Idarucizumab for Dabigatran Reversal — The RE-VERSE AD Trial

Posted by • August 5th, 2015

The RE-VERSE AD Trial Insight Post 8-4-15Despite the increasing frequency of direct oral anticoagulant use, some clinicians may remain uncertain about their safety. Direct oral anticoagulants are easier to use, and for certain patients they may have a decreased risk of bleeding. But there is one major concern: how to rapidly reverse the effects of direct oral anticoagulants when there is an urgent indication for hemostasis. In this week’s issue of NEJM, Pollack et al. present early results that may ease physician doubts about using this new class of drugs.

RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) is an ongoing prospective cohort study on the use of idarucizumab to reverse the effects of the oral thrombin inhibitor dabigatran. Idarucizumab is a monoclonal antibody fragment that acts by binding dabigatran with very high affinity. This multicenter trial is enrolling two classes of patients taking dabigatran: (1) those who develop life-threatening bleeding judged to require anticoagulation reversal, and (2) those who require an urgent invasive procedure for which normal hemostasis is required.

All trial participants received 5 grams of intravenous idarucizumab. Blood samples were drawn at regular intervals to assess for percentage reversal of dabigatran, calculated via use of dilute thrombin time or ecarin clotting time. Adverse events and clinical endpoints relating to bleeding and hemodynamic stability were followed as well. While the study authors aim to enroll up to 300 patients, this week they report on interim results from the first 90 patients enrolled from June 2014 to February 2015.

RE-VERSE AD found that the effects of dabigatran were completely reversed in 88 to 98% percent of anticoagulated patients receiving idarucizumab. For patients admitted with bleeding, median time to cessation of bleeding was 11.4 hours. For those undergoing urgent procedures, 92% were reported to have normal intraoperative hemostasis after receiving idarucizumab. There were five thrombotic events.

When we think about how to treat the next patient on dabigatran who presents with gastrointestinal hemorrhage, RE-VERSE AD provides us with two points to consider. First, the clinical breakthrough: we may soon have a drug that has been shown to effectively reverse the effects of dabigatran. Second, the unalterable reality of studying this breakthrough: because of ethical considerations, RE-VERSE AD does not include a control group.

RE-VERSE AD provides us with groundbreaking results that have a high potential to inform clinical decision making, but with an asterisk. In the accompanying editorial Dr. Ken Bauer expresses cautious optimism about the convincing effectiveness and safety profile of idarucizumab. However, to ensure ideal hemostatic outcomes as well as high-value idarucizumab utilization, he advocates for the development of clear clinical pathways and wider use of appropriate laboratory measurements of direct oral anticoagulant activity.

While continued work in this area may be needed, physicians considering prescribing dabigatran can begin to feel reassured that when serious bleeding occurs, an antibody that quickly reverses dabigatran’s effects may soon be available.

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