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

Summary

Background

Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism.

Methods

We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2·0-3·0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism.

Findings

During 4941 patient-years of exposure (mean 17·4 months, SD 4·1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2·3% per year with warfarin and 1·6% per year with ximelagatran (absolute risk reduction 0·7% [95% Cl -0·1 to 1·4], p=0·10; relative risk reduction 29% [95% Cl -6·5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29·8% vs 25·8% per year; relative risk reduction 14% [4 to 22]; p=0·007). Raised serum alanine amino-transferase was more common with ximelagatran.

Interpretation

In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Introduction

Non-valvular atrial fibrillation carries a substantial risk of ischaemic stroke and systemic embolism.¹ Results of several randomised trials have shown that adjusted-dose warfarin provides highly effective prophylaxis,² reducing stroke by 62% compared with placebo in a meta-analysis. Benefit is tempered, however, by a 7–10-fold increase in intracranial haemorrhage, particularly in elderly patients.2, 3, 4, 5, 6 Interactions of vitamin K antagonists with food, drugs,⁷ and other factors require dose adjustments and regular monitoring of anticoagulation. Expense and inconvenience8, 9, 10 associated with this unpredictability contribute to under-treatment of patients with atrial fibrillation at high risk for stroke,11, 12 creating a need for easily administered safe alternatives.

Ximelagatran is an oral direct thrombin inhibitor under investigation as an anticoagulant for prevention and treatment of thromboembolism.¹³ Its pharmacokinetic profile is predictable and stable over time,14, 15 and unaffected by bodyweight, age, sex, or ethnic origin.15, 16, 17 With a rapid onset of action and metabolism independent of the hepatic cytochrome P450 enzyme system, ximelagatran has a low potential for drug interactions and no known food interactions,14, 15, 18 making coagulation monitoring and dose adjustments unnecessary.15, 16, 17

In this report, we describe the main results of SPORTIF III (Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation), one of two long-term phase III studies comparing safety and efficacy of ximelagatran with warfarin in patients with atrial fibrillation at risk for ischaemic stroke.¹⁹