Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease (STEEL-PCI)

Abstract

Background -Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. Methods -180 aspirin-treated stable CAD patients, who were planned to undergo elective PCI in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg (T90) or 60mg twice-daily (T60), both with 180mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and post-dose at 1 month, by adding adenosine 1 μmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30 and 60 seconds then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T (hsTnT) was measured pre- and 18-24 hours post-PCI. Results -174 patients underwent an invasive procedure, of which 162 patients received PCI (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen post-dose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15s, mean ± SD: clopidogrel 0.274 ± 0.101 μmol/L; T90 0.278 ± 0.134 μmol/L; T60 0.288 ± 0.149 μmol/L; P = 0.37). Similarly no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P > 0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow PRU, 1 month, mean ± SD: pre-dose, T60: 62 ± 47, T90: 40 ± 38, clopidogrel 181 ± 44; post-dose, T60: 34 ± 30, T90: 24 ± 21, clopidogrel 159 ± 57; all P < 0.0001 for ticagrelor vs clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow PRU>208, 1-month post-dose: 0%, 0% and 21%, respectively). Median (IQR) hsTnT increase was 16.9 (6.5-46.9) ng/l for clopidogrel, 22.4 (5.5-53.8) ng/L for T60 and 17.7 (8.1-43.5) ng/L for T90 (P = 0.95). There was a trend towards less dyspnea with T60 versus T90 (7.1% vs 19.0%; P = 0.09). Conclusions -Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release following PCI. Clinical Trial Registration -URL: https://ichgcp.net/clinical-trials-registry/NCT02327624" title="See in ClinicalTrials.gov">NCT02327624.

Keywords: adenosine; clopidogrel; percutaneous coronary intervention; platelets; ticagrelor.

Figures

Figure 1.

Study design. Hs indicates high-sensitivity; LD, loading dose; LTA (ADP), light transmittance aggregometry with ADP; PCI, percutaneous coronary intervention; and R, randomization.

Figure 2.

CONSORT study (Consolidated Standards of Reporting Trials) flow diagram. Number of patients in each of the 3 treatment groups (clopidogrel, ticagrelor 60 mg BID, and ticagrelor 90 mg BID) at each stage of the study. CAD indicates coronary artery disease; PCI, percutaneous coronary intervention; and R, randomization.

Figure 3.

Whole blood in vitro adenosine uptake. Residual adenosine levels at 15 seconds after mixing adenosine 1 μmol/L with blood samples obtained (A) at the time of percutaneous coronary intervention following a standard loading regimen of clopidogrel (n=54) or 180 mg loading dose of ticagrelor (n=50 and 54 for 60 mg and 90 mg groups, respectively), and (B) after 1 month of treatment, premaintenance dose and postmaintenance dose for each of the 3 treatment groups (clopidogrel 75 mg QD: n=45; ticagrelor 60 mg BID: n=46; and ticagrelor 90 mg BID; n=43 and 45). Horizontal bars indicate mean±SD. P values determined using 3-group comparison with Kruskal-Wallis test.

Figure 4.

Plasma adenosine concentration. Plasma adenosine levels (A) at the time of percutaneous coronary intervention following a standard loading regimen of clopidogrel (n=56) or 180 mg loading dose of ticagrelor (n=50 and 54 for 60 mg and 90 mg groups, respectively) and (B) after 1 month of treatment, premaintenance dose and postmaintenance dose for each of the 3 treatment groups (clopidogrel 75 mg QD: n=45; ticagrelor 60 mg BID: n=46; and ticagrelor 90 mg BID: n=43). Horizontal bars show mean±SD. P values determined using 3-group comparison with Kruskal-Wallis test.

Figure 5.

VerifyNow P2Y12 Assay Results. Individual VerifyNow P2Y12 assay results expressed as (A and C) P2Y12 reaction units (PRU) and (B and D) VerifyNow percentage inhibition, (A and B) at the time of percutaneous coronary intervention following a standard loading regimen of clopidogrel (n=59) or 180 mg loading dose of ticagrelor (n=54 and 58 for 60 mg and 90 mg groups, respectively) and (C and D) after 1 month of treatment, premaintenance dose and postmaintenance dose for each of the 3 treatment groups (clopidogrel 75 mg QD: n=52; ticagrelor 60 mg BID: n=52; and ticagrelor 90 mg BID: n=48). The dashed lines indicate a level of 208 PRU as a threshold for high platelet reactivity. Horizontal bars indicate mean±SD. P values determined using 3-group comparison with Kruskal-Wallis test with pairwise comparisons using Mann-Whitney test; * P<0.01; *** P<0.0001.

Figure 6.

ADP-induced platelet aggregation determined by LTA. Individual results for the platelet aggregation measured by light transmittance aggregometry in response to ADP 20 μmol/L (A) at the time of percutaneous coronary intervention following a standard loading regimen of clopidogrel (n=59) or 180 mg loading dose of ticagrelor (n=54 and 55 for 60 mg and 90 mg groups, respectively) and (B) after 1 month, premaintenance dose and postmaintenance dose for each of the 3 treatment groups (clopidogrel 75 mg QD: n=50 and 51; ticagrelor 60 mg BID: n=51 and 52; and ticagrelor 90 mg BID: n=45 and 48). The dashed lines indicate a level of 59% as a threshold value for high platelet reactivity. Horizontal bars indicate mean±SD. P values determined using 3-group comparison with Kruskal-Wallis test with pairwise comparisons using Mann-Whitney test; *** P<0.0001. LTA indicates light transmittance aggregometry; and max, maximum.