Predictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke

doi:10.1016/j.jstrokecerebrovasdis.2009.12.004

Journal of Stroke and Cerebrovascular Diseases

Volume 20, Issue 3, May–June 2011, Pages 227-230

https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.12.004 Get rights and content

Variable platelet response to aspirin and clopidogrel is a well-established phenomenon in patients with coronary artery disease. We sought to determine the predictors of an impaired biochemical response to aspirin and clopidogrel in patients with ischemic stroke. Patients with established cerebrovascular disease who underwent an aspirin/clopidogrel response panel (ie, light transmittance aggregometry) between June 2003 and March 2007 were identified through an electronic database. The medical records of these patients were retrospectively reviewed, and demographic characteristics, medical history, and laboratory results were recorded. Univariate and multivariate logistic regression analyses were performed to assess for factors associated with antiplatelet resistance. Of the 465 patients included in this study, 120 (28%) were biochemical aspirin nonresponders and 83 (28%) were biochemical clopidogrel nonresponders. Of the 270 patients on dual antiplatelet therapy, 25 (9.3%) were dual biochemical nonresponders. In binary logistic regression modeling, patients with congestive heart failure (odds ratio [OR] = 4.54; 95% confidence interval [CI] = 1.33-15.5; P = .02) and those with higher hemoglobin A1c values (OR = 1.41; 95% CI = 1.12-1.79; P = .004) had a significantly greater likelihood of having a biochemical nonresponse to aspirin therapy. African-American patients (OR = 2.19; 95% CI = 1.23-3.91; P < .007) were significantly more likely to be nonresponders to clopidogrel. This preliminary study shows that aspirin and clopidogrel biochemical nonresponse frequently occurs in ischemic stroke patients. In addition, some associated variables may affect the biochemical response to antiplatelet therapy. Further study is needed to explore whether this nonresponse has an impact on clinical outcomes.

Section snippets

Methods

We retrospectively reviewed the electronic medical records of patients admitted to the stroke service between June 2003 and March 2007 at The Cleveland Clinic Foundation after approval from our Institutional Review Board. The inclusion criterion for the study was all patients who underwent a serum aspirin/clopidogrel optical platelet aggregation study 24 hours after hospital admission, presented with an ischemic stroke based on clinical presentation and neuroimaging findings, and were age >18

Results

The study cohort comprised 465 patients (48% females), with a mean age of 63 ± 12 years. The distribution of antiplatelet therapy for this cohort was 166 patients (36%) on aspirin monotherapy, 270 patients (58%) on dual-antiplatelet therapy, and 29 patients (6%) on clopidogrel monotherapy. A total of 436 patients (94%) were on aspirin, and 299 patients (64%) were on clopidogrel. In terms of nonresponse, 120 patients (28%) were biochemical aspirin nonresponders, and 83 patients (28%) were

Discussion

Biochemical antiplatelet resistance and variability of antiplatelet response have received increasing attention in recent years. The definition of biochemical antiplatelet resistance varies widely and is dependent on the platelet function detection technology used and the clinical assessment performed. In this work, we used the most widely accepted definition of aspirin resistance, ≥20% platelet aggregation with 1 mg/mL arachidonic acid and ≥70% aggregation with 10 μmol/L ADP.¹⁴ Although

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Cited by (43)

The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study
2024, Thrombosis Research
Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD.
In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death.
In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers.
Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism.
Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race
2020, American Journal of Obstetrics and Gynecology MFM
Citation Excerpt :
Gene polymorphisms have also been linked to aspirin intolerance in patients with asthma and the risk of aspirin-induced gastrointestinal bleeding.27,28 In a study of predictors of nonresponders to aspirin and clopidogrel among patients with ischemic stroke, black race was a risk factor for nonresponse to clopidogrel but not aspirin.29 A recently published cohort study evaluated the impact of implementing the ACOG-endorsed guidelines for aspirin therapy among pregnant women with chronic hypertension in a population of a majority of non-Hispanic black women and failed to observe a significant decrease in superimposed preeclampsia, SGA, or preterm delivery.30
Low-dose aspirin is recommended for the prevention of preeclampsia among women at a high risk of developing the disease. Aspirin undergoes polymorphic metabolism, and it is well known that common genetic polymorphisms are related to aspirin intolerance. We hypothesized that the efficacy of aspirin prophylaxis may differ by ethnicity and race.
This study aimed to compare the rates of preeclampsia among low- and high-risk women who received aspirin compared with placebo, stratifying results by ethnicity and race as a first-pass approximation of genomic polymorphisms.
This is a secondary analysis of 2 randomized controlled trials previously performed by the Maternal-Fetal Medicine Units Network: the Low-Risk Aspirin trial and the High-Risk Aspirin trial. For the Low-Risk Aspirin trial, normotensive, nulliparous women were enrolled between 13 and 26 weeks’ gestation and randomized to 60 mg aspirin daily or placebo. For the High-Risk Aspirin trial, women with pregestational insulin-treated diabetes mellitus, chronic hypertension, multiple gestations, or a history of preeclampsia in a previous pregnancy were enrolled between 13 and 26 weeks’ gestation and randomized to 60 mg aspirin daily or placebo. The primary outcome of our secondary analysis was preeclampsia. Secondary outcomes included gestational age at delivery, preterm delivery, placental abruption, small for gestational age, stillbirth, and neonatal death. Outcomes were stratified by ethnicity and race (Hispanic, non-Hispanic white, non-Hispanic black, or other).
In the Low-Risk Aspirin trial of 3135 women, the risk of preeclampsia was significantly reduced among non-Hispanic white women who received aspirin compared with non-Hispanic white women who received placebo (relative risk, 0.19; 95% confidence interval, 0.06–0.63; P=.007). The risk of preeclampsia was not different when comparing the aspirin and placebo groups among the Hispanic, non-Hispanic black, or other ethnicity and race groups. The efficacy among non-Hispanic white women persisted after consideration of compliance and gestational age at randomization (relative risk, 0.07; 95% confidence interval, 0.009–0.51; P=.009). As noted in the original trial, there was an increased risk of placental abruption in the aspirin group overall compared with placebo (P=.025). The risk of stillbirth was significantly increased among non-Hispanic black women who received aspirin compared with non-Hispanic black women who received placebo (P=.048). In the High-Risk Aspirin trial of 2539 women, 269 were Hispanic (10.6%), 832 were non-Hispanic white (32.8%), 1426 were non-Hispanic black (56.2%), and 12 were categorized as other (0.5%). Stratification by ethnicity and race did not reveal a decreased incidence of preeclampsia for any of the subgroups (P>.05). Moreover, there was no significant difference in other measured outcomes including preterm delivery at <37 weeks’ gestation, placental abruption, small for gestational age, stillbirth, or neonatal death.
The incidence of preeclampsia was significantly reduced among low-risk non-Hispanic white women who received aspirin compared with placebo (P=.007), but not overall or among Hispanic or non-Hispanic black women. The analysis of high-risk women did not indicate a difference in the efficacy of aspirin by ethnicity and race.
High on-clopidogrel platelet reactivity in ischaemic stroke or transient ischaemic attack: Systematic review and meta-analysis
2020, Journal of Stroke and Cerebrovascular Diseases
To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients.
We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included.
Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24–32%; high heterogeneity: I² = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61–2.70; p = 0.036; low heterogeneity across studies: I² = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47–1.95; p < 0.001; I² = 0.01%, p = 0.475).
This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.
Outcomes After Percutaneous Angioplasty of Arteriovenous Fistulas and Grafts in African American Patients
2019, Canadian Association of Radiologists Journal
Citation Excerpt :
Aspirin is often prescribed to prevent or treat vascular disease. There is, however, a racial component to the degree of anti-platelet effect from aspirin, and in some studies clopidogrel offers less protection to African Americans than white people [33–35]. There is a racial disparity in vascular access for hemodialysis that requires further investigation and favors a personalized approach to improve access outcomes.
Arteriovenous fistulas and grafts, necessary for hemodialysis, may develop stenoses due to neointimal hyperplasia, which often require percutaneous transluminal angioplasty. Patient and lesion characteristics were evaluated prior to angioplasty and were correlated with 1- and 6-month outcomes.
This was an observational study of African American hemodialysis patients who presented for angioplasty of a dysfunctional fistula or graft. Clinical outcomes were ascertained from dialysis facilities 1 month and 6 months after angioplasty. One-month clinical success was defined as dialyzer blood flows of 450 mL/min without complications or interval shunt thrombosis, interventions, or loss of access, which was rarely achieved at 6 months. Logistic regression models were used to evaluate associations of clinical variables with outcomes.
There were 150 stenoses treated during 99 procedures performed on 82 patients. The clinical success rate at one month was 67% with no complications as a result of the percutaneous transluminal angioplasty. Success at 1 month was positively associated with use of aspirin (P = .005) and with referral for high venous pressures (P = .004). Six-month data were available for 81 procedures, with 45.7% requiring repeat angioplasty and 12.3% suffering major complications (thrombectomy, revision surgery, or access abandonment). Major complications were seen predominantly in patients who were not receiving aspirin.
Aspirin use and high venous pressure were associated with 1-month clinical success and fewer major complications at 6 months. Future work should investigate biologic mechanisms of action of aspirin and long-term effects of use to maintain vascular access.
Les fistules et les greffes artérioveineuses, nécessaires à l'hémodialyse, peuvent provoquer la formation de sténoses dues à une hyperplasie néointimale, qui entraînent souvent le recours à une angioplastie transluminale percutanée. Les caractéristiques des patients et des lésions ont été évaluées préalablement à l'angioplastie et ont été corrélées avec les résultats à 1 mois et 6 mois.
Il s'agissait d'une étude observationnelle de patients afro-américains sous hémodialyse se soumettant à une angioplastie pour fistule ou greffe dysfonctionnelle. Les résultats cliniques ont été vérifiés par les établissements de traitement de dialyse 1 mois et 6 mois après l'angioplastie. Les critères de réussite clinique à 1 mois étaient des débits sanguins de dialyseur de 450 mL/min sans complication ou thrombose de shunt, interventions ou perte d'accès, ce qui a rarement été atteint à 6 mois. Des modèles de régression logistique ont été utilisés pour analyser les associations entre les variables cliniques et les résultats.
Un nombre de 150 sténoses a été traité dans le cadre de 99 interventions exécutées sur 82 patients. Le taux de réussite clinique à 1 mois était de 67 % sans complication consécutive à l'angioplastie transluminale percutanée. Une association positive a été obtenue entre la réussite à 1 mois et la prise d'aspirine (P = ,005) et une orientation pour hypertension veineuse (P = ,004). Des données à 6 mois étaient disponibles pour 81 interventions, avec 45,7 % des patients nécessitant la reconduite de l'angioplastie et 12,3 % souffrant de complications majeures (thrombectomie, reprise chirurgicale ou abandon de l'accès). Les complications majeures ont été pour la plupart décelées chez les patients non traités par aspirine.
La prise d'aspirine et l'hypertension veineuse ont été associées à la réussite clinique à 1 mois et à la diminution du nombre de complications majeures à 6 mois. De plus amples études doivent être conduites pour caractériser les mécanismes d'action biologiques de l'aspirine et les effets à long terme relatifs à son utilisation pour entretenir l'abord vasculaire.
Preventive and therapeutic effect of brozopine on stroke in Dahl Salt-sensitive hypertensive rats
2017, Brain Research
Citation Excerpt :
Generally, the acetylsalicylic acid (ASA), which is a cyclooxygenase inhibitor, preventing thromboxane A2 synthesis, has been used as an anti-platelet agent in the prevention of ischemic stroke. However, its use became greatly limited due to severe adverse effects and drug resistance in many patients (Fitzgerald and Pirmohamed, 2011; Fong et al., 2011). Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) is derived from 1-3-n-butylphthalide (NBP) and its chemical structure is similar to that of ASA.
Our aim was to explore the preventive and therapeutic effects of sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP) on stroke in Dahl Salt-sensitive (Dahl-SS) hypertensive rats. Dahl-SS rats were fed a high-salt diet to observe the effect of BZP on blood pressure, and brain, heart, and kidney tissues. Additionally, the incidence of stroke was recorded according to the neurological score. The relative mechanisms investigated included anti-oxidative effects and anti-platelet aggregation. BZP reduced the incidence of stroke, neuronal necrosis in the brain, and cell swelling and inflammatory infiltration in the kidney. Its mechanisms were related to the increased activities of gluthatione peroxidase and catalase and the decreased level of plasma nitric oxide. BZP inhibited arachidonic acid (AA) – induced platelet aggregation (IC₅₀: 12 µM) rather than that of adenosine diphosphate (ADP) – and/or thrombin-induced platelet aggregation in vitro. Interestingly, BZP inhibited ADP-, thrombin-, or AA-induced platelet aggregation and elevated the level of AMP-activated protein kinase, cyclic guanosine monophosphate, and vasodilator-stimulated-phosphoprotein, and attenuated ATP contents and mitogen-activated protein kinase levels in platelet and inhibited thrombus formation in a carotid artery thrombosis model, dose-dependently, in Dahl-SS hypertensive-induced stroke rats. In conclusion, BZP can have therapeutic and preventive effects on stroke in Dahl-SS hypertensive rats, the mechanisms of which may be related to anti-oxidant, anti-platelet aggregation and anti-thrombus formation.
Predictive value of high residual platelet reactivity by flow cytometry for outcomes of ischemic stroke patients on clopidogrel therapy
2015, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
To the best of our knowledge, this is the first prospective trial to use the whole-blood flow-cytometric assay to assess the predictive value of ADP-PAg and platelet activation markers on the risk of clinical outcomes in patients with ischemic stroke on clopidogrel treatment. Using this assay, the incidence of HRPR in ischemic stroke patients on clopidogrel treatment, defined as RPR more than the cutoff values of ADP-PAg, CD62P, CD63, and PAC-1 was 25.8%-56.1% in our patients, which was close to the range of 28%-44% reported in previous studies in ischemic stroke patients on clopidogrel treatment, using multiple platelet function methods including LTA, flow cytometric vasodilator-stimulated phosphoprotein phosphorylation assay, VerifyNow P2Y12 test, platelet function analyzer-100, and multiple electrode platelet aggregometry.18-24 And it is the first study so far to use ROC curve in stroke patients to define the clinical threshold of clopidogrel nonresponders based on the occurrence of poor outcomes.
High residual platelet reactivity (HRPR) assessed by multiple tests has been associated with worse clinical outcomes. However, the clinical impact of HRPR assessed by flow cytometry is unknown. The aim of this study was to validate the predictive value of HRPR measured by flow cytometry for clinical outcomes in ischemic stroke patients during clopidogrel therapy. Overall, 198 consecutive patients with ischemic stroke taking clopidogrel underwent platelet function testing on flow cytometer including adenosine diphosphate (ADP)–induced platelet aggregation (PAg) and platelet activation markers (CD62P, CD63, and PAC-1). Poor outcome was defined as poor prognosis and ischemic events during 12-month follow-up. By receiver operating characteristic curve analysis, residual platelet reactivity assessed by flow cytometry was able to distinguish between patients with and without poor outcomes, when platelet inhibition was evaluated with ADP-PAg (area under the curve [AUC], .77; 95% confidence interval [CI], .69-.84; P < .001), CD62P (AUC, .73; 95% CI, .64-.81; P < .001), CD63 (AUC, .72; 95% CI, .64-.80; P < .001), and PAC-1 (AUC, .70; 95% CI, .62-.78; P < .001). The prevalence of HRPR was 25.8% for ADP-PAg, 32.8% for CD62P, 41.4% for CD63, and 56.1% for PAC-1. The multiple logical regression analysis demonstrated that HRPR was an independent predictor of poor outcomes (ADP-PAg: odds ratio [OR] 13.03, 95% CI 5.66-29.98, P < .001; CD62P: OR 8.55, 95% CI 3.94-18.57, P < .001; CD63: OR 8.74, 95% CI 3.89-19.64, P < .001; PAC-1: OR 4.23, 95% CI 1.98-9.08). In conclusion, HRPR, assessed by flow cytometry, is able to detect ischemic stroke patients at increased risk of 12-month poor outcomes on clopidogrel treatment.

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Original ArticlePredictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke

Section snippets

Methods

Results

Discussion

Thromb Res

Thromb Res

Lancet

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

J Thromb Haemost

Prostagland Leukot Essent Fatty Acids

Aspirin resistance in patients taking small dose of aspirin

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue

Narrative review: Aspirin resistance and its clinical implications

Ann Intern Med

Original Article
Predictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke