Background: High on-treatment platelet reactivity (HTPR) remains a pivotal problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality.

Aims: We aimed to invent a novel, preclinical treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers.

Methods: We conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay and the platelet function analyzer. The primary endpoint was defined as the time period [minutes] in which sufficient inhibition of ADP-induced platelet activation is maintained (< 29 U in MEA analysis). In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor.

Results: All cangrelor bolus infusions resulted in immediate and potent platelet inhibition. Sufficient platelet inhibition could be maintained for up to 25 minutes in half of the subjects receiving the 20 mg dose. Infusion of cangrelor via the IV flow regulator resulted in pronounced platelet inhibition throughout the course of administration. Epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner (rise from 10 U to 30 U and 34 U, respectively).

The four graphs show ADP-induced platelet inhibition over time following cangrelor bolus infusions of 5mg (upper left panel), 10mg (upper right panel), 20mg (lower left panel) and cangrelor bolus infusion followed by a continuous infusion via IV flow regulator (lower right panel). The dashed line marks the arbitrary high on-treatment platelet reactivity threshold of 29 U.
An ex vivo experiment was performed to test the ability of epinephrine to reverse the antiplatelet effects of cangrelor. The three columns in each graph represent the spiked concentration of epinephrine: no epinephrine added (left), epinephrine in a concentration of 200 ng/mL (middle) and epinephrine in a concentration of 500 ng/mL (right).

Conclusions: Fixed-dose bolus infusion and weight-adapted bolus infusion followed by a continuous infusion via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as continuous infusion via IV flow regulator is a feasible option for effective preclinical platelet inhibition. Preparations for a preclinical trial testing this treatment approach in STEMI patients are currently underway.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/pharmacodynamics-of-bolus-with-and-without-infusion-of-cangrelor-in-healthy-volunteers-a-dose-finding-open-label-pilot-trial/