Alternative P2Y12 inhibitors were associated with lower risk of major atherothrombotic events compared to clopidogrel in CYP2C19 loss-of-function allele carriers with scores ≥10 (HR 0.48; P=0.004).
Cohort (n=4,335)
Does alternative P2Y12 inhibitor therapy reduce major atherothrombotic events compared to clopidogrel in post-PCI patients stratified by ABCD-GENE score and CYP2C19 genotype?
Alternative P2Y12 inhibitors (prasugrel or ticagrelor) are more effective than clopidogrel in CYP2C19 loss-of-function carriers after PCI, regardless of their clinical ABCD-GENE score.
Hazard Ratio: 0.89 (95% CI 0.65–1.22)
p-value: p=0.475
BACKGROUND An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.
“One of the problems with genotyping is that genotypes don't explain all the reasons for why a patient may be a clopidogrel nonresponder. There are genetic factors, but there are also nongenetic factors such as clinical factors that contribute to clopidogrel response. So on this background, we thought: why not come up with a scoring system that can improve the accuracy with which we define clopidogrel nonresponse by using both clinical and genetic factors?”
Thomas et al. (2024) conducted a cohort in Percutaneous coronary intervention (n=4,335). Alternative P2Y12 inhibitor (prasugrel or ticagrelor) vs. Clopidogrel was evaluated on Major atherothrombotic events (MAE) within 1 year after PCI (HR 0.89, 95% CI 0.65-1.22, p=0.475). Alternative P2Y12 inhibitors were associated with lower risk of major atherothrombotic events compared to clopidogrel in CYP2C19 loss-of-function allele carriers with scores ≥10 (HR 0.48; P=0.004).