The Dose and Timing of Fentanyl Impacts on Ticagrelor Absorption and Platelet Inhibition During Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial

Abstract

Objective: In this secondary analysis of the PACIFY randomized trial, we assessed whether dose and timing of fentanyl have implications for the pharmacokinetics and pharmacodynamics of ticagrelor loading during percutaneous coronary intervention (PCI).

Methods: Among 212 patients undergoing clinically indicated coronary angiography, a total of 70 required PCI and received 180 mg oral ticagrelor. Of these, thirty-two patients received no fentanyl and 38 received fentanyl (with variability in the timing of administration and cumulative dose among those randomized to fentanyl, given that both were provided at the interventional cardiologist's discretion). A time-weighted cumulative fentanyl exposure variable was calculated based on total dose of fentanyl and proximity in time of fentanyl administrations to the ticagrelor load. Patients were stratified based on receiving above or below the median time-weighted cumulative dose. Outcomes included ticagrelor concentrations by mass spectrometry (24-hour area under the curve) and platelet function measured using both VerifyNow platelet reactivity units (PRU) and light-transmission aggregometry (LTA).

Results: Unadjusted ticagrelor 24-hour area under the curve was significantly lower across the categories of increasing fentanyl exposure (P=.02). In adjusted regression models, this difference only remained when comparing the no-fentanyl group with the time-weighted cumulative dose above the median group (P=.04). Similarly, with the no-fentanyl group as the reference, adjusted models testing 2-hour PRU and LTA values demonstrated significant differences (with less platelet inhibition for both tests) only among those with time-weighted cumulative fentanyl exposures above the median value (5.1 μg/min).

Conclusions: We have previously shown that fentanyl slows absorption of oral ticagrelor, attenuating its effect on platelet inhibition. We now demonstrate this mechanism appears to be dose- and time-dependent.

Keywords: fentanyl; platelet inhibitor; ticagrelor.