Long-term treatment with idraparinux is as effective as vitamin K antagonists for preventing thromboembolism in patients with atrial fibrillation, but it causes significantly more bleeding.
Those results, from the Sanofi Aventis-funded multinational open-label AMADEUS trial, mark the third recent failure to find an acceptable fixed-dose alternative to adjusted-dose vitamin K antagonists for stroke prevention in patients with atrial fibrillation. The study was stopped early after randomization of 4,576 patients because of excess clinically relevant bleeding with the investigational factor X inhibitor idraparinux, compared with vitamin K antagonists (Lancet 2008;371:315–21).
At the time that AMADEUS was halted (mean follow-up of 10.7 months), 2,283 patients had been randomized to subcutaneous idraparinux 2.5 mg/wk and 2,293 to oral adjusted-dose vitamin K antagonists (warfarin or acenocoumarol, target international normalized ratio of 2.0–3.0). All had nonvalvular atrial fibrillation and at least one indication for long-term anticoagulation. They had a mean age of 70 years; almost two-thirds were men.
In the vitamin K antagonist group, the INR was within target range 63% of the time, below target 18% of the time, and higher for 19%. More patients discontinued in the idraparinux group (13% vs. 10%), mainly because of adverse events, Dr. Harry R. Buller of the department of vascular medicine, Academic Medical Centre, Amsterdam, and associates.
Idraparinux was noninferior to vitamin K antagonists in the prevention of all stroke or non-CNS systemic embolism—the primary efficacy outcome—in both the intent-to-treat analysis (0.9 vs. 1.3 per 100 patient-years) and in the per-protocol analysis (0.9 vs. 1.2). However, the idraparinux group had overall excesses of clinically relevant bleeding (19.7 vs. 11.3 per 100 patient-years), nonmajor but clinically relevant bleeding (16.4 vs. 10.3), and intracranial hemorrhage (1.1 vs. 0.4). The differences in bleeding incidence became apparent after about 2 months of treatment.
Hemorrhagic stroke occurred in similar numbers in each group. Despite a higher rate of fatal bleeding with idraparinux (0.7 vs. less than 0.1 per 100 patient-years), overall mortality did not differ significantly between the groups (3.2% vs. 2.9%).
Elderly patients and those with renal insufficiency were at significantly increased risk of clinically relevant bleeding with idraparinux, compared with vitamin K antagonists. And irrespective of treatment allocation, clinically relevant bleeding was more than double in the 971 patients who took aspirin with the anticoagulant and in the 126 who took clopidogrel or ticlopidine than it was in those not taking concurrent platelet inhibitor medication. “This combination should be avoided [when] possible,” the authors said.
Adjusted-dose anticoagulation with vitamin K antagonists lowers the risk of stroke in high-risk patients by about two-thirds, but the complexity of the dose-adjustment regimen makes it difficult to carry out in clinical practice.
But Dr. Alan S. Go of Kaiser Permanente of Northern California, Oakland, and Dr. Daniel E. Singer of Massachusetts General Hospital, Boston, are optimistic an alternative will be found. “On the basis of positive features of recent trial experiences, one or more approaches … will emerge as an alternative to vitamin K antagonists,” they wrote in an accompanying comment. But, “We still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation.”
Bleeding was more than double in those taking warfarin with aspirin or those taking clopidogrel or ticlopidine. DR. BULLER