Another oral thrombin inhibitor for stroke prevention in atrial fibrillation?

Abstract

Atrial fibrillation (AF), the most common arrhythmia, is associated with a five-fold increase in the risk of stroke (1). Furthermore, cardio-embolic strokes in AF patients tend to be severe, and are often fatal or associated with serious morbidity. Vitamin K antagonists, such as warfarin, produce about a 64% reduction in the risk of stroke in AF patients (2), but have numerous limitations that curtail their uptake and diminish their effectiveness. These limitations include a slow onset of action, a variable dose requirement, reflecting common genetic polymorphisms that influence their metabolism, and an unpredictable anticoagulant response because of differences in dietary vitamin K intake and numerous drug-drug interactions, which increase or decrease the anticoagulant effect (3). With the anticoagulant response so variable, routine monitoring is necessary to ensure that the international normalised ratio (INR) is therapeutic because overanticoagulation is associated with an increased risk of haemorrhage, whereas under-anticoagulation increases the risk of thrombosis. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. Because of the complexity of management, only about one-half of eligible patients with AF receive warfarin, and among those who receive such treatment, the INR is frequently outside of the therapeutic range (4). The large unmet need caused by the limitations of warfarin has prompted the development of new oral anticoagulants with potential advantages over existing agents. Ximelagatran, the first oral thrombin inhibitor, was effective for stroke prevention in patients with AF, but was withdrawn in 2006 because of potential hepatic toxicity (5). The effectiveness of ximelagatran prompted development of a second generation of oral thrombin inhibitors. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial demonstrated the effectiveness of dabigatran etexilate, the first of this new generation, for stroke prevention in AF, endorsing thrombin as an appropriate target for new anticoagulants. Two doses of dabigatran etexilate were compared with warfarin in this trial; the higher dose regimen (150 mg twice-daily) was associated with significantly fewer intracranial bleeds and strokes compared with warfarin, whereas the lower dose (110 mg twice-daily) was associated with significantly less major bleeding than warfarin and similar efficacy (6). AZD0837 is the second of the new generation of oral thrombin inhibitors. A follow-up of ximelagatran, AZD0837 is a prodrug of AR-H067637, a selective and reversible inhibitor of free and fibrin-bound thrombin (7). Cytochrome P450 isoenzymes in the liver convert AZD0837 to AR-H069927, an intermediate that undergoes further metabolism to AR-H067637, the active form. In healthy individuals, AR-H067637 has a plasma half-life of 9–14 hours and the drug is cleared in the urine and faeces. An immediate-release preparation was the first formulation of AZD0837 evaluated in clinical trials; a more recent extended-release formulation enables once-daily dosing. In this issue of Thrombosis and Haemostasis, Olsson et al. (8) report the results of a phase II, randomised, controlled, dosefinding study evaluating the safety and tolCorrespondence to: Dr. Jeffrey Weitz Henderson Research Centre 711 Concession Street Hamilton, Ontario L8V 1C3, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: jweitz@thrombosis.hhscr.org