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Meta-analysis: β-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure

Finlay A. McAlister, MD, MSc; Natasha Wiebe, MMath, PStat; Justin A. Ezekowitz, MD, MSc; Alexander A. Leung, MD; and Paul W. Armstrong, MD
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From the University of Alberta, Edmonton, Alberta, Canada.

Acknowledgment: The authors thank Jeff Bakal, PhD, PStat, for advice on the statistical analyses.

Grant Support: No external funding was received for the study. Dr. McAlister is supported by an Alberta Heritage Foundation for Medical Research Health Scholar Award and holds the Merck Frosst/Aventis Patient Health Management Chair at the University of Alberta. Dr. Ezekowitz is supported by the Canadian Institutes of Health Research.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Finlay A. McAlister, MD, MSc, University of Alberta Hospital, 2F1.21 Walter Mackenzie Health Sciences Centre, 8440 112 Street, Edmonton, Alberta T6G 2R7, Canada; e-mail, finlay.mcalister@ualberta.ca.

Current Author Addresses: Dr. McAlister: University of Alberta Hospital, 2F1.21 Walter Mackenzie Health Sciences Centre, 8440 112 Street, Edmonton, Alberta T6G 2R7, Canada.

Dr. Wiebe: University of Alberta, Research Transition Facility, Room 3048, 8308 114 Street, Edmonton, Alberta T6E 6L7 Canada.

Dr. Ezekowitz: Walter Mackenzie Health Sciences Centre, 2C2 Cardiology, 8440 112 Street, Edmonton, Alberta T6G 2B7, Canada.

Dr. Leung: 2F1 Walter Mackenzie Health Sciences Centre, University of Alberta Hospital, 8440 112 Street, Edmonton, Alberta T6G 2R7, Canada.

Dr. Armstrong: University of Alberta, VIGOUR Centre, 251 Medical Sciences Building, Edmonton, Alberta T6G 2H7, Canada.

Author Contributions: Conception and design: F.A. McAlister, N. Wiebe.

Analysis and interpretation of the data: F.A. McAlister, N. Wiebe, J.A. Ezekowitz, P.W. Armstrong.

Drafting of the article: F.A. McAlister, P.W. Armstrong.

Critical revision of the article for important intellectual content: F.A. McAlister, N. Wiebe, J.A. Ezekowitz, A.A. Leung, P.W. Armstrong.

Final approval of the article: F.A. McAlister, N. Wiebe, J.A. Ezekowitz, A.A. Leung, P.W. Armstrong.

Provision of study materials or patients: F.A. McAlister, J.A. Ezekowitz.

Statistical expertise: N. Wiebe.

Administrative, technical, or logistic support: F.A. McAlister.

Collection and assembly of data: F.A. McAlister, J.A. Ezekowitz, A.A. Leung.

Ann Intern Med. 2009;150(11):784-794. doi:10.7326/0003-4819-150-11-200906020-00006
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Background: Guidelines recommend that patients with heart failure receive β-blockers in doses used in the trials that have proven their efficacy. Although the adverse effects of β-blockade are dose-related, it is unclear whether the benefits are.

Purpose: To determine whether the survival benefits of β-blockade in heart failure are associated with the magnitude of heart rate reduction or the β-blocker dose.

Data Sources: MEDLINE, EMBASE, CINAHL, SIGLE, Web of Science, and the Cochrane Central Register of Controlled Trials, supplemented by hand-searches of bibliographies.

Study Selection: Randomized, placebo-controlled heart failure trials that reported all-cause mortality.

Data Extraction: Two reviewers independently extracted data on study characteristics, β-blocker dosing and heart rate reduction, and death.

Data Synthesis: The mean left ventricular ejection fraction in the 23 β-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19 209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I2 = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with β-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and β-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose β-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose β-blocker trials; P for meta-regression = 0.69).

Limitations: The analysis is based on aggregate data and resting heart rates. Few patients in these trials had bradycardia or diastolic dysfunction at baseline.

Conclusion: The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of β-blockers in heart failure, whereas the dose of β-blocker is not.


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Figure 2.
All-cause mortality in trials of 50 or more patients, by agent.

Trial acronyms are defined in Table 1. NA = not applicable; RR = risk ratio.

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Figure 3.
All-cause mortality, by treatment-related HR reduction tertile.

Trial acronyms are defined in Table 1. HR = heart rate; RR = risk ratio.

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Figure 4.
Meta-regression line for magnitude of heart rate reduction and risk ratio of all-cause mortality.

The mortality logarithm of relative risk is plotted against the reduction in heart rate. Circles are the observed estimates; size is based on the inverse of the SE of each trial. The 3 lines are the fitted and the upper and lower bounds of the 95% CIs.

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