Clinical Inquiries

What is the most effective beta-blocker for heart failure?

Neher JO, Safranek S, Grover F Jr. J Fam Pract. 2003 May;52(5):396, 398-9

Evidence-based Answer

Three beta-blockers—carvedilol, metoprolol, and bisoprolol—reduce mortality in chronic heart failure caused by left ventricular systolic dysfunction, when used in addition to diuretics and angiotensin converting enzyme (ACE) inhibitors (strength of recommendation [SOR]: A, based on large randomized placebo-controlled trials). No differences in mortality or patient tolerance have been demonstrated in studies comparing carvedilol and metoprolol (SOR: B, based on small head-to-head trials).

Evidence-based Summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival 2 (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure 3 (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II 4 (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial 5 (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial 1 demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis. 6

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest 7 included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing. 8

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease. 9 A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations. 10 A trend toward improved survival was noted but did not reach statistical significance.

Clinical Commentary

To provide the best care, we must go beyond the conventional ACE inhibitor and diuretic therapy for congestive heart failure patients. Adding 1 of the 3 beta-blockers (carvedilol, metoprolol, or bisoprolol), as recommended above, will further improve the survival rates and decrease hospitalization rates.

Remember these pearls when using beta-blockers in congestive heart failure:

If you encounter difficulties with titration or don’t feel comfortable initiating beta-blocker therapy, consult your cardiologist for help.

Recommendations from Others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Figures

Selected trials of beta-blockers for systolic dysfunction
Study Drug N Mortality reduction (%) 95% CI (%) Statistically significant? NNT Mean duration of follow-up (months)
US Carvedilol 1 Carvedilol 1094 (65) 39–80 Yes 22 6.5
COPERNICUS 2 Carvedilol 2289 (35) 19–48 Yes 14 10.4
MERIT-HF 3 Metoprolol 3991 (34) 19–46 Yes 26 12
CIBIS II 4 Bisoprolol 2647 (34) 19–47 Yes 18 15.6
BEST 5 Bucindolol 2708 (9) –0.2–22 No — 24
CI, confidence interval; NNT, number needed to treat

Chronic heart failure

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References

  1. Packer M, Bristow MR, Cohn JNet al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. 1996. Volume 334. Page(s): 1349-1355.
  2. Packer M, Coats AJS, Fowler MBet al. Effect of carvedilol on survival in severe chronic heart failure. 2001. Volume 344. Page(s): 1651-1658.
  3. No author listed. Effect of metoprolol CR/XL in chronic heart failure: Metotprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). 1999. Volume 353. Page(s): 2001-2007.
  4. No author listed. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. 1999. Volume 353. Page(s): 9-13.
  5. No author listed. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. 2001. Volume 344. Page(s): 1659-1667.
  6. Hart SMnull Influence of beta-blockers on mortality in chronic heart failure. 2000. Volume 34. Page(s): 1440-1451.
  7. Metra M, Giubbini Raffaele, Nodari E, Boldi E, Modena MG, Dei Cas Lnull Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. 2000. Volume 102. Page(s): 546-551.
  8. Poole-Wilson PA, Cleland JG, Di Lenarda Aet al. Rationale and design of the carvedilol or metoprolol European trail in patients with chronic heart failure: COMET. 2002. Volume 4. Page(s): 321-329.
  9. Aronow WS, Ahn C, Kronzon AInull Effect of propranolol versus no propanolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction ≥40% treated with diuretics plus angiotensin-converting enzyme inhibitors. 1997. Volume 80. Page(s): 207-209.
  10. Sturm B, Pacher R, Strametz-Juranek Jet al. Effect of beta 1 blockade with atenolol on progression of heart failure in patients pretreated with high-dose enalapril. 2000. Volume 2. Page(s): 407-412.