Comparison of Ticagrelor Pharmacokinetics and Pharmacodynamics in STEMI and NSTEMI Patients (PINPOINT): protocol for a prospective, observational, single-centre study

Abstract

IntroductionThe most common classification of acute myocardial infarction (AMI) is based on electrocardiographic findings and distinguishes ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). Both types of AMI differ concerning their epidemiology, clinical approach and early outcomes. Ticagrelor is a P2Y12 receptor inhibitor, constituting the first-line treatment for STEMI and NSTEMI. According to available data, STEMI may be associated with lower plasma concentration of ticagrelor in the first hours of AMI, but currently there are no studies directly comparing ticagrelor pharmacokinetics or antiplatelet effect in patients with STEMI versus NSTEMI.Methods and analysisThe PINPOINT study is a phase IV, single-centre, investigator-initiated, prospective, observational study designed to compare the pharmacokinetics and pharmacodynamics of ticagrelor in patients with STEMI and NSTEMI assigned to the invasive strategy of treatment. Based on an internal pilot study, the trial is expected to include at least 23 patients with each AMI type. All subjects will receive a 180 mg loading dose of ticagrelor. The primary end point of the study is the area under the plasma concentration-time curve (AUC(0–6)) for ticagrelor during the first 6 hours after the loading dose. Secondary end points include various pharmacokinetic features of ticagrelor and its active metabolite (AR-C124910XX), and evaluation of platelet reactivity by the vasodilator-stimulated phosphoprotein assay and multiple electrode aggregometry. Blood samples for the pharmacokinetic and pharmacodynamic assessment will be obtained at pretreatment, 30 min, 1, 2, 3, 4, 6 and 12 hours post-ticagrelor loading dose.Ethics and disseminationThe study received approval from the Local Ethics Committee (Komisja Bioetyczna Uniwersytetu Mikołaja Kopernika w Toruniu przy Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy; approval reference number KB 617/2015). The study results will be disseminated through conference presentations and peer-reviewed journals.Trial registration numberNCT02602444; Pre-results.

Comparison of bioavailability and antiplatelet action of ticagrelor in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction: A prospective, observational, single-centre study

“…Main exclusion criteria were: contraindication to ticagrelor, treatment with any P2Y12 receptor inhibitor within 14 days prior to study enrolment, ongoing treatment with oral anticoagulant or chronic therapy with low molecular weight heparin, active bleeding, Killip class III or IV during screening for eligibility and respiratory failure. The complete list of exclusion criteria has been previously published [15]. …”

“…In each patient specimens were collected at the eight pre-defined time. Detailed description of blood sample processing has been published in the study protocol (S1 File) [15]. …”

“…Ticagrelor and AR-C124910XX plasma concentrations were analyzed with liquid chromatography coupled with tandem mass spectrometry, using a validated method [15]. Lower limits of quantification were 4.69 ng/mL for both ticagrelor and AR-C124910XX.…”

“…Based on the results obtained from the analysis of the first 45 consecutively enrolled patients (15 with NSTEMI and 30 with STEMI), and assuming a two-sided alpha value of 0.05, we calculated, using the t-test for independent variables, that enrolment of at least 23 patients in each study arm would provide 95% power to demonstrate a significant difference in AUC (0–6) for ticagrelor between patients with different types of AMI as presented in the study protocol (S1 File) [15]. …”

Impact of mild therapeutic hypothermia on bioavailability of ticagrelor in patients with acute myocardial infarction after out-of-hospital cardiac arrest

“…It has been shown that plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) are diminished in patients with ST-segment elevation MI. This effect is even more pronounced with concomitant morphine administration [13][14][15][16][17][18][19]. In survivors of OHCA due to MI additional factors including mild therapeutic hypothermia (MTH) may further impede ticagrelor's bioavailability [20][21][22].…”