The Food and Drug Administration has approved dabigatran for the prevention of deep venous thrombosis and pulmonary embolism for patients after hip replacement surgery.
The FDA’s approval was based on the results of two randomized, double-blind, phase III trials in patients undergoing total hip replacement, Boehringer Ingelheim, the manufacturer of the direct thrombin inhibitor, announced.
In RE-NOVATE I, the first trial, 3,494 patients were randomly assigned to three groups receiving prophylactic treatment with one of two doses of dabigatran (220 mg or 150 mg) once daily, or to the low-molecular-weight heparin enoxaparin at 40 mg once daily for 28-35 days. The first study drug arm was given 110 mg on the day of surgery and 220 mg daily thereafter; the second study drug arm received a dose of 75 mg on the day of surgery and 150 mg daily thereafter. Patients taking the dabigatran (Pradaxa) at 220 mg had a lower composite total of venous thromboembolism (VTE) and all-cause mortality (6.0%) than did those on enoxaparin 40 mg (6.7%), meeting the noninferiority mark (Lancet. 2007 Sep 15;370[9591]:949-56).
In RE-NOVATE II, 2,055 patients were randomly assigned prophylactic treatment for 28-35 days with the study drug dosed at 220 mg once daily, or enoxaparin 40 mg once daily. Patients receiving the study drug were treated with a dose of 110 mg on the day of surgery and 220 mg daily thereafter. The composite total of VTE and all-cause death occurred in 7.7% of patients in the study group vs. 8.8% of patients in the enoxaparin group, which was within the margin for noninferiority (Thromb Haemost. 2011 Apr;105[4]:721-9).
However, there were higher rates of major bleeding in RE-NOVATE I (2.0%, 1.6%) and II (1.4%, 0.9%) with 220 mg vs. enoxaparin. In both studies, the rate of major gastrointestinal bleeds in patients was the same (0.1%) for both the study and control drugs. The rate of any GI bleeds was 1.4% for the study drug and 0.9% for enoxaparin. The most common adverse events in both studies were GI disorders. The incidence rate was the same across all treatment groups (39.5%). Dyspepsia occurred more frequently in patients receiving the study drug (4.1%), compared with those taking enoxaparin (3.8%). Gastritislike symptoms were less common in patients receiving the study drug (0.6%), compared with enoxaparin (1.0%). Clinical myocardial infarction was reported in two (0.1%) study patients and six (0.3%) enoxaparin patients.
Pradaxa was initially indicated by the FDA in 2010 to reduce stroke and systemic embolism risk in patients with nonvalvular atrial fibrillation. In 2014, the FDA approved two additional indications for the drug for the treatment of VTE in patients treated with a parenteral anticoagulant for 5-10 day and to reduce the risk of recurrent VTE in patients who have been previously treated.
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