Remodelling%20in%20CHF

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COMET -Background, Rationale and Design
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Pharmacological Differences Within the b Blocker
ClassAgents currently evaluated for heart failure
b1 b2 a1
Ancillary blockade blockade blockade
ISA effects
Carvedilol -
Metoprolol - - - - Bisoprolol
- - - - Bucindolol -
-
anti-oxidant, anti-endothelin,
anti-proliferative lack of b1 receptor
upregulation
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Prospective Outcomes Studies of ? Blockers in CHF

• Trial n Hazard Ratio (95 CI)
• US Carvedilol Prog 1,094 0.35 (0.20-0.61)
• CIBIS II 2,647 0.66 (0.54-0.81)
• MERIT-HF 3,991 0.66 (0.53-0.81)
• COPERNICUS 2,289 0.65 (0.52-0.81)
• BEST 2,708 0.90 (0.78-1.02)

Mild to Moderate
Severe
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
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Carvedilol Or Metoprolol European Trial

• 3,029 patients
• with class II-IV heart failure were recruited at
  317 centres in 15 European countries

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Objectives and Design

• To compare the effects of carvedilol with those
  of 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
Metoprolol (n 1,518)
Screening Titration Maintenance
(estimated 4 - 6 yrs)
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Dosing regimen

• Target dose
• Carvedilol 25 mg bd
• Metoprolol tartrate 50 mg bd
• Up-titration at 2-week intervals
• Carvedilol 6.25, 12.5, 25 to 50 mg/day
• Metoprolol 10, 25, 50 to 100 mg/day

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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

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Main Exclusion Criteria

• CVA, AMI or unstable angina in prior 2 months
• Untreated valve disease or arrhythmias
• Other life threatening disease
• Contraindications to ? blocker therapy
• Heart rate lt 60 bpm
• SBP lt 85 mmHg
• AV block, unless treated with a pacemaker
• History of asthma or COPD
• Unstable insulin dependent diabetes mellitus

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Primary Endpoints

• All-cause mortality
• All-cause mortality or all-cause hospitalisation

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Statistical Design

• Event driven, requiring at least 1,020 fatal
  events for the primary analysis
• All randomised patients were included in the ITT
  analysis
• All patients were followed to the end of the
  study, even if study treatment discontinued

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Statistical Analysis

• Co-primary endpoints were analysed by log rank
  test
• Relative risk (Hazard Ratio) calculated using Cox
  proportional hazard model
• Final analysis had to achieve
• P lt 0.039 for all cause mortality
• P lt 0.01 for all cause mortality or
  hospitalisation

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Secondary Endpoints

• All-cause mortality or cardiovascular
  hospitalisation
• Cardiovascular death, non-fatal acute MI, heart
  transplantation or worsening of heart failure
• Cardiovascular death
• NYHA class
• Worsening of heart failure
• Hospital admissions and duration of
  hospitalisations for heart failure and other
  reasons
• Discontinuation of study therapy

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Recruitment by Country (Centres)
725
Germany (71)
397
Sweden (36)
355
Netherlands (27)
278
Spain (37)
238
France (40)
221
Italy (24)
210
UK (16)
163
Denmark (8)
129
Belgium (17)
91
Switzerland (6)
88
Finland (10)
54
Austria (12)
53
Portugal (7)
46
Norway (4)
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Hungary (2)
0
200
400
600
800
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Demography

COMET N 3,029
Male ()
80
62
Age (mean yrs)
Systolic BP (mean mmHg)
126
77
Diastolic BP (mean mmHg)
81
Heart rate (mean bpm)
Weight (kg)
79
1. NEJM 1996 3341349-55, active group 2. Lancet
1999 353 2001-7, active group 3. Lancet 1999
353 9-13, active group
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Contributory Causes of Heart Failure

• COMET N 3,029
• IHD / MI 53 / 41
• Dilated cardiomyopathy 27
• Hypertension 36
• Prior valve surgery 2
• Diabetes 24
• Atrial fibrillation 20

Ischaemic Heart Disease Sole diagnosis
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Severity of Heart Failure

COMET N 3,029
NYHA Class ()
26
LVEF ()
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Background Therapy

• COMET N 3,029
• Diuretic 99
• ACEi 91
• ARB 7
• Spironolactone 11
• Digoxin 59
• Aspirin 37
• Warfarin 46

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COMETRESULTS
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COMETCarvedilol or Metoprolol European Trial

• To compare the effects of carvedilol with those
  of metoprolol on the risk of death and of death
  or hospitalisation in patients with chronic heart
  failure

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Primary endpoints

• All-cause mortality
• Combined risk of death or hospitalisationfor any
  reason
• Power
• Trial was designed to have 80 power to detect
  20 difference in mortality and 15 in composite
  endpoint (? 0.039 for mortality and 0.01 for
  the combined endpoint)

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Flow chart of patients
Randomised 3029
Carvedilol 1511
Metoprolol 1518
Assigned to drug and received at least one tablet
Withdrew consent 10 Lost to follow-up 3
Withdrew consent 18 Lost to follow-up 2
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Dates, timing and follow-up
01-Dec-1996 15-Jan-1999 3029 1511 1518
First patient recruited Last patient
recruited Total recruited Carvedilol Metoprolol

47 71 57.9
Minimum follow-up (months) Maximum follow-up
(months) Average follow-up (months)
175447 (14621 years) 1112
Total patient months of follow-up
Total deaths prior to 15-Nov-2002
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Baseline characteristics
Metoprolol (n1518)
Carvedilol (n1511)
62.3/11.4
61.6/11.3
Age (y, mean/sd)
80.2
79.4
Male ()
54
52
Aetiology (IHD )
42.2/20
42.6/22
Months of HF (mean/median)
81
81
Heart rate (beats/min)
126
126
Systolic BP (mm Hg)
77
77
Diastolic BP (mm Hg)
49/47/4
48/48/3
NYHA class () II/III/IV
19.2
20.5
AF/flutter ()
24.4
23.8
Diabetes
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Primary endpoint of mortality
40
Metoprolol
30
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Carvedilol
Mortality ()
hazard ratio 0.83, 95 CI 0.74-0.93, P 0.0017
10
0
0
1
2
3
4
5
Time (years)
Number at risk Carvedilol 1511 1367 1259
1155 1002 383 Metoprolol 1518 1359 1234
1105 933 352
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Mortality in sub-groups
Carvedilol Metoprolol
deaths n deaths n HR
Sex
male
410 1200 500 1217 0.80
female
102 311 100 301 0.97
Age
lt 65
207 834 231 803 0.84
? 65
305 677 369 715 0.84
NYHA
II
175 730 228 736 0.75
III
309 732 324 716 0.91
IV
28 49 48 66 0.68
Cause
Other
198 735 219 703 0.83
IHD
314 776 381 815 0.85
LVEF
? 25
270 706 285 630 0.79
gt 25
221 743 287 819 0.84
Heart rate
lt 80
234 693 284 733 0.86
? 80
277 816 314 783 0.80
Systolic BP
lt 110
120 245 132 235 0.80
110 - 139
270 817 310 849 0.89
? 140
121 447 158 434 0.71
Diabetes
yes
153 360 178 371 0.85
no
359 1150 419 1143 0.82
Overall
512 1511 600 1518 0.83
Carvedilol better
Metoprolol better
0.50
0.75
1.00
1.25
1.50
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Primary endpoints
P
95 CI
Hazard Ratio
Metoprolol
Carvedilol
Primary endpoints
0.0017
0.736, 0.932
0.828
600/1518 39.5
512/1511 33.9
Mortality
10.0
8.3
Annual mortality
0.1222
0.863, 1.018
0.937
1160/1518 76.4
1116/1511 73.9
Mortality or all cause hosp.
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Dose of drugs
Daily target dose Mean dose
received (given in divided doses
bid) Carvedilol 50 mg 42
mg Metoprolol 100 mg 85 mg
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Heart rate
85
Error bars represent 1 standard error
80
P lt 0.05, P lt 0.01
Metoprolol
Heart rate (beats.min-1)
Carvedilol
75
70



65
0
1
2
3
4
5
Time (years)
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Blood pressure
130
120











110
Error bars represent 1 standard error
P 0.05 P 0.01 P 0.001
Metoprolol
100
Blood pressure (mm Hg)
Carvedilol
90






80
70
0
1
2
3
4
5
Time (years)
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Adverse events and withdrawals
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Events related to ? blockade
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Summary and conclusion

• COMET is the longest and largest study in CHF
• 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)
• 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

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