An interim analysis of the multicentre, prospective cohort phase III RE-VERSE AD patient study demonstrates that 5g of the antidote idarucizumab reversed the anticoagulant effect of dabigatran (Pradaxa, Boehringer Ingelheim) within minutes in patients with serious bleeding complications or requiring urgent procedures.
RE-VERSE AD (Reversal effects of idarucizumab on active dabigatran) is the first study investigating the effect of a specific reversal agent to a non-vitamin K oral anticoagulant (NOAC) with patients in a real-world setting. Results were presented by lead investigator Charles Pollack (Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, USA) at the International Society of Thrombosis and Haemostasis Congress (20-25 June, Toronto, Canada).
The results, published simultaneously in the New England Journal of Medicine (NEJM), demonstrated no safety concerns with the antidote.
Pollack told Cardiac Rhythm News: “This study is relevant in clinical practice because for the first time it has been shown that reversal of a NOAC is possible and safe in a population with high bleeding risks or requiring surgical procedures. We expect the remaining patients (210) will behave in the same way, and we will report on them as soon as possible.”
Pollack acknowledges that the proportion of dabigatran-treated patients requiring an antidote to reverse the effects of dabigatran due to major bleeding or surgical procedures, according to results from the RE-LY study (the largest study which compared dabigatran with warfarin), would be about 1.5% per year. “It is not really a high percentage of patients,” he said, however; “in those patients where major bleeding occurs it provokes clinical anxiety for the clinician and for the patient, so we have an opportunity here to try to demystify that situation and potentially make it more straightforward and streamlined for the physician managing the patient.”
Previous studies in healthy volunteers have demonstrated the potential of idarucizumab for immediate, complete and sustained reversal of dabigatran. This interim analysis of RE-VERSE AD included 90 patients (median age: 76.5 years) in emergency settings from among 184 sites in 35 countries who were taking dabigatran and required reversal with idarucizumab due to serious bleeding (N=51) or prior an emergent or urgent procedure (N=39). Pollack highlighted that more than 90% of the patients were receiving dabigatran for stroke prevention in the context of atrial fibrillation.
The study met its primary endpoint-defined as degree of reversal of the anticoagulant effect of dabigatran achieved by 5g idarucizumab within four hours measured by diluted thrombin time (dTT) and ecarin clotting time (ECT)-achieving 100% maximum reversal as median value across all patients (95% confidence interval, 100-100).
Pollack also reported that after four and 12 hours post-idarucizumab, laboratory tests showed normal coagulation levels in almost 90% of patients. Additionally, normal intraoperative haemostasis during surgery was reported in 92% of the patients who required surgery or invasive procedures.
The results also showed that thrombotic events occurred in five patients after reversal, none of whom were receiving antithrombotic therapy at the time of the event, Pollack noted. There were 18 deaths overall. Mortality within 96 hours of study enrolment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities.
In February and March 2015 idarucizumab was submitted under an accelerated approval pathway to the US Food and Drug Administration (FDA), European Medicines Agency and Health Canada for use in patients who require urgent reversal of dabigatran. The FDA granted idarucizumab both Orphan Drug and Breakthrough Therapy Designation.
Pollack commented that RE-VERSE AD is ongoing and that it is expecting to enrol 300 patients taking dabigatran from more than 400 centres in 38 countries worldwide.