The Hematologist

November-December 2015, Volume 12, Issue 6

Turning the Tide on Dabigatran-Associated Bleeding

Adam Cuker, MD, MS University of Pennsylvania, Philadelphia, PA
Deborah Siegal, MD, MSc, FRCPC Clinical Scholar, Division of Hematology and Thromboembolism
McMaster University, Hamilton, ON

Published on: October 19, 2015

Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520.

Dabigatran etexilate (dabigatran) is an oral direct thrombin inhibitor used for prevention and treatment of thromboembolism. Like all anticoagulants, bleeding is the major complication of treatment with dabigatran and can lead to serious morbidity or death.1,2 Until recently, there were no specific reversal agents to restore hemostasis for dabigatran-treated patients experiencing life-threatening bleeding or requiring urgent surgery. Idarucizumab is a monoclonal antibody fragment, which binds to dabigatran with high affinity and neutralizes its effect.3 In healthy volunteers treated with dabigatran, idarucizumab corrected coagulation test abnormalities and decreased dabigatran plasma concentration, establishing its potential as a specific reversal agent.

The RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study is an ongoing international multicenter prospective cohort study evaluating the efficacy and safety of idarucizumab (5 grams administered intravenously as two 2.5-gram boluses no more than 15 minutes apart) in dabigatran-treated patients presenting with overt uncontrolled or life-threatening bleeding, or requiring urgent surgery or invasive procedures within eight hours.4 Target enrollment is 300 patients. The primary efficacy endpoint is the maximum percentage reversal of the dilute thrombin time or ecarin clotting time (validated assays for measurement of dabigatran levels)5 within four hours of idarucizumab administration. Clinical outcomes include the extent of bleeding and hemodynamic stability (bleeding patients) and degree of hemostasis (surgical patients), which are evaluated by the treating clinician. Thrombotic events or death occurring within 90 days of idarucizumab administration are adjudicated by an independent committee.

Dr. Charles V. Pollack Jr. and colleagues recently reported an interim analysis of RE-VERSE AD after the first 90 patients (51 with acute bleeding and 39 requiring surgery/procedures) were enrolled.4 Subjects were predominantly elderly (median age, 76.5 years) and male (56%), with the majority (96%) receiving dabigatran for thromboprophylaxis in atrial fibrillation. Median creatinine clearance was 58 mL/min. The most common bleeding complication was gastrointestinal (22%) followed by intracranial (20%) and trauma-related (10%). The dilute thrombin time and ecarin clotting time were prolonged in 76 percent and 90 percent of patients, respectively. After idarucizumab administration, the median maximum percentage reversal of the dilute thrombin time and ecarin clotting time was 100 percent (95% CI, 100 to 100) in both patient groups. The reversal effect was evident within minutes of idarucizumab infusion. Four hours after treatment, the unbound dabigatran concentration was near the lower limit of quantification in 97 percent of patients. Dabigatran levels subsequently increased in 7 percent and 21 percent of patients at 12 and 24 hours, respectively. The median time to cessation of bleeding was 11.4 hours in 35 evaluable patients. Among surgical patients, normal intraoperative hemostasis was reported in 92 percent. Five patients experienced thrombotic events, and 18 patients died, including five fatal bleeds during 90-day follow-up.

Dr. Pollack and colleagues show that idarucizumab reverses the anticoagulant effect of dabigatran within minutes in bleeding patients and those requiring urgent surgery, as measured by laboratory endpoints. The clinical usefulness of idarucizumab, however, remains uncertain. The single-cohort prospective design of RE-VERSE AD was chosen due to ethical concerns in the absence of a proven alternative treatment. Without a control group with which to compare outcomes, this raises important questions regarding how to interpret efficacy and safety. Even if idarucizumab is demonstrated to improve clinical outcomes, selection of appropriate patients and dosing strategies may prove difficult in the absence of a readily available laboratory assay for measurement of dabigatran. Approximately one quarter of patients in RE-VERSE AD had no or negligible levels of circulating dabigatran at study entry, as confirmed by a normal dilute thrombin time, and would be unlikely to benefit from reversal. On the other hand, the rebound increase in dabigatran levels at 12 and 24 hours in some patients could reflect redistribution of extravascular dabigatran into the intravascular compartment and raises the possibility that such patients could benefit from additional idarucizumab infusion. There can be no question that idarucizumab rapidly corrects coagulation parameters in dabigatran-treated patients. It is hoped that completion of the full 300-patient study will shed light on whether this translates to improved clinical outcomes.

References

  1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
  2. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
  3. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-3562.
  4. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373:511-520.
  5. Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128-1139.

Conflict of Interests

Dr. Siegal has participated in advisory boards for Boerhinger Ingelheim, Daiichi Sankyo and Portola Pharmaceuticals. Dr. Cuker has no relevant conflicts of interest. back to top