Dabigatran, ROCKET Atrial Fibrillation, and Beyond

Abstract

For >50 years, vitamin K antagonists (eg, warfarin) were the only available oral anticoagulants. Warfarin, however, is associated with >10-fold interindividual variation in dose to achieve therapeutic anticoagulation. The pharmacokinetics and pharmacodynamics of warfarin are influenced by genetic polymorphisms (CYP 2C9 and VKORC1), dietary vitamin K intake, concomitant medications, alcohol use, patient age, body weight, and various disease states, necessitating regular coagulation monitoring to ensure that each patient’s international normalized ratio (INR) remains within the target range. New oral anticoagulants that selectively inhibit either thrombin or factor Xa, via reversible binding to their active enzymatic sites, have been developed. Thrombin plays a central role as a procoagulant by converting fibrinogen to fibrin as well as by activating its other substrates, including factor V, factor VIII, factor XI, factor XIII, and the platelet protease-activated receptors (PAR-1 and PAR-4). The substrate specificity of thrombin derives from specific surface binding sites (eg, exosite 1 for fibrin) for its substrates. Factor Xa is also an attractive target for the design of new anticoagulants because factor Xa is positioned at the start of the common pathway of coagulation. Dabigatran etexilate is an oral prodrug that is converted to dabigatran, a competitive direct thrombin inhibitor (Ki 4.5 nmol/L), by hydrolytic cleavage mediated by plasma esterases in vivo.1 It is not metabolized by the cytochrome P450 enzymes or oxidoreductases. Dabigatran etexilate has relatively low oral bioavailability and is encapsulated with tartaric acid to facilitate absorption in the gastrointestinal tract; consistent absorption of dabigatran etexilate, however, is not dependent on overall gastrointestinal acidity, and dose modifications are not required with the use of proton pump inhibitors. There is no specific antidote to reverse the anticoagulant effect of dabigatran; approaches for managing serious bleeding and monitoring the anticoagulant activity of the drug in such situations have been …