Title of Trial
Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial

Date and Citation of Primary Publication(s) or References
Olsson SB; Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003 Nov 22;362(9397):1691-8

Purpose of the Trial
The purpose of this trial was to compare fixed dose ximelagatran to warfarin in the prevention of stroke and systemic embolization in patients with atrial fibrillation. Ximelagatran is an oral direct thrombin inhibitor, which does not require dose titration or routine monitoring.

Study Category
Atrial fibrillation. Multicenter, randomized, open label.

Inclusion Criteria
To be eligible for enrollment in this trial patients had to fulfill the following 2 inclusion criteria: Age >18 years and persistent or paroxysmal atrial fibrillation documented by at least 2 ECG’s. Patients had to have one or more of the following risk factors for stroke: Hypertension, age>75, previous stroke, TIA or systemic embolus, LVEF<40%, age>65 with CAD, age>65 and diabetes mellitus.

Exclusion Criteria
Patients were excluded from the trial if they fulfilled any of the following criteria: Mitral stenosis or prior valvular surgery, atrial fibrillation caused by a reversible cause, recent stroke or TIA, and conditions associated with an increased risk of bleeding (e.g. intracranial hemorrhage, GI bleeding, etc.). Other exclusion criteria included active endocarditis, myxoma or thrombus, acute coronary syndrome or percutanous coronary intervention in the prior 30 days, indications for anticoagulation other than atrial fibrillation, planned cardioversion, planned major surgery, treatment in the last 10 days with antiplatelet or thrombolytic agent other than aspirin, NSAID use, renal failure, liver disease or persistent LFT abnormality, childbearing potential, drug addiction or anemia.

Study Design
Patients were randomized to receive either fixed dose ximelagatran (36 mg twice daily) or warfarin to achieve an INR of 2.0 to 3.0 in an open label fashion. Treatment with aspirin was allowed up to 100mg daily.

Primary Endpoints
The primary endpoint of the study was the efficacy of ximelagatran compared to warfarin in the prevention of all strokes or embolic events.

Secondary Endpoints
Composite secondary endpoints of the study included: 1) major and minor bleeding, 2) treatment discontinuation, 3) ischemic stroke, TIA, systemic embolization, 4) death, stroke, and acute MI.

Baseline Characteristics

	Ximelagatran (n=1704)	Warfarin (n=1703)
Male (%)	68	70
Age, mean	70.3	70.1
Systolic BP, mean (mm Hg)	139	139
Number of risk factors (%)   1   2   3	30 36 34	32 34 34
Paroxsymal Atrial Fibrillation (%)	9	7
Prior Stroke and/or TIA (%)	24	24
HTN (%)	72	72
LV dysfunction (%)	34	34

Time to Follow-Up
Follow up of 3407 patients was completed in September 2002, with a mean duration of follow up of 17.4 months.

Results
Aspirin was used together with the study drug for at least half the study period by 13% of patients on ximelagatran and by 10% of the patients on warfarin (p=0.010). The mean INR in patients assigned to warfarin was 2.5. The INR was between 2.0 and 3.0 for 66% of the study period, and between 1.8 and 3.2, for 81% of the study period. 56 patients in the warfarin group had primary endpoint events (2.3% annual rate), compared to 40 patients in the ximelagatran group (1.6% annual rate, p=0.1000). There was no difference in mortality between the two groups. In warfarin treated patients with stroke, 25% of events occurred with INRs below 2.0. The combined endpoint of major and minor hemorrhage occurred less often in the ximelagatran group when compared to warfarin (25.8% per year vs. 29.8% per year, p=0.0065). Elevation of alanine aminotransferase (ALT), occurred in 6% of patients receiving ximelagatran compared to 1% taking warfarin (p<0.0001). The rise in ALT typically occurred between 2 and 6 months of initiation of therapy and returned to normal spontaneously or with discontinuation of therapy, without any adverse clinical effects.

Sponsor
Astra Zeneca, Sweden

Trial Status: Completed

Review written by: Jonathan Weinstock, MD