CAPRICORN

Published

Dargie HJ, et al. "Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial". The Lancet. 2001. 357(9266):1385-1390.
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Clinical Question

Among patients with acute myocardial infarction (MI) and left ventricular ejection fraction ≤40%, does treatment with carvedilol improve mortality?

Bottom Line

In patients with acute MI and evidence of LV systolic dysfunction, treatment with carvedilol is associated with decreased mortality

Major Points

Beta-blockers have been used extensively for many decades in the acute and long-term treatment of MI based on RCTs conducted prior to the advent of reperfusion therapies and ACE inhibitors . However, in these studies, patients with heart failure were largely excluded. Prior to the publication of CAPRICORN there were no large-scale RCTs investigating the effect of beta-blockers in patients that develop LV systolic dysfunction post-MI. The MERIT-HF, COPERNICUS, and CIBIS-II trials all showed a mortality benefit with beta-blockers in patients with HFrEF. However, in all these trials, recent MI was an exclusion criteria. Furthermore, in the era of ACE inhibitor use post-MI, it was not known if beta-blockers would confer additional benefit when added to ACE inhibitors in patients with MI and reduced LV function. CAPRICORN was the first and only large-scale RCT investigating the effect of beta blockers in patients with acute MI and reduced LV function (with or without heart failure) in the era of reperfusion and ACE inhibition.

Published in 2001, the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial randomized 1,959 patients with hemodynamically stable MI in the past 3-21 days prior to randomization with reduced LVEF of 40% or less and on an ACE inhibitors (unless with proven intolerance) to receive carvedilol or placebo. With a mean follow-up of 1.3 years, there was no difference in the primary endpoint of all-cause mortality or hospital admission for CV problems (35% vs. 37%, HR 0,92, CI 0.80-1.07, P=0.296) but all-cause mortality alone was significantly lower in the carvedilol group compared to placebo (12% vs. 15%, HR 0.77, CI 0.60-0.98, P=0.031 NNT 43). Treatment with carvedilol was also associated with significant reductions in cardiovascular mortality (11% vs. 14%, HR 0.75, CI 0.58-0.96, P=0.024) and non-fatal MI (3% vs. 6%, HR 0.59, CI 0.39-0.90, P=0.014). The original primary endpoint was all-cause mortality, however given concerns that the trial may be underpowered the primary endpoint was changed from all-cause mortality to all-cause mortality or CV hospital admissions. The revised primary endpoint did not achieve significance while the original and most important outcome, death, did reach significance with a trend towards decreased mortality with carvedilol (23% risk reduction in all-cause mortality).

CAPRICORN is a landmark study and the only RCT that provides evidence for the benefit of beta-blocker therapy in acute MI with LV dysfunction in the era of reperfusion. Based on the results of this trial both the ACC and ESC practice guidelines where changed to incorporate the findings of this trial.

Guidelines

ACCF/AHA STEMI Guidelines (2013, adapted)

• All patients after STEMI except those at low risk (normal or near-normal ventricular function, successful reperfusion, and absence of significant ventricular arrhythmias) and those with contraindications should receive beta-blocker therapy. Treatment should begin within a few days of the event, if not initiated acutely, and continue indefinitely. (Class I, Level of Evidence: A)
• Patients with moderate or severe LV failure should receive beta-blocker therapy with a gradual titration scheme. (Class I, Level of Evidence: B)

ACCF/AHA NSTE-ACS Guidelines (2014, adapted)

• Oral beta-blocker therapy should be initiated within the first 24 hours in patients who do not have any of the following: 1) signs of HF, 2) evidence of low-output state, 3) increased risk for cardiogenic shock, or 4) other contraindications to beta blockade (eg, PR interval >0.24 second, second- or third-degree heart block without a cardiac pacemaker, active asthma, or reactive airway disease). (Class I, Level of Evidence: A)
• In patients with concomitant NSTE-ACS, stabilized HF, and reduced systolic function, it is recommended to continue beta-blocker therapy with 1 of the 3 drugs proven to reduce mortality in patients with HF: sustained-release metoprolol succinate, carvedilol, or bisoprolol. (Class I, Level of Evidence: C)

Design

• N=1,959
  • Carvedilol group: 975
  • Placebo group: 984
• Setting: 17 countries and 163 centers
• Enrollment/Randomization: Double-blind RCT
• Follow-up: Mean 1.3 years
• Analysis: Intention-to-treat
• Primary endpoint: All cause mortality or cardiovascular hospitalization, all cause mortality
• Secondary endpoints: Sudden death, hospitalization for heart failure

Population

Inclusion Criteria

• Age >18 confirmed MI occurring within 3-21 days prior to randomization
• LVEF 40% or less
• Concurrent treatment with ACE inhibitor for >48 hours with the dose being stable for >24 hours, unless proven intolerance of ACE inhibitors

Exclusion Criteria

• Requirement for IV inotropic therapy or uncontrolled heart failure
• Ongoing or expected need for beta-blockage
• Complicating clinical conditions including unstable angina, uncorrected significant valve disease, hypotension <90 mmHg, bradycardia <60 bpm, uncontrolled hypertension, unstable IDDM, significant pulmonary, hepatic or renal impairment
• Ongoing therapy with inhaled beta-2 agonists or steroids, rate-limiting calcium channel blockers, antiarrythmics (except amiodarone), immunosuppressive agents
• Expectation of death from other illness during the course of the trial
• Pregnancy, continuing lactation or planned pregnancy
• Inability of unwillingness to give informed consent

Baseline Characteristics

Comparisons are carvedilol vs. placebo’’

• Demographics
  • Mean age, 63 vs. 63
  • Men, 73% vs 74%
  • Current Smoker, 33% vs. 32%
• Medical History
  • Prior MI, 31% vs 29%
  • Prior angina, 57% vs. 54%
  • Prior HTN, 55% vs. 52%
  • Prior DM, 21% vs. 23%
  • Other vascular disease, 17% vs. 16%
  • Prior revascularization, 12% vs. 11%
  • HLD, 32% vs. 33%
• Infarct characteristics
  • Mean LVEF, 32.9% vs. 32.7%
  • Mean SBP, 121.6 vs. 120.7
  • Mean DBP, 73.7 vs. 73.4
  • Mean HR, 77.3 vs. 77.2
  • Site of MI, Anterior 59 vs. 54%, Inferior 21 vs. 21%, Other 20% vs. 25%
• Treatment for index MI
  • Nitrates, 73% vs. 73%
  • IV BB, 11% vs. 10%
  • IV heparin, 63% vs. 65%
  • Subcutaneous heparin, 47% vs. 49%
  • IV diuretics, 35% vs. 33%
  • Thrombolysis/ primary angioplasty, 45% vs. 47%
• Medications at time of randomization
  • ACE inhibitor, 98% vs. 97%
  • Aspirin, 86% vs. 86%

Interventions

Randomization to:

• Carvedilol (Initial 6.25mg BID uptitrated to max of 25mg BID daily, as tolerated)
• Placebo

Outcomes

Comparisons are carvedilol vs. placebo”

Primary Outcomes

• All cause mortality or cardiovascular hospitalization
  • 35% vs. 37%, HR 0,92, CI 0.80-1.07, P=0.296
• All cause mortality
  • 12% vs. 15%, HR 0.77, CI 0.60-0.98, P=0.031

Secondary Outcomes

• Sudden death
  • 5% vs. 7%, HR 0.74, CI 0.51-1.06, P=0.098
• Hospitalization for heart failure
  • 12% vs. 14%, HR 0.86, CI 0.67-1.09, P=0.215

Other endpoints

• Cardiovascular cause mortality
  • 11% vs. 14%, HR 0.75, CI 0.58-0.96, P=0.024
• Death due to heart failure
  • 2% vs. 3%, HR 0.60, CI 0.33-1.07, P=0.083
• Non-fatal myocardial infarction
  • 3% vs. 6%, HR 0.59, CI 0.39-0.90, P=0.014
• All-cause mortality or non-fatal myocardial infarction
  • 14% vs. 20%, HR 0.71, CI 0.57-0.89, P=0.002

Criticisms

• The major primary endpoint in this trial did not achieve statistical significance despite the more important outcome of mortality reaching significance

Funding

Funding provided by Roche Pharmaceuticals and GlaxoSmithKline