By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first reversal agent for a direct oral anticoagulant (DOAC). Idarucizumab is a humanized monoclonal antibody fragment derived from an IgG1 isotype molecule. The monoclonal antibody directly binds to dabigatran (Pradaxa), rapidly neutralizing its pharmacologic effect. The drug was approved under the FDA’s accelerated approval process. It is marketed as Praxbind by Boehringer Ingelheim.
Idarucizumab is indicated in patients treated with dabigatran when reversal of the anticoagulant effect is needed.1
The recommended dose is 5 g given as two consecutive intravenous infusions or as two consecutive bolus injections.1 Idarucizumab is available as 2.5 g vials.
Idarucizumab effectively reverses the anticoagulant effect of dabigatran1,2 and has minimal side effects.
Reversing the effect of dabigatran exposes patients to thromboembolic risk of their underlying disease.1 Elevated coagulation parameters have been observed between 12 and 24 hours after administration.1 Treatment-emergent, possibly persistent anti-idarucizumab antibodies were observed in 4% of subjects. The formulation contains sorbitol; thus, there is a risk of serious reaction in patients with hereditary fructose intolerance.1
The safety and efficacy of idarucizumab was evaluated in three trials in healthy volunteers (n = 283) and in one study in subjects taking dabigatran who received idarucizumab due to uncontrolled bleeding or requiring emergency surgery (n = 123, with n = 90 evaluable). Compared to placebo, the infusion of idarucizumab significantly reduced coagulation parameters (dTT, aPTT, ECT, TT, and ACT) at the end of the infusion. Reductions ranged from 51%-90% compared to no change for placebo. In the second study, subjects were divided into two groups. Fifty-one had serious bleeding (Group A) and 39 required an urgent procedure (Group B). The primary endpoint was the maximum percentage reversal of anticoagulation effect at any point from the end of the first infusion to 4 hours after the second administration. The median maximum percent reversal was 100%. The effect was evident within minutes. The secondary endpoints included the proportion of subjects who had complete normalization of the dilute thrombin time or ecarin clotting time in the first 4 hours and reduction in the concentration of unbound dabigatran. Dilute thrombin time was normalized in 98% of Group A and 93% in Group B and 89% and 88%, respectively, for ecarin clotting time.2 At 4 hours, 97% had dabigatran levels near the lower limit of quantification. Of the subjects in group B who underwent a procedure, 33 reported normal intraoperative hemostasis restored, with two mildly and one moderately abnormal. Thrombotic events occurred in five subjects ranging from 2 to 26 days after treatments. There were 18 deaths overall, with 10 due to vascular causes and five due to fatal bleeding events.2 Ten fatalities occurred within 96 hours of idarucizumab and the remaining ranged from 4 to 101 days. Early deaths appear to be related to the index event and later deaths to coexisting conditions.2 There is redistribution of dabigatran 12 hours after idarucizumab administration from extravascular compartment into the intravascular compartment.
Idarucizumab is the first agent to effectively reverse the anticoagulant effect of a DOAC. Lack of a reversal agent has been seen as a major drawback for administration of these drugs, especially in individuals who may be at higher risk of bleeding or falls. A reversal agent for the Xa inhibitors (rivaroxaban, apixaban, edoxaban) is in Phase 2 trials. Meanwhile, approval of idarucizumab gives Boehringer Ingelheim a marketing advantage for dabigatran over other DOACs. The wholesale cost is $3500 for a single administration (5 g).
- Praxbind Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. October 2015.
- Pollack CV Jr, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-520.