Oral ximelagatran for secondary prophylaxis after myocardial infarction:: the ESTEEM randomised controlled trial

Background Despite important advances in treatment, the risk of recurrent ischaemic events is high both early and late after an acute coronary syndrome. We aimed to assess the effectiveness of ximelagatran and acetylsalicylic acid for prevention of death, non-fatal myocardial infarction, and severe recurrent ischaemia after a recent myocardial infarction. Methods In this placebo-controlled, double-blind, multicentre, multinational dose-guiding study we assessed 1883 patients who had had recent ST-elevation or non-ST-elevation myocardial infarction. Within 14 days after the index event we randomised the participants in the proportions 1/1/1/1/2 to oral ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg twice daily, or placebo, respectively for 6 months. All patients received acetylsalicylic acid 160 mg once daily. The primary efficacy outcome was the dose response of ximelagatran by comparison with placebo for the occurrence of all-cause death, non-fatal myocardial infarction, and severe recurrent ischaemia. Analysis was by intention to treat. Findings Oral ximelagatran significantly reduced the risk for the primary endpoint compared with placebo from 16.3% (102 of 638) to 12.7% (154 of 1245) (hazard ratio 0.76, 95% CI 0.59-0.98, p=0.036) for the combined ximelagatran groups versus placebo. There was no indication of a dose response between the ximelagatran groups. Major bleeding events were rare, 1.8 % (23 of 1245) and 0.9 % (six of 638) (hazard ratio 1.97, 95% CI 0.80-4.84) in the combined ximelagatran and placebo groups, respectively. We recorded no serious clinically adverse outcomes judged related to the investigational drug. Interpretation Oral direct thrombin inhibition with ximelagatran and acetylsalicylic acid is more effective than acetylsalicylic acid alone in preventing major cardiovascular events during 6 months of treatment in patients who have had a recent myocardial infarction.