Rapid and Sustained Reversal of Ticagrelor–Intervention Trial - REVERSE-IT
Bleeding is a major concern with all anti-thrombotic therapies. In fact, fear of bleeding leads many physicians to withhold otherwise indicated anti-thrombotic medications from patients and also contributes to patient nonadherence. While reversal agents have been developed for anticoagulants, to date, there is no available reversal agent for anti-platelet medications. The P2Y12 platelet receptor inhibitors have been a major advance in cardiovascular medicine. The agents clopidogrel and prasugrel are irreversible anti-platelet drugs, meaning that their effect lingers for the 7- to 10-day lifespan of the platelet. Aspirin is also an irreversible platelet inhibitor. The P2Y12 inhibitor ticagrelor is a reversible agent. That does not mean that it is instantly reversible, but rather refers to its receptor-binding properties. That attribute means that platelet transfusions would not be expected to reverse its action. However, that property of reversibility has allowed the development of a human monoclonal antibody fragment called bentracimab, which binds to free ticagrelor and therefore can reverse its effects. A phase I study (healthy human volunteers) found that bentracimab bolus and intravenous infusion provided immediate and sustained reversal of ticagrelor’s anti-platelet effects.1 That placebo-controlled trial also found very good safety and tolerability of bentracimab. At the American Heart Association 2021 Late-Breaking Science Sessions, the prespecified interim results of the phase III REVERSE-IT were presented.2,3 REVERSE-IT, an open-label, prospective, single-arm study, is examining patients taking ticagrelor who need urgent surgery or invasive procedures or with major bleeding. In consultation with the FDA, a prespecified interim analysis was performed. The results show early and sustained reversal of ticagrelor’s antiplatelet effect using various established platelet function assays. Additionally, independent adjudicators assessed the rate of hemostasis and found it to be good or excellent in over 90% of patients. Furthermore, no drug-related serious adverse events or allergic or infusion-related reactions were noted. The study is ongoing to enroll more patients with bleeding, although the results to date suggest that, if approved, bentracimab could be useful in patients on ticagrelor who need urgent procedures or who are having major bleeding complications.
Disclosure: Brigham and Women’s Hospital receives research funding from PhaseBio for Dr. Bhatt’s role as the study Chair of REVERSE-IT and from AstraZeneca for his role as study co-Chair of THEMIS and THEMIS-PCI.