Prothrombin complex concentrate (Cofact ®) as a potential antidote for novel anticoagulants Dabigatran and Rivaroxaban.

An investigator initiated double blind cross-over study of the activation and inhibition of coagulation in healthy males who receive either Cofact or placebo after the administration of a novel anticoagulant. The two novel anticoagulants given are Dabigatran and Rivaroxaban. Blood samples will be collected at set times to assess coagulation assays.

Based on its general pro-hemostatic potential, prothrombin complex concentrate may be effective in (completely or partially) reversing the anticoagulant effect of the new antithrombotic agents Dabigatran and Rivaroxaban.

Subjects will start their oral medication at day -2. They will be admitted to the study ward on day 0. An i.v. catheter will be placed to withdraw blood samples. Blood samples are collected at the following times:

T= day -2 (before starting the oral anticoagulants), T= 0 (before the administration of Cofact/ Saline), and after the administration of Cofact/Saline at T= 15 min, 30 min, 60 min, 120 min, 240 min, 360 min and at 24 hrs.

The following assays will be performed: aPTT, PT, thrombin time (TT), Ecarin-clotting time (ECT), endogenous thrombin potential (ETP), prothrombin activation fragment F1+2, thrombin-antithrombin complex, thrombelastography, anti-factor Xa (in case of rivaroxaban), anti-factor IIa (in case of dabigatran).

Subjects will be divided into two groups. Subjects in group 1 will take Dabigatran 2dd 150 mg on day -2, -1 and 0. Subjects in group 2 will take Rivaroxaban 2dd 20 mg on day -2, -1 and 0. After the fifth dose (on day 0) subjects will be randomized to receive Cofact ® (50 U/kg) or a similar volume of Saline as a single bolus dose i.v. over 15 minutes. After a 10 day wash-out period the procedure is repeated but the alternative treatment (Saline of Co-fact) is administered.