Another oral thrombin inhibitor for stroke prevention in atrial fibrillation? John W. Eikelboom 1 ; Jeffrey I. Weitz 1,2 1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 2 Department of Biochemistry and Biomedical Sciences and Henderson Research Centre, Hamilton, Ontario, Canada Atrial fibrillation (AF), the most common arrhythmia, is associated with a five-fold increase in the risk of stroke (1). Fur- thermore, cardio-embolic strokes in AF pa- tients tend to be severe, and are often fatal or associated with serious morbidity. Vit- amin K antagonists, such as warfarin, pro- duce about a 64% reduction in the risk of stroke in AF patients (2), but have numer- ous limitations that curtail their uptake and diminish their effectiveness. These limi- tations include a slow onset of action, a variable dose requirement, reflecting com- mon genetic polymorphisms that influence their metabolism, and an unpredictable anticoagulant response because of differ- ences in dietary vitamin K intake and nu- merous drug-drug interactions, which in- crease 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 over- anticoagulation is associated with an in- creased risk of haemorrhage, whereas under-anticoagulation increases the risk of thrombosis. Such monitoring is inconven- ient 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 out- side 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 ad- vantages over existing agents. Ximelagatran, the first oral thrombin inhibitor, was effective for stroke preven- tion in patients with AF, but was withdrawn in 2006 because of potential hepatic toxic- ity (5). The effectiveness of ximelagatran prompted development of a second gener- ation of oral thrombin inhibitors. The Ran- domized Evaluation of Long-Term Anti- coagulant Therapy (RE-LY) trial demon- strated the effectiveness of dabigatran etex- ilate, the first of this new generation, for stroke prevention in AF, endorsing throm- bin as an appropriate target for new anti- coagulants. Two doses of dabigatran etex- ilate were compared with warfarin in this trial; the higher dose regimen (150 mg twice-daily) was associated with signifi- cantly 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 gen- eration of oral thrombin inhibitors. A fol- low-up of ximelagatran, AZD0837 is a pro- drug of AR-H067637, a selective and re- versible inhibitor of free and fibrin-bound thrombin (7). Cytochrome P450 isoenzymes in the liver convert AZD0837 to AR-H069927, an intermediate that under- goes 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 prepara- tion 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 Haemos- tasis, Olsson et al. (8) report the results of a phase II, randomised, controlled, dose- finding study evaluating the safety and tol- Correspondence 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 Received: December 10, 2009 Accepted: December 10, 2009 Prepublished online: January 13, 2010 doi:10.1160/TH09-12-0828 Thromb Haemost 2010; 103: 481–483 Editorial Focus erability of the immediate-release formu- lation of AZD0837 in 250 patients with AF who had at least one risk factor for stroke. Patients were allocated to a three month course of AZD0837, at doses of 150 or 350 mg twice daily, or warfarin, dose-adjusted to achieve an INR of 2–3. There was blind- ing to AZD0837 dose, but the comparison with warfarin was open-label. More than 90% of patients included in the study had previously received warfarin and 60–71% of patients allocated to the warfarin arm had INR values within the target range be- tween study day 12 and 90. Consistent with its anticoagulant effects, AZD0837 pro- duced a dose-dependent prolongation of the activated partial thromboplastin time and thrombin clotting time and suppres- sion of the endogenous thrombin poten- tial. Reductions in the levels of D-dimer and prothrombin fragment 1.2 with AZD0837 were similar to those with warfa- rin. Although rates of adverse events were similar with AZD0837 and warfarin, serious adverse events and adverse events leading to treatment discontinuation were more com- mon in patients randomised to the higher- dose AZD0837 arm than they were in those assigned to lower-dose AZD0837 or to war- farin. Gastrointestinal complaints, such as nausea and diarrhea, were the most frequent adverse events leading to AZD0837 discon- tinuation. Arrhythmic or ischaemic cardiac events occurred in 7% of patients who re- ceived AZD0837 at a dose of 350 mg twice- daily compared with 1% of those given lower-dose AZD0837 and in none who re- ceived warfarin. Both doses of AZD0837 were associated with a 10% increase in serum creatinine, but creatinine levels re- turned to normal within days of stopping treatment. This phenomenon has been at- tributed to AZD0837-induced inhibition of the tubular secretion of creatinine (9). There were no strokes during the study and no dif- ferences in the rates of major bleeding 481 © Schattauer 2010 Thrombosis and Haemostasis 103.3/2010 For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2017-06-16 | IP: 54.191.40.80