Findings from this research demonstrated a significant association between the presence of the CYP2C19*2 allele and ISR within one-year post-PCI in both the univariate (OR 8.4, p < 0.001) and multivariate analysis (OR 22.6, p = 0.001). The risk of developing ISR within one-year post-PCI on clopidogrel therapy was shown to be significantly higher in CYP2C19 *2 carriers than in non-carriers and the signal observed in the previous study by Wirth et al.[24] was confirmed. A recent study by Zhang et al[26] supports these findings, where significantly higher rates of ISR were observed in carriers of the CYP2C19 loss-of-function alleles (*1/*2, *1/*3) on standard dose clopidogrel compared to non-carriers.
Further to CYP2C19*2 carrier status, the multivariate analysis in the present study identified a significant association between non-genetic factors namely previous revascularisation, heart failure and active smoking and incidence of ISR. The finding with respect to previous revascularisation is in accordance with three previous studies, where history of PCI was identified as an independent predictor of DES-ISR. [27–29] As regards heart failure, a similar significant association between heart failure and ISR was reflected in two previous studies. [27, 30] Conflicting evidence on the effect of smoking on ISR has been reported. Similar to the present study, smoking was observed to be a significant predictor of ISR in two studies [31, 32], while three other studies found no association. [33–35] Conversely, it has also been reported that smoking may have a ‘protective effect’ contributing to decreased high platelet reactivity while on clopidogrel therapy and enhanced clinical benefit of clopidogrel in smokers compared to non-smokers, a phenomenon described as the ‘’smoker’s paradox’’. [27, 36–38]
A higher number of cases compared to controls in the present study underwent PCI with multiple stenting, however there was no statistically significant association between ISR and a higher number of stents implanted. This finding contrasts with other studies which demonstrated that the number of stents deployed was an independent predictor of ISR. [30,39−42] This association may be due to the increased probability of vessel trauma causing intimal hyperplasia increases with the increase in number of stents deployed [43, 44]. Vessel trauma caused by an increase in the number stents deployed may precipitate the initiation of the inflammation cascade, causing the recruitment of platelets, neutrophils and fibrin, along with the proliferation of smooth muscle and fibroblasts, leading to the development of ISR. [45–47]
Twenty-six percent of the present study cohort were carriers of one or two CYP2C19 *2 alleles. These patients had an ‘Actionable’ genotype with regards to clopidogrel and were eligible for CYP2C19 genotype-guided intervention according to guidance from the CPIC and the Royal Dutch Association for the Advancement of Pharmacy-Pharmacogenetics Working Group (DPWG), which recommend carriers of CYP2C19*2 to be prescribed alternative P2Y12 inhibitors (prasugrel or ticagrelor) instead of clopidogrel, if there is no-contraindication. [8, 48] Clopidogrel is the only P2Y12 inhibitor available on the Maltese National Health Service (NHS) and prasugrel and ticagrelor are available on the private market for out-of-pocket purchase. Inaccessibility, along with the price of alternative antiplatelet therapy, may have caused prescription hesitancy among cardiologists in the present study.
Over the past decade, clinical decision-making with respect to personalisation of antiplatelet therapy in patients undergoing PCI incorporating pharmacist-led CYP2C19 genotyping along with the consideration of non-genetic risk factors, has been implemented in various institutions, predominantly in the USA. This has come into effect as a result of the increasing reports of improved clinical and economic outcomes, access to guidance from entities such as the CPIC and DPWG, availability of alternative antiplatelet agents to clopidogrel, and the availability of rapid CYP2C19 genotyping. [5, 49–63]
The implementation of CYP2C19-guided antiplatelet therapy has been reported to result in better platelet inhibition and decreased adverse cardiac outcomes compared to patients who did not undergo CYP2C19-guided antiplatelet adjustments, in whom significantly poorer outcomes were observed. [51, 56, 57, 59, 60, 62] Although improved outcomes for patients have been reported, none of the evidence-base resulted from large, prospective clinical trials. As a result, the American Heart Association/American College of Cardiology and European Society of Cardiology guidelines do not presently recommend implementation of routine CYP2C19 pharmacogenetic testing to tailor DAPT. [64, 65] The recent large multi-site TAILOR-PCI trial showed very promising results and provided a signal supporting the benefit of CYP2C19 genotype-guided antiplatelet therapy.[66] Moreover, a sub-study from the POPular genetics trial showed that the genotype-guided group was non-inferior to standard therapy with regards to thrombotic events, with a reduction in thrombotic events in the genotype-guided group and a lower incidence of bleeding and ischaemia.[6] With the emerging evidence of the positive impact of CYP2C19 genotype-guided antiplatelet therapy selection on patient outcomes, particularly post-PCI, pharmacist-led pharmacogenetic programs hold great potential to optimise therapy and decrease adverse outcomes. [67]
The authors acknowledge the following limitations. The lower number of cases than controls with dyslipidaemia identified in clinical records did not match the patients’ medication history of statin therapy. This could be due to statins being prescribed for secondary prevention post-PCI and not to treat diagnosed dyslipidaemia or due to underreporting, causing discrepancies in the data collected. Low-density lipoprotein cholesterol and triglyceride levels were not recorded; hence this discrepancy could not be verified. Moreover, the correlation between lipid profile parameters and ISR would have been interesting to explore if recorded. Adherence to clopidogrel was not evaluated in this study and could be another factor that affects predisposition to ISR.