Title of Trial
Ximelagatran Versus Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation. SPORTIF II: A Dose-Guiding, Tolerability, and Safety Study

Date and Citation of Primary Publication(s) or References
Petersen P. Grind M. Adler J. SPORTIF II Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. Journal of the American College of Cardiology. 41(9):1445-51, 2003 May 7

Purpose of the Trial
The purpose of this study was to compare the safety and tolerability of three different doses of ximelagatran versus warfarin in patients with non-valvular atrial fibrillation. Ximelagatran is an oral direct thrombin inhibitor which does not require dose titration or routine monitoring.

Study Category
Atrial Fibrillation. Prospective, multicenter, randomized, parallel group, dose-guiding study

Patient Population
Not defined

Inclusion Criteria
To be eligible for enrollment patients had to be 18 years of age or older and have a history of intermittent (paroxysmal) or persistent non-valvular atrial fibrillation documented on at least 2 ECG's within the previous year. In addition patients had to have at least one of the following risk factors for stroke: history of HTN, Age>65, previous stroke or TIA, previous systemic embolization, LV dysfunction (EF<40%) or recent symptomatic CHF, Diabetes Mellitus or CAD.

Exclusion Criteria
Patients were excluded from the trial if they fulfilled any of the following: Stroke or systemic embolization within the previous 2 years, conditions associated with increased risk of bleeding, non-valvular AF secondary to reversible causes, mechanical heart valves, MI or revascularization within the previous 3 months, LV aneurysm or atrial myxoma, treatment with NSAIDs or thrombolytic agents in the prior week, creatinine clearance <40ml/min, BP>180/100, history of rheumatic fever, liver insufficiency, Hgb<100 g/l or platelet count < 100,000, contraindications to warfarin therapy.

Study Design
Patients were randomized into four groups in a 1:1:1:1 fashion. Three groups consisted of double blinded 20, 40 or 60 mg ximelagartran twice daily, without loading doses or titrations. The fourth group received open label warfarin to achieve an INR of 2.0-3.0. After a two week run in period, patients were seen at randomization, 0.5, 1, 2, 4, 8, and 12 weeks of drug treatment and 2 weeks after cessation of drug therapy.

Endpoints
Strokes and TIAs were assessed with CT or MRI and classified as hemorrhagic or ischemic. Bleeding events and all adverse events were monitored. Routine studies including chemistry, hematology, PTT and INR, and urinalysis was performed during the study follow up.

 Baseline Characteristics

	20 mg bid n=66	Ximelagartran 40 mg bid n=62	60 mg bid n=59	Warfarin n=67	Total N=254
Median Age (yrs)	70	69	69	71	70
Males (%)	65	68	54	55	61
HTN (%)	62	55	61	51	57

Time to Follow-up
257 patients were enrolled in the study and 207 completed the protocol until the last follow up, fourteen weeks from randomization.

Results
99.6% of the patients had at least one other risk factor for stroke other than AF. Two TIAs occurred in the warfarin group. One TIA and one ischemic stroke occurred in the ximelagartan group (both 60mg dosing). The rate of adverse events in both groups were similar, 48.1% for ximelagatran, and 50.7% for warfarin. 8.6% of patients taking ximelagatran discontinued the drug due to adverse events, the most common of which was hematuria. 4.3% of patients taking ximelagatran experienced an asymptomatic transient increase in liver enzymes.

Sponsor
AstraZeneca Public Limited Company

Trial Status: Completed