increased the bleeding rate when Vincristine leurocristine added to ximelagatran in patients with AF and to warfarin in patients with AF, a prosthetic heart valve, coronary artery disease, or peripheral vascular disease. 82,317,380 The added effects on bleeding when aspirin is combined with dabigatran etexilate were explored in the Prevention of Embolic and Thrombotic Events in Patients With Persistent Atrial Fibrillation trial, a phase 2, parallel group, randomized, doseranging safety study in 502 patients with nonvalvular AF who also had coronary artery disease and/or one or more other risk factors for systemic embolism.
The patients received 12 weeks of treatment with openlabel warfarin alone or with blinded 50 mg, 150 mg, or 300 mg dabigatran etexilate bid plus daily aspirin or a placebo, using a 3 3 3 factorial design to allocate study treatments to patient groups of unequal size. Aspirin increased the chances of major or clinically signifi cant nonmajor bleeding in patients given a supratherapeutic dabigatran dose of 300 mg bid, in whom the bleeding rate was 20% with an aspirin dose of 325 mg/d, 14.7% if the dose was 81 mg/d, and 5.7% in patients given the aspirin placebo. The trends reached statistical signifi cance when the two aspirin groups were pooled. Bleeding risk was not apparently raised when aspirin was added to 50 mg or 150 mg doses of dabigatran, but the sample size was too small to exclude clinically important effects. Low doses of aspirin were permitted in the Randomized Evaluation of Long term Anticoagulant Therapy and Dabigatran in the Treatment of Venous Thromboembolism phase 3 studies of dabigatran etexilate, which compared bid doses of 110 mg and/or 150 mg with warfarin, but subgroup analyses of bleeding risk are not yet available. 381,382 Product information recommends against the combination of dabigatran etexilate with clopidogrel and other thienopyridines, given alone or as dual antiplatelet therapy with aspirin. 2.4 Antithrombotic Effects: A number of recent phase III clinical trials have evaluated the use of dabigatran etexilate for the prevention and treatment of VTE and to prevent systemic embolism in nonvalvular AF.
A phase II study explored its dose response in acute coronary syndromes. The effi cacy and safety of anticoagulant prophylaxis for VTE depends in any given patient population on the dose, timing, duration, and choice of drug therapy. The VTE prevention trials of dabigatran etexilate have evaluated two once daily dabigatran dosing regimens in patients having elective hip or knee arthroplasty: 150 mg/d or 220 mg/d, beginning soon after surgery with a half dose of 75 mg or 110 mg. In addition, these two dabigatran regimens were compared with one ATM Protein of two standard enoxaparin prophylaxis regimens: 40 mg/d starting on the evening before surgery, or 30 mg bid starting 12 to 24 h after surgery. Two of the trials compared both of these dabigatran regimens with the 40 mg/d schedule of enoxaparin in hip or knee arthroplasty, 383,384 one compared both of the dabigatran regimens with 30 mg enoxaparin bid after knee arthroplasty, 385 and one compared only the 220 mg/d dabigatran etexilate regimen with enoxaparin 40 mg/d in hip arthroplasty. 386 In all prophylaxis studies, the primary measure of treatment effectiveness was the rate of.