Antibody-based ticagrelor reversal agent in healthy volunteers.
Dual antiplatelet therapy (DAPT) is frequently used in patients with acute coronary syndrome, coronary stents, or history of myocardial infarction. An inherent risk of DAPT or anticoagulation is the increased risk of bleeding complications, either spontaneous (e.g. intracranial haemorrhage, gastrointestinal bleed) or related to an invasive or surgical procedure.
Among the three P2Y12 receptor antagonists, ticagrelor (an irreversible antagonist) is the most challenging to manage before a non-elective procedure or in the presence of bleeding, as platelet transfusion will not be able to restore platelet function. While there is currently no specific reversal strategy for ticagrelor, a neutralizing monoclonal antibody fragment that binds ticagrelor and its major active metabolites was recently developed (Buchanan A et al. Blood 2015;125:3484-90 [Journal website]).
Bhatt and colleagues performed a randomised controlled single-ascending-dose Phase 1 trial to evaluate the safety (incidence of side effects) and efficacy (reversal of antiplatelet effects) in healthy volunteers treated with ticagrelor. Of the 646 volunteers included in the study, 48 were assigned to receive the reversal agent (named PB2452, formerly MEDI2452) and 16 to receive a placebo.
The agent administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours. There was no evidence of rebound in platelet activity, and only minor adverse events related to the infusion site were noted.
In conclusion, this study by Bhatt et al. offers a promising perspective for reversal of ticagrelor-induced platelet inhibition. Further studies will be needed to assess the safety and efficacy of the reversal agents in patients treated with ticagrelor.
– David Faraoni
