Week 16 – COPERNICUS

“Effect of carvedilol on survival in severe chronic heart failure”

by the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group

N Engl J Med. 2001 May 31;344(22):1651-8. [free full text]

We are all familiar with the role of beta-blockers in the management of heart failure with reduced ejection fraction. In the late 1990s, a growing body of excellent RCTs demonstrated that metoprolol succinate, bisoprolol, and carvedilol improved morbidity and mortality in patients with mild to moderate HFrEF, while the only trial of beta-blockade (with bucindolol) in patients with severe HFrEF failed to demonstrate a mortality benefit. In 2001, the COPERNICUS trial further elucidated the mortality benefit of carvedilol in patients with severe HFrEF.

Population: patients with severe CHF (NYHA class III-IV symptoms and LVEF < 25%) despite “appropriate conventional therapy”

Intervention: carvedilol with protocolized uptitration (in addition to pt’s usual meds)

Comparison: placebo with protocolized uptitration (in addition to pt’s usual meds)

Outcomes: all-cause mortality and combined risk of death or hospitalization for any cause


Results
:
2289 patients were randomized before the trial was stopped early due to higher than expected mortality benefit in the carvedilol arm. Mean follow-up was 10.4 months. Regarding mortality: 190 (16.8%) of placebo patients died, while only 130 (11.2%) of carvedilol patients died (p = 0.0014) (NNT = 17.9). Regarding mortality or hospitalization: 507 (44.7%) of placebo patients died or were hospitalized, while only 425 (36.8%) of carvedilol patients died or were hospitalized (NNT = 12.6). Both outcomes were found to be of similar directions and magnitudes in subgroup analyses (age, sex, LVEF < 20% or >20%, ischemic vs. non-ischemic CHF, study site location, and no CHF hospitalization within year preceding randomization).

Implication/Discussion:
In severe heart failure with reduced ejection fraction, carvedilol significantly reduces mortality and hospitalization risk.

This was a straightforward, well-designed, double-blind RCT with a compelling conclusion. In addition, the dropout rate was higher in the placebo arm than the carvedilol arm! Despite longstanding clinician fears that beta-blockade would be ineffective or even harmful in patients with already advanced (but compensated) HFrEF, this trial definitively established the role for beta-blockade in such patients.

Per the 2013 ACCF/AHA guidelines, “use of one of the three beta blockers proven to reduce mortality (e.g. bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless contraindicated.”

Of note, there are two COPERNICUS trials. This is the first reported study, in NEJM from 2001, which reports only the mortality and mortality + hospitalization results, again in the context of a highly anticipated trial that was terminated early due to mortality benefit. A year later, the full results were published in Circulation, which described findings such as a decreased number of hospitalizations, fewer total hospitalization days, fewer days hospitalized for CHF, improved subjective scores, and fewer serious adverse events (e.g. sudden death, cardiogenic shock, VT) in the carvedilol arm.

Further Reading/References:
1. 2013 ACCF/AHA Guideline for the Management of Heart Failure
2. COPERNICUS, 2002 Circulation version
3. Wiki Journal Club (describes 2001 NEJM, cites 2002 Circulation)
4. 2 Minute Medicine (describes and cites 2002 Circulation)

Summary by Duncan F. Moore, MD

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