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Results of the Longest and Largest Ever
b-Blockade Study in CHF
Mortality Reduction beyond ß1-Blockade
Pub.: Results: Poole-Wilson et al. Lancet 2003;362:7-13
Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:321-329
Pharmacological Differences Within the
b Blocker Class
Agents currently evaluated for heart failure
b1
blockade
b2
blockade
a1
blockade
Carvedilol
+++
+++
+++
-
Metoprolol
+++
-
-
-
-
Bisoprolol
+++
-
-
-
-
Bucindolol
+++
+++
-
++
-
*anti-oxidant, anti-endothelin, anti-proliferative
lack of b1 receptor upregulation
ISA
Ancillary
effects*
+++
The Normal Heart is a b1-Organ that
Functions in a b1-Environment
b1
b1
b1
b1 b1
b1
b1
b1
b1
b1
b1
b2 b2
Normal
Heart Failure Converts the Circulation
From a b1 to a b1/b2/a1-Environment
b1
b1
b1
b1 b1
b1
b1
b1
b1
b1
b1
b1
b2 b2
Normal
b1
b2
b2
b2 b1
b1
b2
b1
a1
b2
b2
b1
b1 b1
Heart failure
a1
Effects of b2-Receptors
 Direct chronotropic, inotropic, lusitropic cAMP mediated
– Coupling to the GS/cAMP pathway greater than via
b1-adrenoceptor, further enhanced by selective
b1-blockade
– Newton et al. Circ 1999; Kaumann et al. Circ 1999
– Hall et al. Circ Res 1990
 Hypertrophy, fibrosis, remodelling
– Du et al. Circulation 2000
 Antiapoptotic
– Communal et al. Circulation 1999
 Arrhythmogenic
– Billman et al. Circulation 1997
 Facilitation of norepinephrine release (presynaptic)
– Boudreau et al. Am J Physiol 1993
Effects of a1 Receptors
 Myocardial hypertrophy, fibrosis, remodeling
– Simpson & McGrath, J Clin Invest 1983
– Morgan & Baker, Circulation 1991
 Cardiotoxicity (with b receptors)
– Mann et al. Circulation 1992
 Arrhythmogenic
– Molina-Viamonte et al. Circulation 1991
 Peripheral vasoconstriction
– Leier et al. Circulation 1990
 Renal hypoperfusion and sodium retention
– Smyth et al. Circ Res 1985
– Hesse et al. Br J Pharmacol 1985
Effects of Different b Blocking Agents
Pharmacological differences
Sympathetic activation
b1
receptors
b2
receptors
Bisoprolol
Metoprolol
Carvedilol
Cardiotoxicity
a1
receptors
Carvedilol, But Not Metoprolol, Reduces
Total Body and Cardiac Sympathetic Drive
Total Body
Norepinephrine Spillover
Cardiac
Norepinephrine Spillover
100
50
0
(nmol/min)
(nmol/min)
0.5
-0.5
0
-50
-1.5
-100
-2.5
*
Carvedilol
-150
Metoprolol
* P < 0.05 vs. baseline and vs. metoprolol
*
Carvedilol
Metoprolol
Azevedo et al. Circulation 2001
Mortality Results of
b Blockers Studies in CHF
Hazard Ratio (95% CI)
Mild to Moderate
n
MERIT-HF
3,991
0.66 (0.53-0.81)
US Carvedilol Prog
1,094
0.35 (0.20-0.61)
CIBIS II
2,647
0.66 (0.54-0.81)
Severe
Trial
BEST
2,708
0.90 (0.78-1.02)
COPERNICUS
2,289
0.65 (0.52-0.81)
0
0.2 0.4 0.6 0.8
1
Packer et al. NEJM 1996; CIBIS II Invest. Lancet 1999; MERIT-HF Study Gp. Lancet 1999
BEST Investigators. Lancet 1999; Packer et al. NEJM 2001
US Carvedilol Programme
Survival
Carvedil
ol
1.0
0.9
100
90
Placeb
o
Carvedilol
80
Placebo
70
Risk reduction = 65%
0.8
Risk reduction = 35%
p<0.001
60
p=0.00013
0
0.7
0
0 50 100 150 200 250300350400
Days
Packer et al (1996)
Survival
0.6
1.0
3
Bisoprolol
0.6
Placebo
800
CIBIS-II Investigators (1999)
0
0
18
21
Packer et al (2001)
MERIT-HF
Risk reduction = 34%
p=0.0062
p<0.0001
200
400
600
Time after inclusion (days)
15
Metoprolol CR/X
5
0
9 12
Months
Placebo
15
10
Risk reduction = 34%
6
Mortality
20
(%)
CIBIS-II
0.5
0.8
0
COPERNICUS
Survival
3
6
9 12 15 18 21
Months of follow-up
The MERIT-HF Study Group (1999)
Herzinsuffizienz: NNT* - Number Needed to
Treat for one year to save one life
30
27
25
23
20
15
15
Carvedilol
(COPERNICUS)
Carvedilol (USStudienprg)
15
10
5
0
NYHA IV
NYHA II-III
Metoprolol
(MERIT-HF)
Bisoprolol
(CIBIS-II)
NYHA II-III
NYHA (II-) III
*NNT= Wie viele Patienten muss man 1 Jahr lang behandeln, um einen Todesfall zu
verhindern? Die NNT basiert auf der absoluten Mortalitätsreduktion gegenüber Placebo über
eine Zeitperiode von genau 1 Jahr, nach Wehling M., J Kardiol 2003;10 (Suppl A) p 20-23
Metaanalyse Betablockade bei Herzinsuffizienz:
Verbesserung der Herzleistung
Veränderung LVEF:
4 direkte Vergleichsstudien
Veränderung LVEF:
15 Placebo-kontrollierte Studien
8
10
8
D LVEF Units
D LVEF Units
P=0,009
6
4
P=0,0002
6
4
2
2
Carvedilol
Metoprolol
Carvedilol
Metoprolol
Veränderung der LV-Auswurffraktion als Marker für die Herzfunktion unter der Therapie mit Carvedilol bzw. Metoprolol. Daten aus einer
Metaanalyse von 4 direkten Vergleichsstudien bzw.
15 Placebo-kontrollierten Studien (Veränderung gegen Placebo) zwischen Carvedilol und Metoprolol
Nach M. Packer, Am Heart J 2001; 141:899-907
Carvedilol Improves Cardiac Performance
to a Greater Extent than Metoprolol
16
LV EDV
-5
14
***
12
-10
-15
10
8
LV ESV
0
P = 0.038
***
ml/m2
Absolute change from baseline
LVEF (%)
LV Ejection Fraction
-20
6
-25
4
-30
2
-35
0
-40
**P < 0.01 ***P < 0.001
vs baseline
**
***
***
***
Metoprolol
Carvedilol
Metra M et al. Circ 2000
Meta-analysis of Direct Comparison Trials
with Metoprolol and Carvedilol in CHF
+12
P = 0.009
LV Ejection
Fraction (%)
+10
+8
+6
+4
+2
0
Metoprolol
(n = 123)
Carvedilol
(n = 125)
Packer M et al. Am Heart J 2001
b Blocker Tolerability in Clinical Trials
Percentage of patients achieving target dose
Bisoprolol (CIBIS II)
Metoprolol (MERIT-HF)
Carvedilol (US Carvedilol)
Carvedilol (COPERNICUS)
0
20
40
60
80
100 %
COMET: Objectives and Design
 To compare the effects of the combined
alpha/betablocker carvedilol with those of the
ß1-selective metoprolol on mortality and morbidity
in patients with chronic heart failure
 No run-in period
Randomisation
Carvedilol (n = 1,511)
Mild,
moderate or
severe CHF
Screening
Metoprolol (n = 1,518)
Titration
Maintenance (estimated 4 - 6 yrs)
COMET Trial
 The COMET trial is not simply a comparison of
the survival effects of Metoprolol and Carvedilol
in patients with heart failure.
 The COMET trial is really a test of whether the
properties of Carvedilol beyond b1-blockade
have favorable effects on survival.
 To verify this theory, Metoprolol and Carvedilol
were used in dosages, that produce equivalent
degrees of b1-blockade (50 mg Metoprolol IR BID
and 25 mg Carvedilol BID)
Dates, Timing and Follow-up
First patient recruited:
Last patient recruited:
Total recruited:
Carvedilol:
Metoprolol:
01-Dec-1996
15-Jan-1999
3029
1511
1518
Minimum follow-up (months): 47
Maximum follow-up (months): 71
Average follow-up (months): 57.9
Total patient months of follow-up: 175447 (=14621 years)
Total deaths prior to 15-Nov-2002: 1112
Flow Chart of Patients
Randomised
3029
Carvedilol
Metoprolol
Assigned to drug
and received at least one tablet
1511
1518
Withdrew consent 10
Lost to follow-up
3
Withdrew consent 18
Lost to follow-up 2
Main Inclusion Criteria
 Symptomatic CHF (NYHA II-IV) on standard treatment
 Stable diuretic treatment  2 weeks
 ACE inhibitor  4 weeks prior to study entry
– use of digitalis and/or vasodilators was discretionary
 LVEF  35%
  1 CVS hospitalisation in the previous 2 years
Severity of Heart Failure
COMET
N=3,029
MERIT-HF1
N=3,991
NYHA Class (%)
II
III
IV
48
48
4
41
55
4
LVEF (%)
26
28
1. Lancet 1999; 353: 2001-7
Background Therapy
Diuretic
ACEi
ARB
Spironolactone
Digoxin
Aspirin
Warfarin
COMET
99%
91%
7%
11%
59%
37%
46%
MERIT-HF
90%
90%
7%
8%
64%
46%
NA
COMET: Baseline Characteristics
Carvedilol
(n=1511)
Metoprolol
(n=1518)
Age (y, mean/sd)
61.6 (11.3)
Male (%)
79.4
Aetiology (IHD %)
52
Months of HF (mean/median) 42.6/22
Heart rate (beats/min)
81
Systolic BP (mm Hg)
126
Diastolic BP (mm Hg)
77
NYHA class (%) II/III/IV
48/48/3
AF/flutter (%)
20.5
Diabetes
23.8
62.3 (11.4)
80.2
54
42.2/20
81
126
77
49/47/4
19.2
24.4
COMET:
Primary Endpoint Total Mortality
40
Metoprolol
Mortality (%)
30
20
Carvedilol
10
Hazard ratio 0.83,
95% CI 0.74 – 0.93, P = 0.0017
0
0
Number at risk
Carvedilol
1511
Metoprolol
1518
1
2
3
4
5
1002
933
383
352
Time (years)
1367
1359
1259
1234
1155
1105
Poole-Wilson et al. Lancet 2003;362:7-13
COMET: Cardiovascular Mortality
Mortality (%)
40
Metoprolol
30
20
Carvedilol
10
0
Survival benefit 20%,
P = 0.0004
0
Number at risk
Metoprolol 1,518
Carvedilol
1,511
1
1,359
1,366
2
3
Time (years)
1,234
1,258
1,105
1,155
4
5
933
1,002
352
383
ESC 2003
COMET:
Fatal or non-fatal myocardial infarction
Event %
15
Metoprolol
Carvedilol
Hazard ratio 0.714
95% CI 0.523 - 0.974,
p=0.0333
10
5
0
- 29%
1
2
3
4
5
Time (years)
K. Swedberg AHF 2003, Las Vegas
COMET-Studie: Unterschiede in der
Mortalität Carvedilol versus Metoprolol
45%
Metoprolol
absolute Mortalität in %
43%
41%
-17%
39%
37%
Dilatrend
-20%
35%
33%
P=0,0017
31%
29%
P=0,0004
27%
25%
Gesamtmortalität
Kardiovaskuläre Mortalität
Poole-Wilson P. et al. Lancer 2003; 362:7-13
COMET: Risikoreduktion gegenüber
kardioselektiven Betablocker Metoprolol
Gesamt-Mortalität
kardiovaskuläre
Mortalität
tödl. / nichttödl.
Herzinfarkte
% Risikoreduktion
0%
-5%
-10%
p=0,0017
p=0,0004
-15%
-20%
-17%
-20%
-25%
-30%
p=0,0333
-29%
Nach P. Poole-Wilson, ESC 2003, Wien und K. Swedberg AHF 2003, Las Vegas
COMET: Mode of Death
Carvedilol
n=1511
Metoprolol
n=1518
Sudden
218 (42.6%)
262 (43.7%)
Circulatory failure
168 (32.8%)
197 (32.9%)
Stroke
13 (2.5%)
38 (6.3%)
Other CV
19 (3.7%)
26 (4.3%)
Non-CV
74 (14.5%)
66 (11.0%)
Unable to classify
20 (3.9%)
11 (1.8%)
COMET: Death from Stroke
Relative Risk Reduction 67% !!
P = 0.0006
Mortality (%)
3
Metoprolol
2
Carvedilol
1
0
0
1
2
3
4
5
Time (years)
ESC 2003
COMET:
Consistent Mortality Reduction in Sub-Groups
Sex
Male (n = 2.417)
Female (n = 612!)
Age
< 65
 65
II
III
IV (n = 115!)
NYHA
Cause
Other
IHD
LVEF
 25%
> 25%
Heart rate
< 80
 80
Systolic BP < 110
110 - 139
 140
Diabetes
yes
no
Overall
Metoprolol better
Carvedilol better
0.50
0.75
1.00
1.25
1.50
Poole-Wilson et al. Lancet 2003;362:7-13
COMET: Secondary Endpoints
Secondary
endpoints
Carvedilol Metoprolol Hazard
ratio
95% CI
Pvalue
Death and
cardiovascular
hospitalisation
963/1511
63.7%
1016/1518
66.9%
0.928
0.85, 1.014
0.0972
Cardiovascular
death, heart
transplantation or
hospitalisation for
non-fatal AMI or
worsening heart
failure
745/1511
49.3%
815/1518
53.7%
0.881
0.798, 0.974
0.0128
Death and
hospitalisation
for worsening
heart failure
774/1511
51.2%
841/1518
55.4%
0.89
0.807, 0.981
0.0191
COMET: New Onset Diabetes
New diabetes (%)
15
Relative Risk Reduction 22%,
P = 0.04
10
Metoprolol
5
Carvedilol
0
0
Number at risk
Metoprolol 1,147
Carvedilol 1,151
1
2
3
4
5
626
705
221
254
ESC 2003
Time (years)
991
1,014
879
908
764
827
COMET – ESC, Wien 2003:
Risikoreduktion Carvedilol im Vergleich zu
Metoprolol
Schlaganfall - Mortalität
Diabetes Erstmanifestation
0%
% Risikoreduktion
-10%
P=0,04
-20%
-22%
-30%
-40%
-50%
-60%
P=0,006
-70%
-67%
Poole-Wilson P. ESC-Wien, 2.9.03
COMET: Events Related to b Blockade
Carvedilol
n = 1511
Metoprolol
n = 1518
Bradycardia as AE
9.5%
8.9%
Bradycardia as SAE
2.6%
2.6%
Hypotension as AE
14.2%
10.5%
Hypotension as SAE
3.2%
1.9%
Summary
 The COMET trial compared dosing
regimens of metoprolol and carvedilol
that produced similar degrees of b1blockade, both at peak and at trough
 The results of the COMET trial indicate
that the actions of carvedilol beyond b1blockade have favorable effects on
survival
Summary and conclusion
 First head-to-head mortality study comparing two
beta-blocking agents in CHF
 Carvedilol saved significantly more lives than
metoprolol (by 17%, P = 0.0017) and reduced
cardiovascular mortality by 20%, p=0,0004
 Carvedilol compared to metoprolol reduced
annual mortality from 10.0% to 8.3% and
prolonged median survival by 1.4 years
 Carvedilol is the preferred beta-blocker for the
treatment of chronic heart failure
Betablockade: Mortalitätsreduktion bei HI
NYHA I
CAPRICORN
(Carvedilol vs Placebo): -23 %
NYHA II
NYHA III
NYHA IV
COPERNICUS
(Carvedilol vs Placebo): -35%
US Carvedilol (Carvedilol vs Placebo): -65 %
CIBIS II (Bisoprolol vs Placebo): -34%
MERIT-HF (Metoprolol vs Placebo): -34%
COMET (Carvedilol vs Metoprolol: -17 %)
COMET: Fakten zur Metoprolol Dosierung
 In COMET wurde nicht retardiertes Metoprolol-Tartrat
eingesetzt, Zieldosis 100 mg
 Retardiertes Metoprolol-Succinat war zu Beginn der
COMET (1996!) nicht verfügbar, die MERIT-HF Daten
wurden erst 1999 publiziert
 Die Bioverfügbarkeit von retardiertem Metoprolol-Succinat
ist um 30-35% niedriger (Poole-Wilson et al. Lancet 2003)
 In MERIT-HF wurde retardiertes Metoprolol-Succinat
eingesetzt, Zieldosis 200 mg, dies entspricht ca. 130 mg
Metoprolol-Tartrat (Poole-Wilson et al. Lancet 2003)
 In MERIT-HF war die Mortalitätsreduktion in der
Hochdosis-Gruppe (ø192 mg) gleich wie in der
Niedrigdosis-Gruppe (ø76 mg) (Wikstrand et al. JACC 2002)
MERIT-HF: Effekt der Dosis auf die Mortalitätsrate
Metoprolol-Succ.
76 mg/Tag
25
38%  Risikored.
P = 0.010
% Mortalität
20
Metoprolol-Succ.
192 mg/Tag
25
38%  Risikored.
P = 0.002
20
15
15
Placebo
n = 1845
Placebo
n = 1845
10
10
Metoprolol Succ.
n = 604
5
0
Metoprolol Succ.
n = 1202
5
0
0
3
6
9
Months
12
15
0
3
6
9
12
15
Months
Wikstrand J et al. J Am Coll Cardiol 2002
MERIT-HF: Metoprolol-Dosisgruppen und
Reduktion der Mortalität
< 100 mg
Metoprolol (ø 76
mg )
> 100 mg
Metoprolol (ø 192
mg)
Mortalität
- 38 %
- 38 %
Plötzl.
Hertod
- 50 %
- 41 %
Endpunkt
nach Wikstrand J. et al., JACC 2002;40:491-498
MERIT-HF: Reduktion der Mortalität in
Abhängigkeit von der Dosis
< 100 mg Metoprolol (ø 76 mg ) > 100 mg Metoprolol (ø 192 mg)
0%
-10%
%
-20%
-30%
-40%
-50%
-60%
Mortalität
Plötzl. Hertod
Nach Wikstrand J. et al., JACC 2002;40:491-498
HI-Erhebung bei 96 Ärzten in Ö:
Betablocker Dosierung bei chron. HI in
der Praxis
Atenolol
Bisoprolol
Carvedilol
Metoprolol-T
Metoprolol-S
Anzahl
Pat.
95
300
276
79
173
Ø Dosis
(mg)
59,5
5,3
27,1
79,1
71,7
% Soll
(ESC)
N.A.
53,3
54,3
52,7
35,8
Austrian Survey OF Treating Herat Failure, 2003, Prof. F. Fruhwald, Prof. P.
Rehak, Graz