The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study evaluated the effect of carvedilol, an adrenergic blocker, on 2,289 patients with severe congestive heart failure (CHF). While previous studies have shown that beta-blocking agents improve functional status and reduce morbidity in patients with mild to moderate heart failure, their benefits in patients with severe CHF have not been established. The initial study, which was published in May 2001, investigated the effects of carvedilol on patient survival. Packer and colleagues did a follow-up study to examine the effect of carvedilol on morbidity.
Patients were included in the study if they had dyspnea lasting two months or more or fatigue at rest or on minimal exertion, and a left ventricular ejection fraction of less than 25 percent. The subjects could be inpatients or outpatients. Key exclusion criteria were acute illness requiring prolonged hospitalization and use of an intravenous positive inotropic agent or a vasodilator within four days of randomization. All subjects received a diuretic and an angiotensin-converting enzyme inhibitor or an angiotensin-II receptor antagonist, if tolerated. Use of other medications (e.g., digitalis, spironolactone, vasodilators, amiodarone) was allowed but not required.
Patients were randomized in a double-blind fashion to treatment with carvedilol in a starting dosage of 3.125 mg twice daily, or placebo. The dosage of carvedilol was increased at two-week intervals to a final target dosage of 25 mg twice daily. The primary end point of the study was all-cause mortality, but there were four secondary end points: combined risk of death or hospitalization for any reason, combined risk of death or hospitalization for a cardiovascular reason, combined risk of death or hospitalization for heart failure, and patient global assessment (i.e., perception of the patient).
The authors conclude that carvedilol reduces not only mortality but also morbidity in patients with severe CHF. Carvedilol also lowers the combined risk of death or hospitalization. Patients in the carvedilol group had fewer hospitalizations for heart failure (17.1 percent versus 23.7 percent of the placebo group), for cardiovascular concerns (21.3 percent versus 27.7 percent), and for any reason (32.2 percent versus 38.1 percent). Patients taking carvedilol reported improvements in their condition and also experienced fewer serious adverse events when compared with placebo.
editor's note:The accompanying table lists the larger trials of beta blockers in patients with CHF (Wollert KC, Drexler H. Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial: carvedilol as the sun and center of the β-blocker world? [Editorial]. Circulation October 22, 2002;106:2164–6.). Of note, only one other study emphasized patients with severe heart failure, New York Heart Association classes III and IV. The Beta-Blocker Evaluation of Survival Trial (BEST) studied bucindolol, a non-selective beta blocker and mild vasodilator, and did not show any significant reduction in mortality (The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med May 31, 2001;344:1659–67.). The reason for different outcomes in the BEST and COPERNI-CUS trials is not fully understood, but clearly more studies on other beta blockers are needed to determine which drugs in the class reduce mortality in patients with CHF.—S.M.S.