AimsThe 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 resultsIn 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.ConclusionsMorphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

Morphine and P2Y12 receptor inhibitors are both recommended in patients with acute myocardial infarction. Morphine may impede gastrointestinal absorption of several oral drugs including P2Y12 platelet receptor inhibitors. The aim of this review was to critically discuss drug-drug interactions between oral P2Y12 receptor inhibitors and morphine according to currently available knowledge based on the findings of experimental, observational and randomized clinical studies. The morphine-clopidogrel pharmacodynamic interaction has been observed in numerous trials and it has been proposed as an explanation for the negative impact of morphine on the clinical outcomes in patients with acute coronary syndromes. An analogous morphine interaction with ticagrelor and prasugrel was found in several observational studies and finally proven in randomized trials in healthy volunteers and acute myocardial infarction patients. Morphine delays and attenuates exposure and antiplatelet action of oral P2Y12 receptor inhibitors in patients with myocardial infarction. Although this interaction may have potentially harmful consequences, routine avoidance of morphine cannot be recommended until clinically powered trials are completed.

BackgroundTicagrelor is an oral platelet P2Y12 receptor antagonist which is recommended for patients suffering from myocardial infarction, both with and without persistent ST segment elevation. Morphine is the first choice drug in pain alleviation in the same clinical subset. Recently a possible negative influence of morphine on the pharmacokinetics and antiplatelet effects of P2Y12 receptor blockers has been postulated.Methods/designThe IMPRESSION study is a phase IV, single center, randomized, double-blind, placebo-controlled clinical trial that is designed to assess the influence of morphine on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with myocardial infarction. The study is planned to include up to 100 patients with myocardial infarction who will be randomized into one of two arms in a 1:1 ratio. Subjects in the intervention arm prior to the loading dose of ticagrelor (180 mg) will receive morphine (5 mg) intravenously, whereas patients in the control arm will receive a placebo prior to the loading dose of ticagrelor (180 mg). The pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) will be assessed by liquid chromatography mass spectrometry. Platelet function testing in each patient will be performed using up to four different methods (platelet vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry, VerifyNow, and light transmission aggregometry).DiscussionThis study is expected to provide essential evidence-based data on the impact of morphine on the absorption of ticagrelor in patients with myocardial infarction as well as to shed some light on the suspected connection between morphine use and antiplatelet activity of ticagrelor in the same group of patients.Trial registrationClinicalTrials.gov identifier: NCT02217878 (14 August 2014).

A group of Polish experts in cardiology and emergency medicine, encouraged by the European Society of Cardiology (ESC) guidelines, have recently published common recommendations for medical emergency teams regarding the pre-hospital management of patients with acute coronary syndrome. Due to the recent publication of the 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation and 2017 focused update on dual antiplatelet therapy in coronary artery disease the current panel of experts decided to update the previous standpoint. Moreover, new data coming from studies presented after the previous document was issued were also taken into consideration.

BackgroundData from available studies suggest that the presence of ST-elevation myocardial infarction (STEMI) may be associated with delayed and attenuated ticagrelor bioavailability and effect compared with non-ST-elevation myocardial infarction (NSTEMI).MethodsIn a single-center, prospective, observational trial 73 patients with myocardial infarction (STEMI n = 49, NSTEMI n = 24) underwent a pharmacokinetic and pharmacodynamic assessment after a 180 mg ticagrelor loading dose (LD). Ticagrelor and its active metabolite (AR-C124910XX) plasma concentrations were determined with liquid chromatography tandem mass spectrometry, and their antiplatelet effect was measured with the VASP assay and multiple electrode aggregometry.ResultsDuring the first six hours after ticagrelor LD, STEMI patients had 38% and 34% lower plasma concentration of ticagrelor and AR-C124910XX, respectively, than NSTEMI (ticagrelor AUC(0–6): 2491 [344–5587] vs. 3991 [1406–9284] ng*h/mL; p = 0.038; AR-C124910XX AUC(0–6): 473 [0–924] vs. 712 [346–1616] ng*h/mL; p = 0.027). STEMI patients also required more time to achieve maximal concentration of ticagrelor (tmax: 4.0 [3.0–12.0] vs. 2.5 [2.0–6.0] h; p = 0.012). Impaired bioavailability of ticagrelor and AR-C124910XX seen in STEMI subjects was associated with diminished platelet inhibition in this group, which was most pronounced during the initial hours of treatment.ConclusionsPlasma concentrations of ticagrelor and AR-C124910XX during the first hours after ticagrelor LD were one third lower in STEMI than in NSTEMI patients. This reduced and delayed ticagrelor bioavailability was associated with weaker antiplatelet effect in STEMI.Clinical trial registrationClinicalTrials.gov identifier: NCT02602444 (November 09, 2015)

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Acute coronary syndromes (ACS) are one of the leading causes of death worldwide. Several landmark trials, followed by a widespread introduction of new agents, have significantly improved ACS outcomes in recent years. However, despite the use of contemporary therapy, a substantial number of ACS patients continue to suffer from cardiovascular events. Areas covered: The aim of this review was to summarize available data on innovative drugs and pharmacological strategies that have potential to amend the current ACS therapy. We present the results of recent large clinical trials, as well as insights from ongoing phase III and phase IV studies, exploring the value of new strategies for the improvement of outcomes in ACS. Expert opinion: More potent platelet inhibition, more profound lipid reduction and possibly anti-inflammatory action are considered to have potential to further reduce the rates of adverse cardiovascular and thrombotic events in ACS patients. 'Hit fast, hit hard' approach regarding novel antiplatelet and lipid-lowering therapy seems attractive, but it has to be considered that these strategies may be associated with increased adverse events rate. Introduction of cangrelor and ezetimibe, and potentially future recognition of proprotein convertase subtilisin/kexin type 9 antibodies, are likely to alter the landscape of ACS pharmacotherapy.

NCT03251859.