Dataset Information

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.

SUBMITTER: Kubica J

PROVIDER: S-EPMC4712351 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAmong 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 methodsWe 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.Results38 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.ConclusionIn 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.

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