The clinical implementation of a de-escalation strategy using CYP2C19 genotyping in patients with an acute coronary syndrome: insights from the FORCE-ACS registry

Abstract Background Current guidelines recommend prasugrel and ticagrelor in patients undergoing percutaneous coronary intervention (PCI), however these potent P2Y12-inhibitors are associated with a higher bleeding risk when compared to clopidogrel. The CYP2C19 gene influences the efficacy of clopidogrel, with carriers of loss-of-function alleles having a higher risk for major adverse cardiovascular events. A genotype-guided strategy whereby noncarriers are treated with clopidogrel has been shown to reduce bleeding without increasing the risk of major adverse cardiovascular events and to be cost-effective. Currently, there are no practical guidelines for implementing a genotype-guided strategy and there are still operational issues regarding the usage of buccal swabs or venous blood samples. Purpose The study aimed to assess the feasibility of a CYP2C19 genotype-guided de-escalation strategy in acute coronary syndrome (ACS) patients treated with dual antiplatelet therapy and to evaluate the de-escalation rate. Methods ACS patients receiving genotype-guided antiplatelet therapy from August 2021 onwards were eligible. Genotyping was done using buccal swabs in a point-of-care (POC) device or by venous blood samples in the lab. Genotyping results were entered into the EHR. Attending physicians received automatic notifications to change antiplatelet therapy based on genotyping results, but subsequent management was at their discretion. The primary endpoint is maintenance therapy with P2Y12 inhibitors, with secondary endpoints being therapy changes, and time until genotype results. Therapy changes based on genotyping method were assessed using the Chi-square and Mann-Witney U test. Results In total, 1,530 patients with suspected ACS were included in the FORCE-ACS registry from June 2021 to January 2023. A CYP2C19 genotype test was performed in 738 ticagrelor treated patients and 260 (35%) patients carried a CYP2C19 LoF-allele. The median time to genetic test result was 6.2 hours, with 84.6% of results known within 24 hours for POCT and 15.4% for blood analysis. Of all 478 CYP2C19 LoF-allele noncarriers eligible for de-escalation, 433 (90.4%) patients were successfully de-escalated from ticagrelor to clopidogrel. De-escalation to clopidogrel occurred within 24 hours in 70.9% of patients and within 48 hours in 93.1%. The time to de-escalation was significantly lower in patients analyzed using POCT (25.4 hours) compared to blood analysis (58.9 hours). Conclusion The implementation of routine genotyping is feasible and de-escalation rates to clopidogrel in non-carriers are acceptable. The quicker time-to-results and de-escalation highlights the potential benefits of using POC testing.Overview of genotype-guided strategy