COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial

1
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial

• Purpose
• To assess the effect of carvedilol, a ß1-, ß2-
  and a1-receptor blocker, on mortality in patients
  with severe chronic heart failure
• Reference
• Packer M, Coats AJS, Fowler M et al. for the
  COPERNICUS Study Group. Effect of carvedilol on
  survival in severe chronic heart failure. N Engl
  J Med 200134416518.

2
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial- TRIAL DESIGN -

• Design
• Multicenter, multinational, randomized,
  double-blind, placebo-controlled
• Patients
• 2289 patients with symptoms of heart failure at
  rest or on minimal exertion and left ventricular
  ejection fraction lt25, receiving standard
  therapy (diuretic plus ACE inhibitor/angiotensin
  II-receptor antagonist)
• Follow up and primary end point
• Mean 10.4 months follow up. Primary endpoint
  all-cause mortality
• Treatment
• Placebo or carvedilol 3.125 mg twice daily for 2
  weeks, increased stepwise over several weeks as
  tolerated to target dose 25 mg twice daily

3
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial- RESULTS -

• Study halted early on recommendation of data and
  safety monitoring board because beneficial effect
  of carvedilol exceeded prespecified interim
  monitoring boundaries
• Significant reduction in all-cause mortality in
  carvedilol group (130 deaths vs. 190 in placebo
  group, 35 relative risk reduction, P0.0014),
  equating to 11.4 cumulative risk of death at 1
  year vs. 18.4 with placebo
• Significant reduction in combined endpoint of
  death or hospitalization for any reason (425 vs.
  507, 24 relative RR, Plt0.001)
• These beneficial effects seen in all subgroups
  examined, including patients at highest risk
• Permanent discontinuation of treatment 23 lower
  in carvedilol group than placebo group at 1 year
  (14.8 vs. 18.5, P0.02)

4
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial- RESULTS continued -

All-cause mortality and hospitalization for any
reason
Survival ()
Event-free survival ()
100
100
Placebo
90
80
Carvedilol
80
60
70
40
35 relative risk reduction
(95 CI 19

48)
P0.00013
24 relative risk reduction
60
20
(95 CI 13

33)
P0.0014 adjusted for
interim analysis
Plt0.001
50
0
0
3
6
9
18
15
12
21
0
3
6
9
18
15
12
21
Months
Months
Packer et al.
N Engl J Med
2001
344
1651

8.
5
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial- RESULTS continued -

Subgroup analysis
Death or hospitalization
All-cause mortality
Favors
Favors
Favors
Favors
carvedilol
placebo
carvedilol
placebo
Male
Female
lt65 years old
gt
65 years old
North or South America
Other continents
LVEF lt0.20
gt
LVEF
0.20
Ischemic
Non-ischemic
No recent hospitalization
Recent hospitalization
All patients
0.0
0.5
1.0
0.0
0.5
1.0
1.5
1.5
Hazard ratio
(and 95 CI)
Packer et al.
N Engl J Med
2001
344
1651

8.
6
COPERNICUS Carvedilol Prospective Randomized
Cumulative Survival trial- SUMMARY -

• In patients with severe chronic heart failure,
  carvedilol in addition to standard therapy
  reduced
• All-cause mortality
• Combined endpoint of all-cause mortality and
  hospitalization for any reason
• Effects were similar across all subgroups