By Dr Megha Agarwal
P2Y12 receptor antagonists such as clopidogrel, ticagrelor, prasugrel are used in acute coronary syndrome for their anti-platelet properties. To date, no reversal agents exist, and clinicians often must plan to withhold these medications for 3-7 days prior to surgery, to prevent major bleeding. Unlike for aspirin reversal, platelet transfusions are of little benefit for reversal of P2Y12 receptor antagonists [1]. Ticagrelor binds reversibly to the P2Y12 receptor on platelets, unlike clopidogrel and prasugrel.
In 2019, Bhatt and colleagues [1] reported findings of a trial of bentracimab (PB2452) – a neutralising recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment which binds ticagrelor and its major active circulating metabolite. The phase I trial, with 64 healthy volunteers (48 who received PB2452, and 16 who received placebo) showed that PB2452 reversed the antiplatelet effects of ticagrelor within 5 minutes, and the effects lasted for over 20 hours.
Now, in a further phase III study (REVERSE-IT) [3,4] performed on 150 patients (142 patients who needed urgent surgery which could not wait 3 days for the effects of ticagrelor to “wear off” or a procedure with high risk of bleeding if on ticagrelor, and 8 patients who had major bleeding), Bhatt et al found that intravenous bentracimab provided “immediate and sustained” reversal of ticagrelor’s antiplatelet effects within 5 – 10 minutes. This was measured using a platelet function assay, and clinically by measuring effectiveness of haemostasis using the GUSTO bleeding scale.
It is important to note that there was no control arm in this trial, therefore direct comparison of bleeding from surgical procedures in patients receiving bentracimab vs placebo cannot be made. Nevertheless, the authors report that GUSTO severe bleeding rates or CABG-related bleeds requiring blood transfusion were lower in this trial compared to those observed in the PLATO trial. Approximately 5% of participants were reported to have thrombotic events, with no reports of allergic reactions to the agent.
Further studies are needed to determine the effects of bentracimab to reverse ticagrelor in patients with bleeding such as intracranial haemorrhage or gastrointestinal bleeding.
Read more:
- Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma Acute Care Surg. 2013 May;74(5):1367-9. doi: 10.1097/TA.0b013e31828cca61. PMID: 23609292.
- Bhatt D, Pollack C, Weitz J, et al. Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers. N Engl J Med 2019;380:1825-1833 DOI: 10.1056/NEJMoa1901778
- Bhatt D, Pollack C, Mazer D, et al. Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery. NEJM Evidence 2021. DOI: 10.1056/EVIDoa2100047 https://evidence.nejm.org/pb-assets/evidence-site/content/EVIDoa2100047-1638377642183.pdf
- https://www.acc.org/latest-in-cardiology/clinical-trials/2021/11/12/21/17/reverse-it
