PBM-MAP Clinical Practice Guideline
for the Pharmacologic Management ofChronic Heart Failure
in Primary Care PracticePharmacy Benefits Management
Strategic Healthcare Group andMedical Advisory Panel
Veterans Health Administration
Department of Veterans Affairs
Publication No. 00-0015
September 2007

Version: Final
Updates may be found at www.pbm.va.gov or http://vaww.pbm.va.gov

VHA PBM-MAP Clinical Practice Guideline: Pharmacologic Management of HF

EXECUTIVE SUMMARY
1.

Treatment of chronic heart failure (HF) is based upon the four-stage classification system developed by theAmerican College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines:
Stage A includes patients who are at high risk for developing HF, but do not have structural heart disease; Stage
B are patients who do have structural damage to the heart, but have not developed symptoms; Stage C refers topatients with past or current HF symptoms and evidence of structural heart damage; and Stage D includes
patients with end-stage disease, requiring special interventions. It is the intent of the ACC/AHA
recommendations to be used in conjunction with the New York Heart Association (NYHA) functionalclassification that estimates the severity of disease based on patient symptoms.

2.

Goals of therapy for HF include improving symptoms, increasing functional capacity, improving quality of life,
slowing disease progression, decreasing need for hospitalization, and prolonging survival.

3.

Nonpharmacologic therapy includes abstaining from alcohol and tobacco, limiting dietary sodium, reducing
weight if appropriate, exercising regularly, and influenza and pneumococcal vaccinations. Other
nonpharmacologic therapies such as automatic implantable defibrillators or cardiac resynchronication therapy
should be considered in appropriate patients but are beyond the scope of this document.

4.

Risk factor modification and treatment of concomitant cardiac conditions and underlying causes should be
implemented in patients in Stage A to potentially reduce the development of HF.

5.

In addition to risk factor modification, patients in Stage B should receive post-myocardial infarction (MI)treatment with an angiotensin-converting enzyme inhibitor (ACEI) and beta-adrenergic blocker, regardless ofthe presence of left ventricular systolic dysfunction, to prevent future development of HF and improve overall
survival (Grade A Recommendation, Good Overall Quality of Evidence). It is also recommended that patientswith evidence of left ventricular systolic dysfunction who are without symptoms should be treated with an
ACEI (Grade A Recommendation, Good Overall Quality of Evidence) and beta-adrenergic blocker (Grade B
Recommendation, Fair Overall Quality of Evidence). An angiotensin II receptor antagonist may be prescribedin patients with a history of MI who have a reduced left ventricular ejection fraction without symptoms of HF if
they are ACEI intolerant (Grade A Recommendation, Good Overall Quality of Evidence).

6.

Patients with HF in Stage C should also be educated on risk factor modification. Pharmacotherapy
recommendations for these patients include:
•
•

•

•

A diuretic should be used in the treatment of patients with signs of fluid overload (Grade B
Recommendation, Fair Overall Quality of Evidence).
All patients should be treated with an ACEI unless contraindicated or not tolerated (Grade A
Recommendation, Good Overall Quality of Evidence). These agents improve HF symptoms, functional
status, and quality of life, while decreasing frequency of hospitalization and mortality. An angiotensin II
receptor antagonist may be considered as an alternative to an ACEI (in patients who are on standard
therapy for HF) and are unable to tolerate an ACEI (Grade A Recommendation, Good Overall Quality of
Evidence).
A beta-adrenergic blocker that has proven to reduce mortality (i.e., bisoprolol, carvedilol, sustained release
metoprolol succinate) should be used in conjunction with an ACEI in all patients who are considered stable(i.e., minimal or no signs of fluid overload or volume depletion and not in an intensive care unit), unlesscontraindicated or not tolerated. These agents have been shown to reduce mortality and decrease thesymptoms of HF (Grade A Recommendation, Good Overall Quality of Evidence).
Low dose of an aldosterone antagonist should be considered in patients with recent New York Heart
Association (NYHA) Class IV HF and current Class III or IV symptoms and left ventricular ejection
fraction (LVEF) < 35%, provided the patient has preserved renal function and normal potassium levels.
This therapy improves symptoms (as assessed by change in NYHA functional class), decreases
hospitalizations for worsening HF, and decreases mortality (Grade A Recommendation, Good Overall
Quality of Evidence). An aldosterone antagonist may also be considered in patients with LVEF < 40% inpatients early post-MI on standard therapy for HF.

ii

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

VHA PBM-MAP Clinical Practice Guideline: Pharmacologic Management of HF

•

•

•

•

7.

The combination of hydralazine and a nitrate should be considered, especially in African American patientswith NYHA Class III or IV HF, who continue to have symptoms despite therapy with an ACEI and betaadrenergic blocker (Grade B Recommendation, Good Overall Quality of Evidence). The combination of
hydralazine and a nitrate may be considered as an alternative to an ACEI in patients who are unable totolerate an ACEI (or angiotensin II receptor antagonist) due to hypotension, renal insufficiency,
hyperkalemia, or possibly, angioedema (Grade C Recommendation, Fair Overall Quality of Evidence).
Addition of an angiotensin II receptor antagonist to standard therapy (i.e., an ACEI and beta-adrenergic
blocker) in patients with systolic HF may be considered to decrease cardiovascular death or HF
hospitalizations (Grade B Recommendation, Fair Overall Quality of Evidence); although routine use of anangiotensin II receptor antagonist, ACEI, and aldosterone antagonist is not recommended.
Digoxin can be used in patients whose symptoms persist despite treatment with an ACEI (or an angiotensin
II receptor antagonist if an ACEI is not tolerated), a beta-blocker, and a diuretic. Digoxin reduces
symptoms associated with HF and decreases the risk for hospitalizations due to HF but does not improvemortality (Grade B Recommendation, Fair Overall Quality of Evidence).
Patients should receive regular follow-up in order to provide the most effective care. At each encounter, aninquiry should be made as to the patient's adherence to the medication regimen, nonpharmacologic
measures, and adverse effects to therapy. Patients should be scheduled for routine laboratory monitoring.
The patient should also be assessed for any change in functional status or frequency of hospitalizations, andmedication therapy should be optimized.

Patients with HF in Stage D may require special treatment interventions including mechanical circulatory
support, continuous therapy with positive inotropic agents, consideration for cardiac transplantation, or hospicecare. In patients where therapeutic interventions may no longer be appropriate, discussions regarding end-oflife care should be considered. Specific recommendations are beyond the scope of this document, and thesepatients should be referred to a HF management program that includes experts on the management of patientswith refractory HF.

iii

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

VHA PBM-MAP Clinical Practice Guideline: The Pharmacologic Management of HF

The Medical Advisory Panel for the
Pharmacy Benefits Management Strategic Healthcare Group
MissionThe mission of the Medical Advisory Panel (MAP) for Pharmacy Benefits Management (PBM) includes thedevelopment of evidence-based pharmacologic management guidelines for improving quality and providing bestvalue patient care.
The MAP comprises practicing VA physicians from facilities across the nation:Thomas Craig, MD
Chief Quality and Performance Officer
Office of Quality and Performance Management
Department of Veterans Affairs
Washington DC

Matthew Goetz, MD
Chief, Infectious Diseases
West Los Angeles VAMC
VA Greater Los Angeles HCS
Professor of Clinical Medicine
David Geffen School of Medicine at UCLA

Gregory W. Dalack, MD
Staff Psychiatrist
VA Ann Arbor Healthcare System
Vice Chair and Associate Chair for Education andAcademic Affairs
Department of Psychiatry
University of Michigan

Chester B. Good, MD, MPH, FACP
Chairman, Medical Advisory Panel
Staff Physician, Department of Medicine
VA Pittsburgh HCS
Associate Professor of Medicine
University of Pittsburgh
Robert C. Goodhope, MD, MBA
Chief Medical Officer
VA Outpatient Clinic
Tallahassee, FL

Sylvain DeLisle, MD, MBA
Associate Chief of Staff, Performance Improvement
VA Maryland HCS
Associate Professor of Medicine & Physiology
University of Maryland, School of Medicine

Robert J. Hariman, MD
Director, Cardiac Electrophysiology
Hines VA Hospital
Professor of Medicine
Loyola University School of Medicine

Thomas H. Dickinson, MD
Co-Service Line Manager, Primary Care
Brockton Division, VA Boston HCS
Clinical Instructor in Medicine
Harvard Medical School

William Korchik, MD
Medical Director, Extended Care Center
VAMC Minneapolis
Assistant Professor of Medicine
University of Minnesota

John R. Downs, MD, FACP
Ambulatory Care
AMLD, South Texas Veterans HCS
Associate Professor of Medicine
University of Texas Health Science Center
Col, USAF (retired)

Alexander M. Shepherd, MD, PhD, FAHA
Professor and Chief, Division of Clinical Pharmacology
Departments of Medicine and Pharmacology
University of Texas Health Science Center at
San Antonio

Peter A. Glassman, MBBS, MSc
Staff Physician
West Los Angeles VAMC
VA Greater Los Angeles HCS
Associate Professor
University of California, Los Angeles (UCLA)

iv

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

VHA PBM-MAP Clinical Practice Guideline: The Pharmacologic Management of HF

Pharmacy Benefits Management (PBM)
Strategic Healthcare Group (SHG)
VHA's PBM-SHG has been directed by the Under Secretary for Health to coordinate the development ofrecommendations for the pharmacologic management of common diseases treated within the VA, establish anational level VA formulary, and to manage pharmaceutical costs, utilization, and measure outcomes as they apply
to patient care. The MAP provides support and direction to the PBM staff, located in Hines, Illinois.

Michael Valentino, RPh, MHSA
Chief Consultant, PBM-SHG

Janet Dailey, PharmD
Clinical Pharmacy Specialist

Virginia S. Torrise, PharmD
Deputy Chief Consultant, PBM-SHG

Elaine Furmaga, PharmD
Clinical Pharmacy Specialist

Joseph Canzolino, RPh
Associate Chief Consultant, PBM-SHG

Mark Geraci, PharmD, BCOP
Clinical Pharmacy Specialist

Vincent Calabrese, PharmD
Assistant Chief Consultant, PBM-SHG

Francine Goodman, PharmD, BCPS
Clinical Pharmacy Specialist

Fran Cunningham, PharmD
Director, Center for Medication Safety PSCI and
Program Manager Pharmacoepidemiologic/
Outcomes Research

Cathy Kelley, PharmD
Clinical Pharmacy Specialist
Deborah Khachikian, PharmD
Clinical Pharmacy Specialist

Muriel Burk, PharmD
Clinical Pharmacy Specialist, Pharmacoepidemiologic
and Outcomes Research

Lisa Longo, PharmD, BCPS
Clinical Pharmacy Specialist
Todd Semla, PharmD, BCPS
Clinical Pharmacy Specialist

Marie Sales, PharmD
Clinical Pharmacy Specialist, Pharmacoepidemiologic
and Outcomes Research

Kathy Tortorice, PharmD, BCPS
Clinical Pharmacy Specialist

Suzanne Lenz, RPh
Pharmacist Specialist/Contract Liaison
Lucy Szudarski
Program Specialist
Lisa Torphy
Program Specialistv

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Acknowledgements
This document was developed in consultation with members of the PBM-MAP and subject matter experts
in cardiology. A draft was then forwarded to the field through the VISN Formulary Leaders for peer
review. The final version was forwarded to the Director of Performance Management and the National
Advisory Council for the Adoption, Development and Implementation of Clinical Practice Guidelines forapproval. The following clinicians provided comments on drafts of this report. The final document
incorporates reviewers’ comments; however, the PBM-SHG takes full responsibility for the content of thisguideline.
Alan Cohen, MD, FACP
Chief of Primary Care,
VA Central California Healthcare System
Gregg C. Fonarow, MD
Member, VA CHF QUERI Executive Committee
Professor of Cardiovascular Medicine and Science,David Geffen School of Medicine at UCLACharles Hoesch, MD
Medical Director, Perry Point VAMC
VA Maryland Healthcare System
David Parra, PharmD, BCPS
Clinical Pharmacy Specialist in Cardiology,
West Palm Beach VAMC
Clinical Assistant Professor,
Department of Experimental and Clinical Pharmacology
University of Minnesota College of Pharmacy
Eugene S. Smith, III, MD
Acting Chief of Cardiology,
Central ArkansasVeterans Healthcare System
Associate Professor of Medicine, Division of Cardiology
University of Arkansas for Medical Sciences________________________________________________________________________________________________* This list does not represent all the clinicians who reviewed the document, only those who agreed to be acknowledged.
Reviewers of prior versions have been previously acknowledged.

TABLE OF CONTENTS

vi

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

EXECUTIVE SUMMARY………………………………………………………………………….. ……….. ii
ABBREVIATIONS…………………………………………………………………………………………viii
INTRODUCTION…………………………………………………………………………………………….. 1
TREATMENT ALGORITHM………………………………………………………………………. ……….. 6
ANNOTATIONS………………………………………………………….…….…………………… .……. 8
A.

Diagnose and Evaluate a Patient at Risk for or Suspected of Having Heart Failure (HF) ........................ 9

B.

Management of Concomitant Cardiac Conditions and Risk Factors, Nonpharmacologic
Interventions, and Treatment of Underlying Causes .............................................................................. 12

C.

Pharmacologic Management of HF with Preserved Left Ventricular Ejection Fraction......................... 15

D.

Interventions in Patients With Asymptomatic Left Ventricular Systolic Dysfunction ........................... 17

E.

Systolic Dysfunction and Assessment for Symptoms of Volume Overload ........................................... 19

F.

Diuretic Therapy ..................................................................................................................................... 20

G.

Angiotensin-Converting Enzyme Inhibitors ........................................................................................... 21

H.

Beta-Adrenergic Blockers ....................................................................................................................... 24

I.

Angiotensin II Receptor Antagonists ...................................................................................................... 27

J.

Hydralazine in Combination with a Nitrate ............................................................................................ 31

K.

Digitalis................................................................................................................................................... 32

L.

Aldosterone Antagonists ......................................................................................................................... 34

M.

Continue Present Management and Schedule Regular Follow-up...................................................... 36

REFERENCES………………………………………………………………………………………… ……38
TABLES
Table 1. Quality of Evidence……..…………………………………………………………………………… 3
Table 2. Overall Quality………………………………………………………………………………………. 3
Table 3. Net Effect of Intervention.…………………………………………………………………………… 3
Table 4. Strength of Recommendation.……………………………………………………………………….. 4
Table 5. Grade for Strength of Recommendation …………………………………………………………….. 4
Table 6. ACC/AHA Class of Recommendation………………………………………………………………. 4
Table 7. ACC/AHA Level of Evidence……………………………………………………………………….. 4
Table 8. ACC/AHA Guidelines for the Evaluation and Management of HF…………………………………. 11
Table 9. NYHA Functional Classification and Objective Assessment of HF..……………………………….. 12
FIGURE
Figure. VA Utilization of Medications for HF by Drug Class ……………….……..………………………..50
APPENDICES
Appendix A. Medications Commonly Used in the Management of Heart Failure………………………….. 51
Appendix B. Common Drug Interactions with Agents Used in Heart Failure……..………………………... 53
Appendix C: Long-term, Randomized, Controlled, Outcome Trials in Systolic HF by Drug Class…………. 56

vii

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

ABBREVIATIONSAIIRA (also ARB)

Angiotensin II receptor antagonist (also referred to as angiotensin receptor blocker)

ACC/AHA

American College of Cardiology/American Heart Association

ACEI

Angiotensin-converting enzyme inhibitor

ARR

Absolute risk reduction

AV

Atrioventricular

BNP

Brain natriuretic peptide

BPH

Benign prostatic hyperplasia

BUN

Blood urea nitrogen

CCB

Calcium channel blockerCI

95% confidence interval

Cr

Creatinine

CrCl

Creatinine clearanceDM

Diabetes mellitus

DOE

Dyspnea on exertion

HCTZ

Hydrochlorothiazide

HF

Heart failure

HFSA

Heart Failure Society of America

HTN

Hypertension

INR

International normalization ratio

ISDN

Isosorbide dinitrate

JVD

Jugular venous distention+

K

Potassium

LV

Left ventricular

LVEF

Left ventricular ejection fraction

LVEDP

Left ventricular end diastolic pressure

LVH

Left ventricular hypertrophy

MI

Myocardial infarction

NNT

Number needed to treat

NSAID

Non-steroidal anti-inflammatory drug

NYHA

New York Heart Association

PND

Paroxysmal nocturnal dyspnea

RR

Relative riskSNS

Sympathetic nervous system

SOB

Shortness of breath

TSH

Thyroid-stimulating hormone (thyrotropin)

TZD

Thiazolidinedione

viii

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

ii

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

INTRODUCTION

1

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

THE PHARMACOLOGIC MANAGEMENT OF CHRONIC HEART FAILURE
Approximately 5 million patients in the United States have heart failure (HF), with 550,000 new cases
diagnosed each year.1,2 The prevalence of HF increases with age, with nearly 5% of patients seen at
Veterans Affairs (VA) Medical Centers having a primary diagnosis of HF. According to a recent reportfrom the American Heart Association, 80% of men and 70% of women with a diagnosis of HF who are lessthan 65 years of age will die within 8 years. In addition, the one year mortality rate was reported as 20%.2
Hospitalizations for HF have increased,1,2 accounting for 6.5 million hospital days annually.1 Heart
failure was also reported to be the main reason for 12 to 15 million clinic visits each year.1 The VA
provides care for approximately 240,000 veterans with HF, with over 42,000 of these patients being
hospitalized during Fiscal Year (FY) 2005 with a primary diagnosis of HF. It has been estimated that thecost for HF in 2006 is $29.6 billion in the United States alone.1
The pharmacologic treatment of HF has advanced significantly over the years, with clinical researchestablishing the benefit of drug therapy in preventing morbidity and mortality in patients with thiscondition.1 The clinical outcomes and resulting economic benefits of drug therapy have also been
documented in the clinical practice setting.3 With HF being such a prevalent disease, especially among theolder patient population, and with it a high rate of morbidity and mortality, it is prudent that evidence-based
therapy and associated clinical practice guidelines be utilized to improve patient outcomes.4,5
Since the beginning of fiscal year (FY) 2003, the VA Office of Quality and Performance has implemented
performance measures evaluating the treatment of HF with the angiotensin-converting enzyme inhibitors(ACEIs), including data on the angiotensin II receptor antagonists as part of the measure in FY2005. Afterannual chart review of approximately 3,000 veterans, the External Peer Review Program reported thatnearly 90% of these veterans with HF were prescribed an ACEI or angiotensin II receptor antagonist (refer
to http://vaww.pdw.med.va.gov/pdwframe.asp for details on the indicators and updated results).
Utilization of beta-adrenergic blockers and renin-angiotensin-aldosterone inhibitors have continued toincrease in veteran patients with HF (refer to the Figure); although use of these drug classes in combinationis less than optimal. Continued efforts to optimize evidence-based therapy should be encouraged.
These clinical practice guidelines for the management of patients with HF focus on the pharmacologic
treatment of the disease. The clinician is referred to the American College of Cardiology/American Heart
Association (ACC/AHA) Guideline Update for the Diagnosis and Management of Chronic Heart Failure in
the Adult1 and other medical literature and cardiology experts for the overall management of patients with
HF.

SummaryThis consensus and evidence-based document on the pharmacologic management of patients with chronic
HF is intended to update the August 2003 publication of the PBM-MAP The Pharmacologic Managementof Chronic Heart Failure. Whenever possible, the PBM and MAP rely upon evidence-based,
multidisciplinary, nationally recognized consensus statements for the basis of VA guidance. Relevant
literature is reviewed and assessed with consideration given to the VA population. Draft documents aresent to the field for comments prior to being finalized.

Development Process and Sources of Information
Development of the recommendations included reference to the following consensus document: Hunt SA,
Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management ofchronic heart failure in the adult: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the
Evaluation and Management of Heart Failure). American College of Cardiology Web site. Available at:
http://www.acc.org/clinical/guidelines/failure/index.pdf.
2

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

To update the August 2003 PBM-MAP guideline “The Pharmacologic Management of Chronic Heart
Failure”, a literature search of the National Library of Medicine’s MEDLINE/PubMed database andEvidence Based Medicine reviews available on OVID was conducted. Preference was given to randomized
controlled trials, meta-analyses, and systematic reviews. The following search terms were used: heart
failure, angiotensin-converting enzyme inhibitor, beta-adrenergic blocker, digoxin, spironolactone,angiotensin receptor blocker, aldosterone antagonist, hydralazine, isosorbide dinitrate, diastolic
dysfunction, clinical trial, review, meta-analysis. The literature was limited to adult human subjects andarticles published in the English language. The bibliographies of articles and consensus documents werereviewed for additional relevant literature. In updating the December 2006 document, 208 abstracts and
144 articles were reviewed. One hundred thirty-seven articles were added to the update of the 2006
document, 49 of which were randomized controlled trials. In addition to randomized controlled trials ofpatients with a diagnosis of chronic HF, the references added to the annotations discussing
recommendations for specific pharmacologic classes or HF in general included 67 pertinent subgroup or
retrospective evaluations, 9 meta-analyses or systematic reviews of controlled trials relevant to therecommendations in the document, 5 case reports and 7 review articles, some that provided acomprehensive inclusion of information and others that discussed patient care considerations not addressedby clinical trials. Literature known to the PBM-MAP on medical history, physical examination, diagnosis
and evaluation, consensus statements and clinical practice guidelines were also included in the document.
Major changes to the 2006 update include addition of pertinent medical evidence published since the last
iteration of the document including data with the angiotensin II receptor antagonists, isosorbide dinitrateand hydralazine, the aldosterone antagonists, and a comparison of an ACEI versus a beta-adrenergic
blocker as initial therapy. The treatment algorithm has been revised to reflect the recommended place intherapy of these drug classes based on this information. The document has been reformatted as per other
VA/DoD clinical practice guidelines. In addition, relevant data from long-term outcome trials in patientswith chronic HF due to systolic dysfunction have been compiled in the Appendix.

Methods to Formulate Recommendations
The literature was critically analyzed and evidence was graded using a standardized format. The evidence
rating system for this document is based on the system used by the U.S. Preventative Services Task Forceand also references the grading system used in the ACC/AHA Practice Guidelines for the Evaluation andManagement of HF. The rating scale of the U.S. Preventive Services Task Force is summarized in Tables 1
to 5.6
Table 1
I
II-1
II-2
II-3
III

Quality of Evidence (QE)
Evidence obtained from at least one properly randomized controlled trial
Evidence obtained from well-designed controlled trials without randomization
Evidence obtained from well-designed cohort or case-control analytic studies
Evidence obtained from multiple time series studies; dramatic results in uncontrolled experiments
Opinions of respected authorities; descriptive studies and case reports; reports of expert committees

Table 2
I
Good
II
Fair
III

Poor

Table 3
Substantial
Moderate
Small
Zero or
Negative

Overall Quality (OQ)High grade evidence (I or II-1) directly linked to health outcome
High grade evidence (I or II-1) linked to intermediate outcome orModerate grade evidence (II-2 or II-3) directly linked to health outcome
Level III evidence or no linkage of evidence to health outcome
Net Effect of Intervention
More than a small relative impact on a frequent condition with a substantial burden of suffering, orA large impact on an infrequent condition with a significant impact on the individual patient level
A small relative impact on a frequent condition with a substantial burden of suffering, orA moderate impact on an infrequent condition with a significant impact on the individual patient level
A negligible relative impact on a frequent condition with a substantial burden of suffering, orA small impact on an infrequent condition with a significant impact on the individual patient level
Negative impact on patients, orNo relative impact on either a frequent condition with a substantial burden of suffering, orAn infrequent condition with a significant impact on the individual patient level3

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Table 4A
B
C
D
I
Table 5Overall
Quality of
Evidence
I
II
III

Strength of Recommendation
A strong recommendation that the intervention is always indicated and acceptable
A recommendation that the intervention may be useful/effective
A recommendation that the intervention be considered
A recommendation that an intervention may be considered not useful/effective, or may be harmful
Insufficient evidence to recommend for or against; clinical judgment should be used
Grade for Strength of Recommendation
Net benefit of intervention
Substantial
A
B
I

Moderate
B
B
I

Small
C
C
I

Zero or Negative
D
D
D

The evidence rating system used in the ACC/AHA Practice Guidelines on the Evaluation and Managementof HF are included below.1 As this is used by ACC/AHA guidelines, this format will also be included in
the recommendations in the text to assist in the application of the recommendations to clinical practice.
Table 6
Class
I
II
IIa
IIb
III

Table 7A
B
C

ACC/AHA Class of Recommendation
Recommendation
Conditions for which there is evidence and/or general agreement that a given procedure/therapy is usefuland effective
Conditions for which there is conflicting evidence and/or a divergence of opinion about usefulness/efficacy
of performing the procedure/therapy
Weight of evidence/opinion is in favor of usefulness/efficacy
Usefulness/efficacy is less well established by evidence/opinion
Conditions for which there is evidence and/or general agreement that a procedure/therapy is notuseful/effective and in some cases may be harmful
ACC/AHA Level of Evidence
Data is derived from multiple randomized clinical trials or meta-analyses
Data is derived from a single randomized trial or nonrandomized studies
Consensus opinion of experts is the primary source of recommendation

Recommendations were based on evidence published in the medical literature. Critical literature review
focused on pharmacologic management of HF. The annotations that include discussion on medical history,
physical examination, diagnosis and evaluation, nonpharmacologic intervention, management ofconcomitant cardiac conditions, and treatment of underlying causes were based on consensus and did notundergo critical literature review. Where evidence was not available, expert opinion of the MAP andcardiology expert reviewers were used. After review and discussion by the PBM-MAP, the draft guideline
was sent to experts in the field of Cardiology for review. After the Cardiologist reviewers’ comments wereconsidered and incorporated into the document where appropriate, the draft was then circulated topracticing clinicians (primarily cardiologists and primary care providers) for input on clarity andapplicability.

Use of the Document
The document is divided into four sections: Executive Summary, Algorithm, Annotations, and Appendices.
The algorithm is intended to provide a systematic approach to the pharmacologic management of patientswith HF. The letters within the boxes in the algorithm refer to the corresponding annotation. The
annotation is further discussion of the evidence for making each recommendation. Details on drug therapy
are provided to encourage the safe and effective implementation of the pharmacotherapy recommendations
made in this guideline. Recommendations discussed in the annotations on pharmacotherapy are referenced
and graded according to the grading system outlined above. The appendices provide additional information
for the clinician when considering treatment options.
The recommendations are meant to focus on the pharmacologic management of patients with HF. Other
sections have been included that highlight areas such as physical examination, diagnosis,
4

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

nonpharmacologic management, etc. Practitioners should refer to comprehensive clinical practiceguideline on HF, cardiology texts or local experts for the finer points of diagnosis and these other areas.
The purpose of the recommendations is to assist practitioners in clinical decision-making, to standardize
and improve the quality of patient care, and to promote cost-effective drug prescribing. This documentattempts to define principles of practice that should produce high quality patient care. They are attuned to
the needs of a primary care practice but are directed to providers at all levels. Care of patients with HF
may occur in several clinical settings including primary care, cardiology, or by multidisciplinary HF
treatment teams. Regardless of the setting in which patients with HF are cared for, the clinician is
encouraged to follow these and other HF guidelines and to use clinical judgment of when to refer to a
specialist. This will depend on the skill and experience of managing patients with HF, and also theresources available to the practitioner. The recommendations also serve as a basis for monitoring local,
regional and national patterns of pharmacologic care.
The recommendations in this document should not be considered inclusive of all proper methods of care or
exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate
judgment regarding the propriety of any course of conduct must be made by the clinician in light ofindividual patient situations.

Plan for Implementation
The document will be available on the PBM home page at www.pbm.va.gov or http://vaww.pbm.va.gov aswell as the VA Office of Quality and Performance at www.oqp.med.va.gov. It is recommended that a hard
copy be kept on file in the medical libraries. Distribution to all clinicians who manage patients with HF isstrongly recommended. Clinicians are encouraged to have a copy of the document or a summary of key
points available for reference when treating patients with HF.
Continuing education programs will be developed.
Departmental and individual education at the facility is also encouraged.

Referencing the Document
This document should be referenced as follows:
The Pharmacologic Management of Chronic Heart Failure. Washington, DC: Pharmacy Benefits
Management Strategic Healthcare Group and the Medical Advisory Panel, Veterans Health Administration,
Department of Veterans Affairs. September 2007 Update. PBM-MAP Publication No. 00-0015.

Updating the Guideline
The PBM will review the guideline routinely. Updating will occur as new information is made available
from well-designed, scientifically valid studies and as outcome data may direct. Any member of the VA
community is encouraged to recommend changes based on such evidence.
A current copy of the pharmacologic management guideline can be obtained from the PBM home page atwww.pbm.va.gov or http://vaww.pbm.va.gov.

5

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

TREATMENT ALGORITHM

6PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

7

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

ANNOTATIONS

8

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

THE PHARMACOLOGIC MANAGEMENT OF CHRONIC HEART FAILURE
Annotations
A.

Diagnose and Evaluate a Patient at Risk for or Suspected of Having Heart Failure(HF)

OBJECTIVES••••

To identify patient factors associated with HF
To distinguish between the diagnosis of HF and other conditions, such as pulmonary, hepatic, renal,
hematopoetic diseases that can produce symptoms or signs suggestive of HF
To distinguish systolic from diastolic dysfunction
To evaluate the patient's functional status

BACKGROUND
As previously discussed in the Introduction, HF is a prevalent condition, especially in the older patient
population, with a high rate of morbidity and mortality.1 This treatment guideline focuses on thepharmacologic management of HF; the clinician is referred to other resources including comprehensive
treatment guidelines or clinical expertise in the diagnosis and evaluation of patients with HF. The
recommendations below are to be used as a general guide and are a summary of Class I Recommendations
where there is evidence/consensus that the treatment/procedure is of benefit as per the ACC/AHA Practice
Guidelines on initial and follow-up assessments of patients with HF.1
RECOMMENDATIONS
The following are Class I recommendations by the ACC/AHA (i.e., there is evidence and/or generalagreement that a given procedure/therapy is useful and effective).1
Initial Assessment• Obtain a thorough medical history and perform a comprehensive physical examination in patientssuspected of having HF to identify risk factors or conditions that may lead to the development or
progression of HF• Obtain a comprehensive medication history (including past and current treatments for HF, alternative
therapies, and antineoplastic agents) and past or current alcohol or illicit drug use• Perform an assessment of the patient’s ability to perform activities of daily living• Document the patient’s height, weight, and body mass index; assess the patient’s volume status andevaluate for orthostatic blood pressure changes• Obtain baseline laboratory parameters including a complete blood count, serum electrolytes withcalcium and magnesium, blood urea nitrogen (BUN), serum creatinine (Cr), fasting blood glucose andglycosylated hemoglobin, lipid profile, liver function tests, and thyroid-stimulating hormone (TSH)• Perform a twelve-lead electrocardiogram and chest radiograph• Perform a two-dimensional echocardiography with Doppler to assess left ventricular ejection fraction(LVEF), left ventricular (LV) size, wall thickness, and valve function; radionuclide ventriculography
to assess LVEF and volumes can also be performed• Perform a coronary arteriography in patients with HF and angina or significant ischemia (unless not
eligible candidate for revascularization)
Follow-Up Evaluations• Perform an assessment of the patient’s ability to perform activities of daily living at each clinic visit• Assess the patient’s volume status and weight at each clinic visit• Inquire as to the patient’s current use of alcohol, illicit drugs, alternative therapies, or antineoplastic
agents; evaluate the patient’s diet and intake of sodium
9

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

DISCUSSION
Heart failure is defined as a “complex clinical syndrome that can result from any structural or functional
cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”1 The leading causes of
HF are coronary artery disease, hypertension (HTN), and dilated cardiomyopathy (i.e., a structuralabnormality).1 In addition, identification of other conditions or risk factors contributing to the development
or progression of HF is important as some of these may be treated or avoided.1
Patients with heart failure typically present with symptoms including dyspnea and fatigue, as well as edema
and rales on physical examination.1 Signs and symptoms of HF are nonspecific and must be distinguishedfrom those of other conditions such as pulmonary disease, liver failure, and/or nephrotic syndrome. Heart
failure due to myocardial muscle dysfunction may be characterized by systolic dysfunction, diastolic
dysfunction, or both. Systolic dysfunction is generally defined as a LVEF of < 40%.1 Patients withdiastolic dysfunction often have impaired ventricular relaxation and distensibility resulting in increased
ventricular filling pressure (LVEDP). The ejection fraction in these patients may be normal or increased.
Medical history1
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

Coronary artery disease
Hypertension
Valvular heart disease
Diabetes
Peripheral vascular disease
Dyslipidemia
Myopathy
Rheumatic fever
Mediastinal irradiation
Sleep-disordered breathing
Exposure to cardiotoxic agents (e.g., anthracyclines, trastuzumab, ephedra, high-dose
cyclophosphamide)
Alcohol or illicit drug use
Smoking
Exposure to sexually transmitted diseases
Thyroid disorder
Pheochromocytoma
Obesity
Family history of atherosclerotic disease, cardiomyopathy, sudden death, conduction system disease,skeletal myopathies, or tachyarrhythmias

Patient presentation: Patients with LV dysfunction generally present in one of the following manners:1•••

Decreased exercise tolerance
Fluid retention
Cardiac enlargement or dysfunction noted during evaluation for a condition other than HF

Patient symptoms of HF:1,7,8 Most patients will present with complaints of exercise intolerance due todyspnea and/or fatigue. However, no symptom is sufficiently sensitive or specific for the diagnosis of HF
to allow ruling in or out disease. Patients with at least one of the following symptoms are at somewhat
higher likelihood of having HF. Some patients with HF may have only signs of the condition without any
active symptoms.
.
• Shortness of breath (SOB)• Fatigue
10

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

•
•
•
•
•
•

Orthopnea
Paroxysmal nocturnal dyspnea (PND)
Dyspnea on exertion (DOE)
Cough
Edema
Weight gain (anorexia may be seen in advanced HF)

Physical examination findings of HF:7,8 No single finding is sufficiently sensitive or specific for use alone
in the diagnosis of HF. However, patients with at least one of the following signs are more likely to have
HF. Some patients with HF may only have symptoms of the condition without any of the physical signs
listed below.
•
•
•
•
•
•
•
•
•

Tachycardia
Increasing weight
Jugular venous distention (JVD) or hepatojugular reflux
Presence of S3 (third heart sound)
Laterally displaced apical impulse
Pulmonary crackles or wheezes
Hepatomegaly
Peripheral (dependent) edema
Abdominal distention or ascites

Laboratory Assessment:1 Laboratory parameters are recommended to evaluate the patient for conditions
that may contribute to the development or exacerbation of HF. The initial assessment should include:
•
•
•
•
•
•
•
•

Complete blood countSerum electrolytes with calcium and magnesium
Blood urea nitrogen, serum Cr
Fasting blood glucose and glycosylated hemoglobin
Lipid profile
Liver function tests
Thyroid-stimulating hormone
B-type natriuretic peptide (BNP): elevated levels may be helpful in diagnosing a patient suspected ofhaving HF or used to consider a diagnosis of HF when the diagnosis is unknown. The ACC/AHA
recommends (i.e., weight of evidence/opinion is in favor of usefulness/efficacy) that the measurementof BNP may be useful in evaluating patients who present short of breath to the urgent care setting
where the diagnosis of HF may be uncertain.1,9 The ACC/AHA also states that the value of serial BNP
measurements to guide therapy is not well established1

Classification of HF
Different classification systems help characterize HF based on cardiac cycle (systolic, diastolic or both),
and/or ventricular involvement (right, left or both). The following recommendations of the ACC/AHA arefor staging patients with HF based on the progression of disease.1
Table 8
Stage
A
B
C
D

1

ACC/AHA Guidelines for the Evaluation and Management of HF
Disease Progression
Patients who are high risk for developing HF, but do not have structural heart disease
Patients who have structural damage to the heart, but have not developed symptoms
Patients with past or current HF symptoms and evidence of structural heart damage
Patients with end-stage disease, requiring special interventions

It is the intent of the ACC/AHA recommendations to be used in conjunction with the New York Heart
Association (NYHA) functional classification10 that estimates the severity of disease based on patient
11

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

symptoms.1 According to the above classification system, once a patient develops symptoms they shouldbe treated according to the recommendations for patients with Stage C (even if NYHA Class I, see below),and do not return to Stage B.1
Table 9
Class
I
II
III
IV

B.

10

NYHA Functional Classification and Objective Assessment of HF
Disease Progression
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation,
dyspnea, or angina
Slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnea, or
anginaMarked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results infatigue, palpitation, dyspnea, or angina
Unable to carry on any physical activity without discomfort. Symptoms are present at rest. With any physicalactivity, symptoms increase

Management of Concomitant Cardiac Conditions and Risk Factors,
Nonpharmacologic Interventions, and Treatment of Underlying Causes

OBJECTIVES•

To provide general interventions to be recommended in patients at risk for developing HF or who havea diagnosis of HF

BACKGROUND
Identification and treatment of chronic medical conditions or risk factors that may impact the development
or progression of HF is important in the overall management of patients at risk for HF or who have been
diagnosed with the condition. Many of these diseases have clinical practice guidelines that have beenreviewed and approved by the VA/DoD Evidence-Based Practice Work Group and can be found on the VA
Office of Quality and Performance Web site at http://www.oqp.med.va.gov/cpg/cpg/htm.
RECOMMENDATIONSControl risk factors
The following are Class I recommendations by the ACC/AHA (i.e., there is evidence and/or generalagreement that a given procedure/therapy is useful and effective)1• Control HTN (http://www.oqp.med.va.gov/cpg/cpg/htm)• Treat hyperlipidemia (http://www.oqp.med.va.gov/cpg/cpg/htm)• Treat DM (http://www.oqp.med.va.gov/cpg/cpg/htm)• Encourage smoking cessation (http://www.oqp.med.va.gov/cpg/cpg/htm) and discourage alcohol
consumption and illicit drug use• Control ventricular rate or restore sinus rhythm in patients with supraventricular tachyarrhythmias• Treat thyroid disorders• Conduct periodic evaluations for signs and symptoms of HF• Manage atherosclerotic vascular disease• For those with a family history of cardiomyopathy or who are receiving cardiotoxic medications,perform a noninvasive evaluation of LVDISCUSSION
Treatment of conditions that may lead to HF
Patients with hypertension, diabetes mellitus, or atherosclerotic vascular disease, or those who smoke
tobacco are at an increased risk for the development of HF.1,11,12 Treatment of these conditions and other
12

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

risk factors can contribute to an improvement in patient outcomes,1,13-19 and it is recommended that patientsbe treated according to the corresponding VA/DoD clinical practice guidelines (available at
http://www.oqp.med.va.gov/cpg/cpg/htm).
Recommendations in selected patients
Atrial fibrillation: In patients with HF due to systolic dysfunction and atrial fibrillation requiring rate
control, a beta-adrenergic blocker is preferred due to its favorable effect on patients with HF (in patientsthat are hemodynamically and otherwise stable).1 Digoxin is also commonly used. Some patients may
require combination therapy with digoxin and a beta-adrenergic blocker.20 Although the long-term use ofdiltiazem and verapamil [calcium channel blockers (CCBs) with atrioventricular (AV) nodal blocking
activity] have been associated with worsening LV dysfunction in patients with HF, patients with atrial
fibrillation and rapid ventricular response resistant to combinations of digoxin and a beta-adrenergic
blocker have responded with better rate control by adding diltiazem or verapamil. The decision to add
diltiazem or verapamil in such patients should be based on weighing the benefit of better rate control
against the deleterious long-term effects of these drugs. If additional rate control is needed, referral should
be made to a cardiologist with expertise in electrophysiology.
Anticoagulation: Warfarin anticoagulation [with a target international normalization ratio (INR) of 2.5;
range 2.0 to 3.0] is recommended in patients with HF and atrial fibrillation, previous systemic or
pulmonary thromboembolism, or mobile LV thrombus.21,22 The routine use of warfarin anticoagulation for
HF has not been confirmed by controlled clinical trials.1,23 The Warfarin and Antiplatelet Therapy inChronic Heart Failure (WATCH) trial, was unable to demonstrate a significant difference between
warfarin, aspirin, and clopidogrel in patients with HF. Another trial comparing warfarin to aspirin inpatients with HF is currently underway.24 Arterial thromboembolism may occur in patients with HF due tosystolic dysfunction as a result of the low cardiac output and poor contractility. Analysis of cohorts in theStudies of Left Ventricular Dysfunction (SOLVD) who received warfarin, compared to those who did not,suggests a 25% risk reduction in all-cause mortality.25 However, a post-hoc analysis of a single study is notevidence enough to recommend anticoagulation in patients with systolic dysfunction. Patients with atrial
fibrillation and HF with contraindications to warfarin (e.g., increased risk of bleeding, difficulty adhering to
the medication regimen or regular INR monitoring, current alcohol abuse or frequent falls) should receive
aspirin unless contraindicated.26,27 For patients with HF who do not have coronary disease, additional
information is needed as to the risk vs. benefit of recommending aspirin therapy.28,29
Concomitant HTN and/or angina: Patients with systolic HF and concomitant HTN should be maximized ontherapy with agents such as diuretics, ACEIs, and beta-adrenergic blockers, or beta-adrenergic blockers andnitrates in patients with concomitant angina, before adding other agents. However, in patients who are notadequately controlled on these agents, treatment with a long-acting dihydropyridine (felodipine or
amlodipine) may be considered based on the following information.
The negative inotropic properties of the CCBs may cause deleterious effects in patients with HF due tosystolic dysfunction. Studies have looked at the use of the long-acting dihydropyridines, felodipine andamlodipine, in patients with systolic dysfunction (Note: neither amlodipine nor felodipine have approval by
the Food and Drug Administration for use in patients with HF and should be used with caution in patientswith this diagnosis).
The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) evaluated patients with NYHA
class IIIB or IV with a LVEF of < 30%, who remained symptomatic despite treatment with digoxin,
diuretics, and an ACEI. There were 571 patients who received amlodipine up to 10mg once daily
compared to 582 patients on placebo. The average follow-up was 13.8 months (range 6-33). There was no
significant difference in the primary endpoint (combined risk of death and major cardiovascularhospitalizations) between groups. There was a trend toward a decrease in all-cause mortality with
amlodipine (p=0.07). Subgroup analysis showed that amlodipine significantly decreased the risk of deathfrom all causes in patients with HF due to nonischemic dilated cardiomyopathy, without a difference inpatients with ischemic dilated cardiomyopathy.30 This result was not considered a priori endpoint. The
13

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

survival benefit of amlodipine in patients with nonischemic dilated cardiomyopathy found in the original
PRAISE trial was not confirmed in PRAISE-2.31
The third Vasodilator Heart Failure Trial (V-HeFT III) included patients with NYHA class II or III HF witha LVEF of 18-42% who remained symptomatic despite treatment with digoxin, diuretics, and an ACEI.
There were 224 patients who received felodipine at a maximum dose of 5mg twice daily compared to 226
patients on placebo. The average follow-up was 18 months (range 3-39). The primary endpoint of thestudy was the effect of treatment on exercise tolerance. There was no significant difference between
groups in death from all causes, worsening HF, or number of hospitalizations. This study was not
sufficiently powered to demonstrate that felodipine did not alter mortality, however. Exercise tolerance
and quality of life significantly improved with felodipine at 27 months.32
Clinical practice guidelines have stated that only trials with amlodipine and felodipine have provided longterm safety data in patients with HF.22 The evidence with amlodipine suggests that this agent does notadversely affect survival in patients with systolic HF. Felodipine or amlodipine may be considered inpatients with HF due to systolic dysfunction for the treatment of hypertension for those who have beenmaximized on pharmacotherapy including diuretics, ACEIs, and beta-adrenergic blockers, and anangiotensin II receptor antagonist, hydralazine/nitrate, or aldosterone antagonist, as indicated; or betaadrenergic blockers and long-acting nitrates in patients with concomitant angina.
Cardiac amyloidosis: If cardiac amyloidosis is known or suspected from echocardiography or clinicalgrounds, further work-up and referral to a cardiologist is warranted for appropriate treatment.
Conventional wisdom has been that digoxin and CCBs should be avoided in patients with amyloid
cardiomyopathy.33,34 However, this point is controversial35 and supported by only weak publishedevidence. Several case reports suggest a sensitivity to digoxin,36-41 however one prospective autopsy study
found no association.42 Digoxin can be useful in controlling rapid ventricular response to atrial fibrillationand might be useful, especially in early stages of systolic dysfunction caused by amyloid cardiomyopathy.35
The data supporting a CCB sensitivity is based on case reports for nifedipine43,44 and verapamil.45 Boththese drugs can exacerbate chronic systolic dysfunction independent of etiology. No case reports of other
CCBs have been found to suggest sensitivity to them. The following recommendations are based on review
of available evidence:
•
•
•
•
•

Avoid verapamil and diltiazem (except in patients with atrial fibrillation and rapid ventricular rate that
do not achieve rate control on a beta-adrenergic blocker and digoxin), and nifedipine in systolic
dysfunction of all etiologies
If digoxin is necessary in a patient with known or suspected amyloid cardiomyopathy (e.g., to control
ventricular response to atrial fibrillation), it should be used very cautiously with careful monitoring forevidence of cardiac toxicity
Use digoxin in severe cases of known or suspected amyloid cardiomyopathy only in close consultation
with a cardiologist and after carefully weighing the potential risks and benefits
Use felodipine or amlodipine only according to prescribing guidelines; monitor patients with known orsuspected amyloid cardiomyopathy very closely when using any CCB
Consider using other agents for diastolic dysfunction before resorting to a CCB in patients with known
or suspected amyloid cardiomyopathy

Medications to avoid or to be used with caution•

Anti-arrhythmic agents: Anti-arrhythmic agents, other than beta-adrenergic blockers, are notrecommended to suppress asymptomatic ventricular arrhythmia or ectopy. Class I antiarrhythmic
agents have been shown to increase the risk of sudden death in patients with HF. Of the class III
agents, treatment with amiodarone or dofetilide does not appear to increase the risk of death in patientswith HF.46-49 Patients with ventricular arrhythmias should be referred to a cardiologist forindividualized treatment
14

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

•
•
•
•

•
•

Calcium channel blockers: Most CCBs (except felodipine and amlodipine; refer to above discussion)
should not be used in patients with systolic dysfunction
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may cause fluid retention and should be
avoided;1,50,51 alternative anti-inflammatory agents may be used (e.g., non-acetylated salicylates)
Antineoplastic agents: Antineoplastic agents such as anthracyclines or trastuzumab may lead to thedevelopment of HF and should be avoided, if possible
Thiazolidinediones (TZDs): TZDs, including rosiglitazone and pioglitazone, are used in the
management of patients with DM and have been found to cause edema, an adverse effect that is morecommon when a TZD is used in combination with other oral hypoglycemic agents or insulin. In
addition, clinical trials with the TZDs generally did not include patients with NYHA class III or IV HF
and an increased risk of HF in patients prescribed the TZDs has been reported, although the risk
appears to be low. Current recommendations include evaluation of the patient’s cardiac and fluid
status prior to prescribing a TZD and upon follow-up. If a TZD is prescribed in patients without HF
but who have one or more risk factors for HF,52 or in patients who have NYHA class I or II HF, a low
dose should be started and the patient should be closely monitored for signs and symptoms of HF
including shortness of breath, edema, or excessive or rapid weight gain, as treatment with a TZD has
been associated with worsening of HF, and a higher rate of hospitalization and cardiovascular related
events. Treatment with a TZD should be reconsidered in patients who develop HF after initiation of
the drug. Clinician discretion may be used in patients receiving a TZD who are stabilized and without
evidence of volume overload. The use of a TZD is contraindicated in patients with NYHA Class III or
IV HF.
Cilostazol: Cilostazol, a phosphodiesterase (PDE) inhibitor used in the management of intermittent
claudication and as antiplatelet therapy, is contraindicated in patients with HF due to the decreased
survival seen in patients with NYHA class III or IV HF receiving other PDE type 3 inhibitors
Metformin: Metformin should not be used in patients with unstable or acute congestive HF due to thepropensity for hypoperfusion or hypoxemia and resultant increased risk of developing lactic acidosis

Additional recommendations22,53,54
•

•
•
•
•

C.

Patients and their families or caregivers should receive education on HF, dietary restrictions including
reducing salt intake and fluid control (especially in advanced HF), weight monitoring to assess fluid
status, moderation of alcohol intake, weight loss if obese, regular physical activity or exercise training
if appropriate, smoking cessation, drug therapy and importance of adherence to the medication
regimen, symptoms associated with worsening HF and what to do if they occur, and prognosis
Unless contraindicated, influenza vaccination should be offered every fall
Pneumococcal immunizations should be provided at diagnosis if not previously vaccinated; if initial
vaccination was at age less than 65 years, revaccinate at age 65 or 5 years after initial immunization,
whichever is later
An implantable cardioverter-defibrillator or cardiac resynchronication therapy should be considered inappropriate patients but are beyond the scope of this document.
Patients should be followed closely by a clinician competent in caring for patients with HF. Care ofpatients with HF may occur in several clinical settings including primary care, cardiology, or bymultidisciplinary HF treatment teams. Regardless of the setting in which patients with HF are caredfor, the clinician is encouraged to follow these and other HF guidelines and to use clinical judgment ofwhen to refer to a specialist. This will depend on the skill and experience of managing patients with
HF, and also the resources available to the practitioner

Pharmacologic Management of HF with Preserved Left Ventricular Ejection
Fraction

OBJECTIVE•

To review the pharmacologic recommendations for patients with HF and preserved LVEF
15

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

BACKGROUND
In patients with HF and normal LVEF the systolic function of the left ventricle is preserved. The defect ofventricular function lies in the reduced LV compliance and difficulty in passive filling. Increased LVEDP
can result in pulmonary congestion indistinguishable clinically from LV systolic dysfunction. As patientswith HF and normal LVEF are often symptomatic, these patients may also be categorized as Stage C HF
according to the ACC/AHA.1 In addition, there is a high rate of morbidity and mortality seen in thesepatients.1,55
Compared to HF due to systolic dysfunction, there is a paucity of data from randomized trials about thepharmacologic management of patients with preserved LVEF,1,56-71 despite the estimate that 20-60% of
patients with HF can be considered to have normal LVEF (depending on the definition for reduced LVEF).1
Since questions remain regarding the optimal treatment of patients with HF and normal LVEF, it isrecommended that these patients be treated in conjunction with a cardiologist if the patient does notadequately respond to initial interventions.

RECOMMENDATIONSDrug Therapy
The following are Class I recommendations by the ACC/AHA (i.e., there is evidence and/or generalagreement that a given procedure/therapy is useful and effective)1• Control HTN• Control ventricular rate in patients with atrial fibrillation• Use diuretics in patients with symptoms of volume overload (e.g., pulmonary congestion or peripheral
edema)
The following are Class IIb recommendations by the ACC/AHA (i.e., the usefulness/efficacy is less wellestablished by evidence/opinion)1• Consider use of beta-adrenergic blockers, ACEIs, non-dihydropyridine calcium channel blockers, or
angiotensin II receptor antagonists in patients with controlled HTN who continue to have symptoms• Use of digoxin to improve symptoms is not well established• Restoring and maintaining sinus rhythm in patients with atrial fibrillation may be useful to improve
symptoms

DISCUSSION
General principles of lowering systolic and diastolic blood pressure, treating myocardial ischemia,
controlling heart rate and blood volume, and providing anticoagulation for patients with atrial fibrillation
apply to these patients as well as to patients with systolic dysfunction. Conditions that can lead to HF witha normal LVEF (e.g., HTN, coronary artery disease, aortic stenosis) should also be treated.1
The main goal of therapy is to improve symptoms by lowering the filling pressures of the left ventricle
without significantly reducing cardiac output. Agents that decrease heart rate can be helpful by increasing
diastolic filling time.
The majority of clinical trials in patients with HF and preserved LVEF have been in a limited number ofpatients. The CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity)
Preserved trial71 enrolled 3023 patients with HF and LVEF > 40% and compared the addition of anangiotensin II receptor antagonist (candesartan) or placebo to current therapy. Median follow-up was 36.6
months. The primary endpoint of cardiovascular mortality or HF hospitalizations occurred in 22% of
16

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

patients receiving candesartan compared to 24% of patients in the placebo group; a difference that was notstatistically significant.
D.

Interventions in Patients With Asymptomatic Left Ventricular Systolic Dysfunction

OBJECTIVE•

To provide recommendations for patients with asymptomatic LV systolic dysfunction (Stage B)

BACKGROUND
The management goals for patients with asymptomatic systolic dysfunction is to prevent the developmentof HF.1 These recommendations are divided into the following patient groups.
RECOMMENDATIONSDrug Therapy••••

Use an ACEI and beta-adrenergic blocker in patients with a recent or remote history of MI, regardlessof LVEF
Use an ACEI in patients with a reduced LVEF who do not have symptoms of HF
A beta-adrenergic blocker is indicated in patients without a history of MI who have reduced LVEF anddo not have symptoms of HF
An angiotensin II receptor antagonist may be given to patients with a history of MI who have a
reduced LVEF and do not have symptoms of HF if they are intolerant of ACEIsDISCUSSION
Patients with a Recent or Remote History of Myocardial Infarction
Prescribing an ACEI in patients with an acute or recent MI72,73 and evidence of left ventricular systolic
dysfunction (generally defined as LVEF < 40%) may reduce mortality and slow the progression tosymptomatic heart failure.74-77 In the Survival and Ventricular Enlargement (SAVE),74 Acute Infarction
Ramipril Efficacy (AIRE),75,76 and Trandolapril Cardiac Evaluation (TRACE)77,78 trials, patients with arecent MI and evidence of HF experienced a significant decrease in all-cause mortality and risk ofdeveloping severe HF when treated with an ACEI compared to placebo. Treatment with an ACEI in
patients recently recovered from an MI can decrease the risk of reinfarction and death in patients withevidence of HF at the time of the infarction.75 Patients with a history of MI without reduced LVEF may
also benefit from treatment with an ACEI.16,79
The use of a beta-adrenergic blocker in patients with asymptomatic left ventricular systolic dysfunction
post-MI reduces the risk of cardiovascular morbidity and mortality.80-83 In the Carvedilol Post-Infarct
Survival Control in LV Dysfunction (CAPRICORN) trial that randomized 1959 patients with a LVEF <40% post-MI to carvedilol or placebo, there was not a statistically significant difference in the primary
endpoint of all-cause mortality or cardiovascular hospitalizations (originally a prespecified secondary
endpoint). The original primary endpoint of all-cause mortality (changed to co-primary endpoint due toinadequate sample size and power) was lower, but not statistically significant in patients on carvedilol
compared to placebo.84 Although the results of this study did not achieve statistical significance, theendpoints were numerically lower in patients treated with carvedilol. Taking this into account with resultsof other trials, there still appears to be a benefit of using a beta-adrenergic blocker in patients withasymptomatic left ventricular systolic dysfunction post-MI.
Combination therapy with a beta-adrenergic blocker and an ACEI may also be beneficial in patients withleft ventricular systolic dysfunction post-MI.85-87
17

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

In the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL),
losartan (target dose 50mg once daily) was compared to captopril (target dose 50mg three times daily) in
5477 high-risk (i.e., signs and symptoms of HF or Q-wave MI) patients with acute MI. After a meanfollow-up of 2.7 years, the primary endpoint of all-cause mortality occurred in 18% of patients on losartan
and 16% of patients on captopril, a difference that was not statistically significant.88 In another trial
comparing an angiotensin II receptor antagonist with an ACEI in patients with MI complicated by HF, LV
dysfunction, or both, the Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14,703
patients to treatment with valsartan (target dose 160mg twice daily), captopril (target dose 50mg threetimes daily), or the combination of valsartan (target dose 80mg twice daily) and captopril (target dose 50mg
three times daily). During a median follow-up of 24.7 months, the primary endpoint of all-cause mortality
was similar in the treatment groups and occurred in 19.9% of patients randomized to valsartan, 19.5%
treated with captopril, and 19.3% receiving the combination. Treatment with valsartan was found to benoninferior to captopril for the endpoint of all-cause mortality.89 Based on these results, an angiotensin II
receptor antagonist can be considered in patients who are intolerant to an ACEI (refer to Annotation G) in
high risk patients following MI.1
Patients with Asymptomatic Left Ventricular Dysfunction
In the Studies of Left Ventricular Dysfunction (SOLVD) Prevention trial, patients with asymptomatic left
ventricular dysfunction treated with an ACEI experienced a significant reduction in the combined risk ofdeath and hospitalization for HF by 20% compared to placebo. However, there was no significant decrease
in all-cause mortality alone in the ACEI group.90 In the Prevention trial component of the 12 year followup of SOLVD (median duration of follow-up for the Prevention trial 11.2 months), there was a significant
reduction in all-cause mortality in patients treated with enalapril (median duration during trial 3.2 years)
compared to those receiving placebo (50.9% vs. 56.4%).91
The benefit of an ACEI in men compared to women with HF was recently evaluated. According to a
subgroup analysis of trials including treatment of patients with asymptomatic LV dysfunction, there did notappear to be a clear benefit of ACEI in women, with a relative risk of 0.96 (95% CI 0.75-1.22). It was
concluded that further investigation is warranted before making a definitive recommendation on the use of
ACEIs in women with asymptomatic left ventricular dysfunction.92 While the benefit, to the extent that one
exists, remains to be quantified, an ACEI should still be considered standard therapy given the current levelof data overall.
Although the benefit of beta-adrenergic blockers in patients with asymptomatic HF (not in the post-MI
setting) has not been critically evaluated, current recommendations include use of a beta-adrenergic blocker
in this patient population.1,83-85
Digoxin is currently recommended in patients with symptomatic HF to improve clinical status and decrease
the risk of hospitalization due to HF,93 after optimization of standard therapy. Since there is not asignificant reduction in disease progression or mortality, digoxin is not recommended in patients withasymptomatic left ventricular dysfunction.1
EVIDENCE
Grading System
Intervention

6

References

18

USPSTF
QE
OQ
SR

1

ACC/AHACR
LE

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Use an ACEI in patients with a recent or remotehistory of MI, regardless of LVEF

Use a beta-adrenergic blocker in patients with arecent or remote history of MI, regardless of LVEF

Use an ACEI in patients with a reduced LVEF who do
not have symptoms of HF

A beta-adrenergic blocker is indicated in patients
without a history of MI who have reduced LVEF anddo not have symptoms of HF

An angiotensin II receptor antagonist may be given topatients with a history of MI who have a reduced
LVEF and do not have symptoms of HF if they areintolerant of ACEIs

E.

SAVE (1992)
AIRE (1993)
GISSI-3 (1994)
ISIS-4 (1995)
TRACE (1995)
AIREX (1997)
HOPE (2000)
TRACE 12yr (2005)
PREAMI (2006)
ACC/AHA (2005)
HFSA (2006)
Norwegian trial (1981)
BHAT (1982)
Chadda (1986)
Gottlieb (1998)
CAPRICORN (2001)
ACC/AHA (2005)
HFSA (2006)
SOLVD (1992)
SOLVD 12yr (2003)
ACC/AHA (2005)
HFSA (2006)
Chadda (1986)
CAPRICORN (2001)
SAVE (1997)
ACC/AHA (2005)
HFSA (2006)
OPTIMAAL (2002)
VALIANT (2003)
ACC/AHA (2005)

I
I
I
I
I
II-1
I
II-1
I
III
III
I
I
II-2
II-2
I
III
III
I
II-1
III
III
II-2
I
II-2
III
III
I
I
III

I

A

I

A

I

A

I

A

I

A

I

A

II

B

I

C

I

A

I

B

Systolic Dysfunction and Assessment for Symptoms of Volume Overload

OBJECTIVE•

To provide recommendations for initial assessment and therapy in patients with a diagnosis of systolic
HF who exhibit symptoms of volume overload

BACKGROUND
The goals of treating patients with HF due to systolic dysfunction are to improve the patient's symptoms
and quality of life, and to reduce the risk of morbidity and mortality by slowing the progression of disease.
Patient's symptoms are often related to volume overload.
RECOMMENDATION
Initial Assessment of Volume Status
The following is a Class I recommendation by the ACC/AHA (i.e., there is evidence and/or generalagreement that a given procedure/therapy is useful and effective)1• Patients presenting with HF should receive an assessment of volume status
DISCUSSION
Symptoms of volume overload include ankle swelling, weight gain, fatigue, orthopnea, PND, DOE, SOB at
rest and nocturnal cough. The physical signs of volume overload are pulmonary crackles, third heartsound, cardiomegaly, JVD, hepatojugular reflux, hepatomegaly, ascites, dependent edema (presacral, flank,
lower extremity), tachypnea, tachycardia, and pulmonary edema.
19

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Chest radiography is useful to identify signs of volume overload (pleural effusion, pulmonary edema,cardiomegaly).
A diuretic is recommended in patients with HF who exhibit signs or symptoms of volume overload (refer to
Annotation F).1
F.

Diuretic Therapy

OBJECTIVE•

To provide recommendations for the appropriate use of diuretics in patients with a diagnosis of systolic
HF (for a discussion on the use of aldosterone antagonists in HF, refer to Annotation L)

BACKGROUND
Many patients with HF will present with symptoms of fluid retention and require treatment with a diuretic.
It is recommended that the diuretic should be continued (particularly in patients with NYHA III or IV
failure) even if symptoms resolve to prevent recurrence of volume overload. Patients should noticesymptomatic improvement early on with diuretic therapy; however, a diuretic should not be prescribedalone in patients with Stage C HF but combined with drug classes that have been shown to reducemorbidity and mortality.1
RECOMMENDATION
Diuretic Therapy in Stage C HF•

A diuretic is indicated in patients with current or previous symptoms of HF with evidence of fluid
retention

DISCUSSION
Diuretics act by inhibiting sodium or chloride reabsorption in the renal tubules. The loop diuretics exert
their effects more proximally and are therefore the most potent of the diuretics. The diuretics primarily
differ in their duration of action (e.g., furosemide 6-8 hours, hydrochlorothiazide 6-12 hours, metolazone
12-24 hours) and in their ability to cause sodium excretion (‘low ceiling’ diuretics like hydrochlorothiazide
or ‘high ceiling’ diuretics like furosemide). As HF progresses, a delay in absorption and failure to filter the
drug in the tubular fluid may be contributing factors to the need for increasing diuretic doses in somepatients.1,94-96
There have been no long-term properly blinded, randomized controlled clinical outcome trials evaluating
the effectiveness of loop or thiazide diuretic therapy in patients with HF.1 Short-term and intermediate
length studies have demonstrated that diuretics can decrease the signs and symptoms of fluid retention, andimprove cardiac conduction and exercise tolerance.1,97-100 The majority of patients enrolled in long-term
trials demonstrating a decreased morbidity or mortality with ACEI or beta-adrenergic blocker therapy,
were also receiving a diuretic.
Some patients with HF may experience a recurrence of symptoms if diuretic therapy is withdrawn.101 In
one trial the risk of requiring reinstitution of diuretic therapy was 36% in patients in the withdrawal groupcompared with controls.102 A LVEF < 27%, diuretic dose greater than 40mg of furosemide daily, or ahistory of HTN were independent risk factors for early reinstitution of diuretic therapy.103
Patients with HF may have symptoms that interfere with their daily activities and, therefore, impact on their
quality of life. A diuretic should be used for preload reduction in patients with HF and current or previous
signs or symptoms of volume overload (e.g., orthopnea, PND, DOE, or edema).1,100 Patients with
20

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

symptoms of fluid overload benefit from treatment with a diuretic in conjunction with an ACEI and betaadrenergic blocker,1 and possibly digoxin.104
Loop diuretics are most commonly used for patients with HF and volume overload. They are effective inpatients with renal insufficiency or creatinine clearance (CrCl) < 30 mL/min, whereas the effectiveness ofthiazides are diminished in patients with CrCl < 40 mL/min.1 Edema resistant to large doses of loop
diuretics may intermittently require combined diuretic therapy (e.g., adding metolazone or thiazide at low
doses two to three times per week or more frequently if needed, one hour prior to a loop diuretic),
consideration of change to another loop diuretic, or intravenous diuretics.1, 94-96,104-111 The use of
combination diuretics increases the risk of electrolyte imbalances and overdiuresis leading to prerenalazotemia. Therefore, combination diuretic therapy requires close monitoring.
Monitoring parameters with diuretics include the following:1
1.
2.
3.

4.

Weight: (initially 1 - 2 pound weight loss per day until “ideal weight” achieved); weight loss may begreater during the first few days when significant edema is present; obtain daily weights
Signs or symptoms of volume depletion: weakness, dizziness, decreased urine output, symptomatic
hypotension, orthostatic hypotension
Serum potassium (K+), BUN or Cr (and serum BUN/Cr ratio) within 1 to 2 weeks after initiating
therapy; consider checking serum levels of magnesium (especially if high doses diuretic used), sodium,
calcium, bicarbonate, uric acid, glucose as indicated. Use of an ACEI (or angiotensin II receptor
antagonist) and/or spironolactone may offset potential diuretic-induced hypokalemia, minimizing theneed for potassium or potassium-sparing diuretics
Diuretic dosage may require adjustment if hypotension or decrease in renal function occurs. Avoid
excessive diuresis, which could also limit ACEI dosage due to hypotension or renal dysfunction

EVIDENCE
Grading System
Intervention
Use a diuretic in patients with evidence of fluid
retentionG.

6

References
Wilson (1981)
Richardson (1987)
Parker (1993)
Patterson (1994)
ACC/AHA (2005)
HFSA (2006)

QE
I
I
I
I
III
III

USPSTF
OQ
SR
II
B

1

ACC/AHA
CR
LE
IC

Angiotensin-Converting Enzyme Inhibitors

OBJECTIVE•

To provide recommendations for the appropriate use of ACEIs in patients with a diagnosis of systolic
HF

BACKGROUND
Due to their beneficial effects on morbidity and mortality, an ACEI should be prescribed in patients with
Stage C HF, unless contraindicated. Therapy should be initiated at low doses and titrated to target doses or
patient tolerability.
RECOMMENDATIONACEI Therapy in Stage C HF•

An ACEI is recommended in all patients with current or prior symptoms of HF and reduced LVEF,
unless contraindicated21

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

DISCUSSION
Angiotensin-converting enzyme (ACE) is responsible for converting angiotensin I to angiotensin II.
Angiotensin II is a potent vasoconstrictor and it stimulates aldosterone secretion, which leads to increased
sodium and water retention. By inhibiting this enzyme, ACEIs ultimately reduce the vasoconstriction
associated with angiotensin II and decrease the sodium and water retention associated with aldosterone.
ACE is structurally similar to kininase II, so it may also inhibit the breakdown of bradykinin, a vasodilator.
The importance of ACE's effect on kinin-mediated prostaglandin synthesis in the management of patientswith HF is not yet known, but it may be as important as angiotensin suppression.1
In addition to improving HF symptoms and functional status,1,112-118 treatment with an ACEI has beenshown to decrease the frequency of hospitalization and the mortality rate91,119-123 (Appendix C).
In the Captopril-Digoxin Multicenter Trial, patients with mild to moderate HF were randomized to placebo,
captopril, or digoxin in addition to treatment with diuretics for 6 months. Compared with placebo, patientson captopril experienced significant improvement in exercise tolerance and decreased frequency of hospitalor emergency care for worsening HF. Similar results were not seen with digoxin.119 Patients with mild tomoderate HF who received enalapril for an average of 41 months in the SOLVD Treatment Trial had asignificant decrease of 16% in all-cause mortality and a 26% decreased risk of death or hospitalizations for
HF compared to patients on placebo.120 The Vasodilator Heart Failure Trial (V-HeFT) II showed thatpatients with mild to moderate HF who received enalapril for an average of 2.5 years experienced asignificant decrease of 28% in the risk of death at 2 years compared to patients on the combination of
isosorbide dinitrate (ISDN) and hydralazine.121 The Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS) evaluated treatment with enalapril for 6 months compared to placebo in patientswith NYHA class IV HF. Treatment with enalapril significantly decreased all-cause mortality at 6 months
by 40%.122
The possibility of racial differences in response to therapy has been seen in a subanalysis of V-HeFT and
V-HeFT II. In V-HeFT I, white patients did not experience the same mortality benefit as black patients on
ISDN and hydralazine (compared to placebo). In V-HeFT II, white patients on an ACEI experienced adecrease in mortality compared to treatment with ISDN and hydralazine. There was not a statisticallysignificant difference in mortality between treatments in black patients.124 When matched cohorts of whitepatients were compared to black patients on an ACEI enrolled in the SOLVD Treatment Trial, whitepatients experienced a decreased risk for hospitalizations due to HF which was not seen in the cohort ofblack patients.125 Based on a pooled relative risk analysis, there was no evidence that mortality differed
substantially with an estimate for white patients of 0.89 (95% CI 0.82-0.97) and 0.89 (85% CI 0.74-1.06)
for black patients.92 Results of a trial comparing treatment with the combination of ISDN and hydralazine
vs. placebo in self-identified black patients (the majority being treated with an ACEI or angiotensin II
receptor antagonist and a beta-adrenergic blocker) are discussed in Annotation J. Further trials will need tobe conducted to determine if therapy with an ACEI for HF should to be modified based on patient
demographics.
It is recommended that an ACEI be offered to all patients with reduced left ventricular systolic dysfunction
unless the patient has specific contraindications:1,126
1.
2.
3.
4.
5.

A history of angioedema, anuric renal failure, or other documented hypersensitivity to an ACEI
Bilateral renal artery stenosis or renal artery stenosis in a solitary kidney
Pregnancy
Serum potassium > 5.5 mEq/L that cannot be reduced
Hypotension in patients at risk of cardiogenic shock

Prior to initiating ACEIs, obtain baseline serum potassium, Cr, and BUN; ACEIs should be used cautiously
in patients with serum Cr > 3mg/dL. Before initiating therapy, patients should first be assessed foradequate volume status. In patients taking diuretics, symptomatic hypotension may occur following
22

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

initiation of an ACEI; if the diuretic cannot be reduced or discontinued, consider a lower starting dose of an
ACEI. If the patient is on a potassium-sparing diuretic when an ACEI is begun, close monitoring ofpotassium is recommended. Alternatively, if the patient is hypokalemic or normokalemic, the potassiumsparing diuretic may be stopped while titrating the ACEI and re-started later, with subsequent closemonitoring of potassium. An ACEI should also be used with caution with an aldosterone antagonist (refer
to Annotation L). Concomitant use with an NSAID should be avoided whenever possible as NSAIDs usedin conjunction with an ACEI may worsen renal function and contribute to hyperkalemia (refer to Appendix
B for common drug interactions). Patients started on an ACEI should be evaluated within 1 to 2 weeks tomonitor blood pressure, serum potassium and creatinine; more frequent monitoring may be warranted
depending on the severity of the patient’s condition.
Doses should initially be low and then titrated upward over several weeks to the maximum dose tolerated,with the target doses based on those used in large scale clinical trials (refer to Appendices A and C).1
Despite the overwhelming evidence in favor of treating HF patients with ACEIs and that a large majority ofpatients are able to tolerate high doses, these agents are often underutilized, and frequently at low doses,127129
although this may depend on the clinical setting.130
There appears to be a dose response benefit as shown in the Assessment of Treatment with Lisinopril andSurvival (ATLAS) study. In this study, patients with NYHA class II-IV HF on maximal doses of lisinopril(average of 33.2 + 5.4mg daily) experienced a significant 12% decrease in the risk of death or
hospitalization for any reason and 24% fewer hospitalizations for HF, compared to patients receiving lower
doses (average of 4.5 + 1.1 mg daily). There was also a nonsignificant 8% lower risk of death in the highdose compared to the low dose treatment group. The authors observed that the decrease in risk with thehigh dose compared to the low dose group in the ATLAS study was approximately half that seen withtarget doses of an ACEI compared to placebo in other trials. This suggests that even patients on suboptimaldoses will derive benefit, although not as great as patients receiving higher doses.131,132 This is importantsince other factors may preclude a patient from achieving target doses. In another trial, patients on highdoses of an ACEI (enalapril 20mg/d) had a decreased risk of HF hospitalizations compared to patients on
medium and lower doses (enalapril 10mg/d and 5mg/d, respectively). There was no difference between
doses in symptoms or mortality.133 There was also no difference in NYHA class, LVEF, or mortality in atrial of patients on standard (17.9 + 4.3mg/d) compared to high (42 + 19.3mg/d) doses of enalapril.134
Every effort should be made to titrate patients to the doses used in clinical trials, although if this is not
feasible, patients should be maintained on the maximum tolerated dose.1 Patients prescribed an ACEI prior
to discharge from the hospital are more likely to be on an ACEI long-term compared to those notdischarged on an ACEI.135 In addition, initiation of a beta-adrenergic blocker should not be delayed due toan inability to achieve target doses of an ACEI,1 as patients treated with a beta-adrenergic blocker derived
benefit regardless if the patient were receiving low or high doses of an ACEI.136
Due to the strong evidence for the beneficial effects of ACEIs in patients with HF, every effort should bemade to adjust the dosage before a patient is documented as intolerant.137 Dosage should be modified if thepatient develops any of the following:128
1.

2.
3.
4.

While creatinine often increases (usually < 25%) after initiation of an ACEI, clinically significant
decline in renal function (suggested by a change in serum Cr concentration of at least 0.5 mg/dL)
should be investigated. Consultation with a nephrologist should be considered for persistent
deteriorations in renal function that cannot be explained or corrected.
Hyperkalemia (potassium > 5.5 mEq/L), after other causes have been excluded
If patient cannot tolerate ACEI due to symptomatic hypotension, consider referral to a cardiologist forassistance in titrating the ACEI dosage
The cough associated with an ACEI has been described as dry, nonproductive, persistent, beginningwith a tickling sensation, and often worse at night. The onset is usually within the first week of ACEI
therapy and continues throughout treatment, resolving within a few days to 4 weeks after the ACEI is
discontinued. The cough is not usually dose-dependent, although in some instances it may beeliminated with a reduction in dose. In addition, fosinopril may be considered in patients who
23

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

experience cough on another ACEI.138-140 Since therapy with an ACEI has proven valuable, it isimportant to consider alternative diagnoses (e.g., asthma, chronic obstructive pulmonary disease,allergic rhinitis, upper respiratory tract infection, heart failure, gastroesophageal reflux disease) before
a diagnosis of ACEI-induced cough is made. If the cough is not bothersome, the benefits of continuing
the ACEI should be discussed with the patient
There is some controversy as to whether use of aspirin decreases the cardiovascular benefit of an ACEI
when used concomitantly. Some of the beneficial effects of ACEIs are thought to be due to inhibiting the
breakdown of bradykinin, which in turn, increases the production of vasodilatory prostaglandins. Aspirin,
which blocks cyclooxygenase, may therefore interfere with the full benefit of an ACEI by inhibiting
vasodilatory prostaglandin synthesis.141,142 Much of the discussion was prompted from the publication ofretrospective analyses of data from large trials evaluating the benefits of treatment with an ACEI.24,143 A
cohort analysis of SOLVD found that treatment with an antiplatelet agent (e.g., aspirin or dipyridamole)
was associated with a reduction in all-cause mortality and a decrease in the risk of death or hospital
admission for HF. In contrast, this association was not apparent in patients treated with an ACEI who wereon an antiplatelet agent at baseline, and patients on an ACEI did not experience a reduction in all-cause
mortality as did patients randomized to enalapril who were not on an antiplatelet agent. There was a
reduction in the combined risk of death or hospital admission for HF in patients on an ACEI andantiplatelet agent.24 In an analysis of CONSENSUS II in patients with acute MI, those in the ACEI
treatment group who were taking aspirin at baseline experienced a lower mortality benefit than patients
who were on an ACEI without aspirin.143 In a retrospective analysis of over 22,000 patients from six longterm randomized controlled trials, treatment with an ACEI decreased the risk of major clinical outcomes(composite death, MI, stroke, HF hospitalization, or revascularization) by 20% in patients also receiving
aspirin, and by 29% in patients not on concomitant aspirin therapy (interaction test not statisticallysignificant).144 Two additional evaluations of patients prescribed an ACEI in conjunction with aspirincompared to an ACEI without aspirin, did not find an association between outcome and concomitant
aspirin use.145,146 A dose-related adverse effect of aspirin was reported in one retrospective evaluation
where there was an increase in mortality in the patients receiving high dose aspirin (> 325mg) compared tothose on low dose or no aspirin.147 It is difficult to determine the clinical significance of these results given
the retrospective nature of the analyses and the potential contribution of differences in the groups atbaseline.24,141-147 A prospective evaluation of patients with systolic HF receiving warfarin, aspirin, or
clopidogrel reported no significant difference in the primary outcome of death, MI, or stroke; although
there was a significant reduction in HF hospitalizations with warfarin compared to aspirin.148,149 This trial
was terminated early due to poor enrollment.148 Therefore, given the benefit of aspirin in patients withcoronary artery disease, there is insufficient evidence to warrant a change in the current recommendations
in patients with coronary artery disease and HF.
EVIDENCE
Grading System
Intervention
An ACEI is recommended in all patients with Stage C
HF, unless contraindicatedH.

6

References
CONSENSUS (1987)
SOLVD (1991)
V-HeFT II (1991)
SOLVD 12yr (2003)
ACC/AHA (2005)
HFSA (2006)

QE
I
I
I
II-1
III
III

USPSTF
OQ
SR
I
A

1

ACC/AHACR
LE
I
C

Beta-Adrenergic Blockers

OBJECTIVE•

To provide recommendations for the appropriate use of beta-adrenergic blockers in patients with adiagnosis of systolic HF
24

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

BACKGROUND
Due to their beneficial effects on morbidity and mortality, a beta-adrenergic blocker should be used inpatients with Stage C HF, unless contraindicated. Therapy should be initiated at low doses and titrated totarget doses or based on patient tolerability. The majority of clinical trials evaluating efficacy of a betaadrenergic blocker in patients with HF were conducted in patients receiving an ACEI and a diuretic.
Patient factors may be taken into consideration when determining whether to initiate therapy first with an
ACEI or beta-adrenergic blocker; with subsequent addition of the alternate drug class.
RECOMMENDATION
Beta-Adrenergic Blocker Therapy in Stage C HF•

Stable patients with current or prior symptoms of HF due to systolic dysfunction should receive
therapy with a beta-adrenergic blocker that has proven to reduce mortality (i.e., bisoprolol, carvedilol,sustained release metoprolol succinate) unless contraindicated

DISCUSSION
Activation of the sympathetic nervous system (SNS) is one of the proposed compensatory mechanisms tomaintain circulation in the presence of left ventricular dysfunction. However, activation of the SNS canresult in beta-receptor down-regulation, LVH, cardiotoxic effects, and arrhythmia. It is thought that one ormore of these effects may contribute to HF progression.1,150 Therefore, using a beta-adrenergic blocker in apatient with HF due to systolic dysfunction could potentially negate some of these adverse effects on theheart.
Numerous trials have been conducted that demonstrate the beneficial effects of beta-adrenergic blockers in
reducing symptoms, hospitalization, and progression of disease in patients with HF due to systolic
dysfunction.1,151-165 However, more recent evidence has demonstrated a mortality benefit with the use ofbeta-adrenergic blockers in this patient population159-167 (Appendix C). The beta-adrenergic blockers thathave been studied for chronic HF and have demonstrated a reduction in mortality include bisoprolol,
carvedilol, and sustained release metoprolol succinate. Bisoprolol, titrated to 10 mg once daily, wascompared to placebo in patients with primarily NYHA class III HF receiving standard therapy in thesecond Cardiac Insufficiency Bisoprolol Study (CIBIS II). The primary endpoint of all-cause mortality was
reduced with bisoprolol, occurring in 11.8% of patients, compared to 17.3% of patients on placebo.160
Carvedilol was studied in patients with NYHA class II and III HF (U.S. Carvedilol Heart Failure Study),161
as well as in patients with more severe HF as in the Carvedilol Prospective Randomized Cumulative
Survival Study (COPERNICUS).162 After a median of 6.5 months, the primary endpoint of death wasreported in 3.2% of patients in the U.S. Carvedilol Study receiving carvedilol (target dose 25 mg twice
daily) compared to 7.8% of patients on placebo.161 In COPERNICUS, the primary endpoint of all-cause
mortality occurred in 11.3% of patients randomized to carvedilol compared to 16.8% of patients receiving
placebo.162 In the Carvedilol Or Metoprolol European Trial (COMET), carvedilol at a target dose of 25 mg
twice daily was compared to the immediate-release formulation of metoprolol tartrate, at target doses of 50
mg twice daily. All-cause mortality was reported to be lower in patients on carvedilol (33.9%) compared topatients receiving metoprolol (39.5%) in this study (additional discussion below).167 All-cause mortality
was also a primary endpoint in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart
Failure (MERIT-HF), and was reported in 7.3% of patients randomized to the extended-release formulationof metoprolol succinate (metoprolol XL at a target dose 200mg once daily) compared to 10.9% of patients
receiving placebo.159
It is unknown if other beta-adrenergic blockers have a similar benefit, as not all beta-adrenergic blockers
studied have shown a clear reduction in mortality.151,167,168

25

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

These agents have also demonstrated efficacy in patients with advanced HF.160,162,169 In a subgroup analysis
of MERIT-HF, 795 patients with NYHA class III or IV HF with a LVEF < 25% who received placebo or
metoprolol XL were compared. Similar to COPERNICUS with carvedilol,162 the mean baseline LVEF was
19.1% and the annual mortality for patients in the placebo group was 19%. Patients randomized tometoprolol XL experienced a significant decrease in risk of total mortality (39%), death due to worsening
HF (55%), hospitalization due to worsening HF (45%), and combined all-cause mortality or all-cause
hospitalization (29%) compared to placebo.169
In another post hoc analysis of MERIT-HF, the beneficial effects on morbidity and mortality withmetoprolol XL were also seen in the subgroup of 898 women, including 183 women with stable severe
HF.170The difference in response to treatment with a beta-adrenergic blocker based on race has also been
evaluated. After subgroup analysis in the Beta-Blocker Evaluation of Survival Trial (BEST), there was asignificant survival benefit in nonblack patients but not in black patients.168 These results are contrary tofindings from a retrospective comparison of patients enrolled in the U.S. Carvedilol Study where thebenefit of carvedilol was not statistically significantly different between black and nonblack patients.171 A
meta-analysis by the U.S. Department of Health and Human Services reported the estimate of pooled
random-effects of the relative risk for mortality in black patients to be 0.67 (95% CI 0.39-1.16) compared
to 0.63 (95% CI 0.52-0.77) for white patients. Results were similar for the pooled estimates from thehazard ratio analysis. The evidence report to address the potential difference in mortality of betaadrenergic blockers depending on race concluded that black patients should derive the same benefits as
white patients when treated with bisoprolol, carvedilol, or metoprolol succinate (the results of BEST were
not included in the pooled analysis).92
The question of whether to use a selective beta-adrenergic blocker (e.g., bisoprolol or metoprolol) versus anon-selective agent with alpha-adrenergic blocking and antioxidant effects (e.g., carvedilol) remains
controversial.167,172-174 Although COMET demonstrated a statistically significant improvement in survivalwith carvedilol compared to immediate-release metoprolol (tartrate), it is unknown whether there is adifference between carvedilol and immediate-release metoprolol tartrate or metoprolol succinate(metoprolol XL) when prescribed at the recommended target doses. Since metoprolol succinate was notavailable at the time of enrollment in COMET, immediate-release metoprolol tartrate was selected as thecomparator to carvedilol, at doses that were expected to result in comparable beta-blockade. Much of the
discussion about the results of COMET includes the difference in target dose and effect on resting heartrate.175 The dose of carvedilol used in COMET achieved a similar reduction in heart rate as seen in U.S.
Carvedilol (i.e., 13 beats per minute).161,167 The mean dose of metoprolol tartrate used in COMET was lessthan the mean dose in the Metoprolol in Dilated Cardiomyopathy (MDC) trial (i.e., 85 vs. 108mg/d), andresulted in less of a decrease in heart rate (i.e., 11.7 vs. 15 beats per minute).151,167 The mean dose in
MERIT-HF was 159mg/d and achieved a reduction in heart rate of 14 beats per minute.159 Whether thesefactors had an influence on the results is unknown. Very few trials with beta-adrenergic blockers that areavailable in the U.S. other than bisoprolol, carvedilol, or metoprolol succinate have been published. It istherefore unknown if treatment with other beta-adrenergic blockers would provide the same benefits asseen with the agents that have demonstrated a reduction in mortality in patients with heart failure.176,177
The majority of patients included in the beta-adrenergic blocker trials received therapy with an ACEI.
Survival benefit in the ACEI trials ranged from 12 to 33%, which was mainly a result of reduction in deaths
from worsening HF. Meta-analyses of the beta-adrenergic blocker trials show a reduction in mortality of
approximately 30 to 35%.85,177-179 It is felt that the use of an ACEI and beta-adrenergic blocker in patientswith HF is synergistic180 and should be used in combination whenever possible.1 Whether to begin
treatment naïve patients with a beta-adrenergic blocker or an ACEI has yet to be resolved; according to theresults from CIBIS III, it appears that initial therapy with bisoprolol may be as safe and efficacious asstarting treatment with enalapril (refer to Appendix C for detailed results).166 In patients with HF,
utilization of the beta-adrenergic blockers is typically not as high as that seen with the ACEIs,4 even thoughpatient tolerability appears to be similar.181 As the majority of clinical trials evaluating efficacy of a betaadrenergic blocker in patients with HF were conducted in patients receiving an ACEI and a diuretic,
26

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

clinicians may choose to initiate therapy with a beta-adrenergic blocker once the patient has been stabilized
on treatment with an ACEI.54 Initiation of therapy with a beta-adrenergic blocker may be considered priorto achieving a target dose of the ACEI, with concomitant titration;53 as benefit with combination therapy,
even at lower doses of an ACEI, has been demonstrated.1,131,133 Every effort should be made to achievetarget doses of both an ACEI and beta-adrenergic blocker as tolerated by the patient. Implementation oftreatment guideline recommendations should be emphasized in order to provide patients with theopportunity for optimal drug therapy benefit.4`
Caution should be exercised when initiating a beta-adrenergic blocker in patients with HF. Initial dosages
should be low and titrated upward slowly and as tolerated. Patients can become transiently worse witheach dosage increase. Since patients may experience fluid retention during initiation, daily weights arerecommended with corresponding adjustments in diuretic dose. Some patients may also experience fatigue
or weakness that may resolve after several weeks or require dosage adjustments. Selection of a different
beta-adrenergic blocker may also be considered.182 Another factor that may contribute to a need for a delay
in titration is a low heart rate;79 although, the absolute increase in risk for hypotension, dizziness, andbradycardia is small and should be weighed against the overall benefit of beta-adrenergic blockers seen inclinical trials.182 Clinicians who do not have experience with beta-adrenergic blockers in patients with HF
should consult with a cardiologist or healthcare provider specializing in the management of HF. Anotheropportunity to initiate therapy may be predischarge, provided the patient is stable and their condition does
not necessitate use of intravenous therapy for HF.1,183 It is important that patients with HF on a betaadrenergic blocker are titrated carefully to a target dose as used in clinical trials or as tolerated (refer toAppendices A and C).184-191 Common drug interactions are listed in Appendix B.
Factors that appear to contribute to a beneficial response are selection of patients who are clinically stable(i.e., not hospitalized in intensive care, no or minimal evidence of volume overload or depletion, no recent
treatment with intravenous positive inotropic agents) when therapy starts, a low initial dosage, a gradualincrease in the dosage (2 week intervals; with optimal doses achieved in 8 to 12 weeks53), and an adequate
duration of treatment (3-12 months before effects are seen).
Beta-adrenergic blockers should not be used in patients with bronchospastic disease, symptomatic
bradycardia, or advanced heart block without a pacemaker. Caution should be used in patients withasymptomatic bradycardia with a HR of less than 60 beats per minute.1 If the patient is on digoxin with a
HR of less than 60 bpm, reconsider digoxin in favor of the benefits of a beta-adrenergic blocker, or
consider referral to a cardiologist for adjustment in therapy. It should be noted that patients with DM orchronic obstructive pulmonary disease were not excluded from the clinical trials.1,159-161,192
EVIDENCE
Grading System
Intervention
Use a beta-adrenergic blocker with proven mortality
benefit in patients with stable Stage C HF

I.

6References
US Carvedilol (1996)
MERIT-HF (1999)
CIBIS-II (1999)
COPERNICUS (2001)
Shibata (2001)
CIBIS I & II (2002)
COMET (2003)
ACC/AHA (2005)
HFSA (2006)

QE
I
I
I
I
I
I
I
III
III

USPSTF
OQ
SR
I
A

1

ACC/AHA
CR
LE
I
A

Angiotensin II Receptor Antagonists

OBJECTIVE•

To provide recommendations for the appropriate use of the angiotensin II receptor antagonists inpatients with a diagnosis of systolic HF
27

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

BACKGROUND
Due to the established beneficial effects of the ACEIs and beta-adrenergic blockers in treating patients with
HF, long-term outcome trials with the angiotensin II antagonists have been conducted in patients alreadyreceiving standard therapy for HF or in patients who are unable to tolerate an ACEI. Treatment with anangiotensin II receptor antagonist has shown a beneficial effect in reducing cardiovascular death and HF
hospitalizations in patients unable to tolerate an ACEI, as well as in addition to standard therapy; althoughdata are conflicting as to the benefit of adding an angiotensin II receptor antagonist to patients receiving an
ACEI and a beta-adrenergic blocker. The effect of treatment with an angiotensin II receptor antagonist on
all-cause mortality has not yet been established.
RECOMMENDATIONS
Angiotensin II Receptor Antagonist in Stage C HF•

An angiotensin II receptor antagonist with demonstrated efficacy (i.e., candesartan and valsartan) in
the treatment of HF is recommended in patients with Stage C HF who are unable to tolerate therapy
with an ACEI•

Addition of an angiotensin II receptor antagonist to standard therapy (i.e., an ACEI and betaadrenergic blocker) may be considered to decrease cardiovascular death or HF hospitalizations inpatients with persistent symptoms (see discussion below); although it should also be noted that routine
use of an ACEI, angiotensin II receptor antagonist, and aldosterone antagonist is not recommended

DISCUSSION
Angiotensin-converting enzyme inhibitors reduce levels of angiotensin II, a potent vasoconstrictor, andinhibit the breakdown of bradykinin, a vasodilator. Production of angiotensin II also occurs throughalternative pathways. The angiotensin II receptor antagonists selectively block the angiotensin II type1
receptor so that the effects of angiotensin II are blocked regardless of how it is produced. The contributionof bradykinin to the favorable results of the ACEI trials in HF patients is unknown, but may be as importantas suppression of angiotensin.1
Trials have been conducted evaluating the majority of the angiotensin II receptor antagonists,demonstrating a favorable effect on patient symptoms or NYHA functional class compared to placebo,191195
with comparable benefits to an ACEI.196-201 Results of long-term effects on morbidity and mortality
have been published in patients treated with the angiotensin II receptor antagonists, candesartan, losartan,and valsartan. The results of these trials are briefly discussed with details found in Appendix C.
One of the first trials to evaluate long-term morbidity and mortality outcomes with an angiotensin II
receptor antagonist in patients with HF was ELITE II (Evaluation of Losartan in the Elderly); which
evaluated the effects of losartan 50mg once daily compared to captopril 50mg three times daily on overallmortality and cardiac events (sudden cardiac death or resuscitated cardiac arrest).202 This trial was afollow-up to the original ELITE Study, that although not hypothesized a priori, reported a favorable
mortality rate with losartan.203 In ELITE II, there was no significant difference in all-cause mortality
between the treatment groups (17.7% on losartan vs. 15.9% on captopril). There was no difference
between the groups in sudden death or resuscitated cardiac arrest, or hospital admissions. However, thiswas a superiority trial not designed to detect equivalence between groups.202
The Val-HeFT (Valsartan Heart Failure Treatment) study was a placebo-controlled trial that evaluated the
addition of valsartan 160 mg twice daily to patients with HF on standard therapy (93% ACEI, 35% betaadrenergic blockers). Overall mortality (a primary endpoint) was similar, occurring in 19.7% of patients inthe valsartan group and 19.4% of patients on placebo. The combined primary endpoint of mortality andmorbidity (i.e., cardiac arrest with resuscitation, HF hospitalization, or intravenous inotropic agents or
28

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

vasodilators for over 4 hours) occurred in 28.8% and 32.1% of patients on valsartan and placebo,
respectively. This included a reduction in hospitalizations for HF (13.8% valsartan vs. 18.2% placebo).
However, death from any cause (as first event) was higher in patients on valsartan compared to patients
receiving placebo (14.2% vs. 12.6%, respectively). According to a subgroup analysis, there was anincreased risk of mortality (p=0.009) and a trend toward an increased risk of combined morbidity andmortality in patients receiving valsartan in conjunction with an ACEI and beta-adrenergic blocker. Patients
who were not on an ACEI or beta-adrenergic blocker experienced a significant reduction in mortality(p=0.012). Patients on valsartan but not on an ACEI (with or without a beta-adrenergic blocker) had alower risk of death and a lower risk of the combined endpoint.204 A subanalysis of the 366 patients in ValHeFT who were not on an ACEI reported a 33% decrease in all-cause mortality (p=0.017) and a 53%
decrease in combined morbidity and mortality (p<0.001).205
The CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) Overall
program combined the results of three placebo-controlled trials evaluating therapy with candesartan titrated
to a target dose of 32mg once daily:206 CHARM-Added evaluated patients with systolic HF on standard
therapy (100% ACEI; 55% beta-adrenergic blockers);207 CHARM-Alternative studied patients with systolic
HF and previous ACEI intolerance;208 and CHARM-Preserved included patients with HF and LVEF >40%.70 In CHARM-Overall, the primary outcome of all-cause mortality was numerically reduced withcandesartan, although the result did not achieve statistical significance. The secondary endpoint of
combined CV death or HF hospitalization was significantly reduced by 16% compared to placebo.206 In apooled analysis of patients with LVEF < 40%, there was a significant 12% reduction in mortality.209
In the CHARM-Added trial, the combined primary endpoint of CV mortality or HF hospitalization was
significantly reduced by 15% compared to placebo in patients on candesartan in addition to standard
therapy including an ACEI. The difference in all-cause mortality was not statistically significant. In thesubgroup of patients on therapy with candesartan in combination with an ACEI and beta-adrenergic
blocker, there was also a significant reduction in the risk of CV death or HF hospitalization compared topatients on placebo; the difference in all-cause mortality in this subgroup was not statistically significant.207
This is in conflict with the increase in mortality seen in the subgroup analysis of Val-HeFT in patients on
combination ACEI, beta-adrenergic blockers, and angiotensin II antagonist.204 Regarding the addition of anangiotensin II receptor antagonist to standard therapy for HF, the ACC/AHA HF clinical practiceguidelines recommend (Class IIb: i.e., usefulness/efficacy is less well established by evidence/opinion) that
this may be considered in patients with persistent symptoms despite standard therapy for HF (Level of
Evidence B).1 It is also important to note that the routine use of an ACEI, angiotensin II receptor
antagonist, and aldosterone antagonist is not recommended.1
The combined primary endpoint of CV mortality or HF hospitalization was reduced by 23% in patientswith a history of ACEI intolerance randomized to candesartan compared to those on placebo in the
CHARM-Alternative trial. There was not a statistically significant reduction in all-cause mortality.208
The angiotensin II receptor antagonists have yet to be shown to be equivalent or superior to the ACEIs in
reducing long-term outcomes of morbidity and mortality in randomized controlled trials of patients with
HF. A meta-analysis of 38,080 patients reported that use of an angiotensin II receptor antagonist in patientswith HF reduced all-cause mortality [OR (odds ratio) 0.83; 95% CI 0.69-1.00] compared to placebo,
although this was influenced largely by data from CHARM-Alternative. There was also a statisticallysignificant reduction in HF hospitalizations (OR 0.64; 95% CI 0.53-0.78) with an angiotensin II receptor
antagonist compared to placebo. There was not a significant difference in all-cause mortality or HF
hospitalizations when data with an angiotensin II receptor antagonist were compared to results with an
ACEI. The analysis also compared an angiotensin II receptor antagonist in combination with an ACEI vs.
an ACEI alone, without a significant difference in all-cause mortality; although there was a statisticallysignificant reduction in HF hospitalizations (OR 0.77; 95% CI 0.69-0.87) favoring combination therapy.210
These results are similar to a previous meta-analysis of 12,469 patients that reported a trend toward
improved mortality and hospitalizations with an angiotensin II receptor antagonist compared to placebo inpatients not on an ACEI, and the combination of an angiotensin II receptor antagonist and ACEI
significantly reduced the risk of hospitalizations compared to patients on an ACEI alone.211 Another meta29

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

analysis reported a reduction in morbidity and mortality, but not mortality alone, in patients receiving anangiotensin II receptor antagonist in combination with an ACEI, regardless of a beta-adrenergic blocker, or
when a beta-adrenergic blocker was not part of therapy. Combined morbidity and mortality, or theendpoint of mortality alone, was not reduced in patients receiving all three classes of medications.212
Use of an angiotensin II receptor antagonist can be considered in patients who are unable to tolerate
treatment with an ACEI due to cough, although there is a slight chance that patients may develop a coughwith an angiotensin II receptor antagonist.213
An angiotensin II receptor antagonist should be used with extreme caution in a patient who has previously
experienced angioedema on an ACEI.1 The incidence of angioedema in patients taking ACEIs is
approximately 0.1-1.2 %.214 It has been reported that black American patients have an increased relativerisk of 4.5 of angioedema associated with use of an ACEI compared to white patients.215 Angioedema has
been reported with the angiotensin II receptor antagonists but to a much lesser degree than ACEIs. The
exact mechanism is unknown; in ACEIs, it is thought to be related to bradykinin accumulation. In the
CHARM-Alternative trial with candesartan in patients with HF and a history of ACEI intolerance, 3 of1013 patients randomized to candesartan experienced angioedema. One of these patients required
discontinuation of the drug (0.1%). All 3 cases occurred out of the 39 patients who previously experienced
angioedema or anaphylaxis on an ACEI (7.7%). None of the 1015 patients who received placebo
experienced angioedema.208 There have been a number of published case reports of angioedema in patientstreated with an angiotensin II receptor antagonist.214,216-230 In approximately one-third of these cases, thepatients previously experienced angioedema with an ACEI. Therefore, extreme caution is warranted inpatients who have previously experienced angioedema.216,224,226,227,231
The angiotensin II receptor antagonists, like the ACEIs, decrease release of aldosterone from the adrenal
cortex, which can lead to decreased potassium excretion. It is unclear at this time if treatment with anangiotensin II receptor antagonist would be an appropriate alternative in patients who develop
hyperkalemia on an ACEI.120,201,203,232 In the CHARM-Overall programme, hyperkalemia resulted indiscontinuation of study drug in 2.2% of patients on candesartan compared to 0.6% patients on placebo(p<0.0001). In the overall analysis, 41% of patients received concomitant treatment with an ACEI andapproximately 17% were on spironolactone.206 As with the ACEIs, it is recommended that patients on anangiotensin II receptor antagonist have their blood pressure, renal function, and potassium reevaluatedwithin one to two weeks after initiating therapy, and monitored after dose adjustments.1 Patients receiving
an angiotensin II receptor antagonist in conjunction with and ACEI, potassium supplements, or potassiumsparing diuretics (including spironolactone) should be monitored closely as combination therapy may resultin an increased potassium level. Other clinically significant drug interactions with the angiotensin II
receptor antagonists are listed in Appendix B.
EVIDENCE
Grading System
Intervention
Use an angiotensin II receptor antagonist in patientson standard therapy for HF who cannot tolerate an
ACEI

Consider an angiotensin II receptor antagonist in
addition to standard therapy (i.e., an ACEI and betablocker) in patients with persistent symptoms

6

References
Val-HeFT (2001)
Maggioni (2002)
Jong (2002)
CHARM-Alternative (2003)
CHARM Overall (2003)
Lee (2004)
ACC/AHA (2005)
HFSA (2006)
Val-HeFT (2001)
Jong (2002)
CHARM-Added (2003)
CHARM Overall (2003)
Lee (2004)
Dimopoulos (2004)
ACC/AHA (2005)
HFSA (2006)

30

USPSTF
QE
OQ
SR
I
A
I
II-2
I
I
I
I
III
III
II
B
I
I
I
I
I
I
III
III

1

ACC/AHA
CR
LE
I
A

IIb

B

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

J.

Hydralazine in Combination with a Nitrate

OBJECTIVE•

To provide recommendations for the appropriate use of hydralazine and a nitrate in patients with adiagnosis of systolic HF

BACKGROUND
An earlier trial compared the combination of hydralazine and isosorbide dinitrate (ISDN) to therapy with an
ACEI and based on these results, the combination of hydralazine and ISDN was considered a therapeutic
option in patients unable to tolerate an ACEI. The combination of hydralazine and ISDN had not beenpreviously studied in addition to standard therapy (i.e., an ACEI and beta-adrenergic blocker); however,results of a recent trial in self-identified black patients reported a significant reduction in mortality and HF
hospitalization with the combination of hydralazine and ISDN. It is not clear whether these results can beextrapolated to the general patient population.
RECOMMENDATION
Therapy with Hydralazine and a Nitrate in Stage C HF•

The combination of hydralazine and a nitrate should be considered, especially in African American
patients with NYHA Class III or IV HF, who continue to have symptoms despite therapy with an
ACEI (or an angiotensin II receptor antagonist if an ACEI is not tolerated) and beta-adrenergic blocker•

The combination of hydralazine and a nitrate may be considered as an alternative to an ACEI in
patients who are unable to tolerate an ACEI (or angiotensin II receptor antagonist) due to hypotension,
renal insufficiency, hyperkalemia, or possibly, angioedema

DISCUSSION
Peripheral vasodilators such as ISDN (venodilator) and hydralazine (arterial vasodilator) can produce
favorable hemodynamic effects in patients with HF.1 Earlier trials evaluated the combination of
hydralazine and ISDN in patients receiving standard therapy for HF (at the time, digoxin and a diuretic). In
the first of these two VA trials, the Vasodilator-Heart Failure Trial I (V-HeFT I), treatment with ISDN andhydralazine was reported to significantly reduce mortality by two years compared to placebo (25.6% vs.
34.3%, respectively).233 The second trial, V-HeFT II, compared treatment with ISDN and hydralazine tothat of an ACEI in HF patients (majority with NYHA class II or III HF). Mortality with ISDN andhydralazine was similar to that seen in V-HeFT I (25%), although mortality after two years was lower inpatients treated with an ACEI (18%) compared to patients on hydralazine and ISDN.121 The authors
concluded that the similar reduction in mortality seen with the combination of hydralazine and ISDN in VHeFT I and V-HeFT II, compared with the mortality in the placebo group, along with the reduction in
mortality seen with an ACEI, suggested that there is benefit in using a vasodilator as part of the treatment
regimen in patients with HF, and that there may be an additional benefit of using the two treatments
together.121
As discussed previously, there may be racial differences in response to therapy with the ACEIs where black
patients may not derive as much benefit as seen in white patients.125 Different results have been found withhydralazine and ISDN, where there has been a greater benefit in black patients compared to whitepatients.124 Racial differences in response to therapy have been reported in subanalyses of the V-HeFT I
and V-HeFT II trials. The annual mortality rate was significantly lower in black patients receiving ISDN
and hydralazine in V-HeFT I compared to black patients receiving placebo (9.7% vs. 17.3%, respectively);a similar effect was not seen in white patients on hydralazine and ISDN vs. placebo (annual mortality rate
16.9% vs. 18.8%, respectively).124 In V-HeFT II, white patients on enalapril experienced a significant
decrease in mortality compared to treatment with hydralazine and ISDN (annual mortality rate 11.0% vs.
31

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

14.9%, respectively), whereas black patients did not have a similar benefit (annual mortality rate withenalapril 12.8% vs. 12.9% with hydralazine and ISDN).124
More recently, the African-American Heart Failure Trial (A-HeFT), a long-term morbidity and mortality
trial in self-identified black patients with NYHA class III to IV HF, evaluated the fixed-dose combinationof hydralazine and ISDN compared to placebo. The majority of patients enrolled in the trial were also
receiving treatment with an ACEI (or angiotensin II receptor antagonist), a beta-adrenergic blocker,
diuretic, and digoxin; over one-third of patients were also receiving an aldosterone antagonist. The trial
was planned for 18 months of follow-up but was terminated early (mean follow-up 10 months) due to asignificant reduction in mortality in patients receiving treatment (6.2%) compared to those on placebo(10.2%). Treatment was associated with a 43% improvement in survival. There was also a significant 33%
reduction in first hospitalization for HF (another pre-specified component of the primary endpoint) withtreatment compared to placebo (16.4% vs. 24.4%, respectively). The primary endpoint was a composite
score (possible range -6 to +2, with a higher score representing a better outcome) with weighted values
based on mortality, survival to the end of the trial, first hospitalization for HF, no hospitalizations, andchange in quality of life. It was reported that patients receiving the combination hydralazine and ISDN hada primary composite score of -0.1+1.9 compared to -0.5+2.0 in the placebo group (p=0.01), indicating abenefit with hydralazine and ISDN in addition to standard drug therapy.234
Side-effects such as headache, tachycardia, flushing, hypotension, and edema, as well as dosing frequency,
preclude the use of this regimen in as many as one third of patients. Other adverse effects reported withhydralazine include rash, arthralgia, and other lupus-like symptoms. Common drug interactions are listed
in Appendix B.
EVIDENCE
Grading System
Intervention
Consider combination of hydralazine and a nitrate,
especially in African American patients in NYHAClass III or IV, who continue to have symptoms
despite therapy with an ACEI (or angiotensin II
receptor antagonist if an ACEI is not tolerated) andbeta-adrenergic blocker
Consider combination of hydralazine and a nitrate inpatients unable to take an ACEI or angiotensin II
receptor antagonist due to hypotension, renal
insufficiency, or drug intolerance

K.

6

References
A-HeFT (2004)
V-HeFT I (1986)
V-HeFT II (1991)
ACC/AHA (2005)
HFSA (2006)

USPSTF
QE
OQ
SR
I
B
I
I
I
III
III

V-HeFT I (1986)
V-HeFT II (1991)
ACC/AHA (2005)
HFSA (2006)

I
I
III
III

II

C

1

ACC/AHA
CR
LE
IIa
A

IIb

C

Digitalis

OBJECTIVE•

To provide recommendations for the appropriate use of digoxin in patients with a diagnosis of systolic
HF

BACKGROUND
Trials with digoxin have shown it to be beneficial in reducing HF associated symptoms and hospitalizations
in patients on standard therapy at trial enrollment (i.e., diuretic and an ACEI), but not in improving
survival.
RECOMMENDATION
Digoxin Therapy in Stage C HF•

Digoxin may be useful in decreasing hospitalizations in patients with current or previous HF symptoms
32

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

DISCUSSION
Digoxin is thought to be beneficial in patients with systolic HF through inhibition of sodium-potassium
adenosine triphosphatase resulting in reduced activation of the neurohormonal system and increased
contractility of the heart.1 The use of agents with positive inotropic activity as the mainstay of therapy for
HF has decreased over the years. This has primarily been due to the increased mortality associated withsome of the agents in this class. Digoxin appears to continue to have a role in the treatment of patients with
HF by improving patient symptoms and decreasing hospitalizations, without adversely affecting
survival.56,119,132,235
According to a meta-analysis, treatment with digoxin in patients with HF due to systolic dysfunction can
reduce the incidence of clinical deterioration235,236 by 12% compared to patients on placebo.235 The
Randomized Assessment of (the effect of) Digoxin on Inhibitors of the Angiotensin-Converting Enzyme(RADIANCE) Study evaluated 178 patients with NYHA class II or III HF stabilized on digoxin, diuretics,
and an ACEI. Patients were randomized to continuation of treatment or withdrawal of digoxin therapy for
12 weeks. Patients who were withdrawn from digoxin experienced worsening HF and a decreased exercise
tolerance, worsening NYHA class, decreased quality of life and LVEF.237 The Prospective Randomized
Study of Ventricular Failure and the Efficacy of Digoxin (PROVED) trial was a study evaluating 88
patients with NYHA class II or III HF on digoxin and diuretics and the effect of digoxin withdrawal orcontinuation of therapy. Patients who had digoxin withdrawn experienced a worsening of maximum
exercise performance, a higher percentage of treatment failures, and a decreased time to treatment
failure.238
These trials demonstrate the benefit of digoxin in reducing symptoms associated with mild to moderate HF.
The Digitalis Investigators Group (DIG) trial evaluated the benefit of digoxin on survival. This trial
enrolled 6,800 patients on diuretics and an ACEI who were randomized to receive digoxin or placebo for amean of 37 months. The results showed that treatment with digoxin significantly decreased the risk for
hospitalizations due to HF by 28%, although there was no significant reduction in mortality with digoxin
treatment.56 In a post hoc analysis of the DIG trial, a decrease in the rate of cardiovascular deaths anddeaths from worsening HF was found in the men, but not in the women who were treated with digoxin.
The death rate in women on digoxin was higher than women randomized to placebo (33.1% vs. 28.9%,
respectively; p=0.078). There was a decrease in hospitalizations for worsening HF in women on digoxincompared to women on placebo (30.2% vs. 34.4%, respectively; p=0.079). The median serum digoxin
concentration was significantly higher in women compared to men (0.9ng/ml based on 475 randomly
selected women vs. 0.8ng/ml in 1653 randomly selected men at one month after randomization; p=0.007);
although, there was not a statistically significant difference at 12 months (0.6ng/ml in randomly selected
men and women, respectively). Due to these findings, the authors suggest that the role of digoxin inwomen be reevaluated.239 Others suggest that a lower dose with a resultant serum concentration < 1ng/ml
be used.239,240
More recently, the relationship between serum digoxin concentrations and morbidity and mortality inwomen in the DIG trial were evaluated. This retrospective analysis demonstrated a reduction in death or
HF hospitalization and no increase in mortality in women with a digoxin concentration 0.5-0.9ng/ml. A
serum digoxin concentration of 1.2-2.0ng/ml was associated with an increase in risk for death in women.241
Another retrospective analysis of the DIG trial did not find a relationship on outcomes based on race.242
Digoxin is recommended in patients with symptomatic HF, without bradycardia, to improve clinical status
and thereby decrease the risk of hospitalization due to HF. Treatment is usually initiated in conjunction
with a diuretic, ACEI, and beta-adrenergic blocker since these latter two classes of agents have been shown
to improve survival in patients with HF.1 If there is no symptomatic improvement after one to two monthsof therapy, the risk vs. benefit of continued digoxin therapy should be considered. Digoxin is particularly
useful to control rapid ventricular response in patients with systolic dysfunction and atrial fibrillation.1

33

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Loading doses are not necessary for patients in normal sinus rhythm. The most commonly prescribed doseof digoxin is 0.125-0.25mg/day. Initial dosing should be conservative (e.g., 0.125mg once daily or every
other day) especially for patients with reduced CrCl, decreased weight and/or decreased muscle mass. The
utility of monitoring serum digoxin levels to assess efficacy has not been established.1 Subgroup analysis
from the DIG trial as well as in the Prospective Randomized Milrinone Survival Evaluation (PROMISE)
trials showed that higher concentrations (even within the therapeutic range) were associated with anincreased risk of mortality.243-246 In both the RADIANCE and PROVED trials, the mean digoxin serum
concentration was 1.2ng/ml and in the DIG trial, the mean serum digoxin level was 0.8 ng/ml at 12
months.237,238,244,246 In a meta-analysis of the PROVED and RADIANCE trials, the clinical efficacy (e.g.,worsening HF, change in LVEF, treadmill time) of low (0.5-0.9ng/ml), moderate (0.9-1.2ng/ml), and high(>1.2ng/ml) serum digoxin concentrations were compared. There was no relationship between theendpoints and the three groups.247 A post hoc analysis of the DIG trial showed a linear relationship for
mortality and increasing serum digoxin concentrations with a lower mortality seen in patients with adigoxin serum concentration of 0.5-0.8ng/ml, no reduction in mortality at 0.9-1.1ng/ml, and an increase inmortality at levels >1.2ng/ml. The analysis was limited to men.248 The authors concluded that lower levels
may provide optimal benefit without the risk of detrimental effects seen with higher levels,246,247 althoughlevels are not typically drawn unless monitoring for toxicity.
In general, trough (or a minimum of 6 hours post dose due to distribution) serum digoxin levels should bemonitored if any of the following occurs:
1. HF worsens or renal function deteriorates
2. Signs of toxicity develop (e.g., confusion, nausea, vomiting, abdominal pain, diarrhea, anorexia,
fatigue, arrhythmias, visual disturbances)
3. Dose adjustments are made4. Medications are added that affect the serum digoxin concentration (e.g., quinidine, verapamil,
amiodarone, antibiotics, anticholinergics) (refer to Appendix B), or the sensitivity to digoxin byaltering potassium levels
EVIDENCE
Grading System
Intervention
Consider digoxin to improve functional status andreduce frequency of hospitalizations if continued
symptoms

L.

6

References
Captopril-Digoxin (1988)
Jaeschke (1990)
RADIANCE (1993)
PROVED (1993)
DIG (1999)
Hood (2004)
ACC/AHA (2005)

QE
I
I
I
I
I
I
III

USPSTF
OQ
SR
II
B

1

ACC/AHA
CR
LE
IIa
B

Aldosterone Antagonists

OBJECTIVE•

To provide recommendations for the appropriate use of aldosterone antagonists in patients with adiagnosis of systolic HF

BACKGROUND
Aldosterone antagonists (e.g., spironolactone, eplerenone) competitively inhibit the effects of aldosterone.
One of the proposed mechanisms for benefit of using ACEIs in patients with HF is that of suppression of
production of aldosterone. Additional therapy with an aldosterone antagonist was originally felt not to benecessary, with concern for an increase in the risk of hyperkalemia due to potential for potassium retention
if aldosterone is decreased. Evidence has shown that addition of an aldosterone antagonist may bebeneficial in patients with severe HF (recent NYHA class IV HF and current class III or IV symptoms and
LVEF < 35%), even in patients already receiving an ACEI.1,249 This suggests that therapy with an ACEI
34

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

may not achieve long-term suppression of aldosterone production. There is insufficient evidence to make a
recommendation as to the use of aldosterone antagonists in patients with mild to moderate HF.
RECOMMENDATION
Aldosterone Antagonist Therapy in Stage C HF•

An aldosterone antagonist is beneficial in selected patients (e.g., moderately severe to severe HF
symptoms with reduced LVEF, or patients with LVEF < 40% early post-MI, and with adequate kidney
function and no hyperkalemia) who can be monitored for hyperkalemia or renal dysfunction

DISCUSSION
The above recommendations are based on the Randomized Aldactone Evaluation Study (RALES), a study
that enrolled 1663 patients with severe class IV HF within the last 6 months (and class III or IV at time ofenrollment), a LVEF < 35% within the last 6 months, and treated with conventional therapy (95% ACEI,
100% loop diuretic, 75% digoxin). In addition, 11% of patients were on a beta-adrenergic blocker.
Patients were randomized to spironolactone 25mg once daily or placebo. The primary endpoint was toevaluate all-cause mortality. After a mean follow-up of 24 months, the trial was discontinued early due to a
30% reduction in the risk of death due to progressive HF and sudden death of a cardiac cause in patients inthe spironolactone group (45.9% on placebo vs. 34.6% on spironolactone). There was also a significant
35% decrease in hospitalizations due to worsening HF in patients on spironolactone; these patients also
experienced significant improvement in symptoms.249
The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy Survival Study (EPHESUS)
compared an aldosterone antagonist, eplerenone (mean dose 42.6mg per day), to placebo in 6642 patientswith acute MI complicated by LV dysfunction, and symptoms of HF (patients with DM could be enrolled
without having HF symptoms), with the majority on standard therapy for this indication. Ninety percent ofpatients had symptomatic HF. Treatment with eplerenone significantly reduced the primary endpoints ofdeath from any cause (14.4% of patients on eplerenone vs. 16.7% of patients in the placebo group) anddeath from cardiovascular causes or first hospitalization for a cardiovascular event, including HF, recurrent
acute MI, stroke, or ventricular arrhythmia (eplerenone 26.7% vs. placebo 30.0%).250 Based on these data,an aldosterone antagonist may also be considered early after an acute MI in patients with LV dysfunctionand HF.1,53
These are highly complex patients with a high mortality rate and should be cared for by a multidisciplinary
HF team including a primary care provider in consultation with a cardiologist.251 The risk vs. benefit ofusing an aldosterone antagonist in these patients needs to be determined. An aldosterone antagonist may
contribute to serious hyperkalemia if not used properly in patients with HF.251,252
In addition to hyperkalemia, aldosterone antagonists can cause gynecomastia, gastrointestinal side effects,
and menstrual irregularities. In RALES, gynecomastia or breast pain was reported in 10% of male patientsin the spironolactone group. The incidence of hyperkalemia was not significant. However, it should be
noted that in both the RALES and EPHESUS trials, patients with serum creatinine > 2.5 mg/dL and serum
potassium > 5.0 mmol/L were excluded and patients were not taking other potassium-sparing diuretics. In
EPHESUS, the mean serum Cr concentration was 1.1 mg/dl at baseline.250 In clinical practice, reports of
discontinuations due to hyperkalemia appear to be higher than seen in the clinical trial.253-255 Hyperkalemia
occurs more frequently in patients receiving potassium supplements and in patients with renal
insufficiency. Use of potassium supplements with an aldosterone antagonist should be avoided unless
hypokalemia develops. The aldosterone antagonists should be used with caution in patients with renal
insufficiency; patients should be scheduled for follow-up electrolytes and renal function after initiation anddose adjustments.256 An aldosterone antagonist should also be used with caution in patients receiving
ACEIs or angiotensin II receptor antagonists due to the potential for hyperkalemia; potassium should bemonitored closely in these patients.257,258 In general, potassium supplements should be discontinued whentherapy with an aldosterone antagonist is initiated.1 Serum potassium should be monitored within 3 days
35

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

and at 1 week, and every 4 weeks for the first 3 months, then every 3 months thereafter.249,252 Morefrequent monitoring may be indicated in patients on concomitant medications that may increase potassium
levels, with renal insufficiency or DM, who are of advanced age, experiencing worsening HF or conditions
that may contribute to dehydration.257-260 If the potassium increases to > 5.5 mEq/L, the aldosterone
antagonist should be discontinued or the dose reduced. If serious hyperkalemia develops, therapy with thealdosterone antagonist should be discontinued.1
The initial dose of spironolactone used in RALES was 25mg once daily. The dose was decreased to 25mg
every other day in patients exhibiting hyperkalemia. The dose was increased to 50mg once daily at 8
weeks in patients who had signs or symptoms of worsening HF and did not have hyperkalemia. Patients
receiving 50mg spironolactone should have their serum potassium measured one week after the dose wasincreased, and then follow-up as described above.252 Refer to Appendix B for common drug interactions.
EVIDENCE
Grading System
Intervention
Consider low dose of an aldosterone antagonist (e.g., 12.5 to
25mg/d spironolactone) in patients with severe HF (recent
NYHA class IV HF and current class III or IV symptoms),
provided the potassium is normal (< 5 mEq/L) and kidney
function is adequate (serum Cr < 2.5 mg/dL in men; < 2.0
mg/dL in women) and in whom potassium and renal function
can be carefully monitored
Consider addition of an aldosterone antagonist in patients onstandard therapy for HF with LVEF < 40% early post-MI, whohave a normal potassium and adequate kidney function;
patients should be monitored for changes in potassium andkidney functionM.

6References
RALES (1999)
ACC/AHA (2005)
HFSA (2006)

QE
I
III
III

EPHESUS (2003)
ACC/AHA (2005)
HFSA (2006)

I
III
III

USPSTF
OQ
SR
I
A

I

A

1

ACC/AHA
CR
LE
I
B

NA

NA

Continue Present Management and Schedule Regular Follow-up

OBJECTIVE•

To provide recommendations for appropriate follow-up of patients with a diagnosis of systolic HF

BACKGROUND
Patients should receive regular follow-up in order to provide the most effective care. At each encounter, aninquiry should be made as to the patient's adherence to the medication regimen, nonpharmacologic
measures, and adverse effects to therapy. Patients should be scheduled for routine laboratory monitoring.
The patient should also be assessed for any change in functional status or frequency of hospitalizations, andmedication therapy should be optimized. A multidisciplinary approach to care and follow-up should be
utilized if appropriate to potentially improve care and outcomes.1,22,53
RECOMMENDATIONSGeneral Recommendation•

Patients should receive regular follow-up

Multidisciplinary Disease Management Programs
The following is a Class I recommendation by the ACC/AHA (i.e., there is evidence and/or generalagreement that a given procedure/therapy is useful and effective)1

36

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

•

Recommended for patients at high risk for hospital admission or clinical deterioration to facilitate
implementation of clinical practice guidelines, address barriers to behavioral change, and to decrease
the risk of HF hospitalization

The following is a Class IIb recommendation by the ACC/AHA (i.e., the usefulness/efficacy is less wellestablished by evidence/opinion)1• Consider for patients at low risk for hospital admission or clinical deterioration to facilitate
implementation of clinical practice guidelines
Performance Measures (refer to discussion in Introduction)
The following is a Class IIa recommendation by the ACC/AHA (i.e., the weight of evidence/opinion is infavor of usefulness/efficacy)1• Performance measures based on clinical practice guidelines may improve quality of patient care
DISCUSSION
Routine follow-up is an essential component of the overall management of patients with HF.1,261 At thistime the patient’s functional status can be evaluated and any adjustments made to the medication regimen.
The presence of any adverse events should also be determined. Evaluation of the patient’s serum
potassium is important due to the influence of medications on this parameter. There is the potential for
hypokalemia with diuretics that may lead to toxicity in a patient receiving digoxin. The ACEIs,
angiotensin II receptor antagonists, and aldosterone antagonists may all increase potassium, leading topotential toxicity.1
Adherence to the medication regimen is often not optimal262,263 and may lead to clinical deterioration inpatients with HF.5 Patients need to be educated on the importance of adherence to the medication regimen
in order to derive the benefits of decreased morbidity and mortality. The reason for not taking a medication
as prescribed should be investigated. If it is a result of an adverse effect, the dosage of the medication canbe adjusted or another class of medication considered.
Some facilities may have interdisciplinary HF disease management clinics or specialized programs toprovide continuity of care and improve treatment outcomes for patients with HF.1,186,265-282 Heart failure
disease management clinics have improved patient outcomes including improved function status,186,272,274
fewer hospitalizations,272-275,282 a reduction in mortality,186,266,275-278 increased utilization of ACEI and/or
beta-adrenergic blockers or their doses.186,266,267,278 In addition, reports suggest the use of these disease
management programs may be cost-effective.186,273
Proper education of patients and their family is imperative so that they may have an understanding of thecause of HF, prognosis, therapy, dietary restrictions, activity, adherence, and the signs and symptoms ofrecurrent HF.1,279 If patients and/or caregivers are cognizant of the signs and symptoms of recurrent HF,
they may have the opportunity to present to the healthcare practitioner before the patient's condition
deteriorates. Patients and caregivers should also be educated on the patient’s prognosis for function andsurvival. Treatment options, a living will, and advanced directives should be discussed with the patient andcaregiver in response to different events that may occur. The availability of hospice care should also be
discussed. Continuity of care is important for the patient’s overall care and for the implementation of thepatient’s request for end of life care.1

37

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

REFERENCES

38

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

1.

2.

3.
4.
5.
6.

7.
8.

9.
10.
11.
12.
13.
14.

15.

16.

17.

18.
19.

20.
21.

22.

Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management ofchronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation andManagement of Heart Failure). American College of Cardiology Web site. Available at:
http://www.acc.org/clinical/guidelines/failure/index.pdf.
Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics-2006 update. A report from theAmerican Heart Association statistics committee and stroke statistics subcommittee. 2006. Circulation. Available
at http://circ.ahajournals.org/cgi/content/short/113/6/e85.
Skrepnek GH, Abarca J, Malone DC, et al. Incremental effects of concurrent pharmacotherapeutic regimens forheart failure on hospitalizations and costs. Ann Pharmacother 2005;39:1785-91.
Komajda M, Lapuerta P, Hermans N, et al. Adherence to guidelines is a predictor of outcome in chronic heart
failure: the MAHLER survey. Eur Heart J 2005;26:1653-9.
Lee DS, Mamdani MM, Austin PC, et al. Trends in heart failure outcomes and pharmacotherapy: 1992 to 2000.
Am J Med 2004;116:581-9.
Harris RP, Helfand M, Woolf SH, et al. for the Methods Work Group, Third U.S. Preventive Services Task Force.
Current methods of the U.S. Preventive Services Task Force. A review of the process. Am J Prev Med
2001;20(3S):21-35.
Badgett RG, Lucey CR, Mulrow CD. Can the clinical examination diagnose left-sided heart failure in adults?
JAMA 1997;277:1712-9.
Thomas JT, Kelly RF, Thomas SJ, et al. Utility of history, physical examination, electrocardiogram, and chest
radiograph for differentiating normal from decreased systolic function in patients with heart failure. Am J Med
2002;112:437-45.
Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and managementof acute dyspnea. N Engl J Med 2004;350:647-54.
Criteria Committee of the American Heart Association. 1994 revisions to the classification of functional capacityand objective assessment of patients with disease of the heart. Circulation 1994;90:644-5.
Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart
failure. JAMA 1996;275:1557-62.
He J, Ogden LG, Bazzano LA, et al. Risk factors for congestive heart failure in US men and women: NHANES I
epidemiologic follow-up study. Arch Intern Med 2001;161:996-1002.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patientsrandomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
2002;288:2981-97.
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular andmicrovascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.
Lancet 2000;355:253-59.
Yusuf S, Sleight P, Pogue J, et al. for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of anangiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med
2000;342:145-53.
Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary arterydisease: randomized, double-blind, placebo-controlled, multicenter trial (the EUROPA study). Lancet
2003;362:782-8.
Braunwald E, Domanski MJ, Fowler SE, et al. for the PEACE Trial Investigators. Angiotensin-converting enzyme
inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.
Waldo AL, Prystowsky EN. Drug treatment of atrial fibrillation in the managed care era. Am J Cardiol
1998;81(5A):23C-9C.
Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation:
the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):429S56S.
The Task Force for the Diagnosis and Treatment of Chronic Heart failure of the European Society of Cardiology.
Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J
2005;26:1115-40.
39

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

23. Baker DW, Wright RF. Management of heart failure IV: Anticoagulation for patients with heart failure due to left
ventricular systolic dysfunction. JAMA 1994;272:1614-18.
24. Thatai D, Ahooja V, Pullicino PM. Pharmacological prevention of thromboembolism in patients with left
ventricular dysfunction. Am J Cardiovasc Drugs 2006;6:41-9.
25. Al-Khadra AS, Salem DN, Rand WM, et al. Warfarin anticoagulation and survival: a cohort analysis from theStudies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998;31:749-53.
26. The Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study. Final
results. Circulation 1991;84:527-39.
27. Hirsch J, Dalen JE, Fuster V, et al. Aspirin and other platelet-active drugs: the relationship among dose,
effectiveness, and side effects. Chest 1995;108(Suppl):247S-57S.
28. Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization forheart failure. Circulation 2006;113:2572-8.
29. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial
comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148:157-64.
30. Packer M, O’Connor M, Ghali JK et al for The Prospective Randomized Amlodipine Survival Evaluation Study
Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med
1996;335:1107-14.
31. Jafary F. Late-breaking clinical trial results – Session III. PRAISE-2: Prospective Randomized Amlodipine
Survival Evaluation. Presented by: Packer M. ACC Scientific Session 2000 http://www.medscape.com/
32. Cohn J, Ziesche S, Smith R et al for the V-HeFT Study Group. Effect of the calcium antagonist felodipine as
supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III.
Circulation 1997;96:856-63.
33. Alexander RW, Schlant RC, Fuster V, eds. Hurst’s the heart, arteries and veins. 9th ed. New York:McGraw Hill;
1998:2050.
34. Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 5th ed. Philadelphia: W. B.
Saunders;1997:1429.
35. Willerson JT, Chen PC, Hartwell EA, Buja LM. Congestive heart failure in a 70-year-old man [clinicalconference]. Circulation 1993;88:1336-47.
36. Brandt K, Cathcart ES, Cohen AS. A clinical analysis of the course and prognosis of forty-two patients withamyloidosis. Am J Med 1968;44:955-69.
37. Buja LM, Khoi NB, Roberts WC. Clinically significant cardiac amyloidosis: clinicopathologic findings in 15
patients. Am J Cardiol 1970;26:394-405.
38. Jacobson DR, Ittmann M, Buxbaum JN, Wieczorek R, Gorevic PD. Cardiac amyloidosis resulting fromtrasthyretin Ile 122 deposition in african-americans: two case reports. Texas Heart Inst J 1997;24:45-52.
39. Cassidy JT. Cardiac amyloidosis: two cases with digitalis sensitivity. Ann Intern Med 1961;55:989.
40. Pomerance A. Senile cardiac amyloidosis. Br Heart J 1965;27:711-8.
41. Ridolfi RL, Bulkley BH, Hutchins GM. The conduction system in cardiac amyloidosis. Clinical and pathologic
features of 23 patients. Am J Med 1977;62:677-86.
42. Hodkinson HM, Pomerance A. The clinical significance of senile cardiac amyloidosis: a prospective clinicopathological study. Q J Med 1977;46:381-7.
43. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA. Worsening of congestive heart failure in amyloid heartdisease treated by calcium channel-blocking agents. Am J Cardiol 1985;55:1645.
44. Griffiths BE, Hughes P, Dowdle R, Stephens MR. Cardiac amyloidosis with asymmetrical septal hypertrophy anddeterioration after nifedipine. Thorax 1982;37:711-2.
45. Pollak A, Falk RH. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest
1993;104:618-20.
46. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R, for the Grupo de Estudio de la Sobrevida'en la Insuficiencia Cardiaca en Argentina (GESICA). Randomized trial of low-dose amiodarone in severecongestive heart failure. Lancet 1994;344:493-8.
47. Singh SN, Fletcher RD, Fisher SG, et al., for the Survival Trial of Antiarrhythmic Therapy in Congestive Heart
Failure. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias. N Engl J
Med 1995;333:77-82.
48. Massie BM, Fisher SG, Radford M, et al. Effect of amiodarone on clinical status and left ventricular function inpatients with congestive heart failure. CHF-STAT Investigators. Circulation 1996;93:2128-34.
49. Torp-Pederson C, Møller M, Bloch-Thomsen PE, et al., for the Danish Investigations of Arrhythmia and Mortality
on Dofetilide Study Group. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N
Engl J Med 1999;341:857-65.
50. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: anunderrecognized public health problem. Arch Intern Med 2000;160:777-84.

40

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

51. Feenstra J, Heerdink ER, Grobbee DE, Stricker BHC. Association of nonsteroidal anti-inflammatory drugs with
first occurrence of heart failure and with relapsing heart failure: the Rotterdam study. Arch Intern Med
2002;162:265-70.
52. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure. A
Consensus Statement From the American Heart Association and American Diabetes Association. Circulation
2003;108:2941-8.
53. Adams KF, Lindenfeld J, Arnold JMO, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J
Cardiac Failure 2006;12:e1-e122.
54. Arnold JMO, Liu P, Demers P, et al. Canadian Cardiovascular Society consensus conference recommendations onheart failure 2006: Diagnosis and management. Can J Cardiol 2006;22:23-45.
55. Ahmed A, Aronow WS, Fleg JL. Higher New York Heart Association classes and increased mortality andhospitalization in patients with heart failure and preserved left ventricular function. Am Heart J 2006;151:444-50.
56. Massie BM, Abdalla I. Heart failure in patients with preserved left ventricular systolic function: do digitalis
glycosides have a role? Prog Cardiovasc Dis 1998;40:357-69.
57. The Digitalis Investigators Group: The effect of digoxin on mortality and morbidity in patients with heart failure.
N Engl J Med 1997;336:525-33.
58. Lenihan DJ, Gerson MC, Hoit BD, Walsh RA. Mechanisms, diagnosis and treatment of diastolic heart failure. Am
Heart J 1995;130:153-66.
59. Goldsmith SR, Dick C. Differentiating systolic from diastolic heart failure: pathophysiologic and therapeutic
considerations. Am J Med 1993;95:645-54.
60. Bonow RO, Edelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure: mechanisms
and management. Ann Intern Med 1992;117:502-10.
61. Vasan RS, Benjamin EJ, Levy D. Congestive heart failure with normal left ventricular systolic function. Arch
Intern Med 1996;156:146-57.
62. Weinberger HD. Diagnosis and treatment of diastolic heart failure. Hosp Pract 1999;34:115-8, 121-2, 125-6.
63. Setaro J, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated withabnormal left ventricular diastolic performance. Am J Cardiol 1990;66:981-6.
64. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a meta-analysisof 109 treatment studies. Am J Hypertens 1992;5:95-110.
65. Gottdiener JS, Reda DJ, Massie BM, et al. Effect of single-drug therapy on reduction of left ventricular mass inmild to moderate hypertension: comparison of six antihypertensive agents. Circulation 1997;95:2007-14.
66. Warner JG, Jr., Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance inpatients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567-72.
67. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part II: causal
mechanisms and treatment. Circulation 2002;105:1503-8.
68. Aronow WS, Kronzon I. Effect of enalapril on congestive heart failure treated with diuretics in elderly patientswith prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993;71:602-4.
69. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal
myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left
ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am
J Cardiol 1997;80:207-9.
70. Little WC, Wesley-Farrington DJ, Hoyle J, et al. Effect of candesartan and verapamil on exercise tolerance indiastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288-93.
71. Yusuf S, Pfeffer MA, Swedberg K, et al. for the CHARM Investigators and Committees. Effects of candesartan inpatients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
Lancet 2003;777-81.
72. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomized factorial trial
assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients withsuspected acute myocardial infarction. Lancet 1995;345:669-85.
73. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3: effects of lisinopril andtransdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute
myocardial infarction. Lancet 1994;343:1115-22.
74. Pfeffer MA, Braunwald E, Moye LA, et al. on Behalf of the SAVE Investigators. Effect of captopril on mortality
and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med
1992;327:669-77.
75. The Acute Infarction Ramipril (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity ofsurvivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
76. Hall AS, Murray GD, Ball SG, on behalf of the AIREX Investigators. Follow-up study of patients randomly
allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension Study (AIREX).
Lancet 1997;349:1493-7.
41

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

77. Kober L, Torp-Pedersen C, Carlsen JE, et al. for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A
clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.
78. Buch P, Rasmussen S, Abildstrom SZ, et al. for the TRACE investigators. The long-term impact of theangiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left
ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J 2005;26:145-52.
79. Ferrari R, for the Perindopril and Remodeling in Elderly with Acute Myocardial Infarction Investigators. Effects
of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome:results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI)
Study. Arch Intern Med 2006;166:659-66.
80. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients
after myocardial infarction. N Engl J Med 1998;339:489-97.
81. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patientssurviving acute myocardial infarction. N Engl J Med 1981;304:801-7.
82. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute
myocardial infarction. I. Mortality results. JAMA 1982;247:1707-14.
83. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patientswith congestive heart failure. Circulation 1986;73:503-10.
84. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with leftventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001;357:1385-90.
85. Vantrimpont P, Rouleau JL, Wun CC, et al., for the SAVE Investigators. Additional beneficial effects of betablockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study.
J Am Coll Cardiol 1997;29:229-36.
86. Exner DV, Dries DL, Waclawiw MA, Shelton B, Domanski MJ. Beta-adrenergic blocking agent use and mortality
in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of thestudies of left ventricular dysfunction. J Am Coll Cardiol 1999;33:916-923.
87. Shlipak MG, Browner WS, Noguchi H, et al. Comparison of the effects of angiotensin converting-enzyme
inhibitors and beta blockers on survival in elderly patients with reduced left ventricular function after myocardial
infarction. Am J Med 2001;110:425-33.
88. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects oflosartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: theOPTIMAAL randomized trial. Lancet 2002;360:752-60.
89. Pfeffer MA, McMurray J, Leizorovicz A, et al. Valsartan, captopril, or both in myocardial infarction complicatedby heart failure, left ventricular dysfunction , or both. (VALIANT). N Engl J Med 2003;349:1893-906.
90. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomaticpatients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.
91. Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life
expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet 2003;361:1843-8.
92. Pharmacologic management of heart failure and left ventricular systolic dysfunction: effect in female, black, anddiabetic patients, and cost-effectiveness. U.S. Department of Health and Human Services, 2003; Evidence
Report/Technology Assessment No. 82.
93. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure.
N Engl J Med 1997;336:525-33.
94. Vargo DL, Kramer WG, Black PK, et al. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide
and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 1995;57:601-9.
95. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int 1984;26:1839.
96. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide
therapy for patients with heart failure. Am J Med 2001;111:513-20.
97. Patterson JH, Adams KF Jr, Applefeld MM, Corder CN, Masse BR, for the Torsemide Investigators Group. Oral
torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte
excretion. Pharmacotherapy 1994;14:514-21.
98. Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect of diuresis on the performance of the failing left
ventricle in man. Am J Med 1981;70:234-9.
99. Parker JQ. The effects of oral ibopamine in patients with mild heart failure: a double-blind placebo controlled
comparison to furosemide. Int J Cardiol 1993;40:221-7.
100. Richardson A, Bayliss J, Scriven AJ, et al. Double-blind comparison of captopril alone against frusemide plus
amiloride in mild heart failure. Lancet 1987;2:709-11.
101. Cleland JGF, Swedberg K, Poole-Wilson PA. Successes and failures of current treatment of heart failure. Lancet
1998;352(1S):19SI-28SI.
42

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

102. Walma EP, Hoes AW, van Dooren C, Prins A, van der Does E. Withdrawal of long term diuretic medication inelderly patients: a double blind randomised trial. Br Med J 1997;315:464-8.
103. Grindstead WC, Francis MJ, Marks GF et al. Discontinuation of chronic diuretic therapy in stable congestive heart
failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73:881-6.
104. Young JB, Gheorghiade M, Uretsky BF, Patterson JH, Adams KF. Superiority of “triple” drug therapy in heart
failure: insights from PROVED and RADIANCE trials. J Am Coll Cardiol 1998;32:686-92.
105. Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med
1991;114:886-94.
106. Brater DC. Diuretic resistance: mechanisms and therapeutic strategies. Cardiology 1994;84(suppl 2):57-67.
107. Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart
failure: a randomized controlled trial. Br Heart J 1994;71:146-50.
108. Oster JR, Epstein M, Smoler S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium
retention. Ann Intern Med 1983;99:405-6.
109. Sica DA, Gehr TWB. Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic
relationships. Clin Pharmacokinet 1996;30:229-49.
110. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:38-50.
111. Kramer BK, Schweda F, Riegger GAJ. Diuretic treatment and diuretic resistance in heart failure. Am J Med
1999;106:90-6.
112. Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive
heart failure. J Am Coll Cardiol 1983;2:755-63.
113. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled,
randomized, double-blind study. Circulation 1984;70:271-8.
114. Chalmers JP, West MJ, Cyran J et al. Placebo-controlled study of lisinopril in congestive heart failure: a multicentre study. J Cardiovasc Pharmacol 1987;9(suppl III):S89-S97.
115. Pflugfelder PW, Baird MG, Tonkon MH, DiBianco R, Pitt B, for the Quinapril Heart Failure Trial Investigators.
Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a doubleblind, placebo-controlled study of quinapril. J Am Coll Cardiol 1993;22:1557-63.
116. Gunderson T, Swedberg K, Amtorp O, Remes J, Milsson B. Absence of an effect on exercise capacity of 12weeks treatment with ramipril in patients with moderate congestive heart failure. Eur Heart J 1994;15:1659-65.
117. Erhardt L, MacLean A, Ilgenfritz JU, Gelperin K, Blumenthal M, for the Fosinopril Efficacy/Safety Trial (FEST)
Study Group. Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart
failure. Eur Heart J 1995;16:1892-9.
118. Lechat P, Garnham SP, Desche P, Bounhoure JP. Efficacy and acceptability of perindopril in mild to moderatechronic congestive heart failure. Am Heart J 1993;126(3 Pt 2):798-806.
119. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin inpatients with mild to moderate heart failure. JAMA 1988;259:539-44.
120. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection
fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
121. Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in thetreatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10.
122. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: resultsof the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:142935.
123. Garg R, Yusuf S. Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-56.
124. Carson P, Ziesche S, Johnson G, Cohn JN, for the Vasodilator-Heart Failure Trial Study Group. Racial differencesin response to therapy for heart failure: analysis of the Vasodilator-Heart Failure Trials. J Cardiac Fail 1999;5:17887.
125. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-converting-enzyme inhibitor
therapy in black as compared to white patients with left ventricular dysfunction. N Engl J Med 2001;344:1351-7.
126. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor
therapy. Ann Intern Med 1992;117:234-42.
127. Masoudi FA, Rathore SS, Wang Y, et al. National patterns of use and effectiveness of angiotensin-converting
enzyme inhibitors in older patients with heart failure and left ventricular systolic dysfunction. Circulation
2004;110:724-31.
128. Bungard TJ, McAlister FA, Johnson JA, Tsuyuki RT. Underutilisation of ACEI inhibitors in patients withcongestive heart failure. Drugs 2001;61:2021-33.
129. Roe CM, Motheral BR, Teitelbaum F, Rich MW. Angiotensin-converting enzyme inhibitor compliance anddosing among patients with heart failure. Am Heart J 1999;138:818-25.
130. Massie BM, Armstrong PW, Cleland JGF, et al. Toleration of high doses of angiotensin-converting enzyme
inhibitors in patients with chronic heart failure: results from the ATLAS trial. Arch Intern Med 2001;161:165-71.
43

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

131. Packer M, Poole-Wilson PA, Armstrong PW et al on behalf of the ATLAS Study Group. Comparative effects of
low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality inchronic heart failure. Circulation 1999;100:2312-18.
132. Majumdar SR, McAlister FA, Cree M, et al. for the Group. Do evidence-based treatments provide incremental
benefits to patients with congestive heart failure already receiving angiotensin-converting enzyme inhibitors? A
secondary analysis of one-year outcomes from the Assessment of Treatment with Lisinopril and Survival(ATLAS) study. Clin Ther. 2004 May;26(5):694-703.
133. The NETWORK investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dosecomparison. Eur Heart J 1998;19:481-9.
134. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al., for the High Enalapril Dose Study Group. Outcome ofpatients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. J
Am Coll Cardiol 2000;36:2090-5.
135. Butler J, Arbogast PG, Daugherty J, et al. Outpatient utilization of angiotensin-converting enzyme inhibitors
among heart failure patients after hospital discharge. J Am Coll Cardiol 2004;43:2036-43.
136. Ghali JK, Dunselman P, Waagstein F, et al. Consistency of the beneficial effect of metoprolol succinate extended
release across a wide range dose of angiotensin-converting enzyme inhibitors and digitalis. J Card Fail
2004;10:452-9.
137. Ahmed A, Centor RM, Weaver MT, Perry GJ. A propensity score analysis of the impact of angiotensin-converting
enzyme inhibitors on long-term survival of older adults with heart failure and perceived contraindications. Am
Heart J 2005;149:737-43.
138. Punzi HA. Safety update: focus on cough. Am J Cardiol 1993;72:45H-8H.
139. Sharif MN, Evans BL, Pylypchuk GB. Cough induced by quinapril with resolution after changing to fosinopril.
Ann Pharmacother 1994;28:720-1.
140. Germino FW, Lastra J, Pool P et al. Evaluation of the cough profile of fosinopril in hypertensive patients with
ACE inhibitor-associated cough: a pilot study. Curr Ther Res 1993;54:469-75.
141. Stys T, Lawson WE, Smaldone GC, Stys A. Does aspirin attenuate the beneficial effects of angiotensin-converting
enzyme inhibition in heart failure? Arch Intern Med 2000;160:1409-13.
142. Olson KL. Combined aspirin/ACE inhibitor treatment for CHF. Ann Pharmacother 2001;35:1653-8.
143. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial
infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS
II). Am J Cardiol 1997;79:115-19.
144. Teo KK, Yusuf S, Pfeffer M, et al. for the ACE Inhibitors Collaborative Group. Effects of long-term treatment
with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet
2002;360:1037-43.
145. Harjai KJ, Solis S, Prasad A, Loupe J. Use of aspirin in conjunction with angiotensin-converting enzyme
inhibitors does not worsen long-term survival in heart failure. Int J Cardiol 2003;88:207-14.
146. Aumegeat V, Lamblin N, de Groote P, et al. Aspirin does not adversely affect survival in patients with stablecongestive heart failure treated with angiotensin-converting enzyme inhibitors. Chest 2003;124:1250-8.
147. Guazzi M, Brambilla R, Reina G, Tumminello G, Guazzi MD. Aspirin-angiotensin-converting enzyme inhibitor
coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin. Arch Intern
Med 2003;163:1574-9.
148. Massie BM, Krol WF, Ammon SE, et al. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH):
rationale, design, and baseline patient characteristics. J Card Fail 2004;10:101-12.
149. Thatai D, Ahooja V, Pullicino PM. Pharmacological prevention of thromboembolism in patients with left
ventricular dysfunction. Am J Cardiovasc Drugs 2006;6:41-9.
150. Pepper GS, Lee RW. Sympathetic activation in heart failure and its treatment with β-blockade. Arch Intern Med
1999;159:225-34.
151. Waagstein F, Bristow MR, Swedberg K et al for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study
Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441-6.
152. White M, Rouleau JL, Pericak D et al, on behalf of the RESOLVD Study Group. Effects of metoprolol-CR inpatients with ischaemic and dilated cardiomyopathy: the RESOLVD pilot study (phase II). (Abstract) Eur Heart J
1998;19(suppl):308.
153. CIBIS Investigators and Committees. A randomized trial of β-blockade in heart failure: The Cardiac Insufficiency
Bisoprolol Study (CIBIS). Circulation 1994;90:1765-73.
154. Colucci WS, Packer M, Bristow MR et al for the US Carvedilol Heart Failure Study Group. Carvedilol inhibits
clinical progression in patients with mild symptoms of heart failure. Circulation 1996;94:2800-6.
155. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of
carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997;349:375-80.
156. Packer M, Colucci WS, Sackner-Bernstein JD et al for the PRECISE Study Group. Double-blind, placebocontrolled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial.
Circulation 1996;94:2793-9.
44

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

157. Bristow MR, Gilbert EM, Abraham WT et al for the MOCHA Investigators. Carvedilol produces dose-related
improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation
1996;94:2807-16.
158. Cohn JN, Fowler MB, Bristow MR et al for the U.S. Carvedilol Heart Failure Study Group. Safety and efficacy of
carvedilol in severe heart failure. J Card Failure 1997;3:173-9.
159. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7.
160. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study (CIBIS-II): a randomised
trial. Lancet 1999;353:9-13.
161. Packer M, Bristow MR, Cohn JN et al for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol
on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55.
162. Packer M, Coats AJS, Fowler MB et al. for the Carvedilol Prospective Randomized Cumulative Survival Study
Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.
163. Packer M, Fowler MB, Roecker EB, et al. for the Carvedilol Prospective Randomized Cumulative Survival Study
Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the Carvedilol
Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002;106:2194-9.
164. Leizorovicz A, Lechat P, Cucherat M, Bugnard F. Bisoprolol for the treatment of chronic heart failure: a metaanalysis on individual data of two placebo-controlled studies-CIBIS and CIBIS II. Am Heart J 2002;143:301-7.
165. Shibata MC, Flather MD, Wang D. Systematic review of the impact of beta blockers on mortality and hospital
admissions in heart failure. Eur J Heart Fail 2001;3:351-7.
166. Willenheimer R, van Veldhuisen DJ, Silke B, et al on behalf of the CIBIS III Investigators. Effect on survival andhospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as comparedwith the opposite consequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
Circulation 2005;112:2426-35.
167. Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomesin patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized
controlled trial. Lancet 2003;362:7-13.
168. The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients withadvanced chronic heart failure. N Engl J Med 2001;344:1659-67.
169. Goldstein S, Fagerberg B, Hjalmarson A et al for the MERIT-HF Study Group. Metoprolol controlled
release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study. J
Am Coll Cardiol 2001;38:932-8.
170. Ghali JK, Piña IL, Gottlieb SS, Deedwania PC, Wikstrand JC, on behalf of the MERIT-HF Study Group.
Metoprolol CR/XL in female patients with heart failure: analysis of the experience in metoprolol extended-releaserandomized intervention trial in heart failure (MERIT-HF). Circulation 2002;105:1585-91.
171. Yancy CW, Fowler MB, Colucci WS et al. for the U.S. Carvedilol Heart Failure Study Group. Race and responseto adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001;344:1358-65.
172. Packer M, Antonopoulos GV, Berlin JA et al. Comparative effects of carvedilol and metoprolol on left ventricularejection fraction in heart failure: results of a meta-analysis. Am Heart J 2001;141:899-907.
173. Adams KF Jr. Which β-blocker for heart failure? Am Heart J 2001;141:884-8.
174. Yancy CW. Clinical trials of β-blockers in heart failure: a class review. Am J Med 2001;110:7S-10S.
175. Dargie HJ. Beta-blockers in heart failure. Lancet 2003;362:2-3.
176. Doughty RN, Rodgers A, Sharpe N, MacMahon S. Effects of beta-blocker therapy on mortality in patients withheart failure: a systematic overview of randomized controlled trials. Eur Heart J 1997;18:560-5.
177. Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a metaanalysis of randomized clinical trials. J Am Coll Cardiol 1997;30:27-34.
178. Lechat P, Packer M, Chalon S et al. Clinical effects of β-adrenergic blockade in chronic heart failure: a metaanalysis of double-blind, placebo-controlled, randomized trials. Circulation 1998; 98: 1184-91.
179. Brophy JM, Joseph L, Rouleau JL. β-blockers in congestive heart failure: a Bayesian meta-analysis. Ann Intern
Med 2001;134:550-60.
180. Gottlieb SS, Fisher ML, Kjekshus J, et al., on behalf of the MERIT-HF Investigators. Tolerability of β-blocker
titration in the metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF).
Circulation 2002;105:1182-88.
181. Komajda M, Lutiger B, Madeira H, et al. for the CARMEN investigators and co-ordinators. Tolerability ofcarvedilol and ACE-Inhibition in mild heart failure. Results of CARMEN (Carvedilol ACE-Inhibitor Remodelling
Mild CHF EvaluatioN). Eur J Heart Fail 2004;6:467-75.
182. Butler J, Khadim G, Belue R, et al. Tolerability to beta-blocker therapy among heart failure patients in clinicalpractice. J Card Fail 2003;9:203-9.
183. Gattis WA, O'Connor CM, Gallup DS, Hasselblad V, Gheorghiade M, IMPACT-HF Investigators andCoordinators. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results
45

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure(IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534-41.
184. Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: aquantitative overview of randomized trials. Arch Intern Med 2004;164:1389-94.
185. Nul D, Zambrano C, Diaz A, et al. for the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en
Argentina. Impact of a standardized titration protocol with carvedilol in heart failure: safety, tolerability, andefficacy-a report from the GESICA registry. Cardiovasc Drugs Ther 2005;19:125-34.
186. Jain A, Mills P, Nunn LM, et al. Success of a multidisciplinary heart failure clinic for initiation and up-titration of
key therapeutic agents. Eur J Heart Fail 2005;7:405-10.
187. Gullestad L, Wikstrand J, Deedwania P, et al. for the MERIT-HF Study Group. What resting heart rate should one
aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled
Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll
Cardiol 2005;45:252-9.
188. Simon T, Mary-Krause M, Funck-Brentano C, Lechat P, Jaillon P. Bisoprolol dose-response relationship in
patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II).
Eur Heart J 2003;24:552-9.
189. Maggioni AP, Sinagra G, Opasich C, et al. Beta blockers in patients with congestive heart failure: guided use inclinical practice Investigators. Treatment of chronic heart failure with beta adrenergic blockade beyond controlled
clinical trials: the BRING-UP experience. Heart 2003;89:299-305.
190. Deedwania PC, Giles TD, Klibaner M, et al. for the MERIT-HF Study Group. Efficacy, safety and tolerability of
metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF. Am Heart J
2005;149:159-67.
191. Riegger GAJ, Bouzo H, Petr P, et al. Improvement in exercise tolerance and symptoms of congestive heart failure
during treatment with candesartan cilexetil. Circulation 1999;100:2224-30.
192. Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensinconverting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure.
Circulation 1999;99:990-2.
193. Warner JG Jr., Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic
dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567-72.
194. Blanchet M, Sheppard R, Racine N, et al. Effects of angiotensin-converting enzyme inhibitor plus irbesartan on
maximal and submaximal exercise capacity and neurohumoral activation in patients with congestive heart failure.
Am Heart J 2005;149:e1-7.
195. O'Meara E, Solomon S, McMurray J, et al. Effect of candesartan on New York Heart Association functional class.
Eur Heart J 2004;25:1920-6.
196. Houghton AR, Harrison M, Cowley AJ. Haemodynamic, neurohumoral and exercise effects of losartan vs.
captopril in chronic heart failure: Results of an ELITE trial substudy. Eur J Heart Fail 1999;1:385-93.
197. Lang RM, Elkayam U, Yellen LG, et al. Comparative effects of losartan and enalapril on exercise capacity andclinical status in patients with heart failure. J Am Coll Cardiol 1997;30:983-91.
198. Dickstein K, Chang P, Willenheimer R, et al. Comparison of the effects of losartan and enalapril on clinical status
and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol
1995;26:438-45.
199. Dunselman PH, Replacement of Angiotensin Converting Enzyme Inhibition I. Effects of the replacement of theangiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patientswith congestive heart failure. The replacement of angiotensin converting enzyme inhibition (REPLACE)
investigators. Int J Cardiol 2001;77:131-8.
200. Willenheimer R, Helmers C, Pantev E, et al. Safety and efficacy of valsartan versus enalapril in heart failure
patients. Int J Cardiol 2002;85:261-70.
201. McKelvie RS, Yusuf S, Pericak D, et al., for the RESOLVD Pilot Study Investigators. Comparison ofcandesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for
Left Ventricular Dysfunction (RESOLVD) Pilot Study. Circulation 1999;100:1056-64.
202. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients withsymptomatic heart failure: randomized trial: the Losartan Heart Failure Survival Study ELITE II. Lancet
2000;355:1582-7.
203. Pitt B, Segal R, Martinez FA, et al. Randomized trial of losartan versus captopril in patients over 65 with heart
failure: Evaluation of Losartan in Elderly Study (ELITE). Lancet 1997;349:747-52.
204. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.
205. Maggioni AP, Anand I, Gottlieb SO, et al on behalf of the Val-HeFT investigators. Effects of valsartan on
morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J
Am Coll Cardiol 2002;40:1414-21.
46

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

206. Pfeffer MA, Swedberg K, Granger CB, et al. for the CHARM Investigators and Committees. Effects ofcandesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
Lancet 2003;362:759-66.
207. McMurray JJV, Östergren J, Swedberg K, et al. for the CHARM Investigators and Committees. Effects ofcandesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin
converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-71.
208. Granger CB, McMurray JJV, Yusuf S, et al. for the CHARM Investigators and Committees. Effects ofcandesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant toangiotensin converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-6.
209. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients withchronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection
fraction trials. Circulation 2004;110:2618-26.
210. Lee VC, Rhew DC, Dylan M, et al. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and highrisk acute myocardial infarction. Ann Intern Med 2004;141(9):693-704.
211. Jong P, Demers C, McKelvie RS, Liu PP. Angiotensin receptor blockers in heart failure: meta-analysis ofrandomized controlled trials. J Am Coll Cardiol 2002;39:463-70.
212. Dimopoulos K, Salukhe TV, Coats AJ, et al. Meta-analyses of mortality and morbidity effects of an angiotensin
receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a betablocker). Int J Cardiol 2004;93:105-11.
213. Conigliaro RL, Gleason PP. Losartan-induced cough after lisinopril therapy. Am J Health-Syst Pharm
1999;56:914-5. Letter.
214. Pylypchuk GB. ACE inhibitor-versus angiotensin II blocker-induced cough and angioedema. Ann Pharmacother
1998;32:1060-6.
215. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting
enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 1996;60:8-13.
216. van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch
Intern Med 1998;158:2063-5.
217. Boxer M. Accupril- and Cozaar-induced angioedema in the same patient (letter). J Allergy Clin Immunol
1996;98:471.
218. Acker CG, Greenberg A. Angioedema induced by the angiotensin II blocker losartan (letter). N Engl J Med
1995;333:1572.
219. Sharma PK, Yium JJ. Angioedema associated with angiotensin II receptor antagonist losartan. South Med J
1997;90:552-3.
220. Frye CB, Pettigrew TJ. Angioedema and photosensitive rash induced by valsartan. Pharmacotherapy 1998;18:8668.
221. Rivera JO. Losartan-induced angioedema. Ann Pharmacother 1999;33:933-5.
222. Cha YJ, Pearson VE. Angioedema due to losartan. Ann Pharmacother 1999;33:936-8.
223. Rupprecht R, Vente C, Grafe A, Fuchs T. Angioedema due to losartan. Allergy 1999;54:81-2.
224. Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitorinduced angioedema. Ann Pharmacother 2000;34:526-8.
225. Kyrmizakis DE, Papadakis CE, Liolios AD, et al. Angiotensin-converting enzyme inhibitors and angiotensin II
receptor antagonists. Arch Otolaryngol Head Neck Surg 2004;130:1416-9.
226. Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting
enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med 2004;164:910-3.
227. Abdi R, Dong VM, Lee CJ, Ntoso KA. Angiotensin II receptor blocker-associated angioedema: on the heels of
ACE inhibitor angioedema. Pharmacotherapy. 2002;22:1173-5.
228. Chiu AG, Krowiak EJ, Deeb ZE. Angioedema associated with angiotensin II receptor antagonists: challenging ourknowledge of angioedema and its etiology. Laryngoscope 2001;111:1729-31.
229. Irons BK, Kumar A. Valsartan-induced angioedema. Ann Pharmacother 2003;37:1024-7.
230. Lo K. Angioedema associated with candesartan. Pharmacotherapy 2002; 22:1176-9.
231. Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitorinduced angioedema? Drug Saf 2002;25:73-6.
232. Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: impact on potassiumin renal failure. VAL-K Study Group. Kidney Int 2000;58:2084-92.
233. Cohn JN, Archibald DG, Ziesche S et al. Effect of vasodilator therapy on mortality in chronic congestive heart
failure: Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.
234. Taylor AL, Ziesche S, Yancy C, et al. for the African-American Heart Failure Trial Investigators. Combination of
isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.
235. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failurein patients in sinus rhythm: a systematic review and meta-analysis. J Card Fail 2004;10:155-64.
H

47

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

236. Jaeschke R, Oxman AD, Guyatt GH. To what extent do congestive heart failure patients in sinus rhythm benefit
from digoxin therapy? A systematic overview and meta-analysis. Am J Med 1990;88:279-86.
237. Packer M, Gheorghiade M, Young JB et al for the RADIANCE Study. Withdrawal of digoxin from patients withchronic heart failure treated with angiotensin-converting enzyme inhibitors. N Engl J Med 1993;329:1-7.
238. Uretsky BF, Young JB, Shahidi E et al. Randomized study assessing the effect of digoxin withdrawal in patientswith mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol
1993;22:955-62.
239. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart
failure. N Engl J Med 2002;347:1403-11.
240. Eichhorn EJ, Gheorghiade M. Digoxin-new perspective on an old drug. N Engl J Med 2002;347:1394-5.
241. Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality andmorbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol
2005;46:497-504.
242. Mathew J, Wittes J, McSherry F, et al., Digitalis Investigation Group. Racial differences in outcome and treatment
effect in congestive heart failure. Am Heart J 2005;150:968-76.
243. Riaz K, Forker AD. Digoxin use in congestive heart failure: current status. Drugs 1998;55:747-58.
244. Gheorghiade M, Pitt B. Digitalis Investigation Group (DIG) trial: a stimulus for further research. Am Heart J
1997;134:3-12.
245. Mancini DM, Benotti JR, Elkayam U et al, and the PROMISE Investigators & Coordinators. Antiarrhythmic drug
use and high serum levels of digoxin are independent adverse prognostic factors in patients with chronic heart
failure [abstr]. Circulation 1991;84:II-243.
246. Terra SG, Washam JB, Dunham GD, Gattis WA. Therapeutic range of digoxin's efficacy in heart failure: what isthe evidence? Pharmacotherapy 1999;19:1123-6.
247. Adams KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart
failure. J Am Coll Cardiol 2002;39:946-953.
248. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration andoutcomes in patients with heart failure. JAMA 2003;289:871-8.
249. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients withsevere heart failure: Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.
250. Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Myocardial Infarction Heart Failure Efficacy andSurvival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.
251. Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of spironolactone in heart failure: when
an old medicine spirals out of new guidelines. J Am Coll Cardiol 2003;41:211-4.
252. The VA Chronic Heart Failure Quality Enhancement Research Initiative. Notice: Safety of spironolactone forheart failure patients. CHF QUERI News. February 2000.
253. Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia inpatients with heart failure. Am Heart J 2004;148:971-8.
254. Sligl W, McAlister FA, Ezekowitz J, Armstrong PW. Usefulness of spironolactone in a specialized heart failure
clinic. Am J Cardiol 2004;94:443-7.
255. Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D. How prevalent is hyperkalemia and renal
dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail
2004;10:297-303.
256. Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated withspironolactone for congestive heart failure. J Am Coll Cardiol 2005;46:845-9.
257. Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of potassium in chronic heart failure
patients administered spironolactone plus furosemide and either enalapril maleate, losartan potassium or
candesartan cilexetil. J Clin Pharm Ther 2005;30: 603-10.
258. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone
Evaluation Study.
N Engl J Med 2004;351:543-51.
259. Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy
with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med
2001;110:438-41.
260. Berry C, McMurray JJV. Serious adverse events experienced by patients with chronic heart failure taking
spironolactone. Heart 2001;85:e8-e9.
261. Oddone EZ, Weinberger M, Horner M, et al. Classifying general medicine readmissions. Are they preventable?
Veterans Affairs Cooperative Studies in Health Services Group on Primary Care and Hospital Readmissions. J
Gen Intern Med 1996;11:597-607.
262. Roe CM, Motheral BR, Teitelbaum F, Rich MW. Angiotensin-converting enzyme inhibitor compliance anddosing among patients with heart failure. Am Heart J 1999;138:818-25.
48

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

263. Cline CM, Bjorck-Linne BY, Willenheimer RB, Erhardt LR. Non-compliance and knowledge of prescribed
medication in elderly patients with heart failure. Eur J Heart Fail 1999;1:145-9.
264. Ghali JK, Kadakia S, Cooper R, et al. Precipitating factors leading to decompensation of heart failure. Arch Intern
Med 1988;148:2013-6.
265. Rich MW. Multidisciplinary interventions for the management of heart failure: where do we stand? Am Heart J
1999;138:599-601.
266. Gattis WA, Hasselblad V, Whellan DJ, O'Connor CM. Reduction in heart failure events by the addition of aclinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment
Recommendation and Monitoring (PHARM) Study. Arch Intern Med 1999;159:1939-45.
267. Whellan DJ, Gaulden L, Gattis WA, et al. The benefit of implementing a heart failure disease management
program. Arch Intern Med 2001;161:2223-8.
268. West JA, Miller NH, Parker KM, et al. A comprehensive management system for heart failure improves clinicaloutcomes and reduces medical resource utilization. Am J Cardiol 1997;79:58-63.
269. Shah NB, Der E, Ruggerio C, Heidenreich PA, Massie BM. Prevention of hospitalizations for heart failure with aninteractive home monitoring program. Am Heart J 1998;135:373-8.
270. Rich MW, Nease RF. Cost-effectiveness analysis in clinical practice: the case of heart failure. Arch Intern Med
1999;159:1690-1700.
271. Ramahi TM, Longo MD, Rohlfs K, Sheynberg N. Effect of heart failure program on cardiovascular utilization anddosage in patients with chronic heart failure. Clin Cardiol 2000;23:909-14.
272. Philbin EF. Comprehensive multidisciplinary programs for the management of patients with congestive heart
failure. J Gen Intern Med 1999;14:130-5.
273. Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary intervention to prevent the readmission of elderly
patients with congestive heart failure. N Engl J Med 1995;333:1190-5.
274. Rich MW. Heart failure disease management: a critical review. J Card Fail 1999;5:64-75.
275. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure
patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol 2004;44:810-9.
276. Hebert KA, Horswell RL, Dy S, et al. Mortality benefit of a comprehensive heart failure disease management
program in indigent patients. Am Heart J 2006;151:478-83.
277. Akosah KO, Schaper AM, Haus LM, et al. Improving outcomes in heart failure in the community: long-term
survival benefit of a disease-management program. Chest 2005;127:2042-8.
278. Hershberger RE, Nauman DJ, Byrkit J, et al. Prospective evaluation of an outpatient heart failure disease
management program designed for primary care: the Oregon model. J Card Fail 2005;11:293-8.
279. Franciosa JA, Massie BM, Lukas MA, et al., COHERE Participant Physicians. Beta-blocker therapy for heart
failure outside the clinical trial setting: findings of a community-based registry. Am Heart J 2004;148:718-26.
280. Ledwidge M, Barry M, Cahill J, et al. Is multidisciplinary care of heart failure cost-beneficial when combinedwith optimal medical care? Eur J Heart Fail 2003;5:381-9.
281. Ansari M, Alexander M, Tutar A, Bello D, Massie BM. Cardiology participation improves outcomes in patientswith new-onset heart failure in the outpatient setting. J Am Coll Cardiol 2003;41:62-8.
282. Gonseth J, Guallar-Castillon P, Banegas JR, Rodriguez-Artalejo F. The effectiveness of disease management
programmes in reducing hospital re-admission in older patients with heart failure: a systematic review and metaanalysis of published reports. Eur Heart J 2004;25:1570-95.

49

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Figure: VA Utilization of Medications for HF by Drug Class80
70

Percent HF Patients

60

Diuretic
BB
ACEI
ARB
ACEI/ARB+BB
AA
Digoxin
H-N

50
40
30
20
10
0
FY03

FY04

FY05

FY06

Denominator=patients with at least one diagnosis of heart failure (i.e., at least one inpatient primary diagnosis or any outpatient
diagnosis within 24 months prior to the end date of the fiscal year) and at least one active prescription during the fiscal year
Active prescription=at least 90 days of therapy during the given year
Combination therapy=prescriptions for both medications overlapping > 50%
AA=aldosterone antagonist; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor antagonist; BB=betaadrenergic blocker; ACEI/ARB+BB=ACEI or ARB in combination with BB; H-N=hydralazine in combination with a nitrate

50

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Appendix A: Medications Commonly Used for the Management of HFa-c
In general, patients should be titrated to target doses as used in randomized controlled trials (refer
to Appendix C), or highest tolerated dose
DRUG
Diuretics
Furosemided

INITIAL DOSEMAXIMUM DOSECOMMENTS/CAUTIONS

20 to 40 mg given
once or twice daily

600 mg in divided doses

Bumetanide

0.5 to 1.0 mg given
once or twice daily

10mg in divided doses

Ethacrynic acid

50 mg once or twice
daily

400mg in divided doses

Torsemide

10 to 20 mg oncedaily

200 mg once daily

Hydrochlorothiazide

25 mg given once or
twice daily

200 mg in divided doses

Chlorthalidone

12.5 to 25 mg oncedaily

100 mg once daily

Indapamide

2.5 mg once daily

5 mg once daily

2.5 to 5 mg oncedaily
0.5 mg once daily

20 mg once dailyf,gMetolazone
Zaroxolyn®
Mykrox®

1 mg once daily

Monitor serum K+ at 1 to 2 weeks after initiating
therapy or changing dose, then every few months;
more frequently if patient is also on digoxin or has
demonstrated hypokalemia
Add potassium supplement or low doseepotassium-sparing diuretic if the patient becomes+
hypokalemic (serum K < 4.0 mEq/L)
Use cautiously in poorly controlled DM,
symptomatic BPH, or in patients with increased
risk of volume depletion
Furosemide usually administered once daily
unless higher doses (e.g., > 160mg/d) areneeded, then more frequent daily dosing should
be considered
Ethacrynic acid may be used in patients withsulfonamide sensitivity
Thiazides lose effectiveness in patients with CrCl
< 40 mL/min
Reserve indapamide for patients with CrCl < 25
mL/minReserve metolazone for intermittent use as an
adjunct to loop diuretics for diuresis in patientswith HF or in patients with CrCl < 25 mL/min;thiazide/loop combinations are also effective andare less expensive

Angiotensin Converting Enzyme Inhibitor
6.25 to 12.5 mg
three times daily

50 mg three times daily

Enalapril

2.5 mg twice daily

10 to 20mg twice daily

Fosinopril

5 to10 mg once daily

20 to 40 mg once daily

Lisinopril

2.5 to 5 mg oncedaily

20 to 40 mg once daily

Captoprilh

Beta-adrenergic blockers
12.5 to 25 mg once
Metoprolol
daily; double dose
succinate (XL)
every 2 weeks totarget dose
1.25 mg once daily;
increase by 1.25 mg
every week until 5
Bisoprolol
mg once daily, thenincrease by 2.5 mg
every 4 weeks totarget dose
3.125 mg twice
Carvedilol
daily; titrate at(alpha & beta
minimum of every 2
antagonist)weeks to target dose
Angiotensin II Receptor Antagonists
Candesartan

4 to 8 mg once daily

d

d

d

d

Start with lower or less frequent doses in patientswith renal insufficiency; use with caution inpatients with renal artery stenosis
Should not be used if K+ > 5.5 mEq/L that cannot
be reduced
Due to the potential risk for fetal abnormalities inpatients taking ACEIs during pregnancy, it isrecommended that therapy be discontinued assoon as a woman becomes pregnant. Alternate
therapy should be considered. ACEIs should only
be prescribed in pregnant women when thebenefit clearly outweighs the potential risk for fetal
abnormalitiesd

200 mg once daily (orhighest dose tolerated)d

10 mg once dailyd

25 mg twice daily(should be titrated as
tolerated to 50mg twice
daily if > 85kg)

32 mg once daily

Low initial doses should be implemented; use
slow gradual increases in the dosage
Effects are generally seen in 3-12 months
Carvedilol should be given with food to reduce theincidence of orthostatic hypotension
Consider separating the ACEI, adjusting dose ofdiuretic, or temporary ACEI dose reduction if
dizziness occurs
Should not be abruptly discontinuedndrdContraindicated in 2 and 3 trimesters
pregnancy due to potential neonatal/fetal

d51

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Valsartan

40 to 80 mg divided
twice daily

320 mg divided twiceddaily

morbidity and deathUse with caution in patients with renal arterystenosisShould not be used if K+ > 5.5 mEq/L that cannot
be reduced
Consider lower doses in patients withintravascular volume depletion

Hydralazine in Combination with a Nitrate
Hydralazine

112.5 to 150 mg
divided three times
daily

225 to 300 mg divideddthree times daily

Isosorbide
dinitrate

30 to 60 mg divided
three times daily

120 to 160 mg divideddthree times daily

Hydralazine: Adverse effects include dizziness,headache, lupus-like syndrome, nausea,
tachycardia, postural hypotension
Advise patient to take with food
ISDN: Adverse effects include flushing,headache, postural hypotension, rash
May cause an increase in ocular pressure;caution with presence of glaucoma

DigoxinDigoxin

0.125 to 0.25
micrograms
once daily

Usually 0.25 micrograms
once daily (0.375 to 0.5
micrograms once daily
may be used rarely)

Initiate therapy with 0.125 micrograms once daily(or every other day) in patients > 70, with
impaired kidney function, or with a low lean body
mass
Lower trough serum digoxin concentrations may
be preferable (i.e., 0.5-0.9ng/ml), and should notexceed 1.1ng/ml
Signs of toxicity include confusion, nausea,
vomiting, abdominal pain, diarrhea, anorexia,
fatigue, arrhythmias, visual disturbances

Aldosterone Antagonists
Spironolactone

12.5 to 25 mg oncedaily

25 mg once daily

Eplerenone

25 mg once daily

50 mg once daily

If CrCl < 50 ml/min, initial dose should be 12.5 mg
once daily or 25 mg every other day forspironolactone and 25 mg once daily ofeplerenone; not recommended if CrCl < 30 ml/min
Monitor closely for hyperkalemia (should not be
used if baseline K+ > 5.0 mEq/L) or renal
dysfunction; patients may also experiencegynecomastia, especially with spironolactoneddaAdapted from McEvoy GK, ed. American Hospital Formulary Service Drug Information, Bethesda, MD:American Society of Health-System
Pharmacists, Inc., 2006.
b
Adapted from Hebel SK ed. Drug Facts and Comparisons, St. Louis, Missouri: Facts and Comparisons Inc., May 2006.
c
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in theadult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee toUpdate the 2001 Guidelines for the Evaluation and Management of Heart Failure). American College of Cardiology Web site. Available at:
http://www.acc.org/clinical/guidelines/failure/index.pdf.
dTarget doses (also refer to Appendix C for target doses in randomized controlled trials)eUnless patients have persistent hypokalemia or are being treated with low dose spironolactone for severe HF (refer to Annotation M),
potassium-sparing diuretics should not be used in combination with ACEI (refer to Appendix B for common diuretic drug interactions)f
The brand names of metolazone are not bioequivalent, therefore doses varygIntermittent use recommended once the response of the patient is stabilizedh
One hour before meals, on an empty stomachi
Also available as a fixed-dose combination product ISDN 20mg/hydralazine 37.5 mg, one to two tablets three times daily; ISMN once daily
has also been used in place of ISDN; hydralazine dosing variable, total daily dose may also be divided two to four times daily

52

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Appendix B. Drug Interactions with Agents Used in HFa,b
DRUG CLASSINTERACTINGDRUG

DESCRIPTIONDIURETICS
ACEI

Bile Acid Resins
Digoxin
Dofetilide
LithiumOralhypoglycemics
K+preparations,
ACEI, ARBs

↑ hypotensive effect in the presence of intensive diuretic therapy due to sodium
depletion and hypovolemia; effects of loop diuretics may be ↓ by inhibition ofantiotensin II production [significance=3]↓ absorption of all diuretics; bile acid resin should be taken at least 2 hours after
diuretic [significance=2]
Loop and thiazide diuretics may induce hypokalemia which may ↑ risk of digitalis
toxicity [significance=2]
Risk of torsade de pointes increased with hypokalemia [significance=1]
With thiazides, a compensatory ↑ in proximal tubule reabsorption of sodium
occurs, which results in ↑ lithium reabsorption (reduce lithium dose by 50%); ↑plasma lithium concentrations may also occur with loop diuretics [significance=2]
Thiazides may ↓ hypoglycemic effects of sulfonylureas possibly due to ↓ insulin+
sensitivity, ↓ insulin secretion or ↓ in K [significance=2]++
K sparing diuretics used concomitantly may ↑ K serum levels [significance=3]

ACEIs
Allopurinol

Lithium
NSAIDsIsolated case reports with allopurinol and captopril or enalapril may have caused
predisposition to hypersensitivity reactions (e.g., Stevens Johnson Syndrome,
anaphylaxis, skin eruptions, fever, arthralgias) [significance=4]Potential for ↑ serum lithium levels and resultant toxicity [significance=2]
NSAIDs ↓ antihypertensive effects due to inhibition of PG synthesis resulting in ↓GFR, ↓ sodium and water excretion, and vasoconstriction [significance=2]+
Concomitant therapy may ↑ K serum levels [significance=1]

K+ preparations
K+-sparing
diuretics
ANGIOTENSIN II RECEPTOR ANTAGONISTS
DigoxinSee digoxin for description of drug interaction [significance=4]
Lithium
Angiotensin II receptor antagonists may ↓ lithium renal secretion and ↑ serum
lithium levels [significance=2]
K+ preparations
Concomitant therapy may ↑ K+ serum levels [significance=1]+
K -sparing
diuretics

53

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

BETA-ADRENERGIC BLOCKERS
Cimetidine

Diltiazem
Verapamil
Epinephrine
Lidocaine
NSAIDs
Neuroleptics

Oral hypoglycemics

Prazosin
Propafenone

Rifampin
Theophylline
CALCIUM CHANNEL BLOCKERS
Beta-blockers
Carbamazepine

Cyclosporine
DigoxinLithium
HMG-CoA
reductase inhibitors

Quinidine
Theophylline

Hypotension and bradycardia have been reported with propranolol andmetoprolol when used with cimetidine due to ↑ serum levels of beta-blockers that
undergo hepatic metabolism [significance=2]
Combination may potentiate the pharmacologic effects of beta-blockers; additiveeffects on cardiac conduction [significance=2]
Noncardioselective agents may ↑ the pressor response resulting in ↑ in HTN/
bradycardia [significance=1]↑ toxicity due to reduced hepatic metabolism of lidocaine [significance=2]
NSAIDs ↓ antihypertensive effect due to inhibition of PG synthesis resulting in ↓GFR, ↓ sodium and water excretion, and vasoconstriction [significance=2]
Some beta-blockers and neuroleptics (chlorpromazine/ thioridazine) may ↑ theplasma concentrations of one another; monitor for enhanced effects of bothdrugs; concomitant use of thioridazine and propranolol or pindolol iscontraindicated [significance=1]↓ hypoglycemic action may occur, may also mask symptoms of hypoglycemia(more likely with nonselective beta-blocker); clinical significance is unclear[significance=5]
Potential for ↑ postural hypotension [significance=2]↑ hypotensive effect has been seen with propranolol and metoprolol due toinhibition of metabolic clearance; HF and nightmares have been reported[significance=2]
May enhance the hepatic metabolism of propranolol and metoprolol; enzyme
induction effect may resolve after a 3-4 week washout period [significance=2]↑ serum concentration in a dose-dependent manner has been seen with
propranolol [significance=2]
See beta-blockers for description of drug interaction [significance=2]↑ toxicity has been noted with verapamil and diltiazem due to ↓ metabolism of
carbamazepine; felodipine bioavailability may be ↓, making it difficult to achieve
therapeutic felodipine concentrations [significance=2]
Blood concentrations have ↑ with verapamil, diltiazem and nicardipine; renal
toxicity has been reported [significance=2]
Verapamil, diltiazem, bepridil, and nisoldipine have ↑ digoxin levels by 20-70%[significance=1]
Combination with verapamil or diltiazem may result in neurotoxicity that may
occur without attendant ↑ in serum level [significance=4]
Diltiazem produces marked ↑ lovastatin and simvastatin concentrations throughinhibition of CYP3A4, therefore potential for ↑ toxicity (rhabdomyolysis reportedwith atorvastatin and simvastatin in combination with diltiazem); ↑ concentrationof simvastatin seen with concomitant verapamil [significance=2]
Verapamil inhibits metabolism of quinidine leading to ↑ toxicity [significance=1];
nifedipine appears to ↓ blood concentrations [significance=4]
Inhibition of hepatic metabolism with verapamil and diltiazem may lead to ↑serum levels [significance=4]

54

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

DIGOXIN
Amiodarone

Beta-blockers
Cyclosporine

Diuretics
Quinidine

Spironolactone
Telmisartan

Verapamil(see also Calcium
Channel Blockers)↑ serum digoxin concentrations; may need to decrease digoxin dose by ∼ 50%;
monitor for digoxin toxicity (i.e., anorexia, nausea, fatigue, vomiting, diarrhea,
visual disturbances, confusion, ventricular tachycardia) [significance=1]
Carvedilol may ↑ serum digoxin concentrations; potential for synergistic
bradycardia with propranolol [significance=2]↑ serum digoxin concentrations; may need to discontinue digoxin or ↓ dosewhen treatment resumed; monitor for toxicity (i.e. anorexia, nausea, vomiting,diarrhea, fatigue, visual disturbances, confusion, and ventricular tachycardia)[significance=1]↑ risk of digitalis toxicity due to diuretic induced hypokalemia [significance=1]↑ serum digoxin concentrations; may need dose ↓ ∼ 50%; monitor for toxicity(i.e. anorexia, nausea, vomiting, diarrhea, fatigue, visual disturbances,confusion, and ventricular tachycardia) [significance=1]
Renal excretion of digoxin may be reduced; false increases in plasma digoxin
concentrations may occur depending on the assay method used [significance=2]
May increase digoxin peak plasma concentrations (49%) and in troughconcentrations (20%); monitor digoxin levels when starting, adjusting, ordiscontinuing therapy with telmisartan [significance=4]↑ digoxin serum concentrations on average ∼70%; dose related; may need to ↓dose be at least 50%; monitor for toxicity (i.e. anorexia, nausea, vomiting,diarrhea, fatigue, visual disturbances, confusion, and ventricular tachycardia)[significance=1]

SPIRONOLACTONE
Digoxin
Mitotane
Potassium, otherpotassiumsparing diuretics,
ACEIs, ARBs
VASODILATORS
Hydralazine

Beta-blockers

Nitrates

PDE 5 inhibitors

See digoxin for description of drug interaction [significance=2]
Spironolactone may antagonize the activity of mitotane; avoid concomitant use[significance=4]
Coadministration may result in hyperkalemia [significance=1]

Serum levels of propranolol or metoprolol may be ↑ with hydralazine use; clinicaleffects may be enhanced [significance=2]
Sildenafil, tadalafil, and vardenafil potentiate the hypotensive effects of nitrates,
severe hypotension may occur; concomitant use is contraindicated[significance=1]aWickersham RM, et al. eds. Drug Facts and Comparisons, St. Louis: Wolters Kluwer Health, Inc., 2006.
Online Facts and Comparisons 4.0 http://online.factsandcomparisons.com/ Accessed August 2006.
Significance: 1=potentially severe or life-threatening; interaction suspected, established or probable in well controlled studies; 2=may cause deteriorationin patient’s clinical status; interaction suspected, established or probable in well controlled studies; 3=causes minor effects; interaction suspected,
established or probable in well controlled studies; 4=may cause moderate to major effects, very limited data; 5=minor to major effects, interaction is unlikely
or not good evidence of an altered clinical effect; Bold=major drug interaction
AUC=area under the curve; CV=cardiovascular; CYP=cytochrome P-450 enzyme system; GFR=glomerular filtration rate; PDE=phosphodiesterase;
PG=prostaglandinb

55

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Appendix C: Long-term, Randomized, Controlled, Outcome Trials in Systolic HF by Drug Class
Angiotensin Converting Enzyme Inhibitors
Patient
Trial
N
Population
SOLVD120
1991
MC, R, DB(vs. placebo)
U.S., Canada,
Belgium
Supported by
NHLBI; Merck
Sharpe andDohme provided
drug/placebo
CONSENSUS122
1987
MC, R, DB,
PG (vs.
placebo)Scandinavia

NYHA I (11%), II(57%), III (30%), IV(2%)
Mean EF 24.8%

All patients with
NYHA IV at
randomization

2569

253

Treatment
Enalapril 10 mg twice daily(target dose)vs.
Placebo

HF therapy
BB: 8%
Digitalis: 67%
Diuretics: 86%
Vasodilators (any): 51%
Enalapril 20 mg twice daily(maximum dose)vs.
Placebo
HF therapy
BB: 3%
Digitalis: 93%
Furosemide: 98%
Hydralazine: 2%
ISDN: 46%
Spironolactone: 53%

Quality
RatingDuration

Results

Study Conclusions

Average 41.4
monthsPrimary Endpoint: Total mortality (16% ↓ with enalapril 95%
CI 0.05-0.26; ARR 4.6%, NNT 22)
EnalaprilPlacebo
Endpoint
p value(N=1285)(N=1284)
Primary452 (35.2%)
510 (39.7%)<0.0036
Death or613 (47.7%)
736 (57.3%)<0.0001
HF hosp
Target dose on monotherapy: Bisoprolol (65%) vs. enalapril(84%)
Mean dose: 16.6 mg per day (patients taking study drug); 11.2
mg per day (all randomized patients)

Enalapril significantly reduced
mortality and HF
hospitalizations in patients with
HF

Good

Average 188
days

Primary Endpoint: All-cause mortality at 6 months (40% ↓with enalapril; ARR 17.7%, NNT 6)
EnalaprilPlacebo
Endpoint
p value(N=127)(N=126)
Primary33 (26%)55 (44%)0.002
Total mortality
50 (39%)68 (54%)0.003
Maximum dose: Enalapril (28 patients) vs. placebo (57patients)
Mean dose: 18.4 mg per day

Enalapril reduced mortality inpatients with severe HF on
conventional therapy (i.e.,
diuretics and digitalis)

Good

Supported by
Merck Sharpeand Dohme
ARR=absolute risk reduction; CI=confidence interval; DB=double-blind; EF=ejection fraction; HF=heart failure; hosp=hospitalizations; ISDN: isosorbide dinitrate; N=number of patients; NNT=number needed to treat;
NYHA=New York Heart Association; PG=parallel group; R=randomized

56

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Beta-Adrenergic Blockers
Patient
Trial
Population
CIBIS III166
2005
MC, PROBE(BB 1st vs.
ACEI 1st)
Europe, Australia,
Tunisia

NYHA II (49%), III(51%)
Mean EF 28.8%

N

Treatment

1010(Initial monotherapy X 6 months)
Bisoprolol 10 mg once daily(target dose)vs.
(Initial monotherapy X 6 months)
Enalapril 10 mg twice daily(target dose)
Followed by combination therapy X 6
to 24 months

Supported by
Merck KGaACOMET167
2003
MC, R, DB, PG(BB vs. BB)
EuropeNYHA II (48%), III(48%), IV (4%)
Mean EF 26%

3029

Supported by F
Hoffmann La
Roche andGlaxoSmithKline
COPERNICUS163
2001
MC, R, DB (vs.
placebo)U.S., Canada,
Mexico, Europe,
S. America, Israel,
S. Africa, Australia
Supported bySmithKline
Beecham andBoehringerMannheim

Severe HF (> 2months dyspnea or
fatigue at rest or
minimal exertion,
EF < 25%)
Mean EF 19.9%

2289

Duration

HF therapy
Cardiac glycoside: 32%
Diuretics: 84%
Aldosterone antagonist: 13%
Carvedilol 25 mg twice daily(target dose)vs.
Metoprolol IR 50 mg twice
daily (target dose)
HF therapy
ACEI: 91%
ARB: 7%
Digoxin: 59%
Diuretics: 99%
Aldosterone antagonist: 11%
Carvedilol 25 mg twice daily(target dose)vs.
Placebo
HF therapy
ACEI or ARB: 97%
Digoxin: 66%
Diuretics: 99%
Spironolactone: 20%

57

Quality
RatingResults

Study Conclusions

Mean 1.22
yrs

Primary Endpoints: Combined all-cause mortality or all-cause
hosp (per protocol analysis bisoprolol 1st vs. enalapril 1st HR
0.97 95% CI 0.78-1.21; ITT 178 (35.2%) vs. 186 (36.8%) HR
0.94 95% CI 0.77-1.16; p=0.019a)
Bisoprolol 1st
Enalapril 1st
Endpoint
p value(N=505b)(N=505b)Primary163 (32.4%)
165 (33.1%)
0.046aCV death c
55 (NR)
56 (NR)
0.86
HF hospd
63 (NR)
51 (NR)
0.23
atest for noninferiority; bN for ITT; c IHR 0.97; dHR 1.25
Target dose on monotherapy: Bisoprolol (65%) vs. enalapril(84%)

Bisoprolol 1st noninferior toenalapril 1st in ITT analysis, but
not by per-protocol analysis;
initial therapy with bisoprolol
may be as safe and efficacious
as starting with enalapril

Fair

Mean 58
monthsPrimary Endpoints: 1) All-cause mortality (↓ with carvedilol
vs. metoprolol; HR 0.83 95% CI 0.74-0.93; ARR 5.6%, NNT18); and 2) Composite all-cause mortality or all-cause
admission (HR 0.94 95% CI 0.86-1.02)
Carvedilol
Metoprolol
Endpoint
p value(N=1511)(N=1518)
Primary1
512 (33.9%)600 (39.5%)
0.017
Primary21116 (73.9%)1160 (76.4%)
0.122
Target dose: Carvedilol (75%) vs. metoprolol IR (78%)
Mean dose: Carvedilol (41.8 + 14.6 mg per day); metoprolol IR(85 + 28.9 mg per day)

Carvedilol had a greater
benefit on survival compared
to metoprolol IR in patientswith chronic HF on standard
therapy (i.e., diuretics plus
ACEI)

Fair

Mean 10.4
months(stopped
early due toimproved
survival)

Primary Endpoint: All-cause mortality (35% ↓ with carvedilol;
95% CI 0.19-0.48; ARR 5.5%, NNT 18)
Carvedilol
Placebo
Endpoint
p value(N=1156)(N=1133)
Primary130 (11.3%)
190 (16.8%)
0.0014
Death or hosp
425 (36.8%)
507 (44.8%)<0.001
Target dose: Carvedilol (65.1%) vs. placebo (78.2%) at 4
monthsMean dose: 37 mg per day

Carvedilol reduced the rate ofdeath in patients with severe
HF on conventional therapy(i.e., diuretics plus ACEI or
ARB)

Good

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Beta-Adrenergic Blockers (continued)
Patient
Trial
N
Population
MERIT-HF159
1999
MC, R, DB(vs. placebo)
U.S., Europe

NYHA II (41%), III(56%), IV (3.4%) HF
Mean EF 28%

3991

NYHA III (83%), IV(17%)
Mean EF 27.5%

2647

Results

Study Conclusions

Mean 1 yr(terminatedearly due tosurvivalbenefit)Primary Endpoints: 1) All-cause mortality (↓ with metoprolol
XL; RR 0.66 95% CI 0.53-0.81; ARR 3.6%, NNT 28); and 2)
Combined all-cause mortality and all-cause hosp admissions(NR)
Metoprolol XL
Placebo
Endpoint
p value(N=1990)(N=2001)
Primary1
145 (7.3%)
217 (10.9%)
0.00009
CV death
128 (6.4%)
203 (10.2%)
0.00003
Target dose: Metoprolol XL (64%) vs. placebo (82%)
Mean dose: 159 mg
Primary Endpoint: All-cause mortality (↓ with bisoprolol; HR
0.66 95% CI 0.54-0.81; ARR 5.5%, NNT 18)
Bisoprolol
Placebo
Endpoint
p value(N=1327)(N=1320)
Primary156 (11.8%)228 (17.3%)<0.0001
CV death
119 (9%)161 (12.2%)
0.0049Target dose: Bisoprolol 10 mg (564 patients); 7.5 mg (152patients); 5 mg (176 patients)
Most common dose: 10 mg
Primary Endpoint: Death (65% ↓ with carvedilol; 95% CI
0.39-0.80; ARR 4.6%, NNT 22)
Carvedilol
Placebo
Endpoint
p value(N=696)(N=398)
Primary22 (3.2%)
31 (7.8%)<0.001
CV hosp
98 (14.1%)
78 (19.6%)
0.036
Target dose: Achieved in 80% of patients
Mean dose: 45 + 27 mg per day

Metoprolol XL significantly
improved survival in patientswith symptomatic HF on
standard therapy for HF (i.e.,
diuretics plus ACEI)

Good

Bisoprolol 10 mg once daily(target dose)vs.
Placebo

Bisoprolol significantly
improved survival in patientswith stable symptomatic HF(NYHA class III to IV) on
standard therapy (i.e., diuretics
plus ACEI)Good

Carvedilol reduced the risk ofdeath in patients withsymptomatic HF on standard
therapy (i.e., diuretics plus
ACEI); individual protocols
designed to assess nonfatal
endpoints, with mortality
prespecified to evaluate safety
and benefit in overall trial

Fair

Mean 1.3 yrs(stopped
early due toimproved
survival)

HF therapy
ACEI: 96%
Digoxin: 52%
Diuretics: 99%

Supported by E
Merck
US
Carvedilol161
1996
MC, R, DB(vs. placebo)
U.S.

Metoprolol XL 200 mg once
daily (target dose)vs.
Placebo

NYHA II (53%), III(44%), IV (3%)
Mean EF 23%

1094

Carvedilol 25 to 50 mg twice
daily (target dose) or 6.25,
12.5, or 25 mg twice daily(dose-ranging protocol)
vs.
Placebo

Quality
RatingDuration

HF therapy
ACEI: 90%
ARB: 7%
Digoxin: 64%
Diuretics: 90%

Supported by
Astra Hässle AB
CIBIS II160
1999
MC, R, DB(vs. placebo)
EuropeTreatment

Median 6.5
months(stopped
early due toimproved
survival)

HF therapy
Supported by
ACEI: 95%
Roche andDigoxin: 91%
GlaxoSmithKline
Diuretics: 95%
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; ARR=absolute risk reduction; CI=confidence interval; CV=cardiovascular; DB=double-blind; EF=ejection fraction; HF=heart failure;hosp=hospitalizations; HR=hazard ratio; IR=immediate-release; ITT=intention-to-treat analysis; N=number of patients; NNT=number needed to treat; NR=not reported; NYHA=New York Heart Association;
PROBE=prospective, randomized, open-label, blinded endpoint evaluation; R=randomized; RR=relative risk; XL=extended-release; yrs=years

58

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Angiotensin II Receptor Antagonists
Patient
Trial
N
Population
CHARMOverall206
2003
MC, R, DB,
PG (vs.
placebo)U.S., Canada,
Europe, S.
Africa, Australia,
Malaysia
Supported by
AstraZeneca
R&D
CHARMAlternative208
2003
MC, R, DB(vs. placebo)
U.S., Canada,
Europe, S.
Africa, Australia,
Malaysia

NYHA II (45%), III(52%), IV (3%) HF
EF < 40% (57%);
EF > 40% (43%)

7601

2028

Supported by
AstraZeneca
R&D

Results

Candesartan 32 mg once daily(target dose)vs.
PlaceboMedian 37.7
monthsPrimary Endpoint: All-cause mortality; no statisticallysignificant difference vs. placebo (unadjusted HR 0.91 95% CI
0.83-1.00)
Candesartan
Placebo
Endpoint
p value(N=3803)(N=3796)
Primary
886 (23%)945 (25%)
0.055
CV death/HF hosp
1150 (30.2%)1310 (34.5%)<0.0001
Target dose: Candesartan (63%) vs. placebo (75%) at 6
monthsMean dose: 24 mg at 6 months

Candesartan significantly
reduced CV deaths and HF
hospitalizations

Good

Median 33.7
monthsPrimary Endpoint: Composite CV death or HF
hospitalizations; ↓ with candesartan (unadjusted HR 0.77 95%
CI 0.67-0.89; ARR 7.0%, NNT 14)
Candesartan
Placebo
Endpoint
p value(N=1013)(N=1015)
Primary
334 (33%)406 (40%)0.0004
CV death
219 (21.6%)
252 (24.8%)
0.072
HF hosp
207 (20.4%)286 (28.2%)<0.0001
No significant difference (p=0.11) in all-cause death (not a prespecified endpoint)
Target dose: Candesartan (59%) vs. placebo (73%) at 6
monthsMean dose: 23 mg at 6 months
Primary Endpoint: Composite CV death or HF
hospitalizations; ↓ with candesartan (unadjusted HR 0.85 95%
CI 0.75-0.96; ARR 4.4%, NNT 23)
Candesartan
Placebo
Endpoint
p value(N=1276)(N=1272)
Primary
483 (37.9%)
538 (42.3%)
0.011
CV death
302 (23.7%)
347 (27.3%)
0.029
HF hosp309 (24.2%)
356 (28.0%)
0.014
No significant difference (p=0.086) in all-cause death (not a
pre-specified endpoint)
Target dose: Candesartan (61%) vs. placebo (73%) at 6
monthsMean dose: 24 mg at 6 months

Candesartan significantly
reduced CV deaths and HF
hospitalizations in patients withsymptomatic HF who are ACEI
intolerant

Good

The addition of candesartan totreatment with an ACEI andother standard therapy for HF
significantly reduced CV
deaths and HF hospitalizations
in patients with symptomatic
HF

Good

Candesartan 32 mg once daily(target dose)vs.
Placebo
HF therapy
BB: 55%
Digoxin: 45%
Diuretics: 85%
Spironolactone: 25%

Supported by
AstraZeneca
R&D
CHARMAdded207
2003
MC, R, DB(vs. placebo)
U.S., Canada,
Europe, S.
Africa, Australia,
Malaysia

Duration

HF therapy
ACEI: 41%
BB: 55%
Digoxin: 43%
Diuretics: 83%
Spironolactone: 17%

NYHA II (48%), III(49%), IV (4%) HF
Mean EF 30%
ACEI intolerant

NYHA II (24%), III(73%), IV (3%)
Mean EF 28%

2548

Quality
RatingTreatment

Candesartan 32 mg once daily(target dose)vs.
Placebo
HF therapy
ACEI: 100%
BB: 55%
Digoxin: 58%
Diuretics: 90%
Spironolactone: 17%

59

Median 41
monthsStudy Conclusions

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Angiotensin II Receptor Antagonists (continued)
Patient
Trial
N
Treatment
Population
Val-HeFT204
2001
MC, R, DB(vs. placebo)
U.S., Europe, S.
Africa, Australia

NYHA II (62%), III(36%), IV (2%)
Mean EF 27%

5010

Supported by
Merck ResearchLaboratories

Valsartan 160 mg twice daily(target dose)vs.
Placebo

Mean 23months

HF therapy
ACEI: 93%
BB: 35%
Digoxin: 67%
Diuretics: 85%
Spironolactone: 5%Supported by
Novartis Pharma
ELITE II202
2000
MC, R, DB(vs. ACEI)U.S., Canada,
Europe, S.
Africa, S.
America

Duration

NYHA II (52%), III(43%), IV (5%)
Mean EF 31%

3152

Losartan 50 mg once daily(target dose)vs.
Captopril 50 mg three times
daily (target dose)
HF therapy
BB: 22%Digoxin: 50%
Diuretics: 78%

Median 1.5
yrs

Quality
RatingResults

Study Conclusions

Primary Endpoint: 1) Overall mortality (no statisticallysignificant difference vs. placebo); and 2) Combined morbidity
and mortality (↓ with valsartan; RR 0.87 97.5% CI 0.77-0.97;
ARR 3.3%, NNT 30)
Valsartan
Placebo
Endpoint
p value(N=2511)(N=2499)
Primary1
495 (19.7%)
484 (19.4%)
0.80
Primary2
723 (28.8%)801 (32.1%)
0.009
HF hosp*346 (13.8%)455 (18.2%)<0.001*adjudicated hosp for worsening HF as 1st event
Target dose: Valsartan (84%) vs. placebo (93%)
Mean dose: 254 mg
Primary Endpoint: All-cause mortality; no statisticallysignificant difference vs. captopril (HR 1.13 95.7% CI 0.951.35)
Losartan
Captopril
Endpoint
p value(N=1578)(N=1574)
Primary280 (17.7%)
250 (15.9%)
0.16
Secondary*
142 (9.0%)
115 (7.3%)
0.08
HF hosp*
270 (17.1%)
293 (18.6%)
0.32*composite sudden cardiac death or resuscitated cardiac arrest
Mean dose: NA
Target dose: NA

Valsartan significantly reduced
the combined morbidity andmortality endpoint when given
to patients with HF currently on
therapy; a post hoc analysis
noted an increase in mortality
in patients receiving
combination of valsartan withan ACEI and BB

Good

Losartan was not found to besuperior to captopril in
reducing all-cause mortality inpatients with HF currently on
therapy; designed as asuperiority trial, unable todetermine equivalence
between losartan and captopril

Good

ACEI=angiotensin-converting enzyme inhibitor; ARR=absolute risk reduction; BB=beta-blockers; CI=confidence interval; CV=cardiovascular; DB=double-blind; EF=ejection fraction; HF=heart failure;hosp=hospitalizations; HR=hazard ratio; N=number of patients; NA=not available; NNT=number needed to treat; PG=parallel-group; R=randomized; RR=relative risk; Sx=symptoms; yrs=years

60

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Hydralazine/Isosorbide Dinitrate
Patient
Trial
Population
A-HeFT234
2004
MC, DB, RCT(vs. placebo)
U.S.

Self-identified blackwith (African
descent)
NYHA III or IV HF >3 months
Mean EF ~24%

Treatment

Duration

Results

Study Conclusions

1050

ISDN/HYD 40 mg/75 mg threetimes daily (120 mg/225 mg
total daily target dose)vs.
Placebo

10 months(terminatedearly due todifference inmortality)

Primary endpoint: Composite score (weighted values for allcause mortality, 1st HF hosp during 18 months, change in QOL
by MLHF at 6 months); possible score -6 to +2
ISDN/HYD
PlacebopEndpoint(N=518)(N=532)value
Primary (score)-0.1+1.9-0.5+2.0
0.01
All-cause death32 (6.2%)
54 (10.2%)
0.02
1st HF hosp
85 (16.4%)
130 (24.4%)
0.001
Change QOL*
-5.6+20.6-2.7+21.2
0.02*lower score reflects better QOL
Survival: 43% improvement with ISDN/HYD (HR 0.57; p=0.01)
Target dose: ISDN/HYD (68%) vs. placebo (88.9%); p<0.001
Mean # tabs/d: ISDN/HYD (3.8+2.5) vs. placebo (4.7+2.2);
p<0.001
Primary Endpoint: Overall and 2-yr mortality; 2-yr mortality ↓with ACEI vs. ISDN/HYD (risk reduction 28.2%; ARR 7.0%,
NNT 14)
ISDN/HYD
ACEI
pMortality(N=401)(N=403)value
Overall153 (38.2%)
132 (32.8%)
0.08
2-yr
NR (25%)NR (18%)0.016
HF hosp
78 (18.4%)
76 (18.9%)
NR
Ave daily dose: ISDN/HYD (100/199 mg); enalapril (15 mg)

Combination ISDN/HYD, in
addition to standard therapy for
HF, improved survival anddecreased rate of first
hospitalizations for HF, in selfidentified black patients with
NYHA class III to IV HF

Fair

Mortality was lower withenalapril compared to
ISDN/HYD, a difference thatwas statistically significant at 2
yrs

Fair

Mortality reduced with
ISDN/HYD compared toplacebo up to 3 yrs; unable todetermine benefit beyond this
point

Fair

HF therapy
ACEI: 69%
ARB: 17%
BB: 74%
Carvedilol: 55%
Digoxin: 60%
Diuretics: 90%
Spironolactone: 39%

Supported by
NitroMedV-HeFT II121
1991
MC (VA), DB,
RCT (vs.
ACEI)
U.S.
Supported by
VA Cooperative
Studies

Males with primarily
NYHA II (51%) or III(43%) HF
Mean EF ~29%

V-HeFT I233
1986
MC (VA), DB,
RCT (vs.
prazosin orplacebo)U.S.

Males with chronic
congestive HF
Mean EF ~30%

Supported by
VA Cooperative
Studies

Quality
Rating

N

804

642

ISDN/HYD 40 mg/75 mg fourtimes daily (160 mg/300 mg
total daily target dose)vs.
Enalapril 10 mg twice daily(20 mg total daily target dose)
HF therapy
DigoxinDiuretics
ISDN/HYD 40 mg/75 mg fourtimes daily (160 mg/300 mg
total daily target dose)vs.
Prazosin 5 mg four times daily(20 mg total daily target dose)vs.
Placebo

Ave 2.5 yrs

Ave 2.3 yrs

Primary Endpoint: Overall and 2-yr mortality; ↓ in 2-yr
mortality with ISDN/HYD (risk reduction 34%, CI 0.04 to 0.54;
ARR 8.7%, NNT=12)
ISDN/HYD
PlacebopMortality(N=186)(N=273)value
Overall*NR (36.2%)
NR (46.9%)
NR2-yr
NR (25.6%)
NR (34.3%)<0.028*by 3 yrs, mortality risk reduction 36% with ISDN/HYD vs.
placebo; small sample size > 3yrs
Ave daily dose: ISDN/HYD (136/270 mg); prazosin (18.6 mg)

HF therapy
DigoxinDiuretics
ACEI=angiotensin-converting enzyme inhibitor; AE=adverse event; ARB=angiotensin II receptor blocker; ARR=absolute risk reduction; Ave=average; BB=beta-adrenergic blocker; DB=double-blind; EF=ejection
fraction; HF=heart failure; hosp=hospitalizations; ISDN/HYD=isosorbide dinitrate and hydralazine; MC=multicenter; n=number of patients; MLHF=-Minnesota Living with Heart Failure questionnaire;
NNT=number needed to treat; NR=not reported; NYHA=New York Heart Association; QOL=quality of life; RCT=randomized controlled trial; VA=Veterans Affairs Medical Center; yrs=years

61

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov

Digitalis
Trial

Patient
Population

DIG93
1997
MC, R, DB(vs. placebo)
U.S., Canada

NYHA I (13%); II(54%); III (31%), IV(2%) HF
Mean EF 29%

N

Treatment

Duration

6800

Digoxin dosed per algorithm(based on age, gender, weight,
and kidney function)
vs.
Placebo

Mean 37
months

Quality
RatingResults

Study Conclusions

Primary Endpoint: All-cause mortality; no statisticallysignificant difference vs. placebo (RR 0.99 95% CI 0.91-1.07)
DigoxinPlacebo
Endpoint
p value(N=3397)(N=3403)
Primary
1181 (34.8%)
1194 (35.1%)
0.8
CV death
1016 (29.9%)1004 (29.5%)
0.78
HF hosp
910 (26.8%)1180 (34.7%)<0.001
Median dose (at randomization): 0.25 mg once daily
Mean serum digoxin concentration (steady state at 12
months): 0.80 ng/ml

All-cause mortality was not
significantly reduced withdigoxin; there was a significant
decrease in HF hospitalizationin patients with HF receiving
treatment with digoxin

Results

Study Conclusions

Primary Endpoints: 1) Time to death (any cause); ↓ witheplerenone (RR 0.85 95% CI 0.75-0.96; ARR 2.3%; NNT 43);
2) Time to death from CV causes or 1st CV hosp; ↓ witheplerenone (RR 0.87 95% CI 0.79-0.95; ARR 3.3%; NNT 30)

Eplerenone significantly
reduced combined death fromCV cause or CV hospitalizationin patients with acute MI
complicated by LVD and HF

GoodSpironolactone significantly
reduced all-cause mortality inpatients with severe HF

Good

Good

NHLBI and VA
HF therapy
Cooperative
ACEI: 95%
study; drug andDiuretics: 82%
placeboprovided by
Glaxo Wellcome
ACEI=angiotensin-converting enzyme inhibitor; CI=confidence interval; CV=cardiovascular; DB=double-blind; EF=ejection fraction; HF=heart failure; hosp=hospitalizations; N=number of patients; NYHA=New York Heart
Association; R=randomized; RR=relative risk

Aldosterone Antagonists
Patient
Trial
Population
EPHESUS250
2003
MC, R, DB(vs. placebo)
U.S., Canada,
Europe, Latin
AmericaDays from MI to R
(7.3)
HF symptoms (90%)
Mean EF 33%

N

Treatment

6632

Eplerenone 25 mg once daily(50 mg once daily target dose)vs.
Placebo

Mean 16monthsDrug therapy
ACEI or ARB: 87%
BB: 75%
Diuretics: 61%

Supported by
Pharmacia
RALES249
1999
MC, R, DB(vs. placebo)
U.S., Canada,
Mexico, Europe,
S. America, S.
Africa, New
Zealand, Japan

Duration

NYHA III (71%), IV(29%) HF
Mean EF 25%

1663

Endpoint

Spironolactone 25 mg once
daily (increased to 50 mg once
daily if signs or symptoms of
HF progression without
hyperkalemia)
vs.
Placebo

Mean 24months(terminatedearly due tosurvivalbenefit)

Eplerenone(N=3319)478 (14.4%)

Placebo(N=3313)554 (16.7%)

Quality
Ratingp valuePrimary1
0.008
CV death or
885 (26.7%)
993 (30.0%)
0.002
hosp
Mean dose: 42.6 mg once daily
Primary Endpoint: All-cause mortality; ↓ with spironolactone(RR 0.70 95% CI 0.60-0.82; ARR 11.4%; NNT=9)
Spironolactone
Placebo
Endpoint
p value(N=841)(N=822)
Primary
284 (34.6%)
386 (45.9%)<0.001CV death
226 (27.5%)
314 (37.3%)<0.001
HF hosp
215 (26.2%)
300 (35.7%)<0.001
Mean dose: 26 mg once daily

HF therapy
ACEI: 95%
Supported by
BB: 11%SearleDigoxin: 74%
Diuretics: 100%
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; ARR=absolute risk reduction; BB=beta-blockers; CI=confidence interval; CV=cardiovascular; DB=double-blind; EF=ejection fraction;
HF=heart failure; hosp=hospitalizations; LVD=left ventricular dysfunction; MI=myocardial infarction; N=number of patients; NYHA=New York Heart Association; NNT=number needed to treat; R=randomized; RR=relative
risk

62

PBM-MAP Publication No. 00-0015; September 2007
Updated versions can be found at www.pbm.va.gov