The poor response to clopidogrel is multifactorial and includes, amongst others, low patient adherence to medication. The aim of this study was to assess the reported patient adherence to treatment with clopidogrel and confront it with adherence assessed by drug availability. We evaluated determinants of adherence and its impact on platelet aggregation and clinical outcome. The study population comprised 184 patients treated with primary percutaneous coronary intervention for acute myocardial infarction. Follow-up visits were scheduled at 3, 6 and 9 months after discharge. Patient adherence to clopidogrel was defined according to self-reported drug intake and verified based on data from the National Health Fund regarding the purchase of prescribed drugs. The patients were judged as adherent when the proportion of drug availability exceeded 80%. According to drug availability, 100 (54.3%) patients were adherent and 84 (45.7%) were nonadherent. The analysis identified the following factors as predictors of low adherence (<80%): adenosine diphosphate-induced platelet aggregation (ADP-PA) during hospitalization ≤45 U, male gender and occurrence of ST-elevation myocardial infarction [(STEMI) vs. non-STEMI (NSTEMI)], while three-vessel disease was predictive of high adherence to medication. Compared with drug availability-based assessment, self-reported drug intake was significantly different: 172 (94.5%) patients reported regular and 10 (5.5%) patients reported irregular intake of clopidogrel. Clinical follow-up suggested that the self-reported nonregular clopidogrel intake may discriminate patients with a high risk of cardiovascular events. We demonstrated a huge discrepancy between the two most widely used methods for the evaluation of adherence to clopidogrel in secondary prevention treatment in patients after STEMI and NSTEMI. ADP-PA during hospitalization ≤45 U, male gender and STEMI (vs. NSTEMI) were independent predictors of nonadherence while three-vessel disease was independently predictive of adherence to treatment with clopidogrel in the investigated population.

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).

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)

Non-adherence rates to antiplatelet drugs in patients with acute myocardial infarction (AMI) range from 13% to 60%. We aimed to evaluate whether individual health education can improve adherence to treatment with clopidogrel in patients after AMI. This was a prospective, single-center, randomized clinical trial with a 12-month follow-up. Patients with AMI treated with percutaneous coronary intervention (PCI) were enrolled. The primary endpoint was defined as non-adherence to clopidogrel during follow-up (drug availability ≤ 80%). Secondary endpoints included platelet function assessment, adverse cardiovascular (CV) events (CV death, PCI for ACS, unscheduled CV hospitalization). There were 191 patients enrolled in the study and divided into two groups: the individual education (IE) group (100 patients) and the standard treatment (ST) group (91 patients). Adherence to the treatment with clopidogrel based on the data from the National Health Fund did not differ significantly between the IE and ST groups [76.7% (30.7-99.7%) v. 84.4% (46.5-99.7%); p = 0.25]. There was a substantial difference in the prevalence of unscheduled CV hospitalizations between both groups, IE and ST respectively [22 (22.0%) v. 10 (11.0%); p = 0.042]. The rate of CV death and ACS treated with PCI during follow-up was low and did not differ between groups.In conclusion, the program of individual health education did not improve adherence to treatment with clopidogrel. The expected benefits of medication are not achievable at current levels of adherence. The self-reported adherence assessment is unreliable and cannot be used for effective treatment guidance.

SummaryAim of this study was assessment of the relationship between concentrations of ticagrelor and its active metabolite (AR-C124910XX) and results of selected platelet function tests. In a single-centre, cohort study, patients with myocardial infarction underwent blood sampling following a 180 mg ticagrelor loading dose intake (predose, 1, 2, 3, 4, 6, 12, 24 hours postdose) to perform pharmacokinetic and pharmacodynamic assessments. Platelet reactivity was evaluated using the VASP-assay, the VerifyNow device and the Multiplate analyzer. Analysis of 36 patients revealed high negative correlations between ticagrelor concentrations and platelet reactivity evaluated with all three platelet function tests (the VASP-assay: RS=-0.722; p<0.0001; the VerifyNow device: RS=-0.715; p<0.0001; the Multiplate analyzer: RS=-0.722; p<0.0001), with no significant differences between correlation coefficients. Similar results were found for AR-C124910XX. Platelet reactivity values assessed with all three methods generally correlated well with each other; however, a significantly higher correlation (p<0.02) was demonstrated between the VerifyNow and Multiplate tests (RS=0.707; p<0.0001) than in other assay combinations (the VASP-assay and the VerifyNow device: RS=0.595; p<0.0001; the VASP-assay and the Multiplate analyzer: RS=0.588; p<0.0001). With respect to the recognition of high platelet reactivity, we found higher measurement concordance between the VerifyNow and Multiplate tests compared with other assay combinations, while for low platelet reactivity, only results of the VerifyNow and Multiplate assay were related to each other. Platelet reactivity measurements performed with the VASP, VerifyNow and Multiplate tests show comparably strong negative correlations with ticagrelor and AR-C124910XX concentrations.

Introduction: Poor medication adherence is associated with unsatisfactory health outcomes, elevated mortality, and high costs of medical care. This study aimed to assess the implementation of therapeutic recommendations in high cardiovascular-risk patients based on self-report questionnaires. Material and methods:The study included 194 patients from the Cardiology Outpatient Clinic. Two self-reported questionnaires were used to assess medication adherence: the Medication Adherence Questionnaire (MAQ) and the Adherence in Chronic Diseases Scale (ACDS).Results: Antihypertensive drugs were prescribed to 65.46% of the patients. According to the MAQ, 54.33% of them reported high adherence, 21.26% medium adherence, and 24.41% low adherence to the treatment. Lipid-lowering drugs were prescribed to 46.39% of the patients, all of whom were treated with statins. Among this group, 34.44% reported high adherence, 27.78% medium adherence, and 37.78% low adherence to pharmacotherapy. According to the ACDS, the majority of patients (45.55%) received a score indicating medium adherence (21-26 points), 39.27% high adherence (> 26 points), and 16.75% low adherence to treatment (< 21 points). A high level of adherence was declared by 61.54% of the patients that reached the therapeutic goal of lipid-lowering therapy, defined as LDL-C of < 2.6 mmol/L (< 100 mg/dL). On the other hand, among the patients whose LDL-C remained elevated, 23.44% declared high adherence to treatment. There were no significant differences in achieving the intended therapeutic goal of blood pressure (BP ≤ 140/90 mmHg) in the groups with high, medium and low adherence (26.53% vs. 23.47% vs. 50.00%; p = 0.1880). Conclusion:Despite higher adherence to treatment in the patients with hypertension compared to patients with hyperlipidemia, the latter more often achieved the therapeutic goal. Declarations regarding high adherence to medication in the MAQ and in the ACDS are consistent in patients with hyperlipidemia and hypertension.

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Background. Many reports have demonstrated excessive variability in response to clopidogrel, the most commonly used P2Y12 receptor antagonist. Clopidogrel resistant patients are at increased risk of cardiovascular (CV) events. Prasugrel is a new P2Y12 inhibitor that provides greater and faster platelet inhibition and reduces CV events more effectively than clopidogrel. The aim of this study was to evaluate the variability and efficacy of prasugrel antiplatelet activity in patients presenting with acute coronary syndrome (ACS). Materials and methods. The study was designed as a prospective, single-center, non-randomized, observational trial. Platelet reactivity (PR) was assessed with the VeryfyNow assay three times during hospitalization in forty-two patients undergoing percutaneous coronary intervention (PCI) for ACS and treated with standard doses of prasugrel. Results. Platelet aggregation with prasugrel displayed relatively high variability. The platelet aggregation was lowest on the 3 rd day of the treatment at 4 p.m. and was significantly different from the measurements obtained on the 3 rd and 4 th day in the morning (6.0 v. 8.5 U; p = 0.0005 and 6.0 v. 36.5 U; p < 0.00001, respectively), with the latter two differing significantly from each other (p = 0.002). All participants were successfully treated with prasugrel achieving PR < 208 PRU in each measurement, whereas 42.9-80.9% (depending on sampling point) of patients presented very low platelet activity. The subgroups of stable and persistent low PR included a higher percentage of active smokers (73.3 v. 40.7%; p = 0.04 and 80.0 v. 43.8%; p = 0.04, respectively). Conclusions. Prasugrel treatment is associated with high variability of PR. Nonetheless, prasugrel is a highly effective antiplatelet drug. Active smoking may predispose to strong and stable on-prasugrel platelet inhibition.