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Carvedilol reduced mortality and hospitalisation in severe chronic heart failure
  1. Goutham Rao, MD
  1. University of Pittsburgh Pittsburgh, Pennsylvania, USA

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

    Design

    Randomised {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 centres in 21 countries.

    Patients

    2289 patients (mean age 63 y, 80% men). Inclusion criteria were dyspnoea 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 oedema; not hospitalised 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 revascularisation, acute myocardial, or cerebral ischaemic event, or ventricular tachycardia or fibrillation; systolic blood pressure < 85 mm Hg; heart rate 68 beats/minute; or serum creatinine level 2.8 mg/dl. Follow up was 100%.

    Intervention

    Patients were allocated to carvedilol 3.125 g twice daily for 2 weeks, which was then titrated to 25 mg twice dailyif 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 hospitalisation 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 hospitalisation in the carvedilol group was lower than that in the placebo group (p < 0.001) (table).

    Carvedilol v placebo for severe chronic heart failure‡

    Conclusion

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

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

    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 metoprolol3 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 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 (eg, 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 hospitalisation, or quality of life.

    We are left with 2 well-designed studies, only 1 of which shows a substantial benefit of β-blocker treatment 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 pharmacological 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 non-black 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 it is forceful enough to block the adverse effects of the sympathetic nervous system and yet 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.

    References

    View Abstract

    Footnotes

    • Sources of funding: Roche Pharmaceuticals and GlaxoSmithKline.

    • * See glossary.

    • †Information provided by author.

    • 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 +1 212 305 7439.

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