Optimizing an antiplatelet therapy after an acute coronary syndrome (ACS) aims at reducing the major adverse cardiac events (MACE) caused by atherosclerotic disease.
Ticagrelor is a potent P2Y12 inhibitor that directly prevents platelet activation. It is characterized by a rapid and consistent onset of action throughout its administration (twice daily) and its proven pleiotropic effects, which make it efficient as an antithrombotic, anti-inflammatory, and vasodilator drug.
Due to these characteristics, it has a proven clinical benefit for the treatment of ACS and stroke.
The major limitation of this potent antiplatelet agent is the risk of bleeding during an emergency surgery/procedure and the risk of spontaneous bleeding. Unlike irreversible antiplatelet agents such as aspirin, clopidogrel, and prasugrel, ticagrelor has a reversible binding to the P2Y12 receptor. Consequently, trying to reverse its effects through a platelet transfusion would not be beneficial in this scenario.
Bentracimab is a recombinant monoclonal antibody that binds to ticagrelor and its active circulating metabolite with high affinity and specificity. Its safety and efficacy have been proven in phase I and phase II studies.
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The objective of this open-label, multicenter, single-arm, ongoing study (REVERSE-IT) is to study the ability to reverse the effect of ticagrelor through the use of bentracimab in patients who require urgent surgery or who have had a major bleeding event.
In this interim analysis, recently published in NEJM evidence, 150 patients on ticagrelor treatment in Europe and the US were randomized; 142 required emergency surgery and 8 had experienced major bleeding.
They were given a 6-g bolus, followed by a 6-g load over 4 hours, and finally, a 6-g maintenance dose over 12 hours. Efficacy outcomes such as the determination of the minimum percentage of P2Y12 inhibition (PRU) and the extent of effective clinical hemostasis were taken into account.
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A significant decrease in PRU (135%) in the reduction of platelet inhibition after bentracimab administration was detected (p < 0.001). The proportion of patients who achieved effective hemostasis (98.4%) was significantly higher—compared with what was expected—in patients who did not receive the drug (p < 0.001).
Thrombotic events requiring restarting ticagrelor occurred in 5.3% of patients. There were complications related to the baseline procedure/intervention, with no infusion-related adverse events such as allergy or anaphylactic reactions.
Conclusions
Bleeding associated with the use of antiplatelet agents considerably increases morbidity and mortality, requiring hospitalization and the need for blood products. Furthermore, as observed in daily practice, requiring some type of invasive intervention while on antiplatelet therapy is not uncommon.
The data from this interim analysis of REVERSE-IT show that treatment with bentracimab is effective in achieving hemostasis rapidly, with an acceptable safety profile (no allergic or infusion-related reactions and low number of thrombotic events).
Its definitive effect remains to be determined through greater patient inclusion and longer follow-up, but these results are undoubtedly encouraging.
Dr. Omar Tupayachi.
Member of the Editorial Board, SOLACI.org
Original Title: Bhatt Deepak L, et al. Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery. NEJM Evid 2022; 1 (3).
Reference: https://evidence.nejm.org/doi/10.1056/EVIDoa2100047.
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