ESTEEM

Efficacy and Safety of the oral direct Thrombin inhibitor ximElagatran in patients with rEcent Myocardial damage (2003)

Condition

Secondary prophylaxis after acute myocardial infarction

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Objective

To compare the efficacy and safety of 4 doses of ximelagatran with placebo for prevention of death, non-fatal myocardial infarction, and severe recurrent ischemia after a recent myocardial infarction

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Trial design

Randomized, double-blind, placebo-controlled study
Active treatment: ximelagatran 24, 36, 48, or 60 mg plus ASA 160 mg once daily (n=307, 303, 311, 324, respectively) 
Control treatment: placebo plus ASA 160 mg once daily (n=638)

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Endpoints

Primary efficacy endpoint: composite of all-cause death, non-fatal myocardial infarction, and severe recurrent ischemia
Secondary efficacy endpoints: composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, severe recurrent ischemia; composite of death or non-fatal myocardial infarction
Safety endpoints: major and minor bleeding, adverse events

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Trial participants

1883 patients admitted for acute myocardial infarction (66% STEMI) within the preceding 14 days

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Results

Efficacy outcome: As no difference in effects was found for the 4 ximelagatran doses, the various ximelagatran dose groups were pooled. Ximelagatran significantly reduced the risk for the primary endpoint compared with placebo from 16.3% (102 of 638 patients) to 12.7% (154 of 1245 patients), equating to a risk reduction of 24%. Ximelagatran was more effective for the secondary endpoints: Death and myocardial infarction occurred in 82 of 1245 patients (7%) in the combined ximelagatran groups compared to 55 of 638 patients (9%) with placebo. Patients on ximelagatran had fewer strokes (11 of 1254) than those in the placebo group (13 of 638)
Safety outcome: Major bleeding events were rare, they occurred in 23 of 1245 (1.8%) in the combined ximelagatran groups and in 6 of 638 (0.9%) in the placebo group. Total bleeding (major and minor) was higher in the ximelagatran groups (22% vs. 13%). Elevated liver enzymes were seen in 6.5% of patients at the lowest ximelagatran dose, 24 mg, and in 12.2–13.0% of patients at the higher doses, but these were not associated with clinical complications

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Summary

Efficacy: Ximelagatran and ASA provided significant additional benefits compared to ASA alone in prevention of major cardiovascular events in patients following acute myocardial infarction
Safety: Treatment with ximelagatran plus ASA resulted in a doubling of bleeding complications and a fourfold excess of liver enzyme elevations, compared to ASA alone

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Reference

Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nyström P, Bylock A, for the ESTEEM investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003;362:789-797

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Corresponding author

Prof. Lars Wallentin, Uppsala Clinical Research Centre, University Hospital, S-751 85 Uppsala, Sweden, e-mail: lars.wallentin@ucr.uu.se 

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