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Although there have been many significant advances over the last 50 years with regards to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in many patients at risk for these complications. Although effective, warfarin has a narrow therapeutic window, necessitating frequent laboratory monitoring for anticoagulant effect. Ximelagatran is an investigational anticoagulant that directly inhibits thrombin, unlike heparin or warfarin, which are indirect inhibitors. Although indirect thrombin inhibitors are mainly only effective at inhibiting circulating thrombin, direct thrombin inhibitors are able to inhibit both free and clot-bound thrombin, thereby producing more effective anticoagulation. Ximelagatran is the first orally available direct thrombin inhibitor to reach phase 3 clinical trials. Ximelagatran is a prodrug for the active metabolite melagatran, and has been demonstrated to have a relatively wide therapeutic window in terms of bleeding and antithrombotic effect compared with warfarin. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to warfarin and low-molecular-weight heparins (LMWH) for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, possible more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Adverse effects with ximelagatran primarily involve bleeding complications, which are more frequent than with placebo, but appear comparable to those occurring with standard anticoagulant treatment (ie, warfarin and LMWH). Ximelagatran has also been demonstrated to cause transient increases in liver enzymes, the significance of which will need to be addressed in ongoing phase 3 studies. Should ongoing trials prove ximelagatran to have at least similar therapeutic efficacy and safety as warfarin, ximelagatran may become a first-line anticoagulant due to its ease of administration and lack of a need for drug monitoring. The results of these trials are eagerly awaited in helping to defining the place in therapy for this promising new agent.