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Idraparinux vs. vitamin K for long-term treatment of atrial fibrillation
Long-term idraparinux treatment was similar to vitamin K antagonists with regard to efficacy against thromboembolism; however, idraparinux was shown to result in significantly more bleeding, according to data from the Amadeus trial.
The Amadeus trial is an open-label, noninferiority study that compared the safety and efficacy of the two treatments in patients with atrial fibrillation who were at risk for developing thromboembolism.
Patients (n=4,576) were randomly assigned to receive either subcutaneous idraparinux 2.5 mg weekly or adjusted-dose vitamin K antagonists and followed up to determine the cumulative incidence of all stroke and systemic embolism.
The researchers stopped the trial after a mean follow-up period of 10.7 months due to an excess of clinically-relevant bleeding in patients assigned to idraparinux (346 cases vs. 226 cases; P,.0001).
There were 18 cases of thromboembolism in patients assigned to idraparinux compared with 27 cases in patients assigned to vitamin K antagonists (HR=0.71; 95% CI, 0.39-1.30), which satisfied the researchers’ noninferiority criterion.
The number of deaths was similar between the treatment groups, with 62 deaths reported in the idraparinux group vs. 61 deaths in the vitamin K antagonists group. – by Cara Dickinson
Lancet. 2008;371:315-321.
The open-label trial by the Amadeus investigators compared idraparinux, a long-acting synthetic pentasaccharide that is given once-weekly by subcutaneous injection at a dose of 2.5 mg, with vitamin K antagonists, dose-adjusted to achieve a target international normalized ratio of 2 to 3 for prevention of stroke and systemic embolism in 4,576 patients with AF. The trial was stopped early because of excessive bleeding, including intracranial bleeding, in the idraparinux-treated arm. Older patients, those with impaired renal function and patients receiving concomitant aspirin had the highest risk for bleeding with idraparinux, a drug that is cleared via the kidneys. Despite early trial cessation, idraparinux was noninferior to vitamin K antagonists in terms of prevention of stroke and systemic embolism.
This trial is not the first disappointment for idraparinux. Previously, the van Gogh investigators compared subcutaneous idraparinux, at the same once-weekly dose of 2.5 mg, with conventional therapy consisting of heparin or low–molecular-weight heparin followed by vitamin K antagonists in 2,904 patients with deep vein thrombosis and 2,215 patients with pulmonary embolism. The primary efficacy outcome was the rate of recurrent venous thromboembolism at three months. Although idraparinux was noninferior to conventional therapy in DVT patients, the rate of recurrent VTE in patients with pulmonary embolism was higher with idraparinux than it was with conventional treatment. In these studies, rates of bleeding were not higher with idraparinux.
So where do we stand with idraparinux? Will careful patient selection or dose titration render this a viable drug for prevention or treatment of thrombosis? Clearly, a lower dose of idraparinux will be needed in patients with AF, whereas higher doses will be necessary in those with pulmonary embolism. We do not know whether idraparinux retains its efficacy at lower doses or whether rates of bleeding will be acceptable when higher doses are used in patients with pulmonary embolism. It is clear, however, that idraparinux has a narrow therapeutic window.
What does the future hold? A biotinylated form of idraparinux has been introduced. The anticoagulant effects of this drug can be rapidly reversed with intravenous avidin. Whether the availability of an antidote will improve the benefit-to-risk profile of idraparinux remains to be determined. At the same time, dabigatran etexilate, an oral thrombin inhibitor, and rivaroxaban and apixaban, oral factor Xa inhibitors, are undergoing phase-3 evaluation for prevention and treatment of thrombosis. Given in fixed doses once or twice daily without coagulation monitoring, these agents are certainly more convenient than vitamin K antagonists. Whether oral factor Xa inhibitors will prove to be at least as effective and safe as vitamin K antagonists for stroke prevention in patients with AF needs to be determined.
– Jeffrey I. Weitz, MD
Professor of Medicine and Biochemistry, and Director, Henderson Research Centre
McMaster University, Ontario, Canada
– Peter L. Gross, MD
Associate Professor of Medicine
McMaster University, Ontario, Canada