By: Svetlana Akbasheva, Staff Editor
Dabigatran etexilate mesylate (Pradaxa®) is an oral anticoagulant that functions as a direct thrombin inhibitor. Like other anticoagulants, this medication carries the risk of serious bleeding and must be stopped temporarily before any surgical procedures, with the length of time depending on a patient’s creatinine clearance and invasiveness of the surgery.1 Until recently, there was no specific reversal agent for patients who experienced bleeding or needed emergency surgery while on dabigatran therapy. Now, Boehringer Ingelheim Pharmaceuticals, the manufacturer of Pradaxa®, has created an antidote that is capable of neutralizing the anticoagulant effect of dabigatran. A humanized monoclonal antibody fragment that exclusively binds dabigatran, idarucizumab was granted Orphan Drug and Breakthrough Therapy Designation by the FDA.2 Preliminary results from a Phase III trial published in June 2015 help elucidate the safety and efficacy of this antidote.3
The study of the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) is an international, multicenter, prospective cohort study assessing the safety and efficacy of idarucizumab in patients on dabigatran who present with severe bleeding or require emergency surgery. This is an ongoing study that began in June 2014 and plans to ultimately recruit up to 300 patients. Recently, the interim data for the first 90 enrolled patients was published. The patients were divided into two groups, group A (n=51) for patients who presented with serious bleeding and group B (n=39) for those who required emergency surgery. Patients were administered a 5 gram dose of idarucizumab intravenously as 2 separate bolus infusions of 2.5 grams/50 mL no more than 15 minutes apart. The baseline patient characteristics of the study sample included a median age of 76.5, predominantly white race, and a median creatinine clearance of 58 mL/min (range 11-187 mL/min). 96% of study subjects were taking dabigatran for atrial fibrillation, and the median time since the last intake of dabigatran was 15.4 hours. The primary endpoint of the study was the maximal percentage reversal of dabigatran’s anticoagulant effect within 4 hours of antidote administration. Only patients with a baseline elevated dilute thrombin time (76%) or ecarin clotting time (90%) were included in the primary efficacy analysis. Secondary endpoints that were studied included restoration of hemostasis as well as general clinical outcomes as judged by clinicians.3
The results of the interim data showed a median maximal percentage reversal of anticoagulation in both groups to be 100%. In group A, the dilute thrombin time normalized in 98% and ecarin clotting time normalized in 89% of patients. In group B, these numbers were 93% and 88%, respectively. Out of 35 patients in Group A in whom time to bleeding cessation could be assessed, the median time to this secondary endpoint was 11.4 hours. In Group B, intraoperative hemostasis was achieved in 92% of patients. Although there were eighteen deaths in the study population during the one-month follow-up, these deaths were not attributed to the antidote but rather to the index event or the patient’s existing comorbidities. Thrombotic events also occurred in five patients, with the occurrence ranging from 2 to 26 days after idarucizumab administration; however, it is notable that the patients were not receiving anticoagulant therapy at the time of these events.3 As this study was designed to mirror real-life clinical practice, there was no set protocol for reinitiating anticoagulant therapy in patients, so it is difficult to assess whether these patients should have been receiving anticoagulant therapy at the time of these events.
On October 16, 2015, the FDA approved idarucizumab under the brand name Praxbind®, making this the first approved reversal agent for a novel oral anticoagulant.4 Meanwhile, Portola Pharmaceuticals is currently in the testing phase of andexanet alfa, an antidote for the factor Xa inhibitors rivaroxaban (Xarelto®) and apixaban (Eliquis®).5 Ultimately, the development of antidotes for potentially dangerous drugs such as the anticoagulants enhances their safety profiles and is favorable for both patients and providers.
- Pradaxa (dabigatran etexilate mesylate) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2015.
- Idarucizumab reverses the anticoagulant effect of dabigatran within minutes in patient study. Boehringer Ingelheim. https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/ 22_june_2015_dabigatranetexilate.html. Published June 22, 2015. Accessed July 25, 2015.
- Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015 [Epub ahead of print]. Doi: 10.1056/NEJMoa1502000.
- FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. US Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm. Published October 16, 2015. Accessed November 19, 2015.
- Andexanet alfa: FXa inhibitor antidote. Portola Pharmaceuticals. http://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/. Accessed July 25, 2015.