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

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.

Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial.

Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration-time curve (AUC0-24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0-24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02683707 (: NCT02683707).

Effect of intravenous fentanyl on ticagrelor absorption and platelet inhibition among patients undergoing percutaneous coronary intervention: Design, rationale, and sample characteristics of the PACIFY randomized trial.

INTRODUCTION: Morphine reduces and delays the absorption of oral P2Y12 platelet inhibitors. Fentanyl is another opiate often administered during percutaneous coronary interventions (PCI). The PACIFY study will test whether intravenous fentanyl also impairs the absorption and action of oral P2Y12 inhibitors. METHODS: PACIFY is a single-center trial randomizing adults undergoing clinically-indicated coronary angiography to have the procedure with or without fentanyl. All patients will receive local anesthetic and intravenous midazolam. Doses of all drugs are at the discretion of treating providers. Patients that require PCI receive 180mg of oral ticagrelor during the angiography procedure. The primary outcome is area under the ticagrelor plasma concentration-time curve. Secondary outcomes include platelet inhibition 2-h after loading, measured both by VerifyNow® (Accriva Diagnostics, San Diego, California) and by light-transmission platelet aggregometry. We will also survey patient comfort and measure high-sensitivity troponin levels. Patients and outcomes assessors are blinded, treating providers are not. RESULTS: A total of 212 patients are participating, 70 of whom required PCI. Baseline characteristics are numerically well balanced in both study arms. Mean age is 63years and 27% are female. There were no differences in total midazolam dose during the index PCI procedure, whereas mean total fentanyl dose was 9 mcg in the no-fentanyl arm (2 participants in this arm required fentanyl for bailout treatment of pain) versus 96 mcg in the fentanyl arm. CONCLUSIONS: This study will provide important information on the impact of fentanyl administered during PCI on the absorption of ticagrelor and its antiplatelet activity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02683707.