Evidence Report/Technology Assessment 

Number 106 

Cardiac Resynchronization Therapy for 

Congestive Heart Failure 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

2101 East Jefferson Street 

Rockville, MD 20852 

http://www.ahrq.gov 

Contract No. 290-02-0023 

Prepared by: 

University of Alberta Evidence-based Practice Center 

Edmonton, Alberta, Canada 

Investigators 

Finlay McAlister, M.D., M.Sc. 

Justin Ezekowitz, M.D. 

Natasha Wiebe, M.Math 

Brian Rowe, M.D., M.Sc. 

Carol Spooner, M.Sc 

Ellen Crumley, M.L.I.S. 

Lisa Hartling, M.Sc. 

Padma Kaul, Ph.D. 

Graham Nichol, M.D. 

Dr. Terry Klassen, M.D., M.Sc. 

AHRQ Publication No. 05-E001-2 

November 2004 
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 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. 

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality 

of health care, reduce its cost, address patient safety and medical errors, and broaden access to 

essential services. AHRQ sponsors and conducts research that provides evidence-based information 

on health care outcomes; quality; and cost, use, and access. The information helps health care 

decisionmakers—patients and clinicians, health system leaders, and policymakers—make more 

informed decisions and improve the quality of health care services. 
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: 

McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, Kaul P, Nichol 

G, Klassen T. Cardiac Resynchronization Therapy for Congestive Heart Failure. Evidence 

Report/Technology Assessment No. 106. (Prepared by the University of Alberta Evidence-based 

Practice Center under Contract No. 290-02-0023.) AHRQ Publication No. 05-E001-2. Rockville 

MD: Agency for Healthcare Research and Quality. November 2004. 
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 healthcare in the United States. The reports and assessments provide organizations 

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

healthcare 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 healthcare 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 healthcare system as a whole by 

providing important information to help improve healthcare 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 

Kenneth S. Fink, M.D., M.G.A., M.P.H. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Margaret Coopey, R.N., M.G.A., M.P.S. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

The authors of this report are responsible for its content. Statements in the report should not be 

construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. 

Department of Health and Human Services of a particular drug, device, test, treatment, or other 

clinical service. 
iv 

Acknowledgments 

 We are grateful to members of the technical expert panel, Dr. Gerald Peden (Medical 

Director of Independent Blue Cross) and Ms Margaret Coopey (Agency for Healthcare Research 

and Quality), who provided direction for the scope and content of the review. 

We would like to thank the peer-reviewers who provided valuable input into the draft report: 

Dr. Bruce Wilkoff (The Cleveland Clinic Foundation, Cleveland, OH), Dr. Donald Casey 

(Catholic Healthcare Partners, Cincinnati, Ohio), Dr. Robert Rea (Mayo Clinic, Rochester, MN), 

Dr. Robert Kowal (UT Southwestern Medical Center, Dallas, TX), Dr. Clyde Yancy (St. Paul 

University Hospital/UT Southwestern Medical Center, Dallas, TX), Dr. David Atkins (Center for 

Outcomes and Evidence Agency for Healthcare Research and Quality), Dr. Cynthia Mulrow, and 

Dr. Joanna E. Siegel (Research Initiative in Clinical Economics, Center for Outcomes and 

Evidence Agency for Healthcare Research and Quality). 

We are also grateful to authors of included studies who provided additional data or 

clarification on study methods and results: Dr. S. Cazeau, Dr. C. Leclercq, Dr. M. Bristrow, and 

Dr. S. Garrigue. 

We thank Ms. Ella Huszti and Mr. John Bridges for their assistance in completing the 

decision analysis. 

Investigating authors acknowledge the following financial support: Dr. Brian Rowe is 

supported by the Canadian Institutes of Health Research (CIHR) as a Canada Research Chair in 

Emergency Airway Diseases (Ottawa, Canada). He is also supported by the Faculty of Medicine 

and Dentistry and the Capital Health Authority, Edmonton, Alberta. Dr. Justin Ezekowitz is 

supported by a CIHR Strategic Training Fellowship. Dr. Finlay McAlister is a Population Health 

Investigator supported by the Alberta Heritage Foundation for Medical Research and is a New 

Investigator of CIHR. Dr. Graham Nichol is supported by two awards—Recipient of Career 

Scientist Award from Ontario Ministry of Health, and Premier's Research Excellence Award 

(Ontario). Dr. William Abraham has received research grants and speaker honoraria from 

Medtronic and Guidant Corporation. 
v 

Structured Abstract 

Context: Congestive heart failure (CHF) is the fastest growing cardiovascular diagnosis in 

North America. 

Objectives: The objectives were to determine the efficacy, safety, and cost-effectiveness of 

cardiac resynchronization therapy (CRT) in adults with symptomatic CHF. 

Data Sources: Electronic databases (the Cochrane Heart Group Trial Registry, Cochrane 

Library, EMBASE, International Pharmaceutical Abstracts, MEDLINE, PubMed, Web of 

Science, and Trial Registries) were searched, reference lists and Food and Drug Administration 

(FDA) reports were checked, and authors of primary studies and manufacturers of CRT devices 

were contacted. 

Study Selection: Randomized controlled trials (RCT) [efficacy review] and/or prospective 

cohort studies [safety review]. Population: patients with symptomatic CHF and reduced left 

ventricular ejection fraction. Intervention: active CRT with medical therapy compared to 

medical therapy alone or non-active/univentricular pacing. Outcomes: mortality, heart failure 

hospitalizations, six-minute walk test distances, functional status (New York Heart Association 

[NYHA] Class), quality of life, and peri/post-implantation risks. 

Data Extraction: Data were extracted using standardized methods by two independent 

abstractors. 

Data Synthesis: Efficacy Review: Data were analyzed using a random effects model in Stata 

7.0. Calculations included: Relative risk (RR) for dichotomous data; weighted mean difference 

(WMD) for continuous data; log hazards ratio for time-to-event data. All results reported with 

95% confidence intervals (95% CI). Safety review: Simple pooled risks and sensitivity analysis 

were conducted. Decision Analysis: Cost-effectiveness of CRT was estimated using a Markov 

model adopting a societal perspective. Future costs and effects were discounted at 3%. Monte 

Carlo simulation and sensitivity analyses were used to assess robustness. 

Main Results: Efficacy: In nine RCTs (3216 patients, 85% with NYHA Class III or IV 

symptoms and 100% with prolonged QRS duration), CRT improved peak oxygen consumption 

(WMD 0.65 ml/kg/min, 95% CI 0.27 to 1.04 ml/kg/min), left ventricular ejection fraction (WMD 

3.35%, 95% CI 1.22% to 5.48%), six-minute walk distance (WMD 23 meters, 95% CI 9 m to 38 

m), quality of life (WMD reduction of 5.5 points, 95% CI 2 to 9 points on the Minnesota Living 

with Heart Failure Questionnaire), and functional class (57% improved at least one NYHA class 

compared to 34% of controls). Heart failure hospitalizations decreased by 32% (RR 0.68, 95% 

CI 0.41 to 1.12), especially in patients with NYHA III/IV symptoms (RR 0.65, 95% CI 0.48 to 

0.88; number needed to treat [NNT]=12). All-cause mortality was reduced by 25% (RR 0.75, 

95% CI 0.60 to 0.93, NNT=27), mainly due to 40% fewer progressive heart failure deaths (RR 

0.60, 95% CI 0.36 to 1.01). Kaplan Meier curves separated at 3 months, and the risk of death 

was reduced 41% after the first 3 months (hazard ratio 0.59, 95% CI 0.43 to 0.81). No 

significant differences were seen in sudden cardiac deaths or non-cardiac deaths. Safety: In 17 

prospective studies (3512 patients with CRT devices), the implant success rate was 89.9% 
vi 

(88.8% to 90.9%) and peri-implant death risk was 0.4% (95% CI 0.2% to 0.7%). Over a median 

6 months of followup, lead dislodgement occurred in 8.5% (7.4% to 9.9%), mechanical 

malfunctions in 6.7% (5.4% to 8.2%), arrhythmias in 1.7% (0.8% to 3.4%), and site infections in 

1.4% (0.8% to 2.3%) of patients. Decision Analysis: Optimal medical therapy for CHF in 

NYHA Class III patients is associated with a median gain of 2.68 (interquartile range [IQR] 2.49 

to 2.85) discounted quality-adjusted life years and median $34,700 (IQR $31,400 to $38,100) 

cost. CRT was associated with a median gain of 3.03 (IQR 2.82 to 3.27) discounted qualityadjusted life years and median $67,600 (IQR $62,000 to $73,800) cost. The incremental costeffectiveness of CRT compared to optimal medical therapy was median $90,700 (IQR $69,500 

to $124,900) per additional quality-adjusted life year; however, costs were highly sensitive to 

changes in several variables, particularly the incidence of complications. The cost-effectiveness 

acceptability curve illustrated that the probability that resynchronization is cost-effective relative 

to medical therapy alone is less than 59%, given a maximum willingness-to-pay for a qualityadjusted life year of $100,000. 

Conclusions: In patients with NYHA Class III or IV CHF despite medical management, 

reduced ejection fractions, and prolonged QRS duration, CRT improves functional and 

hemodynamic markers and reduces morbidity/mortality. Given the moderate implantation 

success rates, biventricular pacemaker insertions should only be done by experienced providers.

The cost-effectiveness of CRT remains uncertain; additional effectiveness and cost data 

surrounding peri-implantation complications are required to determine whether CRT is sufficient 

value to be widely adopted. 
vii 

Contents 

Evidence Report 

Chapter 1. Introduction and Background........................................................................... 3 

 The Problem of Congestive Heart Failure .................................................................... 3 

 Current Risk Factors and Markers in Congestive Heart Failure................................... 4 

 Current Therapeutic Strategies for Congestive Heart Failure....................................... 4 

 Pharmacologic Management ..................................................................................... 5 

 Non-Pharmacologic Management............................................................................. 5 

 Surgical Management................................................................................................ 6 

 Pacing in CHF............................................................................................................... 6 

 Objectives of this Review ............................................................................................. 7 

 Study Questions ............................................................................................................ 8 

Chapter 2. Methods............................................................................................................ 9 

 Methods for the Systematic Reviews............................................................................ 9 

 Literature Search ....................................................................................................... 9 

 Selection and Inclusion ............................................................................................. 9 

 Quality Assessments ............................................................................................... 10 

 Data Extraction........................................................................................................ 10 

 Data Analysis .......................................................................................................... 11 

 Methods for the Decision Analysis............................................................................. 12 

 Structure of the Decision Model ............................................................................. 12 

 Input Data................................................................................................................ 12 

 Uncertainty and Variability Analyses ..................................................................... 14 

 Peer Review ................................................................................................................ 15 

Chapter 3. Results ............................................................................................................ 23 

 Literature Search......................................................................................................... 23 

 Efficacy Review.......................................................................................................... 24 

 Description of Included Studies .............................................................................. 24 

 Methodological Quality of Included Studies .......................................................... 26 

 Safety Review ............................................................................................................. 27 

 Description of Included Studies .............................................................................. 27 

 Quality of Included Studies..................................................................................... 28 

 Quantitative Results.................................................................................................... 29 

 Efficacy Review ...................................................................................................... 29 

 Safety Review ......................................................................................................... 32 

 Decision Analysis ....................................................................................................... 33 

 Effectiveness of Medical Therapy........................................................................... 33 

 Effectiveness of Cardiac Resynchronization Therapy ............................................ 33 

 Cost-Effectiveness of Cardiac Resynchronization Therapy.................................... 33 

 Variability Analyses................................................................................................ 34 
viii 

Chapter 4. Discussion ...................................................................................................... 73 

 Systematic Review...................................................................................................... 73 

 Efficacy and Safety ................................................................................................. 73 

 Potential Limitations of Systematic Review ........................................................... 75 

 Decision Analysis ....................................................................................................... 75 

 Potential Limitations of Decision Analysis............................................................. 76 

 Conclusions................................................................................................................. 77

References......................................................................................................................... 81 

 Included Studies.......................................................................................................... 89 

 Efficacy Review ...................................................................................................... 89 

 Safety Review ......................................................................................................... 89 

 Excluded Studies......................................................................................................... 91 

Figures 

Figure 1: Decision model for medical therapy versus cardiac resynchronization 

 therapy for heart failure ................................................................................. 16 

Figure 2: Markov model of resynchronization therapy of heart failure......................... 17 

Figure 3: Flow diagram of study retrieval and selection for cardiac resynchronization 

 therapy............................................................................................................ 23 

Figure 4: Meta-graph of all-cause mortality .................................................................. 61 

Figure 5: Time to all-cause death................................................................................... 62 

Figure 6: Meta-graph of death due to congestive heart failure...................................... 63 

Figure 7: Meta-graph of sudden cardiac death .............................................................. 64 

Figure 8: Meta-graph of non-cardiac death ................................................................... 65 

Figure 9: Meta-graph of hospitalizations due to congestive heart failure ..................... 66 

Figure 10: Meta-graph of six-minute walk test................................................................ 67 

Figure 11: Meta-graph of changes in NYHA status ........................................................ 68 

Figure 12: Meta-graph of quality of life (based on Minnesota Living with Heart 

 Failure instrument)......................................................................................... 69 

Figure 13: Meta-graph of all-cause mortality by cardioverter defibrillator vs non- 

 cardioverter defibrillator ................................................................................ 70 

Figure 14: Distribution of incremental costs versus incremental effects for 

 cardiac resynchronization versus medical therapy ........................................ 71 

Figure 15: Cost-effectiveness acceptability curve ........................................................... 72 

Figure 16: Analytic framework for treatment options for patients with congestive 

 heart failure ..................................................................................................... 79 

Tables 

Table 1: Prognostic risk factors in congestive heart failure.............................................. 4 

Table 2: Inclusion/exclusion criteria for review on cardiac resynchronization therapy. 10 

Table 3: Input data for decision analysis on cardiac resynchronization in patients with 

 NYHA Class III heart failure............................................................................ 18 
ix 

Table 4: Primary publications and associated publications of trials included in the 

 reviews on cardiac resynchronization therapy in CHF..................................... 35 

Table 5: Description of studies included in the efficacy review: CRT for CHF ........... 38 

Table 6: Baseline characteristics of patients in trials included in the efficacy review: 

 CRT for CHF ................................................................................................... 41 

Table 7: Baseline drug therapy for trials included in the efficacy review: CRT 

 for CHF ............................................................................................................ 43 

Table 8: Methodological quality of randomized trials included in the efficacy review 44 

Table 9: Description of studies included in the safety review: CRT for CHF............... 45 

Table 10: Baseline characteristics of patients in studies included in the safety review: 

 CRT for CHF ................................................................................................... 50 

Table 11: Baseline drug therapy in included patients in the safety review: CRT for 

 CHF.................................................................................................................. 52 

Table 12: Methodological quality assessments of included studies: safety review......... 54 

Table 13: Peri-implant risks for cardiac resynchronization therapy................................ 56 

Table 14: Post-implantation risks of cardiac resynchronization therapy......................... 58 

Table 15: Potential cost-effectiveness of cardiac resynchronization therapy.................. 60 

Appendixes 

Appendix A: Exact Search Strings 

Appendix B: Sample Data Forms 

Appendix C: Evidence Tables 

Appendix D: Technical Experts and Peer Reviewers 

Note: Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.gov/clinic/epcindex.htm 
Introduction

Heart failure is the fastest growing

cardiovascular diagnosis in North America, and it

carries a poor prognosis.1,2 To improve survival in

heart failure patients, therapies need to reduce

either sudden cardiac death (the most common

cause of death in patients with New York Heart

Association [NYHA] Class I or II symptoms) or

progressive heart failure (the predominant cause

of death in those with NYHA Class III or IV

symptoms).3,4

Electrical conduction disturbances are common

in heart failure and are associated with increased

mortality risk.5-7 Atrial-synchronized biventricular

pacing (cardiac resynchronization therapy [CRT])

addresses many of the pathophysiological changes

seen in patients with wide QRS complexes in

whom delayed activation of the left free wall

results in mechanical dyssynchrony. 

The University of Alberta Evidence-based

Practice Center conducted a systematic review to

examine the success rate and safety of

biventricular pacemaker implantation and the

efficacy of CRT in patients with heart failure.

Further, the researchers used these data in a

decision analysis to evaluate the incremental costeffectiveness of CRT versus medical therapy

alone. 

Methods

This report addresses the following questions:

1. In adult patients with symptomatic heart

failure, is CRT more effective than optimal

medical care alone? 

2. Is the implantation of a CRT system safe for

patients?

3. What is the role of CRT in the treatment of

heart failure?

4. What is the cost-effectiveness of CRT in

patients with congestive heart failure?

Literature Search

Detailed searches were conducted of the

Cochrane Heart Group Trial Registry, Cochrane

Library, EMBASE, International Pharmaceutical

Abstracts, MEDLINE®, Web of Science®, and

multiple trial registries. In addition, the

researchers contacted the primary authors of

included studies, sought U.S. Food and Drug

Administration reports, and reviewed the

reference lists of all included articles. Additional

unpublished data were sought from the

companies that produce CRT devices: Medtronic,

Inc., Guidant Corporation, and ELA Medical

(Montrouge, France). The search was not limited

by language or publication status and is

considered up to date as of June 30, 2003.

Selection and Data Extraction

Two investigators independently screened all

titles and abstracts, and another two investigators

independently assessed the full text of potentially

relevant studies and extracted data.

Disagreements were resolved through third-party

adjudication or consensus. 

Data Analysis

Intention-to-treat analyses were done using the

same standardized endpoint definitions employed

in the primary studies. Stata 7.0 (Stata

Evidence Report/Technology Assessment

Number 106

Cardiac Resynchronization Therapy for Congestive

Heart Failure

Summary

McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, 

Kaul P, Nichol G, Klassen T

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

Corporation, version 7.0, 2003) was used to pool data and

calculate summary risk ratios for dichotomous results and

weighted mean differences for continuous variables. Because of

expected differences between studies (particularly in control

group therapies), the researchers decided a priori to combine

results primarily using a random effects model. Fixed effects

models were considered in sensitivity analyses. Statistical

heterogeneity was assessed by the chi-square test and was

quantified and appropriated using the I-squared statistic.8

Time-to-death data were summarized by the log hazards ratio;

Cox proportional hazards and/or Kaplan-Meier curves were

generated where appropriate.9,10

Simple pooling and exact 95-percent confidence intervals

(CIs) were used for the safety analyses. However, given the

possibility that reports may not always have reported zero for

adverse events that did not occur, the researchers performed

sensitivity analyses for safety outcomes in which they assumed

that, if a particular event (for example, peri-implantation death)

was not mentioned in a report, then it did not occur and

assigned a zero for that outcome in that study. 

Decision Analysis Methods

A Markov decision model was constructed to compare the

lifetime effects and costs of CRT versus medical therapy for

patients with symptomatic heart failure. The analysis adopted

the U.S. health care perspective (including costs of

hospitalization, procedures, ambulatory visits, medications, and

laboratory tests), and costs are expressed in 2003 American

dollars. Input data were derived from multiple sources:

1. Outcomes with CRT and risks of the procedure were

derived from a systematic review with annualization using

an exponential approximation.11,12 Transition probabilities

incorporated into the Markov model were adjusted for the

cycle length. 

2. The health-related quality of life of patients with heart

failure was estimated by eliciting utilities. Since the

purpose of the decision analytic model was to consider an

intervention in the context of resource allocation among

different types of interventions, a generic source of

preferences was used.13 A convenience sample (n = 66)

was recruited of members of the general public age 40 and

over and without underlying cardiac disease. Consenting

subjects estimated utilities for standardized health state

descriptions (NYHA Class II, III, and IV) by using the

standard gamble technique.14 Hypothetical scenarios

describing what one would typically feel and experience if

living with each of these health states were developed with

input from an expert panel based on descriptors from the

Health Utilities Index.15

3. The cost of a device capable of CRT was depreciated over

its anticipated lifespan. Physician costs related to CRT

implantation were based on Current Procedural

Terminology codes.16 The costs of a resynchronization

device were based on a survey of manufacturers’ list prices.

The costs of hospitalizations associated with heart failure

were based on estimates derived from a cohort study of

health resource use by patients participating in a previous

randomized trial of medical therapy for heart failure.17

All costs were adjusted for inflation by using the U.S.

Consumer Price Index.18

Structure of Decision Model

The primary analysis considered patients with NYHA Class

III symptoms. The analysis considered the lifetime horizon and

employed a state-transition Markov model with a cycle length

of 1 month. During each cycle, patients who received medical

therapy could die of unrelated causes, die of cardiovascular

disease, be hospitalized for heart failure, or remain stable.

Patients who underwent insertion of a device capable of CRT

could die during the initial implantation of the device or

experience lead infection, lead failure, battery failure, or any of

the health states associated with medical therapy for heart

failure.

Decision analyses were performed with DATA ProTM

software (TreeAge Software, Inc., Williamstown, Massachusetts)

and Excel 2000 software (Microsoft Corporation, Redmond,

Washington). 

Assumptions in Decision Analysis

A number of assumptions were necessary because of the

paucity of several pieces of data. First, it was assumed that unit

costs of heart failure therapy were identical between medical

therapy and CRT. Second, it was assumed that the incidence

of complications associated with CRT was constant over time.

However, since the duration of followup in each trial was

relatively short and the incidence of adverse effects in these

trials was higher than generally accepted for ICD

implantation,19 the researchers considered lower incidences of

device or device-related adverse effects than observed in the

trials in the sensitivity analyses. Third, it was assumed that any

mechanical malfunction of the device required battery

replacement with consequent costs. Finally, age-specific

mortality due to unrelated causes was based on life tables.20
Uncertainty and Variability Analyses

The analysis distinguished between parameter uncertainty

(i.e., variation in costs and effects because of sampling and

measurement error) and variability (i.e., heterogeneity in costs

and effects between groups of patients with systematic

differences in cost or effects). Uncertainty was assessed by

using 10,000 probabilistic Monte Carlo simulations.21,22

Empirical cost variables were assigned log-normal distributions.

Empirical probability variables were assigned beta

distributions.21 Variables without a known distributional form

(i.e., those with assumed values or those with values based on a

range of published reports) were assigned triangular

distributions.23

Variability was assessed by substituting the value of each

variable in the decision model by its upper and lower limits

while holding all other values constant.24-26 For empirical

variables, these limits were the 95-percent confidence limits for

each variable. For assumed variables (e.g., cost of CRT device

insertion and discount rate), these limits were based on

reasonable possible limits (i.e., +50 percent). Threshold

analyses identified the value of each variable across its range, if

any, at which one should be indifferent between medical

therapy alone or CRT (i.e., the incremental cost per qualityadjusted life year was $100,000).26

Results

Literature Search

Nine trials reported on the efficacy of CRT; three included

implantable cardioverter-defibrillators (ICDs).27-34 Seventeen

studies (eight trials and nine prospective studies without control

arms) reported on the safety of CRT. Most of the trials were

associated with multiple publications that either expanded on

the main results or reported secondary outcomes not included

in the primary report. This summary includes the reference to

only the primary report for each trial. However, a full listing of

all publications is available in the full evidence report.

Description of Included Studies

All nine of the trials enrolled only patients with prolonged

QRS duration: >120 millisecond (msec) in three trials,27-29 >130

msec in two trials,30,31 >140 msec in one trial,32 >150 msec in

one trial,33 >180 msec in one trial, and >200 msec in the

remaining trial.34 Left bundle branch block was present in 64

percent of patients, and 95 percent of patients were in sinus

rhythm. All trials also restricted enrollment to patients with

reduced ejection fractions (<35 percent in six trials, <25 percent

in one trial, and <40 percent in the other), and the mean

ejection fractions were similar in all trials (from 21 percent to

26 percent). 

In total, 3,574 patients were enrolled and 3,216 were

randomized to receive CRT (n = 2,063) or control (most

commonly pacemaker turned off, n = 1,153) in the nine trials.

The mean age was 64 years, 74 percent were male, 75 percent

had NYHA Class III symptoms, and 10 percent had NYHA

Class IV symptoms. Two trials included some patients with

NYHA Class II symptoms.27,31 Most of the patients in these

trials had ischemic etiologies for their heart failure (mean 58

percent, range 29 percent to 69 percent). 

Including the nine additional single-arm prospective cohort

studies, a total of 3,512 patients who had undergone CRT

implantation were included in the safety analyses. 

Quantitative Results

All-cause mortality. Based on data pooled from the nine

randomized controlled trials, CRT significantly reduced allcause mortality (relative risk [RR] 0.75, 95-percent CI 0.60 to

0.93). The results were identical when analyses were limited to

patients with NYHA Class III or IV symptoms (RR 0.76, 95-

percent CI 0.60 to 0.95). There was no significant statistical

heterogeneity between trials (p = 0.88, I-squared = 0 percent).

The all-cause mortality rate in the control patients was 14.9

percent, and the number needed to treat (NNT) to prevent one

death in patients with symptomatic heart failure was 27. A

Cox proportional hazards model revealed that the mortality

hazard ratio with CRT was 0.59 (95-percent CI 0.43 to 0.81)

after the first 3 months.

Cardiac mortality. Seven trials reported progressive heart

failure mortality (n = 60 deaths in 1,647 patients); the relative

risk favored CRT (random effects RR 0.60, 95-percent CI 0.36

to 1.01; fixed effects RR 0.59, 95-percent CI 0.35 to 0.98).

Results were similar when analysis was restricted to patients

with NYHA Class III or IV symptoms (random effects RR

0.58, 95-percent CI 0.32 to 1.06). In contrast, CRT did not

significantly reduce overall cardiac deaths (n = 91 in 1,628

patients, RR 0.84, 95-percent CI 0.56 to 1.25) because of a

nonsignificant excess in sudden cardiac deaths (n = 28 in 1,691

patients, RR 1.99, 95-percent CI 0.95 to 4.16). Data on

causes of death for patients in the COMPANION trial28 were

not yet available.

Noncardiac mortality. Using data pooled from the six trials

that reported noncardiac death (RR 0.90, 95-percent CI 0.35

to 2.35), results for CRT and control therapy did not

significantly differ. 

Heart failure hospitalizations. The pooled data revealed

benefits with CRT (random effects RR 0.68, 95-percent CI

0.41 to 1.12; fixed effects RR 0.80, 95-percent CI 0.64 to

3
4

1.003). This result was heterogeneous (p = 0.01, I-squared =

65 percent). Restricting this analysis to patients with NYHA

Class III or IV symptoms revealed homogeneous (p = 0.31, Isquared = 16 percent) and statistically significant reductions in

heart failure hospitalizations (RR 0.65, 95-percent CI 0.48 to

0.88; NNT = 12).

Six-minute walk test. CRT was associated with an

improved 6-minute walk test, with a weighted mean difference

(WMD) of 23 meters (95-percent CI 9 m to 38 m). This

improvement was similar in patients with NYHA Class III or

IV symptoms (WMD 26 m, 95-percent CI 11 m to 41 m).

Although the data from the RD-CHF Trial were not available

for pooling, the RD-CHF investigators reported statistically

significant improvements in 6-minute walk test distances.35

New York Heart Association Functional Class.

Combining the data on change in NYHA class from the three

studies that reported this endpoint revealed that 57 percent of

CRT-treated patients, compared to 34 percent of controls,

improved by at least one NYHA class. Thus, CRT was

associated with an RR for improving at least one NYHA class

of 1.6 (95-percent CI 1.1 to 2.5). Although the data from

MIRACLE-ICD31 and RD-CHF were not reported in a way

that they could be pooled with the other trials, both reported

statistically significant improvements in NYHA class with CRT.

Quality of life. The minimal clinically important difference

for the Minnesota Living With Heart Failure® Questionnaire

has been established in placebo-controlled trials as being 5

points.36-38 Pooled results from the six trials that used the

Minnesota Living With Heart Failure Questionnaire showed a

statistically and clinically significant improvement with CRT

(WMD -5.5 points, 95-percent CI -9 to -2 points). This result

was statistically heterogeneous (p = 0.008, I-squared = 68

percent); however, results were consistent in direction in all six

trials. Restricting the analysis to only patients with NYHA

Class III or IV symptoms increased the difference between the

CRT and control groups (WMD -6.4 points, 95-percent CI 

-9.4 to -3.4 points), and the results were less heterogeneous (p

= 0.07, I-squared = 50 percent). Further, although the use of a

different scale prevented pooling with the other trials, the RDCHF investigators reported statistically significant

improvements in quality of life with CRT.35

Other outcomes. CRT was associated with improvements

in peak oxygen consumption (WMD versus control of 0.7

ml/kg/min, 95-percent CI 0.3 to 1.0 ml/kg/min), ejection

fraction (WMD 3.5 percent, 95-percent CI 1.5 to 5.5 percent),

and QRS interval (WMD 28 msec, 95-percent CI -47 to -9). 

Peri-implantation risks. Ten studies reported data on

deaths while undergoing implantation of a biventricular

pacemaker. There were 13 deaths in 3,113 patients (pooled

risk 0.4 percent, 95-percent CI 0.2 percent to 0.7 percent); a

sensitivity analysis, in which it was assumed any studies that did

not report mortality had zero occurrences, yielded the same

result. Device implantation was successful in 90 percent of

attempts (95-percent CI 89 percent to 91 percent) in 3,475

patients (16 studies). 

Post-implantation risks. Over a median 6 months of

followup, mechanical malfunction of the cardiac

resynchronization device was noted with 7 percent of successful

implants (95-percent CI 5 percent to 8 percent); on sensitivity

analysis, in which it was assumed any studies that did not

report this outcome had zero occurrences, this rate was 4

percent (95-percent CI 4 percent to 5 percent). Lead

dislodgment occurred in 9 percent of patients (95-percent CI 7

percent to 10 percent). There were no differences in lead

dislodgment in studies using specially designed left ventricular

leads; the estimate was reduced to 8 percent (7 percent to 10

percent) on sensitivity analysis. Post-implantation infection

(most commonly in the device pocket) occurred in 1.4 percent

of patients (95-percent CI 0.8 percent to 2.3 percent); the

estimate was reduced to 0.9 percent (95-percent CI 0.5 percent

to 1.4 percent) with sensitivity analysis. Two percent (95-

percent CI 1 percent to 3 percent) of patients had arrhythmias

in followup. 

Sensitivity Analyses for Systematic Review 

Using meta-regression (a between-study nonrandomized

comparison), the researchers explored the impact of CRT when

combined with ICDs. The benefits of CRT on all-cause

mortality and heart failure hospitalizations were not appreciably

different in patients with an ICD and patients without an

ICD. The data from COMPANION were not eligible for this

analysis since only one arm in COMPANION received both

CRT and an ICD.39 Indeed, the COMPANION trial data

permit the only direct comparison between CRT with/without

an ICD. While the chi-square test for all-cause mortality

approached significance (p = 0.07) in favor of cardiac

defibrillators with CRT, the reductions in heart failure

hospitalizations were similar in CRT-treated patients

with/without ICDs.28 However, until detailed data from the

COMPANION subanalyses are made available, the most

conservative conclusion to make is that the benefits of CRT are

similar with/without an ICD. 

Cost-Effectiveness of CRT

In patients with NYHA Class III heart failure, medical

therapy was associated with a median gain of 2.68 discounted

quality-adjusted life years (interquartile range [IQR] = 2.49 to

2.85) and median $34,700 lifetime costs (IQR = $31,100 to

$38,100). CRT was associated with a median gain of 3.03
discounted quality-adjusted life years (IQR = 2.82 to 3.27) and

median $67,600 lifetime costs (IQR = $62,000 to $73,800).

Thus, CRT was associated with an incremental cost of a

median $90,700 (IQR = $69,500 to $124,900) per additional

quality-adjusted life year. The cost-effectiveness acceptability

curve illustrates that the probability that resynchronization is

cost effective is less than 59 percent, given a maximum

willingness to pay for a quality-adjusted life year of $100,000. 

Variability Analyses

The incremental cost-effectiveness of CRT was sensitive to

reasonable changes in the values of several variables, particularly

the incidence of device-related complications.

Discussion

In summary, when added to medical therapy in patients with

symptomatic heart failure who have prolonged QRS duration

and reduced left ventricular ejection fraction, CRT reduces allcause mortality by 25 percent and heart failure hospitalizations

by 32 percent. These benefits were particularly marked in heart

failure patients at higher risk (i.e., those with NYHA Class III

or IV symptoms). These benefits are similar to those reported

for ACE inhibitors, beta-blockers, and aldosterone antagonists

in recent trials.40-43 CRT also conferred statistically and

clinically significant benefits in a variety of surrogate outcomes.

Indeed, a pooled six-point improvement on the Minnesota

Living With Heart Failure® Questionnaire is greater than that

seen in recent heart failure trials testing pharmacologic

therapies.44,45 However, CRT for patients with heart failure is

associated with large uncertainty in the incremental costs per

quality-adjusted life year; in particular, the results are sensitive

to the incidence of device-related adverse effects.

The survival benefits with CRT appear to be attributable

largely to reductions in progressive heart failure deaths and

become apparent by 3 months after implantation. This is not

surprising, as the benefits of CRT are thought to be mediated

through morphometric remodeling of the left ventricle (leading

to increased left ventricular filling time, reduced mitral

regurgitation, and reduced septal dyskinesis) rather than acute

changes in the neurohormonal system.46

While the researchers found a nonsignificant trend toward

increased sudden cardiac death that was consistent across these

trials, it was based on a very small number of events (28 in

total). In particular, the lack of difference in the number of

ventricular arrhythmia episodes between patients with

compared to without CRT in the MIRACLE-ICD Trial (22

percent vs. 26 percent, p = 0.47) suggests that the trend toward

excess sudden cardiac deaths may well be due to small

numbers.31 Regardless, the benefits of CRT are similar in

patients with or without implantable cardioverter-defibrillators,

providing some reassurance that, in those patients who have

indications for both a defibrillator and CRT, the two may be

administered together. The indications for an ICD in heart

failure patients without an ischemic etiology remain uncertain

pending completion of the SCD-HeFT Trial.47

An important finding of this systematic review is the safety

of CRT and its tolerability in patients with advanced heart

failure. Peri-implantation mortality rates were less than 1

percent and post-implantation infection rates were also low.

Although there were few serious complications, implantation of

a biventricular pacemaker (in particular the left ventricular lead)

is technically challenging: the systematic review identified a 10-

percent failure rate. Furthermore, even if implantation is

successful, patients with these devices require close followup, as

7 percent of devices malfunctioned over a median followup of

6 months and 9 percent of left ventricular leads dislodged.

Because these complications necessitate another procedure, the

failure rates have to be incorporated into any policy decisions.

Although the systematic review results are promising, the

results of the decision analysis suggest caution given the

magnitude of the uncertainty in the long-term results. Indeed,

the researchers believe that there are insufficient long-term

effectiveness and cost data to warrant broad implementation of

CRT at this time.

Limitations of Research

A substantial limitation of the trials included in this analysis

is that randomization occurred after implantation of the device

in all but one trial. This design, similar to the run-in period

used in some pharmaceutical trials, does not affect the internal

validity of the trials but does impact the generalizability of the

results, as patients who could not tolerate the procedure or in

whom implantation was unsuccessful were not included. As a

result, these trials likely overestimate the potential benefits from

CRT.48 Because very few patients in these trials had

bradyarrhythmias or atrial fibrillation, the role of CRT in such

patients is unknown and is an important area for further study,

particularly since almost one-third of CHF patients have atrial

fibrillation or indications for conventional pacemakers.49

Finally, it should be emphasized that only selected cases and

experienced providers participated in these trials, so it is

plausible that the observed complication rates may not be

applicable to other settings and, in particular, clinicians less

experienced with device implantation. If so, this decision

analysis overestimates survival and underestimates the

incremental cost of CRT. Conversely, if adverse effects are less

frequent as providers gain experience, the analysis may

underestimate survival and overestimate the incremental cost of

5
6

CRT. This is particularly important, since the results of the

analysis were sensitive to the rate of complications associated

with CRT. 

The decision analysis also has some limitations. First,

although cardiac resynchronization is more costly and more

effective than medical therapy, the incremental costeffectiveness ratio had a large range and there are insufficient

data to determine whether to adopt resynchronization therapy

for broad use. Second, it is likely that the incidence of

complications associated with CRT decreases over time,

although for the purposes of our analysis it had to be assumed

that they were constant. Thus, the model may underestimate

survival and overestimate the incremental cost-effectiveness of

CRT. Long-term followup of patients enrolled in the

previously completed trials will determine whether the

incidence of complications does indeed decline over time.

Third, it is unlikely that the relative benefits of CRT will be

constant, as the severity of heart failure varies. Therefore, as

results from other trials and registries become available, the

analysis should be revised to reflect better estimates of the true

effectiveness and costs of the program in patients with other

classes of CHF. Fourth, it was assumed that heart failure costs

were constant even though CRT will decrease heart failure costs

if ventricular remodeling decreases the frequency of use of

outpatient pharmaceuticals or duration of hospitalization.

Finally, the input data were derived from several sources and

may be confounded by information that was not incorporated

into the model. For example, the effectiveness of CRT was not

adjusted for the patient’s comorbid illnesses. 

Conclusions

CRT exerts a 24-percent relative reduction in all-cause

mortality (largely driven by a 42-percent reduction in

progressive heart failure deaths) and a 35-percent reduction in

heart failure hospitalizations in patients with reduced ejection

fractions, NYHA Class III or IV symptoms despite medical

management, and a prolonged QRS duration on

electrocardiogram. While preliminary data suggest similar

relative benefits in patients with NYHA Class II symptoms, this

is based on very few events. Further data are required before

extending the device indications beyond those currently

authorized by the U.S. Food and Drug Administration (i.e.,

patients with NYHA Class III or IV symptoms). Moreover, as

very few such patients were enrolled in the trials, the role of

CRT in patients with indications for conventional pacemakers

or with atrial fibrillation remains uncertain and requires further

study. Approximately 10 percent of heart failure patients have

NYHA Class III or IV symptoms, reduced ejection fraction,

and a prolonged QRS duration, and up to one-half of these

patients may also have indications for an implantable

cardioverter-defibrillator.50

While CRT should join the list of proven efficacious

therapies for selected patients with heart failure, it is an

expensive therapy and cost-effectiveness analysis reveals

uncertainty in the incremental costs per quality-adjusted life

year. In particular, there are insufficient long-term effectiveness

and cost data to determine whether CRT is sufficient value for

money to warrant its broad implementation at this time. This

is in contradistinction to ACE inhibitors, beta-blockers, and

spironolactone for patients with advanced symptomatic heart

failure. 

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the University of Alberta Evidence-based

Practice Center under Contract No. 290-02-0023. It is

expected to be available in November 2004. At that time,

printed copies may be obtained free of charge from the AHRQ

Publications Clearinghouse by calling 800-358-9295.

Requesters should ask for Evidence Report/Technology

Assessment No. 106, Cardiac Resynchronization Therapy for

Congestive Heart Failure. In addition, Internet users will be able

to access the report and this summary online through AHRQ’s

Web site at www.ahrq.gov.

Suggested Citation

McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C,

Crumley E, Hartling L, Kaul P, Nichol G, Klassen T. Cardiac

Resynchronization Therapy for Congestive Heart Failure.

Summary, Evidence Report/Technology Assessment No. 106.

(Prepared by the University of Alberta Evidence-based Practice

Center under Contract No. 290-02-0023.) AHRQ Publication

No. 05-E001-1. Rockville, MD: Agency for Healthcare

Research and Quality. November 2004.

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November 2004

ISSN 1530-440X

42. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on

morbidity and mortality in patients with severe heart failure.

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43. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone

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Evidence Report 

3 

Chapter 1. Introduction and Background 

The Problem of Congestive Heart Failure 

Congestive heart failure (CHF) leads to significant morbidity and mortality; in 2001 it 

accounted for almost one million hospitalizations in the United States (as the most responsible 

diagnosis) and $24.3 billion in direct and indirect costs.1 CHF is the fastest growing 

cardiovascular diagnosis in North America: the community prevalence is estimated at 0.4% to 

2.4% in adults,1-4 with the incidence approaching 10 cases/1000 in people over 65 years of age.1

 

Indeed, the lifetime risk of developing CHF is estimated at 20% in North America.5

 Despite 

many advances in diagnosis and therapy over the past two decades, heart failure carries a poor 

prognosis (30% to 50% mortality rate at 1 year), which has changed little over that time frame.1,6

Patients with CHF may be classified on the basis of their functional status using the New 

York Heart Association (NYHA) Classification. In this system, CHF patients without limitations 

of physical activity (i.e., ordinary physical exertion does not cause fatigue, palpitations, dyspnea, 

or chest discomfort) are classified as having NYHA Class I disease. CHF patients who develop 

fatigue, palpitations, dyspnea, or chest discomfort with ordinary physical activity (defined as 

walking two blocks or climbing two flights of stairs) are classified as having NYHA Class II 

disease. Those patients who are comfortable at rest but develop symptoms on less than ordinary 

activity are categorized as having NYHA Class III disease. Finally, CHF patients who have 

symptoms at rest or with minimal activity are classified as having NYHA Class IV disease. 

Attempts to reduce mortality in heart failure are directed at the two main ways in which death 

occurs: sudden cardiac death (electrical failure) and progressive heart failure (mechanical 

failure).7 Sudden cardiac death accounts for more deaths than progressive “pump” failure in 

patients with NYHA Class I or II heart failure; on the other hand, progressive heart failure is the 

predominant cause of death in those with NYHA Class III or IV symptoms.8 It is important to 

emphasize that not all therapies that improve functional outcomes (such as symptoms, quality of 

life, ejection fraction, and other hemodynamic measurements) in CHF patients confer survival 

benefits.9 Thus, it is essential that any novel therapies in patients with CHF be evaluated for 

their impact on clinically important outcomes such as death or hospitalization. 

Heart failure is a clinical syndrome characterized by specific symptoms and, in most (but not 

all) cases, accompanied by a depressed ejection fraction.10 Coronary artery disease is the cause 

of heart failure in two-thirds of North American and European patients, with hypertension, 

valvular dysfunction, viral myocarditis, idiopathic dilated cardiomyopathy, and other diseases 

causing the remainder.11 Identification of modifiable risk factors in CHF has lead to the 

development of treatment options for heart failure including the standard pharmacological, nonpharmacological, and electrically based therapies currently recommended in consensus 

guidelines for the care of patients with CHF.10,12,13
4 

Current Risk Factors and Markers 

in Congestive Heart Failure 

Many prognostic risk factors have been established in CHF (Table 1). Well-validated risk 

factors for short- and long-term mortality include demographic factors such as older age and 

male gender;14 differing ethnic background (black patients have a higher mortality rate than 

white patients even after adjustment for important covariates);15,16 co-morbidities such as 

diabetes mellitus,17 anemia,18 and poor renal function;19 and physical examination findings such 

as a third heart sound and elevated jugular venous pressure.20 Biochemical values that predict 

mortality include decreased serum sodium,21 elevated aldosterone, angiotensin II, and arginine 

vasopressin,22 elevated brain natriuretic peptide,23 and elevated levels of other neurohormones.24 

Other prognostic risk factors have been explored (such as genetic and echocardiographic 

markers) and are reviewed elsewhere;25 electrophysiologic prognostic factors are reviewed 

below. 

Table 1. Prognostic risk factors in congestive heart failure 

Demographics: Electrophysiologic findings: 

Older age Ventricular arrhythmias 

Male gender Intraventricular conduction delay 

Ethnic background (blacks have poorer outcomes 

than whites) 

Atrial fibrillation 

T-wave alternans 

 

Comorbidities: 

Diabetes Laboratory findings: 

Anemia Elevated norepinephrine/epinephrine 

Renal failure Low sodium 

 Elevated creatinine 

Clinical Assessment: Elevated aldosterone 

Advanced symptoms (NYHA Class III or IV) Elevated B-type natriuretic peptide 

Elevated jugular venous pressure Elevated Tumor Necrosis Factor-alpha 

Edema Elevated InterLeukin-6 

Third heart sound Elevated endothelin-1 

 Elevated angiotensin II 

Hemodynamics: Elevated renin 

Lower left ventricular ejection fraction Elevated troponin I/T 

Lower right ventricular ejection fraction Elevated arginine vasopressin 

Elevated pulmonary capillary wedge pressure 

Elevated pulmonary vascular resistance 

Source: adapted from Eichhorn EJ. Prognosis determination in heart failure. Am J Med 2001;110 (Suppl 7A);14S-36S25

NYHA=New York Heart Association 

Current Therapeutic Strategies 

for Congestive Heart Failure 

Current therapy for congestive heart failure incorporates a number of strategies to enhance 

the quality of life, improve exercise tolerance, and reduce morbidity and mortality. In the past 

two decades, advances in heart failure management have arisen from randomized clinical trials 
5 

of medications, non-pharmacologic interventions (exercise training, care delivery systems), 

electrophysiologic procedures and devices, and surgery including cardiac transplantation. 

Pharmacologic Management 

Afterload reduction with the combination of isosorbide dinitrate and hydralazine was one of 

the first pharmaceutical combinations tested and used to treat heart failure. It achieved a relative 

risk reduction in mortality of approximately one third when compared to placebo.26,27 While 

enalapril (an angiotensin-converting enzyme [ACE]) inhibitor was subsequently proven to be 

more effective than hydralazine/isosorbide dinitrate, the combination remains useful for 

management of those heart failure patients intolerant of ACE inhibitors or angiotensin-receptor 

blockers (ARB), and in those with advanced renal insufficiency.10

ACE inhibitors were the first medications to show a reduction in mortality in advanced 

congestive heart failure patients (those with NYHA Class IV symptoms), with a relative risk 

reduction for the enalapril group (versus placebo) of 40% at 6 months.28 Since then, 33 other 

randomized placebo-controlled trials29 of ACE inhibitors have confirmed substantial benefits (in 

the order of 25% to 35% reductions in mortality and 27% to 33% reductions in hospitalization 

rates) in patients with all classes of heart failure (even asymptomatic patients with reduced 

ejection fraction). ACE inhibitors are now the cornerstones of treatment for systolic left 

ventricular dysfunction with or without symptoms.30

Beta-blockers are the second choice in the pharmacologic treatment of systolic dysfunction. 

Twenty-two randomized controlled trials have demonstrated consistent benefits in reducing 

mortality (relative risk reduction 35%) and morbidity (relative risk reduction 36% in 

hospitalization),31 and improving NYHA class and quality of life.32

Angiotensin-receptor blockers have been demonstrated to reduce a combined endpoint of 

morbidity and mortality by 13% when added to ACE inhibitor therapy and have an indication as 

primary therapy for heart failure in ACE-inhibitor intolerant patients, either alone or with betablockers. The reduction in hospitalization alone is 27% when added to an ACE inhibitor. 

Caution is urged when patients are concomitantly taking an ACE-inhibitor and beta-blocker, as 

no additional benefit was seen in a group of patients on all three agents.33,34

Aldosterone blockade (with spironolactone or eplerenone) is associated with relative risk 

reductions of 15% to 30% in mortality for patients with NYHA Class III/IV symptoms and an 

ejection fraction <35%,35 or patients with an ejection fraction <40% and a recent myocardial 

infarction.36 These benefits were largely due to reduced rates of sudden cardiac death. 

Furthermore, both agents are associated with 27% to 35% relative risk reductions in heart failure 

hospitalizations.35,36 Digoxin has also been shown to reduce hospitalization rates, but without 

significant impact on mortality in patients with CHF.37

Non-Pharmacologic Management 

Lifestyle modification is important in the management of symptomatic CHF patients. The 

importance of avoiding non-steroidal anti-inflammatory drugs has been highlighted in numerous 

studies where use of anti-inflammatory drugs has been associated with a two- to four-fold 

increase in hospitalizations for acute heart failure.38,39 Non-compliance with sodium restriction 

has been identified as the cause of up to 22% of hospitalizations for CHF, highlighting the 

importance of dietary modification for these patients.39 Finally, addressing concomitant risk 
6 

factors for underlying coronary artery disease (dyslipidemia, tobacco use, hyperglycemia) is 

important in the secondary prevention of myocardial ischemia in CHF patients. Another nonpharmacologic strategy includes specialty clinics that provide a multidisciplinary disease 

management approach to this complex disease.40 While a systematic review of 11 randomized 

trials showed that patients managed in specialized multidisciplinary heart failure clinics had 

better processes of care and outcomes,41 it is unclear whether these benefits can also be expected 

with “specialist” physicians operating outside the bounds of a multidisciplinary clinic. Exercise 

training can also result in substantial improvements in functional status for patients with CHF, 

but existing studies have not reported consistent results or have involved regimens that are not 

practical in an ambulatory care setting.42,43

Surgical Management 

There are some surgical interventions for heart failure that may also improve survival when 

directed to the appropriate patients at risk. Left ventricular assist devices can improve short-term 

cardiac function and provide a bridge to cardiac transplantation for appropriately selected NYHA 

Class IV patients. Indeed, they have recently even been approved as destination therapy for 

patients with end-stage heart failure.44 Valvular repair or replacement, revascularization of 

ischemic myocardium,45 and other surgical approaches to heart failure have been proven or are 

under investigation to improve both survival and quality of life in selected patients. Finally, 

cardiac transplantation is effective. However, this is offered to fewer than 2500 individuals per 

year in the United States and is not a solution for the vast majority of heart failure patients. 

Unfortunately, even with the best care using optimal combinations of these nonpharmacologic, pharmacologic, and surgical approaches, the mortality rate remains high and 

quality of life is usually poor for patients with CHF. As an example, in a specialized heart 

failure clinic where 86% of patients are on ACE inhibitors or ARB, 46% are on a beta-blocker, 

and 45% of patients seen since 1999 are on spironolactone, the mortality rates are still 27%, 

43%, and 74% at 1, 2, and 5 years.46

Clearly, there is a need for additional treatment strategies in CHF that can improve function, 

diminish symptoms, reduce hospitalizations, and/or increase survival. Recent studies have 

shown that cardiac resynchronization therapy (CRT) with biventricular pacemakers offers 

improvements in quality of life, NYHA class, and six-minute walk test results, but have yet to 

demonstrate a conclusive mortality benefit. Implantable cardioverter defibrillators (ICDs) do not 

improve functional outcomes, but do provide a substantial mortality benefit (through the 

prevention of sudden cardiac death) in patients with a history of ventricular arrhythmias or at 

high risk due to ischemic substrate and poor ejection fraction.47 

Pacing in CHF 

Electrical conduction disturbances are common in heart failure, including atrial or ventricular 

dysrhythmias, atrioventricular conduction delay, and inter- and intraventricular conduction 

disturbances. The QRS duration is used as an electrical marker for mechanical activation. In an 

Italian registry of heart failure patients, left bundle branch block was present in 25% of patients 

and was associated with an increased one-year mortality (Hazard Ratio 1.70, [95% Confidence 
7 

Interval [CI] 1.41 to 2.05]).48 Intraventricular conduction delay (exact width of QRS not defined) 

was present in 25% to 50% of the patients in a specialty clinic analysis and was associated with 

increased mortality after adjustment for other important covariates (Hazard ratio 1.84, 95% CI 

1.22 to 2.76).49 In a third study, the 33% of patients with a QRS duration of >120 msec had the 

worst survival.50 

The presence of either left bundle branch block or intraventricular conduction delay are 

associated with physiological changes in cardiac function, including a reduction in ventricular 

dP/dt, prolonged duration of mitral regurgitation, and abnormal or paradoxical ventricular septal 

wall motion. Delay in electrical conduction results in increased duration of mitral regurgitation 

or the opportunity for pre-systolic mitral regurgitation to develop. There is an increase in the 

overall ventricular contraction time due to delayed activation of the left free wall and together 

this results in mechanical dyssynchrony and a reduction in cardiac output. 

Original attempts at pacing in heart failure using right-sided dual-chamber atrioventricular 

(AV) sequential devices produced short-term physiological improvements,51 but subsequent 

randomized trials failed to demonstrate a functional or mortality benefit in CHF.52 

Biventricular pacing (BVP), or CRT, involves pacing simultaneously in the right atrium, 

right ventricle, and left ventricle. It was first tried as a short-term bridge after cardiac surgery; 

subsequent physiological studies demonstrated improved cardiac function with reductions in 

both pulmonary capillary wedge pressure and myocardial oxygen use when compared to 

dobutamine.53-56 Since the first attempts at synchronized atrial-biventricular pacing by Cazeau et 

al.57 many mechanical improvements in the devices, refinements of the implantation technique, 

and advances in patient selection have occurred. 

Objectives of this Review 

The benefits of CRT in congestive heart failure have now been tested in several randomized 

clinical trials, but due to small numbers of events, no definitive mortality benefit has been 

demonstrated. Furthermore, surrogate measures were used as the primary endpoint in many of 

these trials, and the impact of this potentially costly therapy cannot be estimated from the 

existing data. Through performing a systematic review and meta-analysis of these trials, we 

sought to determine if CRT reduces mortality (all-cause, progressive heart failure, sudden 

cardiac death), hospitalization rates, and/or improves functional outcomes and quality of life in 

patients with symptomatic CHF. We also sought to clarify the safety of these devices within 

clinical trials and when used in the non-trial setting. Finally, to clarify the effects of CRT on the 

healthcare system, we performed a decision analysis that incorporated safety, effectiveness, and 

cost data for biventricular pacemakers, taking into account other proven effective therapies in 

CHF (such as ACE inhibitors, beta blockers, aldosterone antagonists, digoxin, and 

multidisciplinary specialty clinics). 
8 

Study Questions 

The specific questions we attempted to address in this project were: 

• In adult patients with symptomatic CHF, is CRT more effective than optimal medical care 

alone or univentricular pacing? 

• Is the implantation of a CRT system safe for patients? 

• What is the role of CRT in the treatment of CHF? 

• Which patients with CHF would most likely benefit from CRT? 

• What is the cost-effectiveness of CRT in patients with CHF? 
9 

Chapter 2. Methods 

Methods for the Systematic Reviews 

Literature Search 

A medical librarian identified relevant databases and developed search strategies based on 

the following terms: biventricular pacing, biventricular pacer, biventricular stimulation, BiV, 

congestive heart failure, CHF, chronic heart failure, artificial cardiac pacing, heart diseases, 

chronic cardiac failure resynchronization therapy, dual-chamber pacing, cardiac 

resynchronization, Medtronic, InSync, ELA medical, randomized controlled trial, controlled 

clinical trial, meta-analysis, multi-center trial, safety, risk, adverse effects, side effects, harm, 

etiology, aetiology, contraindications, causation, causality, predict. 

These search terms were adapted appropriately to search the following electronic resources: 

Cochrane Heart Group Trial Registry, Cochrane Library, EMBASE, International 

Pharmaceutical Abstracts, MEDLINE, PubMed, Web of Science, and Trial Registries 

(http://www2.umdnj.edu/~shindler/trials/trials_a.html; http://www.nhlbi.nih.gov/index.htm; 

http://www.controlled-trials.com/; clinicaltrials.gov; http://www.update-software.com/National/; 

http://www.centerwatch.com/search.asp; and http://www.cardiosource.com). The detailed search 

strategies can be located in Tables A-1 to A-16, which are available on the AHRQ web site. 

In addition, the investigators contacted the primary authors of key studies, sought Food and 

Drug Administration (FDA) reports, and reviewed the reference lists of all included articles. 

Additional unpublished data were also sought from the companies that make biventricular 

devices: Medtronic Inc., Guidant Corporation, and ELA Medical. The search was not limited by 

language or publication status and is considered up-to-date to June 2003. 

Selection and Inclusion 

The librarian screened the initial search results to eliminate all duplicates. Following this, we 

used a two-step eligibility and selection process. First, two heart failure clinicians (JE, FM) 

independently screened all titles and abstracts to determine if an article met the general inclusion 

criteria (i.e., clinical trial, biventricular, dual chamber or multisite pacing, resynchronization 

therapy, human, symptomatic heart failure). Each article was rated as ‘include’, ‘exclude’, or 

‘unclear’. The full text of all articles marked as ‘include’ or ‘unclear’ were retrieved. Second, 

two teams of physicians (JE and FM, and BR and TK) independently assessed the studies using 

specific inclusion and exclusion criteria for the efficacy and safety reviews, respectively (Table 

2). Standard inclusion forms were used for this purpose (Tables B-1 and B-2, available on the 

AHRQ web site). Disagreements were discussed between reviewers until consensus on inclusion 

was reached. If needed, the investigators contacted the authors to clarify that individual 

publications reported on discrete patients. In cases of multiple publications involving the same 

or a portion of the same patients, the article with the most complete data was selected. 
10 

Table 2. Inclusion/exclusion criteria for review on cardiac resynchronization therapy 

Criterion Efficacy review Safety review 

Study Design 

Include: RCT (parallel or crossover) > 2 

weeks duration. 

Exclude: non-RCTs, acute physiological 

studies, studies not involving human 

subjects 

Include: RCT (parallel or crossover) or 

non-RCT (e.g., registry data, prospective 

cohort, FDA document, etc.) > 2 weeks 

duration. 

Exclude: acute physiological studies, 

studies not involving human subjects 

Participants 

Include: symptomatic CHF (NYHA Class ≥

II), decreased LVEF, prolonged QRS. 

Must be receiving stable optimal drug 

therapy 

Include: symptomatic CHF (NYHA Class 

≥ II), decreased LVEF, prolonged QRS. 

Must be receiving stable optimal drug 

therapy 

Intervention 

Treatment with active CRT (also called 

BVP, multi-site pacing, dual chamber 

pacer) compared to either placebo pacing 

or uni-ventricular pacing or optimal drug 

therapy 

Treatment with active CRT (also called 

BVP, multi-site pacing, dual chamber 

pacer). Comparison group not necessary 

Outcome 

measures 

Mortality (all-cause, CHF, sudden cardiac 

death, non-cardiac), CHF hospitalizations, 

6MWT, NYHA class, QOL 

Peri-implant mortality, successful implant 

rate, risks of /during implantation, risks 

following implantation 

BVP = biventricular pacing; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; QOL = quality of 

life; RCT = randomized controlled trial; 6MWT = six-minute walk test. 

Quality Assessments 

Efficacy review. The methodological quality of RCTs was assessed independently by two 

reviewers (JE, CS) using two quality assessment methods. First, allocation concealment was 

assessed as adequate, inadequate, or unclear. Second, a five-point scoring system validated by 

Jadad58 was used to assess randomization, double blinding, and reporting of withdrawals and 

dropouts (Table B-3). In addition, the funding source and whether authors reported use of 

intention-to-treat analysis were noted. Discrepancies were resolved through discussion between 

the two reviewers. 

Safety review. Studies included in the safety review were assessed for quality independently by 

two reviewers (CS, LH) using a partially validated checklist developed by Downs and Black.59 

The checklist includes 28 questions evaluating five criteria (Table B-4). These five criteria are: 

Reporting (10 questions, total score 11), External validity (three questions, total score 3), Internal 

validity – bias (seven questions, total score 7), Internal validity – confounding (six questions, 

total score 6) and Power (two questions, total score 2). Decision rules regarding application of 

the tool were developed a priori through discussions with a cardiologist and a methodologist. 

Discrepancies in quality assessment were resolved through discussion. 

Data Extraction 

Data were extracted using standard forms (Tables B-5 and B-6) designed for either RCTs 

(efficacy and safety reviews) or cohort studies (safety review) and entered into an Excel 

spreadsheet. Data were extracted by one reviewer (JE, CS, NW, or LH) and checked for 

accuracy and completeness by a second (JE, NW, or CS). Extracted data included study 

characteristics, inclusion/exclusion criteria, baseline drug use, characteristics of participants, 

procedural data, and outcomes. Efficacy outcomes included mortality (all cause as well as CHF 

death, sudden cardiac death, non-cardiac death) and time to death; CHF hospitalizations, six-
11 

minute walk test, NYHA class, quality of life, peak oxygen consumption, left ventricular ejection 

fraction, mitral regurgitation jet area, ECG and echocardiogram results. Safety outcomes 

included risks during implantation (death, lead misplacement, device-related malfunctions, 

procedural complications, implant tools, heart function, and patient complaints), risks following 

implantation (mechanical malfunction, lead dislodgment, infection, pain), and successful implant 

rate. 

Data Analysis

Efficacy review. The following imputations and manipulations were performed to form useable 

data. Standard errors were converted into standard deviations. Graph extraction was performed 

using Corel Draw 9.0 (Vector Capital, San Francisco, California) for time to death in the 

COMPANION trial.60 Means were approximated by medians, and 95% empirical intervals were 

used to calculate approximate standard deviations for the MIRACLE trial.61 Change from 

baseline data was used wherever possible for continuous data (PATH CHF62 being the 

exception); however, since correlations between baseline and endpoint data were never reported, 

a correlation of 0.5 was assumed63 to calculate the appropriate standard deviation for change 

from baseline data. Change from baseline and endpoint data were combined; both entities 

estimate differences between treatment groups. Efficacy results were extracted rather than 

intention-to-treat results when provided. 

Numerical results were meta-analyzed primarily in Stata 7.0;64 metagraphs were generated 

using S-plus 6.0.65 For dichotomous results (e.g., CHF hospitalizations), the review included 

relative risks (RR) for each individual study as well as a pooled result among those studies that 

could be combined. Additionally, risk differences were considered where zero total events 

occurred in both groups. Increments of one or more across functional classification (e.g., from 

Class III to Class II) were considered a dichotomous outcome. For continuous variables, mean 

differences (e.g., six-minute walk test) were calculated for separate studies and the weighted 

mean difference (WMD) for the pooled estimate. Time-to-event data (i.e., death) were 

summarized by the log hazards ratio;66 Kaplan Meier curves were generated. An individual 

patient dataset for this analysis was constructed using summary monthly mortality tables in the 

trial manuscripts. The Log Rank test assessed for treatment group differences across curves. All 

results were reported with 95% confidence intervals (CIs) where reasonable. 

Due to the differences expected between studies (particularly in control group therapies), we 

decided a priori to combine results primarily using random effects model;67 fixed effects models 

were considered in sensitivity analyses. Statistical heterogeneity was assessed by the Chi-square 

test; a conservative level of significance (p<0.10) was considered heterogeneous.68 Also, 

heterogeneity was quantified and appropriated using the I-squared statistic.69 Inclusion of 

studies with active control arms62,70 was assessed in sensitivity analyses. Relevant direct 

subgroup comparisons were summarized, including effects of CRT in patients with more severe 

heart failure symptoms (NYHA Class III or IV). Implantable cardioverter defibrillators (ICDs) 

were considered in an indirect subgroup comparison using meta-regression. 

Estimates of carryover effect were extracted from crossover designs. Only period one data 

were used for irreversible outcomes (i.e., death and CHF hospitalizations). Standard errors for 

crossover WMD were calculated according to Curtin.71
12 

Safety review. Numerical results were meta-analyzed primarily in S-plus 6.0. Risks were 

simply pooled and all results were reported with 95% CIs. Statistical heterogeneity was assessed 

by the Chi-square test; p<0.10 was considered heterogeneous.68 Also, heterogeneity was 

quantified and appropriated using the I-squared statistic.69 Exclusion of NYHA class II data and 

studies with active control arms62,70 was assessed in sensitivity analyses but is not reported here. 

The possibility that reports may have been less judicious in reporting adverse events that did 

not occur was considered. Sensitivity analyses were performed where studies (randomized 

controlled or cohort) did not report a particular risk (e.g., death); zero adverse events were 

assumed for these studies. In addition, some implantation risks were reported by event and not 

by patient. This non-independence was small and would not be expected to affect results 

importantly. 

Methods for the Decision Analysis

The purpose of the decision analysis was to provide policy makers with a better 

understanding of the role of this new health technology for the treatment of congestive heart 

failure from a healthcare system perspective. The specific objectives were: 1) to estimate the 

long-term effects and costs of the use of cardiac resynchronization compared with medical 

therapy alone in patients with symptomatic congestive heart failure and reduced left ventricular 

ejection fraction, and 2) to calculate the incremental cost-effectiveness of cardiac 

resynchronization relative to medical therapy alone. The decision model compares the lifetime 

effects and costs of two treatment strategies for congestive heart failure: cardiac 

resynchronization in addition to medical therapy vs. medical therapy alone. 

Structure of the Decision Model 

The primary analysis considered patients with NYHA III heart failure and prolonged QRS 

duration. This analysis considered the lifetime horizon, as recommended.72 A state-transition 

Markov model compared costs and outcomes of congestive heart failure treated by CRT and 

medical therapy vs. medical therapy alone. A cycle length of one month was used. 

During each cycle, patients who received medical therapy could die of unrelated causes, die 

of cardiovascular disease, be hospitalized for heart failure, or remain stable (Figure 1 end of 

chapter). Patients who underwent biventricular pacemaker insertion could die during initial 

implantation of the device, experience lead infection, lead failure, or battery failure, or 

experience any of the health states associated with medical therapy for heart failure. 

Decision analyses were performed with DATA Pro software (TreeAge Software Inc., 

Williamstown, Massachusetts) and Excel 2000 software (Microsoft Inc., Redmond, 

Washington). Statistical analyses were performed with S-Plus (Insightful Inc., Seattle, 

Washington). 

Input Data 

Survival and Hospitalization. Baseline probabilities of adverse events, the probabilities of 

cardiovascular death, arrhythmic death, heart failure death, hospitalization for heart failure, and 
13 

adverse effects associated with the therapy options, as well as estimates of life expectancy 

associated with each therapy, were derived from the meta-analyses described above. Nine trials 

were included in the efficacy analysis: Comparison of Medical Therapy, Pacing, and 

Defibrillation in Chronic Heart Failure (COMPANION),60 CONTAK CD,73 Garrigue et al.,70

Multicenter InSync Randomized Clinical Evaluation (MIRACLE),61 Multicenter InSync 

Randomized Clinical Evaluation ICD (MIRACLE ICD),36 Multisite Stimulation in 

Cardiomyopathies Sinus Rhythm (MUSTIC SR),74 Multisite Stimulation in Cardiomyopathies 

Atrial Fibrillation (MUSTIC AF)75, the Pacing Therapies for Congestive Heart Failure trial 

(PATH CHF)62 , and the RD-CHF Trial (Leclerq C, personal communication, December 2003). 

The rate of events observed among patients randomized to medical therapy was annualized 

by using an exponential approximation.76,77 Transition probabilities incorporated into the 

Markov Model were adjusted for the cycle length. Pooled relative risks were calculated by using 

the Dersimonian and Laird random effects model.67 

The base case analysis considered only the effect of CRT on all-cause mortality since it is 

difficult to subclassify causes of death in patients with cardiovascular disease. Cardiac and noncardiac deaths were only considered in secondary analyses that accounted for the patient age at 

implantation (ie. differences in mortality due to unrelated causes). 

Quality of Life. The health-related quality of life of patients with heart failure was estimated by 

eliciting utilities, since current standards suggest use of such outcome measures, and the relative 

cost-effectiveness of some cardiac therapies is sensitive to the magnitude of the difference 

between the utilities associated with either treatment.78,79 Since the purpose of the decision 

analytic model was to consider an intervention in the context of resource allocation among 

different types of interventions, the use of a generic source of preferences was used as 

recommended.78 A convenience sample (n=90) of members of the general public was recruited. 

Inclusion criteria were: fluent in English, provision of informed consent, age greater than 40, and 

no underlying cardiac disease. Consenting subjects estimated utilities for standardized health 

state descriptions by using the standard gamble technique.80 Four health states were considered: 

NYHA functional class II, III, IV, and congestive heart failure severe enough to require 

hospitalization. Hypothetical scenarios describing what one would typically feel and experience 

if living with each of these health states were developed with input from an expert panel based 

on descriptors from the Health Utilities Index.81 

Costs. The economic analysis was conducted from a health care perspective, including costs of 

hospitalization, procedures, ambulatory visits, medications, and laboratory tests. Costs are 

expressed in 2003 American dollars (Table 3, end of chapter). The costs of a CRT device were 

based on a survey of manufacturers’ list prices. Physician costs related to CRT implantation 

were based on Current Procedural Terminology codes 

(http://www.naspe.org/pdf_files/cpt_coding_form_0304.pdf - accessed on June 15, 2003). The 

costs of hospitalizations associated with congestive heart failure were based on estimates derived 

from a cohort study of health resource use by patients participating in a previous randomized 

trial of medical therapy for heart failure.82 All costs were adjusted for inflation by using the U.S. 

Consumer Price Index (http://stats.bls.gov/cpi accessed on May 30, 2003). 

Assumptions. We made several assumptions about the costs and effects of CRT. First, unit 

costs of complications related to CRT are identical to those for implantable cardioverter 
14 

defibrillators. Second, unit costs of heart failure therapy (ie. costs of out patient or in patient 

care) were otherwise identical between medical therapy and CRT. Third, the incidence of 

complications associated with CRT was constant over time from implantation. Since the 

duration of study followup in each trial was relatively short and the incidence of adverse effects 

observed in the randomized trials was higher than is generally accepted for implantable 

cardioverter defibrillator use (which may reflect relative inexperience with biventricular 

pacemakers),83 the primary analysis assumed that the annual probability of each of lead 

infection, lead failure or mechanical malfunction was 3.0% (range 0% to 10%). We also 

assumed that any mechanical malfunction of the device required battery replacement with 

consequent costs and consequences. Fourth, uncomplicated CRT had identical health-related 

quality of life as that of medical therapy. Fifth, the utility for hospitalization was identical, 

regardless of the reason for hospitalization. The morbidity of hospitalization was incorporated 

into the model by assigning the utility for hospitalization to it’s duration, and assigning the utility 

for the health state prior to hospitalization to the remainder of the cycle. Finally, age-specific 

mortality due to unrelated causes was based on life tables.84 

An intervention that was more effective and less costly than the other was considered to be 

“dominant” and hence preferred to the alternative. 

Uncertainty and Variability Analyses 

The analysis distinguished between parameter uncertainty (i.e., variation in costs and effects 

due to sampling and measurement error) and variability (i.e., heterogeneity in costs and effects 

between groups of patients with systematic differences in cost or effects). Uncertainty was 

assessed by using 10,000 probabilistic Monte Carlo simulations.85,86 Empirical cost variables 

were assigned log-normal distributions. Empirical probability variables were assigned beta 

distributions.85 Variables without a known distribution form (i.e., those with assumed values, or 

those with values based on a range of published reports) were assigned triangular distributions.87 

Since there is no absolute cost-effectiveness criterion,88 the results of the Monte Carlo 

simulations were illustrated as a scatter plot of incremental effects (in quality-adjusted life years) 

versus incremental costs. In such a plot, the incremental cost-effectiveness ratio is represented 

by the slope of incremental costs to incremental effects. The uncertainty in costs and effects was 

also illustrated as a cost-effectiveness acceptability curve. An acceptability curve is a 

conditional probability plot showing the proportion of the observed incremental costeffectiveness density that lies below a threshold ratio, which represents the monetary value of a 

unit of health gain. The plot is conditional on the threshold ratio, and therefore the decision 

maker can interpret the data in light of their threshold willingess to pay for the incremental health 

outcome. 

Variability was assessed by using sensitivity analyses as follows. We substituted the upper 

and lower limits of the value of each variable in the decision model while holding all other 

values constant (Table 3).89,90 For empirical variables, these limits were the 95% confidence 

limits for each variable. For assumed variables (e.g., cost of cardiac resynchronization and 

discount rate), these limits were based on reasonable possible limits (i.e., +50%). Threshold 

analyses identified the value of each variable across its range, if any, at which one should be 

indifferent between medical therapy or CRT (i.e., the incremental costs per quality-adjusted life 

year was $100,000).90
15 

Multiway sensitivity analyses were also performed. Since the effectiveness of both 

interventions may be correlated, we varied simultaneously the probability of arrhythmic death 

with medical therapy, and relative risk of arrhythmic death with CRT. Since the rate of adverse 

effects observed in the randomized trials was higher than is generally accepted for implantable 

cardioverter defibrillator use,83 the incidence of device-related adverse effects observed in the 

trials was substituted into the model. 

A structural sensitivity analysis considered the relative risks of cardiovascular death (heart 

failure death and sudden cardiac death) disaggregated with CRT versus medical therapy alone 

(Figure 2, end of chapter). Since it is difficult to classify cardiovascular deaths as arrhythmic or 

non-arrhythmic,91 the pooled relative risk of arrhythmic death and non-arrhythmic death were 

based on retrospective subgroup analyses of data observed in the randomized trials of CRT. 

There is ongoing debate in the clinical community about whether CRT increases the risk of 

sudden cardiac death. 

Finally, subgroup analyses considered the incremental cost-effectiveness of CRT versus 

medical therapy alone for patients with NYHA II or NYHA IV heart failure by substituting the 

appropriate health-related quality of life weight. 

Peer Review 

We asked 27 external people to peer review a draft of the report—consisting of the two 

completed reviews and the decision analysis. Nine agreed to do so, and we received comments 

from five of them. Authors considered their comments, as well as 6 anonymous peer reviewers 

from the Annals of Internal Medicine, and amended the analyses and document accordingly. 

Peer reviewers are listed in Appendix D, available on the AHRQ web site (except of course the 

anonymous peer reviewers from the Annals of Internal Medicine). 
23 

Chapter 3. Results 

Literature Search 

Of more than 3000 initial references, only nine and 17 studies were accepted for the efficacy 

and safety reviews, respectively (Figure 3). Two of these were unpublished manuscripts 

describing studies that met the inclusion criteria. Another was a report submitted to the FDA on 

the MIRACLE35 trial to enhance data from the published trial results.61 Also included were the 

FDA reports on the MIRACLE ICD93 and CONTAK CD73 trials found on the FDA web site. 

(We used the published report for data on patients with NYHA Class III or IV symptoms in the 

MIRACLE ICD94 Trial, and the FDA report for NYHA Class II data since this was not included 

in the journal publication.) Bristow published the protocol for the COMPANION trial in 2000,95

and the results were presented at the Annual Scientific Conference of the American College of 

Cardiology in Chicago, April 2003. Further unpublished data from this trial were made available 

to us and are included in the analysis. 

Figure 3. Flow diagram of study retrieval and selection for cardiac resynchronization therapy 

 

Initial independent references 

from all databases 

(n=3,405) 

Citations with potential 

relevance (n=1,697) 

Citations with potential 

relevance (n=1,708) 

Full text articles with potential relevance 

(n=80) 

Full text articles with potential relevance 

(n=88) 

Second screening 

with specific criteria 

Met inclusion criteria (n=9) Met inclusion criteria (n=17) 

2 FDA reports and 1 

unpublished article 

2 FDA reports and 2 

conference presentations 

First screening of titles and abstracts 

using general criteria 

Efficacy Review Safety Review
24 

There were three main reasons for exclusion of studies from the review: 1) the intervention 

studied was not CRT; 2) the article was a review, a protocol, or an editorial; and 3) the study did 

not report our outcomes of interest. The list of excluded studies and reasons for exclusion are 

identified at the end of the Reference List. 

Most of the included trials were associated with multiple publications that either expanded on 

the main results or reported secondary outcomes not included in the primary report. We only 

included the primary report for each trial, but did extract data on secondary outcomes if they 

were reported only in these secondary publications. Table 4 (end of chapter) identifies the 

associated publications. 

Efficacy Review 

Description of Included Studies 

Nine randomized trials met the inclusion criteria for the efficacy review: 

Abraham 2002: Multicenter InSync Randomized Clinical Evaluation (MIRACLE trial).61 

Auricchio 2002: Pacing Therapies for Congestive Heart Failure (PATH CHF trial).62

Bristow 2003: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart 

Failure (COMPANION trial).60 

Cazeau 2001: Multisite Stimulation in Cardiomyopathies Sinus Rhythm (MUSTIC SR 

trial).74

Garrigue et al.70

Guidant Corporation: the CONTAK CD trial.73 

Medtronic 2001: Multicenter InSync Randomized Clinical Evaluation ICD (MIRACLE 

ICD).36,93,94 

Leclercq 2000: Multisite Stimulation in Cardiomyopathies Atrial Fibrillation (MUSTIC AF 

trial).96

RD-CHF: presented at the 2003 European Society of Cardiology Meeting and personal 

communication from Dr. C. Leclerq November, 2003. 

Six of these trials have been published, (Garrigue et al., MIRACLE, MIRACLE ICD, 

MUSTIC AF, MUSTIC SR, and PATH CHF) and three (COMPANION, CONTAK CD, RDCHF) were located from other sources as mentioned above. The four largest trials were 

conducted in North America,36,60, 61,73 and the other five were conducted in the European 

Community.62,70,74,75,RD-CHF Characteristics of the trials are summarized in Table 5 (end of 

chapter). 

In total, 3574 patients were enrolled in these trials and 3216 (90%) were randomized to 

receive CRT (n=2063) or control (n=1153). The majority of those who were enrolled but not 

randomized had failed implant attempts. The mean age of enrolled patients was 64 ± 3 years and 

74% were male. Approximately 75% were considered NYHA class III (range 55% to 100%) and 

10% NYHA class IV (range 6% to33%). Two trials included NYHA class II (range 10% to 

38%).36,73 Ethnic background was available from one trial in which 90% were Caucasian.61 

Further details about baseline characteristics for each trial are presented in Table 6. 
25 

No trial specifically recruited patients based on the etiology of their heart failure, although 

patients with uncorrectable valvular disorders and hypertrophic or restrictive cardiomyopathy 

were excluded from all trials. In the three trials that evaluated CRT with ICDs, the majority of 

patients had ischemic etiology (~59%);36,60,73 in the other trials, ischemic etiology ranged from 

37%74 to 55%.61 Other comorbidities such as diabetes mellitus, renal failure, previous cardiac 

history, or a history of sudden cardiac death were reported in only one trial.93

All trials (except PATH CHF, which did not specify an ejection fraction criteria)62 were 

limited to patients with an ejection fraction < 35% or < 40%. The mean ejection fractions were 

similar in all trials, and ranged from 21% to 30%. Six trials also specified a left ventricular end 

diastolic dimension: ≥ 55 mm in two trials36,61 and ≥ 60 mm in the other four trials.60,70,74,75 The 

reported mean left ventricular end diastolic dimension for the trials were similar (68 mm to 73 

mm). 

QRS width was a criteria for all trials, with three trials specifying ≥ 120 msec,60,62,73 two 

trials ≥ 130 msec,36,61 one trial >140 msec,70 one trial >150 msec,74 one trial >180 msec, and one 

trial >200 msec.75 Six of the nine trials had a mean QRS between 159 msec and 175 msec, with 

the MUSTIC AF trial having a mean QRS of 209 msec. Left bundle branch block was present in 

most patients (mean 64%; range 0 to100%). 

Five trials were restricted to patients in normal sinus rhythm,60,62,73,74 but two were restricted 

to patients with atrial fibrillation70,75 In the eighth trial ~14% of patients had atrial fibrillation.93 

Overall, approximately 5% of randomized patients included in this meta-analysis had atrial 

fibrillation. Three trials reported PR intervals that ranged from 196 msec to 215 msec and two 

required a prolonged PR interval >150 msec for inclusion.60,62 Three trials required a six-minute 

walk test result of less than 450 meters as an inclusion criterion.61,74,75 The physical exam 

findings at baseline were similar among trials, with systolic blood pressure (range 113 to 118 

mmHg), diastolic blood pressure (range 67 to 69 mmHg), and heart rate (range 71 to 80 bpm) all 

similar to other trials in heart failure.97

In the three trials where implantable cardioverter defibrillators were tested along with cardiac 

resynchronization therapy,36,60,73 there was a general requirement that study patients meet 

indications for ICD placement. Although it was not specified by which ICD criteria patients 

were evaluated, the indications in MIRACLE ICD36 and CONTAK CD73 were consistent with 

the AHA/ACC/NASPE guidelines for secondary prevention. (Table C-1, available on the AHRQ 

web site, details the inclusion criteria of the individual trials.) 

Medication use was specified in all but the PATH-CHF and RD-CHF trials.62 ACE 

inhibitors were required in all trials, beta-blockers were required in three,60,61,70 and 

spironolactone was only required in COMPANION.60 (Baseline medication use in the efficacy 

review trials is detailed in Table 7 at the end of this chapter.) Importantly, three European trials 

reported 31% use of amiodarone,62,70,74 and 38% of patients in the MIRACLE ICD trial were on 

non-beta-blocker anti-arrhythmic agents.36 Digoxin was used in 48% to 76% of patients, with 

the four largest trials having at least 75% of their patients on digoxin.36,60,61,73

Four of the trials employed a parallel study design.36,60,61,73 One of these had planned a 

crossover period but changed protocol mid-study and excluded crossover data from the 

analysis;73 five others completed a crossover design.62,70,74,75,RD-CHF The duration of treatment 

was 4 weeks in PATH CHF,62 2 months in Garrigue et al.,70 3 months in RD-CHF, 3 

months/phase in MUSTIC AF75 and MUSTIC SR,74 6 months in MIRACLE61 and MIRACLE 

ICD,36 and 12 months in the COMPANION60 trial. Eight of the nine trials used a transvenous 
26 

approach for placement of the epicardial leads (54 patients in CONTAK CD73 required a 

transthoracic approach), while PATH CHF62 used a transthoracic approach. 

Parallel-arm trials. The MIRACLE trial61 enrolled 453 patients (NYHA Class III or IV); 228 

were randomized to CRT ‘on’, 225 to CRT ‘off' (Table 5). The MIRACLE ICD trial36 enrolled 

659 patients (NYHA Class II to IV; 434 in NYHA Class III/IV); 554 patients were randomized 

(364 in NYHA Class III/IV): 272 to CRT ‘on’ and 283 to CRT ‘off’. All patients in MIRACLE 

ICD36 received an implantable cardioverter defibrillator. For both MIRACLE61 and MIRACLE 

ICD,36 the primary outcomes were quality of life, six-minute walk test, and NYHA class. 

COMPANION60 was a three-arm, parallel-group trial that compared optimal 

pharmacological therapy (n=308), cardiac resynchronization therapy (n=617), and cardiac 

resynchronization therapy with cardioverter defibrillator (n=595) randomized in a 1:2:2 fashion 

before device implantation. The primary outcome was a composite of all-cause mortality and 

all-cause hospitalization (including emergency room visits or unscheduled office visits requiring 

>4 hours of intravenous vasoactive or inotropic drug). 

CONTAK CD73 was a two-part trial with an initial pilot crossover involving two 3-month 

phases (n=205 for first 3 month results). We were not able to obtain complete data from the 

second phase; hence this part of the trial was excluded from this report. For part two, they 

conducted a parallel design study with 6-month followup (n=151). The device used also had a 

cardioverter defibrillator. The primary outcome was a composite of all-cause mortality, heart 

failure hospitalizations, and ventricular arrhythmias requiring device intervention. 

Crossover Trials. In MUSTIC SR,74 67 patients were enrolled and implantation attempted, 

followed by an 8- to 12-week observation phase; 58 patients were then randomized into a 3-

month crossover of either CRT ‘on’ or ‘off’ (Phase 1: n=29, Phase 2: n=29). In MUSTIC AF,75

64 patients were enrolled and implantation attempted, followed by 8 to 12 weeks of observation; 

43 were randomized into a 3-month crossover of CRT ‘on’ or ‘off’ (Phase 1: n=25, Phase 2: 

n=18). Both trials used the six-minute walk test as the primary outcome. Neither used a 

‘washout’ period between phases and neither detected a carryover effect. 

PATH CHF62 was a 4-week crossover study in which 42 patients were enrolled and 

implantation attempted; 41 patients were randomized to CRT 'on’ or ‘off’ in two phases with a 4-

week washout period between the two (Phase 1: n=24, Phase 2: n=17). The primary endpoint 

was peak oxygen uptake on a maximal exercise test. This trial did detect a carryover effect. 

Garrigue et al.70 used a 2-month crossover design in which 13 patients had the device 

implanted (plus HIS-bundle ablation). The 13 patients were randomized to either CRT or leftuniventricular pacing alone. The primary endpoint was peak endocardial acceleration time as 

measured by an implantable sensor. Patients were crossed over after 2 months without a 

washout phase. The study did not assess for a carryover effect in the analysis. 

Methodological Quality of Included Studies 

As a measure of methodological quality for the included trials, (end of chapter) the overall 

Jadad58 score (maximum five points) was 5 for one trial,61 4 for three trials,61,62,73 3 for three 

others,60,74,75 and one for the remaining study70 (Table 8). Insufficient details about the RD-CHF 

Trial were provided to be able to grade methodologic quality. 
27 

All trials were described as randomized; however, the description of randomization detail 

varied. As far as blinding, two were open-label,60,70 three were single-blind (i.e., the patient was 

blinded)60,74,75 and four were double-blind (patient and the outcome assessor was 

blinded).36,61,62,73 In CONTAK CD,73 MIRACLE,61 and MIRACLE ICD,36 the independent 

events committee was blinded to which arm of the trial the patient was in; no information was 

available for COMPANION.60 Notably, five trials randomized patients before 

implantation.60,62,73-75 An intention-to-treat statistical analysis was specified in all trials, and 

MIRACLE61 and PATH CHF62 performed an intention-to-treat analysis.61,62 In the remaining 

trials, it was either unclear60,74,75 or multiple analyses were done for the FDA that included an 

intention-to-treat analysis of all patients involved in the trial program36,73 Withdrawals and 

dropouts were clearly described in all trials except COMPANION.60 Unscheduled crossovers 

occurred in zero to nine percent of the patients in these trials and were generally balanced 

between study arms. Withdrawals ranged from zero to 3% for the cardiac resynchronization 

group and from zero to 2.5% for the control groups. Allocation concealment was unclear for all 

but the MIRACLE61 trial. 

Industry sponsored seven of the nine trials; two also received funding from government 

sources.74,75 Guidant Corporation sponsored three,60,62,73 Medtronic Inc. sponsored four,36,61,74,75

and ELA Recherche funded two.74,75 Garrigue et al.70 did not report funding sources. 

Safety Review 

Description of Included Studies 

Seventeen randomized (n=8) and cohort studies (n=9) met the inclusion criteria for the 

review of safety of cardiac resynchronization therapy (Table 9, end of chapter). Eight of the nine 

trials included in the efficacy review were eligible (Garrigue et al.70 did not contain any pertinent 

safety outcomes). The 9 additional studies included one randomized trial that did not report 

efficacy endpoints of interest98 and 8 prospective cohort studies,70,96,99-103 that included one 

unpublished manuscript submitted to us by an author of another included study.104 Thirteen 

studies reported that devices were implanted transvenously, two were transthoracic,62,98 and two 

used both approaches.73,105 Either Medtronic Inc. or Guidant Corporation manufactured all 

implanted devices; however, the models and leads varied among and within trials. 

In total, 3938 patients were enrolled; of these, 3636 patients received CRT. Some patients 

were excluded or withdrew due to unsuccessful implants, death, heart transplantation, or 

miscellaneous reasons. The mean age was 65 ± 3 years, and 78% were male. Approximately 

75% of each study population was NYHA class III (range 32% to100%), and 17% NYHA class 

IV (range 4 to 100%) (Table 10). Five studies73,93,98,101,102 included patients with NYHA class II 

symptoms (range 4% to 38%). Ethnic background was available from one trial in which 90% 

were Caucasian.61

Kuhlkamp102 required participants be survivors of a cardiac arrest and have sustained 

ventricular tachycardia; otherwise no studies specifically based inclusion on the etiology of their 

heart failure. Patients with correctable valvular disorders, hypertrophic or restrictive 

cardiomyopathy, unstable angina, or acute myocarditis were excluded. Four studies did not state 
28 

exclusion criteria.99,102,103,106 Ischemic etiology ranged from 29%62 to 69%.101 Other 

comorbidities such as diabetes mellitus or renal failure were reported in only one study.36 

Eleven studies limited inclusion to patients with an ejection fraction <35%, one restricted it 

to <30%,98 one to <25%,60 and 3 did not specify this criterion.62,99,101 The mean ejection fraction 

ranged from 19% to 26%. Nine studies specified a left ventricular end diastolic dimension 

inclusion criterion of ≥55 mm60,61,74,75,93,96,100,102,104 or ≥ 60 mm. The reported mean left 

ventricular end diastolic dimension for the trials ranged from 68 mm to 74 mm. 

QRS width was a criterion for 13 studies, with six specifying ≥ 120 msec,60,62,73,103,107 four 

studies ≥ 130 msec,61,93,101,102 two trials >150 msec,74,100 and one > 200 msec.75 Ten of the 16 

studies reported a mean QRS between 158 msec and 180 msec, and six ranged from 180 msec to 

213 msec.70,75,96,99,104,106 In the nine studies that reported the presence of left bundle branch 

block, the mean was 68% (range 0 to 100%). 

Five studies were restricted to patients in normal sinus rhythm,60,62,74,100 but two were 

restricted to patients with atrial fibrillation.96,106 In the others, 6% to 38% of patients had atrial 

fibrillation. Eight studies reported PR intervals that ranged from 198 msec to 248 msec, and two 

required a prolonged PR interval >150 msec for inclusion.60,62 Three studies required a sixminute walk test result of ≤ 450 meters as an inclusion criterion.61,74,75 The physical exam 

findings of systolic blood pressure (range 113 mmHg to 118 mmHg), diastolic blood pressure 

(range 67 mmHg to 68 mmHg), and heart rate (range 73 to 78 bpm) at baseline were all similar 

to other studies in heart failure.97 (The inclusion and exclusion criteria for the individual studies 

are detailed in Appendix C: Table C-2). 

Concomitant medication use was specified in all but the PATH CHF62 and Molhoek103

studies (Table 11). ACE inhibitors were required in all studies, beta-blockers were required in 

three,60,61,101 and spironolactone was only required in COMPANION.60 Importantly, four studies 

reported 31% to 50% use of amiodarone,62,74,98,100 and 38% of patients in the MIRACLE ICD 

trial36 were on non-beta-blocker anti-arrhythmic agents. Eleven studies reported that 32% to 

100% of participants were on digoxin and 90% to 100% were taking diuretics. Table 11 (see end 

of chapter) details baseline medication use by study. 

Quality of Included Studies 

Overall, the studies were rated as having ‘good’ quality on the Downs and Black59 scoring 

system. Eight studies were described as randomized (three parallel trials,36,95,108 five crossover 

trials,62,73,74,96,98 and the remaining eight were prospective cohort studies.99,96,100-104,106 Reporting 

was generally good with 8 of 16 rating 11/11, the rest ranging from 7 to 10. External validity 

assessment posed some problems because authors did not report the source population for 

patients or the proportion of eligible patients selected for inclusion, nor compare the distribution 

of main confounding factors with the source population. (For this review we defined the source 

population as those with symptomatic CHF.) Since this procedure can only be performed in 

specialist centers, we determined that all facilities were representative. Internal validity 

concerning assessment of bias ranged from 5/7 to 7/7; the lack of blinding was the main 

shortfall. Four studies were double-blind,36,61,62,73 two were single-blind (i.e., the patient),74,75 

and the remaining trials were open-label. Internal validity assessments concerning confounding 

ranged between 1/6 to 6/6, with only two studies receiving 2 or less.96,100 Many authors did not 

state the period of time over which patients were recruited, the source of patients, or how the 

randomization code was generated and concealed. Withdrawals and dropouts were clearly 
29 

described in all studies except COMPANION.60 Four studies included a power 

calculation,60,61,74,75 and nine had sufficient sample sizes to determine a clinically important 

effect.36,60-62,73-75,98,104 

The majority of studies that reported sponsorship received funding from industry. Three 

were sponsored by Guidant Corporation,60,62,73 six by Medtronic,36,61,74,75,102,106 and three 

received technical support from ELA Recherche.74,75,99 The two MUSTIC trials74,75 and Krahn101

received funds from independent sources. Four studies did not report a funding source.96,98,100,104 

Methodological quality of the trials in the safety review are summarized in Table 12 (end of 

chapter). 

Quantitative Results 

Efficacy Review 

The nine trials included 2755 patients with NYHA Class III or IV CHF, and 461 patients 

with NYHA Class II symptoms. 

All-cause mortality. Based on data pooled from all nine randomized controlled trials (311 

deaths in patients with NYHA class III or IV symptoms at baseline, 14 deaths in those with 

NYHA class II symptoms), CRT significantly reduced all-cause mortality, with a relative risk of 

0.75 (95% CI 0.60 to 0.93) (Figure 4 end of chapter). There was no significant statistical 

heterogeneity between trials (p=0.88, I-squared=0%). The results were identical when the 

analysis was restricted to patients with NYHA Class III or IV symptoms (RR 0.76, 95% CI 0.60 

to 0.95). The all-cause mortality rate in the control patients with symptomatic heart failure 

(NYHA II-IV) was 14.9%, and the number needed to treat (NNT) to prevent one death was 27 in 

patients with symptomatic heart failure. 

Time-to-death analysis. The time-to-death analysis (4 trials; n=2769 patients) demonstrated 

that length of followup affects results with the survival curves separating after 3 months (Figure 

5). Trials with longer followup periods reported greater survival benefits. When data were used 

for trials with a followup of six months or more,36,60 ,61 all-cause mortality remained significant 

with a relative risk of 0.70 (95% CI 0.56 to 0.89). The 12-month survival rate for the CRT group 

was 89% (95% CI 87% to 90%) and 83% (79% to 86%) for the non-CRT group; this difference 

was significant based on the log-rank test (p=0.005). To account for the separation of the curves 

at 3 months and since data were integrated from four studies, we used a Cox proportional 

hazards model (using study as a covariate) and only incorporated data from beyond the first three 

months. The hazard ratio was 0.59 (95% CI 0.43 to 0.81) for mortality after the first 3 months 

post-implantation. 

Cardiac mortality. Seven trials reported progressive heart failure mortality in NYHA Class II 

to IV patients (n=60 deaths/1647 patients); the relative risk strongly favored CRT, although it 

just failed to reach statistical significance using the (methodologically correct, but statistically 

conservative) random effects model (RR 0.60, 95% CI 0.36 to 1.01; Figure 6). Restricting this 
30 

analysis to patients with NYHA Class III or IV symptoms gave similar results (RR 0.58, 95% CI 

0.32 to 1.06). 

Sudden cardiac death. Using data pooled from the eight trials that reported the cause of death, 

sudden cardiac death (n=28 deaths/1691 patients) was higher (although non-significantly) with 

CRT compared to controls (RR 1.99, 95% CI 0.95 to 4.16; Figure 7). This result was not 

statistically heterogeneous (p=0.98, I-squared=0%) and was similar if only trials of six months or 

longer were included or if only patients with NYHA Class III or IV were included (RR 1.89, 

95% CI 0.76 to 4.70). Only one trial that included an implantable cardioverter defibrillator for 

all patients reported the cause of death; the risk for sudden cardiac death was non-significant (RR 

1.89, 95% CI 0.35 to 10.21).36 

Non-cardiac death. Pooled data from six trials (n= 17/1194 patients) did not demonstrate any 

significant differences in non-cardiac deaths between patients with CRT (RR 0.90, 95% CI 0.35 

to 2.35; Figure 8). This result was not statistically heterogeneous (p=0.46, I-squared=0%). 

Restricting the analysis to patients in NYHA Class III or IV CHF did not alter this conclusion 

(RR 1.89, 95% CI 0.35 to 10.21). 

Morbidity and functional outcomes. 

Heart failure hospitalizations. Pooled results from the six trials that reported heart failure 

hospitalizations showed a relative risk of 0.68 (95% CI 0.41 to 1.12; Figure 9 end of chapter) in 

favor of CRT compared to control. This result was heterogeneous (p=0.01, I-squared=65%) and 

was also insignificant in the fixed effects analysis (RR 0.80, 95% CI 0.64 to 1.003). Restricting 

the analysis to patients with more advanced heart failure (those with NYHA Class III or IV 

symptoms) revealed significant reductions (RR 0.65, 95% CI 0.48 to 0.88; NNT=12) and was 

statistically homogeneous (p=0.31, I-squared=16%). 

Six-minute walk test. CRT was associated with an improved six-minute walk test distance, with 

a weighted-mean-difference of 23 meters in favor of CRT (95% CI 9 m to 38 m, Figure 10 end 

of chapter). This improvement was similar in those patients with NYHA Class III or IV 

symptoms (WMD 26 m, 95% CI 11 m to 41 m). However, this result was heterogeneous 

(p=0.06, I-squared=50%) in part due to one trial74 in which the control group worsened by 24 

meters; the control groups in all other trials that reported baseline results showed an 

improvement. Although the data from the RD-CHF Trial were not available for pooling, the 

RD-CHF investigators reported statistically significant improvements in six-minute walk test 

distances with CRT (personal communication, Dr. Christophe Leclercq, November 2003). 

New York Heart Association Functional Class. We were able to meta-analyze data for NYHA 

Class from three studies (although five studies reported baseline and endpoint NYHA Class). 

Combining these three studies showed improvements in NYHA Class in 57% of CRT patients 

and 34% of controls (CRT was associated with a 1.63 times increased chance of improving at 

least one NYHA Class (95% CI 1.05 to 2.52), Figure 11). This result was statistically 

heterogeneous (p=0.04, I-squared=70%). In patients with NYHA Class III or IV symptoms, the 

relative risk improved slightly to 1.68 (95% CI 1.25 to 2.27). The data from MIRACLE ICD61

was not reported in a format that permitted pooling with the other 3 trials; however, the baseline 
31 

median NYHA Class for both groups was III and the endpoint median was II in the CRT group 

and III in the control group. This improvement in NYHA Class was significant (p=0.01) and 

favored CRT; the specific statistical test used was not reported. In contrast, PATH CHF62

(which could also not be combined with the other trials due to the manner in which the data were 

reported) did not find a significant difference (p=0.36; Wilcox on matched-pairs test), although 

both groups showed significant improvement from baseline. Moreover, while the data from the 

RD-CHF Trial could not be pooled with the other trials, the RD-CHF investigators also reported 

statistically significant improvements in NYHA Class with CRT (personal communication, Dr. 

Christophe Leclercq, November 2003). 

Quality of life. Quality of life was measured by the Minnesota Living With Heart Failure 

Instrument109-111 for six of the eight trials; pooled results showed a significant improvement in 

favor of CRT (weighted mean difference –5.5 points (95% CI -9 to -2 points; Figure 12). This 

result was highly statistically heterogeneous (p=0.008, I-squared=68%); however results were 

consistent in direction. Restricting the analysis to only those patients with NYHA Class III or IV 

symptoms increased the difference between the CRT and control groups (WMD –6.4 points, 

95% CI –9.4 to –3.4 points), but the results remained significantly heterogeneous (p=0.07, Isquared=50%). These differences are clinically significant since the minimal clinically 

important difference for the Minnesota Living with Heart Failure Questionnaire has been 

established to be 5 points.109-111 Further, although the use of a different scale prevented pooling 

with the other trials, the RD-CHF Investigators reported statistically significant improvements in 

quality of life with CRT (personal communication, Dr. Christophe Leclercq, November 2003).

Other outcomes. Peak oxygen consumption significantly improved in the CRT patients 

compared to the control patients (1.05 ml/kg/min versus 0.39 ml/kg/min; WMD 0.65 ml/kg/min, 

95% CI 0.27 to 1.04 ml/kg/min). Ejection fraction also significantly improved in the CRT arm 

compared to the control arm (4.17% versus 0.82%; WMD 3.35%, 95% CI 1.22 to 5.48%). The 

QRS interval also showed greater improvement in the CRT group (-30 msec versus -2 msec for 

controls; WMD –28, 95% CI –47 msec to –9 msec). Other echocardiographic indices including 

mitral regurgitation jet area were not significantly different between groups; there were 

insufficient data that could be pooled for left ventricular end-diastolic or end-systolic diameters. 

Sensitivity analyses. Many a priori subgroup and sensitivity analyses (including examining any 

interactions between the effects of CRT in patients with different etiologies of heart failure, or by 

ethnic background, gender, age, comorbidities, and baseline medication use) could not be 

performed due to the paucity of subgroup data in the trial reports and our inability to obtain 

individual patient-level data from each of the trial lists despite our requests. 

Post-hoc, we explored the impact of ICDs on the efficacy of CRT using meta-regression (a 

between-study non-randomized comparison). When the data were pooled for all-cause mortality 

from the two trials that included an ICD in both the experimental and control arms (i.e., 

CRT+ICD versus medical therapy +ICD),36,73 the relative risk was 0.84 (95% CI 0.54 to 1.28). 

On the other hand, pooled data from the other five trials comparing CRT versus medical therapy 

demonstrated a relative risk of 0.78 (95% CI 0.56 to 1.08) with CRT (Figure 13).61,62,74,75 This 

difference was not statistically significant (p=0.80), supporting the assertion that the benefits of 

CRT on all-cause mortality are not appreciably altered by addition of an ICD. Using the same 

meta-regression model, secondary outcomes (including heart failure hospitalizations, six-minute 
32 

walk test, quality of life, and NYHA improvements) were not significantly different in patients 

with, or without an ICD, in addition to their biventricular pacemaker. Of note, while the data 

from COMPANION60 could not be used in the meta-regression for ICDs (since none of the arms 

in COMPANION60 consisted of ICD alone), the COMPANION60 data does provide the only 

direct comparison between CRT plus ICD versus CRT alone. This analysis did approach 

statistical significance (p=0.07) in favor of the CRT plus ICD group for all-cause mortality; 

however, the reductions in heart failure hospitalizations were similar in CRT-treated patients 

with/without ICDs. Until the detailed data from the COMPANION60 sub-analyses are made 

available, the most conservative conclusion that can be made at this stage is that the benefits of 

CRT are similar with or without ICDs. 

Post-hoc we also explored the relationship between the baseline use of beta-blockers and/or 

digoxin with the impact of CRT on all-cause mortality. Both meta-regressions were nonsignificant (p=0.37 and p=0.31, respectively), suggesting that the benefits of CRT are not 

modified by use of these medications. However, and as expected, the linear trends showed 

improved survival with greater use of beta-blockers. 

Publication bias could not be quantitatively measured since all of the smaller studies had 

shorter followup times, hence confounding results. In a post-hoc subgroup analysis examining 

published versus unpublished studies, there was no appreciable difference between effect 

estimates for all-cause mortality (p=0.64). 

Fixed effects estimates did not substantially alter the results of our meta-analysis (although 

the confidence intervals were naturally narrower and, as a result, the analysis for progressive 

heart failure mortality (RR 0.59, 95% CI 0.35 to 0.98) reached statistical significance). 

Safety Review

As previously described, seventeen studies were used to examine the safety of CRT. Tables 

13 and 14 report peri-implantation and post-implantation risks from individual studies as well as 

pooled results. In pooling data, we did not include studies that did not report any data for 

particular outcomes. However, where appropriate, we performed sensitivity analyses by 

assuming zero occurrences of that endpoint in that study. 

Peri-implantation risks. Ten studies reported data on deaths while undergoing implantation of 

a biventricular pacemaker (Table 13, end of chapter). There were 13 deaths in 3113 patients 

(pooled risk 0.4%, 95% CI 0.2% to 0.7%); a sensitivity analysis assuming any studies that did 

not report mortality had zero occurrences yielded the same estimate. Immediate deterioration in 

heart function was noted after 1.3% (95% CI 0.7% to 2.2%) of implantation procedures. 

Implants of devices were successful in 89.9% (95% CI 88.8% to 90.9%) of attempts in 3475 

patients from 17 studies; this rate did not vary, but trended toward improvement, by year of 

publication. 

Problems with implantation of the left-ventricular lead were encountered in 6.0% (95% CI 

4.7% to 7.2%) of cases. Assuming that any studies failing to report any implantation problems 

had zero occurrences in sensitivity analysis led to a reduced estimate of 3.9% (95% CI 3.1% to 

4.8%). The device or battery was problematic in 0.9% (95% CI 0.6% to 1.6%) of cases (0.7%, 

95% CI 0.4% to 1.2% with sensitivity analysis), and the procedure or equipment used for the 

procedure was reported to be a problem in 6.4% (95% CI 5.3% to 7.6%) of cases attempted 

(reduced to 5.6%, 95% CI 4.7% to 6.7% in sensitivity analysis). Further detailed information on 
33 

the type of equipment failure was not uniformly available, so pooling of results was not possible. 

Some of the specific problems in this category included lead fracture, loss of capture, 

inappropriate sensing, and extra-cardiac stimulation. 

Post-implantation risks. Data from 13 studies were used to assess post-implantation risks with 

CRT (Table 14 end of chapter). Over a median 6 months of followup, mechanical malfunction 

of the CRT device was noted in 6.7% (95% CI 5.4% to 8.2%) of successful implants. On 

sensitivity analysis, assuming any studies that failed to report this outcome had zero occurrences, 

this rate fell to 4.4% (95% CI 3.6% to 5.4%). Lead dislodgment occurred in 8.5% (95% CI 7.4% 

to 9.9%) of patients, with no differences in those studies using specially designed left ventricular 

leads (this estimate was reduced to 8.3%, 95% CI 7.1% to 9.6% on sensitivity analysis). Postimplantation infection (most commonly in the device pocket) occurred in 1.4% (95% CI 0.8% to 

2.3%) of patients (reduced to 0.9%, 95% CI 0.5% to 1.4%, with sensitivity analysis). 

Arrhythmias attributed to the CRT device occurred in 1.7% (0.8% to 3.4%) of patients during 

followup. 

Decision Analysis 

Effectiveness of Medical Therapy 

Expanding on the results from our systematic review outlined above, annual event rates were 

calculated (median followup time was 22.8 weeks in these trials). The annual risk of death was 

mean 24.3% (95% CI 20.0% to 29.2%) and the annual risk of heart failure hospitalization was 

56.0% (95% CI: 47.6% to 66.2%). 

 

Effectiveness of Cardiac Resynchronization Therapy 

Based on the results of the systematic review, annual event rates were calculated for patients 

with NYHA Class III heart failure randomized to CRT. The relative risks were: all-cause death 

0.75 (95% CI: 0.60 to 0.93) and CHF hospitalizations 0.68 (95% CI: 0.41 to 1.12). 

Cost-Effectiveness of Cardiac Resynchronization Therapy 

 

In patients with NYHA Class III heart failure, medical therapy had median 2.68 (interquartile 

range, IQR=2.49, 2.85) discounted quality-adjusted life years and median $34,700 (IQR= 

$31,100 to $38,100) lifetime costs (Table 15). Cardiac resynchronization had median 3.03 

(IQR= 2.82 to 3.27) discounted quality-adjusted life years and median $67,600 (IQR= $62,000 to 

$73,800) lifetime costs. Cardiac resynchronization was associated with an incremental cost of 

median $90,700 (IQR= $69,500 to $124,900) per additional quality-adjusted life year. Data 

points from Monte Carlo simulation illustrate that compared to medical therapy, CRT is 

consistently associated with a survival gain and an additional cost (Figure 14). The costeffectiveness acceptability curve illustrates that the probability that CRT is cost-effective relative 

to medical therapy alone is less than 59%, given a maximum willingness-to-pay for a qualityadjusted life year of $100,00 (Figure 15). 
34 

Variability Analyses 

The incremental cost-effectiveness of CRT was sensitive to reasonable changes in values for 

several variables including relative risk of either death or hospitalization with CRT, probability 

of death during either lead failure or battery replacement, and costs of either device insertion or 

battery replacement (Table 3). Also, if CRT were associated with greater health-related quality 

of life than medical therapy, then the incremental cost-effectiveness of CRT was reduced (details 

available from authors). 
73 

Chapter 4. Discussion 

Systematic Review 

Efficacy and Safety 

When added to proven efficacious medical therapy, cardiac resynchronization therapy 

reduces risk of all-cause mortality by 25% in patients with symptomatic CHF who have 

prolonged QRS duration and reduced left ventricular ejection fraction. This relative survival 

benefit is similar to those reported for ACE inhibitors, beta-blockers, and aldosterone antagonists 

in recent trials.30,31,109,138 When added to optimal medical therapy, 27 patients need to 

successfully undergo CRT implantation to prevent one death. This reduction in all-cause 

mortality occurs in both the sickest heart failure patients (those with NYHA Class III or IV 

symptoms) as well as those with milder disease (NYHA Class II symptoms), with identical 

relative benefits in both groups. 

The survival benefits with cardiac resynchronization therapy become apparent by 3 months 

after implantation; after the first 3 months, those patients receiving a biventricular pacemaker 

had 41% lower mortality risk than those without cardiac resynchronization therapy. It is likely 

that the benefits do not appear for several months because long-term benefits of cardiac 

resynchronization therapy are mediated through morphometric remodeling of the left ventricle 

rather than neurohormonal changes.136,139 Indeed, preliminary results have suggested that, while 

brain natriuretic peptide levels are reduced in patients by cardiac resynchronization,94,140 levels 

of norepinephrine, big endothelin, and other markers of inflammation are all unchanged. Thus, 

while drug therapies that impact both the neurohormonal system and ventricular remodeling in 

heart failure patients (such as ACE inhibitors and beta blockers) reduce the incidence of sudden 

cardiac death within weeks of being prescribed (possibly due to their immediate impact on the 

renin-angiotensin and sympathetic systems), several months are required for the benefits of 

cardiac resynchronization to become apparent and these benefits are largely restricted to 

progressive heart failure deaths. 

Most of the survival benefits with cardiac resynchronization therapy appear to be attributable 

to a substantial reduction in the rate of progressive heart failure deaths (a 40% relative 

reduction), which is similar to the 51% relative risk reduction in progressive heart failure deaths 

found in a previous meta-analysis that incorporated four of the eight trials in this analysis.141 

This is not surprising since the putative benefits of cardiac resynchronization therapy are via 

improved cardiac output, reduced mitral regurgitation, and reduced pulmonary capillary wedge 

pressure.35,54,55 While we found a non-significant trend toward increased sudden cardiac death 

that was consistent across these trials, that trend was based on a very small number of events (28 

in total) and thus is not interpretable without further trial data (particularly given the well 

recognized difficulties in sub-classifying cardiac deaths as sudden or non-sudden). In particular, 

the lack of a difference in the number of ventricular arrhythmia episodes between those patients 

with, versus without, CRT in the MIRACLE ICD Trial (22% vs. 26%, p=0.47) suggests that the 

trend toward excess sudden cardiac deaths may well be due to small numbers.94 
74 

Regardless, the benefits of cardiac resynchronization therapy are similar in patients with or 

without implantable cardioverter defibrillators, providing some reassurance that, in those patients 

who have indications for both an ICD and a biventricular pacemaker, the two may be 

administered together. An issue that remains to be resolved by ongoing studies (and is beyond 

the scope of this systematic review) is the role of ICDs for primary prevention in patients with 

heart failure,47 which is particularly controversial in those patients with NYHA Class IV 

symptoms142 or with non-ischemic dilated cardiomyopathy.143,144 A large study, SCD-HeFT, 

which is due to report its findings in December 2003, should help clarify this isue.84 

(http://www.sicr.org/scdheft/index.html accessed August 18, 2003) 

Cardiac resynchronization therapy also led to a 32% reduction in hospitalizations for heart 

failure. This benefit was more marked in those heart failure patients who were more 

symptomatic and thus at higher risk for hospitalization (i.e., those with NYHA Class III or IV 

symptoms): a 35% relative risk reduction. The magnitude of this benefit is similar to those 

reported for ACE inhibitors, beta-blockers, and aldosterone antagonists.29-32,34-36

Cardiac resynchronization therapy also conferred statistically and clinically significant 

benefits in quality of life, peak oxygen capacity, ejection fraction, left ventricular volumes, 

distance walked in six minutes, and NYHA Class in patients with advanced heart failure and 

prolonged QRS duration. Quality of life is an important endpoint for heart failure, and a pooled 

six-point improvement on the Minnesota Living With Heart Failure instrument is larger than that 

seen in other heart failure trials and is greater than the minimal clinically important difference of 

5 reported by the developers of the scale.109-111,145,146

An important finding of this systematic review is the safety of cardiac resynchronization 

therapy and its tolerability in patients with advanced heart failure. Peri-implantation mortality 

rates were less than 1%, despite the increased peri-operative mortality risk many of these patients 

face secondary to their heart failure, age, and frequent comorbidities such as renal failure and 

diabetes mellitus.147 Post-implantation infection rates were also low (approximately 1%). 

However, although there were few serious complications, implantation of a biventricular 

pacemaker (in particular the left ventricular [LV] lead) is technically challenging, even in 

experienced hands. Our systematic review identified a 10% failure rate for implantation of a 

biventricular pacemaker, largely due to problems positioning the LV lead. Furthermore, even if 

successfully implanted, these devices require close followup as 7% of devices malfunctioned 

over a median followup of six months, and 9% of LV leads dislodged. As such device failure 

complications will require another intervention and/or a new device to fix the problems, the 

failure rates have to be incorporated into any cost-effectiveness analyses for these devices. 

Further, the reductions in heart failure hospitalizations observed with CRT therapy may be offset 

to some degree by increased admissions for CRT revisions (although we were unable to obtain 

analyzable data on CRT revision admissions in these trials). 

Location of the ventricular lead may be crucial to determining which patients respond best to 

therapy.148,149 However, although individual trials reported the final location of the implanted 

LV lead, outcomes and other information regarding location were not useable for pooled analysis 

as data were not stratified by final location of the LV lead. It is plausible, though, that current 

implantation success rates may be higher than those documented in these trials, as the experience 

of CRT device implanters, the tools for implantation, and the sophistication of the devices has 

improved over the past few years; however, ongoing surveillance is necessary to substantiate 

this. 
75 

Potential Limitations of Systematic Review 

A substantial limitation of the trials included in this analysis is that randomization occurred 

after implantation of the device in all but one trial. This design, similar to the run-in period in 

some pharmaceutical trials, does not affect the internal validity of the trials, but does impact the 

generalizability of the data because patients who could not tolerate the procedure or in whom 

implantation was unsuccessful were not included. As a result, these trials likely overestimate the 

potential benefits from cardiac resynchronization therapy.150 Thus, costing exercises based on 

our systematic review must take into account the up-front failure rates and peri-implantation 

mortality rates demonstrated in Table 14. 

It deserves emphasis that only selected patients and experienced providers participated in 

these trials; while this also does not affect the internal validity of the trials, it again impacts the 

generalizability of the results. In particular, the observed implant success rates and complication 

rates may not be achievable in other settings with clinicians less experienced with device 

implantation. 

Our analysis incorporated publicly available information from the web site of the FDA; this 

information, although not in the peer-review literature, is valid information for use in a 

systematic review.151 Indeed, a recent meta-analysis of non-steroidal anti-inflammatory agents 

has demonstrated that there is little difference in methodological quality between peer-reviewed 

published reports and the publicly available FDA reports.151 We subjected this and other 

unpublished literature to the same rigorous assessment of quality as we used for the published 

literature. Two of the trials that we incorporated into this review were available directly from the 

FDA and represent over 1,000 patients; we supplemented this information with data from the 

primary investigators and other sources to ensure its validity. One of these trials (n=227) did not 

find any differences in survival or hospitalization (but did find “positive” effects on functional 

outcomes and quality of life scores) and remains unpublished more than two years since final 

data was presented. (CONTAK CD73 was presented in May 2001 at the North American Society 

for Pacing and Electrophysiology 2001.) Exclusion of this trial exaggerates the benefit of 

cardiac resynchronization on all-cause mortality, a common finding amongst meta-analyses that 

exclude unpublished literature.152 

Finally, very few patients in these trials had bradyarrhythmias, which would have 

necessitated conventional pacemakers, or atrial fibrillation. The role of cardiac 

resynchronization therapy in such patients is unknown and is an important area for further study 

(particularly since almost one third of CHF patients have atrial fibrillation or indications for a 

conventional pacemaker).97,153,154

Decision Analysis 

Our analysis shows that CRT plus medical therapy compared to medical therapy alone for 

patients with symptomatic heart failure is associated with a median incremental cost per qualityadjusted life year which is similar to that of other common medical interventions;15 however, 

there is a large degree of uncertainty in these incremental costs per quality-adjusted life year. 

The results were sensitive to the value of several key variables, including the effectiveness of 
76 

CRT, the probability of cardiovascular death without pacing, and the incidence of device-related 

adverse effects. 

The results of this analysis should be interpreted cautiously given the magnitude of the 

uncertainty in results. An intervention that is consistently more effective and less costly than its 

comparator is considered to be strongly dominant and always preferred to the alternative.155 In 

the current example, cardiac resynchronization is likely more costly and more effective than 

medical therapy (i.e. in right upper quadrant of Figure 14). If CRT is as efficacious and 

inexpensive as demonstrated in this study, it may be good value for money. The challenge will 

be to ensure that CRT is used in patients who meet these trials’ inclusion criteria, and that CRT 

devices are inserted by experienced providers who have low complication rates. However, the 

uncertainty about the benefits beyond one year needs to be acknowledged and there is 

insufficient long-term effectiveness and cost data to warrant broad implementation of CRT at 

this time. 

This analysis has several strengths. It used currently recommended methods of economic 

evaluation.78 The effectiveness estimates incorporated into the decision analysis were based on a 

high-quality systematic review. Long-term effects and costs were considered from a health care 

system perspective. Finally, the analysis was based on the framework of a previously published 

economic analysis83 to facilitate comparison of the economics of different interventions in 

patients with cardiovascular disease. 

Potential Limitations of Decision Analysis 

This analysis has several limitations. First, CRT had a different pooled effect on all cause 

mortality versus cardiac mortality. These variable effects may reflect differences in the duration 

of followup since the former analysis was based on longer-term followup than the latter one. 

Conversely, the analysis of cardiac death is susceptible to bias since it is difficult to assign cause 

of death in cardiovascular trials. However, in a separate but related patient population, 

implantable defibrillator insertion was associated with increased early mortality.157 Although the 

pooled effect of implantable defibrillators in patients at risk of sudden death is beneficial,47,158 

use of a combined implantable defibrillator and biventricular pacemaker will not necessarily 

decrease mortality.159 Since patients with heart failure experience lethal bradyarrhythmia and 

tachyarrhythmias, a large randomized trial is evaluating the effect of devices with implantable 

defibrillator and biventricular pacemaking capability. (Personal communication, Dr. ASL Tang, 

August 25, 2003.) 

Second, only selected implant physicians participated in the randomized trials assessing the 

effectiveness of CRT. It is plausible that the experience observed with the selected cases and 

experienced providers in these trials may not apply to other settings. If so, our analysis 

overestimates survival and underestimates the incremental cost of CRT in patients with heart 

failure. Conversely, if adverse effects are less frequent as providers gain experience, our 

analysis underestimates survival and overestimates the incremental cost of CRT in patients with 

heart failure. This is particularly important since the results of our analysis were sensitive to the 

rate of complications associated with CRT. 

Third, the incidence of complications associated with CRT likely decreases over time while 

our analysis assumed that they were constant. If so, then our model underestimates survival and 

overestimates the incremental cost-effectiveness of CRT. Long-term followup of patients 
77 

enrolled in the previously completed trials will determine whether the incidence of complications 

does indeed decline over time. 

Fourth, it is likely that CRT may be associated with significant improvements in healthrelated quality of life relative to medical therapy. These trials demonstrated statistically 

significant differences in six-minute walk distance, functional class, and quality of life. 

Assuming that such short-term benefits persisted would have biased our results in favor of the 

intervention. Instead, the primary analysis assumed no difference in quality of life. Secondary 

analyses demonstrated that if resynchronization is associated with long-term improvements in 

quality of life, then it is even better value compared to medical therapy. 

Fifth, it is unlikely that the relative benefit of CRT will be constant as the severity of heart 

failure increases. Therefore, as results from trials of CRT become available, our analysis should 

be revised to reflect better estimates of the true effectiveness and costs of the program. 

Sixth, the model did not consider short- or long-term benefits and costs of selected surgical 

interventions for patients with heart failure. For example, cardiac transplantation is widely 

available but is infrequently used due to supply constraints and is associated with multiple longterm complications that were outside the scope of our analysis. Similarly, ventricular assist 

devices increase survival and quality of life, but are associated with frequent side effects and 

large costs.44 Surgical remodeling is currently being evaluated in a large National Institutes of 

Health-sponsored trial. None of these interventions have been demonstrated to be effective in 

patients with moderate (NYHA Class II and III) heart failure similar to those composing the bulk 

of patients in the CRT trials. 

Seventh, we assumed that heart failure costs were constant even though implementation of 

CRT will decrease heart failure costs if any associated ventricular remodeling decreases the 

frequency of use of outpatient pharmaceuticals or duration of hospitalization. 

Finally, the input data were derived from several sources and may be confounded by 

information that was not incorporated into the model. For example, the effectiveness of CRT 

was not adjusted for the patient’s comorbid illnesses. Until additional data are available on the 

long-term effectiveness and costs of CRT, device implantation should be limited to patients who 

meet the inclusion criteria of the trials in the absence of comorbid illness. Such device 

implantation should only be performed by experienced providers. 

Conclusions 

We have demonstrated a 24% relative reduction in all-cause mortality (largely driven by a 

40% relative reduction in progressive heart failure deaths) and a 35% relative reduction in CHF 

hospitalizations with cardiac resynchronization therapy in patients with reduced ejection 

fractions, NYHA class III or IV symptoms despite currently accepted medical management

(ACE inhibitors, beta-blockers, and in many cases digoxin and/or spironolactone), and a 

prolonged QRS duration on electrocardiogram. Successful implantation of a CRT device in 

24 such patients would prevent one death and two heart failure hospitalizations. 

We also found statistically and clinically significant improvements in quality of life and 

functional outcomes in patients receiving cardiac resynchronization therapy. 

Up to 10% of CHF patients have reduced ejection fraction, NYHA Class III or IV symptoms, 

and a prolonged QRS duration; half of them would also have indications for an implantable 
78 

cardioverter defibrillator.142,160-162 Thus, approximately 250,000 Americans may be eligible for a 

biventricular pacemaker and another 250,000 for a combined biventricular pacemaker/ICD. 

While preliminary data suggest similar relative benefits (but lower absolute benefits) in 

patients with NYHA Class II symptoms, the role of cardiac resynchronization therapy in lower 

risk CHF patients with prolonged QRS duration is untested; further data are required before 

extending the device indications beyond those authorized by the FDA (i.e., patients with NYHA 

class III or IV symptoms). As very few such patients were enrolled in the trials, the role of 

cardiac resynchronization therapy in patients with either (1) indications for conventional 

pacemakers or (2) atrial fibrillation are unknown at this time and require further study. 

However, some considerations need to be incorporated into any policy decisions about 

cardiac resynchronization therapy. First, although cardiac resynchronization appears to be 

relatively safe, there is a 10% failure rate for implantation; another 9% of patients may require 

the system to be partially or fully changed within six months due to malfunctions or lead 

displacements. As the technology develops, it is likely that the rates of implant failure and postprocedure complications will decrease (although close post-marketing surveillance is required to 

confirm this). Second, a marked paucity of data exists for the efficacy and complication rates 

with CRT devices beyond one year. Finally, none of these trials reported admission rates for 

CRT revisions; it is possible that much of the benefit in reduced heart failure hospitalization may 

well be offset by such admissions 

Although the long-term cost-effectiveness of cardiac resynchronization therapy remains 

uncertain at this time (pending further data on longer term complication rates and benefits), our 

analyses do demonstrate that the incremental cost-effectiveness ratio is similar to other 

commonly used interventions, but has wide uncertainty and is sensitive to multiple inputs. There 

is insufficient long-term effectiveness and cost data to determine whether CRT is sufficient value 

for money to warrant its broad implementation at this time. We believe that, in light of the 

current evidence base, CRT should be reserved for selected heart failure patients with advanced 

disease (NYHA Class III or IV despite optimal medical therapy, reduced ejection fraction, and 

prolonged QRS duration—see Figure 16 for management algorithm), should only be implanted 

by clinicians competent in the technique, and should include close followup for complications. 
79 

Figure 16. Analytic framework for treatment options for patients with congestive heart failure 

Does the patient have a diagnosis of CHF? 

(rule out reversible causes, e.g., ischemia, valvular) 

YES 

EF <35% 

Is the patient on maximally tolerated evidence-based medication? 

(e.g., ACE [e.g., enalapril 10 BID], BB [e.g., bisoprolol 10 qd], spironolactone [25 mg qd]) 

NYHA III/IV 

YES 

NO

LVEDD >55 mm 

QRS >130 msec 

and/or severe MR 

sinus rhythm 

Is the patient a candidate for ICD?*

consider CRT +/- ICD consider CRT 

maximize medical treatment 

and re-evaluate in 3 to 6 months

YES 

YES 

YES 

YES 

YES 

NO

* Primary prevention: 

 QRS >0.12 

 Class III 

 EF <30% 

 >3/12 post-MI/revasc 

Secondary prevention: 

 History of Sudden 

 Cardiac Death/VT/VF 

 Inducible VT/VF 
81 

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89 

Included Studies 

Efficacy Review 

1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac 

resynchronization in chronic heart failure. N Engl J Med 

2002;346(24):1845-53 

2. Auricchio A, Stellbrink C, Sack S, et al. Long-term 

clinical effect of hemodynamically optimized cardiac 

resynchronization therapy in patients with heart failure 

and ventricular conduction delay. J Am Coll Cardiol 

2002;39(12):2026-33. 

3. Bristow MR, et al. Comparison of medical therapy, pacing 

and defibrillation in heart failure (COMPANION Trial). 

Presented at the 52nd Annual Scientific Conference, 

American College of Cardiology, Chicago, Il, USA, 

March 31st: 2003 

4. Cazeau S, Leclercq C, Lavergne T, et al. Effects of 

multisite biventricular pacing in patients with heart failure 

and intraventricular conduction delay. N Engl J Med 

2001;344(12):873-80 

5. Garrigue S, Bordachar P, Reuter S, et al. Comparison of 

permanent left ventricular and biventricular pacing in 

patients with heart failure and chronic atrial fibrillation: 

prospective haemodynamic study. Heart 2002; 87(6):529-

534. 

6. Guidant Corporation, Cardiac Rhythm Management. 

Summary of safety and effectiveness CONTAK-CD CRTD system including CONTAK CD CRT-D pulse generator 

model 1823, and software application model 2848 

(version 3.1). PMA P010012, 1-47. 2002 

7. Leclercq C, Walker S, Linde C, et al. Comparative effects 

of permanent biventricular and right-univentricular pacing 

in heart failure patients with chronic atrial fibrillation. Eur 

Heart J 2002;1780-87 

8. Medtronic, Inc. Summary of Safety and Effectiveness: 

InSync ICD Model 7272 dual chamber implantable 

cardioverter defibrillator with biventricular pacing for 

cardiac resynchronization, Attain Models 2187, 2188, 

4189 leads. PMA: P010031. Food and Drug 

Administration, Dec 3, 2001 

Safety Review 

1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac 

resynchronization in chronic heart failure. N Engl J Med 

2002;346(24):1845-1853 

2. Auricchio A, Stellbrink C, Sack S, et al. Long-term 

clinical effect of hemodynamically optimized cardiac 

resynchronization therapy in patients with heart failure 

and ventricular conduction delay. J Am Coll Cardiol 

2002;39(12):2026-33 

3. Bristow MR, et al. Comparison of medical therapy, pacing 

and defibrillation in heart failure (COMPANION Trial). 

Presented at the 52nd Annual Scientific Conference, 

American College of Cardiology, Chicago, Il, USA, 

March 31st: 2003 

4. Cazeau S, Leclercq C, Lavergne T, et al. Effects of 

multisite biventricular pacing in patients with heart failure 

and intraventricular conduction delay (MUSTIC SR). N 

Engl J Med 2001;344(12):873-80 

5. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for 

end-stage heart failure: early experience. PACE 1996; 

19:1748-57. 

6. Filho M.M., Pedrosa AA, Costa R, et al. Biventricular 

pacing improves clinical behavior and reduces prevalence 

of ventricular arrhythmia in patients with heart failure. 

Arq Bras Cardiol 2002; 78(1):110-3. 

7. Gras D, Leclercq C, Tang AS, et al. Cardiac 

resynchronization therapy in advanced heart failure the 

multicenter InSync clinical study. (InSync) Eur J Heart 

Fail 2002; 4(3):311-20. 

8. Guidant Corporation, Cardiac Rhythm Management. 

Summary of safety and effectiveness CONTAK-CD CRTD system including CONTAK CD CRT-D pulse generator 

model 1823, and software application model 2848 

(version 3.1). PMA P010012, 1-47. 2002 

9. Krahn AD, Snell L, Yee R, et al. Biventricular pacing 

improves quality of life and exercise tolerance in patients 

with heart failure and intraventricular conduction delay. 

Can J Cardiol 2002; 18(4):380-7. 

10. Kuhlkamp V. Initial experience with an implantable 

cardioverter-defibrillator incorporating cardiac 

resynchronization therapy. J Am Coll Cardiol 2003; 

39(5):790-7. 

11. Leclercq C, Victor F, Alonso C, et al. Comparative effects 

of permanent biventricular pacing for refractory heart 

failure in patients with stable sinus rhythm or chronic 

atrial fibrillation. Am J Cardiol 2000; 85(9):1154-6 
90 

12. Leclercq C, Walker S, Linde C, et al. Comparative effects 

of permanent biventricular and right-univentricular pacing 

in heart failure patients with chronic atrial fibrillation. 

(MUSTIC AF) Eur Heart J 2002;1780-7. 

13. Leclercq C, Alonso F, d'Allones FR, et al. [Effets à moyen 

terme de la stimulation multisite biventriculaire dans 

l'insuffisance cardiaque sévère]. Unpublished Work 

14. Leon AR, Greenberg JM, Baker CM, et al. Cardiac 

resynchronization in patients with congestive heart failure 

and chronic atrial fibrillation: effect of upgrading to 

biventricular pacing after chronic right ventricular pacing. 

J Am Coll Cardiol 2002; 39(8):1258-63. 

15. Medtronic, Inc. Summary of Safety and Effectiveness: 

InSync ICD Model 7272 dual chamber implantable 

cardioverter defibrillator with biventricular pacing for 

cardiac resynchronization, Attain Models 2187, 2188, 

4189 leads. PMA: P010031. Food and Drug 

Administration, Dec 3, 2001 (MIRACLE ICD) 

16. Molhoek SG, Bax JJ, Van Erven L, et al. Effectiveness of 

resynchronization therapy in patients with end-stage heart 

failure. Am J Cardiol 2002; 90(4):379-83. 
91

Excluded Studies 

There were five main reasons for exclusion: the study was not a CRT trial; the article was a review, a protocol, an editorial, or it 

did not report required outcomes. 

1. Abraham WT. Cardiac resynchronization therapy for 

heart failure: Biventricular pacing and beyond. Curr 

Opin Cardiol 2002; 17(4):346-352. Review article 

2. Anonymous. Long term benefits of pacemaker-like 

device for heart failure patients. Can J Cardiol 

2000;16 (4):538-39. News report 

3. Auricchio A, Klein HU. Beyond expectations: a 

decade of positive results with cardiac 

resynchronization therapy for heart failure. Eur Heart 

J Supp 2002; 4(D):D95-D101. Review article 

4. Auricchio A, Spinelli JC, Trautmann SI, Kloss M. 

Effect of cardiac resynchronization therapy on 

ventricular remodeling. J Card Fail 2002; 8(2):S549-

S555. No required outcomes 

5. Baumann LS, Kadhiresan VA, Yu Y, et al. 

Optimization of cardiac resynchronization therapy in 

heart failure patients by measuring transient cycle 

length changes. [abst] Eur Heart J 2001; 22, 443. No 

required outcomes 

6. Bongiorni MG, Soldati E, Arena G, et al. Multicenter 

clinical evaluation of a new SSIR pacemaker. Pacing 

Clin Electrophysiol 1992; 15(11 Pt 2):1798-1803. 

Not a CRT trial 

7. Bordachar P, Garrigue S, Reuter S, et al. 

Hemodynamic assessment of right, left, and 

biventricular pacing by peak endocardial acceleration 

and echocardiography in patients with end-stage 

heart failure. Pacing Clin Electrophysiol 2000; 23(11 

Pt 2):1726-1730. Not a CRT trial 

8. Breithardt G, Kuhn H, Hammel D, et al. Cardiac 

resynchronization therapy into the next decade: from 

the past to morbidity/mortality trials. Eur Heart J 

Suppl 2002; 4(D):D102-D110. Review article Review article 

9. Butter C, Meisel E, Tebbenjohanns J, et al. 

Transvenous biventricular defibrillation halves 

energy requirements in patients. Circulation 2001; 

104(21):2533-2538. Not a CRT trial 

10. Capucci A, Romano S, Puglisi A, et al. Dual 

chamber pacing with optimal AV delay in congestive 

heart failure: a randomized study. Europace 1999; 

1(3):174-178. Not a CRT trial 

11. Cazeau S, Gras D, Lazarus A, et al. Multisite 

stimulation for correction of cardiac asynchrony. 

Heart 2000; 84(6):579-581. Editorial 

12. Cuzin B, Kirkorian G, Maisonneuve H. Cardiac 

pacemakers: When clinical evaluation lags behind 

technological progress. Int J Technol Assess Health 

Care 2000; 16(3):910-923. Review article 

13. De Marco T, Foster E, Schafer J, et al. Effect of 

chronic cardiac resynchronization on left ventricular 

remodeling and neurohormonal activation. [abst] J 

Am Coll Cardiol 37[2], 118A-119A. 2001. No 

required outcomes 

14. Filzmaier K, Sinha AM, Breithardt OA, et al. Shortterm effects of cardiac resynchronization on brain 

natriuretic peptide release in patients with systolic 

heart failure and ventricular conduction disturbance. 

[abst] J Am Coll Cardiol 2002; 39(5):111A-111A. 

No required outcomes 

15. Fonarow GC, Feliciano Z, Boyle NG, et al. Improved 

survival in patients with nonischemic advanced heart 

failure and syncope treated with an implantable 

cardioverter-defibrillator. Am J Cardiol 2000; 

85(8):981-985. Not a CRT trial 

16. Gaita F, Bocchiardo M, Porciani MC, et al. Should 

stimulation therapy for congestive heart failure be 

combined with defibrillation backup? Am J Cardiol 

2000; 86(9 SUPPL. 1):165K-168K. Review article 

17. Gerber TC, Nishimura RA, Holmes DR, Jr., J et al. 

Left ventricular and biventricular pacing in 

congestive heart failure. Mayo Clin Proc 2001; 

76(8):803-812. Review article 

18. Gold MR, Brockman R, Peters RW, et al. Acute 

hemodynamic effects of right ventricular pacing site 

and pacing mode in patients with congestive heart 

failure secondary to either ischemic or idiopathic 

dilated cardiomyopathy. Am J Cardiol 2000; 

85(9):1106-1109. Not a CRT trial 

19. Greenberg JM, Baker CM, Mera FV, et al. Cardiac 

resynchronization improves ventricular function and 

symptoms of congestive heart failure in the absence 

of any mechanical atrial contribution. [abst] J Am 

Coll Cardiol 2002; 39[5], 77A-77A. No required 

outcomes 
92

20. Higgins SL, Pak JP, Barone J, et al. The first-year 

experience with the dual chamber ICD. Pace-Pacing 

Clin Electrophysiol 2000; 23(1):18-25. Not a CRT 

trial 

21. Hoppe UC, Erdmann E. Cardiac resynchronization in 

heart failure. Deutsche Medizinische Wochenschrift 

2002; 127(13):677-681. Review article 

22. Kerwin WF, Botvinick EH, O'Connell JW, et al. 

Ventricular contraction abnormalities in dilated 

cardiomyopathy: effect of biventricular pacing to 

correct interventricular dyssynchrony. J Am Coll 

Cardiol 2000; 35(5):1221-1227. No required 

outcomes 

23. Kloss M, Auricchio A, Trautmann S, Klein H. 

Cardiac resynchronization therapy improves 

chronotropic response in patients with heart failure. 

[abst] Eur Heart J 2001; 22, 443-443. Retrospective 

review 

24. Leclercq C, Cazeau S, Ritter P, Daubert C. 

[Stimulation cardiaque et insuffisance cardiaque] 

Pacing and cardiac failure. Archives des Maladies du 

Coeur et des Vaisseaux 1998; 91(11):1389-1397. 

Review article 

25. Lupi G, Brignole M, Oddone D, et al. Effects of left 

ventricular pacing on cardiac performance and on 

quality of life in patients with drug refractory heart 

failure. Am J Cardiol 1909; 86(11):1267-1270. Not 

a CRT trial 

26. Meisel E, Rauwolf T, Burghardt M, Kappenberger L. 

[Pacemaker therapy of hypertrophic obstructive 

cardiomyopathy. PIC (Pacing in Cardiomyopathy) 

Study Group]. [German]. Herz 2000; 25(4):461-466. 

Not a CRT trial 

27. Morichika N, Okamoto M, Honda T, et al. Left 

ventricular wall motion analysis during ventricular 

pacing. J Cardiol 1993; 23(SUPPL. 37):85-88. Not a 

CRT trial 

28. Nagele H, Schomburg R, Petersen B, Rodiger W. 

Dual chamber pacing in patients with severe heart 

failure on beta blocker and amiodarone treatment: 

preliminary results of a randomised study. Heart 

(British Cardiac Society) 2002; 87(6):566-567. Not a 

CRT trial 

29. Padelitti L; Porciani MC, Colella A, et al. Cardiac 

resynchronization reverses left ventricular 

remodeling and reduces cytokine activation in 

patients with dilated cardiomyopathy and left bundle 

branch block. [abst] J Am Coll Cardiol 2002;39 

(5);78A. No required outcomes 

30. Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing 

in heart failure patients with left bundle branch 

block: Impact of pacing site for optimizing left 

ventricular resynchronization. Ital Heart J 2000; 

1(7):464-469. No required outcomes 

31. Perrins EJ, Morley CA, Chan SL, Sutton R. 

Randomised controlled trial of physiological and 

ventricular pacing. Br Heart J 1983; 50(2):112-117. 

Not a CRT trial 

32. Peters RW, Gold MR. Pacing for patients with 

congestive heart failure and dilated cardiomyopathy. 

Cardiol Clin 2000; 18(1):55-66. .Review article 

33. Shinke T, Takeuchi M, Takaoka H, Yokoyama M. 

Beneficial effects of heart rate reduction on cardiac 

mechanics and energetics in patients with left 

ventricular dysfunction. Japanese Circulation Journal 

1999; 63(12):957-964. Not a CRT trial 

34. Stellbrink C, Sinha AM, Diem B, et al. Implantable 

cardioverter-defibrillators with or without cardiac 

resynchronization therapy - multiple therapy in a 

single device: a review with special reference to the 

PACMAN study. Eur Heart J Suppl 2002; 4(D):D88-

D94. Review article 

35. Tatarchenko IP, Iskenderov BG, Koledinov VI. 

Results of 5-year follow-up of patients suffering 

from chronic circulatory insufficiency and having an 

implantable pacemaker. [abst] Kardiologiia 32[2], 

45-48. 1992. Not a CRT trial 

36. Tavazzi L. Electrical stimulation of the failing heart: 

A new therapeutical strategy? Eur Heart J Suppl 

2000; 2(J):J2-J5. Editorial 

37. Tavazzi L. Ventricular pacing: A promising new 

therapeutic strategy in heart failure. For whom? Eur 

Heart J 2000; 21(15):1211-1214. Editorial 

38. Toff WD, Skehan JD, De Bono DP, Camm AJ. The 

United Kingdom pacing and cardiovascular events 

(UKPACE) trial. Heart 1997; 78(3):221-223. 

Protocol 

39. Vogt P, Goy JJ, Kuhn M, et al. Single versus double 

chamber rate responsive cardiac pacing: comparison 

by cardiopulmonary noninvasive exercise testing. 

Pacing Clin Electrophysiol 1988; 11(11 Pt 2):1896-

1901. Not a CRT trial 

40. Walker S, Levy TM, Coats AJS, et al, on behalf of 

Imperial College Cardiac Electrophysiology Group. 

Bi-ventricular pacing in congestive cardiac failure: 

Current experience and future directions. Eur Heart J 

2000; 21(11):884-889. Review article 

41. Walker S, Levy TM, Rex S, et al. Usefulness of 

suppression of ventricular arrhythmia by 

biventricular pacing in severe congestive cardiac 
93

failure. Am J Cardiol 2000; 86(2):231-233. No 

required outcomes 

42. Wilkoff B, Cook JR, Epstein AE, et al. Dualchamber pacing or ventricular backup pacing in 

patients with an implantable defibrillator: the Dual 

Chamber and VVI Implantable Defibrillator 

(DAVID) Trial. JAMA 2002; 288(24):3115-3123. 

Not a CRT trial 
16 

Figure 1. Decision model for medical therapy versus cardiac resynchronization therapy for heart 

failure 
17 

Figure 2. Markov Model of Resynchronization Therapy of Heart Failure 

Rx= treatment 
23 

Chapter 3. Results 

Literature Search 

Of more than 3000 initial references, only nine and 17 studies were accepted for the efficacy 

and safety reviews, respectively (Figure 3). Two of these were unpublished manuscripts 

describing studies that met the inclusion criteria. Another was a report submitted to the FDA on 

the MIRACLE35 trial to enhance data from the published trial results.61 Also included were the 

FDA reports on the MIRACLE ICD93 and CONTAK CD73 trials found on the FDA web site. 

(We used the published report for data on patients with NYHA Class III or IV symptoms in the 

MIRACLE ICD94 Trial, and the FDA report for NYHA Class II data since this was not included 

in the journal publication.) Bristow published the protocol for the COMPANION trial in 2000,95

and the results were presented at the Annual Scientific Conference of the American College of 

Cardiology in Chicago, April 2003. Further unpublished data from this trial were made available 

to us and are included in the analysis. 

Figure 3. Flow diagram of study retrieval and selection for cardiac resynchronization therapy 

 

Initial independent references 

from all databases 

(n=3,405) 

Citations with potential 

relevance (n=1,697) 

Citations with potential 

relevance (n=1,708) 

Full text articles with potential relevance 

(n=80) 

Full text articles with potential relevance 

(n=88) 

Second screening 

with specific criteria 

Met inclusion criteria (n=9) Met inclusion criteria (n=17) 

2 FDA reports and 1 

unpublished article 

2 FDA reports and 2 

conference presentations 

First screening of titles and abstracts 

using general criteria 

Efficacy Review Safety Review
61 

Figure 4. Meta-graph of all-cause mortality 
62 

Figure 5. Time to all-cause death 

Note: The COMPANION Trial consisted of three arms. To avoid "double counting" in 

calculating summary estimates of treatment effect, we divided the 58 deaths in 308 control 

patients into 29 deaths in 154 controls in each comparison. 
63 

Figure 6. Meta-graph of death due to congestive heart failure 
64 

Figure 7. Meta-graph of sudden cardiac death 
65 

Figure 8. Meta-graph of non-cardiac death 
66 

Figure 9. Meta-graph of hospitalizations due to congestive heart failure 
67 

Figure 10. Meta-graph of six-minute walk test 
68 

Figure 11. Meta-graph of changes in NYHA status 
69 

Figure 12. Meta-graph of quality of life (based on Minnesota Living with Heart Failure instrument) 
70 

Figure 13. Meta-graph of all-cause mortality by cardioverter defibrillator vs non-cardioverter 

defibrillator 
Figure 14. Distribution of Incremental Costs versus Incremental Effects for Cardiac Resynchronization versus Medical Therapy 

0

10,00020,00030,00040,00050,00060,00070,000

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 

Incremental Effects (QALYs)

X

Base case point estimate cost = 33,195 $ 

71
72 

Figure 15. Cost-Effectiveness Acceptability Curve 

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Maximum Willingness-To-Pay Per Quality-Adjusted Life Year ($)
79 

Figure 16. Analytic framework for treatment options for patients with congestive heart failure 

Does the patient have a diagnosis of CHF? 

(rule out reversible causes, e.g., ischemia, valvular) 

YES 

EF <35% 

Is the patient on maximally tolerated evidence-based medication? 

(e.g., ACE [e.g., enalapril 10 BID], BB [e.g., bisoprolol 10 qd], spironolactone [25 mg qd]) 

NYHA III/IV 

YES 

NO

LVEDD >55 mm 

QRS >130 msec 

and/or severe MR 

sinus rhythm 

Is the patient a candidate for ICD?*

consider CRT +/- ICD consider CRT 

maximize medical treatment 

and re-evaluate in 3 to 6 months

YES 

YES 

YES 

YES 

YES 

NO

* Primary prevention: 

 QRS >0.12 

 Class III 

 EF <30% 

 >3/12 post-MI/revasc 

Secondary prevention: 

 History of Sudden 

 Cardiac Death/VT/VF 

 Inducible VT/VF 
4 

Current Risk Factors and Markers 

in Congestive Heart Failure 

Many prognostic risk factors have been established in CHF (Table 1). Well-validated risk 

factors for short- and long-term mortality include demographic factors such as older age and 

male gender;14 differing ethnic background (black patients have a higher mortality rate than 

white patients even after adjustment for important covariates);15,16 co-morbidities such as 

diabetes mellitus,17 anemia,18 and poor renal function;19 and physical examination findings such 

as a third heart sound and elevated jugular venous pressure.20 Biochemical values that predict 

mortality include decreased serum sodium,21 elevated aldosterone, angiotensin II, and arginine 

vasopressin,22 elevated brain natriuretic peptide,23 and elevated levels of other neurohormones.24 

Other prognostic risk factors have been explored (such as genetic and echocardiographic 

markers) and are reviewed elsewhere;25 electrophysiologic prognostic factors are reviewed 

below. 

Table 1. Prognostic risk factors in congestive heart failure 

Demographics: Electrophysiologic findings: 

Older age Ventricular arrhythmias 

Male gender Intraventricular conduction delay 

Ethnic background (blacks have poorer outcomes 

than whites) 

Atrial fibrillation 

T-wave alternans 

 

Comorbidities: 

Diabetes Laboratory findings: 

Anemia Elevated norepinephrine/epinephrine 

Renal failure Low sodium 

 Elevated creatinine 

Clinical Assessment: Elevated aldosterone 

Advanced symptoms (NYHA Class III or IV) Elevated B-type natriuretic peptide 

Elevated jugular venous pressure Elevated Tumor Necrosis Factor-alpha 

Edema Elevated InterLeukin-6 

Third heart sound Elevated endothelin-1 

 Elevated angiotensin II 

Hemodynamics: Elevated renin 

Lower left ventricular ejection fraction Elevated troponin I/T 

Lower right ventricular ejection fraction Elevated arginine vasopressin 

Elevated pulmonary capillary wedge pressure 

Elevated pulmonary vascular resistance 

Source: adapted from Eichhorn EJ. Prognosis determination in heart failure. Am J Med 2001;110 (Suppl 7A);14S-36S25

NYHA=New York Heart Association 

Current Therapeutic Strategies 

for Congestive Heart Failure 

Current therapy for congestive heart failure incorporates a number of strategies to enhance 

the quality of life, improve exercise tolerance, and reduce morbidity and mortality. In the past 

two decades, advances in heart failure management have arisen from randomized clinical trials 
10 

Table 2. Inclusion/exclusion criteria for review on cardiac resynchronization therapy 

Criterion Efficacy review Safety review 

Study Design 

Include: RCT (parallel or crossover) > 2 

weeks duration. 

Exclude: non-RCTs, acute physiological 

studies, studies not involving human 

subjects 

Include: RCT (parallel or crossover) or 

non-RCT (e.g., registry data, prospective 

cohort, FDA document, etc.) > 2 weeks 

duration. 

Exclude: acute physiological studies, 

studies not involving human subjects 

Participants 

Include: symptomatic CHF (NYHA Class ≥

II), decreased LVEF, prolonged QRS. 

Must be receiving stable optimal drug 

therapy 

Include: symptomatic CHF (NYHA Class 

≥ II), decreased LVEF, prolonged QRS. 

Must be receiving stable optimal drug 

therapy 

Intervention 

Treatment with active CRT (also called 

BVP, multi-site pacing, dual chamber 

pacer) compared to either placebo pacing 

or uni-ventricular pacing or optimal drug 

therapy 

Treatment with active CRT (also called 

BVP, multi-site pacing, dual chamber 

pacer). Comparison group not necessary 

Outcome 

measures 

Mortality (all-cause, CHF, sudden cardiac 

death, non-cardiac), CHF hospitalizations, 

6MWT, NYHA class, QOL 

Peri-implant mortality, successful implant 

rate, risks of /during implantation, risks 

following implantation 

BVP = biventricular pacing; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; QOL = quality of 

life; RCT = randomized controlled trial; 6MWT = six-minute walk test. 

Quality Assessments 

Efficacy review. The methodological quality of RCTs was assessed independently by two 

reviewers (JE, CS) using two quality assessment methods. First, allocation concealment was 

assessed as adequate, inadequate, or unclear. Second, a five-point scoring system validated by 

Jadad58 was used to assess randomization, double blinding, and reporting of withdrawals and 

dropouts (Table B-3). In addition, the funding source and whether authors reported use of 

intention-to-treat analysis were noted. Discrepancies were resolved through discussion between 

the two reviewers. 

Safety review. Studies included in the safety review were assessed for quality independently by 

two reviewers (CS, LH) using a partially validated checklist developed by Downs and Black.59 

The checklist includes 28 questions evaluating five criteria (Table B-4). These five criteria are: 

Reporting (10 questions, total score 11), External validity (three questions, total score 3), Internal 

validity – bias (seven questions, total score 7), Internal validity – confounding (six questions, 

total score 6) and Power (two questions, total score 2). Decision rules regarding application of 

the tool were developed a priori through discussions with a cardiologist and a methodologist. 

Discrepancies in quality assessment were resolved through discussion. 

Data Extraction 

Data were extracted using standard forms (Tables B-5 and B-6) designed for either RCTs 

(efficacy and safety reviews) or cohort studies (safety review) and entered into an Excel 

spreadsheet. Data were extracted by one reviewer (JE, CS, NW, or LH) and checked for 

accuracy and completeness by a second (JE, NW, or CS). Extracted data included study 

characteristics, inclusion/exclusion criteria, baseline drug use, characteristics of participants, 

procedural data, and outcomes. Efficacy outcomes included mortality (all cause as well as CHF 

death, sudden cardiac death, non-cardiac death) and time to death; CHF hospitalizations, six-
18

Table 3. Input data for decision analysis on cardiac resynchronization in patients with NYHA Class III heart failure 

Variable Best Estimate Lowest Highest Distribution Threshold V

Age of patient (yr.) 60 50 70 Normal n/a Annual probability of cardiac death without CRT (%) 24.3 20.0 29.2 Beta n/a Relative risk of death with CRT 0.75 0.60 0.93 Normal 0.78 Annual probability of heart failure hospitalization without CRT (%) 56.0 47.6 66.2 Beta n/a Relative risk of heart failure hospitalization with CRT 0.68 0.41 1.12 Normal 0.85 Annual rate of cardiac death without CRT (%) 20.3 15.1 27.0 Beta n/a Relative risk of cardiac death with CRT 0.60 0.36 1.01 Normal n/a Relative risk of death due to unrelated causes with CRT 1.0 0.9 1.1 Triangular n/a Annual rate of lead infection (%) 2.0 1.1 3.2 Beta n/a 
19

Table 3. Input data for decision analysis on cardiac resynchronization in patients with NYHA Class III heart failure –continued

Variable Best Estimate Lowest Highest Distribution Thres

Val

Annual rate of lead failure (%) 13.7 11.7 16.1 Beta n/Annual rate of battery replacement (%) 10.8 8.7 13.4 Beta n/Probability of death during insertion (%) 0.4 0.2 0.7 Beta n/Probability of death during lead infection (%) 1.0 0 10 Beta n/Probability of death during lead failure (%) 1.0 0 10 Beta 7.Probability of death during battery replacement (%) 1.0 0 10 Beta 8.Utility of NYHA II heart failure 0.94 0.84 0.99 Triangular n/Utility of NYHA III heart failure 0.84 0.71 0.98 Triangular n/
20

Table 3. Input data for decision analysis on cardiac resynchronization in patients with NYHA Class III heart failure–continued

Variable Best Estimate Lowest Highest Distribution Thres

Val

Utility of NYHA IV heart failure 0.74 0.58 0.91 Triangular n/Utility of hospitalization for heart failure 0.57 0.48 0.80 Triangular n/Relative Utility of heart failure with CRT 1.0 0.9 1.1 Triangular n/Duration of hospitalization for CRT implantation 5 days 0 1 mos. Triangular n/Duration of hospitalization for lead failure 5 days 0 1 mos. Triangular n/Duration of hospitalization for lead infection 5 days 0 1 mos. Triangular n/Duration of hospitalization for battery replacement 5 days 0 1 mos. Triangular n/Discount rate for future costs and effects 3% 0% 10% Triangular n/
21

Table 3. Input data for decision analysis on cardiac resynchronization in patients with NYHA Class III heart failure –concluded

Variable Best Estimate Lowest Highest Distribution Thres

Val

Cost of CRT insertion * $33,495 $16,747 $50,242 Triangular $41,Cost of CRT, per mo. $771 $385 $1,216 Triangular n/Cost of hospitalization for lead infection $30,997 $15,499 $46,496 Triangular n/Cost of hospitalization for lead failure $30,997 $15,499 $46,496 Triangular n/Cost of battery replacement $28,835 $14,417 $43,252 Triangular $38,Cost of heart failure hospitalization $15,427 $10,660 $20,193 Normal n/CRT= cardiac resynchronization therapy; NYHA= New York Heart Association * Cost estimates in U.S. dollars 
35 

Table 4. Primary publications and associated publications of trials included in the reviews on 

cardiac resynchronization therapy in CHF 

COMPANION Study 

Primary report: 60 Bristow MR, et al. Comparison of medical therapy, pacing and defibrillation in heart 

failure. Presented at the 52nd Annual Scientific Conference, American College of Cardiology, Chicago, 

Illinois, USA, March 31st, 2003. 

Other publications associated with COMPANION 

95Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for 

ventricular resynchronization: Comparison of medical therapy, pacing, and defibrillation in chronic heart 

failure (COMPANION) trial. J Card Fail 2000; 6(3):276-85 

CONTAK CD Study 

Primary report: 73GUIDANT Corporation, Cardiac Rhythm Management. Summary of safety and 

effectiveness: Guidant CONTAK CD CRT-D system including the CONTACK CD CRT-D pulse generator 

model 1823, and software application model 2848. PMA: P010012. Food and Drug Administration July 10, 

2002. 

Other publications associated with CONTAK CD 

112Boehmer JP, DeMarco T, Jaski BE, et al. Why ICD patients with heart failure (Class II-IV) are 

hospitalized: Do the reasons differ for patients who are treated with cardiac resynchronization therapy? 

[abst] J Am Coll Cardiol 2002;39(5):159A 

113Higgins SL, Yong P, Sheck D, et al. Biventricular pacing diminishes the need for implantable 

cardioverter defibrillator therapy. Ventak CHF Investigators. J Am Coll Cardiol 2000;36(3):824-7 163Lozano I, Bocchiardo M, Achtelik M, et al. Impact of biventricular pacing on mortality in a 

randomized crossover study of patients with heart failure and ventricular arrhythmias. Pacing Clin 

Electrophysiol 2000;23(11Pt2):1711-12 

114Saxon LA, Boehmer JP, Hummel J, et al. Biventricular pacing in patients with congestive heart 

failure: two prospective randomized trials. The VIGOR CHF and VENTAK CHF Investigators. Am J 

Cardiol 1999;83(5B):120-23D 

115Saxon LA, De Marco T, Schafer J, et al. Effects of long-term biventricular stimulation for 

resynchronization on echocardiographic measures of remodeling. Circulation 2002;105(11):1304-10 

INSYNC Study 

Primary report: 100Gras D, Leclercq C, Tang AS, et al. Cardiac resynchronization therapy in advanced heart 

failure the multicenter InSync clinical study. Eur J Heart Fail 2002;4(3):311-20. 

Other publications associated with InSync 

116Gras D, Mabo P, Tang T, et al. Multisite pacing as a supplemental treatment of congestive heart 

failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol 1998;21(11 

pt2):2249-55

117Gras D, Cazeau S, Ritter P, et al. Long term results of cardiac resynchronization for heart failure 

patients: The InSync Clinical Trial [abst] Circulation 1999;100(18):2714 118Gras D, Cazeau S, Mabo P, et al. Long-term benefit of cardiac resynchronization in heart failure 

patients: The 12 month results of the InSync trial. [abst] J Am Coll Cardiol 2000;35(2):230A. 119Gras D, Mabo P, Bucknall C, et al. Responders and nonresponders to cardiac resynchronization 

therapy: Results from the InSync trial. J Am Coll Cardiol 2000;35(2):230A-230A 120Tang ASL, Gras D, Mabo P, et al. Mortality and outcome differences between survivors and 

nonsurvivors in the InSync cardiac resynchronization trial [abst] Circulation 1999;100(18):2715 121Zardini M, Tritto M, Bargiggia G, et al. The InSync-Italian Registry: analysis of clinical outcome and 

considerations on the selection of candidates to left ventricular resynchronization. Eur Heart J Supp 

2002;2:J16-22 
36 

Table 4. Primary publications and associated publications—continued

Leclercq Studies 

Primary report: 96Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular 

pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J 

Cardiol 2000;85(9):1154-56. Am J Cardiol 2000;85:1154-56 

Other publications associated with Leclercq study 

107Leclercq C, Cazeau S, Ritter P, et al. A pilot experience with permanent biventricular pacing to treat 

advanced heart failure. Am Heart J 2000;140(6): 862-70 

MIRACLE Study 

Primary report: 61Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart 

failure. N Engl J Med 2002;346(24):1845-1853 

Other publications associated with the MIRACLE study 

122Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of 

cardiac resynchronization therapy in patients with advanced heart failure: The Multicenter InSync 

Randomized Clinical Evaluation (MIRACLE). J Card Fail 2000;6(4):369-80 123Abraham WT, Fisher W, Smith A, et al. Cardiac resynchronization therapy reduces morbidity in 

patients with moderate to severe systolic heart failure and intraventricular conduction delays [abst]. J 

Am Coll Cardiol 2002;39(5):171A 

124Abraham WT, Fisher W, Smith A, et al. Long-term improvement in functional status, quality of life 

and exercise capacity with cardiac resynchronization therapy: The MIRACLE Trial experience [abst]. J 

Am Coll Cardiol 2002;39(5):171A 

125Aranda JM, Curtis AB, Conti JB, et al. Rationale and design of a randomized clinical trial to assess 

the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: 

The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) [abst]. J Am Coll Cardiol 

2002;39(5):96A 

126Packer M & Abraham WT. Effect of cardiac resynchronization on a composite clinical status 

endpoint in patients with chronic heart failure: Results of the MIRACLE trial [abst]. Circulation 

2001;104(17):1995 

127Sutton MGS, Plappert T, Abraham WT, et al. Cardiac resynchronization improves diastolic 

ventricular function in advanced heart failure: The MIRACLE trial [abst]. Circulation 2001;104(17):2920 128Wagoner LE, Zengel PW, Abraham WT, et al. Cardiac resynchronization therapy with the InSync 

stimulation system improves exercise performance in patients with heart failure: MIRACLE trial 

substudy results [abst]. Circulation 2001;104(17):2919 

MIRACLE-ICD study 

Primary report: 36Medtronic, Inc. Summary of Safety and Effectiveness: InSync ICD Model 7272 dual 

chamber implantable cardioverter defibrillator with biventricular pacing for cardiac resynchronization, Attain 

Models 2187, 2188, 4189 leads. PMA: P010031. Food and Drug Administration, Dec 3, 2001 

Other publications associated with MIRACLE ICD 

93Medtronic, Inc. Summary of Safety and Effectiveness: InSync ICD Model 7272 dual chamber 

implantable cardioverter defibrillator with cardiac resynchronization therapy and the model 9969 

Application Software. PMA: P010031. Food and Drug Administration, March 5, 2002 94Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable 

cardioversion defibrillation in advanced chronic heart failure The MIRACLE ICD Trial. JAMA 

2003;289(20):2685-94 
37 

Table 4. Primary publications and associated publications—concluded

MUSTIC AF study 

Primary report: 75Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and 

right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002;1780-87 

MUSTIC SR study 

Primary report: 74Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in 

patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344(12):873-80 

Other publications associated with MUSTIC trials 

129Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart 

failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 

2002;40(1):111-18 

PATH CHF study 

Primary report: 62Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically 

optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J 

Am Coll Cardiol 2002;39(12):2026-33 

 

Other publications associated with PATH-CHF 

53Auricchio A, Stellbrink C, Sack S, et al. The Pacing Therapies for Congestive Heart Failure (PATHCHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J 

Cardiol 1999;83(5B):130D 

130Auricchio A, Klein H, Spinelli J. Pacing for heart failure: selection of patients, techniques and 

benefits. Eur J Heart Fail 1999;1(3);275-79 

53Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute 

systolic function of paced patients with congestive heart failure. Circulation 1999;99(23):2993-3001 131Auricchio A, Ding J, Spinelli JC, et al. Cardiac resynchronization therapy restores optimal 

atrioventricular mechanical timing in heart failure patients with ventricular conduction delay. J Am Coll 

Cardil 2002;39(7):1163-69 

132Baumann LS, Kadhiresan VA, Yu Y, et al. Optimization of cardiac resynchronization therapy in heart 

failure patients by measuring transient cycle length changes [abst]. Eur Heart J 2001;22:443 148Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the 

systolic function of heart failure patients. Circulation 2001;104(25):3026-29 133Cuesta F, Sack S, Auricchio A, et al. Long-term benefit of cardiac resynchronization therapy in heart 

failure patients: results of the PATH-CHF study. Eur Heart J 2001;22:130 134Cuesta F, Stellbrink C, Auricchio A, et al. Cardiac resynchronization therapy reduces heart failure 

hospitalization in the PATH-CHF study [abst]. Eur Heart J 2001;22:441 

135Huth C, Friedl A, Klein H, Auricchio A. Pacing therapies for congestive heart failure considering the 

results of the PATH-CHF study] Zeitschrift fur Kardiologie 2001; 90 (Supp 1):10-15 136Stellbrink C, Auricchio A, Butter C, et al. Pacing therapies in congestive heart failure II study. Am J 

Cardiol 2000;86 (9 Supp 1):138K 

136Stellbrink C, Breithardt OA, Franke A, et al. Impact of cardiac resynchronization therapy using 

hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart 

failure and ventricular conduction disturbances. Am J Cardiol 2001;38(7):1957-65 

137Vogt J, Krahnefeld O, Lamp B, et al. Electrocardiographic remodeling in patients paced for heart 

failure. Am J Cardiol 2000;86(Supp 1):152-56K 
38

Table 5. Description of studies included in the efficacy review: CRT for CHF 

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions 

Total randomized 

Treatment* 

Control* 

Withdrawals Device Method of implant Authors' primary outcome(s) 

Abraham 2002 

MIRACLE61

U.S. and 

Canada 

RCT 

parallel 

6 mo. 

Pacer 

"Inactive" 571 4 453 228 225

Treatment 

1 

Control 

8 

InSync model 

8040 

Medtronic 

Transvenous 

NYHA class; 

QOL, 6MWT 

Auricchio 2002 

PATH-CHF62 Germany, Netherlands 

RCT 

X-over 

1 mo. 

Univentricular 

pacing 

(4 right, 

36 left) 

42 1 41 24 17 

Treatment 

2 

Control 

5 

Vigor / 

Discovery with 

LV lead 

Guidant 

Transthoracic

O2 uptake at peak 

exercise; O2

uptake at 

anaerobic 

threshold; 6MWT

Bristow 2003 

COMPANION60 

U.S. 

multicenter 

RCT 

parallel 

3 arms 12 mo. 

OPT - - 1520

CRT=617

CRT-D= 

595 

308 - 

CONTAK TR 

Models 4510-

4513, Model 

1241 CONTAK 

CD Model 

1823 Guidant.

Transvenous 

CRT: all-cause 

mortality & 

hospitalization. 

CRT-ICD: allcause mortality & 

hospitalization 

Cazeau 200174

MUSTIC-SR Europe 

(15 sites) 

RCT 

X-over 

3 mo. 

Pacer 

"Inactive” 67 3 58 29 29 

Treatment 

4 

Control 

3 

Chorum 7336 

ELA Medical 

or InSync 

8040 

Medtronic 

Transvenous 

6MWT 
39

Table 5. Description of studies included in the efficacy review: CRT for CHF—continued

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions 

Total randomized 

Treatment* 

Control* 

Withdrawals Device Method of implant Authors' primary outcome(s) 

Garrigue 

200270 France 

RCT 

X-over 

2 mo. 

Left 

ventricular 

pacing 

- 0 13 6 7 0 

Model 2188 

Medtronic 

Transvenous 

Clinical and 

hemodynamic 

variables 

Guidant 2002 

CONTAK-CD73

FDA Report 

U.S. 

(47 sites) 

RCT 

Phase I 

period 1 

of X-over 

3 mo. 

Phase II 

parallel 

6 mo. 

Pacer 

"Inactive" 581 15 490 245 245

Treatment 

3 

Control 

1 

CONTAK-CD 

Transvenous 

and 

Transthoracic 

All-cause mortality; 

CHF 

hospitalizations; 

ventricular 

tachyarrhythmia 

requiring device 

intervention 

Leclercq 2002 

MUSTIC-AF75 Europe (15 sites) RCT X-over 3 mo. Right ventricular pacing 64 10 43 25 18 

Treatment 

1 

Control 2 

Both 2 

ELA medical, 

Medtronic 

Transvenous 

6MWT 

Leclercq 2003 

RD-CHF** 

Unpublished 

France 

RCT 

X-over 

3 mo. 

Right 

ventricular 

pacing 

56 Un clear 44 22 22 Unclear Transvenous CHF hospitalization 
40

Table 5. Description of studies included in the efficacy review: CRT for CHF—concluded

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions 

Total randomized 

Treatment* 

Control* 

Withdrawals Device Method of implant Authors' primary outcome(s) 

Medtronic 

2001 

MIRACLEICD36

FDA report 

U.S. and 

Canada 

(53 sites) 

RCT 

(post 

implant) 

parallel 

6 mo. 

Pacer 

"Inactive" 659 105 554 272 282

Treatment 

7 

Control 

6 

Model 7272 

InSync ICD, 

Attain LV leads 

models 4189, 

2187, 2188. 

Transvenous 

NYHA; QOL; 

6MWT; 

ADR = adverse reaction; CRT = cardiac resynchronization therapy; CRT ICD = CRT with implanted cardioverter defibrillator; FDA = Food and Drug ventricular ejection fraction; LVEDD = left ventricular end diastolic diameter; N/a = not available; NYHA = New York Heart Association class; QOL 

pharmacological therapy; RCT = randomized control trial; 6MWT = 6-minute walk test; X-over = crossover study 

* the intervention that crossover studies received in the first period ** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared 

t excludes deaths and implant failures, where applicable Note: While the published report for MIRACLE-ICD was used for patients with NYHA Class III or IV symptoms, the FDA report was used for NYH

as they were not included in the published MIRACLE-ICD manuscript
41

Table 6. Baseline characteristics of patients in trials included in the efficacy review: CRT for CHF 

NYHA class ECG Physical exam 

II III IV 

Atrial 

fibrillation PR interval QRS interval LVEDD Systolic BP Diastolic BP 

Trial name Study Group Males n (%) Age mean SD Ischemic % % 

% % n (%) 

mean 

SD 

(msec) 

mean 

SD 

(msec) 

mean 

SD 

(mm) 

mean 

SD 

mean 

SD 

CRT 155 (68) 64 +/- 11 50 - 90 110 0 - 167 +/- 21 70 +/- 10 114 +/- 18 69 +/- 10 

Abraham 

200261

MIRACLE Control 153 (68) 65 +/- 11 58 - 91 9 0 - 165 +/- 20 69 +/- 10 115 +/- 18 68 +/- 10 

CRT first 11 (46) 59 +/- 7 42 - 88 13 0 190 +/- 34 174 +/- 30 71 +/- 10 - - 

Control 

first 10 (59) 60 +/- 5 6 - 82 18 0 207 +/- 30 178 +/- 34 75 +/- 13 - - 

Auricchio 2002 PATH-CHF62

All 21 (50) 60 +/- 7 29 - 86 14 0 196 +/- 33 175 +/- 32 73 +/- 11 - - 

CRT 413 (67) 65 54 - 87 13 0 - 159 - - - 

Control 213 (69) 67 59 - 82 18 0 - 156 - - - 

Bristow 200360 COMPANION 

CRTICD 399 (67) 66 55 - 86 14 0 - 159 - - - 

CRT first 19 (66) 64 +/- 11 - - 100 0 - 172 +/- 22 - - - 

Control 

first 24 (83) 64 +/- 8 - - 100 0 - 175 +/- 19 - - - 

Cazeau 200174 MUSTIC-SR 

All 43 (74) 64 +/- 9 37 - 100 0 215 +/- 43 174 +/- 20 73 +/- 10 - - 

Garrigue 200270 All 13 (100) 64 +/- 12 46 - 77 33 100 - 208+/- 15 - - - 
42

Table 6. Baseline characteristics of patients in trials included in the efficacy review: CRT for CHF—concluded

NYHA class ECG Physical exam 

II III IV 

Atrial 

fibrillation PR interval QRS interval LVEDD Systolic BP Diastolic BP 

Trial name Study Group Males n (%) Age mean SD Ischemic % % 

% % n (%) 

Mean 

SD 

(msec) 

Mean 

SD 

(msec) 

Mean 

SD 

(mm) 

Mean 

SD 

Mean 

SD 

CRT 

II-IV 

210 

(85) 66 +/- 11 67 32 60 8 0 205 +/- 42 160 +/- 27 - 118 +/- 21 67 +/- 12 

Control 

II-IV 

211 

(83) 66 +/- 11 70 33 57 10 0 202 +/- 49 156 +/- 26 - 118 +/- 21 69 +/- 12 

CRT III/IV 90 (77) 66 +/- 11 65 17* 73 10 0 204 +/- 41 164 +/- 27 - 116 +/- 20 68 +/- 12 

Guidant 200273

CONTAK-CD 

FDA report 

Control 

III/IV 86 (78) 66 +/- 11 71 10* 71 19 0 200 +/- 54 152 +/- 24 - 117 +/- 23 67 +/- 14

CRT first 21 (84) 65 +/- 9 - 100 25 (100) - 209 +/- 21 70 +/- 9 - - 7

Control 

first 14 (78) 66 +/- 9 - 100 18 (100) - 208 +/- 12 66 +/- 7 - - 7

Leclercq 200274 MUSTIC-AF 

All 35 (81) 65 +/- 8 43 100 43 (100) - 209 +/- 18 68 +/- 8 - - 7

Leclercq 2003 

RD-CHF**

Unpublished 

N/a N/a 73 +/- 8 N/a 0 N/a N/a 23 (52) N/a N/a N/a N/a N/a 

CRT 

II-IV 

231 

(82) 66 +/- 12 38 32 60 8 16 (6) - 166 +/- 23 71 +/- 9 113 +/- 19 67 +/- 11 

Control 

II-IV 

217 

(80) 66 +/- 11 32 38 55 7 12 (4) - 163 +/- 22 70 +/- 9 113 +/- 17 68 +/- 12 

CRT III/IV 

142 

(76) 67 +/- 11 64 88 12 49 (26) - 165 +/- 22 70 +/- 9 - - 

Medtronic 

200136

MIRACLE-ICD 

FDA report 

Control 

III/IV 

136 

(77) 68 +/- 9 75 89 11 31 (18) - 162 +/ - 22 71 +/- 9 - - 

CRT = cardiac resynchronization therapy; FDA = Food and Drug Administration; HR = heart rate; LVEDD = left ventricular end diastolic diameter; LVEF 

fraction; LBBB = left bundle branch block; N/a = not available; NYHA= New York Heart Association class 

* pre-implant assessment ** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared Note: While the published report for MIRACLE-ICD was used for patients with NYHA Class III or IV symptoms, the FDA report was used for NYHA Cl

as they were not included in the published MIRACLE-ICD manuscript
43

Table 7. Baseline drug therapy for trials included in the efficacy review: CRT for CHF 

Medications 

Trial name Study Groups ACE 

% 

ARB 

% 

BB 

% 

Spironolactone 

% 

Digoxin 

% 

Nitrates 

% 

O

N

Abraham 2002 CRT 93* - 62 - 78 - Diu

61

MIRACLE Control 90* - 55 - 79 - Diu

CRT 96** - 71 - ** 71 Amio

Control 100** - 65 - ** 71 Amio

Auricchio 200262 PATH-CHF All 95** - 67 - ** 69 Amio

CRT 89* * 68 53 - - 

Control 89* * 66 55 - - Bristow 200360 COMPANION CRT-ICD 90* * 68 55 - - Diuretics (1

Cazeau 200174

MUSTIC-SR All 96* * 28 22 48 - Amiodarone 

Garrigue 200270 All 100 - 100 - - Diuretics (100); amio

CRT, II-IV 86* * 48 - 69 - Diu

Control, II-IV 89* * 46 - 68 - Diu

CRT, III/IV 81* * 45 - 72 - Diu

Guidant 200273

CONTAK-CD 

FDA report Control, III/IV 89* * 40 - 68 - Diu

Leclercq 200275

MUSTIC-AF All 100* * 23 16 58 - 

Leclercq 2003 

RD-CHF*** 

Unpublished 

N/a N/a N/a N/a N/a N/a N/a 

CRT, II-IV 93 - 63 - 71 31 

Diuretics (91); anti-

antiarrhythmic (40

anti-co

Control, II-IV 90 - 59 - 72 30 

Diuretics (90); anti-

anti-coagulant (7

positive 

CRT, III/IV 92 - 63 - 76 36 

Diuretics (93); anti-

anti-coagulant(7

positive 

Medtronic 200136

MIRACLE-ICD 

FDA report 

Control, III/IV 88 32 58 - 73 33 

Diuretics (94); anti-

anti-coagulant (8

positive 

ACE= angiotensin converting enzyme inhibitors; ARB= angiotension-receptor blocks; BB= beta blocker; CCB= calcium channel blocker *receiving angiotensin-converting-enzyme inhibitors or angiotension-receptor blockers **receiving angiotensin-converting-enzyme inhibitors or digoxin *** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was preparedN/a =not available
44

Table 8. Methodological quality of randomized trials included in the efficacy review 

Randomization Double-blinding 

Study Stated Method described Stated Method described 

Description of 

withdrawals/ 

drop-outs 

Abraham 2002 MIRACLE61 Yes Adequate Yes Adequate Adequate 

Auricchio 2000 PATH-CHF62 Yes Unclear Yes Adequate Adequate 

Bristow 2003 COMPANION60 Yes Adequate No N/a Unclear 

Cazeau 2001 MUSTIC-SR74 Yes Adequate No N/a Adequate 

Garrigue 200270 Yes Unclear No N/a Unclear 

Guidant 2002 CONTAK-CD73 Yes Unclear Yes Adequate Adequate 

Leclercq 2002 MUSTIC-AF75 Yes Adequate No N/a Adequate 

Leclercq 2003 RD-CHF* (unpublished) Yes N/a No N/a N/a 

Medtronic 2001 MIRACLE-ICD36 Yes Unclear Yes Adequate Adequate 

N/a = not available * detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared 
45

Table 9. Description of studies included in the safety review: CRT for CHF 

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions

t

Total randomized 

Treatment* 

Control* 

Withdrawals

t

Device 

Method of 

implant 

Authors' 

primary 

outcome(s) 

Abraham 2002 

MIRACLE61 US. & Canada RCT parallel 6 mo. Pacer "Inactive" 571 -- 453 228 225 

Treatment 

1 

Control 

8 

InSync model 

8040 Medtronic

Transvenous 

NYHA class; 

QOL, 6MWT 

Auricchio 2002 

PATH-CHF62 Germany & Netherlands 

RCT 

cross-over 

1 mo. 

Univentricular 

pacing 

(4 Rt., 

36 Lt.) 

42 1 41 24 17 

Treatment 

2 

Control 

5 

Vigor / 

Discovery with 

LV lead 

Guidant 

Transthoracic 

O2 uptake at 

peak exercise; 

O2 uptake at 

anaerobic threshold; 

6MWT 

Bristow 200360

COMPANION 

US. 

multicentre 

RCT parallel 

3 arms 12 mo. 

OPT - - 1520

CRT=617

CRT-D= 

595 

308 - 

CONTAK TR 

Models 4510-

4513, Model 

1241 CONTAK 

CD Model 1823 

Guidant. 

Transvenous 

CRT: all-cause 

mortality & 

hospitalization. 

CRT-ICD: allcause mortality 

& hospitalization

Cazeau 200174

MUSTIC-SR 

Europe 

(15 sites) 

RCT 

cross-over 

3 mo. 

Pacer 

"Inactive” 67 3 58 29 29 

Treatment 

4 

Control 

3 

Chorum 7336 

ELA Medical or 

InSync 8040 

Medtronic 

Transvenous 

6MWT 
46

Table 9. Description of studies included in the Safety review: CRT for CHF—continued

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusionst

Total randomized 

Treatment* 

Control* 

Withdrawalst Device Method of implant Authors' primary outcome(s) 

Cazeau 199699 France Single-arm trial 

2 mo.- 1 yr. 

None 8 0 - 6 - 0 

Chorus TM 

6234 Ela 

Medical, 

Medtronic 

Thera 7940 

DR 

Transthoracic 

(7) 

Transvenous 

(1) 

Potential 

hemodynamic 

benefit of CRT 

Filho 200298 Brazil 

RCT crossover 

30, 90, 180 

days 

Rt. univentricular 

pacing 

24 0 - - - 0 

Not reported 

Transthoracic

NYHA 

Gras 2002100

INSYNC Italian 

Registry 

Europe 

Canada 

Single-arm 

trial 

up to 1 yr. 

None 117 0 - 103 - 9 

InSync 

Model 8040, 

Medtronic 

Transvenous 

Feasibility, safety 

and long term 

effects 

Guidant 200273

CONTAK-CD 

FDA Report 

US. 

(47 sites) 

RCT 

Phase I 

period 1 of 

cross-over 

3 mo 

Phase II 

parallel 

6 mo 

Pacer 

"Inactive" 581 15 490 245 245 

Treatment 

3 

Control 

1 

CONTAK-CD

Transvenous 

and 

Transthoracic

All-cause 

mortality; CHF 

hospitalizations; 

ventricular 

tachyarrhythmia 

requiring device 

intervention 
47

Table 9. Description of studies included in the safety review: CRT for CHF—continued

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions

t

Total randomized 

Treatment* 

Control* 

Withdrawals

t

Device 

Method of 

implant 

Authors' 

primary 

outcome(s) 

Krahn 2002101 Canada 

Single-arm 

trial 

1, 3, 6 mo. 

then q 6 mo. 

None 45 0 - 40 - - 

Medtronic 

InSync 

pacemaker or 

ICD or 

Guidant 

ContakTM or 

ICD 

Transvenous 

QOL; NYHA 

Kuhlkamp 

2002102 Germany 

Single-arm 

trial 

3 mo. 

None 84 0 - 81 - - 

InSync 

Model 7272 

Medtronic 

Transvenous 

Not stated 

Leclercq 

200096 France 

Single-arm 

trial 

1, 3, 6 mo. then q 6 m 

None 37 0 34 49 - - 

Various 

models 

Medtronic 

Transvenous 

Transthoracic 

Mortality 

Leclercq 

200275

MUSTIC-AF 

Europe 

(15 sites) 

RCT 

cross-over 

3 mo. 

Rt. 

ventricular 

pacing 

64 10 43 25 18 

Treatment 

1 

Control 

2 

Both 

2 

ELA medical, 

Medtronic 

Transvenous 

6MWT 
48

Table 9. Description of studies included in the safety review: CRT for CHF–continued

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions

t

Total randomized 

Treatment* 

Control* 

Withdrawals

t

Device 

Method of 

implant 

Authors' 

primary 

outcome(s) 

Leclercq104

Unpublished France 

Single-arm 

trial 

1, 3, 6 mo. 

Then q 6 

mo. 

None - - - 125 - - 

Not stated 

Transvenous 

Not stated 

Leclercq 2003 

RD-CHF**

Unpublished 

France 

RCT 

cross-over 

3 mo. 

Rt. 

ventricular 

pacing 56 N/a 44 22 22 N/a Transvenous CHF hospitalization 

Medtronic 

200136 

MIRACLE-ICD 

FDA Report, 

US. & Canada 

(53 sites) 

RCT parallel 

6 mo. 

Pacer 

"Inactive" 660 36 555 272 282 

Treatment 

7 

Control 

6 

Model 7272 

InSync ICD 

Transvenous 

NYHA; QOL; 

6MWT 

Leon 2002106 US. Single-arm trial None 20 0 - 20 - 0 

Revised RV 

pacing system 

to CRT 

Medtronic 

leads 

Transvenous 

Improved 

ventricular 

function 
49

Table 9. Description of studies included in the safety review: CRT for CHF–concluded

Number of Participants 

Study name Country 

Design 

Duration 

Control 

arm 

Total enrolled 

Exclusions

t

Total randomized 

Treatment* 

Control* 

Withdrawals

t

Device 

Method of 

implant 

Authors' 

primary 

outcome(s) 

Molhoek 

2002103 Netherlands 

Single-arm 

trial 

3, 6 mo. 

None 40 0 - 40 - 0 

Easytrack 

4512-80, 

Contak TR or 

CD Guidant, or 

InSync III 

Transvenous 

Clinical benefit, 

long-term 

prognosis 

CRT-ICD = CRT with implanted cardioverter defibrillator; LVEDD = Left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; 

New York Heart Association; OPT = optimal pharmacological therapy; QOL = quality of life; RCT = randomized control trial; 6MWT = 6-minute walk 

* the intervention that cross-over studies received in the first period ** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared 

t excludes deaths and implant failures, where applicable
50

Table 10. Baseline characteristics of patients in studies included in the safety review: CRT for CHF 

NYHA class ECG Physical exam 

II III IV Atrial fibrillation PR interval QRS interval LVEDD Systolic BP Diastolic BP 

Trial name Study Group Males n (%) Age mean SD Ischemic % 

% % % n (%) 

Mean 

SD 

(msec) 

Mean 

SD 

(msec) 

Mean 

SD 

(mm) 

Mean 

SD 

Mean 

SD 

CRT 155 (68) 64 +/- 11 50 - 90 10 0 - 167 +/- 21 70 +/- 10 114 +/- 18 69 +/- 10 

Abraham 

200261

MIRACLE Control 153 (68) 65 +/- 11 58 - 91 9 0 - 165 +/- 20 69 +/- 10 115 +/- 18 68 +/- 10 

CRT 

first 11 (46) 59 +/- 7 42 - 88 13 0 190 +/- 34 174 +/- 30 71 +/- 10 - - 

Control 

first 10 (59) 60 +/- 5 6 - 82 18 0 207 +/- 30 178 +/- 34 75 +/- 13 - - 

Auricchio 200262 PATH-CHF 

All 21 (50) 60 +/- 7 29 - 86 14 0 196 +/- 33 175 +/- 32 73 +/- 11 - - 

CRT 413 (67) 65 54 - 87 13 0 - 159 - - - 

Control 213 (69) 67 59 - 82 18 0 - 156 - - - 

Bristow 200360 COMPANION 

CRTICD 399 (67) 66 55 - 86 14 0 - 159 - - - 

CRT 

first 19 (66) 64 +/- 11 - - 100 - 0 - 172 +/- 22 - - - 

Control 

first 24 (83) 64 +/- 8 - - 100 - 0 - 175 +/- 19 - - - 

Cazeau 200174 MUSTIC-SR 

All 43 (74) 64 +/- 9 37 - 100 - 0 215 +/- 43 174 +/- 20 73 +/- 10 - - 

Cazeau 199699 All 7 (88) 66 +/- 5 50 - 100 3 (38) 200 +/- 20 200 +/- 35 - - - 

Filho 200298 All 23 (96) 55 +/- 13 38 33 67 4 - 225 +/- 80 181 +/- 31 - - - 

Gras 2002100

INSYNC 

Italian Registry All 81 (77) 67 +/- 10 48 0 68 32 0 - 178 +/- 28 72 +/- 10 - - 

CRT 

II-IV 

210 

(85) 66 +/- 11 67 32 60 8 0 205 +/- 42 160 +/- 27 - 118 +/- 21 67 +/- 12 

Control 

II-IV 

211 

(83) 66 +/- 11 70 33 57 10 0 202 +/- 49 156 +/- 26 - 118 +/- 21 69 +/- 12 

CRT III/IV 90 (77) 66 +/- 11 65 17* 73 10 0 204 +/- 41 164 +/- 27 - 116 +/- 20 68 +/- 12 

Guidant 

200273

CONTAK-CD 

FDA report 

Control 

III/IV 86 (78) 66 +/- 11 71 10* 71 19 0 200 +/- 54 152 +/- 24 - 117 +/- 23 67 +/- 14 
51

Table 10. Baseline characteristics of patients in studies included in the safety review: CRT for CHF–concluded

NYHA class ECG Physical exam 

II III IV Atrial fibrillation PR interval QRS interval LVEDD Systolic BP Diastolic BP 

Trial name Study Group Males n (%) Age mean SD Ischemic % 

% % % n (%) 

Mean 

SD 

(msec) 

mean 

SD 

(msec) 

Mean 

SD (mm)

Mean 

SD 

Mean 

SD 

M

Krahn 

2002101 All 37 (82) 65 +/- 10 69 6 76 18 15 (33) 240 +/- 63 166 +/- 20 - - - 

Kuhlkamp 

2002102 All 74 (91) 64 +/- 9 - 32 59 9 

19 (23) 

PAFr 

10 (12 AF 

- 

170 +/- 

30 71 +/- 11 - - 

CRT 

first 21 (84) 65 +/- 9 - - 100 - 25 (100) - 209 +/- 21 70 +/- 9 - - 75 

Control 

first 14 (78) 66 +/- 9 - - 100 - 18 (100) - 208 +/- 12 66 +/- 7 - - 74 

Leclercq 

200275

MUSTIC-AF 

All 35 (81) 65 +/- 8 43 - 100 - 43 (100) - 209 +/- 18 68 +/- 8 - - 74 

Leclercq 

2000107 All 34(92) 68 +/- 8 38 0 70 30 14 (28) 260 +/- 30 181 +/- 23 87 +/- 8 - - 

Leclercq104

unpublished All 110 (88) 68 +/- 9 38 - 68 32 36 (29) 248 +/- 56 183 +/- 29 74 +/- 8.5 - - 

Leclercq 

2003 RDCHF**

Unpublished 

- N/a 73 +/- 8 N/a 0 N/a N/a 23 N/a N/a N/a N/a N/a 

Leon 

2002106 All 17 (85) 70 +/- 11 55 0 60 40 20 (100) - 213 +/- 40 68 +/- 8 - - 

CRT 

II-IV 

217 

(80) 66 +/- 12 38 32 60 8 16 (6) - 166 +/- 23 71 +/- 9 113 +/- 19 67 +/- 11 7

Control 

II-IV 

231 

(82) 66 +/- 11 32 38 55 7 12 (4) - 163 +/- 22 70 +/- 9 113 +/- 17 68 +/- 12 7

CRT III/IV 

142 

(76) 67 +/- 11 64 - 88 12 49 (26) - 165 +/- 22 70 +/- 9 - - 7

Medtronic 

200136

MIRACLEICD 

FDA report 

2001 Control 

III/IV 

136 

(77) 68 +/- 9 75 - 89 11 31 (18) - 162 +/ - 22 71 +/- 9 - - 7

Molhoek 

2002103 All 31 (78) 64 +/- 10 48 mean = 3.3 +/- 0.5 4 (10) - range 120- 240 - - - 

CRT = cardiac resynchronization therapy; FDA = Food and Drug administration; LBBB = left bundle branch block; LVEF = left ventricular ejection fractventricular end diastolic diameter; N/a = not available; NYHA = New York Heart association; SD = standard deviation 

*pre-implant assessment ** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared
52

Table 11. Baseline drug therapy in included patients in the safety review: CRT for CHF 

Medications 

Trial name Study Groups ACE % ARB % BB % Spironolactone % Digoxin % Nitrates % Othe

Name 

Abraham 2002 CRT 93* - 62 - 78 - Diuretics 

61

MIRACLE Control 90* - 55 - 79 - Diuretics 

CRT 96** - 71 - ** 71 Amiodaro

Control 100** - 65 - ** 71 Amiodaro

Auricchio 200262

PATH-CHF 

All 95** - 67 - ** 69 Amiodaro

CRT 89* * 68 53 - - 

Control 89* * 66 55 - - Bristow 200360 COMPANION 

CRT-D 90* * 68 55 - - 

Diuretics (100); 

Cazeau 200174

MUSTIC-SR All 96* * 28 22 48 - Amiodarone (31), 

Cazeau 199699 All 100 - - - - - All on maximal medic

dobutamine &/o

Filho 200298

All 92 - - 42 100 13** Diuretics (100); c

amiodaron

Gras 2002100

INSYNC Italian 

Registry All 70 16 17 - 58 - 

Amiodarone (50)

vasodilators (17

anticoagulants (34); IV 

(2) 

CRT, II-IV 86* * 48 - 69 - Diuretics 

Control, II-IV 89* * 46 - 68 - Diuretics 

CRT, III/IV 81* * 45 - 72 - Diuretics 

Guidant 200273

CONTAK-CD FDA 

report 

Control, III/IV 89* * 40 - 68 - Diuretics 

Krahn 2002101 All 84 - 56 - - - Antiarrhythmic agents 

Kuhlkamp 2002102 All 85 - 54 - 32 31 Diuretics (54); antic

antiarrhythm

Leclercq 200275

MUSTIC-AF All 100* * 23 16 58 - - 
53

Table 11. Baseline drug therapy in included patients in the safety review: CRT for CHF—concluded

Medications 

Trial name Study Groups ACE 

%

ARB 

%

BB 

%

Spironolactone 

%

Digoxin 

%

Nitrates 

%

Othe

Name 

Leclercq 200096 All 100 - - - 60 - Diuretics (100), capto

Leclercq104

unpublished All 98 - 34 - 60 - Diuretics 

Leclercq 2003 RDCHF***

Unpublished 

N/a N/a N/a N/a N/a N/a N/a N/a 

Leon 2002106 All 90 - 25 - 60 - Diuretics 

CRT, II-IV 93 - 63 - 71 31 

Diuretics (91); anti-

CCB (6); antiarrhyth

ionotrope 

anti-coagul

Control, II-IV 90 - 59 - 72 30 

Diuretics (90); anti-

CCB (6); anti-co

antiarrhythm

positive iono

CRT, III/IV 92 - 63 - 76 36 

Diuretics (93); anti-

CCB (7); anti-co

antiarrhythm

positive iono

Medtronic 200136

MIRACLE-ICD FDA 

report 

Control, III/IV 88 32 58 - 73 33 

Diuretics (94); anti-

CCB (6); anti-co

antiarrhythm

positive iono

Molhoek 2002103 All Not stated - - - - - - 

ACE= angiotensin-converting-enzyme inhibitors; ARB= angiotension-receptor blocker; BB= beta blocker; CCB= calcium channel blocker 

*ACE or ARB ** receiving nitrates or hydralazine *** detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared
54

Table 12. Methodological quality assessments of included studies: safety review 

Study name Sponsor Downs and Black Quality Score59

Reporting 

Maximum 11

External 

validity 

Maximum 3 

Internal validity 

[bias] maximum 

7 

Internal validity 

[confounding] 

Maximum 6 

M

Abraham 2002 

MIRACLE61 Medtronic Inc. 11 2 7 6 

Auricchio 200262

PATH-CHF Guidant Corporation 11 2 7 5 

Bristow 200360 

COMPANION Guidant Corporation 8 1 5 4 

Cazeau 200174

MUSTIC-SR 

ELA Recherche, Medtronic, Swedish 

Heart and Lung Association; Swedish 

Medical Research Council 

11 1 6 5 

Cazeau 199699 technical support from ELA Recherche 9 1 5 4 

Filho 200298 None indicated 7 1 5 4 

Gras 2002100

INSYNC Italian 

Registry 

None indicated 9 1 5 1 

Guidant 200173

CONTAK-CD 

FDA report 

Guidant Corporation 11 2 7 4 

Krahn 2002101 Heart and Stroke Foundation of Ontario 10 3 5 4 

Kuhlkamp 2002102 Medtronic Inc. 11 1 5 3 

Leclercq 200275

MUSTIC-AF 

ELA Recherche, Medtronic, 

European Society of Cardiology, 

Centre Hospitalier Universitaire de 

Rennes; Swedish Heart and Lung 

Association, Swedish Medical 

Research Council 

11 2 6 5 

Leclercq 200096 None indicated 10 2 5 2 

Leclercq 

Unpublished104 None indicated 10 2 5 3 

Leclercq 2003 RDCHF*

Unpublished 

N/a N/a N/a N/a N/a 

Leon 2002106 Medtronic provided fellowship support 11 3 5 3 
55

Table 12. Methodological quality assessments of included studies: safety review–concluded

Study name Sponsor Downs and Black Quality Score59

Reporting 

Maximum 11

External 

validity 

Maximum 3 

Internal validity 

[bias] maximum 

7 

Internal validity 

[confounding] 

Maximum 6 

M

Medtronic 200136

MIRACLE-ICD 

FDA report 

Medtronic Inc 11 1 7 3 

Molhoek 2002103 Medtronic Inc. 10 2 5 3 

N/a = not available * detailed data not available for Leclercq 2003 (RD-CHF) at the time report prepared 
56 

Table 13. Peri-implant risks for cardiac resynchronization therapy 

Study n/N 

Simple Pool 

Risk % [95% CI] 

Peri-implant deaths 

MUSTIC-SR 200174 0/64 0 

MUSTIC-AF 200275 0/59 0 

PATH-CHF 200262 0/41 0 

MIRACLE 200261 2/571 0.4 [0.1,1.4] 

MIRACLE-ICD 200394 0/429 0 

COMPANION unpub60 5/617 0.8 [0.3,2.0] 

COMPANION-ICD unpub60 3/595 0.5 [0.1,1.6] 

Cazeau 199699 1/7 14.3 [8.4,54.0] 

Filho 200298 0/24 0 

Leclercq unpub104 0/139 0 

Total [N=10] 13/3113 0.4 [0.2,0.7] 

Sensitivity Total [N=16] 13/3456 0.4 [0.2,0.7] 

Implant successes 

MUSTIC-SR 200174 59/64 92.2 [82.0,97.1] 

MUSTIC-AF 200275 54/59 91.5 [80.6,96.8] 

MIRACLE 200261 528/571 92.5 [89.9,96.8] 

PATH-CHF 200262 41/41 100 

MIRACLE-ICD 200394 379/429 88.3 [84.8,91.1] 

COMPANION unpub60 538/617 87.2 [84.2,89.7] 

COMPANION-ICD unpub60 540/595 90.8 [88.1,92.9] 

CONTAK-CD unpub73 501/567 88.4 [85.4,90.8] 

RD-CHF unpub# 45/56 80.4 [67.2,89.3] 

Cazeau 199699 6/7 85.7 [42.0,99.2] 

Gras 2002100 125/139 89.9 [83.4,94.2] 

Krahn 2002101 40/45 88.9 [75.2,95.8] 

Kuhlkamp 2002102 81/84 96.4 [89.2,99.1] 

Leon 2002106 20/20 100 

Filho 200298 24/24 100 

Molhoek 2002103 40/40 100 

Leclercq unpub104 125/139 89.9 [83.4,94.2] 

Total [N=16]* 3124/3475 89.9 [88.8,90.9] 

Related to left ventricular lead 

MUSTIC-SR 200174 5/64 7.8 [2.9,18.0] 

MUSTIC-AF 200275 5/59 8.5 [3.2,19.4] 

MIRACLE-ICD 200336 31/429 7.2 [5.0,10.2] 

CONTAK-CD unpub73 17/517 3.3 [2.0,5.3] 

Gras 2002100 12/117 10.3 [5.6,17.6] 

Krahn 2002101 6/45 13.3 [5.5,27.5] 

Kuhlkamp 2002102 4/84 4.8 [1.5,12.4] 

Filho 200298 0/24 0 

Total [N=8] 80/1339 6.0 [4.7,7.2] 

Sensitivity Total [N=14]** 80/2055 3.9 [3.1,4.8] 

Related to the device and battery 

PATH-CHF 200262 3/41 7.3 [1.9,21.0] 

MIRACLE 200261 2/571 0.4 [0.06,1.4] 

MIRACLE-ICD 200394 3/429 0.7 [0.2,2.2] 

CONTAK-CD unpub73 7/517 1.4 [0.6,2.9] 

Filho 200298 0/24 0 

Total [N=5] 15/1582 0.9 [0.6,1.6] 

Sensitivity Total [N=14]** 15/2055 0.7 [0.4,1.2] 
57 

Table 13. Peri-Implant risks for cardiac resynchronization therapy—concluded

Study n/N 

Simple Pool 

Risk % [95% CI] 

Related to implant procedure and/or tools 

MIRACLE 200261 35/571 6.1 [4.4,8.5] 

MIRACLE-ICD 200394 19/429 4.4 [2.8,7.0] 

CONTAK-CD unpub73 50/517 9.7 [7.3,12.6] 

Gras 2002100 3/117 2.6 [0.7,7.9] 

Krahn 2002101 4/45 8.9 [2.9,22.1] 

Kuhlkamp 2002102 4/84 4.8 [1.5,12.4] 

Leon 2002106 0/20 0 

Filho 200298 0/24 0 

Total [N=8] 115/1807 6.4 [5.3,7.6] 

Sensitivity Total [N=14]** 115/2055 5.6 [4.7,6.7] 

Related to heart function 

MIRACLE 200261 1/571 0.2 [0.009,1.1] 

MIRACLE-ICD 200394 11/429 2.6 [1.4,4.7] 

Cazeau 199699 1/7 14.3 [8.4,54.0] 

Filho 200298 0/24 0 

Total [N=4] 13/1031 1.3 [0.7,2.2] 

Sensitivity Total [N=14]** 13/2055 0.6 [0.4,1.1] 

* only safety outcome that includes data from RD-CHF 

** COMPANION omitted – full report not available; Leclercq 2002 omitted, - there 

 was 10% or 14/139 failed implants but they did not specify the event 
58 

Table 14. Post-implantation risks of cardiac resynchronization therapy 

Study n/N 

Simple Pool 

Risk % [95% CI] 

Mechanical malfunction 

MUSTIC-SR 200174 2/58 3.4 [0.6,13.0] 

MUSTIC-AF 200275 2/54 3.7 [0.6,13.8] 

CONTAK-CD unpub73 22/448 4.9 [3.2,7.5] 

MIRACLE-ICD unpub36 25/364 6.9 [4.6,10.1] 

Leclercq 200096 3/37 8.1 [2.1,23.0] 

Gras 2002100 4/103 3.9 [1.3, 10.2] 

Kuhlkamp 2002102 1/84 1.2 [0.1,7.4] 

Filho 200298 3/24 12.5 [3.3,33.5] 

Leclercq unpub104 25/125 20.0 [13.6,28.3] 

Total [N=9] 87/1297 6.7 [5.4,8.2] 

Sensitivity Total [N=15]* 87/1968 4.4 [3.6,5.4] 

Lead dislodgement 

MUSTIC-SR 200174 8/58 13.8 [6.6,25.9] 

MUSTIC-AF 200275 5/54 9.3 [3.5,21.1] 

MIRACLE 200261 30/524 5.7 [4.0,8.2] 

CONTAK-CD unpub73 31/448 6.9 [4.8,9.8] 

MIRACLE-ICD unpub36 46/364 12.6 [9.5,16.6] 

Cazeau 199699 2/6 33.3 [6.0,75.9] 

Leclercq 200096 2/37 5.4 [0.9,19.5] 

Gras 2002100 10/103 9.7 [5.0,17.5] 

Krahn 2002101 4/40 10.0 [3.3,24.6] 

Kuhlkamp 2002102 7/84 8.3 [3.7,17.0] 

Filho 200298 0/24 0 

Molhoek 2002 103 3/40 7.5 [2.0,21.5] 

Leclercq unpub104 15/125 12.0 [7.1,19.3] 

Total [N=13] 163/1907 8.5 [7.4,9.9] 

Sensitivity Total [N=15]* 163/1968 8.3 [7.1,9.6] 

Infection 

MIRACLE 200261 7/524 1.3 [0.6,2.9] 

MIRACLE-ICD unpub36 2/364 0.5 [0.1,2.2] 

Gras 2002100 2/103 1.9 [0.3,7.5] 

Kuhlkamp 2002102 2/84 2.4 [0.4,9.1] 

Filho 200298 1/24 4.2 [0.2,23.1] 

Leclercq unpub104 3/125 2.4 [0.6,7.4] 

Total [N=6] 17/1224 1.4 [0.8,2.3] 

Sensitivity Total [N=15]* 17/1968 0.9 [0.5,1.4] 

Arrhythmias associated with CRT 

MUSTIC-AF 200275 1/54 1.9 [0.1,11.2] 

PATH-CHF 200262 4/41 9.8 [3.2,24.1] 

MIRACLE-ICD unpub36 3/364 0.8 [0.2,2.6] 

Filho 200298 0/24 0 

Molhoek 2002103 1/40 2.5 [0.1,14.7] 

Total [N=5] 9/523 1.7 [0.8,3.4] 

Sensitivity Total [N=15]* 9/1968 0.5 [0.2,0.9] 
59 

Table 14. Post-implantation risks of cardiac resynchronization therapy–concluded

Study n/N 

Simple Pool 

Risk % [95% CI] 

Pain 

Krahn 2002101 1/40 2.5 [0.1,14.7] 

Filho 200298 3/24 12.5 [3.3,33.5] 

Total [N=2] 4/64 6.3 [2.0,16.0] 

Sensitivity Total [N=15]* 4/1968 0.2 [0.07,0.6] 

* COMPANION omitted – full report not available 
60

Table 15. Potential cost-effectiveness of cardiac resynchronization therapy 

Discounted Quality-Adjusted 

Life Years 

(QALYs), Median (Interquartile 

Range) 

Discounted Lifetime Cost 

($)*, Median (Interquartile Range) 

Incre

Cost-Eff

($/QALY

(Interqua

Medical Therapy 2.68 (2.49, 2.85) $34,700 ($31,400, $38,100) 

Cardiac Resychronization 

Therapy 3.03 (2.82, 3.27) $67,600 ($62,000, $73,800) $90,700 ($69

* 2003 U.S. $ rounded to nearest hundred 
Appendixes 

to 

Cardiac Resynchronization Therapy for 

Congestive Heart Failure 

(Contract No. 290-02-0023) 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

Prepared by: 

University of Alberta Evidence-based Practice Center 

Edmonton, Alberta, Canada 

Dr. Terry Klassen, MD, MSc, FRCPC / Director 

Dr. Brian Rowe, MD, MSc, CCFP-EM/ Associate Director

Finlay McAlister, MD, MSc, FRCPC 

Brian Rowe, MD, MSc, CCFP(EM) 

Principal Investigators 

William Abraham, MD 

Justin Ezekowitz, MD 

Graham Nichol, MD 

Padma Kaul, PhD 

Ellen Crumley, MLIS 

Lisa Hartling, MSc 

Carol Spooner, MSc 

Natasha Wiebe, MMath 

Appendix A: Exact Search Strings 

Appendix B: Sample Data Forms 

Appendix C: Evidence Tables 

Appendix D: Technical Experts and Peer Reviewers 
Appendix A: Exact Search Strings 

A-1 

Exact Search Strings 

Search Strategies 

Basic Searches 

 Table A-1 Medline – CRT for CHF 

 Table A-2 EMBASE - CRT for CHF 

 Table A-3 International Pharmaceutical Abstracts - CRT for CHF 

Table A-4 PubMed - CRT for CHF 

Table A-5 Web of Science - CRT for CHF 

Safety Review Searches 

 Table A-6 Medline - CRT for CHF 

 Table A-7 EMBASE - CRT for CHF 

 Table A-8 PubMed - CRT for CHF 

 Table A-9 Web of Science - CRT for CHF 

Efficacy Review Searches 

 Table A-10 Medline - CRT for CHF; 1Oct02 (efficacy) 

Table A-11 EMBASE - CRT for CHF; 2Oct02 (efficacy) 

Table A-12 Cochrane Controlled Trials Register (CENTRAL) - CRT for CHF; 2Oct02 

(efficacy) 

Table A-13 Database of Abstracts of Reviews of Effectiveness (DARE) - CRT for CHF; 

2Oct02 (efficacy) 

Table A-14 Cochrane Database of Systematic Review - CRT for CHF; 2Oct02 (efficacy) 

Table A-15 PubMed - CRT for CHF (efficacy) 

Table A-16 Web of Science: CRT for CHF (efficacy) 
Appendix A: Exact Search Strings (continued) 

A-2 

Search Strategies

Electronic Databases 

The search was designed by a medical librarian in consultation with a cardiologist (EC, JE), then 

performed systematically by the librarian (EC). The following electronic resources were 

searched: 

- The Cochrane Central Register of Controlled Trials (22) 

- DARE (2) 

- Cochrane Database of Systematic Reviews (2) 

- EMBASE (basic=4619, safety=1040, efficacy=1415) 

- International Pharmaceutical Abstracts (1) 

- MEDLINE (basic=9817, safety=2168, efficacy=444) 

- PubMed (basic=1558, safety=828, efficacy=449) 

- Web of Science (basic=313, safety=17, efficacy=27) 

The total number of references with duplicates removed were 1697 (for the efficacy part of the 

review) and 1708 (safety). 

Trial Registries

Several trial registries were also searched using keywords from the searches below. These 

included: 

- http://www2.umdnj.edu/~shindler/trials/trials_a.html 

- http://www.nhlbi.nih.gov/index.htm 

- http://www.controlled-trials.com/ 

- clinicaltrials.gov 

- http://www.update-software.com/National/ 

- http://www.centerwatch.com/search.asp 

- http://www.cardiosource.com 

Each trial retrieved from the registries was reviewed independently by two investigators. 

Companies 

The companies that manufacture biventricular devices were contacted: 

- Medtronic 

- Guidant 

- ELA Medical (Montrouge, France) 
Appendix A: Exact Search Strings (continued) 

A-3 

Keywords and Subject Headings 

The search strategies included the following keywords and appropriate subject headings, 

specifically tailored for each resource: Biventricular pacing, biventricular pacer, biventricular 

stimulation, Biv, congestive heart failure, Chf, chronic heart failure, artificial cardiac pacing, 

heart diseases, chronic cardiac failure resynchronization therapy, dual-chamber pacing, cardiac 

resynchronization, Medtronic, Insync, ELA medical; randomized controlled trial, controlled 

clinical trial, meta-analysis, multi-center trial; safety, risk, adverse effects, side effects, harm, 

etiology, aetiology, contraindications, causation, causality, predict. 

The search process also involved: citation searches; contacting the primary author of key, 

ongoing or unpublished studies, and reviewing the reference lists of all selected articles. 

The search was not limited by language or publication status. 

The detailed search strings appear on the following pages. They cover the years 1988 to the 

present (June 2003). 
Appendix A: Exact Search Strings (continued) 

A-4 

Basic Searches

Table A-1 Medline –CRT for CHF: (basic search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 Insync.mp. 

8 "ela medical".mp. 

9 exp cardiac pacing, artificial/ 

10 or/1-8 

11 or/1-9 

12 exp heart failure, congestive/ 

13 "congestive heart failure$".mp. 

14 chf.mp. 

15 exp heart diseases/ 

16 "congestive cardiac failure$".mp. 

17 "chronic cardiac failure$".mp. 

18 "chronic heart failure$".mp. 

19 or/12-18 

20 10 and 19 

21 11 and 19 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-5 

Table A-2 EMBASE: CRT for CHF - (basic search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 exp heart pacing/ 

3 resynchronization therapy.mp. 

4 biv.mp. 

5 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

6 ((cardiac or heart) adj resynchronization).mp. 

7 medtronic.mp. 

8 insync.mp. 

9 "ela medical".mp. 

10 or/1-9 

11 exp Congestive heart failure/ 

12 "congestive heart failure$".mp. 

13 chf.mp. 

14 exp Heart disease/ 

15 "congestive cardiac failure$".mp. 

16 "chronic cardiac failure$".mp. 

17 "chronic heart failure$".mp. 

18 or/11-17 

19 10 and 18 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-6 

Table A-3 nternational Pharmaceutical Abstracts CRT for CHF (basic search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 "cardiac pacing".mp. 

7 medtronic.mp. 

8 insync.mp. 

9 "ela medical".mp. 

10 or/1-9 

11 "congestive cardiac failure$".mp. 

12 "congestive heart failure$".mp. 

13 chf.mp. 

14 heart disease$.mp. 

15 "chronic cardiac failure$".mp. 

16 "chronic heart failure$".mp. 

17 or/11-16 

18 10 and 17 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-7 

Table A-4 PubMed: CRT for CHF (basic search) 

#19 Search #10 AND #18 

#18 Search #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 

#17 Search "CHRONIC HEART FAILURE*" 

#16 Search "CHRONIC CARDIAC FAILURE*" 

#15 Search "CONGESTIVE CARDIAC FAILURE*" 

#14 Search HEART DISEASES[MESH] 

#13 Search CHF 

#12 Search "CONGESTIVE HEART FAILURE" 

#11 Search HEART FAILURE, CONGESTIVE[MESH] 

#10 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 

#8 Search "ELA MEDICAL" 

#7 Search INSYNC 

#6 Search MEDTRONIC 

#5 Search (CARDIAC OR HEART) AND RESYNCHRONIZATION 

#4 Search DUAL-CHAMBER AND (PACING OR PACER* OR STIMULAT*) 

#3 Search BIV 

#2 Search RESYNCHRONIZATION THERAPY 

#1 Search biventricular AND (PACING OR PACER* OR STIMULAT*) 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-8 

Table A-5 Web of Science: CRT for CHF (basic search) 

#3 316

#1 AND #2

#2 84,712

TS=(congestive heart failure* or chf or heart disease or congestive cardiac failure* or chronic cardiac 

failure* or chronic heart failure*)

#1 3,268

TS=(biventricular pacing OR biventricular pacer* OR resynchronization therapy OR biv OR dual chamber 

pacing OR dual chamber pacer* OR dual chamber stimulat* OR cardiac resynchronization OR heart 

resynchronization OR cardiac pacing OR medtronic OR insync OR ela medical) 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-9 

Safety Searches 

Table A-6 Medline: CRT for CHF - (safety search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 insync.mp. 

8 "ela medical".mp. 

9 exp cardiac pacing, artificial/ 

10 or/1-8 

11 or/1-9 

12 exp heart failure, congestive/ 

13 exp heart diseases/ 

14 "congestive cardiac failure$".mp. 

15 "congestive heart failure$".mp. 

16 "chronic cardiac failure$".mp. 

17 "chronic heart failure$".mp. 

18 chf.mp. 

19 or/12-18 

20 10 and 19 

21 11 and 19 

22 (safe or safety).mp. 

23 risk$.mp. 

24 exp risk/ 

25 adverse effect$.mp. 

26 side effect$.mp. 

27 harm.mp. 

28 etiology.mp. 

29 aetiology.mp. 

30 contraindicat$.mp. 

31 (cause or causation or causing or causal$).mp. 

32 exp causality/ 

33 predict$.mp. 

34 or/22-33 

35 20 and 34 

36 21 and 34 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure 
Appendix A: Exact Search Strings (continued) 

A-10 

Table A-7 EMBASE: CRT for CHF- (safety search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 exp heart pacing/ 

3 resynchronization therapy.mp. 

4 biv.mp. 

5 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

6 ((cardiac or heart) adj resynchronization).mp. 

7 medtronic.mp. 

8 insync.mp. 

9 "ela medical".mp. 

10 or/1-9 

11 exp Congestive heart failure/ 

12 "congestive heart failure$".mp. 

13 chf.mp. 

14 exp Heart disease/ 

15 "congestive cardiac failure$".mp. 

16 "chronic cardiac failure$".mp. 

17 "chronic heart failure$".mp. 

18 or/11-17 

19 10 and 18 

20 (safe or safety).mp. 

21 exp risk/ 

22 risk$.mp. 

23 exp Side effect/ 

24 "side effect$".mp. 

25 "HARM".mp. 

26 exp etiology/ 

27 aetiology.mp. 

28 Treatment contraindication/ 

29 contraindicat$.mp. 

30 (cause or causation or causing or causal$).mp. 

31 *Epidemiology/ 

32 exp prediction/ 

33 or/20-32 

34 19 and 33 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-11 

Table A-8 PubMed: CRT for CHF (safety search) 

#30 Search #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR 

#27 OR #28 OR #29

#29 Search predict*

#28 Search CAUSALITY[MESH]

#27 Search cause OR CAUSATION OR CAUSING OR CAUSAL*

#26 Search contraindicat*

#25 Search aetiology

#24 Search etiology

#23 Search HARM

#22 Search side effect*

#21 Search adverse effect*

#20 Search RISK[MESH]

#19 Search RISK*

#18 Search SAFE OR SAFETY

#17 Search #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16

#16 Search CHF

#15 Search "CHRONIC HEART FAILURE*"

#14 Search "CHRONIC CARDIAC FAILURE*"

#13 Search "CONGESTIVE HEART FAILURE*"

#12 Search "CONGESTIVE CARDIAC FAILURE*"

#11 Search HEART DISEASES[MESH]

#10 Search HEART FAILURE, CONGESTIVE[MESH]

#9 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

#8 Search ELA MEDICAL

#6 Search MEDTRONIC

#7 Search INSYNC

#5 Search (CARDIAC OR HEART) AND RESYNCHRONIZATION

#4 Search DUAL-CHAMBER AND (PACING OR PACER* OR STIMULAT*)

#1 Search biventricular AND (PACING OR PACER* OR STIMULAT*)

#3 Search BIV

#2 Search RESYNCHRONIZATION THERAPY

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-12 

Table A-9 Web of Science: CRT for CHF (safety search) 

#4 #1 AND #2 AND #3 

#3 TS=(safe or safety or risk* or adverse effect* or side effect* or harm or etiology or aetiology or contraindicat* or cause or 

causation or causing or causal* or predict*)

#2 TS=(congestive heart failure* or chf or heart disease or congestive cardiac failure* or chronic cardiac failure* or chronic 

heart failure*)

#1

TS=(biventricular pacing or biventricular pacer* or resynchronization therapy or biv or dual-chamber pacing or dualchamber pacer* or dual-chamber stimulat* or cardiac resynchronization or heart resynchronization or cardiac pacing or 

medtronic or insync or ela medical)

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-13 

Efficacy Searches 

Table A-10 Medline: CRT for CHF (efficacy search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 insync.mp. 

8 "ela medical".mp. 

9 exp cardiac pacing, artificial/ 

10 or/1-8 

11 or/1-9 

12 exp heart failure, congestive/ 

13 "congestive heart failure$".mp. 

14 chf.mp. 

15 exp heart diseases/ 

16 "congestive cardiac failure$".mp. 

17 "chronic cardiac failure$".mp. 

18 "chronic heart failure$".mp. 

19 or/12-18 

20 10 and 19 

21 11 and 19 

22 limit 20 to (controlled clinical trial or meta analysis or multicenter study or randomized 

controlled trial) 

23 limit 21 to (controlled clinical trial or meta analysis or multicenter study or randomized 

controlled trial) 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-14 

Table A-11 EMBASE: CRT for CHF -(efficacy search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 exp heart pacing/ 

3 resynchronization therapy.mp. 

4 biv.mp. 

5 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

6 ((cardiac or heart) adj resynchronization).mp. 

7 medtronic.mp. 

8 insync.mp. 

9 "ela medical".mp. 

10 or/1-9 

11 exp Congestive heart failure/ 

12 "congestive heart failure$".mp. 

13 chf.mp. 

14 exp Heart disease/ 

15 "congestive cardiac failure$".mp. 

16 "chronic cardiac failure$".mp. 

17 "chronic heart failure$".mp. 

18 or/11-17 

19 10 and 18 

20 "randomized controlled trial"/ 

21 random$.mp. 

22 exp controlled study/ 

23 "meta analysis"/ 

24 multi center trial$.mp. 

25 "systematic review$".mp. 

26 or/20-25 

27 19 and 26 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-15 

Table A-12 Cochrane Controlled Trials Register (CENTRAL): CRT for CHF -(efficacy search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 insync.mp. 

8 "ela medical".mp. 

9 or/1-8 

10 "congestive heart failure$".mp. 

11 chf.mp. 

12 heart disease$.mp. 

13 "congestive cardiac failure$".mp. 

14 "chronic cardiac failure$".mp. 

15 "chronic heart failure$".mp. 

16 or/10-15 

17 9 and 16 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-16 

Table A-13 Database of Abstracts of Reviews of Effectiveness (DARE): CRT for CHF - (efficacy search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 insync.mp. 

8 "ela medical".mp. 

9 or/1-8 

10 "congestive heart failure$".mp. 

11 chf.mp. 

12 heart disease$.mp. 

13 "congestive cardiac failure$".mp. 

14 "chronic cardiac failure$".mp. 

15 "chronic heart failure$".mp. 

16 or/10-15 

17 9 and 16 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-17 

Table A-14 Cochrane Database of Systematic Reviews: CRT for CHF - (efficacy search) 

Set Search 

1 (biventricular adj (pacing or pacer$ or stimulat$)).mp. 

2 resynchronization therapy.mp. 

3 biv.mp. 

4 (dual-chamber adj (pacing or pacer$ or stimulat$)).mp. 

5 ((cardiac or heart) adj resynchronization).mp. 

6 medtronic.mp. 

7 insync.mp. 

8 "ela medical".mp. 

9 or/1-8 

10 "congestive heart failure$".mp. 

11 chf.mp. 

12 heart disease$.mp. 

13 "congestive cardiac failure$".mp. 

14 "chronic cardiac failure$".mp. 

15 "chronic heart failure$".mp. 

16 or/10-15 

17 9 and 16 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-18 

Table A-15 PubMed: CRT for CHF (efficacy search) 

#25 Search #19 AND #24

#23 Search MULTICENTER STUDY

#24 Search #20 OR #21 OR #22 OR #23

#22 Search meta analysis

#21 Search controlled clinical trial*

#20 Search RANDOMIZED CONTROLLED TRIAL[PT]

#19 Search #10 AND #18

#18 Search #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17

#17 Search "CHRONIC HEART FAILURE*"

#16 Search "CHRONIC CARDIAC FAILURE*"

#15 Search "CONGESTIVE CARDIAC FAILURE*"

#14 Search HEART DISEASES[MESH]

#13 Search CHF

#12 Search "CONGESTIVE HEART FAILURE*"

#11 Search HEART FAILURE, CONGESTIVE[MESH]

#10 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

#8 Search ELA MEDICAL

#7 Search INSYNC

#6 Search MEDTRONIC

#5 Search (CARDIAC OR HEART) AND RESYNCHRONIZATION

#4 Search DUAL-CHAMBER AND (PACING OR PACER* OR STIMULAT*)

#3 Search BIV

#2 Search RESYNCHRONIZATION THERAPY

#1 Search biventricular AND (PACING OR PACER* OR STIMULAT*)

CRT= cardiac resynchronization therapy; CHF= congestive heart failure
Appendix A: Exact Search Strings (continued) 

A-19 

Table A-16 Web of Science: CRT for CHF (efficacy search) 

#4 31

#1 AND #2 AND #3

#3 >100,000

TS=(random* or controlled trial* or clinical trial* or multi-center or meta-analys* or systematic 

review*)

#2 84,712

TS=(congestive heart failure* or chf or heart disease or congestive cardiac failure* or chronic cardiac 

failure* or chronic heart failure*) 

#1 3,268

TS=(biventricular pacing or biventricular pacer* or resynchronization therapy or biv or dual-chamber 

pacing or dual-chamber pacer* or dual-chamber stimulat* or cardiac resynchronization or heart 

resynchronization or cardiac pacing or medtronic or insync or ela medical) 

CRT= cardiac resynchronization therapy; CHF= congestive heart failure

 
Appendix B: Sample Data Forms 

B-1 

Sample Data Forms 

Inclusion/Exclusion Criteria 

Form B-1 Inclusion Form: CRT for CHF: Efficacy Review 

Form B-2 Inclusion Form: CRT for CHF Safety Review 

Quality Assessment 

Form B-3 Assessment of methodology for randomized controlled trials (RCT): 

Efficacy review 

 Form B-4 Assessment of methodology for RCTs and non-RCTs: Safety Review 

Data Extraction 

 Form B-5 Data extraction - CRT for CHF: Efficacy review 

 Form B-6 Data extraction – CRT for CHF: Safety review 
Appendix B: Sample Data Forms (continued) 

B-2 

Form B-1 Inclusion Form: CRT for CHF: Efficacy Review 

Please assess each study according to the criteria below. 

1. Study Design: 

Were patients randomly assigned to parallel treatment groups? 

 or 

Was the study a randomized cross-over trial? Yes No 

1a.Was the study ≥ 2 weeks in duration? Yes No 

2. Population: 

Did the population have class III or IV congestive heart failure 

as measured by decreased left ventricular ejection fraction while 

 receiving stable optimal drug therapy? Yes No

3. Intervention: 

Did one group or period include treatment with an active CRT? 

 Yes No

4. Control: 

Did one group or period include treatment with a placebo pacing 

or optimized medical therapy? 

(in a crossover trial CRT off/on in randomized order) 

Yes No

 

(other names for cardiac resynchronization therapy (CRT), Bi ventricular pacing (CRT); multi-site pacing; dual 

chamber pacer) 

5. Outcome: 

Is any one of the following an outcome in the study: 

quality of life, functional class (NYHA), ability to perform a six-minute walk test, CHF hospitalization, 

emergency department visits, morbidity measures, or mortality (all-cause, cardiac, CHF, sudden 

cardiac death 

 

Yes No 

6. Final decision: 

 

Should this study be included in the next stage? Yes No

 

 

 Unsure 

Put into Unsure group for consensus 

7. Consensus decision: 

Yes No 3rd Party 
Appendix B: Sample Data Forms (continued) 

B-3 

Form B-2 Inclusion Form: CRT for CHF Safety Review 

Please assess each study according to the criteria below. 

1. Study Design: 

INCLUDE: -an RCT (parallel or crossover) Yes Yes No No 

 -registry data 

 -a prospective cohort study 

 -an FDA document 

EXCLUDE: acute physiological studies, non-human studies. 

 

1a. Was the study ≥ 2 weeks in duration? Yes No

2. Population: 

Did the population have class ≥ II congestive heart failure 

as measured by decreased left ventricular ejection fraction while 

receiving stable optimal drug therapy? Yes No

3. Intervention: 

Did one group or period include treatment with an active CRT? 

 Yes No 

4. Control: (If part of the design) 

Did one group or period include treatment with placebo pacing, 

or other pacing mode or accepted standard treatment? Yes No

 

(other names for cardiac resynchronization therapy (CRT), Biventricular pacing (CRT): multi-site pacing, dual 

chamber pacer) 

5. Outcome: (Please highlight which ones were reported) 

Are there any reported outcomes that in any way indicate CRT is either safe or unsafe? E.g. 

Unsafe indicators: A. Risks of/during implantation - Related to the device with battery; left 

ventricular lead, right ventricular lead, or to right atrial lead; to system function; to implant tools. 

Procedure related – patient complaints, heart function, or mortality. 

 B. Risks post implantation -Worsening heart failure; unwanted post surgical 

sequalae – e.g. keloids, pocket infection, pain; mechanical malfunction; lead dislodgment, 

replacement; -arrhythmia’s caused by CRT; emergency department/clinic/outpatient visits; 

hospitalization (all cause and CHF related); mortality (all cause and cardiac related). 

 Yes No 

Other unsafe indicators not listed above (describe) 

e.g. 

Successful implants rate Yes No 

 

6. Final decision: Should this study be included? Yes No

 Unsure 

Put into Unsure group for consensus 

Consensus decision: 

Yes No 3rd party
Appendix B: Sample Data Forms (continued) 

B-4 

Form B-3 Assessment of methodology for randomized controlled trials (RCT) 

CRT Systematic Review 2002 Quality Form Reviewer: 

UAEPC RCT Reference No.: 

Please assess each study according to the criteria below. 

A. JADAD CRITERIA SCORE

 

1. Was the study described as randomized (this includes the use of 

words such as randomly, random, and randomization)? Yes = 1 No = 0 

2. Was the study described as double-blind? Yes = 1 No = 0 

 

3. Was there a description of withdrawals and dropouts? Yes = 1 No = 0 

 

4. Additional points: Add 1 point if: 

a. Method to generate the sequence of randomization was described and was 

appropriate (e.g. IVRS, table of random numbers, etc.) 

b. Method of double blinding described and appropriate (identical placebo, active 

placebo) 

5. Deduction of points: Subtract 1 point if: 

a. Method of randomization described and inappropriate (e.g., 

alternatively, hospital #, etc.) 

b. Method of double blinding described and inappropriate (IV vs. PO w/ no blind) 

OVERALL SCORE (maximum 5) 

B. SCHULZ CRITERIA

 

Concealment of treatment allocation: Adequate 

 Inadequate 

 Unclear 

Adequate: central randomization; numbered/coded containers; drugs prepared from 

pharmacy; serially numbered; opaque sealed envelopes 

Inadequate: alternation; use of case record numbers, DOB or weeks, open lists 

Unclear: Allocation concealment approach not reported or doesn’t fit above categories
Appendix B: Sample Data Forms (continued) 

B-5 

Form B-4 Assessment of methodology for RCTs and non-RCTs: Safety Review 

Quality Form (nonRCTs)

CRT Systematic Review 2002 Reviewer: 

UAEPC Reference No.: 

(from Downs and Black, J Epidemiol Community Health 1998;52:377-384) 

REPORTING 

1. Is the hypothesis/aim/objective of the study clearly described? This question refers to a clear statement of the objective, i.e. to measure the effectiveness of 

x in population y with respect to z, even if x, y and z are not clearly described (see questions 2, 3 and 4) 

Yes 1 

No 0 

2. Are the main outcomes to be measured clearly described in the Introduction or Methods section? If the main outcomes are first mentioned in the Results 

section, the question should be answered no. In case-control studies the case definition should be considered the outcome. 

Yes 1 

No 0 

3. Are the characteristics of the patients included in the study clearly described in the Introduction or Methods section? In cohort studies and trials, inclusion 

and or exclusion criteria should be given. In case-control studies, a case definition and the source for controls should be given. 

Yes 1 

No 0 

4. Are the interventions of interest clearly described in the Introduction or Methods section? Treatments and placebo (where relevant) that are to be compared 

should be clearly described. 

Yes 1 

No 0 

5. Are the distributions of principal confounders in each group of subjects to be compared clearly described? A list of principal confounders is provided. 

Yes 2 

Partially 1 

No 0 

6. Are the main findings of the study clearly described? Simple outcome data (including denominators and numerators) should be reported for all major 

findings so that the reader can check the major analyses and conclusions. This question does not cover statistical tests, which are considered below. 

Yes 1 

No 0 

7. Does the study provide estimates of the random variability in the data for the main outcomes? In non-normally distributed data the inter-quartile range of 

results should be reported. In normally distributed data the standard error, standard deviation or confidence intervals should be reported. If the distribution 

of the data is not described, it must be assumed that the estimates used were appropriate and the question should be answered yes. 

Yes 1 

No 0 

8. Have all important adverse events that may be a consequence of the intervention been reported? This should be answered yes if the study demonstrates 

that there was a comprehensive attempt to measure adverse events. (A list of possible adverse events is provided). 

Yes 1 

No 0 

9. Have the characteristics of patients lost to follow-up been described? This should be answered yes where there were no losses to follow-up or where 

losses to follow-up were so small that findings would be unaffected by their inclusion. This should be answered no where a study does not report the 

number of patients lost to follow-up. 

Yes 1 

No 0 

10. Have 95% CIs and/or actual probability values been reported (e.g. p=0.035 rather than p <0.05) for the main outcomes except where the probability value is 

less than 0.001? (both CI and p value, either CI or p value, neither) 

Yes 1 

No 0 

EXTERNAL VALIDITY 
Appendix B: Sample Data Forms (continued) 

B-6 

Form B-4 Assessment of methodology for RCTs and non-RCTs: Safety Review—continued

11. Were the subjects asked to participate in the study representative of the entire population from which they were recruited? The study must identify the 

source population for patients and describe how the patients were selected. Patients would be representative if they comprised the entire source 

population, an unselected sample of consecutive patients, or a random sample. Random sampling is only feasible where a list of all members of the 

relevant population exists. Where a study does not report the proportion of the source population from which the patients are derived, the question should 

be answered as unable to determine. 

Yes 1 

No 0 

Unable to determine 0 

12. Were those subjects who were prepared to participate representative of the entire population from which they were recruited? The proportion of those 

asked who agreed should be stated. Validation that the sample was representative would include demonstrating that the distribution of the main 

confounding factors was the same in the study sample and the source population. 

Yes 1 

No 0 

Unable to determine 0 

13. Were the staff, places, and facilities where study patients were treated, representative of the treatment the majority of patients receive? For the question to 

be answered yes the study should demonstrate that the intervention was representative of that in use in the source population. The question should be 

answered no if, for example, the intervention was undertaken in a specialist centre unrepresentative of the hospitals most of the source population would 

attend. 

Yes 1 

No 0 

Unable to determine 0 

INTERNAL VALIDITY - BIAS 

14. Was an attempt made to blind study subjects to the intervention they have received? For studies where the patients would have no way of knowing which 

intervention they received, this should be answered yes. 

Yes 1 

No 0 

Unable to determine 0 

15. Was an attempt made to blind those measuring the main outcomes of the intervention? 

Yes 1 

No 0 

Unable to determine 0 

16. If any of the results of the study were based on “data dredging”, was this made clear? Any analyses that had not been planned at the outset of the study 

should be clearly indicated. If no retrospective unplanned subgroup analyses were reported, then answer yes. 

Yes 1 

No 0 

Unable to determine 0 

17. In trials and cohort studies, do the analyses adjust for different lengths of follow-up of patients, or in case-control studies, is the time period between the 

intervention and outcome the same for cases and controls? Where follow-up was the same for all study patients that answer should be yes. If different 

lengths of follow-up were adjusted for by, for example, survival analysis the answer should be yes. Studies where differences in follow-up are ignored 

should be answered no. 

Yes 1 

No 0 

Unable to determine 0 

18. Were the statistical tests used to assess the main outcomes appropriate? The statistical techniques used must be appropriate to the data. For example 

non-parametric methods should be used for small sample sizes. Where little statistical analysis has been undertaken but where there is no evidence of 

bias, the question should be answered yes. If the distribution of the data (normal or not) is not described it must be assumed that the estimates used were 

appropriate and the question should be answered yes. 

Yes 1 

No 0 

Unable to determine 0 
Appendix B: Sample Data Forms (continued) 

B-7 

Form B-4 Assessment of methodology for RCTs and non-RCTs: Safety Review—continued

19. Was compliance with the interventions reliable? Where there was non-compliance with the allocated treatment or where there was contamination of one 

group, the question should be answered no. For studies where the effect of any misclassification was likely to bias any association to the null, the question 

should be answered yes. 

Yes 1 

No 0 

Unable to determine 0 

20. Were the main outcome measures used accurate (valid and reliable)? For studies where the outcomes measured are clearly described, the question 

should be answered yes. For studies that refer to other work or that demonstrate the outcome measures are accurate, the question should be answered as 

yes. 

Yes 1 

No 0 

Unable to determine 0 

INTERNAL VALIDITY – CONFOUNDING (SELECTION BIAS) 

21. Were the patients in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited from the same 

population? For example, patients for all comparison groups should be selected from the same hospital. The question should be answered unable to 

determine for cohort and case-control studies where there is no information concerning the source of patients included in the study. 

Yes 1 

No 0 

Unable to determine 0 

22. Were study subjects in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited over the same 

period of time? For a study which does not specify the time period over which patients were recruited, the question should be answered as unable to 

determine. 

Yes 1 

No 0 

Unable to determine 0 

23. Were the subjects randomized to intervention groups? Studies which state that subjects were randomized should be answered yes except where method of 

randomization would not ensure random allocation. For example alternate allocation would score no because it is predictable. 

Yes 1 

No 0 

Unable to determine 0 

24. Was the randomized intervention assignment concealed from both patients and health care staff until recruitment was complete and irrevocable? All nonrandomized studies should be answered no. If assignment was concealed from patients but not from staff, it should be answered no. 

Yes 1 

No 0 

Unable to determine 0 

25. Was there adequate adjustment for confounding in the analyses from which the main findings were drawn? This question should be answered no for trials 

if: the main conclusions of the study were based on analyses of treatment rather than intention to treat; the distribution of known confounders in the 

different treatment groups was not described; or the distribution of known confounders different between the treatment groups but was not taken into 

account in the analyses. In non-randomized studies if the effect of the main confounders was not investigated or confounding was demonstrated but no 

adjustment was made in the final analyses the question should be answered as no. 

Yes 1 

No 0 

Unable to determine 0 

26. Were losses to patients to follow-up take into account? (yes, no, unable to determine) If the numbers of patients lost to follow-up are not reported, the 

question should be answered as unable to determine. If the proportion lost to follow-up was too small to affect the main findings, the question should be 

answered yes. 

Yes 1 

No 0 

Unable to determine 0 
Appendix B: Sample Data Forms (continued) 

B-8 

Form B-4 Assessment of methodology for RCTs and non-RCTs: Safety Review—concluded

POWER 

27. Was a power calculation reported for the primary outcome? 

Yes 1 

No 0 

Unable to determine 0 

28. Did the study have sufficient power to detect a clinically important effect where the probability value for a difference being due to chance in less than 5%? 

Yes 1 

No 0 

Unable to determine 0 
Appendix B: Sample Data Forms (continued) 

B-9 

Form B-5 Data extraction - CRT for CHF: Efficacy review 

CRT SR 2002 Data Extraction Form Reviewer: 

UAEPC Checker: 

Efficacy RCT Reference No.: 

Study Characteristics 

Authors: 

Title: 

Journal citation: 

Year of publication: Language: Country(ies) where study 

conducted: 

Funding: 

 Private industry 

 Foundation 

 Government 

 Internal 

 Other 

Author’s primary outcome: 

Author’s inclusion criteria: Author’s exclusion criteria: 

Comments: 
Appendix B: Sample Data Forms (continued) 

B-10 

Form B-5 Data extraction Efficacy review—continued

Design Characteristics 

Study design: Parallel Crossover 

Carryover effect? 

Other 

Subject-blinded: Yes No Unclear 

Outcome assessorblinded: Yes No Unclear 

Intent to treat design: Yes No 

Intent to treat 

analysis:

Yes No N/A 

Participants 

Number of eligible participants: Number enrolled in study: 

Exclusions: Yes No Unclear 

If yes, reasons: 

Withdrawals/dropouts Yes No Unclear 

CRT group: 

Placebo group: 

If yes, reasons: 

All participants: 
Appendix B: Sample Data Forms (continued) 

B-11 

Form B-5 Data extraction Efficacy review—continued

Baseline Characteristics Please indicate the statistic, e.g., %, mean, SD, range, etc AND 

the units 

CRT group Placebo group All participants 

Males/females: 

Age: 

Race: 

Ischemic/nonischemic: 

NYHA class: 

I 

II 

III 

IV 

Diabetes 

Mellitus: 

 

Hypertension: 

Coronary artery disease: 

previous MI 

previous PTCA 

CABG 

Strokes: 

History of SCD: 

Atrial fibrillation: 

Renal failure: 

ECG: 

PR interval 

QRS interval 
Appendix B: Sample Data Forms (continued) 

B-12 

Form B-5 Data extraction Efficacy review—continued

More Baseline Characteristics: Indicate the statistic, e.g., %, mean, SD, etc AND the units

ECHO: 

LVEDD 

LVESD 

dp/dt 

MR grade 

Area of MR jet 

Physical exam: 

Systolic Blood 

Pressure 

 

Diastolic Blood 

Pressure 

 

Heart rate 

Weight 

Other Comorbidities:  

Procedural Characteristics: Indicate the statistic, e.g., %, mean, SD, range, IQ, etc AND 

the units

CRT group Placebo group All participants 

Drug therapy: 

ARB 

ACE 

BB 

spironolactone 

digoxin 

nitrates 

lipid lowering 

agent 

 

warfarin 

Device: 

Method of 

implantation: 

Other cointerventions: 
Appendix B: Sample Data Forms (continued) 

B-13 

Form B-5 Data extraction Efficacy review—continued 

Outcomes: Timepoints indicate time since RANDOMIZATION in DAYS. 

 

Biventricular Pacemakers Control 

Time to death: 

 All-cause 

mortality 

Number at 

risk 

Number 

of events 

Number 

censored 

Number at 

risk 

Number of 

events 

Number 

censored 

 Timepoint 0 

 Timepoint 15 

 Timepoint 30 

 Timepoint 45 

 Timepoint 60 

 Timepoint 90 

 Timepoint 120 

 Timepoint 150 

 Timepoint 180 

 Timepoint 210 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 

Biventricular Pacemakers Control 

Time to death: 

 Sudden 

cardiac 

death 

Number at 

risk 

Number 

of events 

Number 

censored 

Number at 

risk 

Number of 

events 

Number 

censored 

 Timepoint 0 

 Timepoint 15 

 Timepoint 30 

 Timepoint 45 

 Timepoint 60 

 Timepoint 90 

 Timepoint 120 

 Timepoint 150 

 Timepoint 180 

 Timepoint 210 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

Indicate which period if it’s a crossover study or which subgroup where necessary:
Appendix B: Sample Data Forms (continued) 

B-14 

Form B-5 Data extraction Efficacy review—continued 

Outcomes: Timepoints indicate time since RANDOMIZATION in DAYS. 

 

Biventricular Pacemakers Control 

Time to death: 

 CHF 

Number at 

risk 

Number 

of events 

Number 

censored 

Number at 

risk 

Number of 

events 

Number 

censored 

 Timepoint 0 

 Timepoint 15 

 Timepoint 30 

 Timepoint 45 

 Timepoint 60 

 Timepoint 90 

 Timepoint 120 

 Timepoint 150 

 Timepoint 180 

 Timepoint 210 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 

Biventricular Pacemakers Control 

Time to death: 

 Cardiac 

mortality 

Number at 

risk 

Number 

of events 

Number 

censored 

Number at 

risk 

Number of 

events 

Number 

censored 

 Timepoint 0 

 Timepoint 15 

 Timepoint 30 

 Timepoint 45 

 Timepoint 60 

 Timepoint 90 

 Timepoint 120 

 Timepoint 150 

 Timepoint 180 

 Timepoint 210 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

Indicate which period if it’s a crossover study or which subgroup where necessary:
Appendix B: Sample Data Forms (continued) 

B-15 

Form B-5 Data extraction Efficacy review—continued

Outcomes: Timepoints indicate time since RANDOMIZATION in DAYS. 

 

Biventricular Pacemakers Control 

Dichotomous 

outcomes: 

n/N

Baseline Timepoint Timepoint Timepoint Baseline Timepoint Timepoint Timepoint 

Death 

 

 

CHF 

hospitalizatio

ns 

 

ED visits 

Other 

 

Biventricular Pacemakers Control 

Continuous 

outcomes: 

 

mean(sd) 

Baseline Timepoint Timepoint Timepoint Baseline Timepoint Timepoint Timepoint 

Ejection 

Fraction 

 

VO2 Max 

6 minute 

walk test 

 

Other 

Indicate which period if it’s a crossover study or which subgroup where necessary:
Appendix B: Sample Data Forms (continued) 

B-16 

Form B-5 Data extraction Efficacy review—concluded

Outcomes: Timepoints indicate time since RANDOMIZATION in DAYS. 

 

Biventricular Pacemakers Control 

Other 

outcomes: 

[indicate 

summary 

measures] 

Baseline Timepoint Timepoint Timepoint Baseline Timepoint Timepoint Timepoint 

NYHA 

functional 

class 

 

Quality of life 

 Name of 

measure? 

 

Global 

Assessment 

 Name of 

measure? 

 

ECG 

PR interval 

QRS interval 

ECHO 

LVEDD 

LVESD 

dp/dt 

MR grade 

Area of MR 

jet 

 

Other 

Indicate which period if it’s a crossover study or which subgroup where necessary:
Appendix B: Sample Data Forms (continued) 

B-17 

Form B-6 Data extraction – CRT for CHF: Safety review 

 

CRT SR 2002 Data Extraction Form Reviewer: 

UAEPC Checker: 

Safety CCT Reference No.: 

Study Characteristics 

Authors: 

Title: 

Journal citation: 

Year of publication: Language: Country(ies) where study 

conducted: 

Funding: 

 Private industry 

 Foundation 

 Government 

 Internal 

 Other 

Author’s primary outcome: 

Authors’s inclusion criteria: Authors’s exclusion criteria: 

Comments: 
Appendix B: Sample Data Forms (continued) 

B-18 

Form B-6 Data extraction Safety review—continued

Design Characteristics 

Allocation: 

Subject-blinded: Yes No Unclear 

Outcome assessorblinded: Yes No Unclear 

Intent to treat design: Yes No N/A 

Intent to treat 

analysis: 

Yes No N/A 

Participants 

Number of eligible participants: Number enrolled in study: 

Exclusions: Yes No Unclear 

If yes, reasons: 

Withdrawals/dropouts Yes No Unclear 

If yes, reasons: CRT group: 

 Didn’t specify 

which group: 

Placebo group: 
Appendix B: Sample Data Forms (continued) 

B-19 

Form B-6 Data extraction Safety review—continued

Baseline Characteristics: Please indicate the statistic, e.g., %, mean, SD, range, etc AND 

the units 

CRT group Placebo group All participants 

Males/females: 

Age: 

Race: 

Ischemic/nonischemic: 

NYHA class: 

I 

II 

III 

IV 

Diabetes 

Mellitus: 

 

Hypertension: 

Coronary artery disease: 

previous MI 

previous PTCA 

CABG 

Strokes: 

History of SCD: 

Atrial fibrillation: 

Renal failure: 

ECG: 

PR interval 

QRS interval 
Appendix B: Sample Data Forms (continued) 

B-20 

Form B-6 Data extraction Safety review—continued

More Baseline Characteristics: Indicate the statistic, e.g., %, mean, SD, etc. AND the 

units

ECHO: 

LVEDD 

LVESD 

dp/dt 

MR grade 

Area of MR jet 

Physical exam: 

Blood pressure 

Heart rate 

Weight 

Other Comorbidities:  

Procedural Characteristics: Indicate the statistic, e.g., %, mean, SD, range, IQ, etc. AND 

the units

CRT group Placebo group All participants 

Drug therapy: 

ARB 

ACE 

BB 

spironolactone 

digoxin 

nitrates 

lipid lowering 

agent 

 

warfarin 

Device: 

Method of 

implantation: 

Other cointerventions: 
Appendix B: Sample Data Forms (continued) 

B-21 

Form B-6 Data extraction Safety review—continued 

Outcomes: These tables are by treatment group and by subgroup (if provided) 

Treatment group (e.g., CRT, Placebo, etc): 

Subgroup (e.g., NYHA Class, Ischemic, etc.): 

Risks of/during Implantation 

Time to death: 

 All-cause 

 Cardiac 

 CHF 

 Sudden cardiac death 

Number at risk Number of 

events 

Number censored 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

If other than n/N, e.g., events per person-months, indicate units 

Dichotomous 

outcomes: n/N

Baseline Timepoint Timepoint Timepoint 

Death 

Related to the device 

with battery 

 

Related to the left 

ventricular lead 

Related to the right 

ventricular lead 

Related to the right 

atrial lead 

Related to the system 

function 

Related to implant tools 

Procedure related – 

patient complaints 

Related to heart 

function 

Other 
Appendix B: Sample Data Forms (continued) 

B-22 

Form B-6 Data extraction Safety review—continued

Outcomes: These tables are by treatment group and by subgroup (if provided) 

Treatment group (e.g., CRT, placebo, etc. AND which period if it’s a crossover study): 

Subgroup (e.g., NYHA Class, ischemic, etc.): 

Risks Post-Implantation 

Time to death: 

 All-cause 

 Cardiac 

 CHF 

 Sudden cardiac death 

Number at risk Number of 

events 

Number censored 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

 Timepoint 

If other than n/N, e.g., events per person-months, indicate units 

Dichotomous 

outcomes: n/N

Baseline Timepoint Timepoint Timepoint 

Death 

 

 

CHF hospitalizations 

ED visits 

Worsening heart failure 

Unwanted post surgical 

sequalae (e.g., keloids, 

pocker infection, pain) 

Mechanical malfunction 

Lead dislodgement 

Arrhythmia’s caused by 

CRT 

Other 
Appendix B: Sample Data Forms (continued) 

B-23 

Form B-6 Data extraction Safety review—concluded

Outcomes: These tables are by treatment group and by subgroup (if provided) 

Treatment group (e.g., CRT, Placebo, etc. AND which period if it’s a crossover study): 

Subgroup (e.g., NYHA Class, Ischemic, etc.): 

Safe Indicators: If other than n/N, e.g., events per person-months, indicate units 

Dichotomous 

outcomes: n/N

Baseline Timepoint Timepoint Timepoint 

Successful implants 

Other 
Appendix C: Evidence Tables 

Table C-1. Inclusion criteria of randomized trials on CRT for CHF: Efficacy review 

Table C-2. Inclusion criteria of trials on CRT for CHF: Safety Review 
Appendix C: Evidence Tables 

C-1 

Table C-1. Inclusion criteria of randomized trials on CRT for CHF: Efficacy review 

Inclusion Criteria Ex

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Abraham 20021 

MIRACLE III or IV <=35% >=130 ms >=55 mm yes yes yes 

6MWT <=450 m; 

expected to remain 

stable 

Had a pa

had 

contraind

pacing; un

cardia

revascul

atrial ar

Auricchio 20022

PATH-CHF III or IV - >=120 ms - no no yes PR interval >=150 ms 

Primary 

disease 

tricuspid r

symptoms 

indica

pacem

cardiover

noncardia

limit exe

Bristow 20033 

COMPANION 

Scientific 

Presentation 

2003 

III or IV <=25% >=120 ms >=60 mm yes yes yes 

> 18 yr.; PR > 150ms; 

diuretic; 

spironolactone; 

digoxin; Hx 

hospitalization <12 mo. 

> 1 mo. prior to 

enrollment; OPT for 

CHF 

Meet indic

antibrady

atrial tachy

< 60 da

unstable 

prothes

transplant o

Cazeau 20014

MUSTIC-SR III <35% >150 ms >60 mm yes no yes diuretics 

Hyper

cardiom

valvulo

synd

revascul

scheduled 

obstructive 
Appendix C: Evidence Tables 

C-2 

Inclusion Criteria Ex

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Garrique 20025 III or IV < 40% > 140 ms >=60 mm yes yes no 

OPT for CHF; diuretics; 

chronic AF; HIS bundle 

ablation 

< 18 or > 8

mo. of s

angiop

Guidant 20026

CONTAK-CD 

FDA report 

II, III or IV <=35% >=120 ms - yes no yes 

Meet indications for 

ICD; diuretics and/or 

digoxin; >=18 yr. 

Meet indica

pacing; ref

require 

surger

Leclercq 20027

MUSTIC-AF III <35% >200 ms >60 mm yes no no 

diuretics; AF >3 mo.; 

requiring pacing (AV 

ablation or 

spontaneously); 6MWT 

<450 m 

Hyper

cardiom

valvulo

synd

revascul

scheduled 

obstructive 

Leclercq 2003 

RD-CHF

*

Unpublished 

III or IV <=35% >180 ms N/a N/a N/a N/a N/a 

Medtronic 20019

MIRACLE-ICD 

FDA report 

II, III or IV <=35% >=130 ms >=55 mm yes no no 

ICD indication; 

 =>18 yr.; previous MI; 

recurrent or sustained 

VT 

Unstable a

TIA o

indications 

against s

systolic B

>140bpm; 

upper li

valvular 

COPD; 
Appendix C: Evidence Tables 

C-3 

Inclusion Criteria Ex

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

ACEi = angiotensin converting enzyme inhibitors; AF = atrial fibrillation; BB = beta blockers; BP = blood pressure; CABG = coronary artery bypass 

heart failure; COPD = chronic obstructive lung disease; CVA = coronary vascular accident; FDA = Food and Drug Administration; HR = heart rate; H

implantable cardioverter-defibrillator; LVEDD = left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; MI = myocardial in

York Heart Association class; OPT= optimal pharmacological therapy; PTCA= percutaneous trans cardiac angioplasty; 6MWT= 6 min. walk test; n/a transient ischemic attack; VT = ventricular tachycardia. * detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared; information included in this report was obtained througwith the author
Appendix C: Evidence Tables 

C-2 

Reference List for Table C-1 

 1. Abraham WT. Cardiac resynchronization therapy for heart failure: Biventricular pacing and beyond. Curr O

17(4):346-352. 

 2. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac r

therapy in patients with heart failure and ventricular conduction delay (PATH CHF Trial). J Am Coll Cardi

2033. 

 3. Bristow M, et al. Comparison of medical therapy, pacing and defibrillation in heart failure (COMPANION 

the 52nd Annual Scientific Conference, American College of Cardiology, Chicago, Illinois, USA, March 3

 4. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failu

intraventricular conduction delay. (MUSTIC SR). N Engl J Med 2001; 344(12):873-880. 

 5. Garrigue S, Bordachar P, Reuter S, et al. Comparison of permanent left ventricular and biventricular pacing 

failure and chronic atrial fibrillation: prospective haemodynamic study. Heart 2002; 87(6):529-534. 

6. Guidant Corporation, Cardiac Rhythm Management. Summary of safety and effectiveness CONTAK-CD C

including CONTAK CD CRT-D pulse generator model 1823, and software application model 2848 (versio

P010012, 1-47. 2002. 

7. Leclercq C, Walker S, Linde C et al. Comparative effects of permanent biventricular and right-univentricula

failure patients with chronic atrial fibrillation. (MUSTIC AF). Eur Heart J 2002; 23:1780-1787. 

8. Leclercq C, Cazeau S, Lellouche D, et al. Upgrading from right-ventricular pacing to biventricular pacing in 

patients with advanced heart failure: a randomized controlled study (RD-CHF trial). [abstract] Presented at of Cardiology, Vienna, Austria, September 1st, 2003. 

 9. Medtronic Inc. Summary of safety and effectiveness: Insync ICD model 7272 dual chamber implantable ca

defibrillator with biventricular pacing for cardiac resynchronization, Attain models 2187, 2188, 4189 leadsTrial). [report] PMA P010031, 1-75. 12-3-2001. 
Appendix C: Evidence Tables 

C-2 

Table C-2. Inclusion criteria of studies included in the safety review on CRT for CHF 

Inclusion Criteria 

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Abraham 20021

MIRACLE III or IV <=35% >=130 ms >=55 mm yes yes yes 

6MWT <=450 m; 

expected to remain 

stable 

Had a pa

an indica

agains

angina; 

event, o

mo.; atr

Auricchio 20022

PATH-CHF III or IV >=120 ms no no yes PR interval >=150 ms 

Primar

disease (

regurgita

due to LV 

conv

implantab

other non

limit e

Bristow 20033

COMPANION 

Scientific 

Presentation 

2003 

III or IV <=25% >=120 ms >=60 mm yes yes yes 

> 18 yr.; PR > 150ms; 

diuretic; spironolactone; 

digoxin; Hx 

hospitalization <12 mo. 

> 1 mo. prior to 

enrollment; OPT for 

CHF 

Meet ind

antibrady

tachyarr

days; u

angina; 

expecte

e

Cazeau 19964 - - - - - - - 

End stage CHF who 

refused or not eligible 

for transplant all had Hx 

of HD >=10 yr. and >=1 

episode of pulmonary 

edema 

No specif
Appendix C: Evidence Tables 

C-3 

Table C-2. Inclusion criteria of studies included in the safety review on CRT for CHF – continued 

Inclusion Criteria 

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Cazeau 20015

MUSTIC-SR III <35% >150 ms >60 mm yes no yes diuretics 

Hyp

cardi

valvu

sy

revasc

schedule

obstructiv

Filho 20026 III or IV < 30% - - - - - 

> 18 yr.; irreversible 

cause of 

cardiomyopathy; 

maximum medical 

therapy; clinically stable 

x 2 weeks; LBBB. 

2nd or 3r

myocardit

Gras 20027

INSYNC 

Italian Registry III or IV <=35 >150ms >60mm no no - Refractory to medical therapy X 1 month 

18 yr.; ha

pacing; u

3mo; perm

oth

Guidant8

CONTAK-CD 

FDA report 2002 

II, III or IV <=35% >=120 ms - yes no yes 

Meet indications for 

ICD; diuretics and/or 

digoxin; >=18 yr. 

Meet ind

pacing; r

require c

not su

Krahn 20029 >=II - >=130 ms - yes yes - 

HF stable x 1 mo. on best medical therapy 

unless intolerant, 

diuretics 

HF caus

unable to 

Kuhlkamp 200210 - <=35 >130 ms >55 mm no no - 

Symptomatic sustained 

ventricular tachycardia 

and/or survival of 

cardiac arrest; 

symptomatic HF despite 

appropriate therapy 
Appendix C: Evidence Tables 

C-4 

Table C-2. Inclusion criteria of studies included in the safety review on CRT for CHF – continued

Inclusion Criteria 

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Leclercq 200211

MUSTIC-AF III <35% >200 ms >60 mm yes no no 

Diuretics; AF >3 mo.; 

requiring pacing (AV 

ablation or 

spontaneously); 6MWT 

<450 m 

Hyp

cardi

valvu

sy

revasc

schedule

obstructiv

Leclercq 200012 III or IV <=35 >=120 ms >=60 mm yes no - Drug refractory CHF; optimal medical therapy; 

diuretics 

Susp

correcta

corona

revascula

Leclercq13

unpublished III or IV <=35% 

>120 ms 

(first 16 pts), 

then 

changed to 

150 ms 

>=60mm - - - - 

Suspic

patients w

revascula

past 12 

"acciden

who c

Leclercq 2003* 

RD-CHF

Unpublished 

III or IV <=35% >180 ms N/a N/a N/a 48 N/a 

Leon 200214 III or IV <=35 - - - - - 

Chronic AF; AV ablation 

and RV pacing >=6 mo.; 

symptoms refractory to 

standard medical care 
Appendix C: Evidence Tables 

C-5 

Table C-2. Inclusion criteria of studies included in the safety review on CRT for CHF – concluded

Inclusion Criteria 

Trial name NYHA class LVEF QRS LVEDD Meds 

required 

Sinus 

rhythm 

(%) 

Other 

ACEi BB 

Medtronic 200115

MIRACLE-ICD 

FDA report 

II, III or IV <=35% >=130 ms >=55 mm yes no no 

ICD indication; 

 =>18 yr.; previous MI; 

recurrent or sustained 

VT 

Unstable 

TIA or CV

for or 

standard 

<80 or 

hepatic fu

normal; p

heart valv

Molhoek 20026 III or IV <=35 >=120 ms or > 200 - - - - LBBB 

ACEi = angiotensin converting enzyme inhibitors; AF = atrial fibrillation; BB =- beta blockers; BP= blood pressure; CABG = coronary artery bypass 

heart failure; COPD = chronic obstructive lung disease; CVA = coronary vascular accident; FDA = Food and Drug Administration; f/u = followup; HD

rate; HX = history; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LVEDD = left ventricular end diastolic diameter; 

ejection fraction; MI = myocardial infarction; N/a = not available; NYHA = New York Heart Association class; OPT = optimal pharmacological thera

cardiac angioplasty; 6MWT = 6 min. walk test; TIA = transient ischemic attack; VT = ventricular tachycardia. * detailed data not available for Leclercq 2003 (RD-CHF) at the time this report was prepared; information included in this report was obtained througwith the author 
Appendix C: Evidence Tables 

C-6 

Reference List for Table C-2 

 1. Abraham WT. Cardiac resynchronization therapy for heart failure: Biventricular pacing and beyond. Curr 

17(4):346-352. 

 2. Auricchio A, Stellbrink C, Sack S et al. Long-term clinical effect of hemodynamically optimized cardiac 

therapy in patients with heart failure and ventricular conduction delay (PATH CHF Trial). J Am Coll Car

39(12):2026-2033. 

 3. Comparison of medical therapy, pacing and defibrillation in heart failure (COMPANION Trial). Presente

Scientific Conference, American College of Cardiology, Chicago, illinois, USA, March 31st: 2003. 

 4. Cazeau S, Ritter P, Lazarus A et al. Multisite pacing for end-stage heart failure: early experience. PACE  5. Cazeau S, Leclercq C, Lavergne T et al. Effects of multisite biventricular pacing in patients with heart fai

intraventricular conduction delay. (MUSTIC SR). N Engl J Med 2001; 344(12):873-880. 

 6. Filho M.M., Pedrosa AA, Costa R et al. Biventricular pacing improves clinical behavior and reduces prev

arrhythmia in patients with heart failure. Arq Bras Cardiol 2002; 78(1):110-113. 

 7. Gras D, Leclercq C, Tang AS et al. Cardiac resynchronization therapy in advanced heart failure the multi

study. Eur J Heart Fail 2002; 4(3):311-320. 

 8. Guidant Corporation, Cardiac Rhythm Management. Summary of safety and effectiveness CONTAK-CD 

including CONTAK CD CRT-D pulse generator model 1823, and software application model 2848 (versPMA P010012, 1-47. 2002. 

 9. Krahn AD, Snell L, Yee R et al. Biventricular pacing improves quality of life and exercise tolerance in pa

failure and intraventricular conduction delay. Can J Cardiol 2002; 18(4):380-387. 

 10. Kuhlkamp V. Initial experience with an implantable cardioverter-defibrillator incorporating cardiac resyn

J Am Coll Cardiol 2003; 39(5):790-797. 
Appendix C: Evidence Tables 

C-7 

 11. Leclercq C, Walker S, Linde C et al. Comparative effects of permanent biventricular and right-univentric

failure patients with chronic atrial fibrillation. (MUSTIC AF). Eur Heart J 2002; 23:1780-1787. 

 12. Leclercq C, Victor F, Alonso C et al. Comparative effects of permanent biventricular pacing for refractor

patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol 2000; 85(9):1154-1156. 

13. Leclercq C, Alonso F, d'Allones FR, Boulmier D, de Place C, Carre F et al. [Effets à moyen terme de la st

biventriculaire dans l'insuffisance cardiaque sévère]. Unpublished Work 

 14. Leclercq C, Cazeau S, Lellouche D, et al. Upgrading from right-ventricular pacing to biventricular pacing 

patients with advanced heart failure: a randomized controlled study (RD-CHF trial). [abstract] Presented 

Society of Cardiology, Vienna, Austria, September 1st, 2003. 

 15. Leon AR, Greenberg JM, Baker CM et al. Cardiac resynchronization in patients with congestive heart fai

fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll C39(8):1258-1263. 

 16. Medtronic Inc. Summary of safety and effectiveness: Insync ICD model 7272 dual chamber implantable 

defibrillator with biventricular pacing for cardiac resynchronization, Attain models 2187, 2188, 4189 leadTrial). [Report] PMA P010031, 1-75. 12-3-2001. 

 17. Molhoek SG, Bax JJ, Van Erven L et al. Effectiveness of resynchronization therapy in patients with end-

Am J Cardiol 2002; 90(4):379-383. 
Appendix D: Technical Experts and Peer Reviewers 

D-1 

Technical Experts and Peer Reviewers 

Technical Experts 

William Abraham 

 The Ohio State University, Columbus, OH 

Justin Ezekowitz 

 University of Alberta, Edmonton, AB 

Padma Kaul 

 University of Alberta, Edmonton, AB 

Terry Klassen 

 University of Alberta, Edmonton, AB 

Finlay McAlister 

 University of Alberta, Edmonton, AB 

Graham Nichol 

 Ottawa Health Research Institute, University of Ottawa, Ottawa, ON 

Gerald Peden 

 Independent Blue Cross 

Brian Rowe 

 University of Alberta, Edmonton, AB 

Peer Reviewers 

Donald Casey 

 Catholic Healthcare Partners, Cincinnati, OH 

Robert Kowal 

 UT Southwestern Medical Center, Dallas, TX 

Robert Rea 

 Mayo Clinic, Rochester, MN 

Bruce Wilkoff 

 The Cleveland Clinic Foundation, Cleveland, OH 

Clyde Yancy 

 St. Paul University Hospital / UT Southwestern Medical Center, Dallas, TX