Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation

Abstract

Introduction: Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y₁₂ inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS.

Materials and methods: In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y₁₂.

Results: The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 μM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed.

Conclusion: In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy.

Clinical trial registration: [ClinicalTrials.gov], identifier [NCT02457130].

Keywords: antiplatelet therapy; chronic coronary syndrome; diabetes mellitus; high platelet reactivity; ticagrelor.

FIGURE 1

Flow diagram of the study design and enrollment process. LD, loading dose.

FIGURE 2

Schematic representation of the light transmission aggregometry assay. (A) Sample preparation. Platelet-rich plasma (PRP) is obtained as a supernatant after centrifugation of citrated blood at 100 g for 10 min; afterward, platelet-poor plasma (PPP) is obtained by a second centrifugation of the blood fraction at 1500 g for 15 min. (B) Methodology. In the aggregometer, light transmission is adjusted to 0% for PRP and to 100% for PPP for each measurement; during light transmission aggregometry, samples are constantly stirred at 1000 rpm; the addition of an agonist (ADP, arachidonic acid, collagen, etc.) to the PRP causes platelet aggregation, which is reflected by an increase in light transmission; platelet aggregation is monitored for at least 6 min. (C) Example of an aggregation curve. Baseline tracings are observed for stability and oscillations before the addition of an agonist (e.g., ADP); which can be seen in the curve as a spike; results are commonly reported as maximal platelet aggregation, which represents the maximal amplitude or% aggregation during the monitoring period. ADP, adenosine diphosphate; MPA, maximal platelet aggregation; PPP, platelet-poor plasma; PRP, platelet-rich plasma.

FIGURE 3

Platelet reactivity across study time points. Comparison of platelet reactivity over time measured with LTA and using 20 μmol ADP as agonists (primary endpoint). Values are expressed as least-squares means. Error bars indicate standard errors of the mean. *p < 0.001; ^§ p < 0.05. ADP, adenosine diphosphate; LTA, Light transmission aggregometry, MPA, maximal platelet aggregation.

FIGURE 4

Platelet function measurements across study time points. (A) Light transmittance aggregometry using 5 μM adenosine diphosphate (ADP) as agonist. (B) Flow cytometric VASP analysis. (C) Multiple electrode aggregometry using ADP as agonist. (D) VerifyNow P2Y₁₂ assay. Values are expressed as least-squares means. Error bars indicate standard errors of the mean. *p < 0.001; ^§p < 0.05. LTA, light transmission aggregometry; MPA, maximal platelet aggregation; VASP, vasodilator-stimulated phosphoprotein.

FIGURE 5

Percentage of patients with high platelet reactivity according to treatment with all platelet function tests and agonists. (A) HPR rates at 2 h; (B) HPR rates at 24 h; (C) HPR rates at 1 week. HPR, high on-treatment platelet reactivity; LTA, light transmission aggregometry; MEA, multiple electrode aggregometry; PRI, platelet reactivity index; PRU, P2Y₁₂ reaction units; VN, VerifyNow; VASP, vasodilator-stimulated phosphoprotein.