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

  • Of the volunteers that took PB2452, 17 (35%) reported 27 adverse events, mainly issues involving the infusion site, and of the volunteers that took placebo, 2 (12%) reported 3 adverse events. There were no toxic effects, or infusion-related reactions. Also, there were no deaths, hospitalizations or discontinuation of the trial drug due to adverse events.
  • Of those who received PB2452, 21 (44%) individuals had detectable antidrug antibodies after exposure, with 15 (31%) already positive before exposure. In those who received placebo, 3 (19%) individuals had antidrug antibodies, with 2 (12%) having preexisting antibodies.
  • 30-minute infusion of 3.0 and 9.0 g PB2452 resulted in a significantly greater increase in platelet aggregation compared to placebo. Maximal reversal occurred at 30 minutes and lasted 1-2 hours.
  • Initial 3.0 g bolus and 8.0 hours infusion of 18.0 g PB2452 resulted in extended reversal of ~12 hours, but onset of reversal was delayed by ~2 hours.
  • Bolus of 6.0 g PB2452 followed by 12 or 16 hours infusion of 18.0 g PB2452 resulted in rapid reversal (within 5 min after bolus) and was sustained for 16-24 hours.
  • In cohorts 7-10 (with initial bolus and prolonged infusion of PB2452), volunteers who received PB2452 had a significantly greater increase in platelet aggregation compared to those who received placebo across all time points (5 min-20 hours, P<0.001). Data was confirmed with point-of-care P2Y12 platelet-reactivity test and vasodilator-stimulated phosphoprotein (VASP) assay (significant correlation for all comparisons).
  • In cohort 9 and 10, mean platelet aggregation was restored after initiation with PB2452 (≥80% of baseline) at all time points up to 20 hours. Similar data were found with point-of-care P2Y12 platelet-reactivity test and VASP assay.
  • No prothrombotic rebound effect in platelet reactivity after acute ticagrelor reversal was detected.


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.


1. Brilinta (ticagrelor). Wilmington, DE: Astra Zeneca, 2016 (package insert).

2. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery. a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123-e210.

3. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39: 213-60.

4. Ducrocq G, Amarenco P, Labreuche J, et al. A history of stroke/transient ischemic attack indicates high risks of cardiovascular event and hemorrhagic stroke in patients with coronary artery disease. Circulation 2013; 127: 730-8.

5. Bhatt DL. Intensifying platelet inhibition — navigating between Scylla and Charybdis. N Engl J Med 2007; 357:2078-81.

6. Buchanan A, Newton P, Pehrsson S, et al. Structural and functional characterization of a specific antidote for ticagrelor. Blood 2015; 125:3484-90.

Find this article online at N Eng J Med

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