The pharmacology behind clopidogrel explains why such variability is possible in the first place. Clopidogrel is a prodrug, meaning it is pharmacologically inert when swallowed and must be converted by hepatic cytochrome P450 enzymes, most notably CYP2C19, into an active thiol metabolite that irreversibly binds the P2Y12 receptor on platelet surfaces. Blocking P2Y12 prevents adenosine diphosphate (ADP) from activating the platelet, which in turn suppresses the cyclic adenosine monophosphate (cAMP) signaling pathway that regulates the phosphorylation state of VASP, an intracellular platelet protein. When P2Y12 is effectively blocked, prostaglandin E1 (PGE1) can drive sustained VASP phosphorylation even in the presence of ADP; when P2Y12 remains active, ADP inhibits VASP phosphorylation. The VASP assay exploits this biochemistry directly: blood samples are incubated with either PGE1 alone or PGE1 plus ADP, platelets are permeabilized, phosphorylated VASP is labeled with a monoclonal antibody, and dual-color flow cytometry compares the two conditions. The PRI is then calculated from the corrected mean fluorescence intensities using the formula PRI = [(MFIc PGE1 − MFIc (PGE1 + ADP)) / MFIc PGE1] × 100. Higher PRI values indicate greater residual platelet reactivity, not greater clopidogrel inhibition, a distinction the researchers emphasize because the terminology around clopidogrel resistance is notoriously slippery.

Indeed, one of the most technically important aspects of this study is its careful handling of definitions. The terms clopidogrel resistance, hyporesponsiveness, high on-treatment platelet reactivity (HPR), and poor metabolizer status are often used interchangeably in the literature, but they reflect distinct concepts. HPR is a pharmacodynamic measurement indicating persistently elevated platelet reactivity despite treatment, whereas poor metabolizer status is a pharmacogenetic classification most often related to CYP2C19 loss-of-function alleles. Because VASP-PRI thresholds have been developed largely in coronary artery disease and percutaneous coronary intervention populations, and no universally accepted stroke-specific threshold exists, the researchers explicitly caution that their cutoffs should be interpreted cautiously in ischemic cerebrovascular populations. The operational threshold of PRI ≥70 percent used to define high residual platelet reactivity in this study was derived from coronary settings, and HPR has also been defined using lower thresholds in other clinical contexts. This lack of standardization is a significant barrier to incorporating platelet function testing into routine clinical practice, since different assays and cutoffs may classify the same patient differently depending on the specific biological pathway assessed.

The study’s design was deliberately structured to minimize system-level confounders. Northern Israel, and the Galilee region in particular, provides a unique setting in which Jewish and Arab populations receive care within the same healthcare system, allowing exploration of ethnic differences while controlling for the environmental and institutional factors that typically differ between separate populations. The prospective cohort was conducted at the Neurology Department of Ziv Medical Center between November 2020 and November 2022, and included 102 patients of whom 57 (55.9 percent) were Jewish and 45 (44.1 percent) were Arab. Ethnicity was self-reported. Patients were enrolled if they fulfilled one of two clopidogrel regimens: either a loading dose of 300 mg (in 62 patients) or 600 mg (in one patient) followed by at least two additional days of 75 mg daily maintenance, or at least 7 consecutive days of 75 mg daily maintenance dosing (39 patients). To avoid potential pharmacokinetic interactions affecting clopidogrel metabolism, patients receiving proton pump inhibitors, calcium channel blockers, or warfarin concurrently were excluded, as were patients with documented nonadherence and those unable to provide informed consent. Blood was drawn with a 19-gauge needle, the first 2.5 mL discarded to minimize artifactual platelet activation, collected into 3.2 percent sodium citrate tubes, stored at room temperature, and processed within 48 hours, a timeframe validated by the assay manufacturer.

The demographic and clinical characteristics of the cohort revealed some expected differences between the two groups. Jewish patients were significantly older than Arab patients, with a median age of 69 versus 64 years (p = 0.008), whereas Arab patients had a significantly higher body mass index, with a median of 28.6 versus 26.8 kg/m² (p = 0.019). No other demographic or clinical variables differed significantly between the groups. The overall cohort had a high prevalence of cardiovascular risk factors: 42.2 percent had diabetes mellitus, 55.9 percent had hypertension, and 58.8 percent had hyperlipidemia. The median age across all patients was 67 years, 62.7 percent were male, and the median BMI was 27.5 kg/m². These similarities in comorbidity profiles across ethnic groups are important because they suggest that the pharmacodynamic comparison was not confounded by grossly different clinical pictures, at least within the limits of what a cohort of this size can detect.

When it came to the primary endpoint, the results were unambiguous in one direction and cautious in the other. A valid VASP-PRI measurement was available for 101 patients, 57 Jewish and 44 Arab, with one Arab patient excluded due to a technical failure of the assay. The median PRI for all 101 patients was 65.5 percent (interquartile range 49.1–80.3), with no statistically significant difference between Jewish patients (median 61.1 percent) and Arab patients (median 68.7 percent), p = 0.251. When patients were categorized according to the operational thresholds, 42.6 percent overall had PRI ≥70 percent, 29.7 percent had PRI 50–69 percent, and only 27.7 percent had PRI <50 percent. Among Jewish patients, 38.6 percent had PRI ≥70 percent, compared with 47.7 percent among Arab patients, but this difference in the distribution of response categories was not statistically significant (p = 0.654). PRI also did not differ significantly between patients who received a loading dose and those treated with maintenance therapy alone (median 64.9 vs. 66.5 percent, p = 0.46). The researchers are careful to note that the ethnic comparison was exploratory and hypothesis-generating, and that the study was not powered to exclude modest between-group differences; the negative finding should not be interpreted as definitive evidence of equivalence.

Multivariable logistic regression analysis identified two factors independently associated with a lower likelihood of high residual platelet reactivity. Male sex was associated with reduced odds (OR = 0.28, 95 percent CI 0.08–0.93, p = 0.038), and smoking was similarly associated with reduced odds (OR = 0.18, 95 percent CI 0.04–0.81, p = 0.026). The smoking finding is consistent with prior reports that cigarette smoking can enhance clopidogrel activation, a phenomenon sometimes described in the cardiology literature. In contrast, age, BMI, Jewish ethnicity, hyperlipidemia, and diabetes mellitus were not significantly associated with high residual platelet reactivity in the regression model. Interestingly, when patients were compared according to their PRI category, BMI was significantly higher among non-responders (median 29.1 kg/m²) compared with adequate and intermediate responders (median 26.6 kg/m², p = 0.009), suggesting that adiposity may play a role in clopidogrel pharmacodynamics even if it did not reach significance in the multivariable model. No significant differences were observed between responders and non-responders with respect to sex, age, or the overall burden of risk factors.

The absence of CYP2C19 genotyping is a central limitation that the researchers acknowledge explicitly. CYP2C19 loss-of-function alleles, particularly the *2 and *3 variants, are well-established determinants of reduced clopidogrel active metabolite formation and increased platelet reactivity. The prevalence of these alleles varies markedly by ethnicity, with higher loss-of-function allele frequencies documented in East Asian populations (up to 65 percent) compared with Caucasian populations (approximately 30 percent). Pharmacogenetic studies have demonstrated variability in allele frequencies across ethnic groups, including among Jewish subpopulations such as Ashkenazi and Sephardi communities and Arab populations in the Middle East. Without genotyping data, the researchers cannot determine whether the observed variability in platelet responsiveness within their cohort reflects underlying genetic polymorphism distribution, clinical factors, or their interaction. This is precisely why they call for larger prospective studies incorporating CYP2C19 genotyping and longitudinal clinical outcomes to better delineate the relative contributions of genetic and clinical determinants of clopidogrel response across ethnic groups.

The clinical implications of this study must be interpreted within the current guideline framework. The 2021 American Heart Association/American Stroke Association guideline for secondary stroke prevention does not recommend routine platelet-function testing to guide antiplatelet therapy, reflecting the limited evidence that test-guided treatment modification improves clinical outcomes. The 2026 AHA/ASA guideline for the early management of acute ischemic stroke similarly identified the reliability and clinical utility of clopidogrel loss-of-function testing, as well as whether changing or increasing antiplatelet therapy based on such testing improves outcomes, as areas requiring further investigation. The researchers emphasize that their findings should not be interpreted as supporting routine platelet-function testing or treatment modification based on VASP-PRI, and that the study does not establish that increasing the clopidogrel dose, switching antiplatelet therapy, or adding antiplatelet agents according to PRI improves clinical outcomes. They also note that prasugrel should not be considered an alternative treatment in patients with a history of stroke or TIA, as prior cerebrovascular events are a contraindication to prasugrel therapy, and that long-term dual antiplatelet therapy is generally not recommended for secondary stroke prevention because of increased bleeding risk.

What makes this study genuinely novel is the direct head-to-head comparison within a single geographic region and healthcare system, minimizing the system-level confounding that has plagued prior pharmacodynamic studies conducted in distinct populations and settings. Previous studies in Jewish and Arab populations separately have reported rates of clopidogrel resistance within globally observed ranges, but these were conducted in different populations and healthcare environments, making direct comparison impossible. A systematic review and meta-analysis of 21 studies including 4,312 patients with ischemic stroke or TIA reported a pooled prevalence of HPR of approximately 28 percent, though with substantial variability depending on the platelet-function assay and cutoff used. The 42.6 percent prevalence of high residual platelet reactivity in this cohort, according to the operational PRI ≥70 percent threshold, is higher than that pooled estimate, though the researchers caution that coronary-derived cutoffs may not be optimal for stroke populations and that the pathophysiological and thrombotic milieu in acute ischemic stroke may differ from coronary disease. The study did not assess recurrent stroke, other vascular events, functional outcomes, or bleeding, so the present findings cannot establish the prognostic significance of the observed PRI values. Nevertheless, the message is clear: clopidogrel resistance is common among patients with ischemic cerebrovascular events in Northern Israel, ethnicity alone does not appear to be the dominant determinant of clopidogrel response in this setting, and larger, adequately powered multicenter prospective studies incorporating pharmacogenomic assessment, standardized definitions of platelet reactivity, and longitudinal clinical outcome follow-up are warranted to clarify the clinical relevance of ethnic and genetic determinants of clopidogrel responsiveness in ischemic cerebrovascular populations.

Subject of Research: clopidogrel resistance in ischemic cerebrovascular events

Article Title: A prospective study evaluating clopidogrel resistance among patients with ischemic cerebrovascular events across different ethnic groups in Israel

Article References: Shbat, F., Beiruti Wiegler, K., Dally, N., Saad, E., Srour, S., Eshel, E., Sharabi Nov, A., Shahien, R., Leker, R., & Simaan, N. (2026). A prospective study evaluating clopidogrel resistance among patients with ischemic cerebrovascular events across different ethnic groups in Israel. Frontiers in Stroke, 5, Article 1908099. https://doi.org/10.3389/fstro.2026.1908099

Image Credits: AI Generated

DOI: 10.3389/fstro.2026.1908099

Keywords: clopidogrel resistance, ischemic stroke, VASP assay, CYP2C19, secondary stroke prevention, platelet reactivity, ethnic differences, Israel, prospective, evaluating, clopidogrel, resistance