Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial

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.

Keywords: Morphine; Myocardial infarction; Pharmacodynamics; Pharmacokinetics; Ticagrelor.

Figure 1

Patient flow diagram. PD, pharmacodynamic; PK, pharmacokinetic; STEMI, ST-elevation myocardial infarction.

Figure 2

Plasma concentrations of ticagrelor and AR-C124910XX. Plasma concentrations of (A) ticagrelor and (B) AR-C124910XX after oral administration of a 180 mg ticagrelor loading dose, which followed intravenous injection of placebo (blue) or morphine (red).

Figure 3

Platelet reactivity over time in morphine vs. placebo-treated patients. Platelet reactivity assessed with (A) MEA (n = 54), (B) VASP (n = 70), and (C) VerifyNow P2Y12 (n = 48) tests at baseline, and at 30 min, 1, 2, 3, 4, 6, and 12 h after administration of a 180 mg ticagrelor loading dose in morphine (red) vs. placebo (blue)-treated patients. ADP, adenosine diphosphate; HPR, high platelet reactivity; MEA, multiple electrode aggregometry; PRU, P2Y12 reaction units; VASP, vasodilator-stimulated phosphoprotein; U, units.

Figure 4

Prevalence of high platelet reactivity over time in morphine vs. placebo-treated patients. Proportion of patients with high platelet reactivity assessed with (A) MEA, (B) VASP, and (C) VerifyNow P2Y12 tests at pre-defined measurement points in relation to administration of morphine (red) or placebo (blue). HPR, high platelet reactivity; MEA, multiple electrode aggregometry; VASP, vasodilator-stimulated phosphoprotein.