Latest COMET data still give nod to carvedilol: unfair comparison with metoprolol? (Carvedilol or Metoprolol European Trial).
But COMET remains dogged by sharp criticism that dosage differences made for an unfair comparison in the trial, sponsored by Hoffmann La Roche and GlaxoSmith-Kline, developers of carvedilol.
COMET was a randomized, double-blind comparison of the effects of two different [beta]-blockers on outcomes in 3,028 patients with congestive heart failure (CHF). Both drugs had previously been shown to reduce mortality in landmark placebo-controlled trials; the question posed in COMET was whether the different pharmacologic profiles of the two drugs 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, said Dr. Philip A. Poole-Wilson, chair of the COMET steering committee.
New-onset diabetes occurred in 221 patients on carvedilol and 254 patients on metoprolol--an adjusted 22% reduction in risk favoring carvedilol, continued Dr. Poole-Wilson, professor and chair of cardiac medicine at Imperial College, London.
The use of 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.... To put that into perspective, that is a bigger effect and more statistically significant than was seen [with ACE inhibitor therapy] in the well-known Studies of Left Ventricular Dysfunction trial," the cardiologist said, adding that "I will admit that the size of this finding did surprise me."
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 its ability to block [beta]-2 receptors in addition to the [beta]-1 receptors targeted by metoprolol.
Discussant Dr. Thomas F. Luscher said questions of fairness arise from the "unfortunate" decision to use immediate-release metoprolol rather than the sustained-release metoprolol succinate that prolonged survival in the landmark Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial.
The mean dose of metoprolol received over 24 hours was 78 mg in COMET and 155 mg in MERIT-HF. This raises doubt as to whether both study arms in COMET experienced the same amount of [beta]-1-receptor blockade, a crucial issue in trying to assess carvedilol's 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.... I don't guess this would explain the whole difference in mortality seen in COMET, but it may have contributed," said Dr. Luscher, professor and head of cardiology at University Hospital, Zurich, Switzerland.
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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|Title Annotation:||Cardiovascular Medicine|
|Publication:||Internal Medicine News|
|Date:||Oct 15, 2003|
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