Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial presented Monday by Charles Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.

Pollack

Charles Pollack

Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data presented by Pollack at the ISTH 2015 Congress were on the first 90 patients of an on-going trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were also published today in the New England Journal of Medicine (Pollack et al N Engl J Med 2015; epub ahead of print June 22).

“Non-vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” he added.

The first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% CI, 100-100) of the anticoagulation effect within four hours.

Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Pollack said.

“Clinical outcomes were quite good in this multi-morbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.

Idarucizumab was generally well-tolerated in the patient population. “There were no serious adverse events related to the reversal agent …and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Pollack said.

“The study is ongoing,” he said, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”

Additionally, Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”

“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.

Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.

He cautioned that providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications.

“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.”

“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.

By Ted Bosworth and Madhu Rajaraman |June 22, 2015