COMET: Carvedilol Or Metoprolol European Trial

1
COMET Carvedilol Or Metoprolol European Trial

• Purpose
• To compare the effects of carvedilol (a ß1-, ß2-
  and a1-receptor blocker) and short-acting
  metoprolol tartrate (a ß1-receptor blocker) on
  clinical outcome in patients with chronic heart
  failure
• Reference
• 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)
  randomised controlled trial. Lancet
  2003362713.

2
COMET Carvedilol Or Metoprolol European Trial-
TRIAL DESIGN -

• Design
• Multicenter, multinational, randomized,
  double-blind, parallel group
• Patients
• 3029 patients in NYHA class IIIV, previously
  hospitalized for a cardiovascular reason, who had
  left ventricular ejection fraction lt0.35 and
  were receiving optimal treatment with diuretics
  and ACE inhibitors unless not tolerated
• Follow up and primary endpoint
• Primary endpoint all-cause mortality. Mean 4.8
  years follow up.
• Treatment
• Short-acting metoprolol tartrate titrated to
  target dose 50 mg twice daily or carvedilol
  titrated to target dose 25 mg twice daily

3
COMET Carvedilol Or Metoprolol European Trial-
TRIAL DESIGN continued-
Baseline characteristics ()
Metoprolol tartrate
Metoprolol tartrate
Carvedilol
Carvedilol
(n1518)
(n1511)
(n1518)
(n1511)
a
Age (years)
Left ventricular
62.3
61.6
0.26
0.26
a
ejection fraction
Male
80
79
NT-proBNP
1185
1298
NYHA class
(
mg/L)b
II
49
48
III
47
48
Medications
IV
4
3
99
99
Diuretics
Heart failure cause
91
92
ACE inhibitors
Ischemic heart disease
54
51
7
6
Angiotensin receptor
Hypertension
18
18
antagonists
Dilated
44
44
cardiomyopathy
11
11
Aldosterone
Previous valve surgery
2
3
antagonists
a
Mean
b
Median
Poole-Wilson et al.
Lancet
2003
362
713.
4
COMET Carvedilol Or Metoprolol European Trial-
RESULTS -

• All-cause mortality significantly reduced in
  carvedilol group compared with short-acting
  metoprolol tartrate (34 vs. 40, P0.0017)
• Cardiovascular mortality significantly reduced
  (29 vs. 35, P0.0004)
• No significant difference in composite secondary
  endpoint of all-cause mortality or admission (74
  vs. 76, hazard ratio 0.94, 95 CI 0.861.02,
  P0.122)
• Withdrawal rate identical (32) and incidence of
  adverse events similar (94 vs. 96) in both
  treatment groups

5
COMET Carvedilol Or Metoprolol European Trial-
RESULTS continued -
All-cause mortality
Mortality
40
()
30
20
10
0
0
1
2
3
4
5
Years after randomization
Poole-Wilson et al. Lancet 2003 362713.

6
COMET Carvedilol Or Metoprolol European Trial-
RESULTS continued -
All-cause mortality and cardiovascular death
Metoprolol tartrate
Hazard ratio
Carvedilol
P
(n1511)
(n1518)
(95 CI)
All deaths
0.002
600 (40)
512 (34)
0.83 (0.740.93)
5 year KaplanMeier
41.0
35.3
Months at riska
45.2 (19.5)
46.8 (18.9)
Yearly mortality rate
10.0
8.3
Cardiovascular deaths
0.0004
534 (35)
438 (29)
0.80 (0.700.90)
a
Mean (SD)
Poole-Wilson et al. Lancet 2003 362713.
7
COMET Carvedilol Or Metoprolol European Trial-
SUMMARY -

• Compared with short-acting metoprolol tartrate,
  in patients with chronic heart failure carvedilol
  reduced
• All-cause mortality
• Cardiovascular death
• Whether COMET compared regimens that were
  equivalent in degree and duration of
  beta-blockade has been debated.a In COMET
• Reduction in resting heart rate and BP were
  significantly greater with carvedilol than
  metoprolol, suggesting under-dosing with
  metoprolol
• Comparing metoprolol groups, mortality rate was
  higher and reduction in heart rate from baseline
  was lower than in MERIT-HF
• COMET did not use the formulation and dose of
  metoprolol approved by authorities in CHF and
  used in MERIT-HF (200 mg metoprolol succinate
  CR/XL)
• a See McMurray JV, Commentary on COMET, in Key
  Opinions, www.InCirculation.net 2003.