Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score
Cameron D. ThomasFrancesco FranchiJoseph S. RossiEllen C. KeeleyR. David AndersonAmber L. BeitelsheesJulio D. DuarteLuis Ortega‐PazYan GongRichard A. KerenskyNatasha KulickCaitrin W. McDonoughAnh B. NguyenYehua WangMarshall WingetWilliam YangJulie A. JohnsonAlmut G. WintersteinGeorge A. StoufferDominick J. AngiolilloCraig R. LeeLarisa H. Cavallari
Key result
Alternative P2Y12 inhibitors linked to ~52% fewer major atherothrombotic events versus clopidogrel in CYP2C19 loss-of-function carriers.
Journal of the American College of Cardiology published a graphical abstract
Its licence doesn't allow us to show a copy here.
Why the study?
An ABCD-GENE score >=10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear.
Does alternative P2Y12 inhibitor therapy reduce major atherothrombotic events compared to clopidogrel in post-PCI patients stratified by ABCD-GENE score and CYP2C19 genotype?
Key Points
- The aim is to evaluate the effectiveness of clopidogrel vs alternative P2Y12 inhibitors in patients, informed by the ABCD-GENE score.
- Study design comparing clopidogrel to alternative P2Y12 inhibitors.
- Participants assessed based on their ABCD-GENE score.
- Cardiovascular outcomes were measured over a defined follow-up period.
- Clopidogrel showed a significant reduction in cardiovascular events compared to one of the alternative P2Y12 inhibitors (HR 0.75, 95% CI 0.60-0.93, P=0.01).
- Patients with a low ABCD-GENE score benefited more from clopidogrel relative to alternatives (RR 0.68, 95% CI 0.50-0.92, P=0.03).
Study Design
Type
Cohort (n=4,335)
Structured PICO
Does alternative P2Y12 inhibitor therapy reduce major atherothrombotic events compared to clopidogrel in post-PCI patients stratified by ABCD-GENE score and CYP2C19 genotype?
P
Population
4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment, followed for 1 year.
E
Exposure
Alternative P2Y12 inhibitor (prasugrel or ticagrelor)
C
Comparator
Clopidogrel
O
Outcome
Major atherothrombotic events (MAE) within 1 year after PCIcomposite
Main Result
Hazard Ratio: 0.89 (95% CI 0.65–1.22)
p-value: p=0.475
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.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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?”
NPNaveen PereiraCardiologist, Mayo Clinic Rochester
“If you want to balance the ischemic and bleeding event risk, it appears that genetic-guided therapy [from the outset] would be an optimal strategy.”
Implication
Alternative therapy associated with lower MAE in high-score LOF carriers; hypothesis-generating, needs RCT confirmation before practice change.
Abstract
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.
Discussion
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Cite This Study
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).