PURPOSE: H 376/95 is a novel, oral direct thrombin inhibitor that shows predictable pharmacokinetics and has not shown clinically significant food or drug interactions. Anticoagulants such as warfarin are used to lower the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). In the SPORTIF II study, the tolerability and safety of three doses of H 376/95 were compared with warfarin in NVAF patients. METHODS: This was a randomized, parallel-group study of NVAF patients who had at least one additional risk factor for stroke. The primary outcome was the number of adverse events, e.g., bleeding and thromboembolic events. The duration of treatment was 12 weeks, during which three groups received H 376/95 (n = 187) 20, 40 or 60 mg bid, given double blind. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an INR of 2.0 ± 3.0. RESULTS: A total of 257 patients were randomized to treatment and 254 patients received study drug. The median age was 70 years (range: 39 ± 95). In addition to NVAF, all patients had one additional risk factor for stroke, 75%had two additional risk factors, and 42%had three or more additional risk factors. The number of minor bleeds was comparable and low in all four groups. There was only one major bleed (vaginal) observed in a patient receiving warfarin and none in the H 376/95 groups. Out of 67 patients in the warfarin group, two patients had transient ischaemic attacks. Of the 187 patients in the H 376/95 groups, one patient had a transient ischaemic attack and one patient had an ischaemic stroke; both patients were in the H 376/95 60-mg bid group. CONCLUSION: Fixed doses of H 376/95 up to 60 mg bid were well tolerated, without the need for dosage adjustment or coagulation monitoring, during a 3-month treatment period in NVAF patients with medium-to-high risk for stroke and systemic embolism.