Which platelet function test best reflects the in vivo plasma concentrations of ticagrelor and its active metabolite?

Abstract

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.

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

“…Multiple regression analysis of the IMPRESSION study revealed that opioid treatment is not the only predictor of lower ticagrelor concentration in AMI patients—in the trial population (STEMI and NSTEMI patients) the presence of STEMI independently correlated with reduced ticagrelor concentration (R 2 = 0.17; beta-coefficient = -0.28; p = 0.014) [10]. Similar conclusions were drawn from a post hoc subanalysis of the HARMONIC study, where STEMI patients had decreased overall and delayed maximum ticagrelor and AR-C124910XX concentrations when compared with NSTEMI patients, which subsequently led to weaker platelet inhibition in STEMI [12]. Likewise, Franchi et al reported that STEMI patients suffer from impaired ticagrelor absorption in comparison with healthy subjects and patients with stable coronary artery disease, which was reflected by delayed onset of platelet inhibition and importantly was also observed in opioid-naive STEMI patients [9].…”

“…This indicates that in case of impaired ticagrelor bioavailability, AMI patients may be at risk of inadequate platelet inhibition at a time when it is most desired. Data from available pharmacokinetic/pharmacodynamic (PK/PD) studies suggest that STEMI diagnosis may be associated with delayed and attenuated ticagrelor plasma concentration and action, when compared with NSTEMI patients [10, 12]. Moreover, this adverse relationship can be further aggravated by the administration of morphine, commonly administered in AMI, especially in STEMI [8, 10, 13].…”

Determinants of high platelet reactivity in patients with acute coronary syndromes treated with ticagrelor

“…Recent pharmacodynamic studies have suggested that ACS patients presenting with ST-segment elevation myocardial infarction (STEMI) and those treated with morphine appear to be at increased risk of impaired and postponed platelet blockade following ticagrelor LD 12–15,17,19 . However, little is known about other potential clinical variables influencing acute response to ticagrelor in the setting of ACS.…”

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

“… 15 20 21 Moreover, subanalyses of two pharmacokinetic/pharmacodynamic trials suggest that STEMI in comparison with NSTEMI is independently associated with lower plasma concentration of ticagrelor. 18 22 …”

“…Currently, there are no data directly comparing ticagrelor pharmacokinetics in the mentioned types of AMI, while patients with STEMI may be at risk of having lower ticagrelor plasma concentration in the most crucial time during the early hours of AMI treatment. 18 22 Similarly, potential differences in ticagrelor antiplatelet action between STEMI and NSTEMI have not been defined yet. Therefore, we decided to explore whether the pharmacokinetics and pharmacodynamics of ticagrelor differ between patients with STEMI and NSTEMI.…”