- Open Access
The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial
© Eichhorn and Bristow; licensee BioMed Central Ltd. 2001
- Received: 15 December 2000
- Accepted: 2 January 2001
- Published: 2 February 2001
Previous trials (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS] II) have demonstrated a mortality benefit of β-adrenergic blockade in patients with mild to moderate heart failure. The recent Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial has extended these results to a more advanced patient population. This trial did not, however, include patients who could not reach compensation, patients with far advanced heart failure symptoms, or a significant number of black patients. Future studies of β-blockade may focus on these patients or patients with asymptomatic left ventricular dysfunction.
- β-adrenergic blocking agents
- heart failure
Heart failure medical therapy has undergone drastic evolution in the past 15 years. The shift in our understanding of how to optimally treat this clinical syndrome has been only slightly less dramatic than the shift in conceptual thought effected by the Polish astronomer Nicolas Copernicus (1473-1543), after whom the COPERNICUS trial is named. Copernicus proposed, based on his observations, the concept of a heliocentric solar system, as opposed to the previously accepted Ptolemiac theory of the earth as a fixed mass in the universe. The theory of giving a beta-blocker, a negatively inotropic and chronotropic agent, to a heart failure patient was perhaps as counter-intuitive and revolutionary as was Copernicus' heliocentric solar system, inasmuch as when first proposed it did not fit the accepted paradigm of the day. Only through years of small mechanistic studies and, ultimately, through large clinical trials has the old 'hemodynamic' paradigm of heart failure treatment fallen. Current theory now proposes that multiple compensatory neurohormonal, cytokine and mechanical stretch signals activate intra-cellular pathways that lead to progressive myocardial dysfunction, pathologic hypertrophy and remodeling, and cell loss . Inhibition of neurohormonal activation by angiotensin converting enzyme (ACE) inhibitors [2,3] or beta-blocking agents [4,5,6,7,8] has shown an attenuation or reversal in the pathological remodeling process [9,10], a shift in phenotype back towards normal , and even a reduction in cell death . Furthermore, clinical trials with β-blockers conducted in mild to moderate heart failure populations have shown a consistent mortality benefit, with large reductions in cardiovascular death, reductions in hospitalization, and improvement in quality of life [4,5,6].
It was unclear prior to the COPERNICUS trial  whether patients with advanced heart failure would derive a benefit from beta-blockade, as these are the patients who are most dependent on adrenergic support. The COPERNICUS trial was a double-blind, placebo-controlled, multicenter study of the effect of carvedilol, a nonselective beta-blocker with alpha1 blocking properties and anti-oxidant effects on mortality in patients with more advanced heart failure. To be randomized in this trial, a patient had to have heart failure symptoms of heart failure at rest or on minimal exertion for at least 2 months. While New York Heart Association (NYHA) class was not assessed in this trial, these criteria fit the NYHA class III or IV criteria. Patients also had to have an ejection fraction of 0.25 or less, and had to be on ACE inhibitors and diuretics for at least 2 months. Importantly, patients with more than minimal evidence of fluid retention (pulmonary or peripheral edema) were excluded, as were patients in the intensive care unit, and patients who had recently received class IV diuretics or inotropes within 4 days.
As the COPERNICUS trial has only been presented orally, the results presented here are preliminary. The COPERNICUS trial recruited 2289 patients from 152 sites who were randomized to carvedilol (n = 1156) or placebo (n = 1133) and were followed for a mean of 316 days . In the United States, 482 patients were randomized at 117 sites, and only 121 patients in the COPERNICUS trial were black. The study was stopped early for a highly significant mortality benefit. Carvedilol reduced mortality by 35% (95% confidence interval, 19-48% reduction) and the annual placebo mortality in this study was 18.5%, suggesting an advanced heart failure population. Subgroup analysis showed a consistent benefit across all strata, and permanent treatment withdrawal was lower in the carvedilol group than in the placebo group, suggesting good tolerability of carvedilol.
The COPERNICUS study is a very important clinical trial that has added significant support to the β-blocker hypothesis and reassures us of the safety and benefit of these drugs in a subset of patients with more advanced heart failure. It would, however, be inappropriate to over-extend the findings of the COPERNICUS trial to advanced heart failure patients who lack potential for reversal and are not in a compensated state.
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