Key result
CYP2C19 loss-of-function carriers linked to ~65% higher on-treatment platelet reactivity after clopidogrel loading.
Why the study?
Does CYP2C19 loss-of-function carrier status affect P2Y12 reaction units in patients receiving clopidogrel after minor acute ischemic stroke or high-risk TIA?
Observational (n=35)
No
Does CYP2C19 loss-of-function carrier status affect P2Y12 reaction units in patients receiving clopidogrel after minor acute ischemic stroke or high-risk TIA?
P2Y12 reaction units are significantly higher in CYP2C19 loss-of-function carriers following minor stroke or TIA, suggesting PRUs may serve as a surrogate marker for clopidogrel nonresponse when genotyping is unavailable.
Answers are grounded in this paper and cite their sources.
Supports PRU as surrogate for CYP2C19 LOF after minor stroke/TIA; hypothesis-generating, requires validation before guiding therapy.
BACKGROUND: Recurrent stroke accounts for substantial morbidity and mortality worldwide, with up to 25% of ischemic strokes occurring in patients with prior strokes. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard for secondary prevention after minor acute ischemic stroke (AIS) or high-risk transient ischemic attack (TIA). However, clopidogrel efficacy is reduced in carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles. Although genotype-guided DAPT has been shown to improve outcomes, the limited availability, high cost, and turnaround time of CYP2C19 genotyping constrain real-world use. P2Y12 reaction units (PRUs) measured by the VerifyNow P2Y12 assay represent a potentially accessible alternative, but their relevance in the cerebrovascular population remains unclear. OBJECTIVE: To investigate the viability of PRUs as a surrogate biomarker for clopidogrel resistance, we aimed to assess the association of PRUs with CYP2C19 genotype, which has been previously proven as predictive of clinical outcomes in patients receiving DAPT after AIS. METHODS: We conducted a prospective observational study of adults with non-cardioembolic minor AIS or high-risk TIA treated with 21 days of DAPT between December 2021 and May 2023. PRUs were measured ≥ 12 h after a clopidogrel loading dose. The primary outcome was the group difference in PRUs by CYP2C19 LOF carrier status. Secondary outcomes included associations between high platelet reactivity (PRU ≥ 208), CYP2C19 genotype, and 30-day stroke recurrence. RESULTS: Of the 35 patients included in the primary analysis, 17% were CYP2C19 LOF carriers. Mean PRUs were significantly higher in LOF carriers (265 vs. 161; p < 0.01), and high platelet reactivity was more frequent among carriers (83% vs. 21%; p < 0.01) compared with noncarriers, respectively. Twenty-seven patients completed 30-day follow-up; 26% reported recurrent stroke symptoms, but neither CYP2C19 LOF status nor high platelet reactivity was associated. Post hoc application of the ABCD-GENE score did not improve prediction of high platelet reactivity or clinical outcomes. CONCLUSIONS: PRUs appear to vary by CYP2C19 genotype in patients receiving DAPT after minor AIS or TIA, suggesting utility as a surrogate marker of clopidogrel nonresponse when genotyping is unavailable. However, PRUs were not associated with short-term clinical outcomes.
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Stone et al. (2026) conducted an observational in Minor acute ischemic stroke or high-risk transient ischemic attack (n=35). CYP2C19 loss-of-function allele carrier status vs. CYP2C19 loss-of-function noncarriers was evaluated on Group difference in P2Y12 reaction units (PRUs) by CYP2C19 loss-of-function carrier status (p=<0.01). CYP2C19 loss-of-function carriers had higher mean P2Y12 reaction units compared to noncarriers after clopidogrel loading for minor stroke or TIA.
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