Anticoagulant Reversal Agents Widen AF Treatment Options

Convened at a special session of the annual Transcatheter Cardiovascular Therapeutics (TCT) meeting, held during October 2015 in San Francisco (CA, USA), the panel discussed the use of the reversal agents, which can swiftly undo the potent effects of anticoagulants during major bleeding episodes or emergency surgery in atrial fibrillation (AF) patients. Numerous questions abound, including how to assess the efficacy of anticoagulation reversal agents, what doses are needed, and optimal intravenous (IV) administration duration and administration.

Leading the way is idarucizumab, a dabigatran reversal agent; it has been used clinically in both major bleeding patients and in patients undergoing emergency surgery with positive results. Other oral anticoagulant reversal agents currently in development are andexanet alfa, a factor Xa decoy has been shown to rapidly attenuate the anti-factor Xa activity of apixaban, rivaroxaban, edoxaban, and enoxaparin and restore thrombin generation in phase 2 studies in healthy human volunteers; reversal is achieved in less than 5 minutes.

Anither is PER977, a water-soluble small-molecule nonspecific reversal agent for multiple anti-Xa and anti-IIa agents. It is currently in phase one to two trials in healthy human volunteers. It has a rapid onset of action, reversing anticoagulation 5 to 10 minutes after IV administration, as evidenced in edoxaban-treated healthy volunteers. Idarucizumab and andexanet alfa received breakthrough therapy designations from the US Food and Drug Administration (FDA); PER977 has received Fast Track status.

“Reversal agents for new anticoagulants are important because anticoagulation is still underused as stroke prevention in patients with atrial fibrillation,” said panel member Prof. Lisa Jennings, PhD, director of the vascular biology center at the University of Tennessee Health Science Center (UTHSC; Memphis, USA). “Underuse persists, although the new anticoagulants overcome some of the difficulties of anticoagulant provided by the Vitamin K antagonists. Perhaps one reason for the lack of wider uptake is the absence of new anticoagulant reversal agents.”

“There is reluctance among physicians to prescribe new anticoagulant agents because there are no available reversible agents,” added Ajay Kirtane, MD, assistant professor of clinical medicine at Columbia University (New York, NY, USA). “At present we don't prefer those newer agents because if somebody were to bleed—not that it happens that frequently—then you would not be able to reverse it. If the reversal agents were available, those scenarios would just go away.”

The pending use of the new oral anticoagulants ranges from 23–36 million people in the developed world by the year 2020, and an estimated 500,000 of these are going to need a drug that can rapidly reverse anticoagulation. It is important to note, however, that while both small-molecule and antibody-based anticoagulant reversal agents are showing promising results, none of these agents are approved for the acute reversal of novel oral anticoagulants.

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University of Tennessee Health Science Center
Columbia University