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

Abstract

Background: Data 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).

Methods: In 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.

Results: During 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.

Conclusions: Plasma 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 registration: ClinicalTrials.gov identifier: NCT02602444 (November 09, 2015).

Conflict of interest statement

Competing Interests: The authors of this manuscript have the following competing interests to declare: Jacek Kubica received a consulting fee from AstraZeneca, Piotr Adamski received honoraria for lectures from AstraZeneca. All other authors have reported no relationships relevant to the contents of this paper that could be construed as a conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Bioavailability of ticagrelor and AR-C124910XX over time in patients with STEMI and NSTEMI.

Plasma concentrations of (A) ticagrelor and (B) AR-C124910XX during the first 6 h after oral administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction.

Fig 2. Platelet reactivity over time in STEMI and NSTEMI patients.

Platelet reactivity evaluated with (A) the VASP assay and (B) Multiplate at baseline, and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 12 h after administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction, VASP: vasodilator-stimulated phosphoprotein.

Fig 3. Prevalence of high platelet reactivity over time in STEMI and NSTEMI patients.

Proportion of patients with high platelet reactivity assessed with (A) the VASP assay and Multiplate (B) at baseline, and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 12 h after administration of a 180 mg ticagrelor loading dose in patients with STEMI and NSTEMI. HPR: high platelet reactivity, NSTEMI: non-ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction, VASP: vasodilator-stimulated phosphoprotein.