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

Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y₁₂ inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose. The results of our study show that mean platelet activity within the first hour was noticeably higher in metoclopramide-naive patients. Moreover, ticagrelor mean plasma concentration was significantly higher within the initial four time points (15, 30, 45, 60 minutes) in patients receiving metoclopramide (p = 0.039; p = 0.009; p = 0.005; p = 0.008, respectively). To conclude, the co-administration of metoclopramide in patients presenting with unstable angina and treated with morphine, has a beneficial effect on the PK/PD profile of ticagrelor and its metabolite; however, its impact on ST-elevation myocardial infarction patients requires further investigation.

Background. Today there are many devices that can be used to study blood clotting disorders by identifying abnormalities in blood platelets. The Total Thrombus Formation Analysis System is an automated microchip flow chamber system that is used for the quantitative analysis of clot formation under blood flow conditions. For several years, researchers have been using a tool to analyse various clinical situations of patients to identify the properties and biochemical processes occurring within platelets and their microenvironment. Methods. An investigation of recent published literature was conducted based on PRISMA. This review includes 52 science papers directly related to the use of the Total Clot Formation Analysis System in relation to bleeding, surgery, platelet function assessment, anticoagulation monitoring, von Willebrand factor and others. Conclusion. Most available studies indicate that The Total Thrombus Formation Analysis System may be useful in diagnostic issues, with devices used to monitor therapy or as a significant tool for predicting bleeding events. However, T-TAS not that has the potential for diagnostic indications, but allows the direct observation of the flow and the interactions between blood cells, including the intensity and dynamics of clot formation. The device is expected to be of significant value for basic research to observe the interactions and changes within platelets and their microenvironment.

Summary: Oral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.

Ischemic stroke is a disease related to abnormal blood flow that leads to brain dysfunction. The early and late phases of the disease are distinguished. A distinction is made between the early and late stages of the disease, and the best effect in treating an ischemic stroke is usually achieved within the first hours after the onset of symptoms. This review looked at studies platelet activity monitoring studies to determine the risks and benefits of various approaches including antiplatelet therapy. A study was conducted on recently published literature based on PRISMA. This review includes 32 research articles directly addressing the importance of monitoring platelet function during antiplatelet therapy (dual or monotherapy) after ischemic stroke. In patients with transient ischemic attack or ischemic stroke, antiplatelet therapy can reduce the risk of stroke by 11–15%, assuming that patients respond well. Secondary prevention results are dependent on platelet reactivity, meaning that patients do not respond equally to antiplatelet therapy. It is very important that aspirin-resistant patients can benefit from the use of dual antiplatelet therapy. The individualized approach to secondary stroke prevention is to administer the most appropriate drug at the correct dose and apply the optimal therapeutic procedure to the individual patient.

Background: The aim of this prospective, a three-year follow-up study, was to establish the role of high on-treatment platelet reactivity (HTPR) in predicting the recurrence of vascular events in patients after cerebrovascular incidents, particularly in the aspect of stroke etiology. Methods: The study included 101 subjects with non-embolic cerebral ischemia (69 patients with ischemic stroke and 32 patients with transient ischemic attack) treated with 150 mg of acetylsalicylic acid (aspirin) a day. The platelet reactivity was tested in the first 24 h after the onset of cerebral ischemia by impedance aggregometry. Recurrent vascular events, including recurrent ischemic stroke, transient ischemic attack, myocardial infarction, systemic embolism, or sudden death of vascular reason, were assessed 36 months after the onset of cerebral ischemia. Results: Recurrent vascular events occurred between 3 and 9 months after onset in 8.5% of all subjects; in the HTPR subgroup, recurrent vascular events occurred in 17.9%; in the normal on-treatment platelet reactivity (NTPR) subgroup, they occurred in 4.6%. We did not notice early or long-term recurrent events. Aspirin resistant subjects had a significantly higher risk of recurrent vascular events than did aspirin sensitive subjects (Odds ratio (OR) = 4.57, 95% Confidence interval (CI) 1.00–20.64; p = 0.0486). Cox proportional hazard models showed that large-vessel disease (Hazard ratio (HR) 12.04, 95% CI 2.43–59.72; p = 0.0023) and high on-treatment platelet reactivity (HR 4.28, 95% CI 1.02–17.93; p = 0.0465) were independent predictors of recurrent vascular events. Conclusion: Aspirin resistance in the acute phase of cerebral ischemia was associated with a higher risk of recurrent medium-term vascular events, coexisting with large-vessel etiology of stroke. Platelet function-guided personalized antiplatelet treatment should be considered for patients with recurrent strokes, especially when due to large-vessel disease.