Prevalence and predictors of high on-treatment platelet reactivity in patients undergoing P2Y12 testing

Clopidogrel requires metabolic activation via hepatic CYP2C19. Insufficient metabolism leads to high on-treatment platelet reactivity (HTPR), which is associated with recurrent ischemic events. This study evaluated the prevalence of HTPR in patients at a comprehensive stroke center and examined clinical correlates with HTPR, including demographic and clinical characteristics. This retrospective cohort study included adults (≥18 years) admitted with a cerebrovascular diagnosis between 1/1/2022 and 1/1/2024 who had adequate clopidogrel exposure before inpatient P2Y12 platelet function testing (PFT). HTPR was defined as P2Y12 reaction units (PRU) ≥ 194 based on VerifyNow PFT assay. Chi-square tests and multivariate logistic regression with Firth correction compared HTPR across 22 covariates, including admission diagnosis, demographics, comorbidities, concomitant medications, and laboratory findings. There were 357 patients; most (n = 274, 77%) were chronic clopidogrel users while 83 patients received therapeutic clopidogrel in-hospital. The most common principal diagnoses were cerebral aneurysm (52%) and AIS (30%). HTPR was identified in 47 patients (13%). Hemoglobin values materially influenced VerifyNow HTPR classification; HTPR rates were 10% when hemoglobin was within normal limits (WNL, 27 of 284 patients), 36% with low hemoglobin (19 of 53), and 0% with elevated hemoglobin (0 of 16), p < 0.001. In the primary adjusted model, low hemoglobin was associated with greater odds of measured HTPR compared with hemoglobin WNL (adjusted odds ratio [aOR], 3.57, 95% CI, 1.66-7.58, p = 0.001); no other covariates were independently associated with HTPR. In the subset of 284 patients with hemoglobin WNL, diabetes was associated with greater odds of HTPR (aOR, 2.89; 95% CI, 1.10-7.25; p = 0.03) and DAPT was inversely associated with HTPR (aOR, 0.37; 95% CI, 0.15-0.97; p = 0.04). These findings underscore the importance of accounting for mediating factors associated with PFT when interpreting values, and recognizing demographic and pharmacologic factors for clopidogrel hyporesponsiveness in a diverse cerebrovascular population.