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Study Summary

The reversible oral P2Y12 inhibitor ticagrelor has shown superiority over clopidogrel for reduction of ischemic events in patients presenting with acute coronary syndromes when combined with aspirin. Unlike the thienopyridine P2Y12 inhibitors clopidogrel and prasugrel, the antiplatelet effects of which can be overcome with platelet transfusion, ticagrelor to date has had no effective reversal agent. Bhatt and colleagues undertook a phase 1 trial of safety and efficacy of PB2452, a recombinant human IgG1 monoclonal antibody antigen-binding fragment, as a novel ticagrelor reversal agent (see accompanying Hurst's Central Illustration). Sixty four patients were assigned to ten sequential cohorts in a 3:1 fashion to either PB2452 (N = 48) or placebo (N = 16), where multiple platelet function assays were used before and after 48 hours of ticagrelor administration. Results demonstrated significant dose-dependent reversal of ~80% for 1-2 hours following single-dose administration of PB2452. In those receiving an initial bolus followed by infusion of PB2452, reversal was noted within 5 minutes and was sustained for 20 hours. In regard to safety, 35% of volunteers receiving PB2452 reported side effects compared to 12% for placebo, principally consisting of infusion site effects (bruising, extravasation).

Commentary

Study Strengths: This carefully designed experiment clearly demonstrated a dose-dependent, rapid-onset inhibitory effect of PB2452 on the antiplatelet effects of ticagrelor with verification and consistency across multiple platelet function assays.

Study Limitations: Patients included in this study were healthy volunteers, recruitment of whom was likely challenging. The generalizability of these results to patients with atherothrombotic disease is uncertain. The small sample size was not powered and the study was not designed to evaluate implications of ticagrelor reversal using PB2452 for either ischemic or bleeding outcomes.

Next Steps/Clinical Perspective: Analogous to prior investigations of novel reversal agents for the target-specific oral anticoagulants (e.g., idarucizumab and andexanet alfa), the principal scenarios for which a reversal agent for ticagrelor might be useful include (a) active bleeding and (b) need for antithrombotic therapy interruption for surgery. The results of this phase 1 study suggest that PB2452 is a promising agent for this purpose, pending future validation in patients with atherothrombotic disease and future study in the specific contexts of bleeding and preoperative assessment. It is essential that future studies are sufficiently powered to evaluate hazard of incident ischemic events, including stent thrombosis, after ticagrelor reversal. As with idarucizumab and andexanet alfa, cost effectiveness of ticagrelor reversal, in comparison with ticagrelor interruption and waiting, will be an important factor driving appropriate use.

Trial Reference

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Bhatt  DL, Pollack  CV, Weitz  JI, et al. Antibody-based ticagrelor reversal agent in healthy volunteers. N Engl J Med. doi: 10.1056/NEJMoa1901778

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