Ximelagatran, the Sacrificial Lamb

• Ximelagatran is the first orally active direct acting thrombin inhibitor.
• It is clearly easier to use and as effective as warfarin, the only other oral antithrombotic agent.
• Because of safety concerns, ximelagatran was not approved and was taken out of development.
• Many patients at risk of thromboses who should receive warfarin do not because of difficulty and risks associated with its use.
• Has this failure to use otherwise indicated warfarin been adequately taken into account in trials comparing it to newer agents?
• Hopefully, lessons were learned in the ximelagatran experience that will make it easier for newer similar agents in the future.

This article confirms what is well known, i.e., that ximelagatran (AstraZeneca), the first orally active direct thrombin inhibitor, is a very effective and good drug. Unfortunately, it was not approved by FDA because of its side effect profile, especially liver toxicity in a small number of patients, and was taken out of development by AstraZeneca. Other direct thrombin inhibitors remain in development, and, hopefully, one of these will eventually be approved. The major advantages of this class of drugs are (1) some can be given orally (unlike heparin or low-molecular weight heparins, e.g. enoxaparin), and (2), they do not require monitoring of blood coagulation (unlike other oral antithrombotic drugs, e.g. warfarin). They do, however, pose a small risk of bleeding complications, as do all antithrombotic agents.

Several clinical trials demonstrated that ximelagatran can be given easily and effectively in a variety of situations associated with risks of thrombotic events like strokes and deep vein thrombosis. Warfarin remains the only antithrombotic agent available for long-term oral use. It is the agent that all new antithrombotic agents are compared to in clinical trials, and such trials confirm the same risks of bleeding with warfarin and the newer agents. What seems to be frequently overlooked in evaluating the relative safety and efficacy of new antithrombotic agents is the difficulty in using warfarin. Patients need to have blood tests regularly to monitor blood coagulation and adjust the dose of warfarin. If under-dosed, there may be lack of efficacy and risk of thrombosis; if overdosed, there is increased risk of bleeding. In addition, many foods and/or drugs interact with warfarin to raise or lower its anticoagulant effect. For these reasons warfarin is difficult to use and many patients who have a clear indication for warfarin do not receive it because of the patient’s unwillingness to take it and/or the physician’s reluctance to prescribe it. Thus, such patients remain at risk for otherwise preventable thrombotic events, and one wonders if this is adequately taken into account when analyzing the results of trials comparing warfarin to direct thrombin inhibitors, like ximelagatran. Hopefully, this will not be the case for new direct thrombin inhibitors that come along, as ximelagatran may have been the “sacrificial lamb.”

NOTE: THIS AUTHOR WAS A CONSULTANT TO ASTRAZENECA IN THE DEVELOPMENT OF XIMELAGATRAN.