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INTRODUCTION

Since its discovery in the early 1940s, warfarin (Coumadin drug, Bristol-Myers Squibb) has been the leading oral anticoagulant agent for various thrombo-embolic events. A vitamin K antagonist, warfarin is the only clinically available oral anticoagulant. Although it is effective, warfarin has certain limitations (Table 1) that make its use complex.

As a result of these limitations, clinical efforts have focused on the development of more specific agents. One approach has been to examine the activation of the coagulation cascade, a key pathophysio-logical mechanism involved in a number of cardiovascular conditions.

Table 1   Limitations of Warfarin Use

1. Slow onset of action, prompting the concurrent use of a parenteral anticoagulant
2. Variation in metabolism, requiring dosage adjustments
3. Multiple drug and food interactions, requiring frequent drug monitoring
4. Narrow therapeutic index, necessitating frequent drug monitoring

In December 2003, AstraZeneca submitted ximelagatran (Exanta™) for regulatory review in the U.S. and European Union. Ximelagatran, the first oral direct thrombin inhibitor, is the first clinically tested oral anticoagulant since the introduction of generic warfarin. This new agent works on thrombin, a major regulator of thrombogenesis, which leads to the formation and stabilization of clots, the reactivation of the coagulation cascade, the inhibition of fibrinolysis, and the activation of platelets. The effects of ximela-gatran, compared with those of warfarin, are depicted in Figure 1.

Figure 1 Schematic diagram of the coagulation cascade showing the effects of warfarin versus those of ximelagatran.

Ximelagatran has been extensively investigated in numerous clinical trials involving more than 30,000 patients. Submissions to the Food and Drug Administration (FDA) have been made for ximelagatran to prevent stroke and other thromboembolic complications in patients with atrial fibrillation, to prevent venous thromboembolism (VTE) after orthopedic surgery, and to treat VTE. However, on September 10, 2004, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voiced doubts about the safety and efficacy of ximelagatran. The Committee also voted against all three of the agent’s proposed indications.

Even though this product has not met current FDA standards for approval, its important anticoagulation benefits and, in some cases, its superiority over canadian warfarin in key clinical trials makes it worthy of this review.