Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Carvedilol reduced mortality and hospitalization in severe chronic heart failure

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ACP J Club. 2001 Nov-Dec;135:85. doi:10.7326/ACPJC-2001-135-3-085

Related Content in this Issue
• Companion Abstract and Commentary: Bucindolol reduced mortality and hospitalization related to cardiovascular causes in advanced chronic heart failure


Source Citation

Packer M, Coats AJ, 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 May 31;344:1651-8. [PubMed ID: 11386263] (All 2001 articles were reviewed for relevancy, and abstracts were last revised in 2007.)


Abstract

Question

In patients with severe chronic heart failure, does carvedilol, a β-blocker, reduce mortality and hospitalization?

Design

Randomized {allocation concealed*}†, blinded (patients and clinicians),* placebo-controlled trial with mean follow-up of 10.4 months (Carvedilol Prospective Randomized Cumulative Survival Study [COPERNICUS]).

Setting

334 centers in 21 countries.

Patients

2289 patients (mean age 63 y, 80% men). Inclusion criteria were dyspnea or fatigue at rest or on minimal exertion for ≥ 2 months; left ventricular ejection fraction ≤ 25%; absence of rales and ascites; minimal or no peripheral edema; not hospitalized for intensive care or continued inpatient care; and no recent intravenous inotropic agents or vasodilators. Exclusion criteria included chronic heart failure caused by uncorrected primary valvular disease or reversible cardiomyopathy; recent coronary revascularization, acute myocardial or cerebral ischemic event, or ventricular tachycardia or fibrillation; systolic blood pressure < 85 mm Hg; heart rate < 68 beats/min; or serum creatinine level > 2.8 mg/dL. Follow-up was 100%.

Intervention

Patients were allocated to carvedilol, 3.125 g twice/d for 2 weeks, which was then titrated to 25 mg twice/d if tolerated (n = 1156) or to placebo (n = 1133). Both groups received usual medications for chronic heart failure.

Main outcome measures

Mortality and combined risk for death or hospitalization for any reason.

Main results

Analysis was by intention to treat and used Kaplan-Meier survival curves. The cumulative risk for death at 1 year was lower in the carvedilol group than the placebo group (adjusted P = 0.001) (Table). The risk for combined death or hospitalization in the carvedilol group was lower than that in the placebo group (P < 0.001) (Table).

Conclusion

Carvedilol reduced mortality and the combined risk for death or hospitalization in patients with severe chronic heart failure.

*See Glossary.

†Information provided by author.

Sources of funding: Roche Pharmaceuticals and Glaxo SmithKline.

For correspondence: Dr. M. Packer, Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. FAX 212-305-7439.


Table. Carvedilol vs placebo for severe chronic heart failure‡

Outcomes at 1 y Carvedilol Placebo RRR (95% CI) NNT (CI)
Risk for death 11% 19% 35% (19 to 48) 15 (10 to 25)
Combined risk for death or hospitalization 42% 53% 24% (13 to 33) 10 (7 to 15)

‡Abbreviations defined in Glossary; NNT and CI calculated from data in article.


Commentary

Do β-blockers improve morbidity and mortality in patients with heart failure? 3 large trials have shown the benefits of bisoprolol (1), carvedilol (2), and metoprolol (3) on morbidity and mortality among patients with NYHA class II or III heart failure and have had important implications for how patients with mild-to-moderate heart failure are treated. On the basis of these studies, it has now become standard practice to treat such patients with one of these β-blockers. Whether patients with severe heart failure would also benefit from β-blockade has been unanswered. Patients with severe heart failure have the highest sympathetic outflow and theoretically may benefit most from β-blockade. These patients also have the least inotropic reserve and thus are most susceptible to decompensation when treated with β-blockade.

These 2 studies (BEST and COPERNICUS) have provided important data that allow us to assess the benefit of β-blockers in patients with severe heart failure. What is certain is that the benefit of β-blockers is largely dependent on the type of patients who receive them. Unfortunately, assessing the value of β-blockers in patients with severe heart failure is problematic. First, measuring and comparing severity is difficult. The NYHA functional classification is a useful guide, but as pointed out by Braunwald (4), it is subjective and thus inherently imprecise. An alternative way of comparing the severity of heart failure among patients in different trials is to use placebo mortality rates. Subsets of patients in whom the annual placebo mortality rate is high (e.g., 20%) are said to have very severe heart failure. This measure also has its limitations because it does not reflect only mortality caused by heart failure and it does not include any measure of severity of symptoms, frequency of hospitalization, or quality of life.

We are left with 2 well-designed studies, only one of which shows a substantial benefit of β-blocker therapy on mortality in patients with severe heart failure. These differing conclusions may have resulted from study populations that were different or from differences in the pharmacologic actions of bucindolol and carvedilol. The benefits of carvedilol may be related to its unique α-adrenergic, antioxidant, or antiendothelin effects.

The positive results from the BEST study—namely, the decrease in mortality specific to cardiovascular causes and the decrease in overall mortality among nonblack patients—should not be ignored. The results of previous studies and these 2 new investigations, coupled with our increasing understanding of the role of the adrenergic nervous system in heart failure, can be used to derive a rational set of recommendations. First, patients with mild or moderate heart failure should receive β-blockers. As heart failure becomes more severe in these same patients, β-blockade must strike a delicate balance so that it is forceful enough to block the adverse effects of the sympathetic nervous system but gentle enough to maintain any positive role this system plays in survival. For this reason, patients receiving β-blockers who develop progressive heart failure must be closely monitored. When patients with mild-to-moderate chronic heart failure who are treated with other β-blockers progress to severe heart failure, switching them to carvedilol should be considered. Additional evidence is needed before more widespread use of β-blockers in patients with severe heart failure can be recommended. Because the type of β-blocker may be very important, a trial directly comparing bucindolol and carvedilol would provide valuable evidence.

Goutham Rao, MD
University of Pittsburgh
Pittsburgh, Pennsylvania, USA


References

1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomised trial. Lancet. 1999;353:9-13. [PubMed ID: 10023943]

2. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-55. [PubMed ID: 8614419]

3. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-7. [PubMed ID: 10376614]

4. Braunwald E. Expanding indications for beta-blockers in heart failure. N Engl J Med. 2001;344:1711-2. [PubMed ID: 11386271]