The experimental drug idarucizumab quickly and effectively reversed the anticoagulant effect of dabigatran within minutes, according to results from an interim analysis presented at the International Society on Thrombosis and Haemostasis (ISTH) meeting by Charles Pollack Jr., MD, from the Hospital of the University of Pennsylvania in Philadelphia. The findings were simultaneously published in The New England Journal of Medicine. According to these findings, idarucizumab, a monoclonal antibody that binds to dabigatran to reverse its effects, can be considered the first “antidote” to one of the novel oral anticoagulants (NOACs).
Dabigatran is approved by the U.S. Food and Drug Administration (FDA) to prevent the risk of stroke in patients with nonvalvular atrial fibrillation and for the prevention and treatment of venous thromboembolism (VTE). These non-vitamin K antagonists are “generally safer than warfarin and provide similar or improved efficacy,” Dr. Pollack said in his presentation, “nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other interventions for which normal hemostasis is required.” In this event, dabigatran can increase the risk of perioperative bleeding, and, therefore, a dabigatran-reversal agent would be beneficial to this patient population.
Idarucizumab is an experimental drug not currently approved by the U.S. FDA, though it is currently under review through the Accelerated Approval Pathway, according to Dr. Pollack.
RE-VERSE AD, an ongoing phase III, multicenter, prospective, cohort trial for which Dr. Pollack and colleagues are investigators, seeks to determine the safety of 5 g of idarucizumab (administered intravenously) and its efficacy in reversing the anticoagulant effects of dabigatran in 90 patients who either experienced serious, overt, life-threatening bleeding that was judged by a treating physician to require a reversal agent (group A; n=51), or who required an urgent invasive procedure that could not be delayed for at least the eight hours required for normal hemostasis (group B; n=39). Patients are eligible for study inclusion if they are 18 years of age or older and taking dabigatran.
The study’s primary endpoint is the maximum percentage reversal of the anticoagulant effect of dabigatran within four hours after administration of idarucizumab. Dr. Pollack presented data from 90 patients in the interim analysis, though he noted that the researchers plan to enroll 300 patients by the end of the trial.
In both groups A and B, idarucizumab provided a median maximum reversal of 100 percent within four hours of its administration (95% CI 100-100).
After four hours, laboratory tests showed that idarucizumab also normalized clotting assay results for the majority of patients who had elevated dilute thrombin time (98% in group A; 93% in group B) or elevated ecarin clotting time (89% in group A; 88% in group B) at baseline.
In most cases, Dr. Pollack said, the reversal effect was evident within minutes, and the effect was durable, as well, with concentrations of unbound dabigatran staying below 20 ng/mL in 79 percent of patients after 24 hours.
“Clinical outcomes were quite good in this multi-morbid patient population,” Dr. Binder reported. Among the 35 patients in group A who could be assessed for restoration of hemostasis (the study’s secondary endpoint), hemostasis was restored at a median of 11.4 hours; for the 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33 patients, and mildly or moderately abnormal hemostasis was reported in two and one patient, respectively.
The experimental drug was generally well-tolerated. Twenty-one patients (13 in group A; 8 in group B) experienced serious adverse events, including gastrointestinal hemorrhage (n=2), postoperative wound infection, delirium, right ventricular failure, and pulmonary edema (n=1 for all).
Thrombotic events occurred in five patients, and 18 deaths occurred in the entire study population. Five of these deaths were attributed to bleeding events.
While idarucizumab appears to ameliorate dabigatran-induced bleeding disorders from the list of concerns with the NOAC, Dr. Pollack cautioned that idarucizumab is not truly an “antidote.” “In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ because the half-life of dabigatran is much shorter than that of warfarin,” he said. “But having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients.”
The researchers noted a major limitation of the study was the lack of a control group, though they commented it was deemed unethical to randomly assign patients to receive placebo in this patient population.
Although this is only an interim analysis, Dr. Pollack told ASH Clinical News, “The interim analysis is important, as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations. Availability of such an agent might improve the perception of safety among providers prescribing anticoagulation therapy for their patients with nonvalvular atrial fibrillation and venous thromboembolism.”
Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015 Jun 22 [Epub ahead of print].