Ximelagatran as a new oral anticoagulant for thrombosis.

The articles in this issue describe the development, pharmacology, and clinical trials of the oral direct thrombin inhibitor ximelagatran. As described by Dr. Gustafsson, ximelagatran represents the first new oral anticoagulant since the vitamin K antagonist (VKA) warfarin. His article considers the evolution of the drug development process in the more than 60 years between the introduction of each of the agents and its clinical use. In particular, although ximelagatran was developed through a program of targeted drug design, the origins of warfarin lie in studies of a bleeding disease in cattle, and its clinical use followed its use as a rodenticide. Drs. Mattsson, Sarich, and Carlsson consider why thrombin was selected as a logical target in developing a new anticoagulant for use in the treatment and prevention of arterial and venous thromboembolic disorders and describe the mechanism of action of melagatran, the active moiety of ximelagatran. VKAs are ineffective for the initial treatment of acute deep vein thrombosis and pulmonary embolism. Although VKAs have proven efficacy in the prevention of venous thromboembolism (VTE), their narrow therapeutic window demands close management to balance effective thromboprophylaxis against the risk of serious bleeding. In practice, the realities of routine clinical use, such as the need for regular coagulation monitoring, restrict the use of the VKAs. Consequently, many patients are left at increased risk of thromboembolic events. The unpredictable anticoagulant effects of the VKAs reflect highly variable pharmacokinetics and pharmacodynamics with numerous food and drug–drug interactions. Ximelagatran, in contrast, has a predictable and reproducible pharmacokinetic/pharmacodynamic profile with few clinically relevant drug interactions, as described in the articles by Drs. Wolzt, Sarich, and Eriksson. The article by Drs. Carlsson and Schulman discusses that, due to its predictable characteristics, coagulation monitoring is not required with ximelagatran. Effects of ximelagatran on a range of coagulation assays are described as guidance to what results can be expected in circumstances where an indication of anticoagulant effect may assist with clinical decision making. Ximelagatran was approved in the European Union in May 2004 for the short-term primary prevention of VTE events in patients undergoing elective hip or knee replacement surgery. Drs. Colwell and Mouret describe the results from the METHRO, EXPRESS, and EXULT studies demonstrating that ximelagatran compares favorably with low-molecular-weight heparin (LMWH) in this orthopedic surgery indication. Ximelagatran has also been evaluated as initial treatment for acute VTE and long-term secondary prevention of VTE (Drs. Huisman and Bounameaux), prevention of stroke in atrial fibrillation (Drs. Olsson and Halperin), and, in a phase II study, prevention of cardiovascular events following recent myocardial infarction (Dr. Wallentin). Regulatory review of the clinical trial program by the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee took place in September 2004. The Committee reviewed applications for the approval of ximelagatran for shortterm use in the prevention of VTE in patients undergoing elective total knee replacement, secondary VTE prevention after 6 months of standard therapy for an acute episode of VTE, and prevention of stroke and systemic embolic events in patients with atrial fibrillation. In each of the indications, the Committee was of the opinion that the benefits of ximelagatran did not outweigh the risks and advised against approval. Specifically, there were concerns about the increased incidence of elevated liver enzyme levels in patients treated with ximelagatran and their potential clinical significance and an apparent increase in the risk of myocardial infarction in the follow-up to one of the four studies (EXULT A) of ximelagatran in the prevention of VTE following total knee replacement. The chairman of the FDA Committee, Dr. Jeffrey Borer, noted the difficulties in discussing the safety of ximelagatran considering its benefits in comparison with the VKAs such as warfarin. The clinical use of warfarin is undoubtedly associated with several troublesome and potentially serious issues. Surveys demonstrate that warfarin is among the leading causes of emergency hospitalization for adverse drug events, which in some cases prove fatal. In a survey of adverse drug events in Australia, 0.2% of patients receiving warfarin suffered a fatal adverse event, consistent with