ABILITY OF PROTHROMBIN COMPLEX CONCENTRATE (COFACT ®) TO REVERSE THE ANTICOAGULANT EFFECT OF NOVEL ANTITHROMBOTIC AGENTS

In recent years a large number of new antithrombotic agents has been developed
and tested in clinical trials and many of these new agents will become
available for clinical practice in the very near future. However, there is no
antidote available for these agents if immediate reversal of their effect is
required, e.g. in case of bleeding or when emergency surgery or invasive
procedures is indicated.
Based on its general pro-hemostatic potential, prothrombin complex concentrate
may be effective in (completely or partially) reversing the anticoagulant
effect of these new antithrombotic agents.

Study question
What is the effect of a single administration of prothrombin complex
concentrate (CoFact) on the anticoagulant effect of a novel oral thrombin
inhibitor (Dabigatran) and a novel oral factor Xa inhibitor (Rivaroxaban) in
healthy human subjects?

Study design
The study will be performed as a double blind cross-over study. Two groups of 6
healthy human subjects will be enrolled (group 1 and 2). 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.

Administration of Rivaroxaban or Dabigatran
Administration of Prothrombin Complex Concentrate or Placebo

Subjects will be screened and instructed. They 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 administer Cofact or saline and can be used 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.
Risk of rivaroxaban and dabigatran is related to the anticoagulant effect and
volunteers will be instructed to avoid trauma (for example contact sports). The
collection of blood will be done as much as possible from the i.v. line.
Separate venipunctures may be associated with limited inconvenience.