Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects

Study Questions:

What is the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of rivaroxaban or dabigatran?


The authors reported the results of a randomized, double-blind, placebo-controlled, crossover trial in 12 healthy male subjects receiving rivaroxaban 20 mg twice daily (n = 6) or dabigatran 150 mg twice daily (n = 6) for 2.5 days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period of 11 days, the groups were crossed over, and the protocol repeated. Anticoagulant effect of rivaroxaban was assessed with prothrombin time (PT) and thrombin generation, as measured by the endogenous thrombin potential (ETP). Dabigatran effect was measured by activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and thrombin time (TT). Results analysis included paired t-tests with repeated measures with ANOVA for validation. Comparison between groups was analyzed with independent-sample t-tests.


The authors reported that PT was prolonged by rivaroxaban (15.8 ± 1.3 vs. 12.3 ± 0.7 seconds at baseline; p < 0.001) that was immediately reversed by PCC (12.8 ± 1.0; p < 0.001). ETP was inhibited by rivaroxaban (51 ± 22%; baseline, 92 ± 22%; p = 0.002) and normalized with PCC (114 ± 26%; p < 0.001). No effect was seen with saline placebo. There was a significant, immediate increase in aPTT, ECT, and TT by dabigatran. PCC had little effect on these parameters after dabigatran.


The authors concluded that PCC immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects, but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.


This very important study is a systematic attempt to answer an essential question regarding the two newest, currently Food and Drug Administration (FDA) approved anticoagulants for clinical use in this country. Rivaroxaban, an Xa inhibitor, is currently FDA approved for venous thromboembolism (VTE) prophylaxis after surgery, but has proven efficacy in large randomized trials for the treatment of VTE and thromboprophylaxis in atrial fibrillation. Dabigatran is a direct thrombin inhibitor currently FDA approved for thromboprophylaxis in atrial fibrillation, but with proven efficacy in large randomized trials for the treatment of VTE and for VTE prophylaxis. Both agents are associated with dramatically, significantly lower rates of intracranial hemorrhage. Both agents require no monitoring, due to highly predictable pharmacokinetics and pharmacodynamics. Unfortunately, neither has clearly efficacious or well studied methods for either measuring anticoagulant status or reversal of anticoagulant effect. The current study goes a long way toward both establishing that the metrics used to measure effect of both agents were clearly abnormal at clinically indicated dosages. Reassuringly, PCC effectively, immediately, and completely normalized all clotting parameters used for rivaroxaban. Although the clotting parameters measured for dabigatran clearly identified the anticoagulant effect, disturbingly, PCC appeared to have no effect on any of these parameters for dabigatran. As these agents are rapidly adopted for clinical use, and indications approved by the FDA expand, the need to assess and reverse their effect will be increasingly important. At this point, highly effective solutions are identified for rivaroxaban, while dabigatran remains without any identified reversal agent. Further evaluation is desperately needed, given the widespread indications for these agents.

Keywords: Prothrombin Time, Partial Thromboplastin Time, Thrombin Time

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