Late-Breaking Clinical Trial
Results of the Carvedilol Vs. Metoprolol European
COMET Trial
Carvedilol is Associated With A Significant
Survival Benefit Over Metoprolol
The largest clinical trial ever in chronic heart
failure (HF) and the first head-to-head comparison
of the effects of 2 beta-blockers on major outcomes
has been reported by the investigators to show
that carvedilol is associated with a significant
survival benefit over metoprolol. The results
of COMET (Carvedilol or Metoprolol European Trial)
were announced at the European heart failure meeting
by Professor Poole-Wilson, chairman of the COMET
steering committee, and the full report is published
in the July 5, 2003, issue of The Lancet.[2] Professor
Poole-Wilson believes that the COMET results will
have a major impact on clinical practice.
COMET was a multicenter, double-blind, randomized,
parallel group trial in patients with mild, moderate,
or severe chronic HF.[3] The trial was set up
to compare the effects on morbidity and mortality
of carvedilol, an adrenoceptor antagonist with
beta1-, beta2-, and alpha1-adrenergic receptor
blocking activity, with that of metoprolol, a
selective antagonist of beta1-adrenergic receptors,
in chronic HF patients. COMET was jointly sponsored
by Hoffmann-La Roche and GlaxoSmithKline.
Between December 1996 and January 1999, COMET
enrolled a total of 3029 patients at 317 centers
in 15 European countries.
Patients were randomized to treatment with either
metoprolol (metoprolol tartrate formulation; n
= 1518) or carvedilol (n = 1511). The drugs were
started at 5 mg twice daily and 3.125 mg twice
daily, respectively, and titrated to the maximum
tolerated dose or target dose of 50 mg twice daily
of metoprolol and 25 mg twice daily of carvedilol.
Follow-up for morbidity and mortality was concluded
on November 15, 2002, when 1112 deaths had occurred.
Average follow-up was 57.9 months, and total follow-up
14,621 years.
For one of the primary endpoints of the study,
all-cause mortality, there was a significant 17%
risk reduction with carvedilol vs metoprolol.
This difference first appeared at about 6 months.
Sensitivity analysis showed this result was not
affected by baseline characteristics, loss to
follow-up, or open-label beta-blockade. The effect
on mortality did not influence the mode of death
and was consistent across all predefined subgroups:
sex, age, NYHA class, cause, LVEF, heart rate,
systolic blood pressure (SBP), diabetes, and overall
effect. The absolute difference in mortality was
5.8%. The annual mortality was 8.3% for carvedilol
vs 10.0% for metoprolol, consistent with or slightly
higher than the results of previous trials, Professor
Poole-Wilson pointed out.
The other primary endpoint, mortality or all-cause
hospitalization, did not differ significantly
between the 2 treatment groups. Professor Poole-Wilson
explained that this endpoint was timed to first
event, and since all patients had a first event,
there was no difference. This result showed that
the benefit of carvedilol over metoprolol was
mainly driven by mortality. This was further supported
by the result for cardiovascular mortality, which
showed a relative risk reduction of 20% in the
carvedilol group (hazard ratio = 0.80 [95% CI
= 0.70-0.90], P = .0004).
Heart Rate and Blood Pressure Differences: Mean
heart rate was 81 beats/min at baseline in both
groups, but after 4 months on treatment, mean
heart rate was lowered by 13.3 beats/min in the
carvedilol group compared with 11.7 beats/min
in the metoprolol group. After 16 months, there
was no difference in heart rate between the 2
treatment groups.
SBP during the treatment was lower in the carvedilol
group by a mean of 1.8 mm Hg. The difference in
SBP between the 2 treatment groups was significant
at many points throughout the trial. No difference
was seen in DBP, however.
The results of COMET are "fairly definitive,"
according to Professor Poole-Wilson, and provide
evidence that carvedilol is the preferred beta-blocker
for the treatment of chronic HF. "This result
is as big and significant as in SOLVD [Studies
of Left Ventricular Dysfunction],"[4] he
said, adding that "Carvedilol's significant
survival benefit could mean thousands of lives
saved each year."
Two spokespersons for European Society of Cardiology
(ESC), which organized the heart failure meeting,
added a further note of caution about the COMET
results in relation to the dose of metoprolol
used in the trial. Another ESC spokesperson spoke
more positively. Professor Michal Tendera, MD
(Silesian School of Medicine, Katowice, Poland),
ESC president-elect, acknowledged that the results
of COMET are spectacular, but stressed that "it
should be noted that the form of metoprolol used
in COMET is different from that used in other
studies, such as MERIT-HF, where metoprolol demonstrated
a 34% increase in survival over placebo, so metoprolol
is clearly an active drug. Perhaps carvedilol
is better, as COMET suggests, but this is not
to say by any means that metoprolol is not clinically
effective."
Poole-Wilson PA, Swedberg K, Cleland JGF, et al,
for the COMET Investigators. Comparison of carvedilol
and metoprolol on clinical outcomes in patients
with chronic heart failure in the Carvedilol Or
Metoprolol European Trial (COMET): a randomized
controlled trial. Lancet. 2003;362:7-13.
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