Lessons From Ximelagatran: Issues for Future Studies Evaluating New Oral Direct Thrombin Inhibitors for Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Venous thromboembolism is a frequent complication of total hip and knee replacement requiring prophylaxis with anticoagulants. A direct thrombin inhibitor— ximelagatran—did not show advantages over other anticoagulants and it was withdrawn from the market; however, new drugs are being developed. We conducted a systematic review and meta-analysis to identify conditions under which ximelagatran might potentially be superior to current standards. Medline, EMBASE, the Cochrane Library, and grey literature were screened for randomized trials comparing ximelagatran with warfarin or low-molecular-weight heparin for thromboprophylaxis in total hip or knee replacement. Two reviewers independently assessed and extracted data. A meta-analysis with especial attention to statistical heterogeneity was conducted. This study suggested that the risk-benefit profile of ximelagatran—and probably other similar agents— depends on the type of surgery, the initial timing of administration, and probably the dose. These issues should be explicitly explored in future trials evaluating new direct thrombin inhibitors.