By Matthew E. Fink, MD

Professor and Chairman, Department of Neurology, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital

Dr. Fink reports he is a retained consultant for Procter & Gamble and Pfizer.

SOURCE: Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017;377:431-441.

Orally administered direct thrombin inhibitors, as well as Factor Xa inhibitors, have become important additions as anticoagulants to stroke prevention therapies in patients with atrial fibrillation. However, one of the major drawbacks has been the inability to reverse the antithrombotic effects during a bleeding emergency, such as trauma or intracranial hemorrhage. Prothrombin complex concentrate is recommended in guidelines to reverse the effects of these agents, but this treatment has never been proven to be effective. Dabigatran, a direct thrombin inhibitor, was the first new oral antithrombotic to be approved by the FDA, and is now the first to have an effective antidote for reversal of its antithrombotic effects. Pollack et al reported the details of the full cohort analysis of the use of the monoclonal antibody, idarucizumab, for reversal of this antithrombotic medication. This trial was a multicenter, prospective, open-label study to determine whether 5 mg of intravenous idarucizumab could reverse the anticoagulant effects of dabigatran in patients who had uncontrolled bleeding (Group A) or were about to undergo an urgent surgical procedure (Group B). The primary endpoint was the percentage reversal of the anticoagulant effects within four hours of administration of idarucizumab, on the basis of a dilute thrombin time or ecarin clotting time. Secondary endpoints were restoration of hemostasis and safety outcomes.

A total of 503 patients were enrolled in the study: 301 in Group A and 202 in Group B. The median percentage reversal of dabigatran was 100%. In Group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage. Median time to cessation of bleeding was 2.5 hours. In group B, the median time to initiation of the surgical procedure was 1.6 hours, and periprocedure hemostasis was normal in 93.4% of the patients. At 90 days of follow-up, thrombotic events occurred in 6.3% of patients in Group A and 7.4% in Group B. Ninety-day mortality was 18.8% and 18.9%, respectively. The mortality was attributed to the complex multi-organ failure that occurred in many of these critically ill patients. No serious adverse safety signals emerged related to the administration of this monoclonal antibody. In conclusion, the administration of idarucizumab is effective and safe for the reversal of the direct thrombin inhibitor, dabigatran, and should be used in appropriate clinical situations.