Laboratory Aspirin Resistance Research Articles

Predicting laboratory aspirin resistance in Chinese stroke patients using machine learning models by GP1BA polymorphism.

This study aims to use machine learning model to predict laboratory aspirin resistance (AR) in Chinese stroke patients by incorporating patient characteristics and single nucleotide polymorphisms of GP1BA and LTC4S. 2405 patients were analyzed to measure the Mutation frequency of GP1BA rs6065 and LTC4S rs730012. 112 patients with first-stroke arteriostenosis were prospectively enrolled to establish machine learning model. GP1BA rs6065 mutation frequency is 5.26% and LTC4S rs730012 is 14.78%. GP1BA rs6065 CT patients have more sensitivity to aspirin than CC genotype. Simple linear regression identified significant associations with age, smoking, HDL and GP1BA rs6065. Random forest (RF) and extreme gradient boosting (XGBoost) demonstrated predictive capabilities for AR. Findings suggest pre-identifying GP1BA rs6065 could optimize aspirin treatment, enabling personalized care and future research avenues.

Effect of PEAR1, PTGS1 gene polymorphisms on the recurrence of aspirin-treated patients with ischemic stroke in the Han population of China: A 4-year follow-up study.

Platelet endothelial aggregation receptor 1 (PEAR1) and prostaglandin endoperoxide synthase 1 (PTGS1) polymorphisms can affect laboratory aspirin resistance. However, the impact of genetic polymorphisms on the recurrence of ischemic stroke (IS) patients treated with aspirin is not fully understood. This study aimed to examine the relationship between gene polymorphisms of PEAR1 and PTGS1 and IS recurrence in patients treated with aspirin. Peripheral blood samples were collected from 174 patients with nonrecurrent IS and 34 with recurrent IS after aspirin treatment. Follow-up was performed on all patients. PEAR1 rs12041331 and PTGS1 rs10306114 polymorphisms were determined using the PCR fluorescence probe method. And the correlations of them with the clinical characteristics were examined by multivariable logistic regression analysis. The distribution frequencies of PEAR1 rs12041331 and PTGS1 rs10306114 genotypes were in Hardy-Weinberg equilibrium, and there was no significant difference in the distribution of PEAR1 rs12041331 polymorphism. Compared to the nonrecurrent group, the AA genotype of the PTGS1 polymorphism was more frequent in the recurrent group (59.77% vs 35.29%, P = .003), and the A allele also showed a higher frequency than the G allele in the recurrent group (P = .001). Multivariable logistic regression analysis showed that smoking (OR = 5.228, 95% CI: 1.938-14.102, P = .001), coronary heart disease (OR = 4.754, 95% CI: 1.498-15.089, P = .008), and the polymorphism at PTGS1(A>G) AA/AG + GG (OR = 2.955, 95% CI: 1.320-6.616, P = .008) were independently associated with IS recurrence in Chinese patients. Our findings suggested that PTGS rs10306114 polymorphisms should receive more attention in the use of aspirin in patients with IS.

The Model for Clinical, Laboratory, and Genetic Prediction of Recurrent Ischemic Stroke against the Background of Laboratory Aspirin Resistance using Machine Learning

The aim of the study was to determine the incidence of laboratory aspirin resistance; and to study the associations of genetic markers and clinical and laboratory parameters (including parameters of the platelet hemostasis) in patients with non-cardioembolic ischemic stroke using machine learning methods to assess the prognosis of recurrent ischemic strokes. Clinical and laboratory data (including induced platelet aggregation) were analyzed from 296 patients with ischemic stroke who were treated in the stroke center of City Clinical Hospital No. 1 named after. N.I. Pirogov. The frequencies of polymorphic variants of the ITGB3, GPIba, TBXA2R, ITGA2, PLA2G7, HMOX1, PTGS1, PTGS2, ADRA2A, ABCB1, PEAR1 genes and intergenic region 9p21.3) in patients with non-cardioembolic ischemic stroke, which were identified using hydrogel biochip technology, were determined. Using the developed machine learning model, additional clinical and genetic factors influencing the development of laboratory aspirin resistance and recurrent ischemic stroke were studied. In the future, the identified factors can be used for differentiated prevention of recurrent ischemic strokes.

Antithrombotic effect of different acetylsalicylic acid drug formulations: is there a difference?

To date, a sufficient volume of clinical studies has been accumulated that have demonstrated a reduced antiplatelet effect of enteric-coated (EC) lowdose acetylsalicylic acid (ASA). Delayed and incomplete absorption from the intestinal alkaline medium, which significantly reduces the bioavailability of drug, is considered the main reason for laboratory aspirin resistance (pseudoresistance) to EC ASA. This phenomenon is of particular importance for patients with acute coronary syndrome, when a quick effect is required, as well as for patients with diabetes and obesity due to additional causes of increased platelet activity, on the one hand, and reduced bioavailability of ASA, on the other. Given the issue of efficacy, the dubious gastroprotective effect and the more pronounced damaging effect on the mucous membrane of small intestine, the use of EC ASA should be avoided, especially in patients with a multifactorial risk of insufficient response to therapy. A good alternative is buffered ASA, which quickly dissolves and is partially absorbed directly in the stomach, having antiplatelet activity comparable to simple ASA and a similar aspirin resistance, is associated with a lower risk of aspirin-induced enteropathy in comparison with ES ASA. In addition, according to a number of small studies and retrospective analyzes, buffered ASA is less likely to cause damage to gastric mucosa compared to EC ASA.

Association among PlA1/A2 gene polymorphism, laboratory aspirin resistance and clinical outcomes in patients with coronary artery disease: An updated meta-analysis

The aim of this study was to investigate the association among the PlA1/A2 gene polymorphism, laboratory aspirin resistance and adverse clinical outcomes in coronary artery disease (CAD) patients who were on aspirin maintainance therapy. A comprehensive literature search was performed and 35 eligible clinical trials including 19025 CAD patients were recruited. Adverse clinical outcomes involving all-cause death, non-fatal myocardial infarction (MI), ischemic stroke and target vessel revascularization (TVR) were analyzed. The definition of aspirin resistance in each study was accepted. Meta-analysis was performed using the Review Manager 5.3.5 System. In CAD patients, the PlA2 gene carriers had similar incidence of laboratory aspirin resistance compared to those with PlA1/A1 genotype [29.7% vs 28.3%, OR = 0.94 (95% CI 0.63 to 1.40, P = 0.74)], and there were no significant differences in the adverse clinical outcomes between the PlA2 carriers and the PlA1/A1 genotype patients. However, the laboratory aspirin non-responders had higher risks of death [7.9% vs. 2.5%, OR = 2.42 (95% CI 1.86 to 3.15, P < 0.00001)] and TVR [4.5% vs. 1.7%, OR = 2.20 (95% CI 1.19 to 4.08, P = 0.01)] compared to the responders. In aspirin-treated CAD patients, the laboratory aspirin resistance predicts all-cause death and TVR. However, the PlA1/A2 gene polymorphism predicts neither the laboratory aspirin response nor the clinical outcomes.

Obesity and laboratory aspirin resistance in high-risk pregnant women treated with low-dose aspirin

Low-dose aspirin is used for preeclampsia prevention in high-risk women, but the precise mechanism and optimal dose are unknown. Evidence suggests that an imbalance in prostacyclin and thromboxane A2 (TXA2) plays a key role in the pathogenesis of preeclampsia. Aspirin has a dose-dependent effect blocking production of TXA2, a potent stimulator of platelet aggregation and promoter of vasoconstriction. Incomplete inhibition of platelet aggregation, designated aspirin resistance, can be reduced by increasing the aspirin dose. Evidence in the nonobstetric literature suggests that aspirin resistance may be more common among patients with a high body mass index. To investigate the association of obesity on platelet-derived thromboxane inhibition in high-risk women treated with low-dose aspirin. This was a secondary analysis of a prospective multi-centered study investigating the effect of low-dose aspirin (60-mg) administration in women at high risk for preeclampsia. Maternal serum TXB2 (an indirect measure of TxA2) levels were drawn at 3 time points: randomization (13-26 weeks' gestation), second trimester (at least 2 weeks after randomization and 24-28 weeks' gestation), and third trimester (34-38 weeks' gestation). Patients were included in the analysis if a TXB2 level was recorded at randomization and at least 1 time point thereafter. Patients were stratified by body mass index category and treatment arm. Median TXB2 levels were calculated at each time point, as well as rates of complete TXB2 inhibition (<0.01 ng/mL). A multivariate logistic regression analysis was performed to generate odds ratios (OR) for complete TXB2 inhibition by body mass index category, adjusting for maternal age, race, high-risk group at randomization, nulliparity, and rate of randomization less than 16 weeks' gestation. A total of 1002 patients were included in the analysis, 496 (49.5%) and 506 (50.5%) in the low-dose aspirin and placebo groups respectively. There were substantial decreases in TXB2 levels among low-dose aspirin-treated women in all body mass index categories. In contrast, women assigned to placebo did not show a marked decrease in TXB2 levels after randomization, and obese women had higher median TXB2 levels in both the second (16.5, interquartile range [IQR] 8.0-31.8 vs 14.0, IQR 6.9-26.7, ng/mL; P= .032) and third (15.7, IQR 7.6-28.5 vs11.9, IQR 4.6-25.9, ng/mL; P= .043) trimesters. When comparing among stratified body mass index low-dose aspirin groups, women with class III obesity had the lowest odds of undetectable TXB2 levels in the second trimester (adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.15-0.72) and third trimester (aOR, 0.30; 95% CI, 0.11-0.78) as well as at both time points (aOR, 0.09; 95% CI, 0.02-0.41). High-risk obese women receiving low-dose aspirin for the prevention of preeclampsia have lower rates of complete inhibition of TXB2. These data suggest that an increase in aspirin dosing or frequency may be necessary in this population.

Aspirin Resistance and Stroke

Stroke is a leading cause of death and disability worldwide. Aspirin is the most commonly used antiplatelet drug in both primary and secondary prevention of cerebrovascular and cardiovascular diseases. A proportion of patients may have stroke recurrence while they are on treatment with aspirin, giving rise to term aspirin resistance or aspirin failure. Studies have suggested that such recurrence could partly be attributed to biochemical aspirin resistance, with an estimated prevalence ranging between 5% and 65% among patients with ischemic stroke in the published studies. Common methods to evaluate laboratory aspirin resistance include light transmission aggregometry, PFA-100, VerifyNow-Aspirin assay, serum thromboxane B2, and urinary 11-dehydrothromboxane B2. Aspirin resistance is multifactorial in origin and involves diverse environmental and genetic factors, including single-nucleotide polymorphisms, miRNAs, drug interactions, and co-morbid risk factors. The current review overviews the concept of aspirin resistance, its evaluation and relationship with stroke recurrence, its outcome, and its implications on stroke management in the future.

Post-pregnancy aspirin resistance appears not to be related with recurrent hypertensive disorders of pregnancy

ObjectiveThe FRUIT-RCT concluded that low-molecular-weight heparin added to aspirin compared to treatment with aspirin alone is beneficial in the prevention of early-onset hypertensive disorders of pregnancy (HD) in women with inheritable thrombophilia and prior HD and/or a small-for-gestational age (SGA) infant leading to delivery before 34 weeks gestation. The aim of this study is to answer the question whether aspirin resistance is associated with recurrent HD. Study designWomen with and without recurrent HD matched for age, study arm, and chronic hypertension were invited for this follow-up study 6–16 years after they participated in the FRUIT-RCT. Aspirin resistance was tested after 10days of aspirin intake using three complementary tests: PFA-200, VerifyNow® and serum thromboxane B2 (TXB2). An independent t-test, Mann-Whitney U test, Fisher’s Exact test and Chi2 test were used for the statistical analyses. ResultsThirteen of 24 women with recurrent HD and 16 of 24 women without recurrent HD participated. The prevalence of laboratory aspirin resistance was 34.5% according to the PFA-200, 3.4% according to the VerifyNow® and 24.1% according to TXB2. The prevalence of aspirin resistance by any test was 51.7%. Aspirin resistance per individual test did not differ between women with and without recurrent HD. Aspirin resistance measured by any test occurred more frequently in women without recurrent HD (p<0.01), irrespective of low-molecular-weight heparin. ConclusionsNo relation could be demonstrated between recurrent HD and aspirin resistance per test, measured up to 16 years after pregnancy. On the contrary, complementary aspirin resistance measurements were encountered more frequently in women without recurrent HD.

Pathophysiologic, Rather than Laboratory-defined Resistance Drives Aspirin Failure in Ischemic Stroke

A significant proportion of ischemic strokes occur while using aspirin and therefore can be considered as clinical aspirin resistance. Apart from this clinical description, aspirin resistance can be defined by laboratory tests of invitro platelet reactivity. The correlation between clinical and laboratory-defined resistance, however, is far from perfect, and the heterogenous nature of stroke pathophysiology might play a role in this discrepancy. The level of invitro platelet inhibition by aspirin was prospectively evaluated using the VerifyNow Aspirin Assay (Accumetrics, San Diego, CA) in patients presenting with ischemic stroke while using aspirin (n = 78). Demographic and clinical features, including stroke etiology, were compared among patients with and without sufficient level of platelet inhibition and an additional set of patients suffering from stroke while not using aspirin (n = 257). Similar analyses were performed in a separate validation cohort. Laboratory evidence of insufficient platelet inhibition was detected in 16 of 78 patients (21%) with clinical aspirin resistance. On the other hand, 30 patients (38%) had stroke etiologies well known to be inadequately responsive to aspirin therapy. Overall, laboratory-defined resistance by itself could be considered to be accountable for the ischemic event in only 15% of these patients. The corresponding figure was 9% in validation cohort. Patients with sufficient level of platelet inhibition were more likely to harbor an anticoagulant responsive etiology compared with aspirin naive patients (odds ratio, 2.0; P=.033). Our findings highlight that laboratory aspirin resistance because of insufficient platelet inhibition is relatively uncommon, whereas pathophysiologic resistance, signifying the presence of etiologies that cannot be efficiently treated with aspirin treatment, is a major contributor of clinical resistance in ischemic stroke.

Laboratory Aspirin Resistance and the Risk of Major Adverse Cardiovascular Events in Patients with Coronary Heart Disease on Confirmed Aspirin Adherence

Previous meta-analyses have demonstrated an increased risk of adverse events in aspirin-resistant patients. In this meta-analysis, we aimed to update clinical evidence regarding the relationship between aspirin resistance and major adverse cardiovascular events (MACEs) in patients with coronary heart disease (CHD) on confirmed aspirin adherence. An electronic literature search of PubMed, EMBASE, Web of Science and the Cochrane Library and a hand search of bibliographies through April 2013 were conducted. Studies were included if they prospectively investigated the association between aspirin resistance and the risk of adverse cardiovascular events during follow-up in CHD patients, mentioned confirmed compliance and provided adequate data for a statistical analysis. Nine prospective studies with a total 1,889 CHD patients who were followed for one month to 2.5 years and study sample sizes ranging from 86 to 496 patients were identified. Overall, 622 of the 1,889 CHD patients (33.0%) were classified as being aspirin resistant with confirmed aspirin adherence. The aspirin-resistant patients exhibited a significantly higher risk of adverse events than the aspirin-sensitive patients (odds ratio 2.44, 95% confidence interval 1.81 to 3.30; p＜0.00001). Among CHD patients, approximately one in three individuals can be diagnosed as aspirin resistant on confirmed aspirin adherence. Patients identified as having laboratory aspirin resistance exhibit a 2.4-fold increased risk of MACE compared with aspirin-sensitive patients.

ASPIRIN RESISTANCE CANDIDATE GENES AND THEIR ASSOCIATION WITH THE RISK OF CARDIOVASCULAR EVENTS

The review presents the current literature evidence on the most likely genetic polymorphisms of aspirin resistance, such as polymorphisms of cyclooxygenase, glycoproteins GP Ib/IIIa, GP Ibα, GP VI, and adenosine diphosphate receptors P2Y1 and P2Y12. The authors discuss the prevalence of these polymorphisms in laboratory and clinical aspirin resistance, as well as their association with the risk of cardiovascular events during aspirin treatment.

Prevalence of laboratory aspirin resistance in 431 old patients

To evaluate correlation between and agreement in light transmittance aggregation (LTA) and thromboelastography (TEG) in laboratory diagnosing aspirin resistance (AR), and to determine the prevalence of AR in old patients. Patients in the Wanshoulu District of Beijing with ischemic atherothrombotic diseases were recruited. Inclusion criteria were age ≥ 65 years, and having received regular aspirin therapy (75-100 mg daily) for at least 4 weeks. On the basis of LTA assay, the definition of AR was taken as aggregation of ≥ 20% with AA (arachidonic acid), and of ≥ 70% with ADP (adenosine diphosphate). Aspirin-sensitivity was indicated by the absence of either of these criteria; aspirinsensitivity was indicated as both criteria being met. The definition of AR by TEG is ≥ 50% via AA-induced whole blood aggregation. There were 13.69% prevalence of aspirin resistance for LTA using AA as the agonist, 30.16% prevalence of aspirin resistance for LTA using ADP as the agonist, and 23.67% prevalence of aspirin resistance for TEG using AA as the agonist. Results from these tests showed poor agreement (Kappa<0.4). However, by the method of LTA using AA and ADP as the agonists, prevalence of AR was 8.35%. By methods of AA-induced LTA and AA-induced TEG, prevalence of AR was 8.82%. Results from these two latter methods showed good agreement (Kappa = 0.793). Combined methods, as described here, have good correlation and agreement in the assays of AR, and the results with them represent a realistic measure of the prevalence of AR. Prevalence of AR of elderly patients from Wanshoulu district of Beijing is about 9%.

Polymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use

We hypothesized that single-nucleotide polymorphisms (SNPs) associated with heightened in vitro platelet function during aspirin exposure (which we define as "laboratory aspirin resistance") would be associated with greater risk for death, myocardial infarction (MI) or stroke among patients with coronary artery disease regularly using aspirin. Duke Databank for Cardiovascular Disease patients with (n = 3,449, CATHeterization GENetics cohort) or without (n = 11,754, nongenetic cohort) banked DNA with ≥1 coronary stenosis >75% were followed up at 6 months, then annually for death, MI, or stroke occurring during periods of reported aspirin use. We evaluated associations of candidate SNPs from GNB3, PEAR1, ITGB3, VAV3, ITGA2, GPVI, PTGS1, F2R, THBS1, A2AR, and GP1BA with events during follow-up using Cox proportional hazards modeling adjusted for clinical characteristics associated with outcomes in the nongenetic cohort. Over a median of 3.5 years, 2,762 (24%) nongenetic cohort patients and 648 (19%) CATHeterization GENetics cohort patients had the composite outcome during reported aspirin use. No candidate SNPs were significantly associated with death, MI, or stroke in either univariable or multivariable analyses. A prospective analysis demonstrated 80% to 88% power to detect a hazard ratio of ≥1.3 for minor allele carriers. Patients with angiographically significant coronary artery disease regularly using aspirin and carrying SNPs associated with laboratory aspirin resistance were not at higher risk for death, MI, or stroke. Using these SNPs to guide more aggressive antiplatelet therapy is not justified by these results. Direct extrapolation from in vitro findings to the clinical setting should be avoided.

Aspirin Resistance in Cardiovascular Disease: Pathogenesis, Diagnosis and Clinical Impact

Aspirin is the cornerstone of treatment in patients with coronary artery disease. However, several studies investigating the in vitro response of platelets to the administration of aspirin showed this response to be variable, with some patients exhibiting non-responsiveness or resistance. Aspirin resistance may be categorised as either 'laboratory' or 'clinical'. Laboratory aspirin resistance is defined as the failure of aspirin to inhibit the production of thromboxane A(2) (TxA(2)) by platelets or to inhibit platelet activation that depends on TxA(2) production. Clinical aspirin resistance is defined as the failure to prevent the occurrence of atherothrombotic ischaemic episodes in patients to whom it is administered. So far, there is no generally accepted method for the ex vivo evaluation of platelet activation or for assessing the degree of platelet activation following aspirin administration and data concerning the clinical impact of aspirin resistance are conflicting. For these reasons it is not possible to suggest specific guidelines for the treatment of patients who show high levels of platelet activation or a low level of platelet inhibition after treatment with aspirin. The aim of this review is to present data from laboratory and clinical studies that are related to resistance to aspirin, and to discuss the possible causes, the clinical significance, and the ways of managing such resistance at a clinical level.

The impact of intravenous aspirin administration on platelet aspirin resistance after on-pump coronary artery bypass surgery

Aspirin resistance continues to be a major challenge in patients after coronary artery bypass grafting (CABG). We investigated the impact of intravenous aspirin on platelet function in this clinical setting. Forty-two patients received 100 mg of oral aspirin once daily, beginning on day 1 after the operation. Between day 6 and 8 post operation one oral dose was replaced by an intravenous dose of 300 mg. Platelet function analyzer (PFA-100™) closure times (CT), turbidimetric platelet aggregation (TPA) and impedance platelet aggregation (IPA) induced by arachidonic acid (AA), collagen and ADP were measured prior to and 1 h and 24 h after intravenous aspirin. Results obtained prior to the intravenous aspirin were compared with respective values from 120 healthy individuals. Despite the postoperative oral aspirin that was given once daily, ADP-induced TPA (ADPTPA) and IPA values induced by AA, ADP or collagen were significantly greater in patients than in controls, while PFA-100™ CT were significantly shorter. Intravenous aspirin induced a significant reduction of platelet aggregability as measured by collagen/epinephrine (CEPI) CT, TPA and IPA induced by AA and collagen 1 h and 24 h after administration. Intravenous aspirin was not found to influence collagen/ADP (CADP) CT and IPA induced by ADP. Concomitantly, the number of patients with laboratory aspirin resistance as measured by CEPI-CT and TPA but not by IPA induced by AA or collagen dropped significantly. Agreement in the detection of aspirin responders and non-responders among platelet function tests was poor. Our findings indicate that the intravenous aspirin appears to be a promising approach for reducing laboratory aspirin resistance during the postoperative phase of CABG.

Clinical implications of aspirin resistance

Aspirin reduces major atherothrombotic events across a wide spectrum of patients with atherosclerotic disease. The occurrence of ischemic events despite of aspirin treatment is a failure of therapy, often denoted 'clinical aspirin resistance'. This is distinguished from laboratory assays showing an insufficient inhibition of platelet function, which indicate 'laboratory aspirin resistance'. Laboratory aspirin resistance has been reported in up to 60% of patients after stroke or peripheral arterial disease, up to 70% in stable coronary heart disease and even up to 80% in acute myocardial infarction. However, this data must be interpreted carefully because of small sample sizes and potential confounding factors such as compliance, co-morbidities and large differences between the laboratory methods used for detection. During the past years, evidence has accumulated that laboratory aspirin resistance is associated with an increased incidence of major atherothrombotic events, with an up to 13-fold increased risk of events in patients with cardiovascular disease. Thus, an individualized antiplatelet therapy will have to consider the possibility of aspirin resistance, and the identification of aspirin non-responders may improve antiplatelet therapy in future. Whether an increased dose of aspirin or another antiplatelet drug (e.g. clopidogrel) instead or in addition to aspirin should be given is unclear. Prospective trials are underway which address this issue. This review gives an overview on the various clinical studies that have investigated the prevalence and clinical importance of laboratory aspirin resistance. Moreover, therapeutic options, as well as future perspectives are discussed.

Association of Laboratory-Defined Aspirin Resistance With a Higher Risk of Recurrent Cardiovascular Events

The risk of recurrence of cardiovascular events among patients using aspirin (acetylsalicylic acid) for secondary prevention of such events remains high. Persistent platelet reactivity despite aspirin therapy, a laboratory-defined phenomenon called aspirin resistance (hereinafter, laboratory aspirin resistance), might explain this in part, but its actual contribution to the risk remains unclear. The objective of this study was to systematically review all available evidence on whether laboratory aspirin resistance is related to a higher risk of cardiovascular recurrent events. Using a predefined search strategy, we searched electronic databases. To be included in our analysis, articles had to report on patients who used aspirin for secondary cardiovascular prevention, had to contain a clear description of a method to establish the effects of aspirin on platelet reactivity, and had to report recurrence rates of cardiovascular events. Odds ratios of cardiovascular outcome of eligible studies were pooled in a random-effects model. We included 15 full-text articles and 1 meeting abstract. Fifteen of these studies revealed an adverse association between laboratory aspirin resistance and occurrence of cardiovascular events. The pooled odds ratio of all cardiovascular outcomes was 3.8 (95% confidence interval, 2.3-6.1) for laboratory aspirin resistance. This systematic review and meta-analysis shows that patients biochemically identified as having laboratory aspirin resistance are more likely to also have "clinical resistance" to aspirin because they exhibit significantly higher risks of recurrent cardiovascular events compared with patients who are identified as (laboratory) aspirin sensitive.

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity

Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infarction via this action mechanism. However, there are individual differences in this action, and aspirin is not effective in some patients, which is referred to as 'aspirin resistance'. In this study, we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine genes involved in platelet aggregation/hemorrhage. Among SNPs involved in platelet aggregation, aspirin was less effective for 924T homozygote of a TXA2 receptor, 924T>C, and 1018C homozygote of a platelet membrane glycoprotein GPIbalpha, 1018C>T, suggesting that 924T and 1018C alleles are involved in aspirin resistance.

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial

We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease. The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01]. The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.