Ximelagatran--promises and concerns.

VITAMIN K (“KOAGULATION”) ANTAGONISTS HAVE been the sole oral anticoagulants available for 60 years, ever since Link identified the components in spoiled sweet clover responsible for bleeding in cattle. Originally developed as a rat poison, vitamin K antagonists such as warfarin are used successfully for the prevention of venous and arterial thromboembolism for a wide range of clinical indications, including atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease, some orthopedic procedures, and congenital or acquired thrombophilia. Since both age and obesity increase the risk of atrial fibrillation and VTE, the need for anticoagulants is increasing. Warfarin treatment is complicated by several inherent problems that have limited its use. These include delayed onset of its antithrombotic action, narrow therapeutic index, unpredictable and variable pharmacological response, and the mandatory regular laboratory monitoring to control its anticoagulant effect and minimize risk of serious bleeding. In addition, numerous drugs, certain dietary supplements, alcohol, and even some foods markedly influence warfarin dose response. As a consequence, a higher level of patient diligence and reliability is required than with almost any other drug; furthermore, warfarin management is labor intensive for the physician and is not reimbursed. In addition, there is the discomforting realization that whereas the hemorrhagic effects of warfarin are visible and often dramatic (usually dose-related), the benefits are imperceptible to the individual patient. The overall annual incidence of major hemorrhage due to oral anticoagulants has ranged from 1.2% to 7.0%, but is lower (0.5%-4.2%) in clinical trials with rigorous management of selected patient populations. In general practice, vitamin K antagonists remain a leading iatrogenic cause of hospitalization. For instance, in France, among an estimated 500000 patients treated each year with anticoagulants, 17000 are hospitalized annually for hemorrhagic events. Unquestionably, less complicated anticoagulants are needed. Ideally, these agents should be available in both parental and oral formulations, have prompt onset of action, have a predictable dose response not requiring laboratory monitoring, and should not interact with other drugs. The profile of ximelagatran, the oral form of the antithrombin agent melagatran, fulfills these requirements, so trials of its clinical effects have been followed with keen interest for some time. Thrombin is the enzyme generated by the coagulation cascade and is directly responsible for clotting fibrinogen and aggregating platelets. Inhibitors of thrombin or antithrombins are effective natural anticoagulants. For instance, hirudin (from the medicinal leech Hirudo medicinalis) and its analogues such as hirulog, argatroban, and melagatran are highly specific thrombin inhibitors that have been developed only for short-term clinical use, since they must be administered parenterally. Melagatran is a small dipeptide analogue which, unlike hirudin, binds only to the active site of thrombin and binds reversibly. This property is relevant since melagatran has been associated with less bleeding than is seen with tighterbinding inhibitors. Like the other direct antithrombins, melagatran inhibits not only free thrombin but also clot-bound thrombin, whereas heparin inhibits only the former. Melagatran also has a more predictable anticoagulant effect than heparin, since it is not protein cofactor–dependent. Ximelagatran is a prodrug form of melagatran, which enables it to be rapidly absorbed in the small intestine. After absorption, ximelagatran is bioconverted to its active form, melagatran, which has about 20% bioavailability. After ingestion of ximelagatran, peak blood levels of melagatran are reached in 2 to 3 hours; its antithrombotic activity is immediate, and it is cleared entirely by renal excretion within 12 hours. At therapeutic doses, melagatran induces prolongation of prothrombin time, partial thromboplastin time, and thrombin time, but since the effect is predictable at a fixed dose, monitoring these parameters is unnecessary. A specific antidote is not available, but when renal function is unimpaired, the rapid clearance of melagatran limits its effect. However, intravenous activated prothrombin complex or activated factor VII preparations could be used to more promptly attenuate the anticoagulant effect of melagatran. No specific food or drug interactions have been reported.