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Efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients after acute myocardial infarction - ESTEEM
Description:
The goal of the ESTEEM trial was to evaluate the safety and efficacy of treatment with the novel oral direct thrombin inhibitor ximelagatran in patients following ST or non-ST elevation myocardial infarction (MI).
Hypothesis:
Treatment with the oral direct thrombin inhibitor ximelagatran will be associated with a reduction in the composite endpoint of death, MI, or severe recurrent ischemia compared with placebo in patients following acute MI.
Study Design
Study Design:
Patients Enrolled: 1,900
Mean Follow Up: Followed through 12 months; results reported through six months
Mean Patient Age: Mean age 68-69 years
Female: 31%
Patient Populations:
Ischemic chest pain within the past 14 days; a raised cardiac marker (troponin T, troponin I, creatine kinase [CK]-MB, or CK > upper limit of normal); and new ischemic electrocardiogram changes; presence of at least one of the following risk factors: age 65 years or older, diabetes mellitus, previous MI, known multivessel coronary disease, previous ischemic stroke, peripheral arterial occlusive disease, symptomatic congestive heart failure, or left ventricular ejection fraction <40%, presumed new left bundle branch block, ST-segment depression of ≥0.1 mV associated with the index event, or a history of hypertension
Exclusions:
Percutaneous coronary intervention (PCI) within four months of randomization or planned PCI within 60 days; conditions known to increase the risk of bleeding including platelet count of <100,000/µl; need for treatment with other oral antiplatelet or anticoagulant drugs; recent stroke; persistent systolic blood pressure of 180 mm Hg or more or diastolic pressure of 100 mm Hg or more; renal dysfunction; or known liver disease or high concentrations of liver enzymes before the index event
Primary Endpoints:
Dose response of ximelagatran compared with placebo for the composite of death, MI, or severe recurrent ischemia
Secondary Endpoints:
Stroke, major bleeding, revascularization, and rehospitalization
Drug/Procedures Used:
Within two weeks of acute MI, patients were randomized in a double-blind manner to placebo (n=638) or one of four doses of ximelagatran (24, 36, 48, or 60 mg twice daily; n=1,245) for six months. All patients received aspirin 160 mg/day.
Concomitant Medications:
All patients received aspirin 160 mg/day.
Principal Findings:
The primary endpoint was lower for pooled ximelagatran compared with placebo (13% vs. 16%, hazard ratio [HR] 0.76, p=0.0317), but there was no dose response (12% for 24 mg, 14% for 36 mg, 12% for 48 mg, and 13% for 60 mg). Similar results were observed with an on-treatment analysis. The composite of death/MI/stroke also occurred more frequently in the placebo arm compared with the combined ximelagatran doses (11% vs. 7%, HR 0.66, p=0.0105), although this was a post-hoc analysis.
Any bleeding increased in a dose-response manner (13% placebo vs. 19%, 20%, 25%, and 24% for 24 mg, 36 mg, 48 mg, and 60 mg, respectively), but there was no difference in major bleeding (1% placebo vs. 2%, 1%, 3%, and 2% for 24 mg, 36 mg, 48 mg, and 60 mg, respectively). Liver function tests were increased in the ximelagatran arm after 2–6 months of treatment, usually returning to normal within 60-90 days with treatment continuation or discontinuation.
Interpretation:
Among patients following ST or non-ST elevation MI, treatment with the novel oral direct thrombin inhibitor ximelagatran was associated with a significant, but not a dose-dependent reduction in the primary endpoint of death, MI, or severe recurrent ischemia at six months.
A major benefit of ximelagatran therapy is that there is no need to monitor international normalized ratio, as is needed with coumadin and warfarin therapy. However, the increase in liver enzymes associated with ximelagatran therapy does require monitoring. The recent SPORTIF III trial evaluated the use of ximelagatran therapy in patients with atrial fibrillation.
References:
Presented by Lars Wallentin at the European Society of Cardiology Congress, Vienna, Austria, September 2003.
Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003;362:789-97.
Keywords: Myocardial Infarction, Creatine Kinase, Warfarin, Troponin T, Risk Factors, Electrocardiography, International Normalized Ratio, Liver Function Tests, Azetidines, Benzylamines, Troponin I, Chest Pain, Heart Failure, Bundle-Branch Block, Stroke Volume, Atrial Fibrillation, Hypertension, Diabetes Mellitus
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