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

2. 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

3. 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)

4. 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

5. 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

6. 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

7. Results
Characteristics of the Patients

9. 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),

10. 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)

13. 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 hours)
the proportion of patients with intracranial bleeding (64% vs. 28%)

14. Dabigatran and Idarucizumab Concentrations

16. 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%).

18. 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

19. 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

20. 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