COPERNICUS

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Packer M, et al. "Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure". Circulation. 2002. 106(17):2194-9.
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Clinical Question

In patients with HFrEF and NYHA class III-IV symptoms, does carvedilol improve survival?

Bottom Line

Carvedilol reduces risk of death or HF hospitalization by 31% compared to placebo in class III-IV HF with EF <25%.

Major Points

The role of beta-blockers in the treatment of chronic compensated HFrEF has been well established in trials like CIBIS-II[1] (1999) and MERIT-HF (1999). The role of beta-blocker use in patients with severely reduced EF was unclear.

The 2002 Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial randomized 2,289 patients with EF <25% to carvedilol or placebo. At 10.4 months, carvedilol had a clear reduction in annual mortality rates compared to placebo (12.8% vs. 19.7% P=0.00013; NNT=15) as well as reductions in rehospitalizations and cardiogenic shock.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[2]

  • Use of bisoprolol, carvedilol, or metoprolol sustained release for all patients with current or prior symptomatic HFrEF unless contraindicated (class I, level A)

Design

  • Double-blind, parallel-group, randomized, placebo-controlled trial
  • N=2,289
    • Carvedilol (n=1,156)
    • Placebo (n=1,133)
  • Mean follow-up: 10.4 months
  • Analysis: Intention-to-treat
  • Primary outcome: Annual mortality

Population

Inclusion Criteria

  • Dyspnea or fatigue at rest or on minimal exertion for >2 months (effectively NYHA class III-IV symptoms)
  • Ischemic or nonischemic HFrEF
  • LVEF <25%
  • Appropriate medical therapy, including:
    • Diuretics, dose-adjusted to achieve euvolemia (absence of rales, minimal peripheral edema)
    • ACE inhibitor or ARB (unless not tolerated)
    • Digitals, nitrates, hydralazine, spironolactone, and amiodarone allowed but not required

Exclusion Criteria

  • Volume overload
  • Acute illness requiring continued hospitalization
  • Therapy with IV inotropic agents within 4 days of screening

Interventions

  • Randomly assigned to carvedilol or placebo in addition to usual HF therapy
  • Starting dose of carvedilol 3.125mg BID
    • Increased at 2-week intervals to target 25mg BID dose
    • Dose reduced or held as clinically appropriate
  • Followed every 2 months until end of study
  • Investigators could add any agent except open label beta-blocker

Outcomes

Comparisons are carvedilol vs. placebo.

Primary Outcomes

Annual mortality
12.8% vs. 19.7% (RR 0.65; 95% CI 0.52-0.81; P=0.00013; NNT=15)

Secondary Outcomes

Death or hospitalization
36.7% vs. 44.7% (RR 0.76; 95% CI 0.67-0.87; P<0.001)
Death or CV hospitalization
30.2% vs. 41.6% (RR 0.73; 95% CI 0.63-0.84; P=0.00002)
Death or HF hospitalization
25.5% vs. 37.9% (RR 0.69; 95% CI 0.59-0.81; P=0.000004)
HF hospitalization
17.1% vs. 23.7% (P=0.0001)
CV hospitalization
21.3% vs. 27.7% (p=0.0003)
Any hospitalization
32.2% vs. 38.1% (P=0.003)

Adverse Events

Serious adverse events
39% vs. 46% (P=0.002)
HF
17% vs. 24% (P<0.001)
Sudden death
3.9% vs. 6.1% (P=0.16)
Hypotension
1.9% vs. 1.6% (P=0.57)
Cardiogenic shock
0.4% vs. 1.7% (P=0.003)
Bradycardia
1.5% vs. 1.2% (P=0.63)

Funding

Funding provided by Roche Pharmaceuticals and GlaxoSmithKline.

Further Reading

  1. CIBIS Authors. "The cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial." The Lancet. (1999):353;9146:9-13.
  2. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.