COMET

Published

Poole-Wilson PA, et al. "Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial". The Lancet. 2003. 362(9377):7-13.
PubMed • Full text • PDF

Clinical Question

In patients with HFrEF and NYHA class II-IV symptoms, how does carvedilol compare with metoprolol tartrate in improving survival?

Bottom Line

In patients with HFrEF (EF ≤35%) and NYHA II-IV symptoms, Carvedilol reduced all-cause mortality compared to metoprolol tartrate.

Major Points

The 2003 Carvedilol Or Metoprolol European Trial (COMET) randomized 3,029 patients with class II-IV heart failure to carvedilol or metoprolol twice daily in addition to other medical therapies. With a mean follow-up of 4.8 years, the carvedilol group outperformed the metoprolol tartrate group in all-cause mortality (34% vs. 40%; P=0.0017).

COMET remains the largest and most well-designed head-to-head trial of beta-blockers. It was intended to build upon data from the earlier MERIT-HF (1999) and COPERNICUS (2002) trials, which demonstrated the survival benefit of metoprolol succinate and carvedilol, respectively, in HFrEF. The generalizability of COMET's findings is limited given that the goal dose of metoprolol is regarded as unequal to the matching carvedilol dose. Also, the twice daily metoprolol tartrate was studied rather than the once-daily metoprolol succinate as was used in MERIT-HF.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)

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

Design

• Multicenter, double-blind, parallel-group, randomized controlled trial
• N=3,029
  • Carvedilol (n=1,511)
  • Metoprolol tartrate (n=1,518)
• Setting: 341 centers in 15 countries in Europe
• Enrollment: 1996-1999
• Analysis: Intention-to-treat
• Mean follow-up: 4.8 years
• Primary outcomes: All-cause mortality; all-cause mortality or any hospital admission

Population

Inclusion Criteria

• LVEF ≤35%
• NYHA class II-IV
• Cardiovascular-related admission in prior two years
• Optimal treatment with diuretics and ACE inhibitors

Exclusion Criteria

• Change in oral medications in prior two weeks
• Need for IV inotropes
• Non-dihydropiridine CCB usage
• Experimental medication in prior 30 days
• UA, MI, coronary revascularization, or CVA in prior 2 months
• SBP >170 mmHg or DBP >105 mmHg
• Valvular disease with hemodynamically-significant changes
• Symptomatic, sustained ventricular arrhythmias in prior 2 months not adequately treated with antiarrhythmics or ICD
• Pregnancy or of childbearing capacity without adequate birth control
• Known drug or alcohol misuse
• Poor compliance with treatment
• Other diseases which would complicate management or reduce life expectancy

Baseline characteristics

From the carvedilol group.

• Demographics: Age 61.6 years, male 79%, white race 99%
• Baseline health data: BMI 26.9 kg/m², BP 126/77 mmHg, HR 81 BPM
• HF-specific:
  • NYHA class:
    • II: 48%
    • III: 48%
    • IV: 3%
  • HF duration: 51.3 months
  • LVEF: 26%
  • HF-specifics: Ischemic 51%, HTN 18%, dilated cardiomyopathy 44%, previous valve surgery 3%
  • NT-proBNP 1,298 ug/L
• PMH: MI 41%, CAD on angiogram 36%, current angina 21%, HTN 37%, DM 24%, CVA 7%, a-fib or flutter on EKG 21%, LBBB on EKG 6%
• PSH: Angioplasty 8%, CABG 15%
• Medications: Diuretics 99%, ACE-inhibitors 92%, ARBs 6%, digitalis 61%, antiarrhythmics 13%, nitrates 33%, aldosterone antagonists 11%, beta blockers 4%, anticoagulants 48%, aspirin 35%, statins 20%

Interventions

• Randomized one of two groups:
  • Carvedilol - started at 3.125 mg BID with target dose of 25 mg BID
  • Metoprolol tartrate - started at 5 mg BID with target dose of 50 mg BID

Outcomes

Comparisons are carvedilol vs. metoprolol.

Primary Outcome

All-cause mortality

34% vs. 40% (HR 0.83; 95% CI 0.74-0.93; P=0.0017), significant by 6 months

All-cause mortality or any hospital admission

(Added as an outcome in 2000.)

74% vs. 76% (HR 0.94; 95% 0.86-1.02; P=0.122)

Secondary Outcomes

CV mortality

29% vs. 35% (HR 0.80; 95% CI 0.70-0.90; P=0.0004)

Non-CV mortality

5% vs. 4% (HR 1.08; 95% 0.77-1.50)

Sudden death

14% vs. 7%

Subgroup Analysis

Reduction in all-cause mortality was similar in direction and in magnitude across the predefined subgroups of sex, NYHA class, cause, LVEF, heart rate, systolic BP, or history of diabetes.

Adverse Events

≥1 adverse event

94% vs. 96%

Bradycardia: 10% vs. 9%

Hypotension: 14% vs. 11%

≥1 serious adverse event: 55% vs. 57%

Severe bradycardia 3% vs. 3%

Severe hypotension: 3% vs. 2%

Criticisms

• COMET compared carvedilol to metoprolol tartrate, which is the short-acting form of metoprolol which has not been demonstrated to have a survival benefit in HF. (The MERIT-HF trial that demonstrated metoprolol's benefit used the long-acting metoprolol succinate formulation.)
• The target dose of metoprolol was only 100mg/day, which is lower than MERIT-HF's goal dose of 200mg/day. (Beta-blockers are thought to have a cumulative dose-response on survival, and for metoprolol succinate, 200mg/day is generally the goal.) However, the goal carvedilol dose was 25mg twice daily, which is generally considered the maximum dose of carvedilol. This may have given the carvedilol arm an unfair advantage.

Funding

• F. Hoffmann La Roche
• GlaxoSmithKline