The NEW ENGLAND JOURNAL of MEDICINE Idarucizumab for Dabigatran Reversal R3 김동연 / F. 김선혜

Introduction Dabigatran etexilate (dabigatran) Idarucizumab non–vitamin K antagonist oral anticoagulants oral thrombin inhibitor prevention of stroke in patients with nonvalvular atrial fibrillation prevention and treatment of venous thromboembolism Idarucizumab monoclonal antibody fragment binds dabigatran with an affinity that is 350 times as high as that observed with thrombin Neutralizes Dabigatran ‘s activity

Prospective cohort study was undertaken to examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran in patients who presented with serious bleeding or who required urgent surgery or intervention present the results from the first 90 patients enrolled in the study of the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD)

Methods Study Design and Oversight Patients ongoing, multicenter, prospective cohort study plan to recruit up to 300 patients at more than 400 centers in 38 countries From June 2014 through February 2015 total of 90 patients (51 patients in group A and 39 in group B) were enrolled at 184 sites in 35 countries Patients 18 years of age or older taking dabigatran group A with overt, uncontrollable, or life-threatening bleeding group B required surgery or other invasive procedures that could not be delayed for at least 8 hours and for which normal hemostasis was required

Study Treatment Study End Points Patients received 5 g of intravenous idarucizumab administered as two 50-ml bolus infusions, each containing 2.5 g of idarucizumab, no more than 15 minutes apart Study End Points Blood samples for pharmacokinetic and pharmacodynamic assessments at baseline, after the first infusion of idarucizumab, and then between 10 and 30 minutes and at 1, 2, 4, 12, and 24 hours after the second infusion

Secondary end points primary end point maximum percentage reversal of the anticoagulant effect of dabigatran dilute thrombin time or ecarin clotting time percentage reversal = (predose test result – minimum postdose test result) (predose test result – upper limit of the normal range) Secondary end points proportion of patients who had complete normalization of the dilute thrombin time or ecarin clotting time in the first 4 hours reduction in the concentration of unbound dabigatran Clinical outcomes × 100

Results Characteristics of the Patients

Reversal of Anticoagulation 22 patients had dilute thrombin times to be within normal limits 9 patients (all of whom had normal dilute thrombin times) were found to have normal ecarin clotting times Excluded from the efficacy analysis because their baseline clotting tests were within the normal range median maximum percentage reversal in the patients in group A and in those in group B was 100% (95% confidence interval, 100 to 100),

Reversal of Anticoagulation median maximum percentage reversal patients in group A and in those in group B was 100% (95% confidence interval, 100 to 100)

Clearance of dabigatran is influenced by renal function 68 patients (with elevated results on the clotting tests at baseline) VS. 22 patients (with normal results) 48 ml per minute VS. 67 ml per minute longer time since the last dose of dabigatran (median, 12.8 hours vs. 30.3 hours) the proportion of patients with intracranial bleeding (64% vs. 28%)

Dabigatran and Idarucizumab Concentrations

Clinical Outcomes median investigator-reported time to the cessation of bleeding was 11.4 hours 36 patients in group B underwent urgent procedures, and normal intraoperative hemostasis was reported in 33 (92%).

Thrombotic Events and Serious Adverse Events occurred in five patients DVT, PTE, left atrial thrombus, NSTEMI, ischemic stroke None of these patients were receiving antithrombotic therapy when the events occurred A total of 21 patients (13 patients in group A and 8 in group B) had serious adverse events during study participation Gastrointestinal hemorrhage, postoperative wound infection, delirium, right ventricular failure, pulmonary edema

Discussion Strengths of this study Limitation Broad inclusion criteria simple study design Confirmation that normalization of the results of the coagulation tests reflected dabigatran reversal by determination of the concentrations of unbound drug Limitation lack of a control group

Conclusion Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88 to 98% of patients There were no safety concerns among the 90 patients involved in this study including patients who were given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline among the more than 200 volunteers who were administered idarucizumab in previous studies