Antiadrenergic therapy in severe chronic heart failure

1
Antiadrenergic therapy in severe chronic heart
failure the COPERNICUS trial

• M Packer, New York, USA

2
Class II
Class I
Class IV
Class III
SOLVD Prevention
CONSENSUS
(enalapril)
(enalapril)
SOLVD Treatment (enalapril)
V-HeFT II (enalapril)
3
Class II
Class I
Class IV
Class III
?
?
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
4
b blockers in class IV heart failure
MERIT-HF
CIBIS II
BEST
0.5
0.25
0.75
1.5
2.0
1.0
Favors treatment
Favors placebo
5
b blocker survival effect in heart
failure Relation to placebo mortality rate
Annual placebo mortality rate
Effect on mortality
US Carvedilol 11.1 65 decrease MERIT-HF 11.0 3
4 decrease CIBIS II 13.2 34
decrease BEST 16.6 10 decrease
6
Carvedilol Prospective Randomized Cumulative
Survival Trial (COPERNICUS)
7
COPERNICUS
Entry criteria

• 2289 patients with heart failure due to ischemic
  or non-ischemic cardiomyopathy
• Symptoms at rest or minimal exertion ? 2 months
• LV ejection fraction lt 25
• Receiving diuretics and an ACE inhibitor ? 2
  months ( digitalis and amiodarone)

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COPERNICUS
Annualised mortality rates
Hazard ratio
Log-rank

(95 CI)
p-value
Placebo
Carvedilol
lt0.0002
0.65 (0.520.81)
19.7
12.8
Risk reduction 35
Follow-up ?29 months
9
COPERNICUS
All-cause mortality
Survival
100
90
Carvedilol
80
Placebo
70
60
35 Risk reduction plt0.0002
50
24
0
20
16
12
8
4
28
Months
.
10
Implications for public health
If we treated 1000 patients with heart failure
similar to those in COPERNICUS with carvedilol
for 3 years, we would save 150200 lives
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COPERNICUS

• There was striking consistency of the mortality
  reduction with carvedilol across all subgroups
  that have been examined to date

12
b blockers in heart failure
Annual placebo mortality rate
MERIT-HF 11.0 US Carvedilol 11.1 CIBIS
II 13.2 BEST 16.6 COPERNICUS 19.7
13
Patients not in COPERNICUS

• Patients hospitalized 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
  vasodilator or positive inotropic drugs within 4
  days of screening
• Diuretics were to be titrated until patients were
  euvolemic. Those with marked fluid retention or
  overload were not randomized

14
Class II
Class I
Class IV
Class III
?
COPERNICUS
(carvedilol)
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
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Class II
Class I
Class IV
Class III
CAPRICORN
COPERNICUS
(carvedilol)
(carvedilol)
US Carvedilol (carvedilol)
CIBIS II (bisoprolol)
MERIT-HF (metoprolol)
16
Class II
Class I
Class IV
Class III
CAPRICORN
COPERNICUS
(carvedilol)
(carvedilol)
COMET
(carvedilol vs metoprolol)
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Metoprolol
Carvedilol
b
receptor
1
blockade
b
receptor
b
receptor
suppression
upregulation
Cardiac
Cardiac
norepinephrine
norepinephrine
Antioxidant
effects
Sympathetic
b
a
and
receptor
antagonism
1
2
blockade
18
19 controlled trials of metoprolol and carvedilol
Trials comparing each drug with placebo (15
trials)
Trials directly comparing the 2 drug to each
other (4 trials)
Metoprolol (974 patients In 6 trials)
Carvedilol (1507 patients In 9 trials)
Metoprolol (151 patients)
Carvedilol (147 patients)
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Comparative effects on ejection fraction in
placebo-controlled trials

0.08


0.06


0.04
0.02
0
25
6.25
12.5
Carvedilol (high dose)
Metoprolol (high dose)
Carvedilol (mg bid)
20
19 controlled trials of metoprolol and carvedilol
Trials comparing each drug with placebo (15
trials)
Trials directly comparing the 2 drug to each
other (4 trials)
Metoprolol (974 patients In 6 trials)
Carvedilol (1507 patients In 9 trials)
Metoprolol (151 patients)
Carvedilol (147 patients)
21
Randomized trials directly comparing metoprolol
with carvedilol

• DiLenarda et al (J Am Coll Cardiol, 1999)
• Kukin et al (Circulation, 1999)
• Sanderson et al (J Am Coll Cardiol, 1999)
• Metra et al (Circulation, 2000)

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Meta-analysis of direct comparison trials with
metoprolol and carvedilol in HF
LV ejection
LV end-diastolic

fraction
()
volume
(ml/m
)
2
12

1
2
6
p0.04
p0.009

1
0

8
0
- 6

6

4
- 12

2
- 18
0
- 24
Metoprolol
Carvedilol
Metoprolol
Carvedilol
23
Results of direct comparison trials of metoprolol
and carvedilol in heart failure

• Metoprolol 19 / 147 12.9
• Carvedilol 9 / 151 6.0

Worsening heart failure
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COMET Carvedilol or Metoprolol European Trial

• gt 3000 patients with class II-IV heart failure
  due to ischemic or non-ischemic cardiomyopathy
• Randomized to carvedilol or metoprolol (in
  addition to usual therapy) for up to 3 years
• Primary endpoints - all-cause mortality-
  all-cause mortality / all-cause hospitalization

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What should be the target dose?
Target dose Mortality effect
Metoprolol MDC 100150 mg No MERIT-HF
200 mg 34 Bisoprolol CIBIS 5
mg 20 (ns) CIBIS II 10 mg
34
26
What should be the target dose?
Cardiovascular hospitalizations
Mortality





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Dosing for b blockers in heart failure
The Medical Letter, June 26, 2000
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)
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Norepinephrine
Angiotensin II
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis
29
Angiotensin I
ACE
Vasopeptidase
inhibitor
inhibitor
Angiotensin II
Aldosterone
AT receptor
Vasodilator
antagonist
Kinins
peptides
Spironolactone
Hypertrophy
Apoptosis
30
Sympathetic activation
b
a
b
1
1
2
receptors
receptors
receptors
Metoprolol
Propranolol
Carvedilol
Cardiotoxicity
31
Norepinephrine
Endothelin
Angiotensin II
Cytokines
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis