Physicians' Academy for Cardiovascular Education

Rapid and sustained reversal of P2Y12 inhibitor-induced platelet inhibition with reversal agent

Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers

Literature - Bhatt DL, Pollack CV, Weitz JI, et al. - N Eng J Med 2019, doi: 10.1056/NEJMoa1901778

Introduction and methods

The oral P2Y12 receptor antagonist ticagrelor is associated with increased bleeding risk, that persists for several days after drug cessation [1]. Guidelines recommend drug cessation at least 3-7 days before surgery {2,3]. Establishing hemostasis can be a challenge in patients who take P2Y12 inhibitors and have spontaneous major bleeding (intracranial or gastrointestinal) or in those who require urgent invasive procedures [4,5]. Platelet transfusions have shown to be ineffective in reversing the antiplatelet effects of ticagrelor.

Currently, there are no reversal agents for P2Y12 receptor antagonists. Ticagrelor is a reversible antagonist, which makes it feasible to develop a specific reversal agent. PB2452 has been developed as a neutralizing monoclonal antibody that binds ticagrelor and its active metabolite with high affinity [6].

This single-center, randomized, double-blind, placebo-controlled, single-ascending-dose, phase 1 trial examined the safety, efficacy and pharmacokinetic profiles of intravenous PB2452 in healthy volunteers (n=64) who were pretreated with ticagrelor 48 hours before. Ten sequential dose cohorts were done and volunteers in all cohorts were randomized in a 3:1 ratio to receive PB2452 (n=48) or placebo (n=16). Primary efficacy outcome was reversal of antiplatelet effects of ticagrelor assessed by platelet aggregation using light transmission aggregometry. Primary safety outcome was frequency and severity of adverse events.

Main results


In this phase 1 trial, infusion of PB2452 appeared to be safe and resulted in rapid and sustained reversal of platelet inhibition by ticagrelor in healthy volunteers, as measured by multiple platelet assays.


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