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

Percutaneous coronary intervention (PCI) is the most common form of revascularisation in the management of ischaemic heart disease. PCI is a prothrombotic process requiring antithrombotic therapy to prevent the formation of stent thrombosis. The standard oral therapy for preventing stent thrombosis is the combination of aspirin and a platelet P2Y12 receptor antagonist (‘P2Y12 inhibitor’). Clopidogrel is an oral thienopyridine P2Y12 inhibitor and produces an active metabolite that binds irreversibly to the P2Y12 receptor. However, clopidogrel is limited by wide interindividual variation in pharmacodynamic efficacy, partly related to genetic variation in activity of cytochrome P450 (CYP) 2C19. Clopidogrel was the standard-of-care in all PCI patients for the last 2 decades until the adoption of ticagrelor in 2012. Ticagrelor is a potent oral P2Y12 inhibitor that binds reversibly to the receptor and, unlike thienopyridines, has a weak effect on cellular adenosine uptake. Ticagrelor is used first-line, at a dose of 90 mg twice daily, in patients with acute coronary syndromes and is also used, at the lower dose of 60 mg twice-daily, in patients who have hade a myocardial infarction more than 1 year previously and are at high risk of further ischaemic events. However, ticagrelor has not previously been studied in patients with stable coronary artery disease (CAD) undergoing PCI, in whom clopidogrel remains the standard-of-care, despite its pharmacodynamic limitations. I, therefore, performed the Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable CAD (STEEL PCI) to characterise ticagrelor at its available doses in comparison to standard therapy with clopidogrel.
STEEL PCI included 180 aspirin-treated stable CAD patients who were planned to undergo elective PCI. Patients were randomised 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg or 60mg twice-daily, both with 180mg loading dose. The primary endpoint was the extent of adenosine uptake within 15 seconds in whole blood using an in vitro assay. Adenosine uptake assay, plasma adenosine concentration and platelet reactivity were assessed at the time of the procedure and pre- and post-maintenance dose at 1 month. High-sensitivity troponin T (hs-TnT) was measured pre- and 18-24 hours post-PCI to assess PCI-related myocardial injury. Plasma levels of ticagrelor and an active metabolite were assessed at the same time as platelet reactivity in the ticagrelor-treated patients. Genetic analyses were performed to assess the effects of variants that influence either clopidogrel active metabolite formation or ticagrelor pharmacokinetics. Adverse events were recorded.
No effect of ticagrelor on in vitro adenosine uptake or plasma adenosine concentration was seen at any timepoint (all P > 0.4). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 % inhibition at 1 month, mean ± SD, pre-dose: ticagrelor 60mg 73 ± 20%, ticagrelor 90mg 83 ± 17%, and clopidogrel 21 ± 17%; post-dose: ticagrelor 60mg 86 ± 13%, ticagrelor 90mg 90 ± 9%, and clopidogrel 32 ± 22%; all P < 0.0001 for ticagrelor vs clopidogrel). The more consistent platelet inhibition with ticagrelor was seen even in those who were predicted, through genetic testing, to have normal CYP2C19 activity. Mean (± SD) hsTnT increase was 50 ± 73 ng/l for the clopidogrel group, 82 ± 157 ng/L for the ticagrelor 60-mg group and 48 ± 76 ng/L for the ticagrelor 90-mg group (all P = ns). There were no PLATO-defined major or minor bleeds and no cases of MACE or stent thrombosis in any of the groups. One non-cardiac death occurred in the ticagrelor 90mg group.
In conclusion, both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel, regardless of genotype, but had no detectable effect on cellular adenosine uptake or troponin release following PCI.