Charles V Pollack1, Paul A Reilly, John Eikelboom, Stephan Glund, Peter Verhamme, Richard A Bernstein, Robert Dubiel, Menno V Huisman, Elaine M Hylek, Pieter W Kamphuisen, Jörg Kreuzer, Jerrold H Levy, Frank W Sellke, Joachim Stangier, Thorsten Steiner, Bushi Wang, Chak-Wah Kam, Jeffrey I Weitz. 1. From Pennsylvania Hospital, Philadelphia (C.V.P.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (P.A.R., R.D., B.W.); McMaster University (J.E., J.I.W.) and Thrombosis and Atherosclerosis Research Institute (J.I.W.) - both in Hamilton, ON, Canada; Boehringer Ingelheim Pharma, Biberach (S.G., J.S.) and Ingelheim (J.K.), Klinikum Frankfurt Höchst, Frankfurt am Main, and Heidelberg University Hospital, Heidelberg (T.S.) - all in Germany; University of Leuven, Leuven, Belgium (P.V.); Northwestern University, Chicago (R.A.B.); Leiden University Medical Center, Leiden (M.V.H.), and University Medical Center Groningen, Groningen, (P.W.K.) - both in the Netherlands; Boston University School of Medicine, Boston (E.M.H.); Duke University Medical Center, Durham, NC (J.H.L.); Brown Medical School and Rhode Island Hospital, Providence, RI (F.W.S.); and Tuen Mun Hospital, Tuen Mun, NT, Hong Kong (C.-W.K.).
Abstract
BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required 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 determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required 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 determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS:Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
Authors: Mauro Molteni; Mario Bo; Giovanni Di Minno; Giuseppe Di Pasquale; Simonetta Genovesi; Danilo Toni; Paolo Verdecchia Journal: Intern Emerg Med Date: 2017-04-24 Impact factor: 3.397
Authors: Stuart J Connolly; Truman J Milling; John W Eikelboom; C Michael Gibson; John T Curnutte; Alex Gold; Michele D Bronson; Genmin Lu; Pamela B Conley; Peter Verhamme; Jeannot Schmidt; Saskia Middeldorp; Alexander T Cohen; Jan Beyer-Westendorf; Pierre Albaladejo; Jose Lopez-Sendon; Shelly Goodman; Janet Leeds; Brian L Wiens; Deborah M Siegal; Elena Zotova; Brandi Meeks; Juliet Nakamya; W Ting Lim; Mark Crowther Journal: N Engl J Med Date: 2016-08-30 Impact factor: 91.245