An antidote for one commercially available novel oral anticoagulant (NOAC) proved safe and effective in an interim analysis of a nonrandomized study, researchers reported online June 22 in the New England Journal of Medicine. Don’t pop the cork on the champagne just yet, though.
Two types of NOACs have been approved by the FDA to reduce the risk of stroke in patients with nonvalvular atrial fibrillation and as a preventative and treatment for venous thromboembolism: one is a direct thrombin inhibitor and the other a factor Xa inhibitor. They provide an alternative to warfarin, which is a vitamin K antagonist, and don’t require the frequent monitoring that is needed with warfarin.
Warfarin’s anticoagulation can be reversed with vitamin K and other known treatments, while the NOACs to date have lacked a reversal agent. That poses a challenge when a patient on NOACs needs urgent surgery or experiences life-threatening bleeding. That risk is a deal-breaker for some physicians and has prompted manufacturers of NOACs to search for antidotes.
Charles V. Pollack, Jr., MD, of Pennsylvania Hospital in Philadelphia, and other participants in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) trial shared data on the first 90 patients in what has been designed as a 300-patient cohort study to assess the safety and efficacy of idarucizumab. The muliticenter study is expected to draw patients from 38 countries who receive the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) and either had serious bleeding (group A) or needed urgent surgery or a procedure (group B). Boehringer Ingelheim funded the study.
The interim analysis included 90 patients enrolled between June 2014 and February 2015. Each patient received 5 g of intravenous idarucizumab, which is a monoclonal antibody fragment that binds to dabigatran. The agent was administered in two doses within 15 minutes of each other. The primary endpoint was the maximum percentage reversal of anticoagulation up to four hours after the second infusion.
Patients with clotting in the normal range in baseline tests were excluded from the efficacy analysis. That left 40 patients in group A and 28 in group B assessed by dilute thrombin test and 47 in group A and 34 in group B assessed by ecarin-clotting-time testing for the efficacy results.
Based on those patients, the median maximum percentage reversal was 100 percent. In groups A and B, the dilute thrombin time was normalized in 98 percent and 93 percent, respectively, and the ecarin clotting time was normalized in 89 percent and 88 percent.
The median reported time for bleeding to stop in group A was 11.4 hours, although that was a challenging metric to perform in some circumstances: 18 patients had intracranial bleeding, for instance.
One patient in group B who had an overdose of dabigatran did not require emergency dialysis after receiving idarucizumab. Two others were deemed too unstable for procedures. Normal hemostasis was achieved in 92 percent of who underwent procedures; the remaining were considered mildly or moderately abnormal.
One patient who had not had dabigatran reinitiated had a thromboembolic event within 72 hours of receiving idarucizumab. Nine patients in each group died.
In an accompanying editorial, Kenneth A. Bauer, MD, of Beth Israel Deaconess Medical Center in Boston, called the results convincing. He pointed out that the study was not randomized, which the researchers explained was based on the ethics of using a control group in these circumstances.
“Without a control group, it is difficult to assess the clinical benefit that is conferred by the administration of idarucizumab in patients with dabigatran-related bleeding,” Bauer wrote. Idarucizumab is one of several reversal agents for NOACs under development. He called for more studies that elucidate the clinical benefits of these agents.