Idarucizumab for Dabigatran Reversal: Approval and the RE-VERSE AD Trial

November 05, 2015
Chris Carter, Pharm.D.
Kylie Scimio, Pharm.D.

The increased use of dabigatran since its approval in 2010 has prompted the need for a reversal agent for patients experiencing life-threatening bleeding or needing urgent surgery. In response, Boehringer Ingelheim has developed idarucizumab, a monoclonal antibody fragment that binds free and thrombin-bound dabigatran and neutralizes its anticoagulant activity. Because of idarucizumab’s success in phase II trials, the company is currently conducting a phase III, multicenter, prospective cohort study called Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD).¹ An interim analysis including the study’s first 90 patients was published in the New England Journal of Medicine in August 2015. Idarucizumab was granted accelerated approval by the U.S. Food and Drug Administration in early October largely because of this analysis.

The analysis included adult patients taking dabigatran who required reversal because of overt bleeding or urgent surgery. Idarucizumab was given as two 2.5-g boluses within 15 minutes. The primary endpoint was the maximum percentage reversal of the thrombin time (TT) or ecarin clotting time (ECT) after the first infusion and for up to 4 hours after the second infusion. Secondary endpoints included the proportion of patients who had complete normalization of TT or ECT and the magnitude of reduction in the concentration of unbound dabigatran. Clinical outcomes included the time to cessation of bleeding and the proportion of patients with normal hemostasis during surgery. Adverse events, thrombotic events, and deaths occurring up to 90 days of follow-up were also recorded.

Patient included in the study were those older than 75 years who had mild renal impairment (median creatinine clearance 58 mL/minute/1.73 m²) and most were taking a dabigatran dose of 110 mg twice daily for non-valvular atrial fibrillation. The maximum percentage reversal was 100%. The TT was normalized in 93%–98% of patients in either group, and the ECT was normalized in 88%–89% of patients. The concentration of unbound dabigatran was less than 20 ng/mL (minimal anticoagulant effect) in the samples obtained after the first idarucizumab infusion in 98.5% of patients. The median time to cessation of bleeding was 11.4 hours, and 92% of patients who required surgery had normal hemostasis during the procedure. Eighteen percent of patients died as a result of their index event, and 8% of patients experienced thrombotic events. Twenty-three percent of patients experienced a serious adverse event. Study authors concluded that idarucizumab completely and rapidly reversed the anticoagulant effect of dabigatran and had no relevant safety concerns.

Key Points:

• Idarucizumab worked very well to bind dabigatran. It also normalized TT and ECT efficiently in most patients.
• Idarucizumab performed well based on surrogate laboratory endpoints, but clinical endpoints like time to cessation of bleeding (11.4 hours) and death rate (18%) were not overwhelmingly positive. In addition, the authors reported an 8% incidence of thrombotic events. This means that a risk of thrombotic events may exist, despite statements to the contrary.
• The interim analysis of RE-VERSE AD did not examine the use of medications that may affect the anticoagulant effect of dabigatran (P-glycoprotein inhibitors and inducers). Patient medication lists should be analyzed and interactions should be considered during decisions to reverse.
• Idarucizumab will likely be expensive, so maximizing efficacy and minimizing waste will be important considerations for individual patients and health systems. One potential cost-savings factor relates to the dose of idarucizumab required for reversal: RE-VERSE AD investigators used 5 g based on reported dabigatran concentrations from the RE-LY trial.² In this interim analysis, most patients had normal TTs and negligible concentrations of unbound dabigatran after the first infusion of 2.5 g.

Bottom Line:

Clinical pharmacists should prepare to recommend dosing of idarucizumab for appropriate indications in critical care settings. Clinicians should stay informed of emerging literature that addresses the lingering questions regarding clinical outcomes and appropriate dosage.

References:

1. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20.
2. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63:321-8.

Dr. Carter is a clinical pharmacy specialist in the intensive care unit at SSM Health St. Clare Hospital in Fenton, Missouri. His research and professional interests include thrombosis and hemostasis, sepsis, and cardiac arrest. Dr. Scimio is a PGY1 pharmacy practice resident at SSM Health St. Clare Hospital.

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