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Comparative effects of fentanyl versus morphine on platelet inhibition induced by ticagrelor in patients with ST-segment elevation myocardial infarction: Full results of the PERSEUS randomized trial


- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
- Department of Cardiology, Cardiocentro Ticino, Lugano, Switzerland, Switzerland
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa, Italian Cardiovascular Network, Genoa, Italy
- Department of Cardiology, Lausanne University Hospital, Lausanne, Switzerland
open access
Abstract
Background: Morphine reduces absorption and delays action onset of potent oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI). We sought to determine the differential effects of fentanyl compared to morphine on the pharmacodynamics and pharmacokinetics of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI). Methods: PERSEUS (NCT02531165) was a prospective, single-center, open-label, randomized controlled study. Patients with STEMI who required analgesia were randomly assigned in a 1:1 ratio to treatment with intravenous fentanyl or morphine after ticagrelor loading dose (LD) administration. The primary endpoint was platelet reactivity at 2 hours after ticagrelor LD assessed by P2Y12 reaction units (PRU). Results: The study was prematurely stopped in June 2017 after enrolment of 38 out of 56 planned patients. PRU at 2 hours following ticagrelor LD was 173.3 ± 89.7 in the fentanyl group and 210.3 ± 76.4 in the morphine group (p = 0.179). At 4 hours, PRU was significantly lower among patients treated with fentanyl as compared to those treated with morphine (90.1 ± 97.4 vs. 168.0 ± 72.2; p = 0.011). Maximal plasma concentrations of ticagrelor and its active metabolite AR-C124910XX tended to be delayed and numerically lower among patients treated with morphine compared to fentanyl. Total exposures to ticagrelor and AR-C124910XX within 6 hours after ticagrelor LD were numerically greater among patients treated with fentanyl compared to those treated with morphine. Conclusions: In patients with STEMI undergoing primary PCI, fentanyl did not improve platelet inhibition at 2 hours after ticagrelor pre-treatment compared with morphine. Fentanyl may, however, accelerate ticagrelor absorption and increase platelet inhibition at 4 hours compared to morphine.
Abstract
Background: Morphine reduces absorption and delays action onset of potent oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI). We sought to determine the differential effects of fentanyl compared to morphine on the pharmacodynamics and pharmacokinetics of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI). Methods: PERSEUS (NCT02531165) was a prospective, single-center, open-label, randomized controlled study. Patients with STEMI who required analgesia were randomly assigned in a 1:1 ratio to treatment with intravenous fentanyl or morphine after ticagrelor loading dose (LD) administration. The primary endpoint was platelet reactivity at 2 hours after ticagrelor LD assessed by P2Y12 reaction units (PRU). Results: The study was prematurely stopped in June 2017 after enrolment of 38 out of 56 planned patients. PRU at 2 hours following ticagrelor LD was 173.3 ± 89.7 in the fentanyl group and 210.3 ± 76.4 in the morphine group (p = 0.179). At 4 hours, PRU was significantly lower among patients treated with fentanyl as compared to those treated with morphine (90.1 ± 97.4 vs. 168.0 ± 72.2; p = 0.011). Maximal plasma concentrations of ticagrelor and its active metabolite AR-C124910XX tended to be delayed and numerically lower among patients treated with morphine compared to fentanyl. Total exposures to ticagrelor and AR-C124910XX within 6 hours after ticagrelor LD were numerically greater among patients treated with fentanyl compared to those treated with morphine. Conclusions: In patients with STEMI undergoing primary PCI, fentanyl did not improve platelet inhibition at 2 hours after ticagrelor pre-treatment compared with morphine. Fentanyl may, however, accelerate ticagrelor absorption and increase platelet inhibition at 4 hours compared to morphine.
Keywords
fentanyl, pharmacodynamics, pharmacokinetics, ST-segment elevation myocardial infarction, ticagrelor


Title
Comparative effects of fentanyl versus morphine on platelet inhibition induced by ticagrelor in patients with ST-segment elevation myocardial infarction: Full results of the PERSEUS randomized trial
Journal
Issue
Article type
Original Article
Pages
591-600
Published online
2022-05-30
Page views
5107
Article views/downloads
936
DOI
Pubmed
Bibliographic record
Cardiol J 2022;29(4):591-600.
Keywords
fentanyl
pharmacodynamics
pharmacokinetics
ST-segment elevation myocardial infarction
ticagrelor
Authors
Juan F. Iglesias
Marco Valgimigli
Federico Carbone
Nathalie Lauriers
Pier-Giorgio Masci
Sophie Degrauwe


- Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018; 39(2): 119–177.
- Bellemain-Appaix A, Bégué C, Bhatt DL, et al. The efficacy of early versus delayed P2Y12 inhibition in percutaneous coronary intervention for ST-elevation myocardial infarction: a systematic review and meta-analysis. EuroIntervention. 2018; 14(1): 78–85.
- Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012; 5(6): 797–804.
- Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol. 2013; 61(15): 1601–1606.
- Hobl EL, Stimpfl T, Ebner J, et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2014; 63(7): 630–635.
- Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2015; 8(1).
- Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2015; 37(3): 245–252.
- Furtado RHM, Nicolau JC, Guo J, et al. Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography. J Am Coll Cardiol. 2020; 75(3): 289–300.
- Schug SA, Ting S. Fentanyl formulations in the management of pain: an update. Drugs. 2017; 77(7): 747–763.
- Lavi S, Jolly SS, Bainbridge D, et al. Sedation, analgesia, and anaesthesia variability in laboratory-based cardiac procedures: an international survey. Can J Cardiol. 2014; 30(6): 627–633.
- McEvoy J, Ibrahim K, Kickler T, et al. Effect of intravenous fentanyl on ticagrelor absorption and platelet inhibition among patients undergoing percutaneous coronary intervention. Circulation. 2018; 137(3): 307–309.
- Ibrahim K, Shah R, Goli RR, et al. Fentanyl delays the platelet inhibition effects of oral ticagrelor: full report of the PACIFY randomized clinical trial. Thromb Haemost. 2018; 118(8): 1409–1418.
- Iglesias JF, Valgimigli M, Carbone F, et al. Effects of fentanyl versus morphine on ticagrelor-induced platelet inhibition in patients with st-segment elevation myocardial infarction: the PERSEUS randomized trial. Circulation. 2020; 142(25): 2479–2481.
- Degrauwe S, Roffi M, Lauriers N, et al. Influence of intravenous fentanyl compared with morphine on ticagrelor absorption and platelet inhibition in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: rationale and design of the PERSEUS randomized trial. Eur Heart J Cardiovasc Pharmacother. 2019; 5(3): 158–163.
- Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010; 56(12): 919–933.
- Franchi F, Rollini F, Cho JR, et al. Impact of escalating loading dose regimens of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of a prospective randomized pharmacokinetic and pharmacodynamic investigation. JACC Cardiovasc Interv. 2015; 8(11): 1457–1467.
- Nimmo WS, Heading RC, Wilson J, et al. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol. 1975; 2(6): 509–513.
- Giannopoulos G, Deftereos S, Kolokathis F, et al. P2Y12 receptor antagonists and morphine: a dangerous liaison? . Circ Cardiovasc Interv. 2016; 9: e004229.
- Puymirat E, Lamhaut L, Bonnet N, et al. Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) programme. Eur Heart J. 2016; 37(13): 1063–1071.
- Furtado RHM, Nicolau JC, Guo J, et al. Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography. J Am Coll Cardiol. 2020; 75(3): 289–300.
- Montalescot G, van 't Hof AW, Montalescot G, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014; 371(11): 1016–1027.
- Franchi F, Rollini F, Rivas A, et al. Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2019; 139(14): 1661–1670.
- Valgimigli M, Tebaldi M, Campo G, et al. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv. 2012; 5(3): 268–277.
- Saad M, Meyer-Saraei R, de Waha-Thiele S, et al. Impact of morphine treatment with and without metoclopramide coadministration on ticagrelor-induced platelet inhibition in acute myocardial infarction: the randomized monAMI trial. Circulation. 2020; 141(16): 1354–1356.
- Mori T, Shibasaki Y, Matsumoto K, et al. Mechanisms that underlie μ-opioid receptor agonist-induced constipation: differential involvement of μ-opioid receptor sites and responsible regions. J Pharmacol Exp Ther. 2013; 347(1): 91–99.