Prothrombin Works as Antidote to Rivaroxaban, Not Dabigatran

Download this article's Factoid in PDF (& PPT for Gold Subscribers)

A concentrated form of prothrombin complex appears to rapidly and permanently reverse the effects of the novel anticoagulant rivaroxaban, a factor Xa inhibitor. But according to results of a small study published online September 6, 2011, ahead of print in Circulation, the same treatment does not reverse the direct thrombin inhibitor dabigatran.

Just last week, a US Food and Drug Administration advisory panel voted to recommend approval of rivaroxaban (Xarelto, Bayer, Leverkusen, Germany) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Dabigatran (Pradaxa, Boehringer-Ingelhiem, Ridgefield, CT) was approved for this indication in October 2010.

But a drawback is the absence of an antidote for either agent, a problem in the event of major bleeding or emergency surgery. Seeking such a substance, investigators led by Elise S. Eerenberg, MD, of Academic Medical Center (Amsterdam, The Netherlands), evaluated a formulation of concentrated prothrombin (Cofact, Sanquin Blood Supply, Amsterdam, The Netherlands) in 12 healthy male volunteers. Subjects were randomized in a crossover design to receive rivaroxaban (20 mg twice daily) or dabigatran (150 mg twice daily for 2.5 days), followed by either a single bolus of prothrombin concentrate (50 IU/kg) or a similar volume of saline. After an 11-day washout period, subjects received the opposite anticoagulant treatment following the same protocol.

Immediate Rivaroxaban Reversal Seen

Rivaroxaban use lengthened prothrombin time compared with baseline (15.8 ± 1.3 seconds vs. 12.3 ± 0.7 seconds; P < 0.001). Prothrombin time was then immediately and completely reversed by the concentrated prothrombin formulation (12.8 ± 1.0 seconds; P < 0.001). This action was sustained for 24 hours. In contrast, saline infusion did not reverse the prothrombin time after rivaroxaban use (16.2 ± 0.8 seconds; P = 0.4), and the lack of effect was still apparent 6 hours later.

Endogenous thrombin potential also was inhibited by rivaroxaban (51 ± 22% vs. 92 ± 22% at baseline; P = 0.002) and normalized by prothrombin concentrate use (114 ± 26%; P< 0.001), whereas saline had no effect.

Dabigatran use, meanwhile, lengthened the activated partial thromboplastin time (59.4 ± 15.8 seconds vs. 33.6 ± 3.3 seconds at baseline; P < 0.001), ecarin clotting time (69 ± 26 seconds after 3 days of dabigatran intake vs. 33 ± 1 seconds at baseline; P = 0.002), and thrombin time, which remained above 120 seconds in all subjects. But in this group, neither concentrated prothrombin nor saline reversed anticoagulation.

There were no major or clinically relevant bleeding complications during treatment, and no other serious adverse events occurred.

Other Options Needed for Dabigatran

According to the study authors, the rivaroxaban findings are consistent with previous research using animal models, but more research is required to determine whether a concentrated prothrombin dose lower than 50 IU/kg could be equally effective.

With regard to dabigatran, however, there is no evidence to support prothrombin use to neutralize its anticoagulant effect, they say.

“The question of how the effect of dabigatran can be antagonized remains unanswered,” Dr. Eerenberg and colleagues write. Although some animal data suggest recombinant factor VIIa is a possible candidate, other strategies include repeated administration of concentrated prothrombin or combining the 2 antidotes. Such methods have yet to be studied, they add.

Study Details

Subjects were an average of 24.4 years, with a mean body mass index of 23 ± 3 kg/m². All had normal blood count, kidney function, and liver function. They were negative for hepatitis B and C as well as HIV. The prothrombin formulation contains a high concentration of the procoagulation factors II, VII, IX, and X, as well as the natural anticoagulants protein C and S and antithrombin.

 

---

Source:
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;Epub ahead of print.

 

 

Related Stories:

• ROCKET AF Published: Rivaroxaban Matches Warfarin in Treating A-Fib Patients
• Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients
• Novel Anticoagulant Increases Bleeding, Reduces Ischemic Outcomes in ACS