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Latest COMET Trial Data Stir Continued Debate on Comparison
New data from the controversial Carvedilol or Metoprolol European Trial continue to demonstrate major clinical advantages for carvedilol.
But COMET remains dogged by sharp criticism that dosage differences made for an unfair comparison in the trial, sponsored by Hoffmann La Roche and GlaxoSmithKline, developers of carvedilol.
COMET was a randomized, double-blind comparison of the effects of two -blockers on clinical outcomes in 3,028 patients with congestive heart failure. Both drugs had been shown to reduce mortality in landmark placebo-controlled trials. The question posed was whether their different pharmacologic profiles might result in differing effects on morbidity and mortality.
The primary end point in the 15-nation trial was reported last summer: After a mean 58 months of follow-up, all-cause mortality was 34% with carvedilol and 40% with metoprolol, for a highly significant 17% relative risk reduction favoring carvedilol (Lancet 362:7-13, 2003).
New secondary end point analyses presented at the annual congress of the European Society of Cardiology included death due to stroke, which occurred in 2.5% of patients on carvedilol and 6.3% of those on metoprolol, for a 67% reduction in risk with carvedilol.
New-onset diabetes occurred in 221 patients on carvedilol and 254 on metoprolol continued Dr. Poole-Wilson, professor and chair of cardiac medicine at Imperial College, London.
Carvedilol prolonged median survival by 1.4 years, compared with metoprolol. A total of 59 patients had to be treated for 1 year with carvedilol instead of metoprolol in order to save one additional life.
The 17% reduction in all-cause mortality with carvedilol constituted “a rather decisive difference,” the cardiologist said. Target dosing in COMET was 25 mg carvedilol b.i.d. or 50 mg metoprolol tartrate b.i.d. Dr. Poole-Wilson attributed the outcome difference to carvedilol’s much broader spectrum of activity, in particular the drug’s ability to block 2-receptors in addition to 1-receptors.
Dr. Thomas F. Luscher said questions of fairness arise from the COMET investigators’ “unfortunate” choice of immediate-release metoprolol rather than the sustained-release metoprolol succinate that significantly prolonged survival in the landmark Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial.
The mean actual dose of metoprolol received over a 24-hour period was 78 mg in COMET vs. 155 mg in MERIT-HF. This raises doubt as to whether both study arms in COMET had the same amount of -1-receptor blockade, a crucial issue in evaluating the clinical impact of carvedilol’s additional pharmacologic effects.
Of particular concern was the mean 1.8 mm Hg greater reduction in systolic blood pressure seen with carvedilol at 4 months.
“We know from the ALLHAT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial] data and other studies that even very small changes in blood pressure—2-3 mm Hg systolic—can make a huge difference. In fact, in subgroup analysis of the black population in ALLHAT, such a blood pressure difference made a 30% difference in the stroke rate,” said Dr. Luscher, professor and head of cardiology at University Hospital, Zurich.
For his part, Dr. Poole-Wilson was unapologetic about the dosing. “The steering committee back in 1996 pondered long and hard over all the evidence we had at that time in picking these doses. We chose those we thought represented a fair comparison between the two drugs. We had a lot of pharmacodynamic and pharmacokinetic data at that time. Since, more has emerged. And it’s certainly my opinion that all the data confirms that we did indeed pick doses which made a fair and reasonable comparison,” he said.
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