A New Anticoagulant for Atrial Fibrillation?
A New Anticoagulant for Atrial Fibrillation?
Abstract & Commentary
By John P. DiMarco, MD, PhD
Source:The Amadeus Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: A randomized, open-label, non-inferiority trial. Lancet. 2008;371: 315-321.
Anticoagulation with vitamin k antagonists is the standard recommendation for patients with nonvalvular atrial fibrillation and risk factors for stroke. The benefits of warfarin in such patients have been well shown in many clinical trials. Therapy with warfarin, however, is often complicated by the dietary and drug interactions, so that even with frequent monitoring, precise control of the anticoagulation level is difficult. Idraparinux is a synthetic pentasaccharide that specifically inhibits activated factor 10. Its pharmacologic properties are such that it may be administered as a fixed-dose, weekly subcutaneous injection without requirement for anticoagulation monitoring. The Amadeus Trial was a multicenter, randomized, open-label, non-inferiority study that compared fixed dose idraparinux with conventional anticoagulation with vitamin K antagonists for the prevention of thromboembolism in patients with atrial fibrillation.
Patients were eligible for inclusion in the Amadeus Trial if they had ECG documented nonvalvular atrial fibrillation and the presence of at least one of the following risk factors: previous ischemic stroke; transient ischemic attack or systemic embolism; hypertension; left ventricular dysfunction; age over 75; or age between 65 to 75 with either diabetes or symptomatic coronary disease. Major exclusion criteria included contraindications to anticoagulation, severe renal insufficiency (calculated creatinine clearance rate < 10 mL per minute), potential for pregnancy, or anticipated need for surgical procedures. Patients were randomized to receive either dose-adjusted treatment with a vitamin K antagonist (warfarin or acenocoumarol), with a target international normalized ratio (INR) of 2-3, or subcutaneous weekly injections of idraparinux, 2.5 mg. Patients with a calculated creatinine clearance between 10 and 30 mL per minute received reduced-dose maintenance therapy with idraparinux at 1.5 mg weekly. INR was determined at least once monthly in patients receiving vitamin K antagonists. The primary efficacy end point was a composite of all stroke or systemic embolism. The primary safety outcome was major bleeding. Major bleeding was defined as bleeding that was either fatal, intracranial, affected another critical anatomical site, resulted in a hemoglobin drop > 20 grams per liter, or required transfusion of two or more units of packed red blood cells. Clinically relevant, non-major bleeding was also recorded. All suspected outcome events were classified by a central adjudication committee unaware of treatment assignment.
A total of 8312 patients were assessed for eligibility and 4673 were eventually randomized. Ninety-seven patients from one center were excluded because of protocol violations. The final number of patients included in the trial was 4576. The trial was terminated before its scheduled completion when the Data Safety Monitoring Board detected excess bleeding in the idraparinux group.
The two treatment groups were well balanced. The mean age was 70.1 ± 9.1 years. Approximately two-thirds were men. An estimated creatinine clearance of less than 50 mL per minute was present in 18% of the patients in both groups. Using the CHADS2 scoring system, 41% had a CHADS2 score of 0 or 1, 31% had a CHADS2 score of 2, and 27% had a CHADS2 score > 3. Seventy-six percent of the patients had previously been anticoagulated with warfarin before study entry. Atrial fibrillation was paroxysmal in 36%, persistent in 10% and permanent in 54%. The mean duration of follow-up was 311 days in the idraparinux group and 339 days in the vitamin K antagonist group.
Idraparinux was not inferior to vitamin K antagonists in terms of the primary efficacy outcome (all stroke and systemic embolism with a hazard ratio of 0.71, 95% CI 0.39-1.30; P = 0.007 for non-inferiority). However, there was an excess of clinically relevant bleeding in the idraparinux group. Clinically relevant bleeding occurred in 19.7% of the patients in the idraparinux group vs 11.3% of the patients on vitamin K antagonists. The percentages for major bleeding (3.9% vs 1.4%), fatal bleeding (0.7% vs less than 0.1%), bleeding associated with a major fall in hemoglobin or requiring transfusion (2.3% vs 0.8%), and non-major clinically relevant bleeding (16.4% vs 10.3%) were all increased in the idraparinux group. Risk factors for increased bleeding on idraparinux therapy included advanced age, reduced creatinine clearance rates, and concomitant use of either aspirin or other antiplatelet agents.
The authors conclude that idraparinux was not inferior to vitamin K antagonists for prevention of stroke or non CNS systemic embolism, but that its use was associated with an increased risk for bleeding.
Commentary
Trials performed over the last 20 years have established vitamin K antagonists as the gold standard for anticoagulation therapy in patients with nonvalvular atrial fibrillation. However, therapy with vitamin K antagonists may be quite difficult. Up to one-third of the patients screened for the trials that established the efficacy of warfarin were excluded because they were thought at baseline to be at high risk for bleeding. During warfarin therapy, particularly in the first few months after initiation, bleeding is common, and it can be difficult to maintain the INR within the specified range in many patients. Warfarin has many interactions with dietary factors and other drugs, and frequent INR monitoring is inconvenient and expensive.
Unfortunately, alternatives to warfarin have not yet been able to resolve these problems. Just within the last three years, we have seen trials with combined antiplatelet therapy (aspirin plus clopidogrel in the ACTIVE-W trial) and with direct thrombin inhibitors (ximelagatran in the SPORTIF trials) that have failed to show those drugs to be safer than, and as effective as, warfarin. This study using an injectable drug, which could be given at weekly intervals, falls into the same category. Although the results in terms of the primary end point (stroke and systemic embolism) showed idraparinux to be non-inferior to warfarin, this was at a cost of increased major and minor bleeding, an unacceptable trade-off.
One of the problems with studies on prevention of stroke in atrial fibrillation is that the stroke rate is relatively low. This requires very large trials and, therefore, sponsors are reluctant to do large trials over a wide range of drug doses. Usually, a single dosage of the compound to be tested is used in the large pivotal trial, and this dose was selected based on relatively limited dose ranging studies in much smaller populations. Whether treatment with thrombin or factor 10 inhibitors will be successful may require companies to do large studies over a range of doses to optimize the risk benefit ratios with these compounds.
Anticoagulation with vitamin k antagonists is the standard recommendation for patients with nonvalvular atrial fibrillation and risk factors for stroke. The benefits of warfarin in such patients have been well shown in many clinical trials. Therapy with warfarin, however, is often complicated by the dietary and drug interactions, so that even with frequent monitoring, precise control of the anticoagulation level is difficult.Subscribe Now for Access
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