The European Society of Cardiology
Oral direct thrombin inhibition for anticoagulation in coronary artery disease – focus on the ESTEEM trial
Department of Cardiology, Uppsala Clinical Research Centre, University Hospital, Uppsala, Sweden
* L. Wallentin, Department of Cardiology, Uppsala Clinical Research Centre, University Hospital, S751 85 Uppsala, Sweden. Tel.: +46-70-631-35-66; fax: +46-18-50-66-38
lars.wallentin{at}ucr.uu.se
Abstract
Long-term treatment with anticoagulation agents in combination with aspirin can be beneficial for the prevention of recurrent thrombotic events, although the limitations of current agents make their use far from ideal. In contrast, the oral direct thrombin inhibitor, ximelagatran, has considerable therapeutic potential in this disease area because it has predictable pharmacokinetics and dynamics and therefore can be used at a fixed dose, does not require coagulation monitoring and has a low potential for drug and food interactions.
The ESTEEM trial, a randomised, placebo-controlled phase II dose-ranging study in 1883 patients with recent myocardial infarction, is the first study to investigate the efficacy of ximelagatran in the prevention of atherothrombotic events. Patients were randomised to 6 months of treatment with twice-daily tablets of ximelagatran 24, 36, 48, or 60 mg or placebo in addition to aspirin 160 mg daily. Ximelagatran was significantly more effective than placebo in reducing the composite endpoint of death, non-fatal myocardial reinfarction, and severe recurrent ischaemia (
), resulting in a mean 24% reduction in relative risk for the combined ximelagatran groups versus placebo. The efficacy of ximelagatran was not dose-dependent; the 24-mg dose was as effective as the 60-mg dose. Major bleeds were rare with ximelagatran and not significantly different from placebo (1.8% combined ximelagatran groups versus 0.9% placebo). Ximelagatran was associated with transient elevations in liver enzymes, which did not result in clinical complications. Discontinuation due to adverse experiences with the lowest dose of ximelagatran tested (24 mg bid) was not different from placebo. Therefore, treatment with ximelagatran 24 mg twice daily in combination with aspirin achieved optimal efficacy with an acceptable safety profile. The ESTEEM trial results highlight the potential for ximelagatran in combination with aspirin as a convenient and well-tolerated, long-term treatment for prevention of arterial thrombotic events.
Key Words: Myocardial infarction • Oral direct thrombin inhibitors • Ximelagatran • ESTEEM • Anticoagulation • Coronary arterial disease