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Ticagrelor vs. Clopidogrel in Elective PCI
Study Questions:
What are the pharmacodynamic effects of ticagrelor and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD)?
Methods:
The STEEL-PCI trial investigators randomized 180 aspirin-treated stable CAD patients, who were scheduled to undergo elective PCI in a single center 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90 mg (T90) or 60 mg twice-daily (T60), both with 180 mg 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 time points. High-sensitivity troponin T (hs-TnT) was measured pre- and 18-24 hours post-PCI. The primary endpoint of the study was in vitro adenosine uptake post-maintenance dose at 1 month, measured as residual adenosine concentration at 15 seconds after ex vivo addition of adenosine. Continuous data were compared using Kruskal-Wallis test, where appropriate using Mann-Whitney test for pairwise comparisons, and categorical variables were compared using Chi-square test or Fisher’s exact test.
Results:
A total of 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 15 seconds, mean ± standard deviation [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 time points, 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 P2Y12 reaction unit [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 (interquartile range) hs-TnT 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:
The authors concluded that both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel, but did not appear to affect troponin release following PCI.
Perspective:
This randomized study reports that the ticagrelor loading dose and maintenance doses achieved greater and more consistent levels of platelet inhibition compared to standard regimens of clopidogrel in stable CAD patients at the time of, and 1 month after, PCI. However, there was no evidence that ticagrelor was more effective than clopidogrel in attenuating troponin release, suggesting that the extent of myocardial injury induced by PCI is not usually sensitive to levels of platelet P2Y12 inhibition in a low-risk population. The current study does not appear to justify routine use of ticagrelor in stable CAD patients undergoing PCI. The ongoing study ALPHEUS (Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) will provide additional insight on safety and efficacy of more potent platelet inhibition with ticagrelor in elective PCI.
Keywords: Adenosine, Aspirin, Biomarkers, Blood Platelets, Chromatography, High Pressure Liquid, Coronary Artery Disease, Dyspnea, Ischemia, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Secondary Prevention, Troponin, Troponin T
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