Warfarin Replacements: Good for Patients, Challenging for Laboratories

Warfarin's monopoly on oral anticoagulation therapy, as well as that of other vitamin K antagonists derived from coumarin, is over. Two new classes of drugs, oral direct thrombin inhibitors (DTI)2 and oral direct factor Xa inhibitors (DFXaI), are steadily obtaining regulatory approval for prevention of thromboembolic events in patients who have atrial fibrillation, undergo hip or knee replacement surgery, or require treatment of pulmonary emboli and deep vein thromboses. The results from an expanding list of large, well-conducted randomized clinical trials confirm the efficacy and safety of DTI and DFXaI drugs as noninferior or superior to standard prophylactic or therapeutic anticoagulation therapies (1). Presently, the US Food and Drug Administration (FDA) and regulatory agencies in other countries have approved one DTI (dabigatran etexilate, Pradaxa®) and two DFXaI (rivaroxaban, Xarelto®; apixaban, Eliquis®) for one or more indications, and clinical trials that were recently completed or are underway will likely bring more drugs in these two classes to market with approval for additional indications (2).The common mechanism of action of these small molecules is reversible blockage of the active enzyme site of thrombin or factor Xa. Thrombin converts fibrinogen to fibrin, and factor Xa converts the zymogen prothrombin to thrombin. Inhibition of either coagulation factor reduces the rate of fibrin clot formation. Unlike warfarin or heparin, DTI and DFXaI activities are not dependent on decreased synthesis of coagulation factors or acceleration of the effects of antithrombin, an endogenous inhibitor of thrombin and factor Xa.DTI and DFXaI have many advantages compared with coumarins, including rapid onset of anticoagulation, no dietary restrictions, few drug–drug interactions, and more predictable pharmacokinetics. As a result, they are prescribed as fixed doses without adjustments on the …