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COPERNICUS
and
carvedilol
Background and
principal results slide kit
December 2000
Angiotensin II
Norepinephrine
Hypertrophy, apoptosis, ischaemia,
arrhythmia, remodelling, fibrosis
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%
(p<0.001)
 Decrease in combined risk of death and
hospitalisation by 20-25% (p<0.001)
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)
Class I
Class II
Class III
SOLVD Prevention
(enalapril)
Class IV
CONSENSUS
(enalapril)
SOLVD Treatment (enalapril)
V-HeFT II (enalapril)
 blockers
 Over 13,000 patients evaluated in placebocontrolled clinical trials
 Consistent improvement in cardiac function,
symptoms and clinical status
 Decrease in all-cause mortality by 30–35%
(p<0.0001)
 Decrease in combined risk of death and
hospitalisation by 25–30% (p<0.0001)
US Carvedilol Study
 blockers in
heart failure all-cause mortality
Survival
1.0
Carvedilol
(n=696)
0.9
Placebo
(n=398)
0.8
Risk reduction = 65%
0.7
p<0.001
0.6
0.5
0 50 100 150 200 250 300 350 400
Days
Mortality %
20
Survival
CIBIS-II
1.0
Packer et al (1996)
MERIT-HF
Placebo
Bisoprolol
15
0.8
Metoprolol CR/XL
10
Risk reduction = 34%
Placebo
Risk reduction = 34%
5
0.6
p=0.0062
p<0.0001
0
0
0
200
400
Time after inclusion (days)
600
800
Lancet (1999)
0
3
6
9
12 15
Months of follow-up
18
21
The MERIT-HF Study Group (1999)
 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?
Class I
?
Class II
Class III
Class IV
?
US Carvedilol Programme (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
Packer, AHA 2000
 blockers in NYHA class IV heart failure
Proportion of patients
with class IV heart failure
US Carvedilol Programme
3%
MERIT-HF
4%
CIBIS-II
BEST
17%
8%
Survival effects of  blockers in
class IV heart failure
MERIT-HF
CIBIS II
BEST
0.25
0.5
Favours treatment
0.75
1.0
1.5
2.0
Favours placebo
Packer, AHA 2000
Effects of metoprolol in
class IV heart failure
Results of MERIT-HF
Death or CHF
hospitalisation
Death or any
hospitalisation
0.25
0.5
Favours treatment
0.75
1.0
1.5
2.0
Favours placebo
Packer, AHA 2000
Class I
?
Class II
Class III
Class IV
COPERNICUS
(carvedilol)
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
Packer, AHA 2000
COPERNICUS
Carvedilol Prospective Randomized
Cumulative 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
COPERNICUS
Patient Characteristics
 Symptoms of heart failure at rest or minimal
exertion for at least 2 months
 LV ejection fraction <25%
 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
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
COPERNICUS
Randomisation
 2289 patients were randomized 1:1
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
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
COPERNICUS monitoring boundaries
Z-score
Mar 00
4
2
Stop trial because highly
positive
Aug 99
Mar 99
0
Nov 98
Continue trial
-2
Stop trial because highly
negative
-4
0
0.2
0.4
0.6
Information fraction
0.8
1.0
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
COPERNICUS
All-cause mortality
100
% Survival
90
80
Carvedilol
70
Placebo
p=0.00013
35% risk reduction
60
0
0
3
6
9
12
Months
15
18
21
Packer, AHA 2000
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
Spectrum of trials in severe heart failure
Stabilised
class IV
Annual
placebo
mortality
rate
Unstable
class IV
18-23%
24-29%
30%
COPERNICUS
RALES
PRAISE-1
PROMISE
CONSENSUS
FIRST
Packer, AHA 2000
COPERNICUS
All-cause mortality
Placebo
24
Carvedilol
19.7
18.5
18
12
11.4
12.8
6
0
1-year KaplanMeier rates
Annual mortality
rates (per pt-year)
Packer, AHA 2000
COPERNICUS
Treatment Effect
p-Value
Death or hospitalisations
for any reason
24%
<0.0001
Death or hospitalisations
for cardiovascular reason
27%
<0.0001
Death or hospitalisations
for heart failure
31%
<0.0001
Packer, AHA 2000
Is the carvedilol benefit a class effect?
Effect in class IV patients
BEST
COPERNICUS
0.25
0.5
Favours treatment
0.75
1.0
1.5
2.0
Favours placebo
Packer, AHA 2000
COPERNICUS
Effect of carvedilol on mortality
Annual placebo mortality rate
(per patient-year)
19.7%
All
patients
28.5%
Recent or recurrent
decompensation
0
0.25
Favours treatment
0.5
0.75
1.0
1.25
Favours placebo
Packer, AHA 2000
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
0.25
Favours treatment
0.5
0.75
1.0
1.25
Favours placebo
Packer, AHA 2000
COPERNICUS
Effects on mortality in patient subgroups
 Consistent reductions in mortality across all
patient subgroups examined to date, e.g. in:
– patients <65 years and 65 years
– men and women
– patients with ischaemic and non-ischaemic
cardiomyopathy
– patients with LVEF <0.20 and 0.20
 The benefits of carvedilol on mortality were
apparent even in the highest-risk subgroups of the
COPERNICUS study
COPERNICUS
Implications for public health
Lives saved by treating
1000 patients for 1 year
HOPE (ramipril)
<1
SOLVD Prevention (enalapril)
SOLVD Treatment (enalapril)
MERIT-HF (metoprolol)
7
17
38
CIBIS-II (bisoprolol)
RALES (spironolactone)
COPERNICUS (carvedilol)
42
52
70
Packer, AHA 2000
COPERNICUS
Safety
 Dizziness
 Bradycardia and heart block
 Fatigue
 Worsening heart failure
Packer, AHA 2000
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
Decrease in dose
4
11
Discontinuation
3
6
Hospitalisation
5
15
Worsening CHF leading to:
Circulation 2000; 101:378-84
MERIT-HF
Permanent withdrawals
% Patients permanently
withdrawn
40
p=NS
Placebo
30
20
Metoprolol
10
0
0
3
6
9
12
15
18
21
Months
Packer, AHA 2000
COPERNICUS
Permanent withdrawals
% Patients permanently
withdrawn
40
p=0.02
Placebo
30
20
Carvedilol
10
0
0
3
6
9
12
15
18
21
Months
Packer, AHA 2000
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
Class I
Class II
Class III
CAPRICORN
(carvedilol)
Class IV
COPERNICUS
(carvedilol)
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
Packer, AHA 2000
CAPRICORN
Carvedilol Post Infarct Survival Control
in Left Ventricular Dysfunction





Study characteristics
1958 patients with acute myocardial infarction
within 21 days
LV ejection fraction <40%, 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
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
Class I
Class II
Class III
CAPRICORN
(carvedilol)
Class IV
COPERNICUS
(carvedilol)
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
Packer, AHA 2000
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
Adrenergic activation
CNS sympathetic
outflow
Cardiac
sympathetic activity
Sympathetic
activity to kidneys
& blood vessels
1 receptors 2 receptors a1 receptors
Myocyte hypertrophy & death,
dilatation, ischaemia & arrhythmia's
Vasoconstriction
Sodium retention
Packer, AHA 2000
Antiadrenergic therapy by  blockade
Sympathetic activation
1 receptors
2 receptors
a1 receptors
Bisoprolol
Metoprolol
Propranolol
Carvedilol
CARDIOTOXICITY
Packer, AHA 2000
Metoprolol
Carvedilol
1 receptor
blockade
 receptor
upregulation
 receptor
suppression
 Cardiac
norepinephrine
Cardiac
norepinephrine
Antioxidant
effects
Sympathetic
antagonism
a1 and 2 receptor
blockade
Packer, AHA 2000
Carvedilol provides comprehensive
adrenergic blockade
 blockade
Cardiac
output
Renal
blood flow
Sodium
retention
Worsening
heart failure
Adapted from M Packer
Carvedilol provides comprehensive
adrenergic blockade
 blockade
Cardiac
output
Renal
blood flow
a1 blockade
Worsening
heart failure
a1 blockade
Sodium
retention
Adapted from M Packer
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
Randomized trials directly comparing
metoprolol with carvedilol
 DiLenarda et al
J Am Coll Cardiol, 1999
– Open-label for 12 months (n=30)
 Kukin et al
Circulation, 1999
– Open-label for 6 months (n=67)
 Sanderson et al
J Am Coll Cardiol, 1999
– Double-blind for 3 months (n=51)
 Metra et al
Circulation, 2000
– Double-blind for 12–15 months (n=150)
Packer, AHA 2000
Results of direct comparison trials with
metoprolol and carvedilol in HF
LV ejection
fraction (%)
LV end diastolic
volume (ml/m2)
0
10
p=0.009
-6
8
6
-12
4
-18
2
p=0.04
-24
0
Carvedilol
Metoprolol
Udelson 2000
Effect of switching patients from metoprolol
to carvedilol for 12 months
+15
+10
Change in
LV ejection
fraction (%)
Change in
end-diastolic
volume (ml)
*
p=0.053
+5
Continued on
Metoprolol (n=16)
0
Switched to
Carvedilol (n=14)
-5
p=0.045
-10
-15
*
-20
Di Lenarda et al (1999)
Double-blind comparison of effects of
metoprolol and carvedilol for 13-15 months
+18
Change in
LV ejection
fraction (%)
*
Change in
pulmonary wedge
pressure (mm Hg)
+12
+6
p=0.002
Carvedilol (n=75)
0
-5
Metoprolol (n=75)
p<0.05
-10
-15
-20
*
Metra et al (2000)
Class I
Class II
Class III
CAPRICORN
(carvedilol)
Class IV
COPERNICUS
(carvedilol)
COMET
(carvedilol vs metoprolol)
Packer, AHA 2000
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
COMET
 >3000 patients with class II-IV heart failure due
to 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
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
What should be the target dose?
Metoprolol
MDC
MERIT-HF
Bisoprolol
CIBIS
CIBIS-II
Target dose
Mortality effect
100-150 mg
200 mg
No 
 34% (sig)
5 mg
10 mg
 20% (ns)
 34% (sig)
What should the target
dose of carvedilol be?
Mortality
Cardiovascular hospitalisations
Mortality %
Mean number per subject
16
0.4
12
0.3
8
p<0.05
0.2
p<0.001
p=0.01
p=0.01
p=0.01
.
4
0.1
p=0.07
0
0
Placebo 6.25 mg bid 12.5 mg bid 25 mg bid
Carvedilol
Placebo 6.25 mg bid 12.5 mg bid 25 mg bid
Carvedilol
Dosing for  blockers in heart failure
Drug
Starting dose
Target dose
Bisoprolol
1.25 mg qd
10 mg qd
Carvedilol
3.125 mg bid
6.25–25 mg bid
Metoprolol
12.5–25 mg qd
(extended-release)
200 mg qd
The Medical Letter, June 26, 2000
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
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
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
COPERNICUS
All-cause mortality
100
% Survival
90
80
Carvedilol
70
p=0.00013
35% risk reduction
60
0
Placebo
0
3
6
9
12
Months
15
18
21
Packer, AHA 2000
COPERNICUS
Implications for public health
Lives saved by treating
1000 patients for 1 year
HOPE (ramipril)
<1
SOLVD Prevention (enalapril)
SOLVD Treatment (enalapril)
MERIT-HF (metoprolol)
7
17
38
CIBIS-II (bisoprolol)
RALES (spironolactone)
COPERNICUS (carvedilol)
42
52
70
Packer, AHA 2000
Implications for public health
If 1000 patients are treated per year
approximately 70 lives would be saved
Packer, AHA 2000
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