ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with rece

1
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction

• Purpose
• To compare the efficacy and safety of four doses
  of oral ximelagatran with placebo in patients
  given acetylsalicylic acid with recent
  ST-elevation or non-ST-elevation myocardial
  infarction, and to investigate any doseeffect
  relation
• Reference
• Wallentin L, Wilcox RG, Weaver WD et al. for the
  ESTEEM Investigators. Oral ximelagatran for
  secondary prophylaxis after myocardial
  infarction the ESTEEM randomised controlled
  trial. Lancet 200336278997.

2
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - TRIAL DESIGN -

• Design
• Multicenter, multinational, randomized,
  double-blind, placebo-controlled, dose guiding
• Patients
• 1883 patients with ST-elevation or
  non-ST-elevation MI within the past 14 days
• Follow up and primary endpoint
• Primary composite endpoint all-cause mortality,
  non-fatal MI and severe recurrent ischemia. 6
  months follow up.
• Treatment
• Ximelagatran 24, 36, 48 or 60 mg twice daily or
  placebo for 6 months. All patients received
  acetylsalicylic acid 160 mg once daily.

3
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - TRIAL DESIGN
continued -
Baseline characteristics ()
Ximelagatran
Placebo
(n638)
24 mg
36 mg
48 mg
60 mg
Combined
(n307)
(n303)
(n311)
(n324)
(n1245)
Demographics
Mean age (years)
69
69
69
68
68
68
Men
69
68
68
68
69
68
Index event
Unstable angina
6
7
7
5
5
6
Non-Q-wave MI
44
45
38
45
43
43
Q-wave MI
49
48
55
50
52
51
Drugs
Beta-blockers
88
86
86
86
88
86
ACE inhibitors
66
65
62
68
66
65
Statins
66
64
66
62
69
66
Wallentin et al. Lancet 200336278997.
4
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - RESULTS -
Cumulative risk of death, MI and severe recurrent
ischemia
20
Cumulative
risk ()
16
12
8
4
P 0.036
0
0
30
60
90
120
150
180
Days after randomization
Wallentin et al.
Lancet
2003
362
789

97.
5
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - RESULTS continued
-
Primary endpoint and its components
Ximelagatran
Placebo
(n638)
24 mg
36 mg
48 mg
60 mg
Combined
(n307)
(n303)
(n311)
(n324)
(n1245)
Primary endpoint
all-cause mortality
nonfatal MI and
16
12
14
12
13
13
severe recurrent
ischemia ()
Hazard ratio
0.72
0.85
0.70
0.78
0.76
95 CI
0.491.05
0.591.21
0.481.02
0.541.12
0.590.98
Wallentin et al.
Lancet
2003
362
789

97.
6
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - RESULTS continued
-
Bleeding events (95 CI)
Oral ximelagatran
Placebo
(n638)
36 mg
48 mg
60 mg
Combined
(n303)
(n311)
(n324)
(n1245)
Major bleeding
1
1
3
2
2
(0.143.48)
(1.249.42)
(0.515.46)
(0.804.84)
Bleeding leading
2
4
9
8
8
to discontinuation
(0.713.72)
(2.258.47)
(1.947.46)
(1.876.01)
of study medication,
or major bleeding
Wallentin et al.
Lancet
2003
362
789

97.
7
ESTEEM Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran in patients with
recent myocardial infarction - RESULTS AND
SUMMARY-

• Oral ximelagatran in combination with
  acetylsalicylic acid was more effective than
  acetylsalicylic acid alone in reducing the risk
  for the composite endpoint of death, nonfatal
  myocardial infarction and severe recurrent
  ischemia (P0.0357)
• The efficacy did not differ between the
  individual ximelagatran doses
• The frequency of major bleeding did not differ
  between the treatment groups. However, the
  cumulative risk of total bleeding (major and
  minor) was higher in those on ximelagatran than
  in those on placebo
• The number of patients with concentrations of
  alanine transaminase that were more than three
  times the upper limit of normal was higher in the
  ximelagatran groups than in the placebo group
  (Plt0.0001)