Idarucizumab for Dabigatran Reversal — Full Cohort Analysis
Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., Joanne van Ryn, Ph.D., John W. Eikelboom, M.B., B.S., Stephan Glund, Ph.D., Richard A. Bernstein, M.D., Ph.D., Robert Dubiel, Pharm.D., Menno V. Huisman, M.D., Ph.D., Elaine M. Hylek, M.D., Chak-Wah Kam, M.D., Pieter W. Kamphuisen, M.D., Ph.D., Jörg Kreuzer, M.D., Jerrold H. Levy, M.D., Gordon Royle, M.D., Frank W. Sellke, M.D., Joachim Stangier, Ph.D., Thorsten Steiner, M.D., Peter Verhamme, M.D., Bushi Wang, Ph.D., Laura Young, M.D., and Jeffrey I. Weitz, M.D.
N Engl J Med 2017; 377:431-441August 3, 2017DOI: 10.1056/NEJMoa1707278
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Background
Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran.
Methods
We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures.
Results
A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.
Conclusions
In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.)
Supported by Boehringer Ingelheim.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on July 11, 2017, at NEJM.org.
We thank Campbell Joyner, M.D. (Sunnybrook Health Sciences Center, Toronto), and Renato Lopes, M.D. (Duke University, Durham, NC), for their service on the RE-VERSE AD Clinical Events Adjudication Committee.
Source Information
From Thomas Jefferson University, Philadelphia (C.V.P.); Boehringer Ingelheim, Ridgefield, CT (P.A.R., R.D., B.W.); Boehringer Ingelheim, Biberach (J.R., S.G., J.S.), Boehringer Ingelheim, Ingelheim am Rhein (J.K.), Klinikum Frankfurt Höchst, Frankfurt (T.S.), and Heidelberg University Hospital, Heidelberg (T.S.) — all in Germany; McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (J.W.E., J.I.W.); Feinberg School of Medicine, Northwestern University, Chicago (R.A.B.); Leiden University Medical Center, Leiden (M.V.H.), and Tergooi Hospital, Hilversum (P.W.K.) — both in the Netherlands; Boston University School of Medicine, Boston (E.M.H.); Tuen Mun Hospital, Hong Kong (C.-W.K.); Duke University School of Medicine, Durham, NC (J.H.L.); Middlemore Hospital (G.R.) and the University of Auckland (L.Y.) — both in Auckland, New Zealand; Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence (F.W.S.); and KU Leuven, Center for Molecular and Vascular Biology, Leuven, Belgium (P.V.).
Address reprint requests to Dr. Pollack at Thomas Jefferson University, 1020 Walnut St., 6th Fl., Philadelphia, PA 19107, or at [email protected].