Comparison of Idraparinux With Vitamin K Antagonists for Prevention of Thromboembolism in Patients With Atrial Fibrillation - AMADEUS
The goal of this trial was to compare the safety and efficacy of idraparinux as prophylaxis against stroke and systemic embolism in patients with nonvalvular atrial fibrillation, compared with vitamin K antagonists.
Idraparinux would be noninferior to traditional vitamin K antagonists in reducing stroke and systemic embolism in patients with atrial fibrillation.
Patients Screened: 8,312
Patients Enrolled: 4,576
Mean Follow Up: 325 days
Mean Patient Age: 70.2
• ECG documented nonvalvular atrial fibrillation
• Indication for long-term anticoagulation based on at least one risk factor: previous ischemic stroke; transient ischemic attack or systemic embolism; hypertension requiring medication; left ventricular dysfunction; age >75 years; and age 65-75 years, with either diabetes mellitus or symptomatic coronary artery disease
Inability to provide informed consent; contraindication to anticoagulation; another reason for anticoagulation; calculated creatinine clearance <10 ml/min; breast-feeding; potential for, or ongoing pregnancy; or recent or anticipated invasive procedures with potential for uncontrolled bleeding
• Efficacy: composite of all strokes (ischemic, hemorrhagic, or undefined) or systemic embolism
• Safety: clinically relevant bleeding
• Efficacy: ischemic stroke (nonischemic stroke [hemorrhagic and undefined]; systemic embolism confirmed by angiography, surgery, or autopsy; cardiovascular death; myocardial infarction; and venous thromboembolic events)
• Safety: major bleeding (fatal, intracranial, another critical anatomical site, bleeding with a fall in hemoglobin ≥2 gm%, or necessitating transfusion of ≥2 U of blood), and nonmajor bleeding (overt bleeding not meeting criteria for major bleeding as above, repetitive epistaxis for >5 minutes at least twice in 2 hours, hematuria, hematemesis, and subcutaneous hematomas >25 cm² if spontaneous or >100 cm² if traumatic)
Patients with atrial fibrillation and an indication for long-term anticoagulation were randomly assigned to open-label dose-adjusted treatment with vitamin K antagonists (Coumadin or acenocoumarol) with target international normalized ratio (INR) 2.0-3.0 or idraparinux 2.5 mg subcutaneously once weekly. In patients with estimated glomerular filtration rate 10-30 ml/min, the second and subsequent doses of idraparinux were 1.5 mg weekly.
Use of nonsteroidal anti-inflammatory drugs and antiplatelet agents was discouraged, but aspirin (≤100 mg/day) or clopidogrel (75 mg/day) was allowed if clinically indicated.
A total of 4,576 patients were randomized over a period of 22 months, with 2,283 assigned to the idraparinux arm, and 2,293 assigned to the vitamin K antagonist arm. The baseline characteristics were fairly similar between the two arms. About 41% of patients randomized were at low risk for systemic thromboembolism, with a CHADS2 score of 0-1. About 76% of the patients had already been on vitamin K antagonists prior to randomization. Atrial fibrillation was paroxysmal in 36%, persistent in 9.6%, and permanent in 54.3% of the patients. The mean duration of follow-up was 311 days in the idraparinux arm, and 339 in the vitamin K antagonist arm. For patients receiving vitamin K antagonists, the INR was within the target range only 63% of the time spent on treatment.
The trial had to be terminated early due to excess bleeding in the idraparinux arm. At the time of cessation of the trial, idraparinux was noninferior to vitamin K antagonists for the primary efficacy outcome of all strokes and systemic embolism (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.39-1.30; p for noninferiority = 0.007). The rates of hemorrhagic stroke (0.3% in each arm), venous thromboembolic events (0.1% vs. 0.2%), myocardial infarction (0.8% vs. 0.6%), and total mortality (3.2% vs. 2.9%) were similar between the two arms.
There was a statistically significant increase in the incidence of clinically relevant bleeding with idraparinux compared with vitamin K antagonists (HR 1.74, 95% CI 1.47-2.06; p < 0.0001). There was also a higher incidence of fatal bleeding (0.7% vs. <0.1%), bleeding associated with a fall in hemoglobin ≥2 gm%, or necessitating transfusion of ≥2 U of blood (2.3% vs. 0.8%), intracranial hemorrhage (1.1% vs. 0.4%), and death from intracranial hemorrhage (0.6% vs. <0.1%). These differences seemed to become apparent about 2 months after initiation of treatment. On subgroup analysis, elderly patients (≥75 years old) and patients with renal insufficiency were at particularly higher risk of bleeding with idraparinux.
The results of this large, randomized trial indicate that idraparinux, a long-acting form of factor Xa inhibitory pentasaccharide, fondaparinux, is noninferior to traditional vitamin K antagonists in reducing stroke or systemic embolism in patients with nonvalvular atrial fibrillation. It is, however, associated with a significantly increased risk of clinically relevant bleeding, especially in elderly patients and those with renal failure.
Even in the controlled environment of this randomized trial, only 63% of the patients on vitamin K antagonists were within the target range for INR. This percentage is likely to be much lower in the real world, which underscores the need to develop safe and efficacious alternatives to these agents. Moreover, given the logistics involved in close monitoring of these patients, including some who need anticoagulation life-long, several agents, including thrombin inhibitors and antiplatelet agents, have been studied with an aim to discover safer, more practical agents that could be prescribed more widely.
Idraparinux, with a fixed once-a-week dose, and without the need for regular monitoring, was an exciting alternative. However, these results indicate that until such time that its bleeding risks are significantly reduced, without altering its efficacy, its routine use in patients needing anticoagulation for atrial fibrillation cannot be recommended.
The AMADEUS Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008;371:315-21.
Keywords: Vitamin K, Oligosaccharides, Polysaccharides, Coronary Artery Disease, Myocardial Infarction, Stroke, Thrombin, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Thromboembolism, Renal Insufficiency, Environment, Controlled, Intracranial Hemorrhages, Glomerular Filtration Rate, Embolism, Ventricular Dysfunction, Left, Hypertension, Diabetes Mellitus
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