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Genotype-Guided P2Y12 Inhibitor De-Escalation Strategy in ACS Patients
Quick Takes
- Use of a genotype-guided de-escalation strategy for DAPT prescribing is associated with improved safety and similar efficacy when compared to standard care.
- Patients who are noncarriers of CYP2C19 loss-of-function allele (ultra-rapid, rapid, or normal metabolizers) can be safely transitioned to clopidogrel from ticagrelor or prasugrel with no apparent increased thrombotic risk.
Study Questions:
Is genotype-guided de-escalation of P2Y12 inhibitors safe and effective in a real-world acute coronary syndrome (ACS) population?
Methods:
Data for this study were obtained from the FORCE-ACS (Future Optimal Research and Care Evaluation in Patients With Acute Coronary Syndrome) registry, which includes patients with ACS undergoing angiography across nine Dutch hospitals since February 2015. Beginning in 2021, one hospital implemented a CYP2C19 genotype-guided P2Y12 inhibitor de-escalation protocol from ticagrelor or prasugrel to clopidogrel in noncarriers (ultra-rapid, rapid, or normal CYP2C19 metabolizers). Loss-of-function carriers (intermediate or poor metabolizers) remained on ticagrelor. Patients were divided into two cohorts: a standard care cohort in which patients were treated with a P2Y12 inhibitor at the discretion of the treating physician, and a genotyped cohort, in which all patients received a CYP2C19 genotype test with a treatment recommendation based on the test result. The primary ischemic endpoint was a composite of cardiovascular mortality, myocardial infarction (MI), and stroke. The primary bleeding endpoint was a composite of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. All patients were monitored for a 1-year follow-up period.
Results:
Between February 2015 and December 2020, 4,915 patients from the registry had ACS and were treated with dual antiplatelet therapy (DAPT) but did not receive CYP2C19 genotype testing (standard care cohort). Another 406 patients with ACS and receiving DAPT who did undergo genotype testing were enrolled between June 2021 and September 2022 (genotyped cohort). The median age was 66 (interquartile range [IQR], 56-74) years in the standard care cohort and 64 (IQR, 55-73) in the genotyped cohort. Overall, 27.8% of patients were female. Patients in the genotyped cohort more often had previous spontaneous bleeding at baseline (10.8% vs. 4.3%) and ST-segment elevation myocardial infarction (STEMI) at initial presentation (57.6% vs. 42.4%) compared to patients in the standard care cohort. Conversely, patients in the standard care cohort more often presented with either unstable angina (7.5% vs. 3%) or NSTEMI (47% vs. 36.2%). Radial access was used to perform angiography at similar rates between genotyped and standard care cohorts (82.3% vs. 83.8%).
At 1-year follow-up, the primary ischemic endpoint occurred in 5.2% (n = 21) of genotyped patients compared to 6.9% (n = 337) in the standard care cohort (adjusted hazard ratio [adjHR], 0.82; 95% confidence interval [CI], 0.53-1.28). The primary bleeding rate was significantly lower in the genotyped cohort compared to the standard care cohort (4.7% vs. 9.8%; adjHR, 0.47; 95% CI, 0.30-0.76).
Conclusions:
Use of a genotype-guided de-escalation of P2Y12 inhibitors in patients with ACS resulted in a lower rate of bleeding without an increased risk of ischemic events compared to standard DAPT prescribing.
Perspective:
This study adds to previous data which showed a genotype-guided de-escalation strategy led to fewer bleeding events without increasing risk of thrombotic events compared to standard care. Additionally, in a meta-analysis, patients with CYP2C19 loss-of-function allele had less thrombotic events when treated with ticagrelor or prasugrel compared to those treated with clopidogrel, while wild type patients (normal metabolizers) demonstrated similar thrombotic rates with any P2Y12 inhibitor including clopidogrel.
Clinical Topics: Acute Coronary Syndromes
Keywords: Acute Coronary Syndrome, Genotype, Receptors, Purinergic P2Y12, Thrombosis
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