Letter by Siasos et al Regarding Article, “Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease”
Authors: Gerasimos Siasos, Demetrios Moris, Dimitris Tousoulis
Journal: Circulation (2017)

We read with great interest the work by Jones et al 1 comparing the efficiency of P2Y 12 receptor inhibitors (clopidogrel versus ticagrelor) as antithrombotic regimens for long-term management in patients with symptomatic peripheral artery disease.Current knowledge in the field demonstrates that in patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management remains unknown. 2 The authors found that ticagrelor did not reduce the primary composite end point of cardiovascular mortality, myocardial infarction, or ischemic stroke compared with clopidogrel in patients with peripheral artery disease and a history of lower extremity revascularization. 1 Although these findings are interesting, it is not clear whether other factors involved in platelet reactivity and cardiovascular outcome were evaluated in depth.As is already highlighted in the literature, individual platelet response to antiplatelet therapy depends on a variety of factors, including genetic background, cellular interactions (accelerated platelet turnover, reduced CYP3A metabolic activity, increased adenosine diphosphate exposure, upregulation of P2Y 12 pathways), clinical factors (age, diabetes mellitus, smoking, left ventricular ejection function, body mass index, vascular function, creatinine clearance, inflammation, comorbidities, underdosing, poor absorption, concurrent medication), and geographic origin. 3,4As the authors demonstrated in Tables 1 and2, many of these factors were adequately randomized among medication groups in the revascularization arm of the study.It is not clear whether patients in the ankle-brachial index arm and patients without previous limb revascularization had any difference in the factors mentioned above.Despite the fact that the authors explained that all patients included in this trial underwent genotype testing for CYP2C19 and those with 2 loss-of-function alleles were excluded from the study, coexisting polymorphisms may affect platelet response variability and clinical outcome more than single polymorphisms.Thus, the individual genomic profile should include not only CYP2C19 polymorphisms but also all the polymorphic genes involved in the pharmacokinetic and pharmacodynamic response to P2Y 12 receptor inhibitor treatment.Moreover, a comparison among carriers of 1 reduced-function allele (CYP2C19*1/*2, heterozygotes) and noncarriers (CYP2C19*1/*1, wild-type homozygotes) would be of great clinical importance because studies of acute coronary disease have shown that the carriers of at least 1 CYP2C19*2 loss-of-function allele had marginally higher platelet reactivity and cardiovascular events compared with noncarriers. 5In addition, the authors did not evaluate the aspirin resistance rates in their population, which would be of interest because in both arms >70% of the patients were on aspirin.Polymorphisms in cyclooxygenase-1 and -2 genes should also be evaluated in the framework of aspirin resistance, which could be translated into clinical aspirin resistance and cardiovascular risk.