Effects of CYP3A4*22 carrier and CYP3A5 expressor status on clinical outcome in patients treated with ticagrelor for acute coronary syndrome

Abstract

Abstract Background Current guidelines recommend using ticagrelor in patients with acute coronary syndrome. Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. CYP3A4*22 allele and the CYP3A5 expressor status influence the metabolization of ticagrelor, increasing plasma concentration and platelet inhibition. Nevertheless, little is known about the impact of the CYP3A4*22 allele or CYP3A5 expressor status on clinical outcomes in ticagrelor treated patients. Purpose Our study aims to assess the effects of the CYP3A4*22 allele and CYP3A5 expressor status in patients with STEMI and treated with ticagrelor, with regards to clinical outcomes and the clinical side-effect dyspnea. Methods Patients from the POPular Genetics trial treated with ticagrelor were genotyped for the CYP3A4*22 and CYP3A5*3 alleles. Patients were divided into two groups based on their CYP3A4 (*22 carriers vs. *22 non carriers) and CYP3A5 status (expressor vs. non-expressors). The primary thrombotic endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis and stroke. The primary bleeding outcome consisted of PLATO major and minor bleeding. The key secondary endpoint was clinically relevant dyspnea. The follow-up duration was one year. Results A total of 1,281 patients with ST-elevation myocardial infarction (STEMI) were used for the analyses. In the first analysis, CYP3A4*22 carriers (n=152) versus CYP3A4*22 non-carriers (n=1,129) were not found to have a significant correlation with the primary thrombotic outcome (1.3% vs. 2.5% adjusted hazard ratio 1.81 [0.43–7.62]) or the primary bleeding outcome (13.2% vs. 11.3% adjusted hazard ratio 0.93 [0.58–1.50]) (See Figure 1 and 2). CYP3A5 expressors (n=196) versus non-expressors (n=926) did not show a significant difference for the primary thrombotic outcome (2.6% versus 2.5% adjusted hazard ratio 1.03 [0.39–2.71] or the primary bleeding outcome (12.8% versus 10.9% adjusted hazard ratio 1.13 [0.73–1.76]). With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers 44.0% vs. 45.0%, risk ratio 1.04 [0.45–2.42] or CYP3A5 expressors versus CYP3A5 non-expressors 35.3% versus 47.8% risk ratio 0.60 [0.27–1.30]. Conclusions In STEMI patients treated with ticagrelor, CYP3A4*22 carriers and CYP3A5 expressors did not affect clinical outcomes with regards to thrombotic events, bleeding rate, or the side-effect dyspnea. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Netherlands Organization for Health Research and Development (ZonMW). The authors are solely responsible for designing and conducting this study, conducting all study analyses, and drafting and editing the manuscript and its final contents.