COPERNICUS and carvedilol

1
COPERNICUSandcarvedilol

• Background and principal results slide kit
• December 2000

2
Norepinephrine
Angiotensin II
Hypertrophy, apoptosis, ischaemia, arrhythmia,
remodelling, fibrosis
3
ACE inhibitors in heart failure

• Approximately 7,000 patients evaluated in
  placebo-controlled clinical trials
• Consistent improvement in cardiac function,
  symptoms and clinical status
• Decrease in all-cause mortality by 20-25
  (plt0.001)
• Decrease in combined risk of death and
  hospitalisation by 20-25 (plt0.001)

4
ACE inhibitors in heart failure

• Consensus recommendations
• All patients with heart failure due to left
  ventricular systolic dysfunction should receive
  an ACE inhibitor unless they have a
  contraindication to its use or cannot tolerate
  treatment with the drug

US Consensus Recommendations (1996)
5
Class I
Class IV
Class II Class III
SOLVD Prevention (enalapril)
CONSENSUS (enalapril)
SOLVD Treatment (enalapril) V-HeFT II (enalapril)
6
? blockers

• Over 13,000 patients evaluated in
  placebo-controlled clinical trials
• Consistent improvement in cardiac function,
  symptoms and clinical status
• Decrease in all-cause mortality by 3035
  (plt0.0001)
• Decrease in combined risk of death and
  hospitalisation by 2530 (plt0.0001)

7
US Carvedilol Study
Survival
1.0 0.9 0.8 0.7 0.6 0.5
Carvedilol (n696)
? blockers in heart failure - all-cause
mortality
Placebo (n398)
Risk reduction 65
plt0.001
0
50
100
150
200
250
300
350
400
Days
Packer et al (1996)
Survival
Mortality
CIBIS-II
1.00.80.6 0
20
MERIT-HF
Placebo
Bisoprolol
15
Metoprolol CR/XL
10
Placebo
Risk reduction 34
Risk reduction 34
5
p0.0062
plt0.0001
0
0 200 400
600 800
0
3
6
9
12
15
18
21
Months of follow-up
Lancet (1999)
Time after inclusion (days)
The MERIT-HF Study Group (1999)
8
? blockers in heart failure

• Consensus recommendations
• All patients with stable class II or III heart
  failure due to left ventricular systolic
  dysfunction should receive a ? blocker (in
  addition to an ACE inhibitor) unless they have a
  contraindication to its use or cannot tolerate
  treatment with the drug
• Why are the recommendations more restrictive
  than for ACE inhibitors despite the available
  evidence?

9
Class II Class III
Class I
Class IV
?
?
US Carvedilol Programme (carvedilol)CIBIS II
(bisoprolol)MERIT-HF (metoprolol)
Packer, AHA 2000
10
? blockers in NYHA class IV heart failure

• Proportion of patients with class IV heart
  failure
• US Carvedilol Programme 3
• MERIT-HF 4
• CIBIS-II 17
• BEST 8

11
Survival effects of ? blockers inclass IV heart
failure
MERIT-HF
CIBIS II
BEST
0.5
0.25
0.75
1.5
2.0
1.0
Favours treatment
Favours placebo
Packer, AHA 2000
12
Effects of metoprolol inclass IV heart failure
Results of MERIT-HF
Death or CHF hospitalisation
Death or any hospitalisation
0.5
0.25
1.5
2.0
1.0
0.75
Favours treatment
Favours placebo
Packer, AHA 2000
13
Class I
Class IV
Class II Class III
?
COPERNICUS (carvedilol)
US Carvedilol (carvedilol)CIBIS II
(bisoprolol)MERIT-HF (metoprolol)
Packer, AHA 2000
14
COPERNICUS
Carvedilol Prospective RandomizedCumulative
Survival Trial

• Objectives and design
• To determine the effect of carvedilol compared
  with placebo on all-cause mortality in patients
  with severe chronic heart failure
• Randomised, placebo-controlled, parallel-group
  multicenter study in patients with ischaemic or
  non-ischaemic cardiomyopathy

15
COPERNICUS

• Patient Characteristics
• Symptoms of heart failure at rest or minimal
  exertion for at least 2 months
• LV ejection fraction lt25
• Receiving diuretics and an ACE inhibitor (
  digitalis) ?2 months. Diuretics optimised to
  achieve euvolaemia
• No need for intensive care and no treatment with
  IV inotropic or IV vasodilator therapy within 4
  days of screening

Packer, AHA 2000
16
Patients not in COPERNICUS

• Hospitalised patients were allowed in the trial
  but not if they were in the CCU/ICU
• Patients receiving IV diuretics were allowed in
  the trial but not if they had received IV
  vasodilator or IV positive inotropic drugs within
  4 days of screening
• Diuretics were to be titrated until patients were
  euvolaemic. Those with marked fluid retention or
  overload were not randomized

17
COPERNICUS

• Randomisation
• 2289 patients were randomized 11
• Placebo
• Carvedilol
• Initial dose 3.125 mg bid with doubling of dose
  every 2 weeks until target dose of 25 mg bid was
  reached. Patients received highest tolerated dose

18
COPERNICUS

• Protocol-specified endpoints
• Primary endpoint
• All-cause mortality
• Secondary endpoints
• All-cause mortality or hospitalisations for any
  reason
• All-cause mortality or cardiovascular
  hospitalisations
• All-cause mortality or CHF hospitalisations

Packer, AHA 2000
19
COPERNICUS monitoring boundaries
Z-score
Mar 00
4
Stop trial because highly positive
2
Aug 99
Mar 99
Continue trial
0
Nov 98
-2
Stop trial because highly negative
-4
0.2
0.4
0.6
0.8
1.0
0
Information fraction
20
COPERNICUS

• DSMB recommendations (14 March 2000)
• Highly significant effect on mortality
• Exceeded predefined criteria for early
  termination
• Consistent across all predefined subgroups
• Serious adverse events more common on placebo
• Unanimous recommendation for early termination
• All patients should be offered open-label
  carvedilol

21
COPERNICUS
All-cause mortality
100
90
Carvedilol
80
Survival
70
Placebo
p0.00013 35 risk reduction
60
0
0
3
6
9
12
15
18
21
Months
Packer, AHA 2000
22
Mortality in ? blocker heart failure trials

• Annual placebo mortality rates
• MERIT-HF 11.0
• US Carvedilol Programme 11.1
• CIBIS II 13.2
• BEST 16.6
• COPERNICUS 19.7
• Class IV meta-analysis 20.7

Packer, AHA 2000
23
Spectrum of trials in severe heart failure
Stabilised class IV
Unstable class IV
Annual placebo mortalityrate
24-29
?30
18-23
PRAISE-1 PROMISE
CONSENSUS FIRST
COPERNICUS RALES
Packer, AHA 2000
24
COPERNICUS
All-cause mortality
Placebo
Carvedilol
Packer, AHA 2000
25
COPERNICUS

• Treatment Effect p-Value
• Death or hospitalisations 24? lt0.0001for any
  reason
• Death or hospitalisations 27? lt0.0001for
  cardiovascular reason
• Death or hospitalisations 31? lt0.0001for heart
  failure

Packer, AHA 2000
26
Is the carvedilol benefit a class effect?
Effect in class IV patients
BEST
COPERNICUS
0.5
0.25
1.5
2.0
1.0
0.75
Favours treatment
Favours placebo
Packer, AHA 2000
27
COPERNICUS
Effect of carvedilol on mortality
Annual placebo mortality rate (per patient-year)
All patients
19.7
Recent or recurrent decompensation
28.5
0.5
0.25
0.75
1.25
1.0
0
Favours treatment
Favours placebo
Packer, AHA 2000
28
COPERNICUS
Effect of carvedilol on morbidity and mortality
Death or any hospitalisations
All patients
Death or cardiovascular hospitalisations
Recent or recurrent decompensation
Death or CHF hospitalisations
0.5
0.25
0.75
1.25
1.0
0
Favours treatment
Favours placebo
Packer, AHA 2000
29
COPERNICUS

• Effects on mortality in patient subgroups
• Consistent reductions in mortality across all
  patient subgroups examined to date, e.g. in
• patients lt65 years and ?65 years
• men and women
• patients with ischaemic and non-ischaemic
  cardiomyopathy
• patients with LVEF lt0.20 and ?0.20
• The benefits of carvedilol on mortality were
  apparent even in the highest-risk subgroups of
  the COPERNICUS study

30
COPERNICUS

• Implications for public health
• Lives saved by treating 1000 patients for 1
  year
• HOPE (ramipril) lt1
• SOLVD Prevention (enalapril) 7
• SOLVD Treatment (enalapril) 17
• MERIT-HF (metoprolol) 38
• CIBIS-II (bisoprolol) 42
• RALES (spironolactone) 52
• COPERNICUS (carvedilol) 70

Packer, AHA 2000
31
COPERNICUS

• Safety
• Dizziness
• Bradycardia and heart block
• Fatigue
• Worsening heart failure

Packer, AHA 2000
32
RESOLVD

• 426 patients with class II-III heart failure were
  randomized to placebo or metoprolol CR/XL for 24
  weeks, added to ACE inhibitor or AT antagonist
• Placebo Metoprolol
• Worsening CHF leading to
• Decrease in dose 4 11
• Discontinuation 3 6
• Hospitalisation 5 15

Circulation 2000 101378-84
33
MERIT-HF
Permanent withdrawals
40
pNS
Placebo
30
Patients permanently withdrawn
20
Metoprolol
10
0
Months
0
3
6
9
12
15
18
21
Packer, AHA 2000
34
COPERNICUS
Permanent withdrawals
40
p0.02
Placebo
30
Patients permanently withdrawn
20
Carvedilol
10
0
Months
0
3
6
9
12
15
18
21
Packer, AHA 2000
35
COPERNICUS Summary

• COPERNICUS establishes the efficacy of carvedilol
  in severe heart failure and extends the benefits
  of this drug first observed in patients with mild
  and moderate symptoms to those with advanced
  disease
• COPERNICUS does not settle the question as to
  whether all other ? blockers are effective in
  patients with severe heart failure.
• The effects of other ? blockers in this patient
  population remain to be determined

36
Class I
Class IV
Class II Class III
CAPRICORN (carvedilol)
COPERNICUS (carvedilol)
US Carvedilol (carvedilol)CIBIS II
(bisoprolol)MERIT-HF (metoprolol)
Packer, AHA 2000
37
CAPRICORN
Carvedilol Post Infarct Survival Controlin Left
Ventricular Dysfunction

• Study characteristics
• 1958 patients with acute myocardial infarction
  within 21 days
• LV ejection fraction lt40, receiving an ACE
  inhibitor
• Randomized to placebo or carvedilol (target 25 mg
  BID)
• Endpoints combined risk of death or
  cardiovascular hospitalisations, all-cause
  mortality
• Data analysis ongoing

Packer, AHA 2000
38
Why do we need another ? blocker trial in
post-infarction patients?

• Earlier post-MI trials with ? blockers were
  performed in a different era and enrolled
  patients who generally were not receiving other
  agents that reduce mortality
• No use of thrombolytic drugs
• Little use of aspirin or heparin
• No use of ACE inhibitors
• Did not have LV systolic dysfunction
• Are ? blockers still effective in the modern era?

Packer, AHA 2000
39
Class I
Class IV
Class II Class III
CAPRICORN (carvedilol)
COPERNICUS (carvedilol)
US Carvedilol (carvedilol)CIBIS II
(bisoprolol)MERIT-HF (metoprolol)
Packer, AHA 2000
40
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients

41
Adrenergic activation
CNS sympathetic outflow
Cardiac sympathetic activity
Sympathetic activity to kidneys blood vessels
b1 receptors
b2 receptors
a1 receptors
Myocyte hypertrophy death, dilatation,
ischaemia arrhythmia's
Vasoconstriction Sodium retention
Packer, AHA 2000
42
Antiadrenergic therapy by ? blockade
Sympathetic activation
b1 receptors
a1 receptors
b2 receptors
Bisoprolol Metoprolol
Propranolol
Carvedilol
CARDIOTOXICITY
Packer, AHA 2000
43
Metoprolol
Carvedilol
b1 receptorblockade
b receptorsuppression
b receptorupregulation
Cardiac
? Cardiac norepinephrine
norepinephrine
Antioxidant
effects
Sympathetic antagonism
a1 and b2 receptorblockade
Packer, AHA 2000
44
Carvedilol provides comprehensive adrenergic
blockade
b blockade
Cardiac output
Renal blood flow
Worsening heart failure
Sodium retention
Adapted from M Packer
45
Carvedilol provides comprehensive adrenergic
blockade
b blockade
a1 blockade
Cardiac output
Renal blood flow
Worsening heart failure
a1 blockade
Sodium retention
Adapted from M Packer
46
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients

47
Randomized trials directly comparing metoprolol
with carvedilol

• DiLenarda et al J Am Coll Cardiol, 1999
• Open-label for 12 months (n30)
• Kukin et al Circulation, 1999
• Open-label for 6 months (n67)
• Sanderson et al J Am Coll Cardiol, 1999
• Double-blind for 3 months (n51)
• Metra et al Circulation, 2000
• Double-blind for 1215 months (n150)

Packer, AHA 2000
48
Results of direct comparison trials with
metoprolol and carvedilol in HF
LV ejection fraction ()
LV end diastolic volume (ml/m2)
0
10
p0.009
-6
8
6
-12
4
-18
2
p0.04
0
-24
Carvedilol
Metoprolol
Udelson 2000
49
Effect of switching patients from metoprolol to
carvedilol for 12 months
Change in LV ejection fraction ()
Change in end-diastolic volume (ml)
Di Lenarda et al (1999)
50
Double-blind comparison of effects of metoprolol
and carvedilol for 13-15 months
Change in LV ejection fraction ()
Change in pulmonary wedge pressure (mm Hg)
Metra et al (2000)
51
Class I
Class IV
Class II Class III
CAPRICORN (carvedilol)
COPERNICUS (carvedilol)
COMET (carvedilol vs metoprolol)
Packer, AHA 2000
52
COMET
Carvedilol Or Metoprolol European Trial

• Objectives and design
• To compare the effects of carvedilol with those
  of metoprolol on the risk of death and
  hospitalisation in patients with chronic heart
  failure
• Randomised, double-blind, parallel-group,
  multicenter study of more than 3 years in duration

53
COMET

• gt3000 patients with class II-IV heart failure
  dueto ischaemic or non-ischaemic cardiomyopathy
• Randomized to carvedilol or metoprolol (in
  addition to usual therapy) for up to 3 years
• Pre-specified endpoints
• all-cause mortality
• death and hospitalisation
• all-cause mortality/all-cause hospitalisation

Packer, AHA 2000
54
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients

55
What should be the target dose?
Target dose Mortality effect Metoprolol MDC 100
-150 mg No ? MERIT-HF 200 mg ? 34
(sig) Bisoprolol CIBIS 5 mg ? 20
(ns) CIBIS-II 10 mg ? 34 (sig)
56
What should the target dose of carvedilol be?
Mortality
Cardiovascular hospitalisations
Mortality
Mean number per subject
1
6
1
2
8

plt0.001
p0.01
plt0.05
p0.01
p0.01
.
4
p0.07
0
Placebo
6.25 mg bid
12.5 mg bid
25 mg bid
Placebo
6.25 mg bid
12.5 mg bid
25 mg bid
Carvedilol
Carvedilol
57
Dosing for b blockers in heart failure
Drug Starting dose Target dose Bisoprolol 1.25
mg qd 10 mg qd Carvedilol 3.125 mg bid 6.2525
mg bid Metoprolol 12.525 mg qd 200 mg
qd(extended-release)
The Medical Letter, June 26, 2000
58
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients

59
Mortality in ? blocker heart failure trials

• Annual placebo mortality rates
• MERIT-HF 11.0
• US Carvedilol Programme 11.1
• CIBIS II 13.2
• BEST 16.6
• COPERNICUS 19.7
• Class IV meta-analysis 20.7

Packer, AHA 2000
60
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients

61
COPERNICUS
All-cause mortality
100
90
80
Carvedilol
Survival
70
Placebo
p0.00013 35 risk reduction
60
0
0
3
6
9
12
15
18
21
Months
Packer, AHA 2000
62
COPERNICUS

• Implications for public health
• Lives saved by treating 1000 patients for 1
  year
• HOPE (ramipril) lt1
• SOLVD Prevention (enalapril) 7
• SOLVD Treatment (enalapril) 17
• MERIT-HF (metoprolol) 38
• CIBIS-II (bisoprolol) 42
• RALES (spironolactone) 52
• COPERNICUS (carvedilol) 70

Packer, AHA 2000
63
Implications for public health

• If 1000 patients are treated per year
  approximately 70 lives would be saved

Packer, AHA 2000
64
Key messages

• Carvedilol is the only drug with ?-blocking
  activity that provides comprehensive adrenergic
  blockade
• Carvedilol is more beneficial than conventional
  ?-blocking agents in mild-to-moderate heart
  failure
• Carvedilol is the only drug with ?-blocking
  activity proven to be effective at lower doses
• COPERNICUS enrolled the most severely affected
  heart failure population of any trial of ?
  blockade
• Carvedilol significantly reduces mortality in
  severe heart failure patients