Morphine Delays and Attenuates Ticagrelor Exposure and Action in Patients With Myocardial Infarction

The Randomized, Double-Blind, Placebo-Controlled IMPRESSION Trial

Jacek Kubica; Piotr Adamski; Małgorzata Ostrowska; Joanna Sikora; Julia Maria Kubica; Wiktor Dariusz Sroka; Katarzyna Stankowska; Katarzyna Buszko; Eliano Pio Navarese; Bernd Jilma; Jolanta Maria Siller-Matula; Michał Piotr Marszałł; Danuta Rość; Marek Koziński

Disclosures

Eur Heart J. 2016;37(3):245-252. 

In This Article

Abstract and Introduction

Abstract

Aims The currently available data indicate a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction.

Methods and results In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0–12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine.

Conclusions Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

Introduction

Dual antiplatelet therapy with a P2Y12 receptor inhibitor and aspirin plays a pivotal role in the treatment of patients with acute coronary syndromes.[1,2] According to the current guidelines, ticagrelor and prasugrel are recommended preferentially over clopidogrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI), with class IB indication.[3,4]

The use of morphine in acute coronary syndromes patients is aimed at alleviation of chest pain, anxiety, and ideally at limitation of sympathetic activation. The guidelines for the management of patients with acute myocardial infarction (AMI) continue to recommend i.v. morphine as the drug of choice for pain relief, with class IC indication.[3,4] The analgesic and sedative action of morphine is expected to reduce heart rate and blood pressure, thereby improving the balance between the demand for and supply of oxygen.[5] However, the correlation between pain relief and the cardioprotective effect of morphine has never been demonstrated in randomized controlled trials.[6] Moreover, the CRUSADE registry revealed higher rates of adverse clinical outcomes in non-ST-segment elevation acute coronary syndromes patients treated with clopidogrel who received i.v. morphine, when compared with those who did not.[7] Interestingly, in the ATLANTIC study early, in-ambulance, administration of ticagrelor in patients with ST-segment elevation myocardial infarction (STEMI) transferred for primary PCI, improved coronary reperfusion only in those who did not receive morphine.[8] These findings are in line with pharmacodynamic observations published by Parodi et al.,[9–11] suggesting that the onset of action of prasugrel and ticagrelor may be delayed by co-administration of morphine in STEMI patients. Although the existing data from non-randomized trials advocates the presence of drug–drug interaction when morphine and a P2Y12 inhibitor are administered concomitantly in the acute coronary syndromes setting, the definitive evidence of such interaction may be obtained only in a randomized trial. Furthermore, a combined pharmacokinetic-pharmacodynamic study is indispensable to confirm the alleged interaction between morphine and ticagrelor, and potentially provide some clues regarding its underlying mechanism.

Bearing in mind the fact that any delay and attenuation of the platelet blockade in interventionally treated AMI patients may increase the risk of thrombotic complications, this trial assessed the influence exerted by intravenously administered morphine on the pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite in this setting.

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