Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation : a randomised, open-label, non-inferiority trial

Background: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists. Methods: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2·5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1·5. This trial is registered with ClinicalTrials.gov, number NCT00070655. Findings: The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10·7 (SD 5·4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19·7 vs 11·3 per 100 patient-years; p<0·0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1·1 vs 0·4 per 100 patient-years; p=0·014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0·9 vs 1·3 per 100 patient-years; hazard ratio 0·71, 95% CI 0·39-1·30; p=0·007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3·2 vs 2·9 per 100 patient-years; p=0·49). Interpretation: In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.