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 dose-effect 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 2003;362:789–97.
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 during a 6 months’ treatment period
Treatment
Ximelagatran 24, 36, 48 or 60 mg twice daily or placebo.
All patients received acetylsalicylic acid 160 mg once daily
ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial infarction - TRIAL DESIGN continued -
Mean age (years)
Baseline characteristics (%)
Men
Unstable angina
Non-Q-wave MI
Q-wave MI
ACE inhibitors
Wallentin et al. Lancet 2003;362:789–97.
Beta-blockers
Statins
Demographics
Index event
Drugs
88
Placebo
(n=638)
69
6
44
49
66
66
69
86
24 mg
(n=307)
69
7
45
48
65
64
68
86
36 mg
(n=303)
69
7
38
55
62
66
68
86
48 mg
(n=311)
68
5
45
50
68
62
68
88
60 mg
(n=324)
68
5
43
52
66
69
69
86
Combined
(n=1245)
68
6
43
51
65
66
68
Ximelagatran
ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial infarction - RESULTS continued -
Days after randomization
Cumulative
risk (%)
0
0
30
60
90
120
150
180
4
8
12
16
20
Cumulative risk of death, MI and severe recurrent ischemia
Wallentin et al.
Lancet
2003;
362
:789
–
97.
P = 0.036
ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial infarction - RESULTS continued -
Primary endpoint:
all-cause mortality
nonfatal MI and
severe recurrent
ischemia (%)
Hazard ratio
95% CI
16
12
0.72
0.49–1.05
14
0.85
0.59–1.21
12
0.70
0.48–1.02
13
0.78
0.54–1.12
13
0.76
0.59–0.98
Primary endpoint and its components
Placebo
(n=638)
Ximelagatran
24 mg
(n=307)
36 mg
(n=303)
48 mg
(n=311)
60 mg
(n=324)
Combined
(n=1245)
Wallentin et al.
Lancet
2003;
362
:789
–
97.
ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial infarction - RESULTS continued -
Major bleeding
1
1
(0.14–3.48)
3
(1.24–9.42)
2
(0.51–5.46)
2
(0.80–4.84)
Bleeding leading
to discontinuation
of study medication,
or major bleeding
2
4
(0.71–3.72)
9
(2.25–8.47)
8
(1.94–7.46)
8
(1.87–6.01)
Bleeding events – % (95% CI)
Placebo
(n=638)
Oral ximelagatran
36 mg
(n=303)
48 mg
(n=311)
60 mg
(n=324)
Combined
(n=1245)
Wallentin et al.
Lancet
2003;
362
:789
–
97.
ESTEEM: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial infarction - RESULTS -
Oral ximelagatran in combination with acetylsalicylic acid was more effective than acetylsalicylic acid alone (placebo) in reducing the risk for the composite endpoint of death, non-fatal myocardial infarction, and severe recurrent ischemia (p=0·0357)
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 (p<0·0001)