Oral anticoagulation with the direct thrombin inhibitor dabigatran etexilate

Prof. Dr. Brückmann, Martina. Boehringer Ingelheim Pharma GmbH & Co. KG Medical Science Department, Binger Straße 173, 55216 Ingelheim am Rhein, Germany.

The direct thrombin inhibitor dabigatran etexilate (Pradaxa®) has been approved for the prevention of venous thromboembolism (VTE) after elective hip and knee replacement, with the pivotal trials RENOVATE (3494 patients), and REMODEL (2076 patients) completed. Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran has been shown to specifically and reversibly inhibit thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen without the need of laboratory monitoring. Peak plasma concentrations of dabigatran (C max) are reached approximately two hours after oral administration in healthy volunteers, with no drug accumulation even at five fold higher doses than those currenty approved for VTE prevention. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. Additional studies have shown that the pharmacokinetic/pharmacodynamic profile of dabigatran is consistent across a broad range of patient populations. The pharmacodynamic profile of dabigatran demonstrates effective anticoagulation combined with a low risk of bleeding. Within the REVOLUTION study program further phase III studies are ongoing, including stroke prevention in patients with nonvalvular atrial fibrillation (RE-LY, 18114 patients included), acute treatment of deep-vein thrombosis and pulmonary embolism and prevention of cardiac events in patients with acute coronary syndromes. The results obtained so far show that dabigatran etexilate is well tolerated and effective in the prevention of thromboembolic events. With the RE-LY study completed in 2009, dabigatran etexilate may represent an attractive alternative to vitamin K antagonists for patients with atrial fibrillation in the near future.