0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction

Victor C. Lee, MD; David C. Rhew, MD; Michelle Dylan, PhD; Enkhe Badamgarav, MD, MPH; Glenn D. Braunstein, MD; and Scott R. Weingarten, MD, MPH
[+] Article and Author Information

From Zynx Health Incorporated and Cedars-Sinai Health System, Los Angeles, California; David Geffen School of Medicine at the University of California, Los Angeles, Westwood, California; and Cerner Health Insights, Beverly Hills, California.


Acknowledgments: The authors thank Anacleto Gano Jr., MPH, for technical assistance in preparation of the manuscript and Cris Sevilla-Pappas for managing the reference database.

Grant Support: By a research grant from Cedars-Sinai Health System.

Potential Financial Conflicts of Interest: Stock ownership or options (other than mutual funds): D.C. Rhew (Merck, Pfizer); Grants received: Zynx Health Incorporated has received grants from AstraZeneca, Aventis, Bristol-Myers Squibb, Merck, Novartis, and Pfizer.

Requests for Single Reprints: Victor C. Lee, MD, Zynx Health Incorporated, 10880 Wilshire Boulevard, Suite 1450, Los Angeles, CA 90024; e-mail, vlee@zynx.com.

Current Author Addresses: Drs. Lee, Rhew, and Weingarten: Zynx Health Incorporated, 10880 Wilshire Boulevard, Suite 1450, Los Angeles, CA 90024.

Drs. Dylan and Badamgarav: Cerner Health Insights, 9100 Wilshire Boulevard, Suite 655E, Beverly Hills, CA 90212.

Dr. Braunstein: Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.


Ann Intern Med. 2004;141(9):693-704. doi:10.7326/0003-4819-141-9-200411020-00011
Text Size: A A A

Background: The role of angiotensin-receptor blockers (ARBs) in treating patients with chronic heart failure and high-risk acute myocardial infarction (MI) has been controversial, and recent clinical trials provide more information on this topic.

Purpose: To quantify the effect of ARBs when compared with placebo (with and without background angiotensin-converting enzyme [ACE] inhibitors) and ACE inhibitors on all-cause mortality and heart failure hospitalizations in patients with chronic heart failure and high-risk acute MI.

Data Sources: Data from original research published through 13 November 2003.

Study Selection: Predefined criteria were used to identify 24 trials.

Data Extraction: 2 reviewers independently collected information on study characteristics and data on all-cause mortality and heart failure hospitalization.

Data Synthesis: 24 trials involving 38 080 patients were included. Analysis of chronic heart failure trials revealed that 1) ARBs were associated with reduced all-cause mortality (odds ratio [OR], 0.83 [95% CI, 0.69 to 1.00]) and heart failure hospitalizations (OR, 0.64 [CI, 0.53 to 0.78]) as compared with placebo; 2) for ARBs versus ACE inhibitors, all-cause mortality (OR, 1.06 [CI, 0.90 to 1.26]) and heart failure hospitalization (OR, 0.95 [CI, 0.80 to 1.13]) did not differ; 3) and for combinations of ARBs plus ACE inhibitors versus ACE inhibitors alone, all-cause mortality was not reduced (OR, 0.97 [CI, 0.87 to 1.08]) but heart failure hospitalizations were reduced (OR, 0.77 [CI, 0.69 to 0.87]). For patients with high-risk acute MI, 2 randomized trials compared ARBs with ACE inhibitors but did not reveal differences in all-cause mortality or heart failure hospitalization.

Limitations: Comparative economic data between ARBs and ACE inhibitors are lacking.

Conclusions: Because ACE inhibitors and ARBs do not differ in efficacy for reducing all-cause mortality and heart failure hospitalizations in patients with chronic heart failure and in patients with high-risk acute MI, ARBs should be regarded as suitable alternatives to ACE inhibitors.

Figures

Grahic Jump Location
Figure 1.
Article flow.

ARB = angiotensin-receptor blocker; RCT = randomized, controlled trial.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Funnel plot of angiotensin-receptor blockers versus all comparison groups for all-cause mortality in chronic heart faiure (n < 20).

OR = odds ratio; SE = standard error.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Forest plots for angiotensin-receptor blockers (ARBs) versus placebo in patients with chronic heart failure.

ARCH-J = Assessment of Response to Candesartan in Heart Failure in Japan; CHARM = Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; MI = myocardial infarction; OR = odds ratio; SPICE = Study of Patients Intolerant of Converting Enzyme Inhibitors; STRETCH = Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Forest plots for angiotensin-receptor blockers (ARBs) versus angiotensin-converting enzme (ACE) inhibitors in patients with chronic heart failure.

ELITE = Evaluation of Losartan in the Elderly Study; HEAVEN = Heart Failure Valsartan Exercise Capacity Evaluation; MI = myocardial infarction; OR = odds ratio; REPLACE = Replacement of Angiotensin Converting Enzyme Inhibition; RESOLVD = Randomized Evaluation of Strategies for Left Ventricular Dysfunction.

Grahic Jump Location
Grahic Jump Location
Figure 5.
Forest plots for angiotensin-receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor combinations versus ACE inhibitors in patients with chronic heart failure.

ADEPT = Addition of the AT1 Receptor Antagonist Eprosartan to ACE Inhibitor Therapy in Chronic Heart Failure Trial; CHARM = Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; MI = myocardial infarction; OR = odds ratio; RESOLVD = Randomized Evaluation of Strategies for Left Ventricular Dysfunction; V-HeFT = Vasodilator Heart Failure Trial; Val-HelFT = Valsartan Heart Failure Trial.

Grahic Jump Location
Grahic Jump Location
Figure 6.
Cumulative meta-analysis for angiotensin-receptor blockers versus placebo comparison all-cause mortality outcome, in patients with chronic heart failure.

Cumulative odds ratios (ORs) and 95% CIs are presented for each study along with the publication date, study size, and cumulative sample size. ARCH-J = Assessment of Response to Candesartan in Heart Failure in Japan; CHARM = Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; SPICE = Study of Patients Intolerant of Converting Enzyme Inhibitors; STRETCH = Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
ARBs: Dose and side effect considerations
Posted on November 4, 2004
Loren D. Regier
www.RxFiles.ca - Saskatoon City Hospital, Saskatoon, SK, Canada S7K 0M7
Conflict of Interest: None Declared

The Meta-Analysis on ARBs appears to have missed out on two points that could be important for optimizing patient outcomes. First, in the Post-MI setting, the target dose for Valsartan in VALIANT was 160mg twice daily, much higher than the 80mg twice daily reported in the meta-analysis (see Table: Study Characteristics). The dose of the captopril was 50mg three times daily. (Mean doses at one year were 247mg/day for valsartan and 117mg/day in the captopril group, both clearly above the "target" dose reported in the meta-analysis). Dosing considerations are important because in the earlier OPTIMAL trial, losartan 50mg daily had worse cardiovascular death outcomes than captopril 50mg three times daily. One proposed explanation for this was that the losartan dose may have been too low. Based on the few outcome trials to date, it appears that higher doses of ARBs may be needed in the Post-MI setting if we are to consider them equivelent alternatives to ACE inhibitors.

A second item of note is the lack of additional outcome benefit but increase in adverse events for the combination arm (valsartan plus captopril) of VALIANT.

1. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators (VALIANT). Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003 Nov 13;349(20):1893- 906. Epub 2003 Nov 10.

2. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Lancet 2002 Sep 7;360(9335):752-60.

Conflict of Interest:

None declared

Dosing of ACE inhibitors and ARBs in chronic heart failure and acute myocardial infarction
Posted on November 11, 2004
Michael J. Peeters
Texas Tech University HSC- School of Pharmacy
Conflict of Interest: None Declared

It would be remissed not to draw attention to the dosing of the angiotensin- converting-enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in the recent article by Lee et al.(1) In the recent ARB trials newly incorporated into this meta-analysis, much larger doses of ARBs were utilized than in prior trials. Earlier comparison trials showing trends towards ACEi superiority over ARBs, used routine ACEi doses but lower ARB doses.(2,3) When ACEi and ARBs are used in the higher doses examined more recently, ARBs appear to be a suitable alternative to ACEi.(4,5) (ie. in OPTIMAAL, losartan 50 mg/day was used versus VALIANT's valsartan 320 mg/day, while both compared to captopril 150 mg/day.)

The volume of evidence favoring ACEi in both chronic heart failure (CHF) and acute myocardial infarction (AMI) are vastly greater than with ARBs, and current JACHO quality indicators should remain unchanged. ACEi intolerance necessitating ARB use represents a relatively small population, and would not likely lead to a significant increase in indicator measure numbers. Current AHA/ACC recommendations suggest multiple ACEi attempts if ACEi-induced cough is suspected. Quality indicators are meant as a measure and comparison of an institution's implementation of evidence-based best practices. Moreover, current ARB product labeling and monograph information, except for valsartan, does not state the higher dosing required in CHF or AMI, but rather contains the lower hypertension dosing suggestions. In addition, simple economic comparison when ARBs are used in these higher doses (and assuming comparable efficacy to ACEi), the difference in medication cost vastly favors ACEi by a ten-fold margin. Subtherapeutic ARB dosing is a potential problem, especially among practitioners not familiar with this specific study literature. While ACEi use is improving nationally and providers are becoming more familiar with target ACEi doses, routine use of ARB therapy seems fraught with errors at present.

1. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004; 141:693-704.

2. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial- the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355:1582-87.

3. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Lancet 2002; 360:752-60.

4. JJV McMurray, Ostergren J, Swedburg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan 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.

5. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349: 1893-906.

Conflict of Interest:

None declared

The ACE inhibitor/ARB Controversy: Solution to a Vexing Measurement Problem
Posted on December 6, 2004
Jerod M Loeb
Joint Commission on Accreditation of Healthcare Organizations
Conflict of Interest: None Declared

As noted in the article, "Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction," the evidence for use of angiotensin-receptor blockers (ARBs) for chronic heart failure (HF) and acute myocardial infarction (AMI) with left ventricular systolic dysfunction has evolved, and relevant performance measures now need to be revised. The Centers for Medicare & Medicaid Services (CMS) and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) have been working toward this goal with the American Heart Association (AHA), the American College of Cardiology (ACC) and the Heart Failure Society of America (HFSA) since the publication of the VALsartan In Acute myocardial iNfarcTion (VALIANT) (1) and Candesartan in Heart Failure Assessment of Reduction in Morbidity and mortality (CHARM) (2) trials. In response to this growing body of evidence, CMS and JCAHO have concluded that ARBs should no longer be excluded from measures of quality care in the treatment of these conditions and have agreed to change the ACE inhibitor performance measures for AMI and HF, effective January 1, 2005.

Several clinical practice guidelines still recommend angiotensin converting enzyme (ACE) inhibitors as the first choice of therapy because of the greater amount of evidence, with ARBs recommended in ACE intolerant patients (3,4,5). However, the new ST-elevation myocardial infarction (STEMI) guidelines give ARBs a Class IIa recommendation, indicating that the weight of evidence favors their use as an alternative to ACE inhibitors. With the support of the evidence and the guidelines, JCAHO and CMS -- at a summit of stakeholders sponsored by the Agency for Healthcare Research and Quality (AHRQ) and the National Quality Forum (NQF) on November 3rd, 2004 -- proposed revised AMI and HF measures that would allow the prescription of either ACE inhibitors or ARBs to satisfy the measure. The revised measures were supported by the American Heart Association, the American College of Cardiology, the Heart Failure Society of America, the National Committee for Quality Assurance, the Agency for Healthcare Research and Quality and were endorsed by the National Quality Forum.

As the science of measuring performance in healthcare is relatively new, there are currently no explicit rules for changing an accepted measure in response to advances in research. Assuring that measures reflect current scientific knowledge is imperative. One of the most remarkable aspects of the aforementioned measure revision process has been the process itself, which has required a closely integrated effort on the part of the many organizations that have been involved in the definition and endorsement of these measures. The relatively timely implementation of these updated measures became possible only through the collaborative effort of many organizations committed to high quality care.

The measure change will be accomplished in two phases for practical reasons relating to the feasibility of making rapid changes in measure software being employed around the country. Beginning with January 1, 2005 discharges, the CMS and JCAHO data dictionary will be changed to capture any discharge prescription for an ACE inhibitor or an ARB as meeting the intent of the measure. A notation of "˜contraindication to both ACEI and ARB' will exclude patients from the measure. Full implementation of the change is anticipated to be effective next fall and will capture ACE inhibitors and ARBs separately, along with separate exclusion criteria for "˜contraindication to ACEI' and "˜contraindication to ARB.'

Mark B. McClellan, MD, PhD Administrator of the Centers for Medicare & Medicaid Services (CMS)

Jerod M. Loeb, PhD Executive Vice President, Division of Research Joint Commission on Accreditation of Healthcare Organizations (JCAHO)

Carolyn M. Clancy, MD Director, Agency for Healthcare Research and Quality (AHRQ)

Gary S. Francis, MD President, Heart Failure Society of America (HFSA)

Alice K. Jacobs, MD, FACC, FAHA President, American Heart Association (AHA)

Kenneth W. Kizer, MD, MPH President and Chief Executive Officer of the National Quality Forum (NQF)

Margaret E. O'Kane President, National Committee for Quality Assurance (NCQA)

Michael J. Wolk, MD, FACC President, American College of Cardiology (ACC)

References:

1) Pfeffer MA, McMurray JJ, Velazquez EF, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.

2) Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772-776.

3) Antman EM, Anbe DT, Armstrong PW, et al. American College of Cardiology; American Heart Association; Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction "“ executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004 Aug 4;44(3):671-719.

4) Hunt SA, Baker DW, Chin MH et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001 Dec 11;104(24): 2996-3007. .

5) Mosca L, Appel LJ, Benjamin EJ, Berra K et al. Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women. Circulation. 2004;109:672-692

6) Executive Council of the Heart Failure Society of America. Implications of recent clinical trials for heart failure performance measures. HFSA Position Statement. J Card Fail. 2004;10:4-5

7) 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;110:724-731.

Conflict of Interest:

None declared

In Response:
Posted on January 3, 2005
Victor C Lee
Zynx Health Incorporated
Conflict of Interest: None Declared

To the Editor:

We are pleased to hear that the Centers for Medicare and Medicaid Services (CMS), Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and several other collaborating organizations concur that angiotensin-receptor blockers (ARBs) will no longer be excluded from the CMS and JCAHO quality indicators for heart failure and acute myocardial infarction (MI). The implementation of the revised heart failure and acute MI measures in two phases makes practical sense as described in the letter by McClellan and colleagues as well as on the JCAHO Web site(1).

We respectfully disagree with Dr. Peeters' statement that the current quality indicators should remain unchanged. A prior meta-analysis by Jong and colleagues (2) showed no statistically significant difference in mortality or heart failure hospitalization rates between ARBs and placebo in patients with heart failure and left ventricular dysfunction. Thus, it was logical that ARB therapy was not part of the JCAHO and CMS quality measures for CHF and AMI at that time. However, current data (3) show that ARB therapy results in statistically significant reductions in mortality and heart failure hospitalizations for patients with heart failure and left ventricular dysfunction. Irrespective of whether ARBs are considered to be first- or second-line agents to ACE inhibitors, ARBs should be included as part of the heart failure and acute MI quality indicators because these agents improve clinical outcomes.

We agree with Dr. Peeters and Mr. Regier that the efficacy of ACE inhibitors and ARBs may be dependent upon their relative dosing. We did not perform separate analyses based on dosing, however, because the target doses for the ARBs in our study varied widely and we are not aware of standardized criteria for the interconversion of ARB doses.

Finally, we agree with Mr. Regier that in our table of study characteristics, the doses of valsartan and captopril in the VALIANT study were reported as the target doses from the initial hospitalization, but should have been the target doses upon 3-month follow-up, which were twice as high.

Victor C. Lee, MD Zynx Health Incorporated Los Angeles, CA 90024

David C. Rhew, MD Zynx Health Incorporated Los Angeles, CA 90024

Glenn D. Braunstein, MD Cedars-Sinai Health System Los Angeles, CA 90048

References

(1) Joint Commission on Accreditation of Healthcare Organizations. Change in ACEI for LVSD measures (HF-3, AMI-3): Incorporation of ARBs. Accessed at http://www.jcaho.org/pms/core+measures/changeinaceiforlvsdmeasuresincorparbs.pdf on 23 December 2004.

(2) Jong P, Demers C, KcKelvie RS, Liu PP. Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2002;39:463-70.

(3) Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med. 2004 Nov 2;141(9):693-704.

(4) Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldmanmd AM, Francis GS, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001;104:2996-3007.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)