SUMMARY: The FDA on October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®) for the treatment of patients treated with Dabigatran (PRADAXA®), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention.
To address this concern, the RE-VERSE AD study was conducted to evaluate the efficacy and safety of Idarucizumab, to reverse the anticoagulant effects of PRADAXA®, in patients who had serious bleeding (Group A) or required an urgent surgical procedure (Group B). PRAXBIND® (Idarucizumab) is a humanized monoclonal antibody fragment with high affinity for both free and thrombin-bound PRADAXA® and neutralizes the anticoagulant activity of PRADAXA®. In this prospective cohort study, results from the first 90 patients enrolled in the study were presented (Interim analysis). Group A included 51 patients and Group B included 39 patients and PRAXBIND® 5 grams IV was administered, to reverse the anticoagulant effects of PRADAXA®. The median age was 76 years and the median creatinine clearance was 58 ml/minute. The primary end point was the maximum percentage reversal of the anticoagulant effect of PRADAXA® within 4 hours after the administration of PRADAXA®, based on the dilute thrombin time or ecarin clotting time. An important secondary end point was the restoration of hemostasis. Among the patients with an elevated dilute thrombin time and ecarin clotting time at baseline, the median maximum percentage reversal was 100% and this benefit was seen within minutes after the first infusion with PRAXBIND®. The median time to restoration of hemostasis in Group A was 11.4 hours. In Group B, normal intraoperative hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of PRAXBIND®.
The authors concluded that PRAXBIND® was, within minutes, able to completely reverse the anticoagulant effect of PRADAXA®. This reversal agent will fulfill an unmet need and with the availability soon of Factor Xa inhibitor antidotes, it is anticipated that Health Care Providers will be more willing to replace COUMADIN® with the Newer Oral Anticoagulants. Idarucizumab for Dabigatran Reversal. Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015; 373:511-520