced cardiomyopathy. Journal of Heart & 

Lung Transplantation 1997; 16(7):765-773. 

Excluded because adult blood not measured 

Alvelos M, Ferreira A, Bettencourt P, Serrao P, Pestana M, Cerqueira-Gomes M et al. The effect of 

dietary sodium restriction on neurohumoral activity and renal dopaminergic response in patients with 

heart failure. European Journal of Heart Failure 2004; 6(5):593-599. 

Excluded because adult blood not measured 

Anan F, Takahashi N, Ooie T, Hara M, Yoshimatsu H, Saikawa T et al. Candesartan, an angiotensin II 

receptor blocker, improves left ventricular hypertrophy and insulin resistance. Metabolism: Clinical & 

Experimental 2004; 53(6):777-781. 

Excluded because this is a case report or series with 10 subjects 
D-3 

Anderson H, Wang F, Gardner D, Anderson HD, Wang FaGDG. Role of the epidermal growth factor 

receptor in signaling strain-dependent activation of the brain natriuretic peptide gene. Journal of Biological 

Chemistry 2004; 279(10):9287-9297. 

Excluded because adult blood not measured 

Anderson T. The birth of love. Practising Midwife 2000; 3(3):4-5. 

Excluded because not a report of a primary study 

Andreassi M, Del Ry S, Palmieri C, Clerico A, Biagini A, and Giannessi D. Up-regulation of 'clearance' 

receptors in patients with chronic heart failure: A possible explanation for the resistance to biological 

effects of cardiac natriuretic hormones. European Journal of Heart Failure 2001; 3(4):407-414. 

Excluded because BNP assay method is not an included one 

Anker S, Coats A, Anker S, and Coats AJ. Plasma brain natriuretic peptide as an indicator of left 

ventricular systolic function and long-term survival after acute myocardial infarction. Circulation 2001; 

95(2):538-539. 

Excluded because not a report of a primary study 

Anker S, R. The syndrome of cardiac cachexia. International Journal of Cardiology 2002; 85(1):51-66. 

Excluded because not a report of a primary study 

Anker S, Steinborn W, and Strassburg S. Cardiac cachexia. Annals of Medicine 2004; 36(7):518-529. 

Excluded because not a report of a primary study 

Apple F, Trinity E, Steen J, Prawer S, Wu A, Apple FS et al. BNP test utilization for CHF in community 

hospital practice. Clinica Chimica Acta 2003; 328(1-2):191-193. 

Excluded because not a report of a primary study 

Arad M, Elazar E, Shotan A, Klein R, Rabinowitz B, Arad M et al. Brain and atrial natriuretic peptides in 

patients with ischemic heart disease with and without heart failure. Cardiology 1996; 87(1):12-17. 

Excluded because BNP assay method is not an included one 

Arai M, Matsui H, and Periasamy M. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and 

heart failure. Circulation Research 1994; 74(4):555-564. 

Excluded because not a report of a primary study 

Arakawa N, Nakamura M, Aoki H, Hiramori K, Arakawa N, Nakamura M et al. Relationship between 

plasma level of brain natriuretic peptide and myocardial infarct size. Cardiology 1994; 85(5):334-340. 

Excluded because BNP assay method is not an included one 

Arakawa N, Nakamura M, Aoki H, Hiramori K, Arakawa N, Nakamura M et al. Plasma brain natriuretic 

peptide concentrations predict survival after acute myocardial infarction. Journal of the American College 

of Cardiology 1996; 27(7):1656-1661. 

Excluded because BNP assay method is not an included one 

Arakawa N, Nakamura M, Endo H, Sugawara S, Suzuki T, Hiramori K et al. Brain natriuretic peptide and 

cardiac rupture after acute myocardial infarction. Internal Medicine 2001; 40(3):232-236. 

Excluded because not a report of a primary study 

Arendt R, Schmoeckel M, Wilbert-Lampen U, Heucke L, Werdan K, Arendt R et al. Neurohumoral 

regulation of endothelin release by opioid and natriuretic peptides. Transplantation Proceedings 1995; 

27(3):2092-2096. 

Excluded because adult blood not measured 
D-4 

Arjamaa O, Makinen T, Turunen L, Huttunen P, Leppaluoto J, Vuolteenaho O et al. Are the blood 

pressure and endocrine responses of healthy subjects exposed to cold stress altered by an acutely 

increased sodium intake? European Journal of Applied Physiology 2001; 84(1-2):48-53. 

Excluded because adult blood not measured 

Arjamaa O, Makinen T, Turunen L, Huttunen P, Leppaluoto J, Vuolteenaho O et al. Blood pressure and 

endocrine responses of healthy subjects in cold pressor test after acutely increased dietary sodium 

intake. Journal of Physiological Anthropology & Applied Human Science 2001; 20(3):207-212. 

Excluded because BNP assay method is not an included one 

Aronson D, Burger A, Aronson DaBAJ. Intravenous nesiritide (human B-type natriuretic peptide) reduces 

plasma endothelin-1 levels in patients with decompensated congestive heart failure. American Journal of 

Cardiology 1908; 90(4):435-438. 

Excluded because BNP assay method is not an included one 

Aronson D, Burger A, Aronson DaBAJ. Neurohumoral activation and ventricular arrhythmias in patients 

with decompensated congestive heart failure: role of endothelin. Pacing & Clinical Electrophysiology 

2003; 26(3):703-710. 

Excluded because BNP assay method is not an included one 

Aronson D, Burger A, Aronson DaBAJ. Prognosis assessment in patients with decompensated heart 

failure. Simple clinical parameters or neurohormonal factors. Italian Heart Journal: Official Journal of the 

Italian Federation of Cardiology 2004; 5(7):494-497. 

Excluded because not a report of a primary study 

Ationu A, Burch M, Elliott M, Carter N, Ationu A, Burch M et al. Brain natriuretic peptide and fluid volume 

homeostasis--studies during cardiopulmonary bypass surgery. Clinical Autonomic Research 1993; 

3(4):275-280. 

Excluded because BNP assay method is not an included one 

Ationu A, Burch M, Singer D, Littleton P, Carter N, Ationu A et al. Cardiac transplantation affects 

ventricular expression of brain natriuretic peptide. Cardiovascular Research 1993; 27(2):188-191. 

Excluded because BNP assay method is not an included one 

Ationu A, Carter N, Ationu A, and Carter ND. Brain and atrial natriuretic peptide plasma concentrations in 

normal healthy children. British Journal of Biomedical Science 1993; 50(2):92-95. 

Excluded because BNP assay method is not an included one 

Attenhofer Jost C, Oechslin E, Seifert B, Maly F, Fatio R, Turina J et al. Remodelling after surgical repair 

of atrial septal defects within the oval fossa. Cardiology in the Young 2002; 12(6):506-512. 

Excluded because adult blood not measured 

Auvin-Guette C, Baraguey C, Blond A, Pousset J, and Bodo B. Cyclogossine B, a cyclic octapeptide from 

Jatropha gossypifolia. Journal of Natural Products 1997 Nov;60(11):1155-7. 

Excluded because adult blood not measured 

Baggish A, Cameron R, Anwaruddin S, Chen A, Krauser D, Tung R et al. A clinical and biochemical 

critical pathway for the evaluation of patients with suspected acute congestive heart failure: The proBNP 

Investigation of Dyspnea in the Emergency Department (PRIDE) algorithm. Critical Pathways in 

Cardiology: A Journal of Evidence-Based Medicine 2004; 3(4):171-176. 

Excluded because not a report of a primary study 

Bail D, Kofler M, Ziemer G, Bail D, Kofler M, and Ziemer G. Brain natriuretic peptide (BNP) in patients 

undergoing coronary artery bypass grafting. Thoracic & Cardiovascular Surgeon 2004; 52(3):135-140. 

Excluded because BNP assay method is not an included one 
D-5 

Bank A, Shammas R, Mullen K, and Chuang PP. Effects of short-term forearm exercise training on 

resistance vessel endothelial function in normal subjects and patients with heart failure. Journal of 

Cardiac Failure 1998; 4(3):193-201. 

Excluded because BNP assay method is not an included one 

Barclay T, Kim J, and Lee AJ. Nesiritide for acute decompensated heart failure. Journal of Pharmacy 

Technology 2002; 18(6):295-304. 

Excluded because not a report of a primary study 

Barkoukis H, Fiedler K, Lerner E, and Beyer PL. Solution center. A combined high-fiber, low-glycemic 

index diet normalizes glucose tolerance and reduces hyperglycemia and hyperinsulinemia in adults with 

hepatic cirrhosis. Journal of the American Dietetic Association 2002; 102(10):1503-1508. 

Excluded because BNP assay method is not an included one 

Barleta G, Lazzeri C, Del Bene R, Messeri G, Sbarba A, Mannella M et al. Low-dose C-type natriuretic 

peptide does not affect cardiac and renal function in humans. Hypertension 1998; 31(3):802-808. 

Excluded because BNP assay method is not an included one 

Barletta G, Stefani L, Del Bene R, Fronzaroli C, Vecchiarino S, Lazzeri C et al. Effects of exercise on 

natriuretic peptides and cardiac function in man.[see comment]. International Journal of Cardiology 1998; 

65(3):217-225. 

Excluded because BNP assay method is not an included one 

Barlow J, J.F. New rapid laboratory test for congestive heart failure B-type natriuretic peptide (BNP). 

South Dakota Journal of Medicine 2002; 55(11):467. 

Excluded because not a report of a primary study 

Baroletti S, Wahlstrom H, Baroletti SA, and Wahlstrom HD. Interaction between nesiritide and a heparincoated pulmonary artery line during an infusion for decompensated heart failure. Pharmacotherapy 2004; 

24(11):1634-1637. 

Excluded because this is a case report or series with 10 subjects 

Barst R, McGoon M, Torbicki A, Sitbon O, Krowka M, Olschewski H et al. Diagnosis and differential 

assessment of pulmonary arterial hypertension. Journal of the American College of Cardiology 2004; 

43(12 SUPPL.):40S-47S. 

Excluded because not a report of a primary study 

Baughman KL. B-type natriuretic peptide - A window to the heart. New England Journal of Medicine 2002; 

347(3):158-159. 

Excluded because not a report of a primary study 

Bayerle-Eder M, Zangeneh M, Kreiner G, Raffesberg W, Nowotny P, Vierhapper H et al. ANP but not 

BNP reflects early left diastolic dysfunction in type 1 diabetics with myocardial dysinnervation. Hormone & 

Metabolic Research 2003; 35(5):301-307. 

Excluded because BNP assay method is not an included one 

Bech J, Svendsen K, Nielsen C, Pedersen E, Bech J, Svendsen K et al. The systemic and renal response 

to NO inhibition is not modified by angiotensin-II-receptor blockade in healthy humans. Nephrology 

Dialysis Transplantation 1999; 14(3):641-647. 

Excluded because BNP assay method is not an included one 

Belenky A, Smith A, Zhang B, Lin S, Despres N, Wu A et al. The effect of class-specific protease 

inhibitors on the stabilization of B-type natriuretic peptide in human plasma. Clinica Chimica Acta 2004; 

340(1-2):163-172. 

Excluded because adult blood not measured 
D-6 

Bell DSH. Treatment of heart failure in patients with diabetes: Clinical update. Ethnicity & Disease 2002; 

12(1). 

Excluded because not a report of a primary study 

Bentzen H, Pedersen R, Nyvad O, Pedersen E, Bentzen H, Pedersen R et al. Influence of training habits 

on exercise-induced changes in plasma atrial and brain natriuretic peptide and urinary excretion of 

aquaporin-2 in healthy man. Scandinavian Journal of Clinical & Laboratory Investigation 2002; 62(7):541-

551. 

Excluded because BNP assay method is not an included one 

Bentzen H, Pedersen R, Pedersen H, Nyvad O, Pedersen E, Bentzen HPRS et al. Abnormal rhythmic 

oscillations of atrial natriuretic peptide and brain natriuretic peptide in heart failure. Clinical Science 2003; 

104(3):303-312. 

Excluded because BNP assay method is not an included one 

Bentzen H, Pedersen R, Nyvad O, Pedersen E, Bentzen HPRS, Nyvad OaPEB. Effect of exercise on 

natriuretic peptides in plasma and urine in chronic heart failure. International Journal of Cardiology 2004; 

93(2-3):121-130. 

Excluded because BNP assay method is not an included one 

Berendes E, Schmidt C, Van Aken H, Hartlage M, Rothenburger M, Wirtz S et al. A-type and B-type 

natriuretic peptides in cardiac surgical procedures. Anesthesia & Analgesia 98(1):11-19. 

Excluded because BNP assay method is not an included one 

Berendes E, Schmidt C, Van Aken H, Hartlage M, Wirtz S, Reinecke H et al. Reversible cardiac 

sympathectomy by high thoracic epidural anesthesia improves regional left ventricular function in patients 

undergoing coronary artery bypass grafting: a randomized trial.[see comment]. Archives of Surgery 2003; 

138(12):1283-1290. 

Excluded because BNP assay method is not an included one 

Berendes E, Van Aken H, Raufhake C, Schmidt C, Assmann G, Walter M et al. Differential secretion of 

atrial and brain natriuretic peptide in critically ill patients. Anesthesia & Analgesia 2001; 93(3):676-682. 

Excluded because BNP assay method is not an included one 

Berendes E, Walter M, Cullen P, Prien T, Van Aken H, Horsthemke J et al. Secretion of brain natriuretic 

peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet 2001; 349(9047):245-249. 

Excluded because BNP assay method is not an included one 

Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B et al. B-type natriuretic peptide predicts 

sudden death in patients with chronic heart failure.[see comment]. Circulation 2005; 105(20):2392-2397. 

Excluded because BNP assay method is not an included one 

Berton G, P. Risk stratification after acute myocardial infarction: Role of neurohormones, inflammatory 

markers and albumin excretion rate. Italian Heart Journal: Official Journal of the Italian Federation of 

Cardiology 2003; 4(5):295-304. 

Excluded because not a report of a primary study 

Bettencourt P, Paulo. NT-proBNP and BNP: biomarkers for heart failure management. European Journal 

of Heart Failure 2003; 6(3):359-363. 

Excluded because not a report of a primary study 

Bevilacqua M, Vago T, Baldi G, Norbiato G, Masson S, Latini R et al. Analytical agreement and clinical 

correlates of plasma brain natriuretic peptide measured by three immunoassays in patients with heart 

failure. Clinical Chemistry 1997; 43(12):2439-2440. 

Excluded because not a report of a primary study 
D-7 

Bhalla S, Robitaille L, Nemer M, Bhalla S, Robitaille L, and Nemer M. Cooperative activation by GATA-4 

and YY1 of the cardiac B-type natriuretic peptide promoter. Journal of Biological Chemistry 2001; 

276(14):11439-11445. 

Excluded because adult blood not measured 

Bhat G, Costea A, Bhat GaCA. Reversibility of medically unresponsive pulmonary hypertension with 

nesiritide in a cardiac transplant recipient. ASAIO Journal 2003; 49(5):608-610. 

Excluded because adult blood not measured 

Bilkovski R, Kulstad E, Bilkovski RN, and Kulstad EB. Elevations of B-type natriuretic peptide in 

pulmonary embolism: a case series. Journal of Emergency Medicine 2003; 25(4):415-420. 

Excluded because this is a case report or series with 10 subjects 

Billiot E, Macossay J, Thibodeaux S, Shamsi S, Warner I, Billiot E et al. Chiral separations using dipeptide 

polymerized surfactants: effect of amino acid order. Analytical Chemistry 1998; 70(7):1375-1381. 

Excluded because adult blood not measured 

Billiot F, Billiot E, Warner I, Billiot FHBEJ, and Warner IM. Depth of penetration of binaphthyl derivatives 

into the micellar core of sodium undecenoyl leucyl-leucinate surfactants. Journal of Chromatography 

2003; A.. 950(1-2):233-239. 

Excluded because adult blood not measured 

Birney M, D.G. Atrial natriuretic peptide: a hormone with implications for clinical practice. Heart & Lung: 

Journal of Critical Care 1990; 19(2):174-185. 

Excluded because not a report of a primary study 

Bittner V. Exercise testing in heart failure: Maximal, submaximal, or both? Journal of the American 

College of Cardiology 2003; 42(1):123-125. 

Excluded because not a report of a primary study 

Blom J, 't Hof A, Henriques J, Hans GJ, Slingerland R, Hoorntje J et al. NT-proBNP: a marker for 

successful myocardial reperfusion in AMI patients treated with primary percutaneous coronary 

intervention. European Journal of Heart Failure 2004; 6(6):749-752. 

Excluded because BNP assay method is not an included one 

Blommendahl J, Janas M, Laine S, Miettinen A, and Ashorn P. Comparison of procalcitonin with CRP and 

differential white blood cell count for diagnosis of culture-proven neonatal sepsis. Scandinavian Journal of 

Infectious Diseases 2002; 34(8):620-622. 

Excluded because adult blood not measured 

Bobadilla R, Oppelt T, Hirshy T, Bobadilla RV, Oppelt TF, and Hirshy TC. Nesiritide treatment of 

noncardiogenic pulmonary edema. Annals of Pharmacotherapy 2003; 37(4):530-533. 

Excluded because adult blood not measured 

Bock JL. Test strategies for the detection of myocardial damage. Clinics in Laboratory Medicine 2002; 

22(2):357-375. 

Excluded because not a report of a primary study 

Boehm M, E.G. Clinical implications of basic research. Angiotensin-converting enzyme 2 -- a new cardiac 

regulator. New England Journal of Medicine 1920; 347(22):1795-1797. 

Excluded because not a report of a primary study 

Bokesch H, Pannell L, Cochran P, Sowder R, McKee T, and Boyd MR. A novel anti-HIV macrocyclic 

peotide from Palicourea condensata. Journal of Natural Products 2001 Feb;64(2):249-50. 

Excluded because adult blood not measured 
D-8 

Bonatti J, Dichtl W, Lercher A, Puschendorf B, Bonatti J, Dichtl W et al. Natriuretic peptides stimulate 

cyclic guanosine monophosphate production in human saphenous vein and internal mammary artery. 

European Journal of Cardio-Thoracic Surgery 2000; 17(2):175-181. 

Excluded because adult blood not measured 

Boonen S, Broos P, Verbeke G, Aerssens J, Van Herck E, Jans I et al. Calciotropic hormones and 

markers of bone remodeling in age-related (type II) femoral neck osteoporosis: alterations consistent with 

secondary hyperparathyroidism-induced bone resorption. Journals of Gerontology 1997; Series 

A(5):M286-M293. 

Excluded because BNP assay method is not an included one 

Borghi C, Esposti D, Immordino V, Cassani A, Boschi S, Bovicelli L et al. Relationship of systemic 

hemodynamics, left ventricular structure and function, and plasma natriuretic peptide concentrations 

during pregnancy complicated by preeclampsia. American Journal of Obstetrics & Gynecology 2000; 

183(1):140-147. 

Excluded because BNP assay method is not an included one 

Boxer R, Yang S, and Hager WD. Congestive heart failure and the elderly. Connecticut Medicine 2003; 

67(8):497-503. 

Excluded because not a report of a primary study 

Braddock M, R. Chronic stress and stress disorders: the effects of stress system malfunction. Surgical 

Technologist 2002; 34(11):18-25. 

Excluded because not a report of a primary study 

Braunschweig F, Linde C, Eriksson M, Hofman-Bang C, Ryden L, Braunschweig F et al. Continuous 

haemodynamic monitoring during withdrawal of diuretics in patients with congestive heart failure.[see 

comment]. European Heart Journal 2002; 23(1):59-69. 

Excluded because this is a case report or series with 10 subjects 

Braunschweig F, Sorensen J, Von Bibra H, Olsson A, Ryden L, Langstrom B et al. Effects of biventricular 

pacing on myocardial blood flow and oxygen consumption using carbon-11 acetate positron emission 

tomography in patients with heart failure. American Journal of Cardiology 2003; 92(1):95-99. 

Excluded because this is a case report or series with 10 subjects 

Briest W. Do we have a new early marker of chronic transplant dysfunction now? Cardiovascular 

Research 2002; 54(3):492-494. 

Excluded because not a report of a primary study 

Briguori C, Betocchi S, Manganelli F, Gigante B, Losi M, Ciampi Q et al. Determinants and clinical 

significance of natriuretic peptides and hypertrophic cardiomyopathy.[see comment]. European Heart 

Journal 2001; 22(15):1328-1336. 

Excluded because BNP assay method is not an included one 

Brookes C, Kemp M, Hooper J, Oldershaw P, Moat N, Brookes C et al. Plasma brain natriuretic peptide 

concentrations in patients with chronic mitral regurgitation. Journal of Heart Valve Disease 1997; 

6(6):608-612. 

Excluded because BNP assay method is not an included one 

Brooks D, S.D. From mechanisms and targets to risk assessment and treatment of cardiovascular and 

renal diseases. Current Opinion in Pharmacology 2002; 2(2):119-120. 

Excluded because not a report of a primary study 

Brueckmann M, Bertsch T, Hoffmann U, Lang S, Kaden J, Wolpert C et al. N-terminal pro-atrial natriuretic 

peptide as a biochemical marker of long-term interventional success after radiofrequency catheter 
D-9 

ablation of paroxysmal supraventricular tachyarrhythmias. Clinical Chemistry & Laboratory Medicine 

2004; 42(8):896-902. 

Excluded because BNP assay method is not an included one 

Brunner-La Rocca H, Kaye D, Woods R, Hastings J, Esler M, Brunner-La Rocca H et al. Effects of 

intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure 

as compared with healthy control subjects. Journal of the American College of Cardiology 2001; 

37(5):1221-1227. 

Excluded because BNP used as treatment 

Brunner-La Rocca H, Woods R, Kaye D, Hastings J, Thomas C, Lambert E et al. Divergent effects of 

ANP and BNP in acute heart failure: evidence for a putative BNP-selective receptor? Journal of 

Hypertension 2002; 20(6):1195-1201. 

Excluded because adult blood not measured 

Bruun E, C. The effect of Buserelin versus conventional antiandrogenic treatment in patients with T2-

4NXM1 prostatic cancer. A prospective, randomized multicentre phase III trial. The 'Danish Buserelin 

Study Group'. Scand J Urol Nephrol 1996 Aug;30(4):291-7. 

Excluded because adult blood not measured 

Buckley M, Marcus N, Yacoub M, Singer D, Buckley M, Marcus N et al. Prolonged stability of brain 

natriuretic peptide: importance for non-invasive assessment of cardiac function in clinical practice. Clinical 

Science 1998; 95(3):235-239. 

Excluded because BNP assay method is not an included one 

Buckley M, Marcus N, Yacoub M, Buckley M, Marcus N, and Yacoub MH. Cardiac peptide stability, 

aprotinin and room temperature: importance for assessing cardiac function in clinical practice. Clinical 

Science 1999; 97(6):689-695. 

Excluded because BNP assay method is not an included one 

Buckley M, Markandu N, Miller M, Sagnella G, MacGregor G, Buckley M et al. Plasma concentrations and 

comparisons of brain and atrial natriuretic peptide in normal subjects and in patients with essential 

hypertension. Journal of Human Hypertension 1993; 7(3):245-250. 

Excluded because BNP assay method is not an included one 

Buckley M, Markandu N, Sagnella G, MacGregor G, Buckley M, Markandu N et al. Brain and atrial 

natriuretic peptides: a dual peptide system of potential importance in sodium balance and blood pressure 

regulation in patients with essential hypertension. Journal of Hypertension 1994; 12(7):809-813. 

Excluded because BNP assay method is not an included one 

Buckley M, Saggar-Malik A, Markandu N, Sagnella G, MacGregor G, Buckley M et al. Effects of changes 

in dietary sodium intake on plasma brain natriuretic peptide levels in patients with autosomal dominant 

polycystic kidney disease. Journal of Human Hypertension 1996; 10(6):415-416. 

Excluded because BNP assay method is not an included one 

Buckley M, Sethi D, Markandu N, Sagnella G, Singer D, MacGregor G et al. Plasma concentrations and 

comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac 

transplant recipients and patients with dialysis-independent or dialysis-dependent chronic renal failure. 

Clinical Science 1992; 83(4):437-444. 

Excluded because BNP assay method is not an included one 

Buckley M, Yacoub M, Singer D, Buckley M, Yacoub M, and Singer DR. Investigation of the plasma 

concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients. Journal 

of Human Hypertension 1998; 12(12):825-826. 

Excluded because BNP assay method is not an included one 
D-10 

Burger A, Aronson D, Horton D, Burger M, Burger AJ, Aronson DHDP et al. Comparison of the effects of 

dobutamine and nesiritide (B-type natriuretic peptide) on ventricular ectopy in acutely decompensated 

ischemic versus nonischemic cardiomyopathy. American Journal of Cardiology 2003; 91(11):1370-1372. 

Excluded because adult blood not measured 

Burger A, D. Effect of vasoactive therapy on heart rate variability in patients with acutely decompensated 

congestive heart failure. American Journal of Cardiology 1999; 84(4):476-478. 

Excluded because adult blood not measured 

Burger A, Elkayam U, Neibaur M, Haught H, Ghali J, Horton D et al. Comparison of the occurrence of 

ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving 

dobutamine versus nesiritide therapy. American Journal of Cardiology 2001; 88(1):35-39. 

Excluded because BNP assay method is not an included one 

Burger A, Horton D, LeJemtel T, Ghali J, Torre G, Dennish G et al. Effect of nesiritide (B-type natriuretic 

peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely 

decompensated congestive heart failure: the PRECEDENT study. American Heart Journal 2002; 

144(6):1102-1108. 

Excluded because BNP assay method is not an included one 

Burgher A, Aslan D, Laudi N, Bowman R, Burgher AH, Aslan DLNaBRJ. Use of brain natriuretic peptide 

to evaluate transfusion-related acute lung injury. Transfusion 2004; 44(10):1533-1534. 

Excluded because adult blood not measured 

Butler J, Emerman C, Peacock W, Mathur V, Young J, VMAC siBJECPW et al. The efficacy and safety of 

B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated 

congestive heart failure. Nephrology Dialysis Transplantation 2004; 19(2):391-399. 

Excluded because adult blood not measured 

Califf RM. Cardiac markers in acute coronary syndromes - Refining our knowledge. European Heart 

Journal 2003; 24(2):136-137. 

Excluded because not a report of a primary study 

Campbell D, Aggarwal A, Esler M, and Kaye D. Beta-blockers, angiotensin II, and ACE inhibitors in 

patients with heart failure. Lancet 1920; 358(9293):1609-1610. 

Excluded because not a report of a primary study 

Campbell D, Mitchelhill K, Schlicht S, Booth R, Campbell D, Mitchelhill K et al. Plasma amino-terminal 

pro-brain natriuretic peptide: a novel approach to the diagnosis of cardiac dysfunction. Journal of Cardiac 

Failure 2000; 6(2):130-139. 

Excluded because BNP assay method is not an included one 

Campbell D, Munir V, Hennessy O, Dent A, Campbell D, Munir V et al. Plasma amino-terminal pro-brain 

natriuretic peptide levels in subjects presenting to the Emergency Department with suspected acute 

coronary syndrome: possible role in selecting patients for follow up? Internal Medicine Journal 2001; 

31(4):211-219. 

Excluded because BNP assay method is not an included one 

Campbell D, Woodward M, Chalmers J, Colman S, Jenkins A, Kemp B et al. Prediction of heart failure by 

amino terminal-pro-B-type natriuretic peptide and C-reactive protein in subjects with cerebrovascular 

disease. Hypertension 2005; 45(1):69-74. 

Excluded because BNP assay method is not an included one 
D-11 

Campbell R, Ruggenenti P, and Remuzzi G. Halting the progression of chronic nephropathy. Journal of 

the American Society of Nephrology 2002; 13(SUPPL. 3):S190-S195. 

Excluded because not a report of a primary study 

Canaan-Kuhl S, Jamison R, Myers B, Pratt R, Canaan-Kuhl S, Jamison R et al. Identification of "B" 

receptor for natriuretic peptide in human kidney.[erratum appears in Endocrinology 1992 

Apr;130(4):2283]. Endocrinology 1992; 130(1):550-552. 

Excluded because adult blood not measured 

Cappellin E, Gatti R, Spinella P, De Palo C, Woloszczuk W, Maragno I et al. Plasma atrial natriuretic 

peptide (ANP) fragments proANP (1-30) and proANP (31-67) measurements in chronic heart failure: a 

useful index for heart transplantation? Clinica Chimica Acta 2001; 310(1):49-52. 

Excluded because BNP assay method is not an included one 

Cargill R, Barr C, Coutie W, Struthers A, Lipworth B, Cargill R et al. C-type natriuretic peptide levels in cor 

pulmonale and in congestive heart failure. Thorax 1994; 49(12):1247-1249. 

Excluded because BNP assay method is not an included one 

Cargill R, Clarkson P, MacDonald T, Lipworth B, Cargill R, Clarkson P et al. Profound vagal reactions to 

brain natriuretic peptide. Journal of Molecular Medicine 1995; 73(3):149-150. 

Excluded because not a report of a primary study 

Cargill R, Coutie W, Lipworth B, Cargill R, Coutie W, and Lipworth BJ. The effects of angiotensin II on 

circulating levels of natriuretic peptides. British Journal of Clinical Pharmacology 1994; 38(2):139-142. 

Excluded because BNP assay method is not an included one 

Cargill R, Lipworth B, Cargill R, and Lipworth BJ. Pulmonary vasorelaxant activity of atrial natriuretic 

peptide and brain natriuretic peptide in humans. Thorax 1995; 50(2):183-185. 

Excluded because BNP assay method is not an included one 

Cargill R, Lipworth B, Cargill R, and Lipworth BJ. Acute effects of ANP and BNP on hypoxic pulmonary 

vasoconstriction in humans. British Journal of Clinical Pharmacology 1995; 40(6):585-590. 

Excluded because BNP assay method is not an included one 

Cargill R, Lipworth B, Cargill R, and Lipworth BJ. Atrial natriuretic peptide and brain natriuretic peptide in 

cor pulmonale. Hemodynamic and endocrine effects.[see comment]. Chest 1996; 110(5):1220-1225. 

Excluded because BNP assay method is not an included one 

Cargill R, McFarlane L, Coutie W, Lipworth B, Cargill R, McFarlane L et al. Acute neurohormonal 

responses to hypoxaemia in man. European Journal of Applied Physiology & Occupational Physiology 

1996; 72(3):256-260. 

Excluded because BNP assay method is not an included one 

Cargill R, Struthers A, Lipworth B, Cargill R, Struthers A, and Lipworth BJ. Comparative effects of atrial 

natriuretic peptide and brain natriuretic peptide on the aldosterone and pressor responses to angiotensin 

II in man. Clinical Science 1995; 88(1):81-86. 

Excluded because BNP assay method is not an included one 

Carrillo-Jimenez R, Treadwell T, Goldfine H, Buenano A, Lamas G, Hennekens C et al. Brain natriuretic 

peptide and HIV-related cardiomyopathy. AIDS Reader 50 A.D.; 12(11):501-503. 

Excluded because this is a case report or series with 10 subjects 

Carson RJ. Clinical: the mechanisms involved in the initiation of term labour. Modern Midwife 1997; 

7(7):12-16. 

Excluded because not a report of a primary study 
D-12 

Carstens J, Jensen K, and Pedersen EB. Effect of urodilatin infusion on renal haemodynamics, tubular 

function and vasoactive hormones. Clinical Science 1997; 92(4):397-407. 

Excluded because BNP assay method is not an included one 

Casco V, Veinot J, Kuroski de Bold M, Masters R, Stevenson M, de Bold A et al. Natriuretic peptide 

system gene expression in human coronary arteries. Journal of Histochemistry & Cytochemistry 2002; 

50(6):799-809. 

Excluded because adult blood not measured 

Casulari L, Costa K, Albuquerque R, Naves L, Suzuki K, and Domingues L. Differential diagnosis and 

treatment of hyponatremia following pituitary surgery. Journal of Neurosurgical Sciences 2004; 48(1):11-

18. 

Excluded because not a report of a primary study 

Cataliotti A, Malatino L, Jougasaki M, Zoccali C, Castellino P, Giacone G et al. Circulating natriuretic 

peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a 

biomarker for ventricular remodeling. Mayo Clinic Proceedings 2001; 76(11):1111-1119. 

Excluded because BNP assay method is not an included one 

Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C et al. Oral insulin administration 

and residual s-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. 

Lancet 2000; 356(9229):545-549. 

Excluded because BNP assay method is not an included one 

Chambers J, Francis D, and Coats AJS. Recovery oxygen uptake and brain natriuretic peptide as 

markers of exercise capacity in chronic heart failure. Journal of Sports Sciences 2000; 18(7):490. 

Excluded because not a report of a primary study 

Chambers J, J.S. Diagnosis and risk stratification of unstable angina and non ST-segment elevation 

myocardial infarction. Continuing Medical Education - Cardiology 2002; 2(1):15-29. 

Excluded because not a report of a primary study 

Chan R, Sealey J, Michelis M, Swan A, Pfaffle A, Devita M et al. Renin-aldosterone system can respond 

to furosemide in patients with hyperkalemic hyporeninism. Journal of Laboratory and Clinical Medicine 

1998; 132(3):229-235. 

Excluded because BNP assay method is not an included one 

Chanalaris A, Lawrence K, Townsend P, Davidson S, Jashmidi Y, Stephanou A et al. Hypertrophic effects 

of urocortin homologous peptides are mediated via activation of the Akt pathway. Biochemical & 

Biophysical Research Communications 2005; 328(2):442-448. 

Excluded because adult blood not measured 

Chandar S, Pawsey C, and Kritharides L. Diastolic heart failure: A clinical update. Medicine Today 2001; 

2(10):22-30. 

Excluded because not a report of a primary study 

Chang R, Elatre W, Heywood J, Chang REWA, and Heywood JT. Effect of nesiritide on length of hospital 

stay in patients with decompensated heart failure. Journal of Cardiovascular Pharmacology & 

Therapeutics 2004; 9(3):173-177. 

Excluded because BNP used as treatment 

Channick R, Simonneau G, Sitbon O, Robbins I, Frost A, Tapson V et al. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled 

study. Lancet 2001; 358(9288):1119-1123. 

Excluded because adult blood not measured 
D-13 

Charles C, Lainchbury J, Lewis L, Rademaker M, Richards A, Yandle T et al. The role of adrenomedullin. 

American Journal of Hypertension 1999; 12(2 I):166-173. 

Excluded because adult blood not measured 

Chau W, J, Jr. Treatment of congestive heart failure in the elderly: Emphasis on renal functional changes 

and impact of therapy. Coronary Artery Disease 1997; 8(8-9):505-509. 

Excluded because not a report of a primary study 

Chello M, Mastroroberto P, Perticone F, Cirillo F, Bevacqua E, Olivito S et al. Plasma levels of atrial and 

brain natriuretic peptides as indicators of recovery of left ventricular systolic function after coronary artery 

bypass. European Journal of Cardio-Thoracic Surgery 2001; 20(1):140-146. 

Excluded because BNP assay method is not an included one 

Chen H, Redfield M, Nordstrom L, Horton D, Burnett J, Jr et al. Subcutaneous administration of the 

cardiac hormone BNP in symptomatic human heart failure. Journal of Cardiac Failure 2004; 10(2):115-

119. 

Excluded because adult blood not measured 

Cheung B, B.M. Plasma concentration of brain natriuretic peptide is related to diastolic function in 

hypertension. Clinical & Experimental Pharmacology & Physiology 1997; 24(12):966-968. 

Excluded because not a report of a primary study 

Cheung B, Brown M, Cheung B, and Brown MJ. Plasma brain natriuretic peptide and C-type natriuretic 

peptide in essential hypertension. Journal of Hypertension 1994; 12(4):449-454. 

Excluded because BNP assay method is not an included one 

Cheung B, Dickerson J, Ashby M, Brown M, Brown J, Cheung B et al. Effects of physiological increments 

in human alpha-atrial natriuretic peptide and human brain natriuretic peptide in normal male 

subjects.[erratum appears in Clin Sci (Colch) 1994 Dec;87(6):following xxv]. Clinical Science 1994; 

86(6):723-730. 

Excluded because BNP assay method is not an included one 

Cheung B, Kumana C, Cheung B, and Kumana CR. Natriuretic peptides--relevance in cardiovascular 

disease. JAMA: Journal of the American Medical Association 1919; 280(23):1983-1984. 

Excluded because adult blood not measured 

Cheung B, M.J. 'New' natriuretic peptides and blood pressure [1]. Lancet 1993; 342(8877):984. 

Excluded because not a report of a primary study 

Choy A, Darbar D, Lang C, Pringle T, McNeill G, Kennedy N et al. Detection of left ventricular dysfunction 

after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal 

methods.[see comment]. British Heart Journal 1994; 72(1):16-22. 

Excluded because BNP assay method is not an included one 

Chua G, Kang-Hoe L, Chua GaK-HL. Marked elevations in N-terminal brain natriuretic peptide levels in 

septic shock. Critical care (London, England) 2004; 8(4):R248-R250. 

Excluded because this is a case report or series with 10 subjects 

Chugh R. Management of pregnancy in patients with congenital heart disease and systemic ventricular 

failure. Progress in Pediatric Cardiology 2004; 19(1):47-60. 

Excluded because not a report of a primary study 

Cittadini A, Ines CL, Longobardi S, Rocco PVCC, Passamano L, Merola B et al. A preliminary randomized 

study of growth hormone administration in Becker and Duchenne muscular dystrophies.[see comment]. 
D-14 

European Heart Journal 2003; 24(7):664-672. 

Excluded because BNP assay method is not an included one 

Clark A, J.G.F. Optimising delivery of care for chronic heart failure. Journal of Clinical Excellence 2000; 

1(4):209-215. 

Excluded because not a report of a primary study 

Clarkson P, Wheeldon N, MacLeod C, Coutie W, MacDonald T, Clarkson P et al. Brain natriuretic peptide: 

effect on left ventricular filling patterns in healthy subjects. Clinical Science 1995; 88(2):159-164. 

Excluded because BNP assay method is not an included one 

Clarkson P, Wheeldon N, MacFadyen R, Pringle S, MacDonald T, Clarkson P et al. Effects of brain 

natriuretic peptide on exercise hemodynamics and neurohormones in isolated diastolic heart failure.[see 

comment]. Circulation 1996; 93(11):2037-2042. 

Excluded because BNP assay method is not an included one 

Cleland J, Cowburn P, and Struthers AD. Neutral endopeptidase inhibitors: Effects on peptide metabolism 

and potential therapeutic use in the treatment of heart failure. Heart Failure 1996; 12(2). 

Excluded because not a report of a primary study 

Cleland J, Cowburn P, and Morgan K. Neuroendocrine activation after myocardial infarction: Causes and 

consequences. Heart (British Cardiac Society) 1996; 76(3 SUPPL. 3):53-59. 

Excluded because not a report of a primary study 

Clemens L, Almirez R, Baudouin K, Mischak R, Grossbard E, Protter A et al. Pharmacokinetics and 

biological actions of subcutaneously administered human brain natriuretic peptide. Journal of 

Pharmacology & Experimental Therapeutics 1998; 287(1):67-71. 

Excluded because adult blood not measured 

Clerico A, Emdin M, Clerico AaEM. Endocrine paradox in heart failure: resistance to biological effects of 

cardiac natriuretic hormones.[comment]. Clinical Chemistry 2004; 50(12):2465-2467. 

Excluded because adult blood not measured 

Clerico A, Iervasi G, Del Ry S, and Giannessi D. Immunoassay methods for the measurement of 

natriuretic cardiac hormones - ANP, BNP, and related peptides - In humans. Journal of Clinical Ligand 

Assay 1999; 22(2):194-204. 

Excluded because not a report of a primary study 

Clough JD. BNP looks like a winner. Cleveland Clinic Journal of Medicine 2002; 69(3):179. 

Excluded because not a report of a primary study 

Cocco G, Kohn S, and Sfrisi C. Comparison of the effects of cilazapril and of the combination of cilazapril 

plus valsartan in patients with advanced heart failure. Heartdrug 2002; 2(6):286-294. 

Excluded because BNP assay method is not an included one 

Cohn JN. New approaches to screening for vascular and cardiac risk. American Journal of Hypertension 

2001; 14(6 II):218S-220S. 

Excluded because not a report of a primary study 

Cohn JN. Global structural ventricular remodeling: Summation. Journal of Cardiac Failure 2002; 8(6 

SUPPL.):S269-S270. 

Excluded because not a report of a primary study 

Cohn JN. Valsartan attenuates heart failure progression. Cardiology Review 2002; 19(12 SUPPL.). 

Excluded because not a report of a primary study 
D-15 

Cohn JN. Lessons learned from the Valsartan- Heart Failure Trial (Val-HeFT): Angiotensin receptor 

blockers in heart failure. American Journal of Cardiology 2002; 90(9):992-993. 

Excluded because not a report of a primary study 

Cohn J, J.N. Is there a common mechanism of benefit for effective treatment of heart failure? European 

Journal of Heart Failure 1999; 1(1):31-34. 

Excluded because not a report of a primary study 

Cohn J, Quyyumi A, Hollenberg N, and Jamerson KA. Surrogate markers for cardiovascular disease: 

Functional markers. Circulation 2004; 109(25). 

Excluded because not a report of a primary study 

Cohn PF. EECP - New data on possible mechanisms of action. European Heart Journal 2001; 

22(16):1363-1364. 

Excluded because not a report of a primary study 

Collinson P, G. Natriuretic peptides - Physiology and clinical application. Cpd Bulletin Clinical 

Biochemistry 2003; 5(2):48-52. 

Excluded because not a report of a primary study 

Colucci W, Elkayam U, Horton D, Abraham W, Bourge R, Johnson A et al. Intravenous nesiritide, a 

natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study 

Group.[erratum appears in N Engl J Med 2000 Nov 16;343(20):1504]. New England Journal of Medicine 

1907; 343(4):246-253. 

Excluded because adult blood not measured 

Conaway D, Sullivan R, McCullough P, Conaway DG, Sullivan RaMPA. Improved symptoms, physical 

limitation, and self-efficacy after resynchronization in a patient with heart failure and a prolonged QRS 

duration. Reviews in Cardiovascular Medicine 2004; 5(1):53-57. 

Excluded because this is a case report or series with 10 subjects 

Conraads V, Bosmans J, and Vrints CJ. Chronic heart failure: An example of a systemic chronic 

inflammatory disease resulting in cachexia. International Journal of Cardiology 2002; 85(1):33-49. 

Excluded because not a report of a primary study 

Cooper A, M. Clinical update. IV fluid therapy: part 1; water balance and hydration assessment. 

Australian Nursing Journal 1999; 7(5):insert-4. 

Excluded because not a report of a primary study 

Corboy J, Walker R, Simmonds M, Wilkins G, Richards A, Espiner E et al. Plasma natriuretic peptides 

and cardiac volume during acute changes in intravascular volume in haemodialysis patients. Clinical 

Science 1994; 87(6):679-684. 

Excluded because BNP assay method is not an included one 

Corti R, Ruschitzka F, Hurlimann D, Luscher T, and Noll G. Vasopeptidase inhibitors: A new class of 

drugs. Heartdrug 2001; 1(2):96-102. 

Excluded because not a report of a primary study 

Cossa F, Fabiani M, Farinato A, Laiacona M, Capitani E, Cossa F et al. The 'preliminary 

neuropsychological battery'. An instrument to grade the cognitive level of minimally responsive patients. 

Brain Injury 1999; 13(8):583-592. 

Excluded because adult blood not measured 

Cotter G, Kaluski E, Stangl K, Pacher R, Richter C, Milo-Cotter O et al. The hemodynamic and 

neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with 
D-16 

acute heart failure. European Journal of Heart Failure 2004; 6(5):601-609. 

Excluded because BNP assay method is not an included one 

Cowie M, A. Recent developments: Management of chronic heart failure. British Medical Journal 2002; 

325(7361):422-425. 

Excluded because not a report of a primary study 

Cowie M, M.R. BNP: soon to become a routine measure in the care of patients with heart failure?[see 

comment]. Heart (British Cardiac Society) 2000; 83(6):617-618. 

Excluded because not a report of a primary study 

Cowie M, Struthers A, Wood D, Coats A, Thompson S, Poole-Wilson P et al. Value of natriuretic peptides 

in assessment of patients with possible new heart failure in primary care.[see comment]. Lancet 1997; 

350(9088):1349-1353. 

Excluded because BNP assay method is not an included one 

Cowley C, Bradley J, Shaddy R, Cowley C, Bradley J, and Shaddy RE. B-type natriuretic peptide levels in 

congenital heart disease. Pediatric Cardiology 2004; 25(4):336-340. 

Excluded because adult blood not measured 

Crilley J, Farrer M, Crilley J, and Farrer M. Left ventricular remodelling and brain natriuretic peptide after 

first myocardial infarction.[see comment]. Heart (British Cardiac Society) 2001; 86(6):638-642. 

Excluded because BNP assay method is not an included one 

Crook J, F.A. Tech update. Rapidly identify CHF with POC advances. Nursing Management 2003; 

34(1):48-49. 

Excluded because adult blood not measured 

Daggubati S, Parks J, Overton R, Cintron G, Schocken D, Vesely D et al. Adrenomedullin, endothelin, 

neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure 

indicators.[erratum appears in Cardiovasc Res 1999 Nov;44(2):452-3]. Cardiovascular Research 1997; 

36(2):246-255. 

Excluded because BNP assay method is not an included one 

Dastoor H, Bernieh B, Boobes Y, Abouchacra S, Eltayeb E, Elhuda M et al. Plasma BNP in patients on 

maintenance haemodialysis: A guide to management? Journal of Hypertension 2005; 23(1):23-28. 

Excluded because not a report of a primary study 

Daugaard G, Lassen U, Bie P, Pedersen E, Jensen K, Abildgaard U et al. Natriuretic peptides in the 

monitoring of anthracycline induced reduction in left ventricular ejection fraction. European Journal of 

Heart Failure 2005; 7(1):87-93. 

Excluded because BNP assay method is not an included one 

Davidson N, Coutie W, Webb D, Struthers A, Davidson N, Coutie W et al. Hormonal and renal differences 

between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with 

chronic heart failure. Heart (British Cardiac Society) 1996; 75(6):576-581. 

Excluded because BNP assay method is not an included one 

Davidson N, Coutie W, Struthers A, Davidson N, Coutie W, and Struthers AD. N-terminal proatrial 

natriuretic peptide and brain natriuretic peptide are stable for up to 6 hours in whole blood in vitro. 

Circulation 2002; 91(4):1276-1277. 

Excluded because not a report of a primary study 

Davidson N, Naas A, Hanson J, Kennedy N, Coutie W, Struthers A et al. Comparison of atrial natriuretic 

peptide B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left 
D-17 

ventricular systolic dysfunction. American Journal of Cardiology 2004; 77(10):828-831. 

Excluded because BNP assay method is not an included one 

Davidson N, Pringle S, Pringle T, McNeill G, Struthers A, Davidson N et al. Right coronary artery stenosis 

is associated with impaired cardiac endocrine function during exercise. European Heart Journal 1997; 

18(11):1749-1754. 

Excluded because BNP assay method is not an included one 

Davis M, Espiner E, Richards G, Billings J, Town I, Neill A et al. Plasma brain natriuretic peptide in 

assessment of acute dyspnoea.[see comment]. Lancet 1994; 343(8895):440-444. 

Excluded because BNP assay method is not an included one 

de Boer R, Henning R, Suurmeijer A, Pinto Y, Olthof E, Kirkels J et al. Early expression of natriuretic 

peptides and SERCA in mild heart failure: association with severity of the disease. International Journal of 

Cardiology 2001; 78(1):5-12. 

Excluded because adult blood not measured 

de Feo M, La Villa G, Lazzeri C, Tosti-Guerra C, Becorpi A, Pupilli C et al. Urinary endothelin-1 excretion 

is enhanced by low-dose infusion of brain natriuretic peptide in normal humans. Hypertension 1997; 29(1 

Pt 1):70-74. 

Excluded because adult blood not measured 

de Jong R, Blanksma P, Cornel J, Van den Heuvel A, Siebelink H, Vaalburg W et al. Endothelial 

dysfunction and reduced myocardial perfusion reserve in heart failure secondary to coronary artery 

disease. American Journal of Cardiology 2002; 91(4):497-500. 

Excluded because BNP assay method is not an included one 

de Lemos J, McGuire D, Drazner M, de Lemos JA, McGuire DK, and Drazner MH. B-type natriuretic 

peptide in cardiovascular disease.[see comment]. Lancet 1907; 362(9380):316-322. 

Excluded because not a report of a primary study 

de Lemos J, Morrow D, Bentley J, Omland T, Sabatine M, McCabe C et al. The prognostic value of Btype natriuretic peptide in patients with acute coronary syndromes.[see comment]. New England Journal 

of Medicine 2001; 345(14):1014-1021. 

Excluded because BNP assay method is not an included one 

De Servi S, Mazzone A, James S, and Wallentin L. Are levels of C-reactive protein and troponin T the 

best predictors of mortality after acute coronary syndrome? [5] (multiple letters). Journal of the American 

College of Cardiology 2003; 42(6):1144-1146. 

Excluded because not a report of a primary study 

Deary A, Schumann A, Murfet H, Haydock S, Foo R, Brown M et al. Influence of drugs and gender on the 

arterial pulse wave and natriuretic peptide secretion in untreated patients with essential hypertension.[see 

comment]. Clinical Science 2002; 103(5):493-499. 

Excluded because BNP assay method is not an included one 

deBruin J, Schaefer M, Krohne H, and Dreyer A. Preoperative anxiety, coping, and intraoperative 

adjustment: are there mediating effects of stress-induced analgesia? Psychology and Health 2001; 

16(3):253-271. 

Excluded because adult blood not measured 

Demetriou D, C.S. Investigating the patient with cardiac failure. Medicine Today 2002; 3(8):55-63. 

Excluded because not a report of a primary study 
D-18 

DeSantiago S, Alonso L, Halhali A, Larrea F, Isobard F, and Bourges H. Negative calcium balance during 

lactation in rural Mexican women. American Journal of Clinical Nutrition 2002; 76(4):845-851. 

Excluded because adult blood not measured 

Diaz T, Alderman J, Diaz TaAJ. Nesiritide for the treatment of diastolic dysfunction. Congestive Heart 

Failure 2004; 10(3):154-157. 

Excluded because this is a case report or series with 10 subjects 

Dickerson RN. Hyponatremia in neurosurgical patients: Syndrome of inappropriate antidiuretic hormone 

or cerebral salt wasting syndrome? Hospital Pharmacy 2002; 37(12):1336-1342. 

Excluded because not a report of a primary study 

Dickstein K. Natriuretic peptides in detection of heart failure. Lancet 1998; 351(9095). 

Excluded because not a report of a primary study 

Dobrev D. Transcription factors for ion channels: Active or passive players in cardiac remodeling? 

Cardiovascular Research 2003; 60(2):226-227. 

Excluded because not a report of a primary study 

Doggrell SA. Is vasopressin-receptor antagonism an advancement in the treatment of heart failure? 

Expert Opinion on Pharmacotherapy 2004; 5(10):2181-2184. 

Excluded because not a report of a primary study 

Dorner T, Gagelmann M, Hock D, Herbst F, Forssmann W, Dorner T et al. Separation of synthetic 

cardiodilatin/atrial natriuretic factor and related peptides by reversed-phase high-performance liquid 

chromatography. Journal of Chromatography 2005; A.. 490(2):411-417. 

Excluded because adult blood not measured 

Downie P, Talwar S, Squire I, Davies J, Barnett D, Ng L et al. Assessment of the stability of N-terminal 

pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction. Clinical 

Science 1999; 97(3):255-258. 

Excluded because BNP assay method is not an included one 

Doyama K, Fukumoto M, Takemura G, Tanaka M, Oda T, Hasegawa K et al. Expression and distribution 

of brain natriuretic peptide in human right atria. Journal of the American College of Cardiology 1998; 

32(7):1832-1838. 

Excluded because adult blood not measured 

Drazner M, McGuire D, de Lemos J, Drazner MMDK, and de Lemos JA. Nesiritide in acute heart failure. 

Lancet 1909; 362(9388):998-999. 

Excluded because not a report of a primary study 

Drewnowski A. Why do we like fat?... Reducing dietary fat: putting theory into practice, December 10-11, 

1996, New York, NY. Journal of the American Dietetic Association 1997; 97(7):S58-S62. 

Excluded because not a report of a primary study 

Drummer C, Heer M, Dressendorfer R, Strasburger C, and Gerzer R. Reduced natriuresis during 

weightlessness. Clinical Investigator 1993; 71(9):678-686. 

Excluded because this is a case report or series with 10 subjects 

Dubin N, Monahan L, Yu-Yahiro J, Michael R, Zimmerman S, Hawkes W et al. Serum concentrations of 

steroids, parathyroid hormone, and calcitonin in postmenopausal women during the year following hip 

fracture: effect of location of fracture and age. Journals of Gerontology 1999; Series A(9):M467-M473. 

Excluded because BNP assay method is not an included one 
D-19 

Dubrey S, T.C. Natriuretic peptides and heart failure: Diagnosis, prognosis and treatment. British Journal 

of Cardiology 2000; 7(4). 

Excluded because not a report of a primary study 

Dudman N, Hunt D, MacMahon S, Neal B, Richards M, Simes J et al. Effects of the vasopeptidase 

inhibitor, omapatrilat, in 723 patients with coronary heart disease. Journal of the Renin-AngiotensinAldosterone System 2002; 3(4):270-276. 

Excluded because BNP assay method is not an included one 

Dunn A, Chow M, and Kluger J. Nesiritide: A natriuretic peptide with hemodynamic benefits in patients 

with acute decompensated CHF. Formulary 1999; 34(2):123-131. 

Excluded because not a report of a primary study 

Dzimiri N, Moorji A, Afrane B, Al Halees Z, Dzimiri N, Moorji A et al. Differential regulation of atrial and 

brain natriuretic peptides and its implications for the management of left ventricular volume overload. 

European Journal of Clinical Investigation 2002; 32(8):563-569. 

Excluded because adult blood not measured 

Ebell M. Does elevated BNP predict adverse outcomes in pulmonary embolism? Evidence-Based 

Practice 2002; 6(9):11. 

Excluded because not a report of a primary study 

Ebell M. Does pro-brain natriuretic peptide level predict the clinical course for pulmonary embolism? 

Evidence-Based Practice 2002; 6(7):12. 

Excluded because not a report of a primary study 

Ebell M. Can B-natriuretic peptide distinguish patients with congestive heart failure from those with 

intrinsic lung disease? Evidence-Based Practice 2002; 5(4):6. 

Excluded because not a report of a primary study 

Ebina T, Takahashi N, Mitani I, Sumita S, Ishigami T, Ashino K et al. Clinical implications of cardiac 

(123)I-meta-iodobenzylguanidine scintigraphy and cardiac natriuretic peptides in patients with heart 

disease. Nuclear Medicine Communications 2002; 23(8):795-801. 

Excluded because BNP assay method is not an included one 

Eguchi K, Kario K, Shimada K, Mori T, Nii T, Ibaragi K et al. Circadian variation of blood pressure and 

neurohumoral factors during the acute phase of stroke. Clinical & Experimental Hypertension (New York) 

2002; 24(1-2):109-114. 

Excluded because BNP assay method is not an included one 

Ekman B, Ohman P, Arnqvist H, Lindstrom T, Nystrom F, Ekman BOPK et al. Individualized growth 

hormone substitution with normalized IGF-I levels does not stimulate the renin-angiotensin-aldosterone 

system. Clinical Endocrinology 2002; 57(4):473-479. 

Excluded because BNP assay method is not an included one 

El Gamel A, Campbell C, Yonan N, Keevil B, Warbuton R, Woodcock A et al. Atrial natriuretic peptide 

release after cardiac transplantation. Journal of Thoracic & Cardiovascular Surgery 1996; 112(4):1128-

1129. 

Excluded because not a report of a primary study 

El Gamel A, Yonan N, Keevil B, Warbuton R, Kakadellis J, Woodcock A et al. Significance of raised 

natriuretic peptides after bicaval and standard cardiac transplantation. Annals of Thoracic Surgery 1997; 

63(4):1095-1100. 

Excluded because BNP assay method is not an included one 
D-20 

Elin R, Winter W, Elin RJ, and Winter WE. Laboratory and clinical aspects of B-type natriuretic peptides. 

Archives of Pathology & Laboratory Medicine 2004; 128(6):697-699. 

Excluded because not a report of a primary study 

Elkayam U, Akhter M, Singh H, Khan S, Usman A, Elkayam UAMW et al. Comparison of effects on left 

ventricular filling pressure of intravenous nesiritide and high-dose nitroglycerin in patients with 

decompensated heart failure. American Journal of Cardiology 2001; 93(2):237-240. 

Excluded because adult blood not measured 

Elovic EP. Update on pharmacology. Anterior pituitary dysfunction after traumatic brain injury, part II. 

Journal of Head Trauma Rehabilitation 2004; 19(2):184-187. 

Excluded because not a report of a primary study 

Emdin M, Marini C, Passino C, Giuggioli D, Formichi B, Ferri C et al. Right ventricular overload and 

cardiovascular neuroendocrine derangement in systemic sclerosis. European Heart Journal Supplements 

2004; 6(SUPPL. 6):F68-F73. 

Excluded because BNP assay method is not an included one 

Emdin M, Passino C, Del Ry S, Prontera C, Galetta F, Clerico A et al. Influence of gender on circulating 

cardiac natriuretic hormones in patients with heart failure. Clinical Chemistry & Laboratory Medicine 2003; 

41(5):686-692. 

Excluded because BNP assay method is not an included one 

Enoch J. Misoprostol (Cytotec): a new method of inducing labor. Midwifery Today 1999;(49):22-30. 

Excluded because not a report of a primary study 

Eskafi M, Mahmoud. Sleep apnoea in patients with stable congestive heart failure an intervention study 

with a mandibular advancement device. Swedish Dental Journal - Supplement 2004;(168):1-56. 

Excluded because not a report of a primary study 

Espiner E, Leikis R, Ferch R, MacFarlane M, Bonkowski J, Frampton C et al. The neuro-cardio-endocrine 

response to acute subarachnoid haemorrhage. Clinical Endocrinology 2002; 56(5):629-635. 

Excluded because BNP assay method is not an included one 

Evans M, Livesey J, Ellis M, Yandle T, Evans M, Livesey J et al. Effect of anticoagulants and storage 

temperatures on stability of plasma and serum hormones. Clinical Biochemistry 2001; 34(2):107-112. 

Excluded because BNP assay method is not an included one 

Ewald B. Abnormal laboratory results - B-type natriuretic peptide: A new diagnostic tool for congestive 

heart failure. Australian Prescriber 2003; 26(3):64-65. 

Excluded because not a report of a primary study 

Falcao L, Pinto F, Ravara L, van Zwieten P, Falcao LMPFRLavZPA. BNP and ANP as diagnostic and 

predictive markers in heart failure with left ventricular systolic dysfunction. Journal of the ReninAngiotensin-Aldosterone System 2004; 5(3):121-129. 

Excluded because BNP assay method is not an included one 

Fang V, Juan C, Won J, Ho L, Fang V, Juan C et al. Further study of aldosterone secretion-inhibitory 

factor and brain natriuretic peptide on cortisol production of guinea pig zona fasciculata cells. Chinese 

Journal of Physiology 1920; 43(4):141-147. 

Excluded because adult blood not measured 

Feldman D, Ikonomidis J, Uber W, Van Bakel A, Pereira N, Crumbley A et al. Human B-natriuretic peptide 

improves hemodynamics and renal function in heart transplant patients immediately after surgery. Journal 
D-21 

of Cardiac Failure 2004; 10(4):292-296. 

Excluded because this is a case report or series with 10 subjects 

Ferdinand KC. Advances in antihypertensive combination therapy: Benefits of low-dose thiazide diuretics 

in conjunction with omapatrilat, a vasopeptidase inhibitor. Journal of Clinical Hypertension 2001; 3(5):307-

312. 

Excluded because not a report of a primary study 

Ferreira A, Bettencourt P, Dias P, Pestana M, Serrao P, Soares-Da-Silva P et al. Neurohormonal 

activation, the renal dopaminergic system and sodium handling in patients with severe heart failure under 

vasodilator therapy. Clinical Science 2001; 100(5):557-566. 

Excluded because this is a case report or series with 10 subjects 

Fethiere J, De Lean A, Fethiere J, and De Lean A. Pharmacological evidence for the heterogeneity of 

atrial natriuretic factor-R1 receptor subtype. Molecular Pharmacology 1991; 40(6):915-922. 

Excluded because adult blood not measured 

Fiedler B, Lohmann S, Smolenski A, Linnemuller S, Pieske B, Schroder F et al. Inhibition of calcineurinNFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proceedings 

of the National Academy of Sciences of the United States of America 1908; 99(17):11363-11368. 

Excluded because adult blood not measured 

Figlewicz D, Schwartz M, Seeley R, Chavez M, Baskin D, Woods S et al. Endocrine regulation of food 

intake and body weight. Journal of Laboratory and Clinical Medicine 1996; 127(4):328-332. 

Excluded because not a report of a primary study 

Fleischer D, Espiner E, Yandle T, Livesey J, Billings J, Town I et al. Rapid assay of plasma brain 

natriuretic peptide in the assessment of acute dyspnoea. New Zealand Medical Journal 2003; 

110(1039):71-74. 

Excluded because BNP assay method is not an included one 

Floras JS. Vasopeptidase inhibition: A novel approach to cardiovascular therapy. Canadian Journal of 

Cardiology 2002; 18(2):177-182. 

Excluded because not a report of a primary study 

Florkowski C, Hassan E, Yandle T, Livesey J, Espiner E, and Donald RA. Growth hormone replacement 

increases cardiac muscle mass and reduces brain natriuretic peptide response to exercise in adults with 

growth hormone deficiency. Endocrinology & Metabolism, Supplement 1997; 4(3):167-171. 

Excluded because BNP assay method is not an included one 

Florkowski C, Richards A, Espiner E, Yandle T, Frampton C, Florkowski C et al. Renal, endocrine, and 

hemodynamic interactions of atrial and brain natriuretic peptides in normal men. American Journal of 

Physiology 1994; 266(4 Pt 2):R1244-R1250. 

Excluded because BNP assay method is not an included one 

Florkowski C, Richards A, Espiner E, Yandle T, Sybertz E, Frampton C et al. Low-dose brain natriuretic 

peptide infusion in normal men and the influence of endopeptidase inhibition. Clinical Science 1997; 

92(3):255-260. 

Excluded because BNP assay method is not an included one 

Foex P. Pre-operative evaluation and risk assessment of patients undergoing vascular surgery. Bailliere's 

Best Practice in Clinical Anaesthesiology 2000; 14(1):1-16. 

Excluded because not a report of a primary study 
D-22 

Fonarow GC. B-type natriuretic peptide: Spectrum of application. Nesiritide (recombinant BNP) for heart 

failure. Heart Failure Reviews 2003; 8(4):321-325. 

Excluded because not a report of a primary study 

Fonarow GC. Clinical update on the use of natriuretic peptides in the treatment of heart failure. Reviews 

in Cardiovascular Medicine 2003; 4(SUPPL. 7):S1-S2. 

Excluded because not a report of a primary study 

Fonarow G, T.B. Prevention of heart failure: Effective strategies to combat the growing epidemic. Reviews 

in Cardiovascular Medicine 2003; 4(1):8-17. 

Excluded because not a report of a primary study 

Forssmann W, Magert H, Meyer M, and Schulz-Knappe P. Cardiac peptides are also regulatory peptides 

in the autonomic nervous system and in paraneuronal systems. Journal of the Autonomic Nervous 

System 1991; 33(2):117-118. 

Excluded because not a report of a primary study 

Forssmann W, Meyer M, and Forssmann K. The renal urodilatin system: Clinical implications. 

Cardiovascular Research 2001; 51(3):450-462. 

Excluded because not a report of a primary study 

Fox K. How to do it - Set up a heart failure clinic. Continuing Medical Education - Cardiology 2003; 

2(3):160-165. 

Excluded because not a report of a primary study 

Foy S, Crozier I, Richards A, Nicholls M, Turner J, Frampton C et al. Neurohormonal changes after acute 

myocardial infarction: Relationships with haemodynamic indices and effects of ACE inhibition. European 

Heart Journal 1995; 16(6):770-778. 

Excluded because BNP assay method is not an included one 

Frape D, Williams N, Scriven A, Palmer C, O'Sullivan K, and Fletcher RJ. Diurnal trends in responses of 

blood plasma concentrations of glucose, insulin, and C-peptide following high- and low-fat meals and their 

relation to fat metabolism in healthy middle-aged volunteers. British Journal of Nutrition 1997; 77(4):523-

535. 

Excluded because adult blood not measured 

Frape D, Williams N, Rajput-Williams J, Maitland B, Scriven A, Palmer C et al. Effect of breakfast fat 

content on glucose tolerance and risk factors of atherosclerosis and thrombosis. British Journal of 

Nutrition 1998; 80(4):323-331. 

Excluded because BNP assay method is not an included one 

Frey N, E.N. Modulating cardiac hypertrophy by manipulating myocardial lipid metabolism? Circulation 

2002; 105(10):1152-1154. 

Excluded because not a report of a primary study 

Friedl W, Mair J, Pichler M, Paulweber B, Sandhofer F, Puschendorf B et al. Insertion/deletion 

polymorphism in the angiotensin-converting enzyme gene is associated with atrial natriuretic peptide 

activity after exercise. Clinica Chimica Acta 2006; 274(2):199-211. 

Excluded because BNP assay method is not an included one 

Friedl W, Mair J, Thomas S, Pichler M, Puschendorf B, Friedl W et al. Natriuretic peptides and cyclic 

guanosine 3',5'-monophosphate in asymptomatic and symptomatic left ventricular dysfunction. Heart 

(British Cardiac Society) 1996; 76(2):129-136. 

Excluded because BNP assay method is not an included one 
D-23 

Friedl W, Mair J, Thomas S, Pichler M, Puschendorf B, Friedl W et al. Relationship between natriuretic 

peptides and hemodynamics in patients with heart failure at rest and after ergometric exercise. Clinica 

Chimica Acta 1999; 281(1-2):121-126. 

Excluded because BNP assay method is not an included one 

Fujii T, Otsuka T, Tanaka S, Kanazawa H, Hirata K, Kohno M et al. Plasma endothelin-1 level in chronic 

obstructive pulmonary disease: relationship with natriuretic peptide.[comment]. Respiration 1999; 

66(3):212-219. 

Excluded because BNP assay method is not an included one 

Fujita M, Miyamoto S, Tambara K, and Budgell B. Trepopnea in patients with chronic heart failure. 

International Journal of Cardiology 2002; 84(2-3):115-118. 

Excluded because not a report of a primary study 

Fujiwara Y, Tatsumi T, Imai J, Nakagawa Y, Kimura T, Akaji K et al. Syntheses and biological activities of 

several newly isolated natriuretic peptides. Journal of Pharmacobio-Dynamics 1991; 14(5):s-105. 

Excluded because not a report of a primary study 

Fukui S, Nawashiro H, Otani N, Ooigawa H, Toyooka T, Tsuzuki N et al. Focal brain edema and 

natriuretic peptides in patients with subarachnoid hemorrhage. Acta Neurochirurgica - Supplement 2003; 

86:489-491. 

Excluded because BNP assay method is not an included one 

Funder JW. Why Cardiovascular Endocrinology? Endocrinology 2003; 144(6):i-ii. 

Excluded because not a report of a primary study 

Furst P. 2000 Jonathan E. Rhoads Lecture. A thirty-year odyssey in nitrogen metabolism: from 

ammonium to dipeptides. JPEN: Journal of Parenteral and Enteral Nutrition 2000; 24(4):197-209. 

Excluded because not a report of a primary study 

Furuhashi N, Kimura H, Nagae H, Yajima A, Kimura C, Saito T et al. Brain natriuretic peptide and atrial 

natriuretic peptide levels in normal pregnancy and preeclampsia. Gynecologic & Obstetric Investigation 

1994; 38(2):73-77. 

Excluded because BNP assay method is not an included one 

Futterman L, Lemberg L, Futterman LG, and Lemberg L. Novel markers in the acute coronary syndrome: 

BNP, IL-6, PAPP-A. American Journal of Critical Care 2002; 11(2):168-172. 

Excluded because not a report of a primary study 

Gackowski A, Isnard R, Golmard J, Pousset F, Carayon A, Montalescot G et al. Comparison of 

echocardiography and plasma B-type natriuretic peptide for monitoring the response to treatment in acute 

heart failure. European Heart Journal 2004; 25(20):1788-1796. 

Excluded because BNP assay method is not an included one 

Gade W, Hainaut C, Gade J, Gade WHCaGJ. Accelerated cardiac protocols in emergency laboratory 

medicine: four case studies. Clinical Laboratory Science 2003; 16(3):180-187. 

Excluded because adult blood not measured 

Galatius S, Gustafsson F, Atar D, and Hildebrandt PR. Tolerability of beta-blocker initiation and titration 

with bisoprolol and carvedilol in congestive heart failure - A randomized comparison. Cardiology 2004; 

102(3):160-165. 

Excluded because not a report of a primary study 
D-24 

Gardner DG. Molecular biology of the natriuretic peptides. Trends in Cardiovascular Medicine 1994; 

4(4):159-165. 

Excluded because not a report of a primary study 

Garlichs C, Zhang H, Schmeisser A, Daniel W, Garlichs C, Zhang H et al. Priming of superoxide anion in 

polymorphonuclear neutrophils by brain natriuretic peptide. Life Sciences 1999; 65(10):1027-1033. 

Excluded because adult blood not measured 

Gegenhuber A, Mueller T, Firlinger F, Lenz K, Poelz W, Haltmayer M et al. Time course of B-type 

natriuretic peptide (BNP) and N-terminal proBNP changes in patients with decompensated heart failure. 

Clinical Chemistry 2004; 50(2):454-456. 

Excluded because not a report of a primary study 

Gempp E, Blatteau J, Louge P, Drouillard I, and Galland F-M. N-Terminal pro brain natriuretic peptide 

increases after 1-h scuba dives at 10 m depth. Aviation Space & Environmental Medicine 2005; 

76(2):114-116. 

Excluded because this is a case report or series with 10 subjects 

Geny B, Charloux A, Lampert E, Lonsdorfer J, Haberey P, Piquard F et al. Enhanced brain natriuretic 

peptide response to peak exercise in heart transplant recipients. Journal of Applied Physiology 1998; 

85(6):2270-2276. 

Excluded because BNP assay method is not an included one 

Geny B, Follenius M, Epailly E, Charpentier A, Brandenberger G, Eisenmann B et al. Transient reduction 

without normalization of brain natriuretic peptide early after heart transplantation. Journal of Thoracic & 

Cardiovascular Surgery 1998; 115(2):473-475. 

Excluded because BNP assay method is not an included one 

Geny B, Hardy H, Lonsdorfer J, Eisenmann B, Haberey P, Piquard F et al. Enhanced natriuretic response 

to neutral endopeptidase inhibition in heart-transplant recipients. Hypertension 1999; 33(4):969-974. 

Excluded because BNP assay method is not an included one 

Georges A, Forestier F, Valli N, Plogin A, Janvier G, Bordenave L et al. Changes in type B natriuretic 

peptide (BNP) concentrations during cardiac valve replacement. European Journal of Cardio-Thoracic 

Surgery 2004; 25(6):941-945. 

Excluded because BNP assay method is not an included one 

Georgiadou P, Babu-Narayan S, Francis D, Kremastinos D, and Gatzoulis MA. Periodic breathing as a 

feature of right heart failure in congenital heart disease. Heart (British Cardiac Society) 2004; 90(9):1075-

1076. 

Excluded because not a report of a primary study 

Gerbes A, Nemer M, Gerbes A, and Nemer M. Detection of C-type natriuretic peptide compared with 

brain and atrial natriuretic peptide transcripts in human heart by the polymerase chain reaction. Clinical 

Investigator 1993; 71(8):672. 

Excluded because adult blood not measured 

Gerlach H, Dhainaut J, Harbarth S, Reinhart K, Marshall J, and Levy M. The PIRO Concept: R is for 

response. Critical Care (London) 2003; 7(3):256-259. 

Excluded because not a report of a primary study 

Gheorghiade M, Gattis W, Adams K, Jr, Jaffe A, O'Connor C et al. Rationale and design of the pilot 

randomized study of nesiritide versus dobutamine in heart failure (PRESERVD-HF). American Heart 

Journal 2003; 145(2 Suppl):S55-S57. 

Excluded because not a report of a primary study 
D-25 

Ghitelman J, Krumerman D, Latif F, Le Jemtel T, Ghitelman JKDLFaLJTH. Serum brain natriuretic 

peptide level in a patient with chronic obstructive pulmonary disease and chronic heart failure. Congestive 

Heart Failure 2004; 10(2):106-108. 

Excluded because this is a case report or series with 10 subjects 

Gibbons G, Liew C, Goodarzi M, Rotter J, Hsueh W, Siragy H et al. Genetic markers: Progress and 

potential for cardiovascular disease. Circulation 2004; 109(25). 

Excluded because not a report of a primary study 

Gibson N. B-natriuretic peptide levels had high sensitivity and specificity for detecting abnormal 

ventricular function. ACP Journal Club 2002; v136(2):68. 

Excluded because not a report of a primary study 

Givertz M, E. Neurohormones in heart failure: Predicting outcomes, optimizing care. European Heart 

Journal 2004; 25(4):281-282. 

Excluded because not a report of a primary study 

Gobinet-Georges A, Valli N, Filliatre H, Dubernet M, Dedeystere O, Bordenave L et al. Stability of brain 

natriuretic peptide (BNP) in human whole blood and plasma. Clinical Chemistry & Laboratory Medicine 

2000; 38(6):519-523. 

Excluded because BNP assay method is not an included one 

Goetze J, Christoffersen C, Perko M, Arendrup H, Rehfeld J, Kastrup J et al. Increased cardiac BNP 

expression associated with myocardial ischemia. FASEB Journal 2003; 17(9):1105-1107. 

Excluded because adult blood not measured 

Goetze J, Gore A, Moller C, Steinbruchel D, Rehfeld J, Nielsen L et al. Acute myocardial hypoxia 

increases BNP gene expression. FASEB Journal 2004; 18(15):1928-1930. 

Excluded because adult blood not measured 

Goetze J, Kastrup J, Pedersen F, Rehfeld J, Goetze JPKJPFaRJF. Quantification of pro-B-type natriuretic 

peptide and its products in human plasma by use of an analysis independent of precursor 

processing.[see comment]. Clinical Chemistry 2002; 48(7):1035-1042. 

Excluded because BNP assay method is not an included one 

Goetze J, Kastrup J, Rehfeld J, Goetze JPKJaRJF. The paradox of increased natriuretic hormones in 

congestive heart failure patients: does the endocrine heart also fail in heart failure? European Heart 

Journal 2003; 24(16):1471-1472. 

Excluded because not a report of a primary study 

Goetze J, Videbaek R, Boesgaard S, Aldershvile J, Rehfeld J, Carlsen J et al. Pro-brain natriuretic 

peptide as marker of cardiovascular or pulmonary causes of dyspnea in patients with terminal 

parenchymal lung disease. Journal of Heart & Lung Transplantation 2004; 23(1):80-87. 

Excluded because BNP assay method is not an included one 

Gohlke P. Role of neutral endopeptidase and angiotensin-converting enzyme in deoxycorticosterone 

acetate-salt hypertension. Journal of Hypertension 2002; 20(5):821-823. 

Excluded because not a report of a primary study 

Goldman D, C.S. Clinical implications of basic research. Restoring the addicted brain. New England 

Journal of Medicine 2002; 347(11):843-845. 

Excluded because adult blood not measured 
D-26 

Goldsmith SR. Vasopressin antagonists in CHF: Ready for clinical trials? Cardiovascular Research 2002; 

54(1):13-15. 

Excluded because not a report of a primary study 

Gomes M, R.E. B-type (brain) natriuretic peptide: A new therapeutic agent for the treatment of heart 

failure. Prevention & Management of Congestive Heart Failure 1998; 4(3):15-21. 

Excluded because not a report of a primary study 

Goswami K, Maisel A, and Wanner EC. Brain-type (B-type) natriuretic peptide (BNP) levels: Truly costeffective in diagnosis of congestive heart failure (CHF)? Journal of Critical Illness 2003; 18(1). 

Excluded because not a report of a primary study 

Grammatopoulos D, E.W. Role of corticotropin-releasing hormone in onset of labour. Lancet 1919; 

354(9189):1546-1549. 

Excluded because not a report of a primary study 

Grauer K. Clinical viewpoint. How I use BNP. Family Practice Recertification 2004; 26(1):20-22. 

Excluded because not a report of a primary study 

Gremmler B, Kisters K, Funke C, Schleiting H, Kunert M, and Ulbricht LJ. The role of electrolytes and NTproBNP determination in cases of severe heart failure drug treatment. Trace Elements & Electrolytes 

2004; 21(3):206. 

Excluded because not a report of a primary study 

Gremmler B, Ulbricht L, Kosch M, Hausberg M, and Kisters K. Combined antihypertensive therapy 

improves moderate heart failure [1]. Journal of Hypertension 2003; 21(11):2195. 

Excluded because not a report of a primary study 

Groenning B, Nilsson J, Sondergaard L, Kjaer A, Larsson H, Hildebrandt P et al. Evaluation of impaired 

left ventricular ejection fraction and increased dimensions by multiple neurohumoral plasma 

concentrations. European Journal of Heart Failure 2001; 3(6):699-708. 

Excluded because adult blood not measured 

Groenning B, Nilsson J, Hildebrandt P, Kjaer A, Fritz-Hansen T, Larsson H et al. Neurohumoral prediction 

of left-ventricular morphologic response to beta-blockade with metoprolol in chronic left-ventricular 

systolic heart failure. European Journal of Heart Failure 2002; 4(5):635-646. 

Excluded because BNP assay method is not an included one 

Groop P, M.C. Brain natriuretic peptide: Microalbuminuria for cardiac disease and diabetes? Diabetologia 

2005; 48(1):3-5. 

Excluded because not a report of a primary study 

Gutierrez C, D.G. Diastolic heart failure: Challenges of diagnosis and treatment. American Family 

Physician 2004; 69(11):2609-2616. 

Excluded because not a report of a primary study 

Hachey D, Smith T, Hachey DM, and Smith T. Use of nesiritide to treat acute decompensated heart 

failure. Critical Care Nurse 2003; 23(1):53-55. 

Excluded because not a report of a primary study 

Hachida M, Saitou S, Nonoyama M, Hoshi H, Hanayama N, Ohkado A et al. Mechanisms of exercise 

response in the denervated heart after transplantation. Transplantation Proceedings 1999; 31(5):1966-

1969. 

Excluded because BNP assay method is not an included one 
D-27 

Hadase M, Azuma A, Zen K, Asada S, Kawasaki T, Kamitani T et al. Very low frequency power of heart 

rate variability is a powerful predictor of clinical prognosis in patients with congestive heart failure. 

Circulation Journal 2004; 68(4):343-347. 

Excluded because BNP assay method is not an included one 

Hakala T, Hedman A, Turpeinen A, Kettunen R, Vuolteenaho O, Hippelainen M et al. Prediction of atrial 

fibrillation after coronary artery bypass grafting by measuring atrial peptide levels and preoperative atrial 

dimensions. European Journal of Cardio-Thoracic Surgery 2002; 22(6):939-943. 

Excluded because BNP assay method is not an included one 

Halapas A, Tenta R, Pantos C, Cokkinos D, and Koutsilieris M. Parathyroid hormone-related peptide and 

cardiovascular system. In Vivo 2003; 17(5):425-432. 

Excluded because not a report of a primary study 

Hall C. The value of natriuretic peptides for the management of heart failure: Current state of play. 

European Journal of Heart Failure 2001; 3(4):395-397. 

Excluded because not a report of a primary study 

Hama N, Itoh H, Shirakami G, Suga S, Komatsu Y, Yoshimasa T et al. Detection of C-type natriuretic 

peptide in human circulation and marked increase of plasma CNP level in septic shock patients. 

Biochemical & Biophysical Research Communications 2002; 198(3):1177-1182. 

Excluded because BNP assay method is not an included one 

Hamad A, Clayton A, Islam B, and Knox AJ. Guanylyl cyclases, nitric oxide, natriuretic peptides, and 

airway smooth muscle function. American Journal of Physiology - Lung Cellular & Molecular Physiology 

2003; 285(5 29-5):L973-L983. 

Excluded because not a report of a primary study 

Hamberg O, T.P. Effects of xylitol on urea synthesis in normal humans: relation to glucagon. JPEN: 

Journal of Parenteral and Enteral Nutrition 1996; 20(2):139-144. 

Excluded because adult blood not measured 

Hamid S, G.F. Adrenomedullin: Regulator of systemic and cardiac homeostasis in acute myocardial 

infarction. Pharmacology & Therapeutics 2005; 105(2):95-112. 

Excluded because not a report of a primary study 

Hamrahian A, Oseni T, and Arafah BM. Measurements of serum free cortisol in critically ill patients. New 

England Journal of Medicine 2004; 350(16):1629-1638. 

Excluded because adult blood not measured 

Handa S. Treatment of primary pulmonary hypertension. Internal Medicine 2002; 41(10):757-758. 

Excluded because not a report of a primary study 

Hansen-Schwartz J, Sviri G, Edvinsson L, Hansen-Schwartz J, Sviri G, and Edvinsson L. Influence of 

brain natriuretic peptide on phenotypic change of cerebral vasculature. Acta Neurochirurgica - 

Supplement 2001; 77:37-40. 

Excluded because adult blood not measured 

Harada M, Itoh H, Nakagawa O, Ogawa Y, Miyamoto Y, Kuwahara K et al. Significance of ventricular 

myocytes and nonmyocytes interaction during cardiocyte hypertrophy: evidence for endothelin-1 as a 

paracrine hypertrophic factor from cardiac nonmyocytes. Circulation 1919; 96(10):3737-3744. 

Excluded because adult blood not measured 

Harada T, Ohtaki E, Misu K, Sumiyoshi T, and Hosoda S. Congestive heart failure caused by digitalis 

toxicity in an elderly man taking a licorice-containing Chinese herbal laxative [3]. Cardiology 2002; 
D-28 

98(4):218. 

Excluded because not a report of a primary study 

Harada T, Ohtaki E, Kitahara K, Sumiyoshi T, and Hosoda S. Carvedilol-induced changes in cardiac 

diastolic performance in a patient with isolated noncompaction of the myocardium. Internal Medicine 

2002; 41(8):642-647. 

Excluded because not a report of a primary study 

Haria M, Plosker G, and Markham A. Felodipine/metoprolol: A review of the fixed dose controlled release 

formulation in the management of essential hypertension. Drugs 2000; 59(1):141-157. 

Excluded because not a report of a primary study 

Harrison A, Bhalla V, Gardetto N, Maisel A, Harrison ABVGNaMAS. Evolving use of B-type natriuretic 

peptide in clinical practice. Clinical Chemistry 2004; 50(9):1714-1715. 

Excluded because adult blood not measured 

Hartmann F, Kurowski V, Maghsoudi A, Kurz T, Schwarz M, Bonnemeier H et al. Plasma catecholamines 

and N-terminal proBNP in patients with acute myocardial infarction undergoing primary angioplasty. 

Relation to left ventricular function and clinical outcome. Zeitschrift fur Kardiologie 2003; 92(1):73-81. 

Excluded because BNP assay method is not an included one 

Hasegawa K, Fujiwara H, Doyama K, Miyamae M, Fujiwara T, Suga S et al. Ventricular expression of 

brain natriuretic peptide in hypertrophic cardiomyopathy. Circulation 1993; 88(2):372-380. 

Excluded because adult blood not measured 

Hasegawa K, Fujiwara H, Doyama K, Mukoyama M, Nakao K, Fujiwara T et al. Ventricular expression of 

atrial and brain natriuretic peptides in dilated cardiomyopathy. An immunohistocytochemical study of the 

endomyocardial biopsy specimens using specific monoclonal antibodies. American Journal of Pathology 

1993; 142(1):107-116. 

Excluded because BNP assay method is not an included one 

Haug C, Metzele A, Kochs M, Hombach V, Grunert A, Haug C et al. Plasma brain natriuretic peptide and 

atrial natriuretic peptide concentrations correlate with left ventricular end-diastolic pressure. Clinical 

Cardiology 1993; 16(7):553-557. 

Excluded because BNP assay method is not an included one 

Haug C, Metzele A, Steffgen J, Kochs M, Hombach V, Grunert A et al. Increased brain natriuretic peptide 

and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in 

patients with elevated left ventricular filling pressure. Clinical Investigator 1994; 72(6):430-434. 

Excluded because BNP assay method is not an included one 

Haug C, Metzele A, Steffgen J, Grunert A, Haug C, Metzele A et al. Changes in brain natriuretic peptide 

and atrial natriuretic peptide plasma concentrations during hemodialysis in patients with chronic renal 

failure. Hormone & Metabolic Research 1994; 26(5):246-249. 

Excluded because BNP assay method is not an included one 

Hayabuchi Y, Matsuoka S, Kuroda Y, Hayabuchi Y, Matsuoka S, and Kuroda Y. Plasma concentrations of 

atrial and brain natriuretic peptides and cyclic guanosine monophosphate in response to dobutamine 

infusion in patients with surgically repaired tetralogy of fallot. Pediatric Cardiology 1999; 20(5):343-350. 

Excluded because adult blood not measured 

Hayashi Y, Ohtani M, Sawa Y, Hiraishi T, Akedo H, Kobayashi Y et al. Synthetic Human a-Atrial 

Natriuretic Peptide Improves the Management of Postoperative Hypertension and Renal Dysfunction after 

the Repair of Abdominal Aortic Aneurysm. Journal of Cardiovascular Pharmacology 2003; 42(5):636-641. 

Excluded because BNP assay method is not an included one 
D-29 

Hayes DL. Cardiac arrhythmias and implantable devices. Journal of the American College of Cardiology 

2003; 42(2):392-393. 

Excluded because not a report of a primary study 

He Q, Mendez M, LaPointe M, He QMMaLMC. Regulation of the human brain natriuretic peptide gene by 

GATA-4. American Journal of Physiology - Endocrinology & Metabolism 2002; 283(1):E50-E57. 

Excluded because adult blood not measured 

Heaney R, McCarron D, Dawson-Hughes B, Oparil S, Berga S, Stern J et al. Dietary changes favorably 

affect bone remodeling in older adults. Journal of the American Dietetic Association 1999; 99(10):1228-

1233. 

Excluded because BNP assay method is not an included one 

Heaney R, Rafferty K, and Dowell MS. Effect of yogurt on a urinary marker of bone resorption in 

postmenopausal women. Journal of the American Dietetic Association 2002; 102(11):1672-1674. 

Excluded because adult blood not measured 

Heidenreich P, Gubens M, Fonarow G, Konstam M, Stevenson L, Shekelle P et al. Cost-effectiveness of 

screening with B-type natriuretic peptide to identify patients with reduced left ventricular ejection fraction. 

Journal of the American College of Cardiology 2003; 43(6):1019-1026. 

Excluded because adult blood not measured 

Henriksen J, S. Hypertension and liver disease. Current Hypertension Reports 2004; 6(6):453-461. 

Excluded because not a report of a primary study 

Heringlake M, Heide C, Bahlmann L, Eichler W, Pagel H, Schmucker P et al. Effects of tilting and volume 

loading on plasma levels and urinary excretion of relaxin, NT-pro-ANP, and NT-pro-BNP in male 

volunteers. Journal of Applied Physiology 2004; 97(1):173-179. 

Excluded because adult blood not measured 

Hernandez A, G.M. Using BNP levels in the assessment of dyspnea. Journal of Respiratory Diseases 

2004; 25(10):402-403. 

Excluded because not a report of a primary study 

Herold K, Hagopian W, Auger J, Poumian-Ruiz E, Taylor L, Donaldson D et al. Anti-CD3 monoclonal 

antibody in new-onset type 1 diabetes mellitus. New England Journal of Medicine 2005; 346(22):1692-

1698. 

Excluded because adult blood not measured 

Herten M, Lenz W, Gerzer R, Drummer C, Herten M, Lenz W et al. The renal natriuretic peptide urodilatin 

is present in human kidney. Nephrology Dialysis Transplantation 1998; 13(10):2529-2535. 

Excluded because adult blood not measured 

Herzog CA. How to manage the renal patient with coronary heart disease: The agony and the ecstasy of 

opinion-based medicine. Journal of the American Society of Nephrology 2003; 14(10):2556-2572. 

Excluded because not a report of a primary study 

Hetmanski D, Sparrow N, Curtis S, Cowley A, Hetmanski D, Sparrow N et al. Failure of plasma brain 

natriuretic peptide to identify left ventricular systolic dysfunction in the community. Heart (British Cardiac 

Society) 2000; 84(4):440-441. 

Excluded because not a report of a primary study 

Hickman P, J.M. Abnormal laboratory results: New cardiac markers. Australian Prescriber 2003; 26(4):88-

90. 

Excluded because not a report of a primary study 
D-30 

Hill J, Hsu K, Pauly D, Schofield R, Aranda J, Jr et al. Sustained use of nesiritide to aid in bridging to 

heart transplant. Clinical Cardiology 2003; 26(5):211-214. 

Excluded because this is a case report or series with 10 subjects 

Hjortdal V, Stenbog E, Ravn H, Emmertsen K, Jensen K, Pedersen E et al. Neurohormonal activation late 

after cavopulmonary connection. Heart (British Cardiac Society) 2000; 83(4):439-443. 

Excluded because adult blood not measured 

Hobbs F, Davis R, and Lip GYH. Heart failure in general practice. British Medical Journal 2000; 

320(7235):626-629. 

Excluded because not a report of a primary study 

Hobbs F, E. Heart failure and venous thromboembolism: A major hidden risk. British Journal of 

Cardiology 2004; 11(1):27-32. 

Excluded because not a report of a primary study 

Hobbs R, Miller L, Bott-Silverman C, James K, Rincon G, Grossbard E et al. Hemodynamic effects of a 

single intravenous injection of synthetic human brain natriuretic peptide in patients with heart failure 

secondary to ischemic or idiopathic dilated cardiomyopathy. American Journal of Cardiology 1919; 

78(8):896-901. 

Excluded because adult blood not measured 

Hobbs R, R.M. Therapeutic potential nesiritide (recombinant b-type natriuretic peptide) in the treatment of 

heart failure. Expert Opinion on Investigational Drugs 1999; 8(7):1063-1072. 

Excluded because not a report of a primary study 

Hocher B, Ziebig R, Krause R, Asmus G, Neumayer H, Liefeldt L et al. Relaxin is an independent risk 

factor predicting death in male patients with end-stage kidney disease. Circulation 2005; 109(19):2266-

2268. 

Excluded because BNP assay method is not an included one 

Holcberg G, Miodovnik M, Rosenn B, Kossenjans W, Myatt L, Holcberg G et al. Interaction of angiotensin 

II and brain natriuretic peptide in the placentas of normal and diabetic women. Obstetrics & Gynecology 

1995; 85(3):428-432. 

Excluded because adult blood not measured 

Hollien J. A hormone receptor springs into action. Nature Structural Biology 2001; 8(10):832. 

Excluded because not a report of a primary study 

Holmes S, Espiner E, Richards A, Yandle T, Frampton C, Holmes S et al. Renal, endocrine, and 

hemodynamic effects of human brain natriuretic peptide in normal man. Journal of Clinical Endocrinology 

& Metabolism 1993; 76(1):91-96. 

Excluded because this is a case report or series with 10 subjects 

Holtzman E, D.A. Nephrogenic diabetes insipidus: causes revealed. Hospital Practice 1997; 29(3):89-93. 

Excluded because not a report of a primary study 

Honisko M, Fink J, Militello M, Mauro V, Alexander K, Honisko ME et al. Compatibility of argatroban with 

selected cardiovascular agents. American Journal of Health-System Pharmacy 1920; 61(22):2415-2418. 

Excluded because adult blood not measured 

Hopkins W, Chen Z, Fukagawa N, Hall C, Knot H, LeWinter M et al. Increased atrial and brain natriuretic 

peptides in adults with cyanotic congenital heart disease: enhanced understanding of the relationship 

between hypoxia and natriuretic peptide secretion. Circulation 2006; 109(23):2872-2877. 

Excluded because adult blood not measured 
D-31 

Horan D, Hill L, and Schulkin J. Childhood sexual abuse and preterm labor in adulthood: an 

endocrinological hypothesis. Women's Health Issues 2000; 10(1):27-33. 

Excluded because not a report of a primary study 

Horio T, Shimada K, Kohno M, Yoshimura T, Kawarabayashi T, Yasunari K et al. Serial changes in atrial 

and brain natriuretic peptides in patients with acute myocardial infarction treated with early coronary 

angioplasty. American Heart Journal 1993; 126(2):293-299. 

Excluded because BNP assay method is not an included one 

Hosoda K, Nakao K, Mukoyama M, Saito Y, Jougasaki M, Shirakami G et al. Expression of brain 

natriuretic peptide gene in human heart. Production in the ventricle. Hypertension 1991; 17(6 Pt 2):1152-

1155. 

Excluded because adult blood not measured 

Hughes D, Talwar S, Squire I, Davies J, Ng L, Hughes D et al. An immunoluminometric assay for Nterminal pro-brain natriuretic peptide: development of a test for left ventricular dysfunction. Clinical 

Science 1999; 96(4):373-380. 

Excluded because adult blood not measured 

Hunt P, Espiner E, Nicholls M, Richards A, Yandle T, Hunt P et al. Differing biological effects of equimolar 

atrial and brain natriuretic peptide infusions in normal man. Journal of Clinical Endocrinology & 

Metabolism 1996; 81(11):3871-3876. 

Excluded because this is a case report or series with 10 subjects 

Hunt P, Espiner E, Nicholls M, Richards A, Yandle T, Hunt P et al. The role of the circulation in 

processing pro-brain natriuretic peptide (proBNP) to amino-terminal BNP and BNP-32. Peptides 1997; 

18(10):1475-1481. 

Excluded because adult blood not measured 

Hunt P, Espiner E, Richards A, Yandle T, Frampton C, Nicholls M et al. Interactions of atrial and brain 

natriuretic peptides at pathophysiological levels in normal men. American Journal of Physiology 1995; 

269(6 Pt 2):R1397-R1403. 

Excluded because adult blood not measured 

Hunt P, Richards A, Espiner E, Nicholls M, Yandle T, Hunt P et al. Bioactivity and metabolism of C-type 

natriuretic peptide in normal man. Journal of Clinical Endocrinology & Metabolism 1994; 78(6):1428-1435. 

Excluded because BNP assay method is not an included one 

Hunt P, Yandle T, Nicholls M, Richards A, Espiner E, Hunt P et al. The amino-terminal portion of pro-brain 

natriuretic peptide (Pro-BNP) circulates in human plasma. Biochemical & Biophysical Research 

Communications 1909; 214(3):1175-1183. 

Excluded because adult blood not measured 

Hursting M, Slaughter T, Stead A, Szewczyk K, Witt D, and Greenberg CS. Standardization of 

prothrombin fragment 1.2 measurement: effects of preanalytical variables and calibrator selection. 

Archives of Pathology & Laboratory Medicine 1998; 122(1):31-36. 

Excluded because BNP assay method is not an included one 

Hussey L, S. Sex-related differences in heart failure. Heart & Lung: Journal of Acute & Critical Care 2003; 

32(4):215-223. 

Excluded because not a report of a primary study 

Hussey S, F.H. Shortness of breath in a 74-year old woman. Laboratory Medicine 2004; 35(7):408-412. 

Excluded because not a report of a primary study 
D-32 

Hutcheon S, Gillespie N, Struthers A, McMurdo M, Hutcheon SD, Gillespie ND et al. B-type natriuretic 

peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age & Ageing 2002; 

31(4):295-301. 

Excluded because BNP assay method is not an included one 

Iascone M, Vittorini S, Collavoli A, Cupelli A, Kraft G, Biagini A et al. A rapid procedure for the quantitation 

of natriuretic peptide RNAs by competitive RT-PCR in congenital heart defects. Journal of 

Endocrinological Investigation 1999; 22(11):835-842. 

Excluded because adult blood not measured 

Igaki T, Itoh H, Suga S, Hama N, Ogawa Y, Komatsu Y et al. C-type natriuretic peptide in chronic renal 

failure and its action in humans. Kidney International - Supplement 1996; 55:S144-S147. 

Excluded because BNP assay method is not an included one 

Ikeda T, Matsuda K, Itoh H, Shirakami G, Miyamoto Y, Yoshimasa T et al. Plasma levels of brain and 

atrial natriuretic peptides elevate in proportion to left ventricular end-systolic wall stress in patients with 

aortic stenosis. American Heart Journal 1997; 133(3):307-314. 

Excluded because BNP assay method is not an included one 

Inagaki T, Yamamoto M, Tsubouchi K, Miyaoka T, Uegaki J, Maeda T et al. Echocardiographic 

investigation of pericardial effusion in a case of anorexia nervosa. International Journal of Eating 

Disorders 2003; 33(3):364-366. 

Excluded because not a report of a primary study 

Inamura T, Ueno H, Nishiyama T, Nakamura M, Ikezaki K, Inoha S et al. Severe hyponatremia in a case 

of severe spinal injury: Sequential examination of factors affecting water-electrolyte balance. Brain & 

Nerve 2002; 54(1):23-27. 

Excluded because this is a case report or series with 10 subjects 

Ishikawa S, Miyauchi T, Ueno M, Sagawa K, Sakai S, Ushinohama H et al. Abnormal neurohumoral 

responses to exercise in patients with heart disease: inhibition of an increase in endothelin-1 production 

during exercise. Journal of Cardiovascular Pharmacology 1998; 31 Suppl 1:S406-S411. 

Excluded because BNP assay method is not an included one 

Ishikawa Y, Bach J, Minami R, Ishikawa Y, Bach J, and Minami R. Cardioprotection for Duchenne's 

muscular dystrophy. American Heart Journal 1999; 137(5):895-902. 

Excluded because adult blood not measured 

Ishizaka Y, Yamamoto Y, Fukunaga T, Yokota N, Kida O, Kitamura K et al. Plasma concentration of 

human brain natriuretic peptide in patients on hemodialysis. American Journal of Kidney Diseases 1994; 

24(3):461-472. 

Excluded because BNP assay method is not an included one 

Ishizaka Y, Yamamoto Y, Tanaka M, Kato F, Ishizaka Y, Yokota N et al. Molecular forms of human brain 

natriuretic peptide (BNP) in plasma of patients on hemodialysis (HD). Clinical Nephrology 1995; 

43(4):237-242. 

Excluded because BNP assay method is not an included one 

Isnard R, Pousset F, Trochu J, Chafirovskaia O, Carayon A, Golmard J et al. Prognostic value of 

neurohormonal activation and cardiopulmonary exercise testing in patients with chronic heart failure. 

American Journal of Cardiology 1908; 86(4):417-421. 

Excluded because BNP assay method is not an included one 

Isnard R, Pousset F, Chafirovskaia O, Carayon A, Hulot J, Thomas D et al. Combination of B-type 

natriuretic peptide and peak oxygen consumption improves risk stratification in outpatients with chronic 
D-33 

heart failure. American Heart Journal 2003; 146(4):729-735. 

Excluded because BNP assay method is not an included one 

Iso T, Arai M, Wada A, Kogure K, Suzuki T, Nagai R et al. Humoral factor(s) produced by pressure 

overload enhance cardiac hypertrophy and natriuretic peptide expression. American Journal of 

Physiology 1997; 273(1 Pt 2):H113-H118. 

Excluded because adult blood not measured 

Isotani E, Suzuki R, Tomita K, Hokari M, Monma S, Marumo F et al. Alterations in plasma concentrations 

of natriuretic peptides and antidiuretic hormone after subarachnoid hemorrhage. Stroke 1994; 

25(11):2198-2203. 

Excluded because BNP assay method is not an included one 

Isotani H, Kameoka K, Sasaki I, Hida H, Kakutani S, Tasaki T et al. Plasma brain natriuretic peptide levels 

in normotensive type 2 diabetic patients without cardiac disease. Diabetes Care 2000; 23(6):859-860. 

Excluded because not a report of a primary study 

Itoh H, Sagawa N, Hasegawa M, Nanno H, Kobayashi F, Ihara Y et al. Expression of biologically active 

receptors for natriuretic peptides in the human uterus during pregnancy. Biochemical & Biophysical 

Research Communications 1908; 203(1):602-607. 

Excluded because adult blood not measured 

Itoh H, Sagawa N, Mori T, Mukoyama M, Nakao K, Imura H et al. Plasma brain natriuretic peptide level in 

pregnant women with pregnancy-induced hypertension. Obstetrics & Gynecology 1993; 82(1):71-77. 

Excluded because BNP assay method is not an included one 

Itoh H, Sagawa N, Nanno H, Mori T, Mukoyama M, Itoh H et al. Impaired guanosine 3',5'-cyclic phosphate 

production in severe pregnancy-induced hypertension with high plasma levels of atrial and brain 

natriuretic peptides. Endocrine Journal 1997; 44(3):389-393. 

Excluded because BNP assay method is not an included one 

Iwao T, Oho K, Nakano R, Sakai T, Sato M, Miyamoto Y et al. High plasma cardiac natriuretic peptides 

associated with enhanced cyclic guanosine monophosphate production in preascitic cirrhosis. Journal of 

Hepatology 2000; 32(3):426-433. 

Excluded because BNP assay method is not an included one 

Jackson G, Gibbs C, Davies M, and Lip GY. ABC of heart failure: pathophysiology. BMJ 2001; 

320(7228):167-170. 

Excluded because not a report of a primary study 

Jackson K, Robertson M, Fielding B, Frayn K, and Williams CM. Second meal effect: modified sham 

feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal. British 

Journal of Nutrition 2001; 85(2):149-156. 

Excluded because BNP assay method is not an included one 

Jacoby D, D.J. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. 

Archives of Internal Medicine 2005; 163(10):1155-1164. 

Excluded because not a report of a primary study 

Jang T, Aubin C, Naunheim R, and Char D. Ultrasonography of the internal jugular vein in patients with 

dyspnea without jugular venous distention on physical examination. Annals of Emergency Medicine 2004; 

44(2):160-168. 

Excluded because this is a case report or series with 10 subjects 
D-34 

Jensen K, Carstens J, Ivarsen P, Pedersen E, Jensen K, Carstens J et al. A new, fast and reliable 

radioimmunoassay of brain natriuretic peptide in human plasma. Reference values in healthy subjects 

and in patients with different diseases. Scandinavian Journal of Clinical & Laboratory Investigation 1997; 

57(6):529-540. 

Excluded because not a report of a primary study 

Jensen K, Carstens J, Pedersen E, Jensen K, Carstens J, and Pedersen EB. Effect of BNP on renal 

hemodynamics, tubular function and vasoactive hormones in humans. American Journal of Physiology 

1998; 274(1 Pt 2):F63-F72. 

Excluded because BNP assay method is not an included one 

Jensen K, Eiskjaer H, Carstens J, Pedersen E, Jensen K, Eiskjaer H et al. Renal effects of brain 

natriuretic peptide in patients with congestive heart failure. Clinical Science 1999; 96(1):5-15. 

Excluded because BNP assay method is not an included one 

Jernberg T, James S, Lindahl B, Stridsberg M, Venge P, Wallentin L et al. NT-proBNP in unstable 

coronary artery disease--experiences from the FAST, GUSTO IV and FRISC II trials. European Journal of 

Heart Failure 2003; 6(3):319-325. 

Excluded because not a report of a primary study 

Jimenez C, Koulmann N, Mischler I, Allevard A, Launay J, Savourey G et al. Plasma compartment filling 

after exercise or heat exposure. Medicine and Science in Sports and Exercise 2002; 34(10):1624-1631. 

Excluded because this is a case report or series with 10 subjects 

Johannsson G, Sverrisdottir Y, Ellegard L, Lundberg P, Herlitz H, Johannsson GSYBELLPAaHH. GH 

increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing 

pressure natriuresis. Journal of Clinical Endocrinology & Metabolism 2002; 87(4):1743-1749. 

Excluded because this is a case report or series with 10 subjects 

John JP. Vasopeptide inhibition: A novel approach to blood pressure management. P & T 2000; 

25(5):217-224. 

Excluded because not a report of a primary study 

Johnson M, McDonagh T, Harkness A, McKay S, and Dargie HJ. Morphine for the relief of breathlessness 

in patients with chronic heart failure - A pilot study. European Journal of Heart Failure 2002; 4(6):753-756. 

Excluded because BNP assay method is not an included one 

Jones A, Kline J, Jones AE, and Kline JA. Elevated brain natriuretic peptide in septic patients without 

heart failure. Annals of Emergency Medicine 2003; 42(5):714-715. 

Excluded because not a report of a primary study 

Jones C, Goodfellow J, Bleasdale R, and Frenneaux MP. Modulation of interaction between left 

ventricular ejection and the arterial compartment: Assessment of aortic wave travel. Heart & Vessels 

2000; 15(6):247-255. 

Excluded because not a report of a primary study 

Jorgensen M, Pedersen M, Siggaard C, Sorensen T, Mulvad G, Hansen J et al. Ethnic, geographic and 

dietary influences upon vasoactive hormones and blood pressure among Greenland Inuit and Danes. 

Blood Pressure 2003; 12(5-6):298-306. 

Excluded because BNP assay method is not an included one 

Jortani S, Prabhu S, and Valdes JR. Strategies for Developing Biomarkers of Heart Failure. Clinical 

Chemistry 2004; 50(2):265-278. 

Excluded because adult blood not measured 
D-35 

Josephson S, Barnett P, Josephson SaBPP. Nesiritide: practical approach and benefits in the outpatient 

setting. Journal of Cardiovascular Nursing 2004; 19(5):358-363. 

Excluded because BNP used as treatment 

Kaaja R, Moore M, Yandle T, Ylikorkala O, Frampton C, Nicholls M et al. Blood pressure and vasoactive 

hormones in mild preeclampsia and normal pregnancy. Hypertension in Pregnancy 1999; 18(2):173-187. 

Excluded because BNP assay method is not an included one 

Kagaya Y, Otani H, Tanikawa T, Namiuchi S, Isoyama S, Shirato K et al. Concentrations of angiotensin II, 

endothelin-1, and BNP in the coronary sinus and ascending aorta of patients with heart disease. Heart 

(British Cardiac Society) 1999; 81(1):102-103. 

Excluded because not a report of a primary study 

Kajita M, Ezura Y, Iwasaki H, Ishida R, Yoshida H, Kodaira M et al. Association of the -381T/C promoter 

variation of the brain natriuretic peptide gene with low bone-mineral density and rapid postmenopausal 

bone loss. Journal of Human Genetics 2003; 48(2):77-81. 

Excluded because BNP assay method is not an included one 

Kalra P, A.D. More evidence for bedside BNP in heart failure assessment. International Journal of 

Cardiology 2002; 86(2-3):149-152. 

Excluded because not a report of a primary study 

Kalra P, A.J.S. Therapeutic potential of the natriuretic peptide system. British Journal of Cardiology 2002; 

9(5). 

Excluded because not a report of a primary study 

Kalra P, Clague J, Bolger A, Anker S, Poole-Wilson P, Struthers A et al. Myocardial production of C-type 

natriuretic peptide in chronic heart failure. Circulation 2003; 107(4):571-573. 

Excluded because BNP assay method is not an included one 

Kalra P, S. Regulation of lipolysis: Natriuretic peptides and the development of cachexia. International 

Journal of Cardiology 2002; 85(1):125-132. 

Excluded because adult blood not measured 

Kambayashi Y, Nakao K, Mukoyama M, Saito Y, Ogawa Y, Shiono S et al. Isolation and sequence 

determination of human brain natriuretic peptide in human atrium. FEBS Letters 1990; 259(2):341-345. 

Excluded because adult blood not measured 

Kammula U, Marincola F, and Rosenberg SA. Real-time quantitative polymerase chain reaction 

assessment of immune reactivity in melanoma patients after tumor peptide vaccination. Journal of the 

National Cancer Institute 1908; 92(16):1336-1344. 

Excluded because adult blood not measured 

Kanda T, Inoue M, Kotajima N, Fujimaki S, Hoshino Y, Kurabayashi M et al. Circulating interleukin-6 and 

interleukin-6 receptors in patients with acute and recent myocardial infarction. Cardiology 2000; 

93(3):191-196. 

Excluded because BNP assay method is not an included one 

Kanegae K, Hiroshige K, Suda T, Iwamoto M, Ohta T, Nakashima Y et al. Pharmacokinetics of bisoprolol 

and its effect on dialysis refractory hypertension. International Journal of Artificial Organs 1999; 

22(12):798-804. 

Excluded because BNP assay method is not an included one 
D-36 

Kaneko T, Shirakami G, Nakao K, Nagata I, Nakagawa O, Hama N et al. C-type natriuretic peptide (CNP) 

is the major natriuretic peptide in human cerebrospinal fluid. Brain Research 2005; 612(1-2):104-109. 

Excluded because BNP assay method is not an included one 

Kang YJ. Molecular and cellular mechanisms of cardiotoxicity. Environmental Health Perspectives 2001; 

109(SUPPL. 1):27-34. 

Excluded because adult blood not measured 

Karagiannis A, Tziomalos K, and Zamboulis C. Plasma B-type natriuretic peptide is related to left 

ventricular mass in hypertensive patients [4]. European Heart Journal 2004; 25(21):1967. 

Excluded because not a report of a primary study 

Karjalainen A, Ruskoaho H, Vuolteenaho O, Heikkinen J, Backstrom A, Savolainen M et al. Effects of 

estrogen replacement therapy on natriuretic peptides and blood pressure. Maturitas 2003; 47(3):201-208. 

Excluded because BNP assay method is not an included one 

Karmazyn M. Inhibitors of sodium-hydrogen exchange as therapeutic agents for the treatment of heart 

disease. Expert Opinion on Therapeutic Patents 2003; 13(9):1411-1425. 

Excluded because not a report of a primary study 

Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Tange S et al. Dobutamine stress 99mTctetrofosmin quantitative gated SPECT predicts improvement of cardiac function after carvedilol treatment 

in patients with dilated cardiomyopathy. Journal of Nuclear Medicine 2004; 45(11):1878-1884. 

Excluded because BNP assay method is not an included one 

Kasuya H, Onda H, Yoneyama T, Sasaki T, and Hori T. Bedside monitoring of circulating blood volume 

after subarachnoid hemorrhage. Stroke 2003; 34(4):956-960. 

Excluded because BNP assay method is not an included one 

Katayama T, Nakashima H, Furudono S, Honda Y, Suzuki S, Yano K et al. Evaluation of neurohumoral 

activation (adrenomedullin, BNP, catecholamines, etc.) in patients with acute myocardial infarction. 

Internal Medicine 2004; 43(11):1015-1022. 

Excluded because BNP assay method is not an included one 

Katayama T, Nakashima H, Takagi C, Honda Y, Suzuki S, Yano K et al. Predictors of mortality in patients 

with acute myocardial infarction and cardiogenic shock. Circulation Journal 2005; 69(1):83-88. 

Excluded because BNP assay method is not an included one 

Kato H, Katori T, Nakamura Y, and Kawarasaki H. Moderate-term effect of epoprostenol on severe 

portopulmonary hypertension. Pediatric Cardiology 2003; 24(1):50-53. 

Excluded because BNP assay method is not an included one 

Kato H, Yasue H, Yoshimura M, Tanaka H, Miyao Y, Okumura K et al. Suppression of hyperventilationinduced attacks with infusion of B-type (brain) natriuretic peptide in patients with variant angina. American 

Heart Journal 1994; 128(6 Pt 1):1098-1104. 

Excluded because BNP assay method is not an included one 

Kato M, Kinugawa T, Omodani H, Osaki S, Ogino K, Hisatome I et al. Augmented response in plasma 

atrial natriuretic peptide to dynamic exercise in patients with congestive heart failure. Japanese 

Circulation Journal 1996; 60(12):909-916. 

Excluded because BNP assay method is not an included one 

Katz SD. Nesiritide (hBNP): A new class of therapeutic peptide for the treatment of decompensated 

congestive heart failure. Prevention & Management of Congestive Heart Failure 2001; 7(2):78-87. 

Excluded because not a report of a primary study 
D-37 

Kawakami R, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N et al. Overexpression of brain 

natriuretic peptide facilitates neutrophil infiltration and cardiac matrix metalloproteinase-9 expression after 

acute myocardial infarction. Circulation 1920; 110(21):3306-3312. 

Excluded because adult blood not measured 

Kawamura T, Wago M, Kawaguchi H, Tahara M, Yuge M, Kawamura T et al. Plasma brain natriuretic 

peptide concentrations in patients with Kawasaki disease. Pediatrics International 2000; 42(3):241-248. 

Excluded because adult blood not measured 

Kawamura T, Wago M, Kawamura TaWM. Brain natriuretic peptide can be a useful biochemical marker 

for myocarditis in patients with Kawasaki disease. Cardiology in the Young 2002; 12(2):153-158. 

Excluded because adult blood not measured 

Kawut S, H.I. New answers raise new questions in pulmonary arterial hypertension. European 

Respiratory Journal 2004; 23(6):799-801. 

Excluded because not a report of a primary study 

Kelley WS. Therapeutic peptides: The devil is in the details. Bio-Technology 1996; 14(1):28. 

Excluded because not a report of a primary study 

Kellner M, Yassouridis A, Hua Y, Wendrich M, Jahn H, Wiedemann K et al. Intravenous C-type natriuretic 

peptide augments behavioral and endocrine effects of cholecystokinin tetrapeptide in healthy men. 

Journal of Psychiatric Research 2002; 36(1):1-6. 

Excluded because BNP assay method is not an included one 

Kelly C, Newby D, McDonagh T, Mackay T, Barr J, Boon N et al. Randomised controlled trial of 

continuous positive airway pressure and standard oxygen therapy in acute pulmonary oedema; effects on 

plasma brain natriuretic peptide concentrations.[see comment]. European Heart Journal 2002; 

23(17):1379-1386. 

Excluded because BNP assay method is not an included one 

Kelly P, MacAulay-Hunter E, Astridge P, Lowry P, Perrins E, and Kaye GC. Failure of plasma atrial 

natriuretic peptide levels to increase during exercise in patients with chronic atrial fibrillation. Pacing and 

Clinical Electrophysiology 1997; 20(1 part 1):10-16. 

Excluded because BNP assay method is not an included one 

Kemp M, Donovan J, Higham H, and Hooper J. Biochemical markers of myocardial injury. British Journal 

of Anaesthesia 2004; 93(1):63-73. 

Excluded because not a report of a primary study 

Kerkela R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H, Kerkela RPSM-PTTHaRH. 

Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated 

regulation of B-type natriuretic peptide gene. Journal of Biological Chemistry 2002; 277(16):13752-13760. 

Excluded because adult blood not measured 

Kerzner R, M.W. Management of heart failure in the elderly. Current Cardiology Reports 2003; 5(3):223-

228. 

Excluded because not a report of a primary study 

Kihara T, Biro S, Ikeda Y, Fukudome T, Shinsato T, Masuda A et al. Effects of repeated sauna treatment 

on ventricular arrhythmias in patients with chronic heart failure. Circulation Journal 2004; 68(12):1146-

1151. 

Excluded because BNP assay method is not an included one 
D-38 

Kihara T, Biro S, Imamura M, Yoshifuku S, Takasaki K, Ikeda Y et al. Repeated sauna treatment 

improves vascular endothelial and cardiac function in patients with chronic heart failure. Journal of the 

American College of Cardiology 2002; 39(5):754-759. 

Excluded because BNP assay method is not an included one 

Kinoshita M, Tsutamoto T, Kinoshita M, and Tsutamoto T. Roles of neurohumoral factors in the 

progression of heart failure. Internal Medicine 1996; 35(1):58-59. 

Excluded because not a report of a primary study 

Kinugawa T, Kato M, Ogino K, Osaki S, Igawa O, Hisatome I et al. Effects of Angiotensin II Type 1 

Receptor Antagonist, Losartan, on Ventilatory Response to Exercise and Neurohormonal Profiles in 

Patients with Chronic Heart Failure. Japanese Journal of Physiology 2004; 54(1):15-21. 

Excluded because BNP assay method is not an included one 

Kirchhoff W, Gradaus R, Stypmann J, Deng M, Tian T, Scheld H et al. Vasoactive peptides during longterm follow-up of patients after cardiac transplantation. Journal of Heart & Lung Transplantation 2004; 

23(3):284-288. 

Excluded because BNP assay method is not an included one 

Kirsch J, Muro J, Stansbury D, Fischer C, Monfore R, and Light RW. Effect of naloxone on maximal 

exercise performance and control of ventilation in COPD. Chest 1989; 96(4):761-766. 

Excluded because adult blood not measured 

Kita H, Ohi M, Chin K, Noguchi T, Otsuka N, Tsuboi T et al. The nocturnal secretion of cardiac natriuretic 

peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive 

airway pressure. Journal of Sleep Research 1998; 7(3):199-207. 

Excluded because BNP assay method is not an included one 

Kitzman D, Little W, Brubaker P, Anderson R, Hundley W, Marburger C et al. Pathophysiological 

characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA: Journal of 

the American Medical Association 2002; 288(17):2144-2150. 

Excluded because BNP assay method is not an included one 

Kjaer A, Appel J, Hildebrandt P, Petersen C, Kjaer AAJHPaPCL. Basal and exercise-induced 

neuroendocrine activation in patients with heart failure and in normal subjects. European Journal of Heart 

Failure 2004; 6(1):29-39. 

Excluded because BNP assay method is not an included one 

Klein L, M. Therapeutic strategies for patients hospitalized with worsening heart failure. Italian Heart 

Journal: Official Journal of the Italian Federation of Cardiology 2003; 4(2):71-74. 

Excluded because not a report of a primary study 

Klemola R, Tikkanen I, Vuolteenaho O, Toivonen L, Laine M, Klemola R et al. Plasma and pericardial 

fluid natriuretic peptide levels in postinfarction ventricular dysfunction. European Journal of Heart Failure 

2001; 3(1):21-26. 

Excluded because BNP assay method is not an included one 

Knight E, Fish L, Kiely D, Marcantonio E, Davis K, and Minaker KL. Atrial natriuretic peptide and the 

development of congestive heart failure in the oldest old: a seven-year prospective study. Journal of the 

American Geriatrics Society 1999; 47(4):407-411. 

Excluded because BNP assay method is not an included one 

Knudsen C, Omland T, Clapton P, and Henriksson P. Chest radiographs and BNP levels provided 

complementary information beyond clinical findings for diagnosing heart failure. Evidence Based 
D-39 

Medicine 2004; 9(5):152. 

Excluded because not a report of a primary study 

Kodama-Takahashi K, Kurata A, Ohshima K, Yamamoto K, Uemura S, Watanabe S et al. Effect of 

cilostazol on the ventricular escape rate and neurohumoral factors in patients with third-degree 

atrioventricular block.[see comment]. Chest 2003; 123(4):1161-1169. 

Excluded because BNP assay method is not an included one 

Koerner M, Loebe M, Lisman K, Stetson S, Lafuente J, Noon G et al. New strategies for the management 

of acute decompensated heart failure. Current Opinion in Cardiology 2001; 16(3):164-173. 

Excluded because not a report of a primary study 

Kohno M, Horio T, Toda I, Akioka K, Tahara A, Teragaki M et al. Cosecretion of atrial and brain natriuretic 

peptides during supraventricular tachyarrhythmias. American Heart Journal 1992; 123(5):1382-1384. 

Excluded because BNP assay method is not an included one 

Kohno M, Horio T, Yasunari K, Yokokawa K, Ikeda M, Kurihara N et al. Stimulation of brain natriuretic 

peptide release from the heart by thyroid hormone. Metabolism: Clinical & Experimental 1993; 

42(8):1059-1064. 

Excluded because BNP assay method is not an included one 

Kohno M, Horio T, Yokokawa K, Murakawa K, Yasunari K, Akioka K et al. Brain natriuretic peptide as a 

cardiac hormone in essential hypertension. American Journal of Medicine 1992; 92(1):29-34. 

Excluded because BNP assay method is not an included one 

Kohno M, Horio T, Yokokawa K, Akioka K, Ikeda M, Takeda T et al. Pulmonary arterial brain natriuretic 

peptide concentration and cardiopulmonary hemodynamics during exercise in patients with essential 

hypertension. Metabolism: Clinical & Experimental 1992; 41(12):1273-1275. 

Excluded because BNP assay method is not an included one 

Kohno M, Horio T, Yokokawa K, Murakawa K, Yasunari K, Kurihara N et al. Atrial and brain natriuretic 

peptides: secretion during exercise in patients with essential hypertension and modulation by acute 

angiotensin-converting enzyme inhibition. Clinical & Experimental Pharmacology & Physiology 1992; 

19(3):193-200. 

Excluded because BNP assay method is not an included one 

Kohno M, Horio T, Yokokawa K, Yasunari K, Ikeda M, Minami M et al. Brain natriuretic peptide as a 

marker for hypertensive left ventricular hypertrophy: changes during 1-year antihypertensive therapy with 

angiotensin-converting enzyme inhibitor. American Journal of Medicine 1995; 98(3):257-265. 

Excluded because BNP assay method is not an included one 

Kohno M, Minami M, Kano H, Yasunari K, Maeda K, Hanehira T et al. Effect of angiotensin-converting 

enzyme inhibitor on left ventricular parameters and circulating brain natriuretic peptide in elderly 

hypertensives with left venticular hypertrophy. Metabolism: Clinical & Experimental 2000; 49(10):1356-

1360. 

Excluded because BNP assay method is not an included one 

Kohno M, Yasunari K, Yokokawa K, Horio T, Kano H, Minami M et al. Plasma brain natriuretic peptide 

during ergometric exercise in hypertensive patients with left ventricular hypertrophy. Metabolism: Clinical 

& Experimental 1996; 45(11):1326-1329. 

Excluded because BNP assay method is not an included one 

Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Hanehira T et al. Changes in plasma cardiac 

natriuretic peptides concentrations during 1 year treatment with angiotensin-converting enzyme inhibitor 

in elderly hypertensive patients with left ventricular hypertrophy. International Journal of Clinical 
D-40 

Pharmacology & Therapeutics 1997; 35(1):38-42. 

Excluded because BNP assay method is not an included one 

Kohno M, Yokokawa K, Minami M, Kano H, Yasunari K, Hanehira T et al. Association between 

angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in 

patients treated with angiotensin-converting enzyme inhibitors. American Journal of Medicine 1999; 

106(5):544-549. 

Excluded because BNP assay method is not an included one 

Kohse K, Feifel K, Mayer-Wehrstein R, Kohse K, Feifel K, and Mayer-Wehrstein R. Differential regulation 

of brain and atrial natriuretic peptides in hemodialysis patients. Clinical Nephrology 1993; 40(2):83-90. 

Excluded because BNP assay method is not an included one 

Koller K, Lowe D, Bennett G, Minamino N, Kangawa K, Matsuo H et al. Selective activation of the B 

natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 1991; 252(5002):120-123. 

Excluded because adult blood not measured 

Komarek M, Bernheim A, Schindler R, Steden R, Kiowski W, Brunner-La Rocca H et al. Vascular effects 

of natriuretic peptides in healthy men. Journal of Cardiovascular Pharmacology & Therapeutics 2004; 

9(4):263-270. 

Excluded because BNP assay method is not an included one 

Konishi C, Shiraishi J, Muraguchi N, Ohtsuki K, Inoue M, Tatsumi T et al. Beneficial effect of cibenzoline 

on left ventricular pressure gradient with sigmoid septum. Circulation Journal 2004; 68(10):968-971. 

Excluded because this is a case report or series with 10 subjects 

Konstantinides S. Should thrombolytic therapy be used in patients with pulmonary embolism? American 

Journal of Cardiovascular Drugs 2004; 4(2):69-74. 

Excluded because not a report of a primary study 

Koseki Y, Watanabe J, Shinozaki T, Sakuma M, Komaru T, Fukuchi M et al. Characteristics and 1-year 

prognosis of medically treated patients with chronic heart failure in Japan. Circulation Journal 2003; 

67(5):431-436. 

Excluded because not a report of a primary study 

Koshkina N, Waldrep J, and Knight V. Camptothecins and lung cancer: Improved delivery systems by 

aerosol. Current Cancer Drug Targets 2003; 3(4):251-264. 

Excluded because not a report of a primary study 

Kosmala W, Kucharski W, Przewlocka-Kosmala M, and Mazurek W. Comparison of left ventricular 

function by tissue Doppler imaging in patients with diabetes mellitus without systemic hypertension versus 

diabetes mellitus with systemic hypertension. American Journal of Cardiology 2004; 94(3):395-399. 

Excluded because BNP assay method is not an included one 

Kosmala W, Spring A, Zysko D, Halawa B, and Witkowska M. Effects of exercise on left ventricular 

diastolic dysfunction and neurohormonal activity in patients with essential hypertension. Kardiologia 

Polska 1999; 50(3):217-224. 

Excluded because BNP assay method is not an included one 

Kotajima N, Kimura T, Kanda T, Kuwabara A, Fukumura Y, Murakami M et al. Reciprocal increase of 

circulating interleukin-10 and interleukin-6 in patients with acute myocardial infarction. Heart (British 

Cardiac Society) 2001; 86(6):704. 

Excluded because BNP assay method is not an included one 
D-41 

Kraemer W, Fleck S, Maresh C, Ratamess N, Gordon S, Goetz K et al. Acute hormonal responses to a 

single bout of heavy resistance exercise in trained power lifters and untrained men. Canadian Journal of 

Applied Physiology 1999; 24(6):524-537. 

Excluded because BNP assay method is not an included one 

Krause A, Liepke C, Meyer M, Adermann K, Forssmann W, Maronde E et al. Human natriuretic peptides 

exhibit antimicrobial activity. European Journal of Medical Research 2005; 6(5):215-218. 

Excluded because adult blood not measured 

Kucher N, S.Z. Clinician update. Cardiac biomarkers for risk stratification of patients with acute pulmonary 

embolism. Circulation 2003; 108(18):2191-2194. 

Excluded because adult blood not measured 

Kuhn M, Voss M, Mitko D, Stypmann J, Schmid C, Kawaguchi N et al. Left ventricular assist device 

support reverses altered cardiac expression and function of natriuretic peptides and receptors in endstage heart failure. Cardiovascular Research 2004; 64(2):308-314. 

Excluded because adult blood not measured 

Kumagai J, Yorioka N, Kawanishi H, Moriishi M, Komiya Y, Asakimori Y et al. Relationship between 

erythropoietin and chronic heart failure in patients on chronic hemodialysis. Journal of the American 

Society of Nephrology 1999; 10(11):2407-2411. 

Excluded because BNP assay method is not an included one 

Kuntzen C, Gulberg V, Gerbes A, Kuntzen CGVaGAL. Use of a mixed endothelin receptor antagonist in 

portopulmonary hypertension: a safe and effective therapy? Gastroenterology 2005; 128(1):164-168. 

Excluded because adult blood not measured 

Kurabayashi H, Tamura K, Tamura J, Kubota K, Kurabayashi H, Tamura K et al. The effects of hydraulic 

pressure on atrial natriuretic peptide during rehabilitative head-out water immersion. Life Sciences 1907; 

69(9):1017-1021. 

Excluded because BNP assay method is not an included one 

Kurian D, Wagner I, Klapholz M, Kurian DC, Wagner IJ, and Klapholz M. Nesiritide in pulmonary 

hypertension. Chest 2004; 126(1):302-305. 

Excluded because not a report of a primary study 

Kurosaki H, Tawada T, Kawasoe S, Ohashi Y, Goto M, Kurosaki H et al. A model for ZnII-containing-betalactamase: synthesis, X-ray crystal structure of a zinc(II) complex bearing thiol group and hydrolysis of 

phosphate diester. Bioorganic & Medicinal Chemistry Letters 2000; 10(12):1333-1337. 

Excluded because adult blood not measured 

Kurose M, Yoshimura M, Yasue H, Kurose M, Yoshimura M, and Yasue H. Raised plasma BNP in a 

patient with acute pulmonary thromboembolism. Heart (British Cardiac Society) 1997; 78(3):320-321. 

Excluded because not a report of a primary study 

Kuznar W. Admissions, BNP levels drop with valsartan. Cardiology Review 2002; 19(3). 

Excluded because not a report of a primary study 

Kyriakides Z, Markianos M, Michalis L, Antoniadis A, Nikolaou N, Kremastinos D et al. Brain natriuretic 

peptide increases acutely and much more prominently than atrial natriuretic peptide during coronary 

angioplasty.[see comment]. Clinical Cardiology 2000; 23(4):285-288. 

Excluded because BNP assay method is not an included one 
D-42 

La Villa G, Bisi G, Lazzeri C, Fronzaroli C, Stefani L, Barletta G et al. Cardiovascular effects of brain 

natriuretic peptide in essential hypertension. Hypertension 1995; 25(5):1053-1057. 

Excluded because BNP assay method is not an included one 

La Villa G, Fronzaroli C, Lazzeri C, Porciani C, Bandinelli R, Vena S et al. Cardiovascular and renal 

effects of low dose brain natriuretic peptide infusion in man. Journal of Clinical Endocrinology & 

Metabolism 1994; 78(5):1166-1171. 

Excluded because adult blood not measured 

La Villa G, Mannelli M, Lazzeri C, Vecchiarino S, de Feo M, Tosti GC et al. Different effects of atrial and 

C-type natriuretic peptide on the urinary excretion of endothelin-1 in man. Clinical Science 1998; 

95(5):595-602. 

Excluded because adult blood not measured 

La Villa G, Padeletti L, Lazzeri C, Salvi S, Michelucci A, Fronzaroli C et al. Plasma levels of natriuretic 

peptides during ventricular pacing in patients with a dual chamber pacemaker. Pacing & Clinical 

Electrophysiology 1994; 17(5 Pt 1):953-958. 

Excluded because BNP assay method is not an included one 

La Villa G, Riccardi D, Lazzeri C, Casini RVDSA, Tosti GC, Fronzaroli C et al. Blunted natriuretic 

response to low-dose brain natriuretic peptide infusion in nonazotemic cirrhotic patients with ascites and 

avid sodium retention. Hepatology 1995; 22(6):1745-1750. 

Excluded because BNP assay method is not an included one 

La Villa G, Romanelli R, Casini RVT-GC, de Feo M, Marra F, Laffi G et al. Plasma levels of brain 

natriuretic peptide in patients with cirrhosis. Hepatology 1992; 16(1):156-161. 

Excluded because BNP assay method is not an included one 

La Villa G, Stefani L, Lazzeri C, Zurli C, Guerra C, Barletta G et al. Acute effects of physiological 

increments of brain natriuretic peptide in humans. Hypertension 1995; 26(4):628-633. 

Excluded because BNP assay method is not an included one 

La Villa G, Vena S, Conti A, Fronzaroli C, Brat A, Lazzeri C et al. Plasma levels of brain natriuretic 

peptide in healthy subjects and patients with essential hypertension: response to posture. Clinical 

Science 1993; 85(4):411-416. 

Excluded because BNP assay method is not an included one 

Lader E. Doppler echocardiography was more accurate than B-type natriuretic peptide assay for 

detecting CHF in acute dyspnea. ACP Journal Club 2003; v139(1):22. 

Excluded because not a report of a primary study 

Lainchbury J, A.M. Exercise testing in the assessment of chronic congestive heart failure. Heart (British 

Cardiac Society) 2002; 88(5):538-543. 

Excluded because not a report of a primary study 

Lainchbury J, Nicholls M, Espiner E, Ikram H, Yandle T, Richards A et al. Regional plasma levels of 

cardiac peptides and their response to acute neutral endopeptidase inhibition in man. Clinical Science 

1998; 95(5):547-555. 

Excluded because BNP assay method is not an included one 

Lainchbury J, Nicholls M, Espiner E, Yandle T, Lewis L, Richards A et al. Bioactivity and interactions of 

adrenomedullin and brain natriuretic peptide in patients with heart failure. Hypertension 1999; 34(1):70-

75. 

Excluded because BNP assay method is not an included one 
D-43 

Lainchbury J, Richards A, Nicholls M, Hunt P, Ikram H, Espiner E et al. The effects of pathophysiological 

increments in brain natriuretic peptide in left ventricular systolic dysfunction. Hypertension 1997; 30(3 Pt 

1):398-404. 

Excluded because BNP assay method is not an included one 

Lainchbury J, Richards A, Nicholls M, Espiner E, Yandle T, Lainchbury J et al. Brain natriuretic peptide 

and neutral endopeptidase inhibition in left ventricular impairment. Journal of Clinical Endocrinology & 

Metabolism 1999; 84(2):723-729. 

Excluded because this is a case report or series with 10 subjects 

Lainchbury J, Troughton R, Lewis L, Yandle T, Richards A, and Nicholls MG. Hemodynamic, hormonal, 

and renal effects of short-term adrenomedullin infusion in healthy volunteers. Journal of Clinical 

Endocrinology & Metabolism 2000; 85(3):1016-1020. 

Excluded because this is a case report or series with 10 subjects 

Lan Y, Chang R, Alejos J, Burch C, Wetzel G, Lan YTCRKAJC et al. B-type natriuretic peptide in children 

after cardiac transplantation. Journal of Heart & Lung Transplantation 2004; 23(5):558-563. 

Excluded because adult blood not measured 

Lang C, Choy A, Henderson I, Coutie W, Struthers A, Lang C et al. Effect of haemodialysis on plasma 

levels of brain natriuretic peptide in patients with chronic renal failure. Clinical Science 1992; 82(2):127-

131. 

Excluded because BNP assay method is not an included one 

Lang C, Choy A, Struthers A, Lang C, Choy A, and Struthers AD. Atrial and brain natriuretic peptides: a 

dual natriuretic peptide system potentially involved in circulatory homeostasis. Clinical Science 1992; 

83(5):519-527. 

Excluded because not a report of a primary study 

Lang C, Choy A, Turner K, Tobin R, Coutie W, Struthers A et al. The effect of intravenous saline loading 

on plasma levels of brain natriuretic peptide in man. Journal of Hypertension 1993; 11(7):737-741. 

Excluded because BNP assay method is not an included one 

Lang C, Coutie W, Khong T, Choy A, Struthers A, Lang C et al. Dietary sodium loading increases plasma 

brain natriuretic peptide levels in man. Journal of Hypertension 1991; 9(9):779-782. 

Excluded because BNP assay method is not an included one 

Lang C, Coutie W, Struthers A, Dhillon D, Winter J, Lipworth B et al. Elevated levels of brain natriuretic 

peptide in acute hypoxaemic chronic obstructive pulmonary disease. Clinical Science 1992; 83(5):529-

533. 

Excluded because BNP assay method is not an included one 

Lang C, McAlpine H, Choy A, Pringle T, Coutie W, Struthers A et al. Effect of pericardiocentesis on 

plasma levels of brain natriuretic peptide in cardiac tamponade. American Journal of Cardiology 1919; 

70(20):1628-1629. 

Excluded because BNP assay method is not an included one 

Lang C, Motwani J, Coutie W, Struthers A, Lang C, Motwani J et al. Influence of candoxatril on plasma 

brain natriuretic peptide in heart failure.[erratum appears in Lancet 1991 Aug 10;338(8763):394]. Lancet 

1907; 338(8761):255. 

Excluded because not a report of a primary study 

Lang C, Motwani J, Coutie W, Struthers A, Lang C, Motwani J et al. Clearance of brain natriuretic peptide 

in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against 
D-44 

an atrial natriuretic peptide clearance receptor mechanism. Clinical Science 1992; 82(6):619-623. 

Excluded because adult blood not measured 

Lang C, Motwani J, Rahman A, Coutie W, Struthers A, Lang C et al. Effect of angiotensin-converting 

enzyme inhibition on plasma brain natriuretic peptide levels in patients with heart failure. Clinical Science 

1992; 83(2):143-147. 

Excluded because BNP assay method is not an included one 

Lang C, Prasad N, McAlpine H, MacLeod C, Lipworth B, MacDonald T et al. Increased plasma levels of 

brain natriuretic peptide in patients with isolated diastolic dysfunction. American Heart Journal 1994; 

127(6):1635-1636. 

Excluded because BNP assay method is not an included one 

Langenickel T, Buttgereit J, Pagel I, Dietz R, Willenbrock R, and Bader M. Forced Homodimerization SiteDirected Mutagenesis Alters Guanylyl Cyclase Activity of Natriuretic Peptide Receptor B. Hypertension 

2004; 43(2 II):460-465. 

Excluded because adult blood not measured 

Lapp H, Boerrigter G, Costello-Boerrigter L, Jaekel K, Scheffold T, Krakau I et al. Elevated plasma human 

urotensin-II-like immunoreactivity in ischemic cardiomyopathy. International Journal of Cardiology 2004; 

94(1):93-97. 

Excluded because BNP assay method is not an included one 

Latini R, Masson S, Staszewsky L, and Maggioni AP. Valsartan for the treatment of heart failure. Expert 

Opinion on Pharmacotherapy 2004; 5(1):181-193. 

Excluded because not a report of a primary study 

Lauria M, Standley C, Sorokin Y, Todt J, Bottoms S, Yelian F et al. Brain natriuretic peptide and cyclic 

guanosine-3',5' monophosphate in pre-eclampsia. Journal of Maternal-Fetal Medicine 1996; 5(3):128-131. 

Excluded because BNP assay method is not an included one 

Lauria M, Standley C, Sorokin Y, Yelian F, and Cotton DB. Adrenomedullin levels in normal and 

preeclamptic pregnancy at term. Journal of the Society for Gynecologic Investigation 1999; 6(6):318-321. 

Excluded because BNP assay method is not an included one 

Law Y, Keller B, Feingold B, Boyle G, Law YM, Keller BB et al. Usefulness of plasma B-type natriuretic 

peptide to identify ventricular dysfunction in pediatric and adult patients with congenital heart disease. 

American Journal of Cardiology 2002; 95(4):474-478. 

Excluded because adult blood not measured 

Lazzeri C, Franchi F, Porciani C, Fronzaroli C, Casini RVdFM, Mannelli M et al. Systemic hemodynamics 

and renal function during brain natriuretic peptide infusion in patients with essential hypertension. 

American Journal of Hypertension 1995; 8(8):799-807. 

Excluded because BNP assay method is not an included one 

Lazzeri C, La Villa G, Bisi G, Boddi V, Messeri G, Strazzulla G et al. Cardiovascular function during brain 

natriuretic peptide infusion in man. Cardiology 1995; 86(5):396-401. 

Excluded because BNP assay method is not an included one 

Le B, Addo T, and de Lemos JA. The endocrine heart: B-type natriuretic peptide as a diagnostic and 

therapeutic agent in cardiovascular disease. Endocrinologist 2003; 13(2):97-105. 

Excluded because not a report of a primary study 

Lebech A, Gerstoft J, Hesse B, Petersen C, Kjaer A, Lebech AMGJHBPCLaKA. Right and left ventricular 

cardiac function in a developed world population with human immunodeficiency virus studied with 
D-45 

radionuclide ventriculography.[see comment]. American Heart Journal 2004; 147(3):482-488. 

Excluded because BNP assay method is not an included one 

Lee Y, Lin S, Shin S, Lai Y, Lin Y, Tsai J et al. Brain natriuretic peptide is synthesized in the human 

adrenal medulla and its messenger ribonucleic acid expression along with that of atrial natriuretic peptide 

are enhanced in patients with primary aldosteronism. Journal of Clinical Endocrinology & Metabolism 

1994; 79(5):1476-1482. 

Excluded because adult blood not measured 

Lenz T, Foral P, Malesker M, Hunter C, Hilleman D, Lenz TL et al. Impact of nesiritide on health care 

resource utilization and complications in patients with decompensated heart failure. Pharmacotherapy 

2004; 24(9):1137-1146. 

Excluded because adult blood not measured 

Leuchte H, Baumgartner R, and Behr J. Treatment of Severe Pulmonary Hypertension with Inhaled 

Iloprost [5]. Annals of Internal Medicine 2003; 139(4):306. 

Excluded because not a report of a primary study 

Levy T, Jenkins G, Walker S, Grieve L, Webb C, Buckley M et al. Does the mechanism of action of biatrial 

pacing for atrial fibrillation involve changes in cardiac haemodynamics? Assessment by Doppler 

echocardiography and natriuretic peptide measurements. Europace 2000; 2(2):127-135. 

Excluded because BNP assay method is not an included one 

Lewis D, Gurram N, Abraham W, Akers W, Lewis DA, Gurram NR et al. Effect of nesiritide versus 

milrinone in the treatment of acute decompensated heart failure. American Journal of Health-System 

Pharmacy 1908; 60 Suppl 4:S16-S20. 

Excluded because BNP used as treatment 

Liang F, Kovacic-Milivojevic B, Chen S, Cui J, Roediger F, Intengan H et al. Signaling mechanisms 

underlying strain-dependent brain natriuretic peptide gene transcription. Canadian Journal of Physiology 

& Pharmacology 2001; 79(8):640-645. 

Excluded because adult blood not measured 

Liang F, Webb P, Marimuthu A, Zhang S, Gardner D, Liang FWPMAZSaGDG. Triiodothyronine increases 

brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene 

transcription and hypertrophy in neonatal rat ventricular myocytes. Journal of Biological Chemistry 2004; 

278(17):15073-15083. 

Excluded because adult blood not measured 

Lim P, Donnan P, Struthers A, MacDonald T, Lim PO, Donnan PT et al. Exercise capacity and brain 

natruiretic peptide in hypertension. Journal of Cardiovascular Pharmacology 2002; 40(4):519-527. 

Excluded because BNP assay method is not an included one 

Lim P, Morris-Thurgood J, and Frenneaux MP. Vascular mechanisms of sudden death in hypertrophic 

cardiomyopathy, including blood pressure responses to exercise. Cardiology in Review 2002; 10(1):15-

23. 

Excluded because not a report of a primary study 

Lindaman C. S.I.A.D.H.: is your patient at risk? Nursing 1992; 22(6):60-63. 

Excluded because not a report of a primary study 

Lindstedt G. Multifactorial regulation of plasma natriuretic peptides calls for supplementary 

measurements. Scandinavian Cardiovascular Journal 2001; 35(6):355-358. 

Excluded because not a report of a primary study 
D-46 

Lipshultz S, Fisher S, Lai W, and Miller TL. Cardiovascular monitoring and therapy for HIV-infected 

patients. Annals of the New York Academy of Sciences 2001; 946(pp 236-273):236-273. 

Excluded because not a report of a primary study 

Lipshultz S, Fisher S, Lai W, and Miller TL. Cardiovascular risk factors, monitoring, and therapy for HIVinfected patients. AIDS 2003; 17(SUPPL. 1):S96-S122. 

Excluded because not a report of a primary study 

Lok B, Mukerjee D, Timms P, Ashrafian H, and Coghlan JG. Natriuretic peptides, respiratory disease, and 

the right heart. Chest 2004; 126(4):1330-1336. 

Excluded because not a report of a primary study 

Loke I, Squire I, Davies J, Ng L, Loke ISIB, Davies JE et al. Reference ranges for natriuretic peptides for 

diagnostic use are dependent on age, gender and heart rate. European Journal of Heart Failure 2003; 

5(5):599-606. 

Excluded because BNP assay method is not an included one 

Lombardi F. Sympathetic activation and sub-clinical inflammation: A new combination to identify high risk 

subjects. European Heart Journal 2004; 25(5):359-360. 

Excluded because not a report of a primary study 

Loureiro Soares LG. Brain natriuretic peptide: A marker for dyspnea? [3]. Journal of Pain & Symptom 

Management 2002; 24(5):457-458. 

Excluded because not a report of a primary study 

Luckey A, Parsa C, and Harken AH. Reversible Cardiac Sympathectomy by High Thoracic Epidural 

Anesthesia Improves Regional Left Ventricular Function in Patients Undergoing Coronary Artery Bypass 

Grafting, A Randomized Trial: Invited critique. Archives of Surgery 2003; 138(12):1291. 

Excluded because not a report of a primary study 

Luft FC. Escalator-driven. Journal of Molecular Medicine 2004; 82(5):275-277. 

Excluded because not a report of a primary study 

Luscher T, Ruschitzka F, Anand I, Konstam M, McMurray J, Notter T et al. EARTH: EndothelinA receptor 

antagonist trial in heart failure. Heartdrug 2001; 1(6):294-298. 

Excluded because not a report of a primary study 

Macdonald J, Kennedy N, Struthers A, Macdonald J, Kennedy N, and Struthers AD. Effects of 

spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other 

prognostic markers in patients with mild heart failure already taking optimal treatment. Heart (British 

Cardiac Society) 2004; 90(7):765-770. 

Excluded because BNP assay method is not an included one 

Maeder M, Ammann P, Rickli H, Diethelm M, Maeder MAPRHaDM. Elevation of B-type natriuretic peptide 

levels in acute respiratory distress syndrome. Swiss Medical Weekly 1909; 133(37-38):515-518. 

Excluded because this is a case report or series with 10 subjects 

Magga J, Puhakka M, Hietakorpi S, Punnonen K, Uusimaa P, Risteli J et al. Atrial natriuretic peptide, Btype natriuretic peptide, and serum collagen markers after acute myocardial infarction. Journal of Applied 

Physiology 2004; 96(4):1306-1311. 

Excluded because BNP assay method is not an included one 

Maggioni A, R. RAAS inhibitors in the cardiovascular continuum: What is still missing. Cardiovascular 

Drugs & Therapy 2004; 18(4):311-320. 

Excluded because not a report of a primary study 
D-47 

Mair P, Mair J, Bleier J, Hormann C, Balogh D, Puschendorf B et al. Augmented release of brain 

natriuretic peptide during reperfusion of the human heart after cardioplegic cardiac arrest. Clinica Chimica 

Acta 1997; 261(1):57-68. 

Excluded because BNP assay method is not an included one 

Maisel A. B-type natriuretic peptide levels: Diagnostic and prognostic in congestive heart failure: What's 

next? Circulation 2002; 105(20):2328-2331. 

Excluded because not a report of a primary study 

Maisel A, A.S. B-type natriuretic peptide (BNP) levels: diagnostic and therapeutic potential. [Review] [10 

refs]. Reviews in Cardiovascular Medicine 2001; 2 Suppl 2:S13-S18. 

Excluded because not a report of a primary study 

Maisel A, E.C. Measuring BNP levels in the diagnosis and treatment of CHF. Journal of Critical Illness 

2002; 17(11):434-442. 

Excluded because not a report of a primary study 

Maisel A, Krishnaswamy P, Nowak R, and Lader E. B type natriuretic peptide levels had high sensitivity 

but moderate specificity for detecting CHF in the emergency department. Evidence Based Medicine 2003; 

8(1):28. 

Excluded because not a report of a primary study 

Maki N, Yoshiyama M, Omura T, Yoshimura T, Kawarabayashi T, Sakamoto K et al. Effect of diltiazem on 

cardiac function assessed by echocardiography and neurohumoral factors after reperfused myocardial 

infarction without congestive heart failure. Cardiovascular Drugs & Therapy 2001; 15(6):493-499. 

Excluded because BNP assay method is not an included one 

Mallamaci F, Zoccali C, Tripepi G, Benedetto F, Parlongo S, Cataliotti A et al. Diagnostic potential of 

cardiac natriuretic peptides in dialysis patients. Kidney International 2001; 59(4):1559-1566. 

Excluded because BNP assay method is not an included one 

Mallat Z, Heymes C, Corbaz A, Logeart D, Alouani S, Cohen-Solal A et al. Evidence for altered interleukin 

18 (IL)-18 pathway in human heart failure. FASEB Journal 2004; 18(14):1752-1754. 

Excluded because not a report of a primary study 

Marantz P, Kuwabara Y, Derby C, Tobin J, and Cohen MV. Plasma atrial natriuretic peptide factor is 

elevated in elderly patients with occult valvular insufficiency. Cardiology in the Elderly 1993; 1(3):195-201. 

Excluded because BNP assay method is not an included one 

Marcus L, Hart D, Packer M, Yushak M, Medina N, Danziger R et al. Hemodynamic and renal excretory 

effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, 

placebo-controlled, randomized crossover trial. Circulation 1919; 94(12):3184-3189. 

Excluded because BNP assay method is not an included one 

Margulies K, J.C. Neutral endopeptidase 24.11: A modulator of natriuretic peptides. Seminars in 

Nephrology 1993; 13(1):71-77. 

Excluded because not a report of a primary study 

Margulies K, Jaffer S, Pollack P, Ennis K, Margulies K, Jaffer S et al. Physiological significance of early 

deceleration time prolongation in asymptomatic elderly subjects. Journal of Cardiac Failure 1999; 5(2):92-

99. 

Excluded because BNP assay method is not an included one 

Marian A, V. Biomarkers of cardiac disease. Expert Review of Molecular Diagnostics 2004; 4(6):805-820. 

Excluded because not a report of a primary study 
D-48 

Marschall KE. Natriuretic peptides in the diagnosis and treatment of heart failure: An overview. Seminars 

in Anesthesia, Perioperative Medicine & Pain 2004; 23(4):302-311. 

Excluded because not a report of a primary study 

Martin J, H. Eplerenone GD Searle & Co. Current Opinion in Investigational Drugs 2001; 2(4):521-524. 

Excluded because not a report of a primary study 

Marumoto K, Hamada M, Aburaya M, Hiwada K, Marumoto K, Hamada M et al. Augmented secretion of 

atrial and brain natriuretic peptides during dynamic exercise in patients with old myocardial infarction. 

Japanese Circulation Journal 1995; 59(11):715-724. 

Excluded because BNP assay method is not an included one 

Marumoto K, Hamada M, Hiwada K, Marumoto K, Hamada M, and Hiwada K. Increased secretion of atrial 

and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients 

with angina pectoris. Clinical Science 1995; 88(5):551-556. 

Excluded because BNP assay method is not an included one 

Marwick TH. Techniques for comprehensive two dimensional echocardiographic assessment of left 

ventricular systolic function. Heart (British Cardiac Society) 2003; 89(SUPPL. 3):iii2-iii8. 

Excluded because not a report of a primary study 

Masters R, Davies R, Veinot J, Hendry P, Smith S, de Bold A et al. Discoordinate modulation of natriuretic 

peptides during acute cardiac allograft rejection in humans. Circulation 1907; 100(3):287-291. 

Excluded because BNP assay method is not an included one 

Matsumoto A, Hirata Y, Kakoki M, Nagata D, Momomura S, Sugimoto T et al. Increased excretion of nitric 

oxide in exhaled air of patients with chronic renal failure. Clinical Science 1999; 96(1):67-74. 

Excluded because BNP assay method is not an included one 

Matsuo S, Nakae I, Takada M, Murata K, and Nakamura Y. Noninvasive identification of myocardial 

sympathetic and metabolic abnormalities in a patient with restrictive cardiomyopathy - In comparison with 

perfusion imaging. Annals of Nuclear Medicine 2002; 16(8):569-572. 

Excluded because this is a case report or series with 10 subjects 

McBride B, C.M. Levosimendan: Implications for clinicians. Journal of Clinical Pharmacology 2003; 

43(10):1071-1081. 

Excluded because not a report of a primary study 

McClean D, Ikram H, Garlick A, Richards A, Nicholls M, Crozier I et al. The clinical, cardiac, renal, arterial 

and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure. 

Journal of the American College of Cardiology 2000; 36(2):479-486. 

Excluded because BNP assay method is not an included one 

McClure S, Caruana L, Davie A, Goldthorp S, and McMurray JJV. Cohort study of plasma natriuretic 

peptides for identifying left ventricular systolic dysfunction in primary care. British Medical Journal 1998; 

317(7157):516-519. 

Excluded because BNP assay method is not an included one 

McClure S, J.J.V. Natriuretic peptides for assessment of left ventricular systolic dysfunction in primary 

care. Cardiovascular Reviews & Reports 2000; 21(4):193-199. 

Excluded because not a report of a primary study 

McCord JK. The future of cardiac markers in the emergency department. Critical Pathways in Cardiology: 

A Journal of Evidence-Based Medicine 2004; 3(3):107-109. 

Excluded because not a report of a primary study 
D-49 

McCullough PA. B-type natriuretic peptides: A diagnostic breakthrough in heart failure. Minerva 

Cardioangiologica 2003; 51(2):121-129. 

Excluded because not a report of a primary study 

McCullough PA. Clinical applications of B-type natriuretic peptide levels in the care of cardiovascular 

patients. Minerva Cardioangiologica 2004; 52(6):479-489. 

Excluded because not a report of a primary study 

McDonagh TA. Use of natriuretic peptides to identify heart failure. Hospital Practice (Office Edition) 1998; 

33(4):26. 

Excluded because not a report of a primary study 

McDonagh T, Cunningham A, Morrison C, McMurray J, Ford I, Morton J et al. Left ventricular dysfunction, 

natriuretic peptides, and mortality in an urban population. Heart (British Cardiac Society) 2001; 86(1):21-

26. 

Excluded because BNP assay method is not an included one 

McDonagh T, Holmer S, Raymond I, Luchner A, Hildebrant P, Dargie H et al. NT-proBNP and the 

diagnosis of heart failure: a pooled analysis of three European epidemiological studies. European Journal 

of Heart Failure 2003; 6(3):269-273. 

Excluded because not a report of a primary study 

McDonagh T, Robb S, Murdoch D, Morton J, Ford I, Morrison C et al. Biochemical detection of leftventricular systolic dysfunction.[see comment]. Lancet 1998; 351(9095):9-13. 

Excluded because BNP assay method is not an included one 

McDougall J, N.A. Natriuresis and inhibition of Na+/K+-ATPase: Modulation of response by physiological 

manipulation. Clinical & Experimental Pharmacology & Physiology 1998; 25(SUPPL.):S57-S60. 

Excluded because adult blood not measured 

McDowell G, Coutie W, Shaw C, Buchanan K, Struthers A, Nicholls D et al. The effect of the neutral 

endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive 

peptides. British Journal of Clinical Pharmacology 1997; 43(3):329-332. 

Excluded because adult blood not measured 

McGeoch G, Lainchbury J, Town G, Toop L, Espiner E, Richards A et al. Plasma brain natriuretic peptide 

after long-term treatment for heart failure in general practice. European Journal of Heart Failure 2002; 

4(4):479-483. 

Excluded because BNP assay method is not an included one 

McGregor A, Richards M, Espiner E, Yandle T, Ikram H, McGregor A et al. Brain natriuretic peptide 

administered to man: actions and metabolism. Journal of Clinical Endocrinology & Metabolism 1990; 

70(4):1103-1107. 

Excluded because BNP assay method is not an included one 

McGregor D, Buttimore A, Lynn K, Yandle T, Nicholls M, McGregor DO et al. Effects of long and short 

hemodialysis on endothelial function: a short-term study. Kidney International 2003; 63(2):709-715. 

Excluded because this is a case report or series with 10 subjects 

McKelvie RS. The therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure. 

Expert Opinion on Investigational Drugs 2004; 13(3):245-253. 

Excluded because not a report of a primary study 

McKelvie R, Yusuf S, and Pericak D. Comparison of candesartan, enalapril, and their combination in 

congestive heart failure: Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) 
D-50 

pilot study. Prevention & Management of Congestive Heart Failure 1999; 5(6):286-287. 

Excluded because adult blood not measured 

McKelvie R, Yusuf S, Pericak D, Avezum A, Burns R, Probstfield J et al. Comparison of candesartan, 

enalapril, and their combination in congestive heart failure: Randomized evaluation of strategies for left 

ventricular dysfunction (RESOLVD) pilot study: The RESOLVD pilot study investigators. Circulation 1999; 

100(10):1056-1064. 

Excluded because BNP assay method is not an included one 

McKenna K, Smith D, Tormey W, Thompson C, McKenna K, Smith D et al. Acute hyperglycaemia causes 

elevation in plasma atrial natriuretic peptide concentrations in Type 1 diabetes mellitus. Diabetic Medicine 

2000; 17(7):512-517. 

Excluded because this is a case report or series with 10 subjects 

McKenna K, Smith D, Moore K, Glen A, Tormey W, Thompson C et al. Brain natriuretic peptide increases 

urinary albumin and alpha-1 microglobulin excretion in Type 1 diabetes mellitus. Diabetic Medicine 2001; 

18(12):973-978. 

Excluded because this is a case report or series with 10 subjects 

McLean A, Huang S, and Ting I. B-type natriuretic peptide: Is there a place in the critical care setting? 

Critical Care & Shock 2004; 7(3):117-124. 

Excluded because not a report of a primary study 

McMahon EG. Eplerenone, a new selective aldosterone blocker. Current Pharmaceutical Design 2003; 

9(13):1065-1075. 

Excluded because not a report of a primary study 

Mead M. GP use of beta blockers in heart failure. British Journal of Cardiology 2002; 9(8). 

Excluded because not a report of a primary study 

Medeiros MS, Balmforth A, Vaughan P, Kenny A, Turner A, Medeiros M et al. Hydrolysis of natriuretic 

peptides by the human astrocytoma clone D384. Biochemical Society Transactions 1990; 18(5):888-889. 

Excluded because adult blood not measured 

Medeiros MS, Balmforth A, Vaughan P, Turner A, Medeiros M, Balmforth A et al. Hydrolysis of atrial and 

brain natriuretic peptides by the human astrocytoma clone D384 and the neuroblastoma line SH-SY5Y. 

Neuroendocrinology 1991; 54(3):295-302. 

Excluded because adult blood not measured 

Mehrotra S, Ather S, and Chandra M. Brain natriuretic peptide - A cardiologist's blood count. Journal of 

Internal Medicine of India 2004; 7(1):167-171. 

Excluded because not a report of a primary study 

Melzi dG, Tagnochetti T, Nauti A, Klersy C, Papalia A, Vadacca G et al. Biological variation of N-terminal 

pro-brain natriuretic peptide in healthy individuals [3]. Clinical Chemistry 2003; 49(9):1554-1555. 

Excluded because not a report of a primary study 

Meng F, Yoshikawa T, Baba A, Moritani K, Suzuki M, Satoh T et al. beta-Blockers Are Effective in 

Congestive Heart Failure Patients With Atrial Fibrillation. Journal of Cardiac Failure 2003; 9(5):398-403. 

Excluded because BNP assay method is not an included one 

Meschia JF. Not so accidental outcomes following cerebrovascular accidents. Current Neurology & 

Neuroscience Reports 2004; 4(5):341-342. 

Excluded because not a report of a primary study 
D-51 

Messaoudi L, Donckier J, Stoffel M, Ketelslegers J, Kolanowski J, Messaoudi L et al. Changes in blood 

pressure and in vasoactive and volume regulatory hormones during semistarvation in obese subjects. 

Metabolism: Clinical & Experimental 1998; 47(5):592-597. 

Excluded because BNP assay method is not an included one 

Meyer G, Roy P, Sors H, and Sanchez O. Laboratory tests in the diagnosis of pulmonary embolism. 

Respiration 2003; 70(2):125-132. 

Excluded because not a report of a primary study 

Michaels A, Klein A, Madden J, Chatterjee K, Michaels AD, Klein AMJA et al. Effects of intravenous 

nesiritide on human coronary vasomotor regulation and myocardial oxygen uptake. Circulation 2003; 

107(21):2697-2701. 

Excluded because this is a case report or series with 10 subjects 

Miliotis T, Marko-Varga G, Nilsson J, and Laurell T. An automated and integrated protein workstation 

interfacing capillary HPLC with MALDI-TOF mass spectrometry using piezoelectric microdispensing. 

JALA: Journal of the Association for Laboratory Automation 2000; 5(6):93-95. 

Excluded because not a report of a primary study 

Militello MA. Role of nesiritide in decompensated heart failure. Journal of Pharmacy Practice 2002; 

15(4):326-333. 

Excluded because not a report of a primary study 

Miller W, J.C. Circulating paracrine and autocrine mechanisms in heart failure. Current Opinion in 

Cardiology 1993; 8(3):376-382. 

Excluded because not a report of a primary study 

Mills R, LeJemtel T, Horton D, Liang C, Lang R, Silver M et al. Sustained hemodynamic effects of an 

infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, 

placebo-controlled clinical trial. Natrecor Study Group. Journal of the American College of Cardiology 

1999; 34(1):155-162. 

Excluded because BNP assay method is not an included one 

Milner S, M.R. Reduced antimicrobial peptide expression in human burn wounds. Burns 1999; 25(5):411-

413. 

Excluded because adult blood not measured 

Milo O, Cotter G, Kaluski E, Brill A, Blatt A, Krakover R et al. Comparison of inflammatory and 

neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic 

causes. American Journal of Cardiology 1907; 92(2):222-226. 

Excluded because BNP assay method is not an included one 

Milting H, EL Banayosy A, Kassner A, Fey O, Sarnowski P, Arusoglu L et al. The time course of 

natriuretic hormones as plasma markers of myocardial recovery in heart transplant candidates during 

ventricular assist device support reveals differences among device types. Journal of Heart & Lung 

Transplantation 2001; 20(9):949-955. 

Excluded because BNP assay method is not an included one 

Minamino N, Makino Y, Tateyama H, Kangawa K, Matsuo H, Minamino N et al. Characterization of 

immunoreactive human C-type natriuretic peptide in brain and heart. Biochemical & Biophysical Research 

Communications 1908; 179(1):535-542. 

Excluded because adult blood not measured 

Missouris C, Grouzmann E, Buckley M, Barron J, MacGregor G, Singer D et al. How does treatment 

influence endocrine mechanisms in acute severe heart failure? Effects on cardiac natriuretic peptides, the 
D-52 

renin system, neuropeptide Y and catecholamines. Clinical Science 1998; 94(6):591-599. 

Excluded because BNP assay method is not an included one 

Missouris C, Varma C, Ward D, MacGregor G, Missouris C, Varma C et al. Cardiac peptides and plasma 

renin activity in acute dilated cardiomyopathy. European Journal of Heart Failure 2001; 3(1):109-111. 

Excluded because not a report of a primary study 

Mistry S, Hawksworth G, Struthers A, McLay J, Mistry S, Hawksworth G et al. Differential expression and 

synthesis of natriuretic peptides determines natriuretic peptide receptor expression in primary cultures of 

human proximal tubular cells. Journal of Hypertension 2001; 19(2):255-262. 

Excluded because adult blood not measured 

Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Itoh M, Amaha K et al. Increased plasma concentrations of 

brain natriuretic peptide in patients with acute lung injury. Journal of Critical Care 1997; 12(2):66-71. 

Excluded because BNP assay method is not an included one 

Mitaka C, Hirata Y, Nagura T, Tsunoda Y, and Amaha K. Beneficial effect of atrial natriuretic peptide on 

pulmonary gas exchange in patients with acute lung injury. Chest 1998; 114(1):223-228. 

Excluded because BNP assay method is not an included one 

Mitka M, Mike. Peptides prove predictive for heart failure patients. JAMA: Journal of the American Medical 

Association 2004; 287(15):1926. 

Excluded because not a report of a primary study 

Miyagawa S, Sawa Y, Fukushima N, Nishimura M, Matsumiya G, Taketani S et al. Analysis of 

sympathetic nerve activity in end-stage cardiomyopathy patients receiving left ventricular support. Journal 

of Heart & Lung Transplantation 2001; 20(11):1181-1187. 

Excluded because this is a case report or series with 10 subjects 

Miyamoto S, Tambara K, Tamaki S, Nagaya N, Hasegawa K, Nohara R et al. Effects of right lateral 

decubitus position on plasma norepinephrine and plasma atrial natriuretic peptide levels in patients with 

chronic congestive heart failure. American Journal of Cardiology 2002; 89(2):240-242. 

Excluded because BNP assay method is not an included one 

Mizuno T, Katafuchi T, Hagiwara H, Ito T, Kangawa K, Matsuo H et al. Human adrenal tumor cell line SW13 contains a natriuretic peptide receptor system that responds preferentially to ANP among various 

natriuretic peptides. Biochemical & Biophysical Research Communications 1919; 173(3):886-893. 

Excluded because adult blood not measured 

Moazami N, Damiano R, Bailey M, Hess R, Lawton J, Moon M et al. Nesiritide (BNP) in the management 

of postoperative cardiac patients. Annals of Thoracic Surgery 2003; 75(6):1974-1976. 

Excluded because adult blood not measured 

Moazemi K, Chana J, Willard A, and Kocheril AG. Intravenous vasodilator therapy in congestive heart 

failure. Drugs & Aging 2003; 20(7):485-508. 

Excluded because not a report of a primary study 

Modesti P, Cecioni I, Costoli A, Poggesi L, Galanti G, Serneri G et al. Renal endothelin in heart failure 

and its relation to sodium excretion. American Heart Journal 2000; 140(4):617-622. 

Excluded because BNP assay method is not an included one 

Mohapatra S, Lockey R, Vesely D, and Gower Jr WR. Natriuretic peptides and genesis of asthma: An 

emerging paradigm? Journal of Allergy & Clinical Immunology 2004; 114(3):520-526. 

Excluded because not a report of a primary study 
D-53 

Mohideen M, M.R. Brain natriuretic peptide is more than a marker. Ceylon Medical Journal 2002; 

47(3):81-82. 

Excluded because not a report of a primary study 

Molkentin JD. A friend within the heart: Natriuretic peptide receptor signaling. Journal of Clinical 

Investigation 2003; 111(9):1275-1277. 

Excluded because not a report of a primary study 

Moller D, Lind P, Strunge B, and Pedersen EB. Abnormal vasoactive hormones and 24-hour blood 

pressure in obstructive sleep apnea. American Journal of Hypertension 2003; 16(4):274-280. 

Excluded because BNP assay method is not an included one 

Montgomery H, Clarkson P, Dollery C, Prasad K, Losi M, Hemingway H et al. Association of angiotensinconverting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical 

training. Circulation 1997; 96(3):741-747. 

Excluded because BNP assay method is not an included one 

Mori K, Manabe T, Nii M, Hayabuchi Y, Kuroda Y, Tatara K et al. Plasma levels of natriuretic peptide and 

echocardiographic parameters in patients with Duchenne's progressive muscular dystrophy. Pediatric 

Cardiology 2002; 23(2):160-166. 

Excluded because adult blood not measured 

Mori M, Kinugawa T, Endo A, Kato M, Kato T, Osaki S et al. Effects of hypoxic exercise conditioning on 

work capacity, lactate, hypoxanthine and hormonal factors in men. Clinical & Experimental Pharmacology 

& Physiology 1999; 26(4):309-314. 

Excluded because this is a case report or series with 10 subjects 

Morimoto T, Hayashino Y, Shimbo T, Izumi T, Fukui T, Morimoto THYSTITaFT. Is B-type natriuretic 

peptide-guided heart failure management cost-effective? International Journal of Cardiology 2004; 

96(2):177-181. 

Excluded because adult blood not measured 

Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M, Matsumura T et al. Increased plasma levels of 

brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1993; 88(1):82-91. 

Excluded because BNP assay method is not an included one 

Morita T, Tei Y, Inoue S, Suga A, Chihara S, Morita TTYISSAaCS. Fluid status of terminally ill cancer 

patients with intestinal obstruction: an exploratory observational study. Supportive Care in Cancer 2002; 

10(6):474-479. 

Excluded because this is a case report or series with 10 subjects 

Moser DK. Pathophysiology of heart failure update: the role of neurohumoral activation in the progression 

of heart failure. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 1998; 9(2):157-171. 

Excluded because not a report of a primary study 

Motwani J, McAlpine H, Kennedy N, Struthers A, Motwani J, McAlpine H et al. Plasma brain natriuretic 

peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction.[see 

comment]. Lancet 1993; 341(8853):1109-1113. 

Excluded because BNP assay method is not an included one 

Mudambo K, Coutie W, Rennie M, Mudambo K, Coutie W, and Rennie MJ. Plasma arginine vasopressin, 

atrial natriuretic peptide and brain natriuretic peptide responses to long-term field training in the heat: 

effects of fluid ingestion and acclimatization. European Journal of Applied Physiology & Occupational 

Physiology 1997; 75(3):219-225. 

Excluded because BNP assay method is not an included one 
D-54 

Muders F, Kromer E, Griese D, Pfeifer M, Hense H, Riegger G et al. Evaluation of plasma natriuretic 

peptides as markers for left ventricular dysfunction. American Heart Journal 1997; 134(3):442-449. 

Excluded because BNP assay method is not an included one 

Mueller C, Scholer A, and Laule-Kilian K. BNP testing improves outcomes in evaluation of dyspnea. 

Journal of Family Practice 2004; 53(5):354. 

Excluded because not a report of a primary study 

Mueller T, Gegenhuber A, Poelz W, Haltmayer M, Mueller TGAPWaHM. Preliminary evaluation of the 

AxSYM B-type natriuretic peptide (BNP) assay and comparison with the ADVIA Centaur BNP assay. 

Clinical Chemistry 2004; 50(6):1104-1106. 

Excluded because not a report of a primary study 

Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S et al. Increased human brain natriuretic 

peptide in congestive heart failure. New England Journal of Medicine 1909; 323(11):757-758. 

Excluded because not a report of a primary study 

Mukoyama M, Nakao K, Obata K, Jougasaki M, Yoshimura M, Morita E et al. Augmented secretion of 

brain natriuretic peptide in acute myocardial infarction. Biochemical & Biophysical Research 

Communications 1919; 180(1):431-436. 

Excluded because BNP assay method is not an included one 

Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y et al. Brain natriuretic peptide as a novel 

cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic 

peptide and brain natriuretic peptide. Journal of Clinical Investigation 1991; 87(4):1402-1412. 

Excluded because BNP assay method is not an included one 

Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S et al. Human brain natriuretic peptide, a 

novel cardiac hormone. Lancet 2003; 335(8692):801-802. 

Excluded because not a report of a primary study 

Murchie P, Mendez G, Campbell N, Patterson Y, Reid J, and Cowie MR. Left ventricular dysfunction in 

the diabetic population. British Journal of General Practice 2002; 52(475):153-154. 

Excluded because not a report of a primary study 

Murdoch D, Byrne J, Farmer R, Morton J, Murdoch D, Byrne J et al. Disparity between studies of the 

stability of BNP in blood: comparison of endogenous and exogenous peptide. Heart (British Cardiac 

Society) 1999; 81(2):212-213. 

Excluded because BNP assay method is not an included one 

Murray M, Young J, Morrow D, Weiner M, Tu W, Hoke S et al. Methodology of an ongoing, randomized, 

controlled trial to improve drug use for elderly patients with chronic heart failure. American Journal 

Geriatric Pharmacotherapy 2004; 2(1):53-65. 

Excluded because BNP assay method is not an included one 

Mussalo H, Vanninen E, Ikaheimo R, Hartikainen J, Mussalo HVEIRaHJ. NT-proANP and BNP in 

renovascular and in severe and mild essential hypertension. Kidney & Blood Pressure Research 2003; 

26(1):34-41. 

Excluded because BNP assay method is not an included one 

Muta H, Ishii M, Maeno Y, Akagi T, Kato H, Muta H et al. Quantitative evaluation of the changes in 

plasma concentrations of cardiac natriuretic peptide before and after transcatheter closure of atrial septal 

defect. Acta Paediatrica 2002; 91(6):649-652. 

Excluded because adult blood not measured 
D-55 

Nagaya N. Drug therapy of primary pulmonary hypertension. American Journal of Cardiovascular Drugs 

2004; 4(2):75-85. 

Excluded because not a report of a primary study 

Nakagawa K, Yamaguchi T, Seida M, Tanaka Y, Yoshino M, Nakagawa KYTSMTYaYM. Plasma 

concentrations of atrial and brain natriuretic peptides in a case with hypertensive encephalopathy. 

Neurological Research 2002; 24(6):627-630. 

Excluded because this is a case report or series with 10 subjects 

Nakamura M, Kawata Y, Yoshida H, Arakawa N, Koeda T, Ichikawa T et al. Relationship between plasma 

atrial and brain natriuretic peptide concentration and hemodynamic parameters during percutaneous 

transvenous mitral valvulotomy in patients with mitral stenosis. American Heart Journal 1992; 

124(5):1283-1288. 

Excluded because BNP assay method is not an included one 

Nakamura S, Isaji M, and Ishimori M. Plasma adrenomedullin concentration in patients with Graves' 

disease. Internal Medicine 2004; 43(7):628-629. 

Excluded because BNP assay method is not an included one 

Nakamura S, Ishimori M, Nakamura S, and Ishimori M. Plasma brain natriuretic peptide concentration in 

patients with Graves' disease. Endocrine Journal 2001; 48(3):403-404. 

Excluded because not a report of a primary study 

Nakamura S, Naruse M, Naruse K, Kawana M, Nishikawa T, Hosoda S et al. Atrial natriuretic peptide and 

brain natriuretic peptide coexist in the secretory granules of human cardiac myocytes. American Journal 

of Hypertension 1991; 4(11):909-912. 

Excluded because adult blood not measured 

Nakamura S, Yoshimura M, Nakayama M, Ito T, Mizuno Y, Harada E et al. Possible association of heart 

failure status with synthetic balance between aldosterone and dehydroepiandrosterone in human heart. 

Circulation 1909; 110(13):1787-1793. 

Excluded because adult blood not measured 

Nakanishi T, Tomita K, Nonoguchi H, Marumo F, Nakanishi T, Tomita K et al. Heterogeneity of glomerular 

cGMP production by atrial natriuretic peptide and brain natriuretic peptide. Contributions to Nephrology 

1991; 95:71-75. 

Excluded because adult blood not measured 

Nakao K, Mukoyama M, Hosoda K, Suga S, Ogawa Y, Saito Y et al. Biosynthesis, secretion, and receptor 

selectivity of human brain natriuretic peptide. Canadian Journal of Physiology & Pharmacology 1991; 

69(10):1500-1506. 

Excluded because BNP assay method is not an included one 

Nakao K, Ogawa Y, Suga -i S aIH. Molecular biology and biochemistry of the natriuretic peptide system. 

II: Natriuretic peptide receptors. Journal of Hypertension 1992; 10(10):1111-1114. 

Excluded because not a report of a primary study 

Nakao K, Saito Y, Itoh H, Ogawa Y, Nakagawa O, Harada M et al. Roles of natriuretic peptides in heart 

failure. Journal of Cardiac Failure 1996; 2(4 Suppl):S129-S133. 

Excluded because not a report of a primary study 

Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y et al. Activation of gp130 transduces 

hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase 

SHP2 in cardiomyocytes.[see comment]. Circulation Research 2003; 93(3):221-229. 

Excluded because adult blood not measured 
D-56 

Nakayama T, Nomura M, Fujinaga H, Ikefuji H, Kimura M, Chikamori K et al. Does coronary artery 

stenting for acute myocardial infarction improve left ventricular overloading at the chronic stage? 

Japanese Heart Journal 2004; 45(2):217-229. 

Excluded because BNP assay method is not an included one 

Nakazato M. Guanylin family: new intestinal peptides regulating electrolyte and water homeostasis. 

Journal of Gastroenterology 2001; 36(4):219-225. 

Excluded because not a report of a primary study 

Naruse M, Takeyama Y, Tanabe A, Hiroshige J, Naruse K, Yoshimoto T et al. Atrial and brain natriuretic 

peptides in cardiovascular diseases. Hypertension 1994; 23(1 Suppl):I231-I234. 

Excluded because BNP assay method is not an included one 

Nawata H, Ohashi M, Haji M, Takayanagi R, Higuchi K, Fujio N et al. Atrial and brain natriuretic peptide in 

adrenal steroidogenesis. Journal of Steroid Biochemistry & Molecular Biology 1991; 40(1-3):367-379. 

Excluded because adult blood not measured 

Nexo E. Reflections of the jury. Scandinavian Journal of Clinical & Laboratory Investigation 2004; 

64(5):478. 

Excluded because not a report of a primary study 

Ng L, Geeranavar S, Jennings S, Loke I, O'Brien R, Ng L et al. Diagnosis of heart failure using urinary 

natriuretic peptides.[see comment]. Clinical Science 2004; 106(2):129-133. 

Excluded because BNP assay method is not an included one 

Ng L, L.L. Brain naturetic peptide (BNP) and diabetes mellitus. Diabetic Medicine 2004; 21 Suppl 3:8-10. 

Excluded because not a report of a primary study 

Ng L, Loke I, Davies J, Khunti K, Stone M, Abrams K et al. Identification of previously undiagnosed left 

ventricular systolic dysfunction: community screening using natriuretic peptides and electrocardiography. 

European Journal of Heart Failure 2003; 5(6):775-782. 

Excluded because BNP assay method is not an included one 

Ng L, Loke I, O'Brien R, Squire I, Davies J, Ng LL et al. Plasma urocortin in human systolic heart failure. 

Clinical Science 2004; 106(4):383-388. 

Excluded because BNP assay method is not an included one 

Nicholls MG. Calorie-restricted weight reduction, blood pressure, and atrial natriuretic peptides. Nutrition 

1993; 9(4):381-382. 

Excluded because not a report of a primary study 

Nicholls M, Charles C, Lainchbury J, Lewis L, Rademaker M, Richards A et al. Adrenomedullin in heart 

failure. Hypertension Research 2003; 26(SUPPL.):S135-S140. 

Excluded because not a report of a primary study 

Nicholls M, Lainchbury J, Richards A, Troughton R, Yandle T, Nicholls M et al. Brain natriuretic peptideguided therapy for heart failure. Annals of Medicine 2001; 33(6):422-427. 

Excluded because not a report of a primary study 

Nicholls M, Richards A, Crozier I, Espiner R, and Ikram H. Cardiac natriuretic peptides in heart failure. 

Annals of Medicine 1993; 25(6):503-505. 

Excluded because not a report of a primary study 

Nicholson S, Richards M, Espiner E, Nicholls G, Yandle T, Nicholson S et al. Atrial and brain natriuretic 

peptide response to exercise in patients with ischaemic heart disease. Clinical & Experimental 
D-57 

Pharmacology & Physiology 1993; 20(7-8):535-540. 

Excluded because BNP assay method is not an included one 

Nielsen O, McDonagh T, Robb S, Dargie H, Nielsen OW, McDonagh TA et al. Retrospective analysis of 

the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic 

dysfunction in the general population. Journal of the American College of Cardiology 2003; 41(1):113-

120. 

Excluded because BNP assay method is not an included one 

Nielsen O, Rasmussen V, Christensen N, Hansen J, Nielsen O, Rasmussen V et al. Neuroendocrine 

testing in community patients with heart disease: plasma N-terminal proatrial natriuretic peptide predicts 

morbidity and mortality stronger than catecholamines and heart rate variability. Scandinavian Journal of 

Clinical & Laboratory Investigation 2004; 64(7):619-628. 

Excluded because BNP assay method is not an included one 

Nishigaki K, Tomita M, Kagawa K, Noda T, Minatoguchi S, Oda H et al. Marked expression of plasma 

brain natriuretic peptide is a special feature of hypertrophic obstructive cardiomyopathy. Journal of the 

American College of Cardiology 1996; 28(5):1234-1242. 

Excluded because BNP assay method is not an included one 

Nishikimi T, Matsuoka H, Ishikawa K, Yoshihara F, Kawano Y, Kitamura K et al. Antihypertensive therapy 

reduces increased plasma levels of adrenomedullin and brain natriuretic peptide concomitant with 

regression of left ventricular hypertrophy in a patient with malignant hypertension. Hypertension Research 

- Clinical & Experimental 1996; 19(2):97-101. 

Excluded because BNP assay method is not an included one 

Nishino M, Kimura T, Kanda T, Kotajima N, Yoshida A, Kuwabara A et al. Circulating interleukin-6 

significantly correlates to thyroid hormone in acute myocardial infarction but not in chronic heart failure. 

Journal of Endocrinological Investigation 2000; 23(8):509-514. 

Excluded because BNP assay method is not an included one 

Nitta K, Kawashima A, Yumura W, Naruse M, Oba T, Kabaya T et al. Plasma concentration of brain 

natriuretic peptide as an indicator of cardiac ventricular function in patients on hemodialysis. American 

Journal of Nephrology 1998; 18(5):411-415. 

Excluded because BNP assay method is not an included one 

Node K, Fujita M, Kitakaze M, Hori M, and Liao JK. Short-term statin therapy improves cardiac function 

and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 2003; 108(7):839-843. 

Excluded because BNP assay method is not an included one 

Noll B, Goke B, Simon B, Maisch B, Noll B, Goke B et al. Cardiac natriuretic peptide hormones during 

artificial cardiac pacemaker stimulation and left heart catheterization. Clinical Investigator 1992; 

70(12):1057-1060. 

Excluded because BNP assay method is not an included one 

Nordmeyer J, Eder S, Mahmoodzadeh S, Martus P, Fielitz J, Bass J et al. Upregulation of myocardial 

estrogen receptors in human aortic stenosis. Circulation 1920; 110(20):3270-3275. 

Excluded because adult blood not measured 

Norman J, Little D, Bolgar M, Di Donato G, Norman J, Little D et al. Degradation of brain natriuretic 

peptide by neutral endopeptidase: species specific sites of proteolysis determined by mass spectrometry. 

Biochemical & Biophysical Research Communications 2002; 175(1):22-30. 

Excluded because adult blood not measured 
D-58 

not found in reference. New B-type natriuretic peptide test (pro-BNP) for heart failure. Cardiovascular 

Journal of Southern Africa 13(5):272-Oct. 

Excluded because not a report of a primary study 

not found in reference. Glutathione, reduced (GSH). Alternative Medicine Review 2001 Dec;6(6):601-7. 

Excluded because not a report of a primary study 

not found in reference. Pain and beta-endorphins. BackLetter 1999; 14(7):74. 

Excluded because not a report of a primary study 

not found in reference. ... And assay of brain natriuretic peptide. Hospital Practice (Office Edition) 2000; 

35(6):30. 

Excluded because not a report of a primary study 

not found in reference. Rapid BNP blood test useful for diagnosing heart failure. British Journal of 

Cardiology 2000; 7(5):267. 

Excluded because not a report of a primary study 

not found in reference. Aha pearls. Formulary 2001; 36(1):60-67. 

Excluded because adult blood not measured 

not found in reference. Detecting asymptomatic left ventricular dysfunction. Medicine Today 2001; 

2(10):10. 

Excluded because not a report of a primary study 

not found in reference. Trauma technology. Diagnosing acute venous thrombosis. International Journal of 

Trauma Nursing 2001; 6(1):30-Mar. 

Excluded because not a report of a primary study 

not found in reference. Brain natriuretic peptide (BNP): A diagnostic tool. Medicine Today 2002; 3(4):8-9. 

Excluded because not a report of a primary study 

not found in reference. Case report: Tracking a growing epidemic. Cardiology Review 2002; 19(9):36. 

Excluded because this is a case report or series with 10 subjects 

not found in reference. BNP better than clinician judgment for chronic heart failure assessment. 

Cardiology Review 2003; 20(12):12. 

Excluded because not a report of a primary study 

not found in reference. Use of plasma brain natriuretic peptide concentration to aid in the diagnosis of 

heart failure. Prevention & Management of Congestive Heart Failure 2003; 9(3):180. 

Excluded because not a report of a primary study 

not found in reference. Rising to the challenge of heart failure in the UK. Care of the Critically Ill 2003; 

19(4):139. 

Excluded because not a report of a primary study 

not found in reference. Nesiritide shortens hospital stay in heart failure. Pharmaceutical Journal 2003; 

270(7244):506. 

Excluded because not a report of a primary study 

not found in reference. Post-test. Cardiology Review 2003; 20(4 SUPPL.). 

Excluded because not a report of a primary study 
D-59 

not found in reference. New aid to diagnosis of congestive heart failure: a bedside blood test for B-type 

natriuretic peptide provides both diagnostic and prognostic information in acute dyspnea. Emergency 

Medicine 2003; 35(1):11-12. 

Excluded because not a report of a primary study 

not found in reference. A is for... Natriuretic peptides. Science & Medicine 2003; 9(2):120. 

Excluded because not a report of a primary study 

not found in reference. Elevated plasma natriuretic peptide levels were associated with cardiovascular 

events. ACP Journal Club 2004; v141(2):50. 

Excluded because not a report of a primary study 

not found in reference. Rapid measurement of B-type natriuretic peptides reduced time to discharge and 

treatment costs in patients with acute dyspnea. ACP Journal Club 2004; v141(2):35. 

Excluded because not a report of a primary study 

not found in reference. Primary results of the rapid emergency department heart failure outpatient trial. 

Indian Heart Journal 2004; 56(4):360. 

Excluded because not a report of a primary study 

not found in reference. Community echocardiography for heart failure. British Journal of Cardiology 2004; 

11(5):399-402. 

Excluded because not a report of a primary study 

not found in reference. Natriuretic peptide understanding prompts development of new drugs. South 

African Medical Journal 2004; 94(5):353. 

Excluded because not a report of a primary study 

not found in reference. Heart failure beyond maximum medical management. British Journal of 

Cardiology 2004; 11(1):22-23. 

Excluded because not a report of a primary study 

not found in reference. RCT of BNP. Bandolier 2004; 11(8):7-8. 

Excluded because not a report of a primary study 

not found in reference. BNP for CHF. Bandolier 2004; 11(3):7-8. 

Excluded because not a report of a primary study 

not found in reference. FDA grants clearance to NT-proBNP for prognosis of congestive heart failure. 

Medical Letter on the CDC & FDA 2004;19-20. 

Excluded because not a report of a primary study 

not found in reference. New CHF drug shown to ease breathing distress among hospitalized patients. 

Clinical Resource Management 2005; 3(5):68-70. 

Excluded because BNP used as treatment 

Nousiainen T, Jantunen E, Vanninen E, Remes J, Puustinen J, Rantala A et al. Acute neurohumoral and 

cardiovascular effects of idarubicin in leukemia patients. European Journal of Haematology 1998; 

61(5):347-353. 

Excluded because BNP assay method is not an included one 

Nousiainen T, Jantunen E, Vanninen E, Remes J, Vuolteenaho O, Hartikainen J et al. Natriuretic peptides 

as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma. European Journal 

of Haematology 1999; 62(2):135-141. 

Excluded because BNP assay method is not an included one 
D-60 

Nousiainen T, Vanninen E, Jantunen E, Remes J, Ritanen E, Vuolteenaho O et al. Neuroendocrine 

changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma 

patients. Clinical Science 2001; 101(6):601-607. 

Excluded because BNP assay method is not an included one 

Nousiainen T, Vanninen E, Jantunen E, Puustinen J, Remes J, Rantala A et al. Natriuretic peptides 

during the development of doxorubicin-induced left ventricular diastolic dysfunction. Journal of Internal 

Medicine 2002; 251(3):228-234. 

Excluded because BNP assay method is not an included one 

Nowatzke W, T.G. Stability of N-terminal pro-brain natriuretic peptide after storage frozen for one year 

and after multiple freeze-thaw cycles [8]. Clinical Chemistry 2003; 49(9):1560-1562. 

Excluded because not a report of a primary study 

Nunes J, es D, Dias P, and Faria DB. Troponin I elevation after pericardiocentesis for cardiac tamponade: 

A role for myocardial strain? [4]. International Journal of Cardiology 2001; 81(2-3):277-278. 

Excluded because not a report of a primary study 

O'Connor J, L.N. B-type natriuretic peptide is an accurate predictor of heart failure in the emergency 

department. Journal of Family Practice 2002; 51(10):816. 

Excluded because not a report of a primary study 

Obi T, Takatsu M, Konishi T, Mizoguchi K, Nishimura Y, Obi T et al. Secretion of natriuretic peptides 

caused by an epileptic attack. Acta Neurologica Scandinavica 2002; 106(4):225-228. 

Excluded because not a report of a primary study 

Odent M. Why labouring women don't need "support"... reprinted with permission. Copyright Mothering, 

1996. MIDIRS Midwifery Digest 1997; 7(1):61-64. 

Excluded because not a report of a primary study 

Ogawa A, Iwase T, Yamamoto T, Nishiyama S, Narui K, and Momomura S. Improvement of CheyneStokes respiration, central sleep apnea and congestive heart failure by noninvasive bilevel positive 

pressure and medical treatment. Circulation Journal 2004; 68(9):878-882. 

Excluded because this is a case report or series with 10 subjects 

Ogawa E, Saito Y, Harada M, Kamitani S, Kuwahara K, Miyamoto Y et al. Outside-in signalling of 

fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes. Journal of 

Molecular & Cellular Cardiology 2000; 32(5):765-776. 

Excluded because adult blood not measured 

Ogawa M, Hirose N, Ogimoto M, Matsuki H, Miki K, Kinoshita M et al. Chronic beneficial effects of type 1 

angiotensin II receptor antagonist in patients with chronic hypoxemic pulmonary diseases. Cardiology 

2002; 97(2):111-112. 

Excluded because not a report of a primary study 

Ogawa S, Matsumura S, Yoshikawa T, Satoh T, Kumagai H, Mitamura H et al. A case of dilated 

cardiomyopathy with end-stage heart failure treated by prolonged continuous hemodiafiltration. Keio 

Journal of Medicine 2002; 51(3):165-177. 

Excluded because this is a case report or series with 10 subjects 

Ogawa S, Takeuchi K, Ito S, Ogawa STKaIS. Plasma BNP levels in the treatment of type 2 diabetes with 

pioglitazone. Journal of Clinical Endocrinology & Metabolism 2003; 88(8):3993-3996. 

Excluded because BNP assay method is not an included one 
D-61 

Ogawa T, Vatta M, Bruneau B, de Bold A, Ogawa T, Vatta M et al. Characterization of natriuretic peptide 

production by adult heart atria. American Journal of Physiology 1999; 276(6 Pt 2):H1977-H1986. 

Excluded because adult blood not measured 

Ogawa Y, Itoh H, and Nakao K. Molecular biology of brain natriuretic peptide. Japanese Heart Journal 

1994; 35(4):496-497. 

Excluded because adult blood not measured 

Ogimoto A, Hamada M, Nakura J, Miki T, Hiwada K, Ogimoto AHMNJMTaHK. Relation between 

angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic 

cardiomyopathy. Journal of Human Genetics 2002; 47(4):184-189. 

Excluded because BNP assay method is not an included one 

Ohata T, Sakakibara T, Takano H, Izutani H, Ohata TSTTHaIH. Plasma brain natriuretic peptide reflects 

left ventricular function during percutaneous cardiopulmonary support. Annals of Thoracic Surgery 2004; 

77(1):164-167. 

Excluded because this is a case report or series with 10 subjects 

Ohba H, Takada H, Musha H, Nagashima J, Mori N, Awaya T et al. Effects of prolonged strenuous 

exercise on plasma levels of atrial natriuretic peptide and brain natriuretic peptide in healthy men. 

American Heart Journal 2001; 141(5):751-758. 

Excluded because this is a case report or series with 10 subjects 

Ohbayashi Y, Tsutamoto T, Sakaguchi T, Tanaka T, Kanamori T, Yokohama H et al. Effect of an 

angiotensin II type 1 receptor blocker, valsartan, on neurohumoral factors in patients with hypertension: 

comparison with a long-acting calcium channel antagonist, amlodipine. Journal of Cardiovascular 

Pharmacology 2003; 42 Suppl 1:S71-S74. 

Excluded because BNP assay method is not an included one 

Ohkusa T, Noma T, Ueyama T, Hismatsu Y, Yano M, Kensuke E et al. Differences in sarcoplasmic 

reticulum gene expression in myocardium from patients undergoing cardiac surgery. Quantification of 

steady-state levels of messenger RNA using the reverse transcription-polymerase chain reaction. Heart & 

Vessels 1997; 12(1):1-9. 

Excluded because adult blood not measured 

Ohmichi N, Iwai N, Kinoshita M, Ohmichi N, Iwai N, and Kinoshita M. Expression of angiotensin 

converting enzyme and chymase in human atria. Journal of Hypertension 1997; 15(9):935-943. 

Excluded because adult blood not measured 

Ohsaki Y, Gross A, Le P, Oie H, Johnson B, Ohsaki Y et al. Human small cell lung cancer cells produce 

brain natriuretic peptide. Oncology 1999; 56(2):155-159. 

Excluded because adult blood not measured 

Ohtsuka T, Hamada M, Saeki H, Ogimoto A, Hara Y, Shigematsu Y et al. Serum levels of matrix 

metalloproteinases and tumor necrosis factor-a in patients with idiopathic dilated cardiomyopathy and 

effect of carvedilol on these levels. American Journal of Cardiology 2003; 91(8):1024-1027. 

Excluded because BNP assay method is not an included one 

Ohuchi H, Suzuki H, Toyohara K, Tatsumi K, Ono Y, Arakaki Y et al. Abnormal cardiac autonomic 

nervous activity after right ventricular outflow tract reconstruction. Circulation 1920; 102(22):2732-2738. 

Excluded because BNP assay method is not an included one 

Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S et al. Prolonged endoplasmic 

reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of 
D-62 

endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 2004; 110(6):705-712. 

Excluded because adult blood not measured 

Okumura K, Yasue H, Fujii H, Kugiyama K, Matsuyama K, Yoshimura M et al. Effects of brain (B-type) 

natriuretic peptide on coronary artery diameter and coronary hemodynamic variables in humans: 

comparison with effects on systemic hemodynamic variables. Journal of the American College of 

Cardiology 1995; 25(2):342-348. 

Excluded because BNP assay method is not an included one 

Okuno S, Hamada H, Yasuoka M, Watanabe H, Fujiki Y, Yamada N et al. Brain natriuretic peptide (BNP) 

and cyclic guanosine monophosphate (cGMP) levels in normal pregnancy and preeclampsia. Journal of 

Obstetrics & Gynaecology Research 1999; 25(6):407-410. 

Excluded because BNP assay method is not an included one 

Omland T. N-terminal proBNP: Marker of systolic dysfunction or nonspecific indicator of cardiac disease? 

Heartdrug 2003; 3(3):122-124. 

Excluded because BNP assay method is not an included one 

Omland T, Richards A, Wergeland R, Vik-Mo H, Omland TRA, Wergeland RaV-MH. B-type natriuretic 

peptide and long-term survival in patients with stable coronary artery disease. American Journal of 

Cardiology 2005; 95(1):24-28. 

Excluded because BNP assay method is not an included one 

Onuoha G, Nicholls D, Patterson A, Beringer T, Onuoha G, Nicholls D et al. Neuropeptide secretion in 

exercise. Neuropeptides 1998; 32(4):319-325. 

Excluded because BNP assay method is not an included one 

Onuoha G, Nugent A, Hunter S, Alpar E, McEneaney D, Campbell N et al. Neuropeptide variability in 

man.[see comment]. European Journal of Clinical Investigation 2000; 30(7):570-577. 

Excluded because adult blood not measured 

Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T et al. Secretion of A-type and Btype natriuretic peptides into the bloodstream and pericardial space in children with congenital heart 

disease. Journal of Thoracic & Cardiovascular Surgery 2003; 126(5):1411-1416. 

Excluded because adult blood not measured 

Owen A. NICE try but a long way to go in heart failure. British Journal of Cardiology 2004; 11(5):339-341. 

Excluded because not a report of a primary study 

Ozawa T, Tanaka H, Nakano R, Sato M, Inuzuka T, Soma Y et al. Nocturnal decrease in vasopressin 

secretion into plasma in patients with multiple system atrophy. Journal of Neurology, Neurosurgery and 

Psychiatry 1999; 67(4):542-545. 

Excluded because BNP assay method is not an included one 

Papp A, Uusaro A, Parviainen I, Hartikainen J, Ruokonen E, Papp A et al. Myocardial function and 

haemodynamics in extensive burn trauma: evaluation by clinical signs, invasive monitoring, 

echocardiography and cytokine concentrations. A prospective clinical study. Acta Anaesthesiologica 

Scandinavica 2003; 47(10):1257-1263. 

Excluded because this is a case report or series with 10 subjects 

Park M, Scott R, Uber P, Mehra M, Park MH, Scott RL et al. Bedside b-type natriuretic peptide and acute 

non-cellular cardiac allograft rejection. Journal of Heart & Lung Transplantation 2002; 21(5):613-614. 

Excluded because adult blood not measured 
D-63 

Patel A, M.A. Recent advances in the treatment of heart failure. Circulation Journal 2002; 66(2):117-121. 

Excluded because not a report of a primary study 

Patel D, Bailey S, Patel DN, and Bailey SR. Role of BNP in patients with severe asymptomatic aortic 

stenosis. European Heart Journal 2004; 25(22):1972-1973. 

Excluded because not a report of a primary study 

Patel J, J.A. Immunosuppression, diagnosis, and treatment of cardiac allograft rejection. Seminars in 

Thoracic & Cardiovascular Surgery 2004; 16(4):378-385. 

Excluded because not a report of a primary study 

Paulus W, W.J. Natriuretic peptides to probe haemodynamic overload in hypertrophic 

cardiomyopathy.[comment]. European Heart Journal 2001; 22(15):1249-1251. 

Excluded because not a report of a primary study 

Pearl A, Wright S, Gamble G, Doughty R, Sharpe N, Pearl AWSGGDRaSN. Randomised trials in general 

practice--a New Zealand experience in recruitment.[see comment]. New Zealand Medical Journal 1920; 

116(1186):U681. 

Excluded because not a report of a primary study 

Pedersen E, Pedersen H, Jensen K, Pedersen E, Pedersen H, and Jensen KT. Pulsatile secretion of 

atrial natriuretic peptide and brain natriuretic peptide in healthy humans. Clinical Science 1999; 97(2):201-

206. 

Excluded because BNP assay method is not an included one 

Pei Y, Chan C, Cattran D, Cardella C, Zaltzman J, Lopez M et al. Sustained vasoconstriction associated 

with daily cyclosporine dose in heart and lung transplant recipients: potential pathophysiologic role of 

endothelin. Journal of Laboratory and Clinical Medicine 1995; 125(1):113-119. 

Excluded because BNP assay method is not an included one 

Pepperell J, Maskell N, Jones D, Langford-Wiley B, Crosthwaite N, Stradling J et al. A randomized 

controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. American Journal of 

Respiratory & Critical Care Medicine 2003; 168(9):1109-1114. 

Excluded because BNP assay method is not an included one 

Perin E, Dohmann H, Borojevic R, Silva S, Sousa A, Mesquita C et al. Transendocardial, autologous 

bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 

107(18):2294-2302. 

Excluded because BNP assay method is not an included one 

Petrie M, McClure S, Love M, McMurray J, Petrie M, McClure S et al. Novel neuropeptides in the 

pathophysiology of heart failure: adrenomedullin and endothelin-1. European Journal of Heart Failure 

1999; 1(1):25-29. 

Excluded because not a report of a primary study 

Philipp S, Monti J, Pagel I, Langenickel T, Notter T, Ruschitzka F et al. Treatment with darusentan over 

21 days improved cGMP generation in patients with chronic heart failure. Clinical Science 2002; 103 

Suppl 48:249S-253S. 

Excluded because BNP assay method is not an included one 

Piccini J, Klein L, Gheorghiade M, and Bonow RO. New insights into diastolic heart failure: Role of 

diabetes mellitus. American Journal of Medicine 2004; 116(5 SUPPL. 1):64S-75S. 

Excluded because not a report of a primary study 
D-64 

Pidgeon G, Richards A, Nicholls M, Bailey R, Lynn K, Lewis L et al. Effect of ouabain on pressor 

responsiveness in normal man. American Journal of Physiology - Endocrinology & Metabolism 1994; 

267(5 30-5):E642-E647. 

Excluded because this is a case report or series with 10 subjects 

Pidgeon G, Richards A, Nicholls M, Lewis L, and Yandle TG. Acute effects of intravenous ouabain in 

healthy volunteers. Clinical Science 1994; 86(4):391-397. 

Excluded because this is a case report or series with 10 subjects 

Pidgeon G, Richards A, Nicholls M, Espiner E, Yandle T, Frampton C et al. Differing metabolism and 

bioactivity of atrial and brain natriuretic peptides in essential hypertension. Hypertension 1996; 27(4):906-

913. 

Excluded because BNP assay method is not an included one 

Piquard F, Geny B, Elero B, Canguilhem B, Mettauer B, Epailly E et al. Role of immunosuppressive 

therapy in neuroendocrine activation after human heart, renal, and liver transplantation. Transplantation 

Proceedings 1998; 30(5):2124-2126. 

Excluded because BNP assay method is not an included one 

Poole-Wilson PA. Tailored treatment for heart failure: An emerging concept. American Heart Journal 

1999; 138(6 I):1005-1006. 

Excluded because not a report of a primary study 

Poole-Wilson P, S.-R. New therapies for the management of acute heart failure. Current Cardiology 

Reports 2003; 5(3):229-236. 

Excluded because not a report of a primary study 

Porcel J, Vives M, Cao G, Esquerda A, Rubio M, Rivas M et al. Measurement of pro-brain natriuretic 

peptide in pleural fluid for the diagnosis of pleural effusions due to heart failure.[see comment]. American 

Journal of Medicine 2003; 116(6):417-420. 

Excluded because adult blood not measured 

Potter LR. CNP, cardiac natriuretic peptide? Endocrinology 2004; 145(5):2129-2130. 

Excluded because not a report of a primary study 

Prandota J. Furosemide: progress in understanding its diuretic, anti-inflammatory, and bronchodilating 

mechanism of action, and use in the treatment of respiratory tract diseases. American Journal of 

Therapeutics 2002; 9(4):317-328. 

Excluded because not a report of a primary study 

Prasad K, Fredericks S, Holt D, Prasad K, Fredericks S, and Holt DW. Measuring brain natriuretic 

peptide.[see comment]. Lancet 1908; 348(9027):626. 

Excluded because not a report of a primary study 

Prasad N, Bridges A, Lang C, Clarkson P, MacLeod C, Pringle T et al. Brain natriuretic peptide 

concentrations in patients with aortic stenosis. American Heart Journal 1997; 133(4):477-479. 

Excluded because BNP assay method is not an included one 

Prasad N, Lang C, McAlpine H, Choy A, MacDonald T, Struthers A et al. Raised plasma concentrations of 

brain natriuretic peptide in pulmonary arterial hypertension.[see comment]. Respiratory Medicine 1995; 

89(6):445-447. 

Excluded because BNP assay method is not an included one 
D-65 

Prasun MA. The effects of a diuretic titration protocol on clinical outcomes in heart failure patients. 

University of Illinois at Chicago, Health Sciences Center ** Ph D.(142 p):2002. 

Excluded because not a report of a primary study 

Prasun M, Kocheril A, Klass P, Dunlap S, Piano M, Prasun MA et al. The effects of a sliding scale diuretic 

titration protocol in patients with heart failure. Journal of Cardiovascular Nursing 2005; 20(1):62-70. 

Excluded because BNP assay method is not an included one 

Prestle J, Dieterich S, Preuss M, Bieligk U, Hasenfuss G, Prestle J et al. Heterogeneous transmural gene 

expression of calcium-handling proteins and natriuretic peptides in the failing human heart.[see 

comment]. Cardiovascular Research 1999; 43(2):323-331. 

Excluded because adult blood not measured 

Pritchett A, D.L. Neurohormonal therapy for congestive heart failure. Current Treatment Options in 

Cardiovascular Medicine 2004; 6(6):499-507. 

Excluded because not a report of a primary study 

Prontera C, Emdin M, Zucchelli G, Ripoli A, Passino C, Clerico A et al. Natriuretic peptides (NPs): 

Automated electrochemiluminescent immunoassay for N-terminal pro-BNP compared with IRMAs for 

ANP and BNP in heart failure patients and healthy individuals. Clinical Chemistry 2003; 49(9):1552-1554. 

Excluded because not a report of a primary study 

Pu W, S. Transcription factors and heart failure: Does the stressed heart need a hand? Journal of 

Molecular & Cellular Cardiology 2001; 33(10):1765-1767. 

Excluded because not a report of a primary study 

Pucci A, Wharton J, Arbustini E, Grasso M, Diegoli M, Needleman P et al. Atrial amyloid deposits in the 

failing human heart display both atrial and brain natriuretic peptide-like immunoreactivity. Journal of 

Pathology 1991; 165(3):235-241. 

Excluded because adult blood not measured 

Puschendorf B, B. Strategies for cardiac marker measurement. Clinical Chemistry & Laboratory Medicine 

1999; 37(11-12):997-999. 

Excluded because not a report of a primary study 

Putsep K, Carlsson G, Boman H, and Andersson M. Mechanisms of disease. Deficiency of antibacterial 

peptides in patients with morbus Kostmann: an observation study. Lancet 1920; 360(9340):1144-1149. 

Excluded because adult blood not measured 

Qi W, Mathisen P, Kjekshus J, Simonsen S, Endresen K, Bjornerheim R et al. The effect of aortic valve 

replacement on N-terminal natriuretic propeptides in patients with aortic stenosis. Clinical Cardiology 

2002; 25(4):174-180. 

Excluded because BNP assay method is not an included one 

Rabinstein A, E.F.M. Hyponatremia in Critically III Neurological Patients. Neurologist 2003; 9(6):290-300. 

Excluded because not a report of a primary study 

Rahimtoola SH. The year in valvular heart disease. Journal of the American College of Cardiology 2005; 

45(1):111-122. 

Excluded because not a report of a primary study 

Rahmutula D, Nakayama T, Soma M, Takahashi Y, Uwabo J, Sato M et al. A C2077T polymorphism of 

the type B human natriuretic peptide receptor gene is not associated with myocardial infarction. Medical 

Science Monitor 2000; 6(6):1056-1060. 

Excluded because adult blood not measured 
D-66 

Rahmutula D, Nakayama T, Soma M, Sato M, Izumi Y, Kanmatsuse K et al. Systematic screening of type 

B human natriuretic peptide receptor gene polymorphisms and association with essential hypertension. 

Journal of Human Hypertension 2001; 15(7):471-474. 

Excluded because adult blood not measured 

Rao G. What is an ROC curve? Journal of Family Practice 2003; 52(9):695. 

Excluded because not a report of a primary study 

Ravnan S, P.C. The rational use of diuretics in heart failure. Current Cardiology Reports 2003; 5(3):237-

242. 

Excluded because not a report of a primary study 

Redfield M, Margaret M. The Breathing Not Proper trial: enough evidence to change heart failure 

guidelines? Journal of Cardiac Failure 2002; 8(3):120-123. 

Excluded because not a report of a primary study 

Ribeiro A, Dos Reis A, Barros M, de Sousa M, Rocha A, Perez A et al. Brain natriuretic peptide and left 

ventricular dysfunction in Chagas' disease. Lancet 2002; 360(9331):461-462. 

Excluded because not a report of a primary study 

Ribeiro A, Dos Reis A, Barros M, de Sousa M, Rocha A, Perez A et al. Brain natriuretic peptide and left 

ventricular dysfunction in Chagas' disease.[see comment]. Lancet 2002; 360(9331):461-462. 

Excluded because BNP assay method is not an included one 

Ribeiro A, Reis A, Teixeira M, and Rocha MOC. Brain natriuretic peptide in Chagas' disease: further 

insights... Walther T, Heringer-Walther S, Wessel N et al. Brain natriuretic peptide as a predictor of 

cardiomyopathy in Chagas' disease. Lancet 2003; 361:1567. Lancet 1907; 362(9380):333. 

Excluded because not a report of a primary study 

Richards AM. Vasopeptidase inhibitors for heart failure: Where do we go from here? European Journal of 

Heart Failure 2003; 5(4):411-413. 

Excluded because not a report of a primary study 

Richards A, Crozier I, Espiner E, Yandle T, Nicholls M, Richards A et al. Plasma brain natriuretic peptide 

and endopeptidase 24.11 inhibition in hypertension. Hypertension 1993; 22(2):231-236. 

Excluded because BNP assay method is not an included one 

Richards A, Crozier I, Yandle T, Espiner E, Ikram H, Nicholls M et al. Brain natriuretic factor: regional 

plasma concentrations and correlations with haemodynamic state in cardiac disease. British Heart 

Journal 1993; 69(5):414-417. 

Excluded because BNP assay method is not an included one 

Richards A, Crozier I, Holmes S, Espiner E, Yandle T, Frampton C et al. Brain natriuretic peptide: 

natriuretic and endocrine effects in essential hypertension. Journal of Hypertension 1993; 11(2):163-170. 

Excluded because this is a case report or series with 10 subjects 

Richards A, Doughty R, Nicholls M, MacMahon S, Ikram H, Sharpe N et al. Neurohumoral prediction of 

benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure 

Group. Circulation 2002; 99(6):786-792. 

Excluded because BNP assay method is not an included one 

Richards A, Nicholls M, Yandle T, Ikram H, Espiner E, Turner J et al. Neuroendocrine prediction of left 

ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine 

Research Group. Heart (British Cardiac Society) 1999; 81(2):114-120. 

Excluded because BNP assay method is not an included one 
D-67 

Roberts A. The adrenal gland 2. Nursing Times 1919; 91(50):31-33. 

Excluded because not a report of a primary study 

Roberts A. Systems of life. The pituitary... part 1. Nursing Times 1995; 91(19):35-37. 

Excluded because not a report of a primary study 

Robertson M, Livesey G, Hampton S, and Mathers JC. Evidence for altered control of glucose disposal 

after total colectomy. British Journal of Nutrition 2000; 84(6):813-819. 

Excluded because BNP assay method is not an included one 

Robson J. What happened to evidence in NICE guidance on heart failure? [7]. British Medical Journal 

2003; 327(7420):932. 

Excluded because not a report of a primary study 

Rodeheffer R, Richard J. Epidemiology and screening of asymptomatic left ventricular dysfunction. 

Journal of Cardiac Failure 2002; 8(6 Suppl):S253-S257. 

Excluded because not a report of a primary study 

Rosen S, Taneja A, Coats A, and Flather M. Assessment of the patient with heart failure. Continuing 

Medical Education - Cardiology 2002; 2(2):95-105. 

Excluded because not a report of a primary study 

Rosenberg K. BNP assay for assessing cardiac function. Cardiology Review 2001; 18(6):15. 

Excluded because not a report of a primary study 

Rosenkranz S, Diet F, Karasch T, Weihrauch J, Wassermann K, Erdmann E et al. Sildenafil improved 

pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis 

and the raynaud phenomenon. Annals of Internal Medicine 1920; 139(10):871-873. 

Excluded because not a report of a primary study 

Ross J, Jr. Thematic review series IX: New therapeutic targets for the treatment of heart failure: 

Introduction. Proceedings of the Association of American Physicians 1999; 111(5):396-398. 

Excluded because not a report of a primary study 

Rossi A, Enriquez-Sarano M, Burnett J, Jr, Lerman A, Abel M et al. Natriuretic peptide levels in atrial 

fibrillation: a prospective hormonal and Doppler-echocardiographic study. Journal of the American 

College of Cardiology 2000; 35(5):1256-1262. 

Excluded because BNP assay method is not an included one 

Rouleau J, Pfeffer M, Stewart D, Isaac D, Sestier F, Kerut E et al. Comparison of vasopeptidase inhibitor, 

omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS 

randomised trial. Lancet 2000; 356(9230):615-620. 

Excluded because BNP assay method is not an included one 

Rousseau M, Gurne O, Duprez D, Van Mieghem W, Robert A, Ahn S et al. Beneficial neurohormonal 

profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal 

substudy.[erratum appears in J Am Coll Cardiol. 2003 Nov 19;42(10):1865]. Journal of the American 

College of Cardiology 2002; 40(9):1596-1601. 

Excluded because BNP assay method is not an included one 

Roy B, Dauphin M, and Kelly TM. Idiotypic and anti-idiotypic antibodies interfere in a standard 

radioimmunoassay for beta-endorphin. Journal of Laboratory and Clinical Medicine 1995; 125(1):79-85. 

Excluded because BNP assay method is not an included one 
D-68 

Rubinstein I, D. Circulating natriuretic peptides: A biologic marker of tissue injury? Chest 1999; 115(1):7-

8. 

Excluded because not a report of a primary study 

Ruck A, Gustafsson T, Norrbom J, Nowak J, Kallner G, Soderberg M et al. ANP and BNP but not VEGF 

are regionally overexpressed in ischemic human myocardium. Biochemical & Biophysical Research 

Communications 2004; 322(1):287-291. 

Excluded because adult blood not measured 

Ruschitzka F, Corti R, Quaschning T, Hermann M, and Luscher TF. Vasopeptidase inhibitors-Concepts 

and evidence. Nephrology Dialysis Transplantation 2001; 16(8):1532-1535. 

Excluded because not a report of a primary study 

Ruskoaho H. Atrial natriuretic peptide: Synthesis, release, and metabolism. Pharmacological Reviews 

1992; 44(4):481-602. 

Excluded because not a report of a primary study 

Ruskoaho H, Hall C, Holmstrom H, and McDonagh TA. S-10. New analyses in the evaluation of heart 

failure. Scandinavian Journal of Clinical and Laboratory Investigation Supplement 2000; 60(232):44-45. 

Excluded because not a report of a primary study 

Russell S, T. Vasopressin receptor antagonists: Therapeutic potential in the management of acute and 

chronic heart failure. American Journal of Cardiovascular Drugs 2003; 3(1):13-20. 

Excluded because not a report of a primary study 

Ry S, Andreassi M, Clerico A, Biagini A, Giannessi D, Ry S et al. Endothelin-1, endothelin-1 receptors 

and cardiac natriuretic peptides in failing human heart. Life Sciences 2001; 68(24):2715-2730. 

Excluded because adult blood not measured 

Sabbah HN. Biologic rationale for the use of beta-blockers in the treatment of heart failure. Heart Failure 

Reviews 2004; 9(2):91-97. 

Excluded because not a report of a primary study 

Saijo M, Takemura G, Koda M, Okada H, Miyata S, Ohno Y et al. Cardiomyopathy with prominent 

autophagic degeneration, accompanied by an elevated plasma brain natriuretic peptide level despite the 

lack of overt heart failure. Internal Medicine 2004; 43(8):700-703. 

Excluded because BNP assay method is not an included one 

Sakamoto T, Mizuno Y, Ogawa H, Yoshimura M, Kugiyama K, and Yasue H. B-type natriuretic peptide 

after percutaneous transluminal septal myocardial ablation. International Journal of Cardiology 2002; 

83(2):151-158. 

Excluded because this is a case report or series with 10 subjects 

Sakurai S, Adachi H, Hasegawa A, Hoshizaki H, Oshima S, Taniguchi K et al. Brain natriuretic peptide 

facilitates severity classification of stable chronic heart failure with left ventricular dysfunction. Heart 

(British Cardiac Society) 2003; 89(6):661-662. 

Excluded because not a report of a primary study 

Salo J, Jimenez W, Kuhn M, Gines A, Gines P, Fernandez-Esparrach G et al. Urinary excretion of 

urodilatin in patients with cirrhosis. Hepatology 1996; 24(6):1428-1432. 

Excluded because adult blood not measured 

Salzmann J, Flitcroft D, Bunce C, Gordon D, Wormald R, Migdal C et al. Brain natriuretic peptide: 

identification of a second natriuretic peptide in human aqueous humour. British Journal of Ophthalmology 
D-69 

1998; 82(7):830-834. 

Excluded because adult blood not measured 

Samson WK. Natriuretic peptides: A family of hormones. Trends in Endocrinology & Metabolism 1992; 

3(3):86-90. 

Excluded because not a report of a primary study 

Sanderson J, Chan W, Hung Y, Chan S, Shum I, Raymond K et al. Effect of low dose beta blockers on 

atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of 

metoprolol and a third generation vasodilating beta blocker. British Heart Journal 1995; 74(5):502-507. 

Excluded because BNP assay method is not an included one 

Sanderson J, John E. BNP or echocardiography for monitoring heart failure? European Heart Journal 

2004; 25(20):1763-1764. 

Excluded because not a report of a primary study 

Sankaralingam A. Increase in circulating levels of cardiac natriuretic peptides after hormone replacement 

therapy in postmenopausal women (S Maffei, S Del Ry, C Clerico. Clin Scie 2001; 101: 447-53). Cpd 

Bulletin Clinical Biochemistry 2002; 4(3):81. 

Excluded because not a report of a primary study 

Saper C, C.B. Of hearts and minds: natriuretic peptides in the brain. Journal of Comparative Neurology 

2005; 356(2):166-167. 

Excluded because not a report of a primary study 

Saribulbul O, Alat I, Coskun S, Apaydin A, Yagdi T, Kiliccioglu M et al. The role of brain natriuretic peptide 

in the prediction of cardiac performance in coronary artery bypass grafting. Texas Heart Institute Journal 

2003; 30(4):298-304. 

Excluded because BNP assay method is not an included one 

Sasaki T, Kubo T, Komamura K, Nishikimi T, Sasaki T, Kubo T et al. Effects of long-term treatment with 

pimobendan on neurohumoral factors in patients with non-ischemic chronic moderate heart failure. 

Journal of Cardiology 1999; 33(6):317-325. 

Excluded because BNP assay method is not an included one 

Sato Y, Kita T, Takatsu Y, and Kimura T. Biochemical markers of myocyte injury in heart failure. Heart 

(British Cardiac Society) 2004; 90(10):1110-1113. 

Excluded because not a report of a primary study 

Sato Y, Taniguchi R, Makiyama T, Nagai K, Okada H, Yamada T et al. Serum cardiac troponin T and 

plasma brain natriuretic peptide in patients with cardiac decompensation. Heart (British Cardiac Society) 

2002; 88(6):647-648. 

Excluded because not a report of a primary study 

Savoia C, E.L. Significance of recently identified peptides in hypertension: Endothelin, natriuretic 

peptides, adrenomedullin, leptin. Medical Clinics of North America 2004; 88(1):39-62. 

Excluded because not a report of a primary study 

Schaufelberger M, Bergh C, Caidahl K, Eggertsen R, Furenas E, Lindstedt G et al. Can brain natriuretic 

peptide (BNP) be used as a screening tool in general practice? Scandinavian Journal of Primary Health 

Care 2004; 22(3):187-190. 

Excluded because BNP assay method is not an included one 

Schenk S, McCarthy P, Starling R, Hoercher K, Hail M, Ootaki Y et al. Neurohormonal response to left 

ventricular reconstruction surgery in ischemic cardiomyopathy.[see comment]. Journal of Thoracic & 
D-70 

Cardiovascular Surgery 2004; 128(1):38-43. 

Excluded because BNP assay method is not an included one 

Schmitt M, Gunaruwan P, Payne N, Taylor J, Lee L, Broadley A et al. Effects of exogenous and 

endogenous natriuretic peptides on forearm vascular function in chronic heart failure. Arteriosclerosis, 

Thrombosis & Vascular Biology 2004; 24(5):911-917. 

Excluded because BNP assay method is not an included one 

Schmitt M, Qasem A, McEniery C, Wilkinson I, Tatarinoff V, Noble K et al. Role of natriuretic peptides in 

regulation of conduit artery distensibility.[erratum appears in Am J Physiol Heart Circ Physiol. 2004 

Nov;56(5):H2367]. American Journal of Physiology - Heart & Circulatory Physiology 2004; 287(3):H1167-

H1171. 

Excluded because adult blood not measured 

Schoenfeld J, Tom J, Lowe D, Schoenfeld J, Tom J, and Lowe DG. Mutations in B-type natriuretic peptide 

mediating receptor-A selectivity. FEBS Letters 1997; 414(2):263-267. 

Excluded because adult blood not measured 

Schrier R, Gurevich A, and Cadnapaphornchai MA. Pathogenesis and management of sodium and water 

retention in cardiac failure and cirrhosis. Seminars in Nephrology 2001; 21(2):157-172. 

Excluded because not a report of a primary study 

Schulz H, Langvik T, Lund SE, Smith J, Ahmadi N, Hall C et al. Radioimmunoassay for N-terminal 

probrain natriuretic peptide in human plasma. Scandinavian Journal of Clinical & Laboratory Investigation 

2001; 61(1):33-42. 

Excluded because BNP assay method is not an included one 

Schunemann HJM. Rapid measurement of B-type natriuretic peptides reduced time to discharge and 

treatment costs in patients with acute dyspnea. ACP Journal Club 2005; v142(1):A14. 

Excluded because not a report of a primary study 

Schwam E, Eric. B-type natriuretic peptide for diagnosis of heart failure in emergency department 

patients: a critical appraisal. Academic Emergency Medicine 2004; 11(6):686-691. 

Excluded because not a report of a primary study 

Schwartz M, R.J. The new biology of body weight regulation. Journal of the American Dietetic Association 

1997; 97(1):54-60. 

Excluded because not a report of a primary study 

Scotland R, Ahluwalia A, Hobbs A, Scotland RS, Ahluwalia AaHAJ. C-type natriuretic peptide in vascular 

physiology and disease. Pharmacology & Therapeutics 2005; 105(2):85-93. 

Excluded because adult blood not measured 

Segev G, J.F. B-type natriuretic peptide: a novel clinical tool for diagnosis and management of heart 

failure. Hospital Physician 2003; 39(9):19-24. 

Excluded because not a report of a primary study 

Seidler T, Pemberton C, Yandle T, Espiner E, Nicholls G, Richards M et al. The amino terminal regions of 

proBNP and proANP oligomerise through leucine zipper-like coiled-coil motifs. Biochemical & Biophysical 

Research Communications 2002; 255(2):495-501. 

Excluded because adult blood not measured 

Sekiguchi K, Kanda T, Ono Z, Tanaka T, Yokoyama T, Aihara Y et al. Augmented responses of 

angiotensin I and II in patients with ischemic heart disease: relation to left ventricular function. Japanese 
D-71 

Heart Journal 2000; 41(3):269-278. 

Excluded because BNP assay method is not an included one 

Selvais P, Donckier J, Robert A, Laloux O, Van Linden F, Ahn S et al. Cardiac natriuretic peptides for 

diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary 

artery disease on cardiac hormonal activation. European Journal of Clinical Investigation 1998; 28(8):636-

642. 

Excluded because BNP assay method is not an included one 

Selvais P, Robert A, Ahn S, Van Linden F, Ketelslegers J, Pouleur H et al. Direct comparison between 

endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of 

survival in congestive heart failure. Journal of Cardiac Failure 2000; 6(3):201-207. 

Excluded because BNP assay method is not an included one 

Selvais P, Rousseau L, Ahn S, Van Linden F, Ketelslegers J, Rousseau M et al. Usefulness of the 

supine-rest maneuver before neurohormonal sampling. American Journal of Cardiology 2003; 89(6):772-

774. 

Excluded because BNP assay method is not an included one 

Sengenes C, Berlan M, De GILM, Galitzky J, Sengenes C, Berlan M et al. Natriuretic peptides: a new 

lipolytic pathway in human adipocytes. FASEB Journal 2000; 14(10):1345-1351. 

Excluded because adult blood not measured 

Sengenes C, Stich V, Berlan M, Hejnova J, Lafontan M, Pariskova Z et al. Increased lipolysis in adipose 

tissue and lipid mobilization to natriuretic peptides during low-calorie diet in obese women. International 

Journal of Obesity & Related Metabolic Disorders: Journal of the International Association for the Study of 

Obesity 2002; 26(1):24-32. 

Excluded because adult blood not measured 

Setsuta K, Seino Y, Ogawa T, Arao M, Miyatake Y, and Takano T. Use of cytosolic and myofibril markers 

in the detection of ongoing myocardial damage in patients with chronic heart failure. American Journal of 

Medicine 2002; 113(9):717-722. 

Excluded because BNP assay method is not an included one 

Seymour AA. The pharmacology of SQ 28,603, an inhibitor of neutral endopeptidase 3.4.24.11. 

Cardiovascular Drug Reviews 1991; 9(3):285-298. 

Excluded because not a report of a primary study 

Shand B, Gilchrist N, Nicholls M, and Caesar M. Effect of lacidipine on blood pressure, vasoactive 

hormones, and haemorheology in elderly patients with essential hypertension. Journal of Human 

Hypertension 2000; 14(7):473-475. 

Excluded because not a report of a primary study 

Sharabi Y, Dagan Y, and Grossman E. Sleep apnea as a risk factor for hypertension. Current Opinion in 

Nephrology & Hypertension 2004; 13(3):359-364. 

Excluded because not a report of a primary study 

Sharp R, Gregory A, Mowdy M, Sirajuddin R, Sharp RP, Gregory AMMH et al. Nesiritide for treatment of 

heart failure due to right ventricular dysfunction. Pharmacotherapy 2004; 24(9):1236-1240. 

Excluded because this is a case report or series with 10 subjects 

Sheedy W, Stewart A, Morice A, Sheedy W, Stewart A, and Morice AH. Plasma levels of atrial natriuretic 

peptide and brain natriuretic peptide following intravenous saline infusion in oedematous chronic 

obstructive pulmonary disease and non-oedematous chronic obstructive pulmonary disease. Respiration 
D-72 

1996; 63(6):376-380. 

Excluded because BNP assay method is not an included one 

Shehab A, MacFadyen R, McLaren M, Tavendale R, Belch J, and Struthers AD. Sudden unexpected 

death in heart failure may be preceded by short term, intraindividual increases in inflammation and in 

autonomic dysfunction: A pilot study. Heart (British Cardiac Society) 2004; 90(11):1263-1268. 

Excluded because BNP assay method is not an included one 

Shenker Y. Natriuretic peptides and adrenal cortex. Endocrinologist 2000; 10(4):219-224. 

Excluded because not a report of a primary study 

Shephard RJ. Exercise under hot conditions: a major threat to the immune response? Journal of Sports 

Medicine and Physical Fitness 2002; 42(3):368-378. 

Excluded because adult blood not measured 

Sheth T, Parker T, Block A, Hall C, Adam A, Pfeffer M et al. Comparison of the effects of omapatrilat and 

lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure. American 

Journal of Cardiology 2002; 90(5):496-500. 

Excluded because BNP assay method is not an included one 

Shiba N, Watanabe J, Shinozaki T, Koseki Y, Sakuma M, Kagaya Y et al. Analysis of chronic heart failure 

registry in the Tohoku district: third year follow-up. Circulation Journal 2004; 68(5):427-434. 

Excluded because not a report of a primary study 

Shih W, Romero R, Timothy M, and Milan PP. 99mTc-depreotide chest SPECT demonstrates pulmonary 

metastases from renal cell carcinoma. Journal of Nuclear Medicine Technology 2004; 32(1):19-21. 

Excluded because adult blood not measured 

Shimizu H, Aono K, Masuta K, Asada H, Misaki A, Teraoka H et al. Stability of brain natriuretic peptide 

(BNP) in human blood samples. Clinica Chimica Acta 1999; 285(1-2):169-172. 

Excluded because this is a case report or series with 10 subjects 

Shimizu H, Masuta K, Asada H, Sugita K, Sairenji T, Shimizu HMKAHSKaST. Characterization of 

molecular forms of probrain natriuretic peptide in human plasma. Clinica Chimica Acta 2003; 334(1-

2):233-239. 

Excluded because adult blood not measured 

Shimoyama M, Murata Y, Sumi K, Hamazoe R, and Komuro I. Docetaxel induced cardiotoxicity. Heart 

(British Cardiac Society) 2001; 86(2):219. 

Excluded because not a report of a primary study 

Shimoyama M, Ochi H, Takeda S, Doi T, Kinugasa Y, Endoh A et al. Effect of controlled-release 

nifedipine on left ventricular hypertrophy in Japanese patients with hypertension: An open-label, 

uncontrolled study. Current Therapeutic Research, Clinical & Experimental 2001; 62(11):773-782. 

Excluded because BNP assay method is not an included one 

Shinohara H, Fukuda N, Soeki T, Sakabe K, Onose Y, Tamura Y et al. Effects of angiotensin II receptor 

antagonists on [(123)I]metaiodobenzylguanidine myocardial imaging findings and neurohumoral factors in 

chronic heart failure. Heart & Vessels 2002; 17(2):47-52. 

Excluded because BNP assay method is not an included one 

Shirakami G, Magaribuchi T, Shingu K, Suga S, Tamai S, Nakao K et al. Positive end-expiratory pressure 

ventilation decreases plasma atrial and brain natriuretic peptide levels in humans. Anesthesia & 

Analgesia 1993; 77(6):1116-1121. 

Excluded because BNP assay method is not an included one 
D-73 

Shirakami G, Murakawa M, Shingu K, Mashima S, Suga S, Magaribuchi T et al. Perioperative plasma 

concentrations of endothelin and natriuretic peptides in children undergoing living-related liver 

transplantation. Anesthesia & Analgesia 1996; 82(2):235-240. 

Excluded because adult blood not measured 

Shirakami G, Shingu K, Tamai S, Ando A, Suga S, Nakao K et al. A case of "stunned myocardium" after 

noncardiac surgery: increased concentration of plasma brain natriuretic peptide. Anesthesia & Analgesia 

1994; 79(1):175-179. 

Excluded because not a report of a primary study 

Sica D, Liao W, Gehr T, Khan S, Jemal M, Delaney C et al. Disposition and safety of omapatrilat in 

subjects with renal impairment. Clinical Pharmacology & Therapeutics 2000; 68(3):261-269. 

Excluded because adult blood not measured 

Sica D, Midha M, Aronoff G, and Bergen G. Atrial natriuretic factor in spinal cord injury. Archives of 

Physical Medicine and Rehabilitation 1993; 74(9):969-972. 

Excluded because adult blood not measured 

Sica D, P. Pharmacotherapy in congestive heart failure: Vasopeptidase inhibition and its role in 

congestive heart failure. Prevention & Management of Congestive Heart Failure 2000; 6(3):158-163. 

Excluded because not a report of a primary study 

Sigurdsson A, Eriksson S, Hall C, Kahan T, and Swedberg K. Early neurohormonal effects of trandolapril 

in patients with left ventricular dysfunction and a recent acute myocardial infarction: A double-blind, 

randomized, placebo-controlled multicentre study. European Journal of Heart Failure 2001; 3(1):69-78. 

Excluded because BNP assay method is not an included one 

Silver MA. Are you ready for another paradigm shift? Prevention & Management of Congestive Heart 

Failure 2001; 7(5):242-243. 

Excluded because not a report of a primary study 

Silver M, Horton D, Ghali J, Elkayam U, Silver MA, Horton DP et al. Effect of nesiritide versus dobutamine 

on short-term outcomes in the treatment of patients with acutely decompensated heart failure. Journal of 

the American College of Cardiology 2002; 39(5):798-803. 

Excluded because BNP assay method is not an included one 

Silverberg D, Wexler D, Blum M, Wollman Y, and Iaina A. The cardio-renal anaemia syndrome: Does it 

exist? Nephrology Dialysis Transplantation 2003; 18(SUPPL. 8):viii7-viii12. 

Excluded because not a report of a primary study 

Silverberg D, Wexler D, Blum M, Schwartz D, Wollman Y, and Iaina A. Erythropoietin should be part of 

congestive heart failure management. Kidney International - Supplement 2003; 64(87):S40-S47. 

Excluded because not a report of a primary study 

Sim V, Hampton D, Phillips C, Lo S, Vasishta S, Davies J et al. The use of brain natriuretic peptide as a 

screening test for left ventricular systolic dysfunction- cost-effectiveness in relation to open access 

echocardiography. Family Practice 2003; 20(5):570-574. 

Excluded because BNP assay method is not an included one 

Smith H, Pickering R, Struthers A, Simpson I, Mant D, Smith H et al. Biochemical diagnosis of ventricular 

dysfunction in elderly patients in general practice: observational study.[see comment]. BMJ 2000; 

320(7239):906-908. 

Excluded because BNP assay method is not an included one 
D-74 

Smith M, Espiner E, Yandle T, Charles C, Richards A, Smith M et al. Delayed metabolism of human brain 

natriuretic peptide reflects resistance to neutral endopeptidase. Journal of Endocrinology 2000; 

167(2):239-246. 

Excluded because adult blood not measured 

Smith T, Rosen D, Russo P, Berkenbosch J, Gustafson R, Siu B et al. Nesiritide during extracorporeal 

membrane oxygenation. Paediatric Anaesthesia 2005; 15(2):152-157. 

Excluded because adult blood not measured 

Snowden J, Hill G, Hunt P, Carnoutsos S, Spearing R, Espiner E et al. Assessment of cardiotoxicity 

during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow 

Transplantation 2000; 26(3):309-313. 

Excluded because BNP assay method is not an included one 

Soares L, Luis Guilherme Loureiro. Brain natriuretic peptide: a marker for dyspnea? Journal of Pain & 

Symptom Management 2002; 24(5):457-458. 

Excluded because not a report of a primary study 

Sodian R, Loebe M, Schmitt C, Potapov E, Siniawski H, Muller J et al. Decreased plasma concentration 

of brain natriuretic peptide as a potential indicator of cardiac recovery in patients supported by 

mechanical circulatory assist systems. Journal of the American College of Cardiology 2001; 38(7):1942-

1949. 

Excluded because BNP assay method is not an included one 

Song S, Kamath S, Mosquera D, Zigova T, Sanberg P, Vesely D et al. Expression of brain natriuretic 

peptide by human bone marrow stromal cells. Experimental Neurology 2004; 185(1):191-197. 

Excluded because adult blood not measured 

Sonoda K, Ikeda S, Miyahara Y, Kohno S, Sonoda KISMYaKS. Successful treatment of chronic 

pulmonary thromboembolism by long-term intermittent administration of milrinone, a phosphodiesterase-ill 

inhibitor. Internal Medicine 2002; 41(11):961-966. 

Excluded because not a report of a primary study 

SoRelle R, R. Cardiovascular news. VMAC. Circulation 2000; 102(25):E9050-E9051. 

Excluded because not a report of a primary study 

Sowers JR. Hypertension, angiotensin II, and oxidative stress. New England Journal of Medicine 2006; 

346(25):1999-2001. 

Excluded because not a report of a primary study 

Sparrow N, Adlam D, Cowley A, Hampton J, Sparrow NADCAaHJR. The diagnosis of heart failure in 

general practice: implications for the UK National Service Framework. European Journal of Heart Failure 

2003; 5(3):349-354. 

Excluded because BNP assay method is not an included one 

Spevack D, Matros T, Shah A, Dweck E, Tunick P, Spevack DM et al. Clinical improvement with repeated 

courses of intravenous B-type natriuretic peptide in refractory heart failure. European Journal of Heart 

Failure 2004; 6(5):611-613. 

Excluded because this is a case report or series with 10 subjects 

Squire I, Evans J, Ng L, Loftus I, Thompson M, Squire IB et al. Plasma MMP-9 and MMP-2 following 

acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of 

left ventricular dysfunction. Journal of Cardiac Failure 2004; 10(4):328-333. 

Excluded because BNP assay method is not an included one 
D-75 

Stambler BS. Atrial tachycardia and congestive heart failure: New insights from an old experimental 

model. Journal of Cardiovascular Electrophysiology 2004; 15(8):933-935. 

Excluded because adult blood not measured 

Stanek B. BNP Testing in Heart Failure - One Fits All? Journal of Clinical & Basic Cardiology 2003; 6(1-

4):15-18. 

Excluded because not a report of a primary study 

Steele I, McDowell G, Moore A, Campbell N, Shaw C, Buchanan K et al. Responses of atrial natriuretic 

peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control 

subjects. European Journal of Clinical Investigation 1997; 27(4):270-276. 

Excluded because BNP assay method is not an included one 

Stenvinkel P, Pecoits-Filho R, and Lindholm B. Leptin, ghrelin, and proinflammatory cytokines: 

compounds with nutritional impact in chronic kidney disease? Advances in Renal Replacement Therapy 

2003; 10(4):332-345. 

Excluded because adult blood not measured 

Stepan H, Walther T, Walther D, and Faber R. Detection of C-type natriuretic peptide in normal 

pregnancy. Journal of Perinatal Medicine 1998; 26(1):56-58. 

Excluded because BNP assay method is not an included one 

Stevens T, Rasmussen T, Wei C, Kinoshita M, Matsuda Y, and Burnett J et al. Renal role of the 

endogenous natriuretic peptide system in acute congestive heart failure. Journal of Cardiac Failure 1996; 

2(2):119-125. 

Excluded because adult blood not measured 

Stevenson LW. Clinical use of inotropic therapy for heart failure: Looking backward or forward? Part I: 

Inotropic infusions during hospitalization. Circulation 2003; 108(3):367-372. 

Excluded because not a report of a primary study 

Stompor TP. Can we ask the lab how much extra fluid patients carry? Nephron Clinical Practice 2004; 

97(4):c123-c124. 

Excluded because not a report of a primary study 

Storti S, Prontera C, Emdin M, Passino C, Prati P, Fontani G et al. Analytical performance and clinical 

results of a fully automated MEIA system for brain natriuretic peptide assay: comparison with a point of 

care testing method. Clinical Chemistry & Laboratory Medicine 2004; 42(10):1178-1185. 

Excluded because adult blood not measured 

Strain WD. The use of recombinant human B-type natriuretic peptide (nesiritide) in the management of 

acute decompensated heart failure. International Journal of Clinical Practice 2004; 58(11):1081-1087. 

Excluded because not a report of a primary study 

Strametz-Juranek J, Pacher R, Kos T, Woloszczuk W, Grimm M, Zuckermann A et al. Sequential big 

endothelin plasma levels in heart transplant recipients during bridging therapy and after successful heart 

transplantation. Journal of Heart & Lung Transplantation 2003; 22(7):731-737. 

Excluded because BNP assay method is not an included one 

Struthers AD. The effect of ACE inhibitors and atrial natriuretic factor on the cardiorenal axis in man. 

British Journal of Clinical Pharmacology 1992; 34(1):21-24. 

Excluded because not a report of a primary study 
D-76 

Struthers AD. Careful screening to target interventions to prevent sudden cardiac death. Clinical & 

Experimental Pharmacology & Physiology 2001; 28(3):219-222. 

Excluded because not a report of a primary study 

Struthers A, A.D. Plasma concentrations of brain natriuretic peptide: will this new test reduce the need for 

cardiac investigations? British Heart Journal 1993; 70(5):397-398. 

Excluded because not a report of a primary study 

Struthers A, A.D. The diagnosis of heart failure. Heart (British Cardiac Society) 2000; 84(3):334-338. 

Excluded because not a report of a primary study 

Suda M, Komatsu Y, Tanaka K, Yasoda A, Sakuma Y, Tamura N et al. C-Type natriuretic 

peptide/guanylate cyclase B system in rat osteogenic ROB-C26 cells and its down-regulation by 

dexamethazone. Calcified Tissue International 1999; 65(6):472-478. 

Excluded because adult blood not measured 

Suguta M, Hara K, Nakano A, Amano A, Hasegawa A, Kurabayashi M et al. Serum atrial natriuretic 

peptide concentration is a useful predictor of atrial standstill in patients with heart failure. Japanese 

Circulation Journal 2000; 64(7):537-540. 

Excluded because this is a case report or series with 10 subjects 

Sundell J, Engblom E, Koistinen J, Ylitalo A, Naum A, Stolen K et al. The effects of cardiac 

resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in 

patients with dilated cardiomyopathy and heart failure. Journal of the American College of Cardiology 

2004; 43(6):1027-1033. 

Excluded because this is a case report or series with 10 subjects 

Sundqvist P, Feuk U, Haggman M, Persson A, Stridsberg M, Wadstrom J et al. Hand-assisted 

retroperitoneoscopic live donor nephrectomy in comparison to open and laparoscopic procedures: a 

prospective study on donor morbidity and kidney function. Transplantation 1907; 78(1):147-153. 

Excluded because adult blood not measured 

Suo M, Hautala N, Foldes G, Szokodi I, Toth M, Leskinen H et al. Posttranscriptional control of BNP gene 

expression in angiotensin II-induced hypertension. Hypertension 2002; 39(3):803-808. 

Excluded because adult blood not measured 

Suter T, B. Detection of anthracycline-induced cardiotoxicity: Is there light at the end of the tunnel? 

Annals of Oncology 2002; 13(5):647-649. 

Excluded because not a report of a primary study 

Sutovsky I, Katoh T, Ohno T, Honma H, Takayama H, Takano T et al. Relationship between brain 

natriuretic peptide, myocardial wall stress, and ventricular arrhythmia severity. Japanese Heart Journal 

2004; 45(5):771-777. 

Excluded because BNP assay method is not an included one 

Suzuki T, Hayashi D, Yamazaki T, Mizuno T, Kanda Y, Komuro I et al. Elevated B-type natriuretic peptide 

levels after anthracycline administration.[comment]. American Heart Journal 1998; 136(2):362-363. 

Excluded because adult blood not measured 

Svitil K. Needlepoint. Arthritis Today 1997; 11(3):32-37. 

Excluded because not a report of a primary study 

Tabrizchi R. Dual ACE and Neutral Endopeptidase Inhibitors: Novel Therapy for Patients with 

Cardiovascular Disorders. Drugs 2003; 63(20):2185-2202. 

Excluded because not a report of a primary study 
D-77 

Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M et al. Effects of enhanced external 

counterpulsation on hemodynamics and its mechanism. Circulation Journal 2004; 68(11):1030-1034. 

Excluded because BNP assay method is not an included one 

Takahashi K, Ashizawa N, Minami T, Suzuki S, Sakamoto I, Hayashi K et al. Malignant 

pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial 

embolization. Internal Medicine 1999; 38(4):349-354. 

Excluded because not a report of a primary study 

Takahashi K, Sone M, Totsune K, Satoh F, Murakami O, Ohneda M et al. Immunoreactive endothelin in 

the human kidney: comparison with natriuretic peptides. Journal of Cardiovascular Pharmacology 1995; 

26 Suppl 3:S510-S512. 

Excluded because adult blood not measured 

Takahashi K, Totsune K, Sone M, Ohneda M, Murakami O, Itoi K et al. Human brain natriuretic peptidelike immunoreactivity in human brain. Peptides 1992; 13(1):121-123. 

Excluded because adult blood not measured 

Takahashi T, Allen P, Izumo S, Takahashi T, Allen P, and Izumo S. Expression of A-, B-, and C-type 

natriuretic peptide genes in failing and developing human ventricles. Correlation with expression of the 

Ca(2+)-ATPase gene. Circulation Research 1992; 71(1):9-17. 

Excluded because adult blood not measured 

Takahashi T, Anzai T, Yoshikawa T, Maekawa Y, Asakura Y, Satoh T et al. Serum C-reactive protein 

elevation in left ventricular remodeling after acute myocardial infarction - Role of neurohormones and 

cytokines. International Journal of Cardiology 2003; 88(2-3):257-265. 

Excluded because BNP assay method is not an included one 

Takahashi T, Sakuma M, Ikeda J, Nawata J, Demachi J, Kitamukai O et al. Effects and problems of 

continuous infusion of epoprostenol for patients with primary pulmonary hypertension. Internal Medicine 

2002; 41(10):784-788. 

Excluded because BNP assay method is not an included one 

Takano H, I. beta-blockers have beneficial effects even on unclassified cardiomyopathy such as isolated 

ventricular noncompaction. Internal Medicine 2002; 41(8):601-602. 

Excluded because not a report of a primary study 

Takemura G, Fujiwara H, Takatsu Y, Fujiwara T, Nakao K, Takemura G et al. Venticular expression of 

atrial and brain natriuretic peptides in patients with myocarditis. International Journal of Cardiology 1995; 

52(3):213-222. 

Excluded because adult blood not measured 

Takemura G, Takatsu Y, Doyama K, Itoh H, Saito Y, Koshiji M et al. Expression of atrial and brain 

natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis. Journal of the 

American College of Cardiology 2003; 31(4):754-765. 

Excluded because BNP assay method is not an included one 

Takemura K, Yasumura Y, Hirooka K, Hanatani A, Nakatani S, Komamura K et al. Low-dose amiodarone 

for patients with advanced heart failure who are intolerant of beta-blockers. Circulation Journal 2002; 

66(5):441-444. 

Excluded because BNP assay method is not an included one 

Talwar S, Downie P, Squire I, Davies J, Barnett D, Ng L et al. Plasma N-terminal pro BNP and 

cardiotrophin-1 are elevated in aortic stenosis. European Journal of Heart Failure 2001; 3(1):15-19. 

Excluded because BNP assay method is not an included one 
D-78 

Talwar S, Siebenhofer A, Williams B, Ng L, Talwar S, Siebenhofer A et al. Influence of hypertension, left 

ventricular hypertrophy, and left ventricular systolic dysfunction on plasma N terminal proBNP. Heart 

(British Cardiac Society) 2000; 83(3):278-282. 

Excluded because BNP assay method is not an included one 

Talwar S, Squire I, Davies J, Barnett D, and Ng LL. Plasma N-terminal pro-brain natriuretic peptide and 

the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population. European 

Heart Journal 1999; 20(23):1736-1744. 

Excluded because BNP assay method is not an included one 

Talwar S, Squire I, Downie P, Davies J, Ng L, Talwar S et al. Plasma N terminal pro-brain natriuretic 

peptide and cardiotrophin 1 are raised in unstable angina. Heart (British Cardiac Society) 2000; 

84(4):421-424. 

Excluded because BNP assay method is not an included one 

Talwar S, Squire I, Downie P, Mccullough A, Campton M, Davies J et al. Profile of plasma N-terminal 

proBNP following acute myocardial infarction; correlation with left ventricular systolic dysfunction.[see 

comment]. European Heart Journal 2000; 21(18):1514-1521. 

Excluded because BNP assay method is not an included one 

Tamura N, Ogawa Y, Yasoda A, Itoh H, Saito Y, Nakao K et al. Two cardiac natriuretic peptide genes 

(atrial natriuretic peptide and brain natriuretic peptide) are organized in tandem in the mouse and human 

genomes. Journal of Molecular & Cellular Cardiology 1996; 28(8):1811-1815. 

Excluded because adult blood not measured 

Tan F, Moravec C, Li J, Apperson-Hansen C, McCarthy P, Young J et al. The gene expression fingerprint 

of human heart failure. Proceedings of the National Academy of Sciences of the United States of America 

2002; 99(17):11387-11392. 

Excluded because adult blood not measured 

Tan L, Schlosshan D, and Williams SG. The benefits of valsartan in the treatment of heart failure: Results 

from Val-HeFT. International Journal of Clinical Practice 2004; 58(2):184-191. 

Excluded because not a report of a primary study 

Tanabe A, Naruse M, Wasada T, Naruse K, Yoshimoto T, Omori Y et al. Effects of acute 

hyperinsulinemia on plasma atrial and brain natriuretic peptide concentrations. European Journal of 

Endocrinology 1995; 132(6):693-698. 

Excluded because BNP assay method is not an included one 

Tanabe K, Yamamoto A, Suzuki N, Akashi Y, Seki A, Samejima H et al. Exercise-induced changes in 

plasma atrial natriuretic peptide and brain natriuretic peptide concentrations in healthy subjects with 

chronic sleep deprivation. Japanese Circulation Journal 1999; 63(6):447-452. 

Excluded because this is a case report or series with 10 subjects 

Tanaka M, Hiroe M, Nishikawa T, Sato T, Marumo F, Tanaka M et al. Cellular localization and structural 

characterization of natriuretic peptide-expressing ventricular myocytes from patients with dilated 

cardiomyopathy. Journal of Histochemistry & Cytochemistry 1994; 42(9):1207-1214. 

Excluded because adult blood not measured 

Tanaka M, Ishizaka Y, Ishiyama Y, Kato J, Kida O, Kitamura K et al. Exercise-induced secretion of brain 

natriuretic peptide in essential hypertension and normal subjects. Hypertension Research - Clinical & 

Experimental 1995; 18(2):159-166. 

Excluded because BNP assay method is not an included one 
D-79 

Tanaka M, Ishizaka Y, Ishiyama Y, Kato J, Kida O, Kitamura K et al. Chronic effect of beta-adrenoceptor 

blockade on plasma levels of brain natriuretic peptide during exercise in essential hypertension. 

Hypertension Research - Clinical & Experimental 1996; 19(4):239-245. 

Excluded because BNP assay method is not an included one 

Tanaka T, Hasegawa K, Fujita M, Tamaki S, Yamazato A, Kihara Y et al. Marked elevation of brain 

natriuretic peptide levels in pericardial fluid is closely associated with left ventricular dysfunction. Journal 

of the American College of Cardiology 1998; 31(2):399-403. 

Excluded because BNP assay method is not an included one 

Tang W, G.S. Chronic heart failure: 10 Questions physicians often ask. Consultant 2002; 42(6):678-686. 

Excluded because not a report of a primary study 

Tang W, G.S. Evolving concepts in left ventricular systolic and diastolic remodeling: Implications for 

therapy. Current Cardiology Reports 2004; 6(3):200-204. 

Excluded because not a report of a primary study 

Tapanainen J, Lindgren K, Makikallio T, Vuolteenaho O, Leppaluoto J, Huikuri H et al. Natriuretic 

peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the 

beta-blocking era.[see comment]. Journal of the American College of Cardiology 2004; 43(5):757-763. 

Excluded because BNP assay method is not an included one 

Tateyama H, Hino J, Minamino N, Kangawa K, Minamino T, Sakai K et al. Concentrations and molecular 

forms of human brain natriuretic peptide in plasma. Biochemical & Biophysical Research Communications 

2006; 185(2):760-767. 

Excluded because BNP assay method is not an included one 

Tavi P, Laine M, Weckstrom M, and Ruskoaho H. Cardiac mechanotransduction: From sensing to 

disease and treatment. Trends in Pharmacological Sciences 2001; 22(5):254-260. 

Excluded because not a report of a primary study 

Tayama K, Takamori S, Mitsuoka M, Hayashi A, Tamura K, Mifune H et al. Natriuretic peptides after 

pulmonary resection. Annals of Thoracic Surgery 2002; 73(5):1582-1586. 

Excluded because BNP assay method is not an included one 

Tendera M. The epidemiology of heart failure. Journal of the Renin-Angiotensin-Aldosterone System 

2004; 5(SUPPL. 1):S2-S6. 

Excluded because not a report of a primary study 

Terasako K, K. Perioperative plasma concentrations of atrial and brain natriuretic peptides in patients 

undergoing hip arthroplasty. Anaesthesia & Intensive Care 2002; 30(5):588-590. 

Excluded because BNP assay method is not an included one 

Tharaux P, Dussaule J, Hubert-Brierre J, Vahanian A, Acar J, Ardaillou R et al. Plasma atrial and brain 

natriuretic peptides in mitral stenosis treated by valvulotomy. Clinical Science 1994; 87(6):671-677. 

Excluded because BNP assay method is not an included one 

Theorell T, H. Endocrinological and immunological variables sensitive to psychosocial factors of possible 

relevance to work-related musculoskeletal disorders. Work & Stress 2002; 16(2):154-165. 

Excluded because not a report of a primary study 

Therapondos G, Flapan A, Dollinger M, Garden O, Plevris J, Hayes P et al. Cardiac function after 

orthotopic liver transplantation and the effects of immunosuppression: a prospective randomized trial 

comparing cyclosporin (Neoral) and tacrolimus. Liver Transplantation 2002; 8(8):690-700. 

Excluded because BNP assay method is not an included one 
D-80 

Thiriet N, Esteve L, Aunis D, Zwiller J, Thiriet N, Esteve L et al. Immediate early gene induction by 

natriuretic peptides in PC12 phaeochromocytoma and C6 glioma cells. Neuroreport 2001; 8(2):399-402. 

Excluded because adult blood not measured 

Thorens J, Ritz M, Reynard C, Righetti A, Vallotton M, Favre H et al. Haemodynamic and 

endocrinological effects of noninvasive mechanical ventilation in respiratory failure. European Respiratory 

Journal 1997; 10(11):2553-2559. 

Excluded because BNP assay method is not an included one 

Tiret L, Mallet C, Poirier O, Nicaud V, Millaire A, Bouhour J et al. Lack of association between 

polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. 

Journal of the American College of Cardiology 2000; 35(1):29-35. 

Excluded because adult blood not measured 

Tjeerdsma G, van Wijk L, Molhoek G, Boomsma F, Haaksma J, and van Veldhuisen DJ. Autonomic and 

hemodynamic effects of a new selective dopamine agonist, CHF1035, in patients with chronic heart 

failure. Cardiovascular Drugs & Therapy 2001; 15(2):139-145. 

Excluded because BNP assay method is not an included one 

Togashi K, Ando K, Hasegawa N, Kawakami M, Marumo F, Togashi K et al. Concentrations of brain 

natriuretic peptide in treated congestive heart failure. Clinical Chemistry 1991; 37(5):765. 

Excluded because not a report of a primary study 

Togashi K, Fujita S, Kawakami M, Togashi K, Fujita S, and Kawakami M. Presence of brain natriuretic 

peptide in urine. Clinical Chemistry 1992; 38(2):322-323. 

Excluded because adult blood not measured 

Togashi K, Hirata Y, Ando K, Takei Y, Kawakami M, Marumo F et al. Brain natriuretic peptide-like 

immunoreactivity is present in human plasma. FEBS Letters 1989; 250(2):235-237. 

Excluded because adult blood not measured 

Togashi K, Kameya T, Ando K, Marumo F, Kawakami M, Togashi K et al. Brain natriuretic peptides in 

human plasma, spinal cord and cerebrospinal fluid. Clinica Chimica Acta 1909; 201(3):193-200. 

Excluded because adult blood not measured 

Tomiyama H, Kushiro T, Imai S, Suzuki Y, Akutsu N, Ebuchi T et al. Changes in the E/A ratio induced by 

handgrip-exercise are related to changes in the plasma atrial natriuretic peptide level, but not to changes 

in brain natriuretic peptide in mild essential hypertension. Japanese Circulation Journal 1995; 59(9):617-

623. 

Excluded because BNP assay method is not an included one 

Totsuka N, Awata N, Takahashi K, Yamamura H, Nakamura J, Tsuchikane E et al. A single-center, openlabel, randomized, parallel-group study assessing the differences between an angiotensin II receptor 

antagonist and an angiotensin-converting enzyme inhibitor in hypertensive patients with congestive heart 

failure: The research for efficacy of angiotensin II receptor antagonist in hypertensive patients with 

congestive heart failure study. Current Therapeutic Research, Clinical & Experimental 2003; 64(2):81-94. 

Excluded because BNP assay method is not an included one 

Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, and Mouri T. Elevated plasma C-type natriuretic 

peptide concentrations in patients with chronic renal failure. Clinical Science 1994; 87(3):319-322. 

Excluded because BNP assay method is not an included one 

Totsune K, Takahashi K, Satoh F, Sone M, Ohneda M, Satoh C et al. Urinary immunoreactive brain 

natriuretic peptide in patients with renal disease. Regulatory Peptides 1996; 63(2-3):141-147. 

Excluded because adult blood not measured 
D-81 

Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, Ohneda M et al. Immunoreactive brain 

natriuretic peptide in human adrenal glands and adrenal tumors. European Journal of Endocrinology 

1996; 135(3):352-356. 

Excluded because adult blood not measured 

Trinity E, F.S. Brain natriuretic peptide in the diagnosis and management of congestive heart failure. 

Laboratory Medicine 2002; 33(10):793-796. 

Excluded because not a report of a primary study 

Troughton R, Prior D, Pereira J, Martin M, Fogarty A, Morehead A et al. Plasma B-type natriuretic peptide 

levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic 

function. Journal of the American College of Cardiology 2004; 43(3):416-422. 

Excluded because BNP assay method is not an included one 

Troughton R, Richards A, Nicholls M, Troughton R, Richards A, and Nicholls MG. Individualized treatment 

of heart failure. Internal Medicine Journal 2001; 31(3):138-141. 

Excluded because not a report of a primary study 

Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutrition Reviews 

1999; 57(8):231-240. 

Excluded because adult blood not measured 

Tsubokawa T, Shiokawa Y, Kurita H, and Kaneko N. High plasma concentration of brain natriuretic 

peptide in patients with ruptured anterior communicating artery aneurysm. Neurological Research 2004; 

26(8):893-896. 

Excluded because BNP assay method is not an included one 

Tsuji T, Imagawa K, Masuda H, Haraikawa M, Shibata K, Kono M et al. Stabilization of human brain 

natriuretic peptide in blood samples. Clinical Chemistry 1994; 40(4):672-673. 

Excluded because not a report of a primary study 

Tsutamoto T, Wada A, Maeda K, Hayashi M, Tsutsui T, Ohnishi M et al. Transcardiac gradient of 

aldosterone before and after spironolactone in patients with congestive heart failure. Journal of 

Cardiovascular Pharmacology 2003; 41 Suppl 1:S19-S22. 

Excluded because this is a case report or series with 10 subjects 

Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S et al. Angiotensin II type 2 receptor 

is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its 

expression. Circulation Research 1998; 83(10):1035-1046. 

Excluded because adult blood not measured 

Tuinenburg A, Brundel B, Van Gelder I, Henning R, van den Berg M, Driessen C et al. Gene expression 

of the natriuretic peptide system in atrial tissue of patients with paroxysmal and persistent atrial fibrillation. 

Journal of Cardiovascular Electrophysiology 1999; 10(6):827-835. 

Excluded because adult blood not measured 

Twickler MT. Cardiovascular endocrinology. Seminars in Vascular Medicine 2004; 4(2):105-106. 

Excluded because not a report of a primary study 

Ueda R, Yokouchi M, Suzuki T, Otomo E, Katagiri T, Ueda RYMSTOEaKT. Plasma brain natriuretic 

peptide levels increase in proportion to changes in pulmonary artery pressure in old-old persons. Journal 

of the American Geriatrics Society 2003; 51(6):891-893. 

Excluded because not a report of a primary study 
D-82 

Ueki R, Okutani R, Fukushima A, Tsuji T, Ohata H, and Tashiro C. Perioperative endocrinological findings 

in a patient with Bartter's syndrome and living-related renal transplantation. Journal of Anesthesia 2000; 

14(2):105-108. 

Excluded because BNP assay method is not an included one 

Ueno S, Ikeda U, Hojo Y, Arakawa H, Nonaka M, Yamamoto K et al. Serum hepatocyte growth factor 

levels are increased in patients with congestive heart failure. Journal of Cardiac Failure 2001; 7(4):329-

334. 

Excluded because BNP assay method is not an included one 

Usuki S, Nakauchi T, Higa S, and Someya K. The improvement of luteal insufficiency in fecund women by 

Tokishakuyakusan treatment. American Journal of Chinese Medicine 2002; 30(2/3):327-338. 

Excluded because adult blood not measured 

Uusimaa P, Ruskoaho H, Vuolteenaho O, Niemela M, Lumme J, Ikaheimo M et al. Plasma vasoactive 

peptides after acute myocardial infarction in relation to left ventricular dysfunction. International Journal of 

Cardiology 2004; 69(1):5-14. 

Excluded because BNP assay method is not an included one 

Uusimaa P, Tokola H, Ylitalo A, Vuolteenaho O, Ruskoaho H, Risteli J et al. Plasma B-type natriuretic 

peptide reflects left ventricular hypertrophy and diastolic function in hypertension. International Journal of 

Cardiology 2004; 97(2):251-256. 

Excluded because BNP assay method is not an included one 

Valli N, Georges A, Corcuff J, Barat J, Bordenave L, Valli N et al. Assessment of brain natriuretic peptide 

in patients with suspected heart failure: comparison with radionuclide ventriculography data. Clinica 

Chimica Acta 2001; 306(1-2):19-26. 

Excluded because BNP assay method is not an included one 

van den Berg M, Tjeerdsma G, Lefrandt J, Smit A, van den Meiracker A, Van Roon A et al. Effect of lower 

body negative pressure in patients with mild congestive heart failure. American Journal of Cardiology 

2003; 91(6):759-762. 

Excluded because BNP assay method is not an included one 

Van den Berghe GHA. The neuroendocrine stress response and modern intensive care: the concept 

revisited. Burns 1999; 25(1):7-16. 

Excluded because not a report of a primary study 

van der Merwe D, Henley R, Lane G, Field R, Frenneaux M, Dunstan F et al. Effect of different sample 

types and stability after blood collection of N-terminal pro-B-type natriuretic peptide as measured with 

Roche Elecsys system. Clinical Chemistry 2004; 50(4):779-780. 

Excluded because not a report of a primary study 

van der ZK, Houben A, Kroon A, de Leeuw P, van der Zander K, Houben A et al. Effects of brain 

natriuretic peptide on forearm vasculature: comparison with atrial natriuretic peptide. Cardiovascular 

Research 1999; 44(3):595-600. 

Excluded because BNP assay method is not an included one 

van der ZK, Houben A, Kroon A, De Mey J, Smits P, de Leeuw P et al. Nitric oxide and potassium 

channels are involved in brain natriuretic peptide induced vasodilatation in man. Journal of Hypertension 

2002; 20(3):493-499. 

Excluded because adult blood not measured 

van der ZK, Houben A, Hofstra L, Kroon A, de Leeuw P, van der Zander KHAJ et al. Hemodynamic and 

renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled 
D-83 

crossover study. American Journal of Physiology - Heart & Circulatory Physiology 2003; 285(3):H1206-

H1212. 

Excluded because adult blood not measured 

van der ZK, Houben A, Kroon A, Wierema T, Fuss-Lejeune M, Koster D et al. Does brain natriuretic 

peptide have a direct renal effect in human hypertensives? Hypertension 2003; 41(1):119-123. 

Excluded because BNP assay method is not an included one 

van Veldhuisen D, Genth-Zotz S, Brouwer J, Boomsma F, Netzer T, Man in 't Veld AJ PY et al. Highversus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of 

imidapril. Journal of the American College of Cardiology 1998; 32(7):1811-1818. 

Excluded because BNP assay method is not an included one 

van Veldhuisen D, W.H. Vasopeptidase inhibition in heart failure [8]. Lancet 2000; 356(9240):1526. 

Excluded because not a report of a primary study 

Vasan RS. Diastolic heart failure. British Medical Journal 2003; 327(7425):1181-1182. 

Excluded because not a report of a primary study 

Vesely DL. Congestive heart failure update: new cardiac peptides in diagnosis and treatment. Consultant 

259; 40(2):253-256. 

Excluded because not a report of a primary study 

Vesely DL. Atrial natriuretic peptides in the diagnosis and treatment of congestive heart failure. 

Prevention & Management of Congestive Heart Failure 1999; 5(4). 

Excluded because not a report of a primary study 

Villarreal D, Freeman R, and Reams GP. Natriuretic peptides and salt sensitivity: Endocrine cardiorenal 

integration in heart failure. Prevention & Management of Congestive Heart Failure 2002; 8(1):29-36. 

Excluded because not a report of a primary study 

Vincent SR. The ascending reticular activating system - From aminergic neurons to nitric oxide. Journal of 

Chemical Neuroanatomy 2000; 18(1-2):23-30. 

Excluded because not a report of a primary study 

Von Kaisenberg C, Huggon I, Hyett J, Farzaneh F, Nicolaides K, Von Kaisenberg C et al. Cardiac gene 

expression of GATA-4 transcription factor in human trisomy 21 fetuses with increased nuchal 

translucency. Prenatal Diagnosis 1998; 18(3):267-271. 

Excluded because adult blood not measured 

Wagoner L, W.T. The use of B-type natriuretic peptide (BNP, nesiritide) for the treatment of congestive 

heart failure. Today's Therapeutic Trends 1999; 17(2):113-131. 

Excluded because not a report of a primary study 

Wakaumi M, Shiga T, Nozaki K, Fujiu K, Shimaya K, Ishizuka N et al. Plasma brain natriuretic peptide as 

a parameter to assess efficacy of continuous intravenous infusion of prostacyclin (epoprostenol) to treat 

severe primary pulmonary hypertension: a case report. Heart & Vessels 2000; 15(3):144-146. 

Excluded because BNP assay method is not an included one 

Wakaumi M, Shiga T, Naganuma M, Matsuda N, Tatami S, Kasanuki H et al. Plasma concentration profile 

of orally administered pimobendan and plasma brain natriuretic peptide level in patients with severe heart 

failure. Cardiovascular Drugs & Therapy 2003; 17(3):291-293. 

Excluded because not a report of a primary study 
D-84 

Wallbridge D, MacIntyre H, Gray C, Oldroyd K, Rae A, Cobbe S et al. Role of endogenous opioids and 

catecholamines in vasovagal syncope.[see comment]. European Heart Journal 1996; 17(11):1729-1736. 

Excluded because BNP assay method is not an included one 

Walter M, Berendes E, Claviez A, Suttorp M, Walter M, Berendes E et al. Inappropriate secretion of 

natriuretic peptides in a patient with a cerebral tumor. JAMA: Journal of the American Medical Association 

1999; 282(1):27-28. 

Excluded because not a report of a primary study 

Walther T, Heringer-Walther S, Wessel N, Schultheiss H, Moreira MC, Walther TH-WSWNSHPaMMdC. 

Brain natriuretic peptide as a predictor of cardiomyopathy in Chagas' disease.[see comment][comment]. 

Lancet 2003; 361(9368):1567. 

Excluded because not a report of a primary study 

Walther T, Stepan H, Pankow K, Gembardt F, Faber R, Schultheiss H et al. Relation of ANP and BNP to 

their N-terminal fragments in fetal circulation: evidence for enhanced neutral endopeptidase activity and 

resistance of BNP to neutral endopeptidase in the fetus. BJOG: an International Journal of Obstetrics & 

Gynaecology 2004; 111(5):452-455. 

Excluded because adult blood not measured 

Wambach G, Koch J, Wambach G, and Koch J. BNP plasma levels during acute volume expansion and 

chronic sodium loading in normal men. Clinical & Experimental Hypertension (New York) 1995; 17(4):619-

629. 

Excluded because BNP assay method is not an included one 

Wang C, Cherng W, Chen F, and Lee N. Short-term hormone replacement therapy in postmenopausal 

women improves Doppler-derived aortic flow parameters and aortic root function. Journal of Medical 

Ultrasound 2000; 8(1):22-28. 

Excluded because BNP assay method is not an included one 

Wang D, Dowling T, Meadows D, Ayala T, Marshall J, Minshall S et al. Nesiritide does not improve renal 

function in patients with chronic heart failure and worsening serum creatinine. Circulation 2004; 

110(12):1620-1625. 

Excluded because BNP assay method is not an included one 

Wang T, H. Intravenous morphine reduces plasma endothelin 1 concentration through activation of 

neutral endopeptidase 24.11 in patients with myocardial infarction. Annals of Emergency Medicine 2001; 

37(5):445-449. 

Excluded because BNP assay method is not an included one 

Wang W, Ou Y, Shi Y, Wang WOYaSY. AlbuBNP, a recombinant B-type natriuretic peptide and human 

serum albumin fusion hormone, as a long-term therapy of congestive heart failure. Pharmaceutical 

Research 2004; 21(11):2105-2111. 

Excluded because adult blood not measured 

Watanabe H, Lau D, Guyn H, Wong N, Watanabe H, Lau D et al. Effect of progesterone therapy on 

arginine vasopressin and atrial natriuretic factor in premenstrual syndrome. Clinical & Investigative 

Medicine - Medecine Clinique et Experimentale 1997; 20(4):211-223. 

Excluded because BNP assay method is not an included one 

Watanabe Y, Nakajima K, Shimamori Y, Fujimoto Y, Watanabe Y, Nakajima K et al. Comparison of the 

hydrolysis of the three types of natriuretic peptides by human kidney neutral endopeptidase 24.11. 

Biochemical & Molecular Medicine 1997; 61(1):47-51. 

Excluded because adult blood not measured 
D-85 

Wei C, Heublein D, Perrella M, Lerman A, Rodeheffer R, McGregor C et al. Natriuretic peptide system in 

human heart failure. Circulation 1993; 88(3):1004-1009. 

Excluded because BNP assay method is not an included one 

Wei T, Zeng C, Chen L, Chen Q, Zhao R, Lu G et al. Bedside tests of B-type natriuretic peptide in the 

diagnosis of left ventricular diastolic dysfunction in hypertensive patients. European Journal of Heart 

Failure 2005; 7(1):75-79. 

Excluded because BNP assay method is not an included one 

Weinberg E, Shimpo M, Hurwitz S, Tominaga S, Rouleau J, Lee R et al. Identification of serum soluble 

ST2 receptor as a novel heart failure biomarker. Circulation 2003; 107(5):721-726. 

Excluded because BNP assay method is not an included one 

White M, Rouleau J, Hall C, Arnold M, Harel F, Sirois P et al. Changes in vasoconstrictive hormones, 

natriuretic peptides, and left ventricular remodeling soon after anterior myocardial infarction. American 

Heart Journal 2001; 142(6):1056-1064. 

Excluded because BNP assay method is not an included one 

Wians F, Jr, Wilson B, Grant A, Bailey J, Gheorghiu I et al. Evaluation of the analytical performance 

characteristics of the Bayer ACS:180(R) B-type natriuretic peptide (BNP) assay. Clinica Chimica Acta 

2005; 353(1-2):147-155. 

Excluded because BNP assay method is not an included one 

Wijdicks E, Heublein D, Burnett J, Jr, Wijdicks E, Heublein D et al. Increase and uncoupling of 

adrenomedullin from the natriuretic peptide system in aneurysmal subarachnoid hemorrhage. Journal of 

Neurosurgery 2001; 94(2):252-256. 

Excluded because BNP assay method is not an included one 

Wijdicks E, Schievink W, Burnett J, Jr, Wijdicks E, Schievink W et al. Natriuretic peptide system and 

endothelin in aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 1997; 87(2):275-280. 

Excluded because BNP assay method is not an included one 

Wijeysundera H, Hansen M, Stanton E, Cropp A, Hall C, Dhalla N et al. Neurohormones and oxidative 

stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine. 

American Heart Journal 2003; 146(2):291-297. 

Excluded because BNP assay method is not an included one 

Wiley K, Davenport A, Wiley K, and Davenport AP. Physiological antagonism of endothelin-1 in human 

conductance and resistance coronary artery. British Journal of Pharmacology 2001; 133(4):568-574. 

Excluded because adult blood not measured 

Wilkins MR. Clinical potential of endopeptidase-24.11 inhibitors in cardiovascular disease. Biochemical 

Society Transactions 1993; 21(3):673-678. 

Excluded because not a report of a primary study 

Wilkins M, Redondo J, and Brown LA. The natriuretic-peptide family. Lancet 1997; 349(9061):1307-1310. 

Excluded because not a report of a primary study 

Wilkins M, Su X, Palayew M, Yamashiro Y, Rolli P, McKenzie J et al. The effects of posture change and 

continuous positive airway pressure on cardiac natriuretic peptides in congestive heart failure. Chest 

1995; 107(4):909-915. 

Excluded because BNP assay method is not an included one 

Williams DG. New "wheys" to raise glutathione levels. ALTERNATIVES 1997; 7(6):41-44. 

Excluded because adult blood not measured 
D-86 

Williams S, L.B. Aldosterone antagonists: Current and future perspectives. Current Opinion in 

Cardiovascular, Pulmonary & Renal Investigational Drugs 2000; 2(4):310-315. 

Excluded because not a report of a primary study 

Williams S, Ng L, O'Brien R, Taylor S, Wright D, Tan L et al. Is plasma N-BNP a good indicator of the 

functional reserve of failing hearts? The FRESH-BNP study. European Journal of Heart Failure 2004; 

6(7):891-900. 

Excluded because BNP assay method is not an included one 

Williams S, Ng L, O'Brien R, Taylor S, Li Y, Tan L et al. Comparison of plasma N-brain natriuretic peptide, 

peak oxygen consumption, and left ventricular ejection fraction for severity of chronic heart failure. 

American Journal of Cardiology 2006; 93(12):1560-1561. 

Excluded because BNP assay method is not an included one 

Winter R, Laurent G, Gauldie J, Lever J, Peacock A, Reeves J et al. Attenuation of pulmonary vascular 

remodelling by natriuretic peptides. European Respiratory Review 1993; 3(16):576-580. 

Excluded because adult blood not measured 

Winter W, R.J. The role and assessment of ventricular peptides in heart failure. Clinics in Laboratory 

Medicine 2004; 24(1):235-274. 

Excluded because not a report of a primary study 

Witteles R, Matsuda K, Fowler M, Witteles RMKaFMB. B-type natriuretic peptide is effective therapy 

before care. Annals of Internal Medicine 2004; 141(11):895. 

Excluded because not a report of a primary study 

Witthaut R, Busch C, Fraunberger P, Walli A, Seidel D, Pilz G et al. Plasma atrial natriuretic peptide and 

brain natriuretic peptide are increased in septic shock: impact of interleukin-6 and sepsis-associated left 

ventricular dysfunction. Intensive Care Medicine 2003; 29(10):1696-1702. 

Excluded because BNP assay method is not an included one 

Witzel K. Effects of emergency ambulance transportation on heart rate, blood pressure, corticotropin, and 

cortisol. Annals of Emergency Medicine 1999; 33(5):598-599. 

Excluded because not a report of a primary study 

Wong F, Siu S, Liu P, Blendis L, Wong F, Siu S et al. Brain natriuretic peptide: is it a predictor of 

cardiomyopathy in cirrhosis? Clinical Science 2001; 101(6):621-628. 

Excluded because BNP assay method is not an included one 

Woo M, P.B. Fludrocortisone in the treatment of subarachnoid hemorrhage-induced hyponatremia. 

Annals of Pharmacotherapy 1997; 31(5):637-639. 

Excluded because not a report of a primary study 

Worthley M, Corti R, and Worthley SG. Vasopeptidase inhibitors: Will they have a role in clinical practice? 

British Journal of Clinical Pharmacology 2004; 57(1):27-36. 

Excluded because not a report of a primary study 

Wozakowska-Kaplon B, Beata. Effect of sinus rhythm restoration on plasma brain natriuretic peptide in 

patients with atrial fibrillation. American Journal of Cardiology 2006; 93(12):1555-1558. 

Excluded because BNP assay method is not an included one 

Wu AHB. Analytical and clinical evaluation of new diagnostic tests for myocardial damage. Clinica 

Chimica Acta 1998; 272(1):11-21. 

Excluded because not a report of a primary study 
D-87 

Wu AHB. B-type natriuretic peptide for congestive heart failure. Journal of Clinical Ligand Assay 2002; 

25(2):155-159. 

Excluded because not a report of a primary study 

Wu A, Smith A, Wu AH, and Smith A. Biological variation of the natriuretic peptides and their role in 

monitoring patients with heart failure. [Review] [9 refs]. European Journal of Heart Failure 2003; 6(3):355-

358. 

Excluded because not a report of a primary study 

Yakubo S, Yagi H, Yamaoka K, Hanakawa K, Ariga H, Takase H et al. A case with heart failure improved 

by Moku-boi-to of Chinese origin by decreased blood concentration of brain natriuretic peptide. Nihon 

University Journal of Medicine 1998; 40(5):309-314. 

Excluded because BNP assay method is not an included one 

Yamahara K, Itoh H, Yamamoto A, Sasano H, Masatsugu K, Sawada N et al. New diagnostic procedure 

for primary aldosteronism: Adrenal venous sampling under adrenocorticotropic hormone and angiotensin 

II receptor blocker - Application to a case of bilateral multiple adrenal microadenomas. Hypertension 

Research 2002; 25(2):145-152. 

Excluded because not a report of a primary study 

Yamamoto K, Dang Q, Maeda Y, Huang H, Kelly R, Lee R et al. Regulation of cardiomyocyte 

mechanotransduction by the cardiac cycle.[see comment]. Circulation 2003; 103(10):1459-1464. 

Excluded because adult blood not measured 

Yamazaki H, Senju Y, Kinoshita N, Katsukawa F, Onishi S, Yamazaki H et al. Plasma brain natriuretic 

peptide in athletes. American Journal of Cardiology 2000; 85(11):1393-1394. 

Excluded because not a report of a primary study 

Yancy C, Saltzberg M, Berkowitz R, Bertolet B, Vijayaraghavan K, Burnham K et al. Safety and feasibility 

of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial). 

American Journal of Cardiology 2004; 94(5):595-601. 

Excluded because adult blood not measured 

Yandle T, Fisher S, Livesey J, Espiner E, Richards M, Nicholls G et al. Exponential increase in clinical 

use of plasma brain natriuretic peptide (BNP) assays. New Zealand Medical Journal 2004; 

117(1197):U956. 

Excluded because adult blood not measured 

Yandle T, Richards A, Gilbert A, Fisher S, Holmes S, Espiner E et al. Assay of brain natriuretic peptide 

(BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart 

failure. Journal of Clinical Endocrinology & Metabolism 1993; 76(4):832-838. 

Excluded because BNP assay method is not an included one 

Yano Y, Gabazza E, Katsuki A, Furuta M, Tanaka T, Araki-Sasaki R et al. Plasma levels of natriuretic 

peptides are correlated with renin activity in normotensive type 2 diabetic patients. Diabetes Care 2000; 

23(12):1853-1855. 

Excluded because not a report of a primary study 

Yarabe H, Rugutt J, McCarroll M, Warner I, Yarabe H, Rugutt J et al. Capillary electrophoretic separation 

of binaphthyl enantiomers with two polymeric chiral surfactants: 1H-nuclear magnetic resonance and 

fluorescence spectroscopy study. Electrophoresis 2000; 21(10):2025-2032. 

Excluded because adult blood not measured 
D-88 

Yasue H, Yoshimura M, Yasue H, and Yoshimura M. Natriuretic peptides in the treatment of heart failure. 

Journal of Cardiac Failure 1996; 2(4 Suppl):S277-S285. 

Excluded because BNP used as treatment 

Yasumoto K, Takata M, Ueno H, Tomita S, Tomoda F, Inoue H et al. Relation of plasma brain and atrial 

natriuretic peptides to left ventricular geometric patterns in essential hypertension. American Journal of 

Hypertension 1999; 12(9 Pt 1):921-924. 

Excluded because BNP assay method is not an included one 

Yasumura Y, Miyatake K, Okamoto H, Miyauchi T, Kawana M, Tsutamoto T et al. Rationale for the use of 

combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart 

failure. Circulation Journal 2004; 68(4):361-366. 

Excluded because BNP assay method is not an included one 

Yasumura Y, Takemura K, Sakamoto A, Kitakaze M, Miyatake K, Yasumura YTKSAKMaMK. Changes in 

myocardial gene expression associated with beta-blocker therapy in patients with chronic heart failure. 

Journal of Cardiac Failure 2003; 9(6):469-474. 

Excluded because this is a case report or series with 10 subjects 

Yeo K, Wu A, Apple F, Kroll M, Christenson R, Lewandrowski K et al. Multicenter evaluation of the Roche 

NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clinica Chimica Acta 2003; 338(1-

2):107-115. 

Excluded because BNP assay method is not an included one 

Ylitalo K, Uusimaa P, Vuolteenaho O, Ruskoaho H, Peuhkurinen K, Ylitalo K et al. Vasoactive peptide 

release in relation to hemodynamic and metabolic changes during rapid ventricular pacing. Pacing & 

Clinical Electrophysiology 1999; 22(7):1064-1070. 

Excluded because BNP assay method is not an included one 

Yoshibayashi M, Kamiya T, Saito Y, Matsuo H, Yoshibayashi M, Kamiya T et al. Increased plasma levels 

of brain natriuretic peptide in hypertrophic cardiomyopathy. New England Journal of Medicine 1993; 

329(6):433-434. 

Excluded because not a report of a primary study 

Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M et al. Hemodynamic, renal, and 

hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. 

Circulation 1991; 84(4):1581-1588. 

Excluded because BNP assay method is not an included one 

Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M, Mukoyama M et al. Different secretion 

patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. 

Circulation 1993; 87(2):464-469. 

Excluded because BNP assay method is not an included one 

Yoshimura M, Yasue H, Tanaka H, Kikuta K, Sumida H, Kato H et al. Responses of plasma 

concentrations of A type natriuretic peptide and B type natriuretic peptide to alacepril, an angiotensinconverting enzyme inhibitor, in patients with congestive heart failure.[see comment]. British Heart Journal 

1994; 72(6):528-533. 

Excluded because BNP assay method is not an included one 

Yoshimura N, Yamaguchi M, Oshima Y, Oka S, Ootaki Y, Hasegawa T et al. Suppression of the secretion 

of atrial and brain natriuretic peptide after total cavopulmonary connection. Journal of Thoracic & 

Cardiovascular Surgery 2000; 120(4):764-769. 

Excluded because adult blood not measured 
D-89 

Yoshimura T, Yoshimura M, Yasue H, Ito M, Okamura H, Mukoyama M et al. Plasma concentration of 

atrial natriuretic peptide and brain natriuretic peptide during normal human pregnancy and the postpartum 

period. Journal of Endocrinology 1994; 140(3):393-397. 

Excluded because BNP assay method is not an included one 

Young J, Correia N, Francis G, Maisel A, Michota F, Young JB et al. Testing for B-type natriuretic peptide 

in the diagnosis and assessment of heart failure: what are the nuances? Cleveland Clinic Journal of 

Medicine 2004; 71 Suppl 5:S1-17. 

Excluded because not a report of a primary study 

Yu C, Sanderson J, Shum I, Chan S, Yeung L, Hung Y et al. Diastolic dysfunction and natriuretic peptides 

in systolic heart failure. Higher ANP and BNP levels are associated with the restrictive filling pattern.[see 

comment]. European Heart Journal 1996; 17(11):1694-1702. 

Excluded because BNP assay method is not an included one 

Yu C, Sanderson J, Yu C, and Sanderson JE. Plasma brain natriuretic peptide--an independent predictor 

of cardiovascular mortality in acute heart failure. European Journal of Heart Failure 1999; 1(1):59-65. 

Excluded because BNP assay method is not an included one 

Zheng B, Wen J, Han M, Zhou A, Zheng BWJKHMaZAR. hhLIM protein is involved in cardiac 

hypertrophy. Biochimica et Biophysica Acta 2004; 1690(1):1-10. 

Excluded because adult blood not measured 

Zinchuk V. Histology and histochemistry of heart muscle: Toward function with structure in mind. 

Microscopy Research & Technique 2002; 58(5):377. 

Excluded because not a report of a primary study 

Zoccali C, Mallamaci F, Benedetto F, Tripepi G, Parlongo S, Cataliotti A et al. Cardiac natriuretic peptides 

are related to left ventricular mass and function and predict mortality in dialysis patients. Journal of the 

American Society of Nephrology 2001; 12(7):1508-1515. 

Excluded because BNP assay method is not an included one 

Zolle O, Lawrie A, Simpson A, Zolle O, Lawrie A, and Simpson AW. Activation of the particulate and not 

the soluble guanylate cyclase leads to the inhibition of Ca2+ extrusion through localized elevation of 

cGMP. Journal of Biological Chemistry 1908; 275(34):25892-25899. 

Excluded because adult blood not measured 
E-1 

Appendix E: Technical Expert Panel 

Robert Christenson, PhD, DABCC, FACB 

Professor 

Director of Rapid Response Laboratories 

University of Maryland School of Medicine 

John G. Cleland, MD 

Academic Department of Cardiology 

Castle Hill Hospital 

Carla Herrerias, BS, MPH 

Clinical Research Analyst 

American College of Chest Physicians 

Allan Jaffe, MD 

Cardiovascular Diseases 

Mayo Medical School/Clinic 

Ijaz Khan, 

Associate Professor of Medicine 

University of Maryland School of Medicine 

Theresa McDonagh 

Honorary Clinical Senior Lecturer 

Royal Brompton Hospital 

Thomas Moyer 

Mayo Clinic 

Rochester, Minnesota 

Mark Richards 

Professor 

Christchurch School of Medicine and Health Sciences 

Scott Silvers, MD 

Assistant Professor of Medicine 

Mayo Clinic 

Vincenza Snow 

American College of Physicians 
E-2 

Peer Reviewers 

Fred Apple, PhD, University of Minnesota School of Medicine, Minneapolis, MN, USA 

Brad Brimhall, MD, MPH, University of Colorado Hospital, Denver, CO, USA 

Robert Christenson, PhD, DABCC, FACB, University of Maryland School of Medicine, 

Baltimore, MD, USA 

John G. Cleland MD, Castle Hill Hospital, Kingston upon Hull, UK 

Jenny Doust, BMBS, FRACGP, University of Queensland, Herston, Queensland, 

Australia 

Carla Herrerias, BS, MPH, American College of Chest Physicians, Northbrook, IL, USA 

Ijaz Khan, MD, University of Maryland School of Medicine, Baltimore, MD, USA 

Stephen C. Mockrin, Ph.D., National Institutes of Health, Bethesda, MD, USA 

Amir Qaseem, MD, PhD, MHA, American College of Physicians, Philadelphia, PA, USA 

Scott Silvers, MD, Mayo Clinic, Jacksonville, FL, USA 

Wilson Tang, MD, FACC, Cleveland Clinic Foundation, Cleveland OH, USA 

David Atkins, MD, MPH, Agency for Healthcare Research and Quality, Rockville, MD, 

USA, 
E-3 

Structured format for collecting referee comments 

We are pleased that you have agreed to review this interim report and thank you 

in advance for your time. We greatly value your feedback and have provided a 

series of questions to collect your comments. We have structured these queries 

into two parts: the first asks for your global impressions of the report and the 

second part concerns specific components of the systematic review. Lastly, we 

provide a section for you to write any additional comments that we did not directly 

probe. 

Please note that we are constrained to the format and style of the report as 

prescribed by AHRQ publication guidelines. However, within this framework, we 

also ask that you comment on the style and format of the report for purposes of 

disseminating these findings. 

Please complete this form providing as much information as possible including 

any references or website links. Thank you again for reviewing this report. 

Part I – General comments for the AHRQ report 

1. Is the Abstract clear and does it provide the pertinent findings? 

2. Would you like to see the Executive Summary highlighting different 

information? Is there information that is excessive or lacking? 

3. Is the information in the introduction (Chapter1) sufficient background to 

prepare the reader for grasping the complexities of the topic and research 

questions being undertaken in the systematic review? 

4. Does the analytic framework convey the essence of how the report was 

conceptualized? 

5. Were the selection criteria appropriate and clearly presented? Do you have 

any concerns about them and how they may have affected the relevance of 

the report? 

6. Was there conceptual clarity and methodological rigor? (clarity of 

assumptions and results, treatment of literature, logical reasoning) 

7. Do you have any general concerns about the applicability of this report? 

8. What are the strengths of this report or those components you valued most? 
E-4 

Part II – Question specific section comments for the AHRQ 

report

Study Identification 

• Is there a thorough search for relevant data using appropriate resources? 

• Are there unbiased explicit searching strategies that are appropriately 

matched to the question? 

Study Selection 

• Are appropriate inclusion and exclusion criteria used to select articles? 

• Are selection criteria applied in a manner that limits bias? 

• Are efforts made to identified unpublished data, if this is appropriate? 

• Are major changes in selection criteria avoided during the review process? 

• Are reasons for excluding studies from the report stated? 

Appraisal of Studies 

• Is the validity of individual studies addressed in a reliable manner? 

• Are important parameters (e.g., setting, study population, study design) that 

could affect study results systematically addressed? 

Data Collection 

• Is there a minimal amount of missing information regarding outcomes and 

other variables considered key to interpretation of results? 

• Are efforts made to reduce bias in the data collection process? 

Data Synthesis 

• Are important parameters, such as study designs, considered in the 

synthesis? 

• Are reasonable decisions made concerning whether and how to combine the 

data? 

• Are results sensitive to changes in the way the analysis was done? 

• Is precision of results reported? 

 

Discussion 

• Are limitations and inconsistencies of studies stated? 

• Are limitations of the review process stated? 

• Are review finding integrated within the context of relevant indirect evidence? 

• Are implications for research discussed 

• Are implications for practice discussed? 
E-5 

Conclusions 

• Are conclusions supported by the data reviewed? 

• Are plausible competing explanations of observed effects addressed? 

• Is evidence appropriately interpreted as inconclusive (no evidence of effect) 

or as showing a particular strategy did not work (evidence of no effect)? 

• Are important considerations for decision makers identified, including values 

and contextual factors that might influence decisions? 

• Is a summary of pertinent findings provided? 

Future Recommendations 

• Are the future directions described relevant? 

Open Comments 

• Are there any other comments or suggestions you would like to make ? 

This is the end 

. 

Thank you for your expertise in reviewing this report for us.