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. 2024 Apr 2:11:1324641.
doi: 10.3389/fcvm.2024.1324641. eCollection 2024.

Differential impact of fentanyl and morphine doses on ticagrelor-induced platelet inhibition in ST-segment elevation myocardial infarction: a subgroup analysis from the PERSEUS randomized trial

Dorian Garin  1 , Sophie Degrauwe  1 , Federico Carbone  2   3 , Yazan Musayeb  1 , Nathalie Lauriers  4 , Marco Valgimigli  5 , Juan F Iglesias  1
Affiliations

Differential impact of fentanyl and morphine doses on ticagrelor-induced platelet inhibition in ST-segment elevation myocardial infarction: a subgroup analysis from the PERSEUS randomized trial

Dorian Garin et al. Front Cardiovasc Med. .

Abstract

Introduction: Among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), intravenous fentanyl does not enhance ticagrelor-induced platelet inhibition within 2 h compared to morphine. The impact of the total dose of fentanyl and morphine received on ticagrelor pharmacodynamic and pharmacokinetic responses in patients with STEMI remains however undetermined.

Materials and methods: We performed a post-hoc subanalysis of the prospective, open-label, single-center, randomized PERSEUS trial (NCT02531165) that compared treatment with intravenous fentanyl vs. morphine among symptomatic patients with STEMI treated with primary PCI after ticagrelor pretreatment. Patients from the same population as PERSEUS were further stratified according to the total dose of intravenous opioids received. The primary outcome was platelet reactivity using P2Y12 reaction units (PRU) at 2 h following administration of a loading dose (LD) of ticagrelor. Secondary outcomes were platelet reactivity and peak plasma levels of ticagrelor and AR-C124910XX, its active metabolite, at up to 12 h after ticagrelor LD administration. Generalized linear models for repeated measures were built to determine the relationship between raw and weight-weighted doses of fentanyl and morphine.

Results: 38 patients with STEMI were included between December 18, 2015, and June 22, 2017. Baseline clinical and procedural characteristics were similar between low- and high-dose opioid subgroups. At 2 h, there was a significant correlation between PRU and both raw [regression coefficient (B), 0.51; 95% confidence interval (CI), 0.02-0.99; p = 0.043] and weight-weighted (B, 0.54; 95% CI, 0.49-0.59; p < 0.001) doses of fentanyl, but not morphine. Median PRU at 2 h was significantly lower in patients receiving low, as compared to high, doses of fentanyl [147; interquartile range (IQR), 63-202; vs. 255; IQR, 183-274; p = 0.028], whereas no significant difference was found in those receiving morphine (217; IQR, 165-266; vs. 237; IQR, 165-269; p = 0.09). At 2 h, weight-weighted doses of fentanyl and morphine were significantly correlated to plasma levels of ticagrelor and AR-C124910XX.

Conclusion: In symptomatic patients with STEMI who underwent primary PCI after ticagrelor pretreatment and who received intravenous opioids, we found a dose-dependent relationship between the administration of intravenous fentanyl, but not morphine, and ticagrelor-induced platelet inhibition.

Keywords: ST-segment elevation myocardial infarction; dose; fentanyl; pharmacodynamics; pharmacokinetics; ticagrelor.

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Conflict of interest statement

JFI has disclosed receiving research funding for his institution (Lausanne University Hospital, Switzerland) and personal compensation from AstraZeneca during the study; institutional research grants and personal fees from Abbott Vascular, Biotronik, Biosensors, Concept Medical, Philips Volcano, Terumo Corporation, in addition to personal fees from AstraZeneca, Biotronik, Biosensors, Concept Medical, Terumo Corporation, Medtronic, Medalliance, Novartis, Pfizer, Bristol Myers Squibb, and Cordis, related to activities outside the submitted manuscript; MV has acknowledged receiving both grants and personal fees from Abbott, Terumo Corporation, and AstraZeneca, personal fees from Bayer, Daiichi Sankyo, Amgen, Alvimedica, Idorsia, Coreflow, Vifor, BristolMyers Squibb, and iVascular, and funding from Medicare, all concerning endeavors outside the submitted work; SD has reported obtaining grants and personal fees from Biotronik, also unrelated to the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pharmacodynamic assessment in patients treated with low vs. high doses of fentanyl and morphine. Line chart with P2Y12 reaction units (PRU) for low (in red) and high (in blue) doses of fentanyl (A) and morphine (B) at 1, 2, 4, 6, and 12 h after ticagrelor loading dose administration. P-values for differences between the two treatment groups are shown.
Figure 2
Figure 2
Pharmacokinetic assessment in patients treated with low vs. high doses of fentanyl and morphine. Line chart with pharmacokinetic profiles of ticagrelor (A,C) and AR-C124910XX (B,D) for low (in red) and high (in blue) doses of fentanyl (A,B) and morphine (C,D) at 1, 2, 4, 6 and 12 h after ticagrelor loading dose administration. P-values for differences between the two groups treatment are shown.
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