CArvedilol Post-infaRct survIval COntRol in LV dysfunctioN

1
CArvedilol Post-infaRct survIval COntRol in LV
dysfunctioN

• Principal results

Lancet 2001 357 1385 -90
2
Rationale

• Beta blocker trials in acute myocardial
  infarction (MI) were conducted mostly during the
  1970/80s
• no thrombolysis or primary angioplasty
• much less use of aspirin
• no ACE inhibitors
• Generally patients with heart failure were
  excluded
• left ventricular (LV) function was not assessed

3
Objective / Design

• To evaluate the effect of carvedilol on clinical
  outcome in patients with LV dysfunction following
  an acute MI treated in the modern era
• Multicentre, randomised, placebo-controlled,
  parallel-group trial in patients with LV ejection
  fraction ? 40 with or without heart failure

4
Study Organisation

• Steering CommitteeH Dargie (UK), W Colucci (US),
  JL Lopez-Sendon (E), W Remme (NL), N Sharpe (NZ)
• Endpoint CommitteeJ McMurray (UK) , L Kober
  (DK), J Sackner-Bernstein (US), J Soler-Soler
  (E), Faiez Zannad (F)
• DSMBD Julian (UK), I Ford (UK), B Massie (US), S
  Thompson (UK), L Wilhelmson (DK)
• CAPRICORN involved 163 investigators in 17
  countries (Europe, Israel, North-America,
  Australia, New Zealand)

5
Global Involvement
6
Study Plan
Uptitration
Downtitration
Maintenance
Carvedilol (n975)
(n1959)
Placebo (n984)
Initiation with 6.25 mg or 3.125 mg
bidUptitration to maximum tolerated dose over 2
4 weeks. Target dose 25 mg bid
Optimum therapyat investigatorsdiscretion
Normally 3 5 days but up to 21 days post MI
Time to 633 events Mean follow up 1.3 years
7
Inclusion Criteria

• Confirmed acute MI within 3 - 21 days (mean of 10
  days)
• LV ejection fraction ? 40
• Receiving an ACE inhibitor for ? 48 hours
• All appropriate treatments for MI including
  thrombolysis and percutaneous interventions
• Patients were usually hospitalized, but may have
  been recently discharged

8
Endpoints

• Primary Endpoints
• All-Cause Mortality
• All-Cause Mortality or Cardiovascular (CV)
  Hospitalisation
• Secondary Endpoints
• Sudden Death
• Hospitalisation for Heart Failure
• Additional Analyses
• Recurrent, Non-Fatal MI
• CV Mortality or Recurrent, Non-Fatal MI
• All-Cause Mortality or Recurrent, Non-Fatal MI

9
Baseline Characteristics

• Placebo Carvedilol (n 984) (n 975)
• Age (years) 63 63
• Male/ Female () 74 / 26 73 / 27
• Ejection fraction () 32.7 32.9
• Reperfusion for index MI () 47 45
• IV Nitrates for index MI () 73 73
• IV Diuretics for index MI () 33 35
• Aspirin at randomisation () 86 86
• ACE inhibitors at randomisation () 97 98

10
Primary Endpoint All-Cause Mortality

• Placebo Carvedilol Hazard Log rank (n
  984) (n 975) Ratio P value (95 CI)
• 151 (15) 116 (12) 0.77 0.031 (0.60-0.98)

11
Primary Endpoint All-Cause Mortality
1
23 ? vs. placeboP 0.031
0.95
0.9
Carvedilol
Proportion event free
0.85
0.8
Placebo
0.75
0.7
0
0.5
1
1.5
2
2.5
Years
12
Primary Endpoint All-Cause Mortality or CV
Hospitalisation

• Placebo Carvedilol Hazard Log rank (n
  984) (n 975) Ratio P value (95 CI)
• 367 (37) 340 (35) 0.92 0.296 (0.80-1.07)

13
Primary Endpoint All-Cause Mortality or CV
Hospitalisation
1
8 ? vs. placeboP 0.296
0.9
0.8
Proportion event free
0.7
0.6
Carvedilol
Placebo
0.5
0
0.5
1
1.5
2
2.5
3
Years
14
Secondary EndpointsSudden Death and
Hospitalisation for Heart Failure
15
Additional AnalysesNon-Fatal MI and Mortality
log rankP value
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6

Hazard Ratio / 95 CI
Am J Cardiol 2004 93(suppl) 13B -16B
16
Additional AnalysesNon-Fatal MI
1
41 ? vs. placeboP 0.014
0.98
Carvedilol
Proportion event free
0.96
0.94
Placebo
0.92
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Years
17
Additional AnalysesCV Mortality or Non-Fatal MI
1
30 ? vs. placeboP 0.002
0.9
Carvedilol
Proportion event free
0.8
Placebo
0.7
0
0.5
1
1.5
2
2.5
Years
18
Additional AnalysesAll-Cause Mortality or
Non-Fatal MI
1
29 ? vs. placeboP 0.002
0.9
Carvedilol
Proportion event free
0.8
Placebo
0.7
0
0.5
1
1.5
2
2.5
Years
19
Tolerability

• Placebo Carvedilol
• Max. dose during maintenance
• 12.5 mg bid 52 / 942 (6) 103 / 940 (11)
• 25 mg bid 784 / 942 (83) 692 / 940 (74)
• Permanent withdrawal 174 / 984 (18) 192 / 975
  (20)(excluding deaths)
• Patients with ? 1 SAE 429 / 980 (44) 396 /
  969 (41)

20
Summary

• In patients with LV dysfunction following an
  acute MI carvedilol treatment was associated
  with
• 23 lower risk of all-cause mortality
• 8 lower risk of mortality or CV hospitalisations
• 26 lower risk of sudden death
• 25 lower risk of CV mortality
• 41 lower risk of non-fatal MI
• Carvedilol was well tolerated (withdrawals
  comparable to placebo) and target doses for
  treatment were reached in the majority of patients

21
Conclusions

• CAPRICORN is the only large scale study on the
  benefits of ? blocker therapy in patients with LV
  dysfunction after acute MI
• The benefits of carvedilol treatment were shown
  on top of current state-of-the-art therapy for
  post MI patients
• In the absence of specific contraindications,
  carvedilol should be considered in all patients
  with LV dysfunction following an acute MI
• Carvedilol therapy in post MI patients should be
  started early and should be continued long-term

22
Antiarrhythmic Effect of Carvedilol after
Myocardial Infarction. Results of the Capricorn
Trial

• J. McMurray et al.
• J Am Coll Cardiol 2005 45 525 -30

23
Carvedilol
Placebo
P0.0015
24
Carvedilol
Placebo
P0.0003
25
Carvedilol
Placebo
Plt0.0001
26
Carvedilol
Placebo
Plt0.0001
27
Bibliographie Capricorn

• 1) The Capricorn Investigators. Effect of
  carvedilol on outcome after myocardial infarction
  in patients with left-ventricular dysfunction
  the Capricorn randomised trial. Lancet 2001 357
  1385 -90
• 2) J. McMurray et al. Antiarrhythmic Effect of
  Carvedilol After Acute Myocardial Infarction.
  Results of the Carvedilol Post-Infarct Survival
  Control in Left Ventricular Dysfunction
  (CAPRICORN) Trial. J Am Coll Cardiol 2005 45
  525 -30
• 3) W. Colucci. Landmark Study The Carvedilol
  Post-Infarct Survival Control in Left Ventricular
  Dysfunction Study (Capricorn).
• Am J Cardiol 2004 93(suppl) 13B -16B
• 4) R. Doughty et al. Effects of Carvedilol on
  Left Ventricular Remodeling After Acute
  Myocardial Infarction. The Capricorn Echo
  Substudy. Circulation 2004 109 201 -206
• 5) C. Pratt. Three Decades of Clinical Trials
  With Beta-Blockers. The contribution of the
  CAPRICORN Trial and the Effect of Carvedilol on
  Serious Arrythmias. J Am Coll Cardiol 2005 45
  531 -532
• 6) Résumé des Caractéristiques du Produit
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