Biochemical Aspirin Resistance Research Articles

Biochemical aspirin resistance in acute stroke patients and its association with clinical factors: aprospective pilot study.

Aspirin is still widely used in treatment and prevention of cardiovascular diseases. To predict which patients cannot benefit from aspirin due to aspirin resistance remains agreat clinical challenge. Fifty one acute stroke/transient ischemic attack (TIA) patients (ASG) with ahistory of regular aspirin intake for the previous 7 days or more were included to the study within 24 hours of symptoms onset. Twenty nine patients admitted to our department for other reasons were the controls (CG). Each patient underwent routine blood tests (white blood cells, platelets, total cholesterol, C-reactive protein) and additional blood test: glycated haemoglobin (HbA1c), insulin, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Biochemical aspirin resistance was measured using the VerifyNow Aspirin platelet function analyzer. There were 9 aspirin resistance patients in ASG (17.5%) and 3 in CG (10.3%) (p = 0.38). There were no differences in either age or gender between those groups. Twelve aspirin-resistant patients differed from aspirin nonresistant patients in age, NT-proBNP and total cholesterol levels (univariate model, p = 0.004, 0.04, 0.02, respectively). In amultivariate model patients aged 76 years and more would likely to be aspirin resistant with odds ratio = 9 (95% confidence interval: 1-78). Patients aged 76 and more can be more likely aspirin resistant than younger patients. We believe that especially in the elderly with congestive heart failure there is astrong need for further investigations in this field, including searching for alternative antiplatelet therapies.

Biochemical Aspirin Resistance and Clinical Outcome in Indian Patients with Ischemic Stroke (2537)

Biochemical Aspirin Resistance and Clinical Outcome in Indian Patients with Ischemic Stroke (2537)

Acetylsalicylic acid resistance in patients with acute ischemic stroke

This paper investigates the sensitivity to aspirin in patients with ischemic stroke in the early recovery period by optical aggregometry. The obtained results revealed individuals insensitive to aspirin. The aim is to detect the incidence of biochemical aspirin resistance among patients with history of ischemic stroke on the background of aspirin. Material and methods. Clinical and laboratory analysis of 80 patients with acute ischemic stroke who received 75 mg of acetylsalicylic acid (ASA) before bedtime as a preventive measure. Sensitivity to aspirin was determined by optical aggregatometry with adrenaline inducer. With an increase in optical permeability above 60%, aspirin resistance was ascertained. Results. It was found that among the surveyed patients, 20 (25%) were aspirin resistant, that is, the use of ASA for the purpose of secondary prevention in them will not prevent the recurrence of a vascular catastrophe. Conclusions. Monitoring the state of platelet link using optical aggregatometry allows timely to detect the lack of response to ASA and necessitates correction of the applied antiplatelet therapy.

RESISTANCE TO ANTIPLATELET DRUGS IN PATIENTS WITH CEREBROVASCULAR DISEASE

INTRODUCTION: Cardiovascular diseases and stroke are steadily the leading causes of death in Latvia. Therefore, the greatest efforts should be given to recognize associative factors which may be modifiable to decrease the burden of ischemic events.
 OBJECTIVES: The aim of this study was to examine the frequency of aspirin and clopidogrel resistance and its associated risk factors in patients with acute cerebrovascular events.
 METHODS: The prospective, descriptive study included 204 patients. Patients were considered biochemical resistant to aspirin if platelet aggregation was ≥550 ARU, whereas biochemical clopidogrel resistance was defined when platelet inhibition was >230 PRU.
 RESULTS: Biochemical aspirin resistance was found in 27 (13%) patients, whereas clopidogrel resistance - in 44 (22%) patients. Five patients (2%) had resistance to both antiplatelet drugs. In the analysis of blood parameters, none were associated with aspirin resistance, except the level of triglycerides which were lower in the aspirin resistance group (p=0.001; r=0.26). In the analysis of clopidogrel sensitivity there was a difference in diabetes prevalence where it was more frequent in the clopidogrel resistance group (15.6% vs. 40.9%; p=0.001; r=0.255). Patients with clopidogrel resistance had higher levels of triglycerides 1.7 (1.3-2.6) than patients grouped as sensitive 1.4 ((1.1-2.0), p=0.033; r=0.16).
 CONCLUSION: Biochemical aspirin and clopidogrel resistance are quite common in patients with cerebrovascular diseases in Latvia. Our study found that patients with diabetes and elevated glycosylated hemoglobin level were more prone to clopidogrel biochemical resistance. However, the association between aspirin resistance and clinical, laboratory data remains inconclusive.

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.

Biochemical aspirin resistance is associated with increased stroke severity and infarct volumes in ischemic stroke patients.

To explore the correlation of aspirin resistance (AR) with clinical stroke severity and infarct volume using diffusion-weighted imaging (DWI) in 224 Chinese ischemic stroke patients who were taking aspirin before stroke onset. In those patients, the median age was 64 years (IQR, 56-75 years), and males accounting for 54.9%(123)of the total subjects. Fifty of 224 enrolled patients (22.3%; 95% confidence interval (CI), 16.9% to 27.7%) showed AR. In the median regression model, significant increase was estimated in NIHSS score of 0.04 point for every 1-point increase in aspirin reaction units (ARU) (95% CI, 0.02 to 0.06; P<0.001). Diffusion-weighted MRI (DWI)-measured infarct volume were significantly higher in patients with AR as compared with those with AS [13.21 (interquartile ranges [IQR], 8.51-23.88) vs.4.26 (IQR, 1.74-11.62); P<0.001). Furthermore, a statistically significant increase was also measured in NIHSS score of 0.05 point for every 1-point increase in ARU in the median regression model (95% CI, 0.03 to 0.08; P<0.001). The median DWI infarct volume was significantly larger in the highest ARU quartile when compared to that in the low 3 quartiles (P<0.001). In conclusion, stroke patients with AR indicated higher risk of severe strokes and large infarcts compared to patients in the aspirin-sensitive group.

Biochemical aspirin resistance in stroke patients - a cross-sectional single centre study.

Aspirin use is known to reduce the recurrence of stroke. However, the clinical response to aspirin has been mixed. The rate of stroke recurrence whilst on aspirin treatment is still unacceptably high. A plausible explanation for this may be resistance to the effects of aspirin. The causes of aspirin resistance are manifold and multi-factorial. We conducted a study to investigate the prevalence rate of biochemical aspirin resistance in a cohort of aspirin-naïve stroke patients. We also sought to determine the inherent factors that may predispose towards the development of aspirin resistance. This was a cross-sectional, observational study conducted on patients admitted to our centre with an acute stroke who were aspirin-naïve. The diagnosis of an acute stroke was confirmed by clinical history and brain imaging. Fifty consecutive patients were prospectively enrolled. Socio-demographic data were collected and baseline blood investigations were performed. Patients were tested for biochemical aspirin resistance using Multiplate platelet analyser (Dynabyte, Munich, Germany) after 5 doses of aspirin, corresponding to a total dose of 900 mg. The median age of patients was 65.5 years and 54 % of patients were female. There were 11 smokers; of these 10 were male. Twenty-six (52 %) patients were Chinese, 21 (41 %) were Malay and 3 (6.0 %) were Indian. Aspirin resistance was present in 14 % of our patients. There was an inverse relationship between the presence of aspirin resistance and plasma HDL levels (r = -0.394; p = 0.005). There was no relationship observed between aspirin resistance and total cholesterol, triglycerides, LDL, HbA1c, ALT, ALP, urea and creatinine levels. There were no significant differences in demographic profiles or smoking status between the aspirin resistant and non-aspirin resistant groups. We did not find any link between ethnicity and aspirin resistance. Our results indicate that a lower HDL level is associated with biochemical aspirin resistance. This may increase platelet aggregation and consequently increase the risk of a recurrent stroke. The clinical implications for aspirin resistance are far reaching. Any evidence that correctable factors may negatively influence the action of aspirin warrants further investigation. The prevalence rate of biochemical aspirin resistance in our study is comparable to the findings in other studies performed in an Asian population. Further research is required to determine how our findings translate into clinical aspirin resistance and stroke recurrence.

Clinical and biochemical aspirin resistance in patients with recurrent cerebral ischemia

Background and aimStroke recurrence is an important public health concern. One half of survivors remain disabled, and one seventh requires institutional care. Aspirin remains the cornerstone of primary and secondary stroke prevention; meanwhile, aspirin resistance is one of the possible causes of stroke recurrence. We aimed to evaluate the clinical and biochemical aspirin resistance in patients with recurrent ischemic stroke. Patients and methodsWe studied demographic characteristics, vascular risk factors, stroke subtypes, radiologic findings and biochemical aspirin resistance tests using both arachidonic acid (AA) and adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) on admission and 24h after observed aspirin ingestion. ResultsOf the 82 patients with recurrent cerebral ischemia included in this study, 37 (45%) patients were poor compliant with aspirin. There were no statistically significant differences between the two groups regarding the demographic characteristics, stroke severity, laboratory tests, radiological findings or vascular risk factors. On admission, 19.6% and 4.8% of patients showed aspirin resistance, while 24h after supervised 300mg single aspirin dose ingestion, it was 9.8% and 2.4% using ADP and AA-induced LTA respectively. Of the eight aspirin resistant patients, two only showed resistance using both AA and ADP. Aspirin resistance was statistically significantly higher in the male gender, older age, hyperlipidemia, smokers and in all lacunar strokes using AA. ConclusionBiochemical aspirin resistance in one's series was rather rare (2.4%) and was more prevalent in patients with lacunar strokes. Clinical aspirin failure may often be contributed to poor compliance with aspirin intake.

Relationship between acute stroke outcome, aspirin resistance, and humoral factors

BackgroundThe relationship between biochemical aspirin resistance (AR) and functional outcome of acute ischemic stroke is uncertain. MethodsProspectively, 269 patients with acute ischemic stroke were recruited. Their responsiveness to aspirin was evaluated by platelet function analyzer (PFA-100). All patients received blood tests for fibrinogen, high-sensitivity C-reactive protein (hs-CRP), CD40-ligand, P-selectin, intercellular adhesion molecule -1, von Willebrand factor (vWF), and D–dimer. The patients' National Institutes of Health Stroke Scale and modified Rankin Scale scores were recorded on admission, at 30 days, and at 90 days after stroke. ResultsClosure-time measured by PFA-100 equipped with epinephrine/collagen cartridge (Epi-CT) was <193 seconds (defined as AR) in 83 patients (30.9%). Patients with AR were less likely to have favorable outcome at 30 days (47.0%, p = 0.047; odds ratio: 0.69, 0.48–0.99) and 90 days (57.8%, p = 0.037; odds ratio: 0.69, 0.47–0.97) after stroke compared with those of patients without AR (60.2% and 71.0%, respectively). The Epi-CT correlated with closure-time measured by adenosine diphosphate/collagen cartridge (r = 0.241, p < 0.001), blood white cell count (r = −0.125, p = 0.041), low density lipoprotein cholesterol (r = 0.120, p = 0.050), hs-CRP (r = −0.150, p = 0.015), vWF (r = −0.134, p = 0.028), and body mass index (r = 0.143, p = 0.019). Multivariate logistic regression analysis showed that higher National Institutes of Health Stroke Scale at admission, atrial fibrillation, increased plasma levels of hs-CRP, and D–dimer were independent predictors for unfavorable stroke outcome at 90 days. ConclusionAspirin resistance evaluated by PFA-100 test was associated with unfavorable 90-day outcome. However, AR determined by PFA-100 dose not predict 90-day functional outcome. The results of PFA-100 testing represented a complex interaction between drug effect, inflammatory reaction, and prothrombotic activity.

Polymorphism of the cyclooxigenase-1 gene and aspirin resistance

Literature data concerning the structure of cyclooxigenase-1—a key enzyme in prostaglandin biosynthesis and the main target of antiplatelet therapy with the use of acetylsalicylic acid—are presented in this review. Data are presented on the cyclooxigenase-1 gene polymorphism, distribution of the revealed variants in different populations, as well as their possible correlation with biochemical and functional aspirin resistance.

Biochemical Aspirin Resistance and Recurrent Lesions in Patients with Acute Ischemic Stroke

Background: The effect of biochemical aspirin resistance (BAR) on ischemic stroke has not been well established. Early recurrent ischemic lesions (ERILs) on diffusion-weighted imaging (DWI) are proposed as potential surrogate markers of clinically recurrent stroke. Methods: We included 117 consecutive patients who (1) were admitted within 24 h of symptom onset; (2) had an ischemic stroke confirmed by DWI; (3) underwent follow-up DWI within seven days after onset, and (4) received aspirin treatment. BAR was measured using the VerifyNow® Aspirin Assay. We analyzed the associations between BAR and any ERILs (overall ERILs), and between BAR and ERILs occurring outside the vascular territories of index stroke (distant ERILs). Results: BAR was observed in 16 (13.7%) patients. Overall ERILs were detected in 34 (29.1%), and distant ERILs in 10 (8.5%) patients. Patients with BAR were more likely to develop ERILs, but the association was not significant (OR 2.13; 95% CI 0.72–6.29; p = 0.234). However, BAR was independently related to distant ERILs by logistic regression analysis (OR 6.01; 95% CI 1.29–28.09; p = 0.023). Conclusions: BAR was associated with distant ERILs but not with overall ERILs during the first week after ischemic stroke.

The Clinical Significance of Aspirin Resistance in Patients With Chest Pain

There are conflicting data in the literature about the clinical significance of aspirin resistance. We aimed to prospectively evaluate the prevalence of biochemical aspirin resistance in patients on aspirin therapy who were admitted to the emergency clinic with chest pain. We also aimed to evaluate the relation between acute coronary syndromes (ACS) and aspirin resistance. A total of 338 patients were included in the study. Platelet reactivity was measured with the PFA-100 system (Dade Behring Inc, Deerfield, IL). Aspirin resistance determined by the PFA-100 was defined as a normal collagen and/or epinephrine closure time despite aspirin treatment (<165 s). Patients were divided into 4 groups: stable angina pectoris (SAP), unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI), ST-elevation myocardial infarction (STEMI), and rule out ACS. Aspirin resistance was found in 81 (24%) patients in all groups. Patients with ACS had significantly more aspirin resistance than patients with rule out ACS or patients with SAP (P < .001). In the SAP group, 31 (19.6%) patients; in the UA/NSTEMI group, 19 (35.8%) patients; in the STEMI group, 14 (50%) patients; and in the rule out ACS group, 17 (17.2%) patients had aspirin resistance (P < .001). In the multivariate analysis, cardiac biomarker elevation on admission to emergency department and platelet count appeared as independent factors predictive of aspirin resistance. We demonstrated that incidence of aspirin resistance was significantly higher in patients who were finally diagnosed as ACS, especially in aspirin-taking patients admitted to the emergency clinic with STEMI.

Aspirin Resistance: Disparities and Clinical Implications

Abstract Aspirin is one of the most widely prescribed drugs for the prevention of thrombosis in patients with vascular disease. Yet, aspirin is unable to prevent thrombosis in all patients. The term "aspirin resistance" has been used to broadly define the failure of aspirin to prevent a thrombotic event. Whether this is directly related to aspirin itself through biochemical aspirin resistance or treatment failure, or if it is because of aspirin's inability to overcome the thrombogenic aspects of the disease process itself, has not been elucidated. This can have dramatic clinical implications for a variety of vascular disease subsets and is cause for concern, considering the high prevalence of aspirin use for both primary and secondary prevention. Disparities exist in the rates of aspirin resistance among certain patient populations, such as women, patients with diabetes mellitus, and those with heart failure, and across clinical conditions, such as cardiovascular and cerebrovascular disease. Clinical trial data from studies observing resistance have revealed that regardless of study size, dose of aspirin, control for drug interactions and adherence, or assay used to measure platelet function, aspirin resistance is associated with an increased risk for adverse events. Although the evidence is mounting, there has yet to be a consensus on the appropriate clinical response to aspirin resistance.

Aspirin resistance and diabetes mellitus

Despite multiple interventions to reduce the risk of cardiovascular disease, the majority of people with diabetes develop macrovascular complications, and mortality following myocardial infarction remains unacceptably high [1]. Antiplatelet agents are used for both the primary and secondary prevention of cardiovascular disease, although current guidelines are not consistent in their recommendation for the use of aspirin in diabetes [2]. In fact, there is little direct evidence supporting its efficacy in this group of patients. Instead, there is convincing data in the literature to suggest inadequate cardiovascular protection by aspirin in diabetes. In a meta-analysis of 287 randomised trials, antiplatelet treatment (aspirin in most studies) reduced the risk of ischaemic events by 22%, but the risk reduction in the subgroup with diabetes was only 7%, which was not statistically significant [3]. This outcome was mirrored in the Primary Prevention Project trial, which reported that cardiovascular risk reduction with aspirin was marginal and non-significant in the presence of diabetes [4]. Despite this, there are no published studies specifically designed to evaluate the clinical efficacy of aspirin in individuals with diabetes, a surprising omission in the era of ‘evidencebased’ medicine. These findings from clinical trials raise the question as to why there should be a reduction in the clinical efficacy of aspirin in patients with diabetes compared with a nondiabetic population. Diabetes is intrinsically associated with particular biochemical abnormalities that may have the capacity to diminish the effects of aspirin on platelet function and cardiovascular risk—a possibility that has led to the hotly debated concept of aspirin resistance [5, 6]. Unfortunately, aspirin resistance suffers from a lack of a standardised definition, although now generally thought of as either (1) reflecting clinical aspirin resistance (or perhaps, more accurately, treatment failure), characterised by the occurrence of a thrombotic episode despite treatment with aspirin; or (2) biochemical aspirin resistance where platelet responses persist despite platelet exposure to aspirin. Controversy remains as to the cause of biochemical aspirin resistance, its relevance to clinical outcomes, and the place of aspirin treatment in the management of cardiovascular risk in diabetes patients. All of this highlights the urgent need to understand the mechanisms that underpin the interactions between diabetes and aspirin, to establish the role of aspirin in particular, and antiplatelet therapy in general, in the amelioration of cardiovascular events in individuals with diabetes. Diabetologia (2008) 51:385–390 DOI 10.1007/s00125-007-0898-3

Flow cytometric assessment of platelet aspirin resistance using light scattering

A simple and reliable assay is needed for the prediction of the clinical efficacy of antiplatelet aspirin therapy. We have devised another method for the evaluation of platelet function and aspirin resistance (AR), via conventional flow cytometry (FCM). To devise an optimized protocol for the assessment of platelet AR, various analytic variables of FCM were investigated. Using this devised protocol, AR was assessed in healthy subjects as an example. The protocol utilized herein is as follows: citrate-anticoagulated platelet-rich plasma was mixed 1:1 with HEPES-buffered saline in two tubes, one of which is treated with aspirin. During the acquisition of FCM, arachidonate is added to the tube. The response of the aspirin-treated platelets is then compared with those of nontreated ones on a time/forward scatter plot. In the 61 total subjects, none was identified as aspirin resistant by this assay. Using light scattering, platelet aggregation and aspirin's antiplatelet effects can be readily and cost-effectively detected. According to this assay, biochemical AR appears to be rare. This new protocol may prove useful in a clinical setting or as a research tool.

Assessment of biochemical aspirin resistance at rest and immediately after exercise testing

Some aspirin-treated patients experience thromboembolic events, a phenomenon termed 'aspirin resistance', which may be clinical or biochemical by definition. Physical exercise is known to enhance platelet secretion and aggregability. To evaluate the presence of biochemical aspirin resistance at rest and immediately after exercise in individuals with stable coronary artery disease or coronary artery disease risk factors. We prospectively enrolled 101 patients who had received 100 or 300 mg/day enteric-coated aspirin for at least 7 days. Biochemical aspirin resistance (defined as normal collagen-epinephrine closure time < 165 s) was studied using the standardized platelet function analyzer. Of the 101 patients, 63 were aspirin sensitive both at rest and immediately after exercise, 18 exhibited biochemical aspirin resistance both at rest and after exercise, and 20 were aspirin sensitive at rest but exhibited biochemical aspirin resistance immediately after exercise. The results of exercise testing were similar in all three groups (each P > 0.05). Our results indicate that in almost 20% of the patients, aspirin did not seem to protect against exercise-induced platelet activation, despite the presence of aspirin sensitivity at rest. We did not, however, determine the extent to which the biochemical aspirin resistance noted in our study applied to clinical events.

Invited commentary

Aspirin is widely used to reduce graft thrombosis after coronary artery bypass grafting. However, aspirin only prevents approximately 25% of all ischemic vascular events and there are many causes, including all the causes of aspirin resistance for the other events. Aspirin resistance is the inability of aspirin to block platelet production of thromboxane A2 and subsequent platelet activation and aggregation. Increasing degrees of aspirin resistance may correlate independently with increasing risk of cardiovascular events. The study by Lim and colleagues [1Lim E. Carballo S. Cornelissen J. et al.Dose-related efficacy of aspirin after coronary surgery in patients with PlA2 polymorphism (NCT00262275).Ann Thorac Surg. 2007; 83: 134-139Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar] analyzed a genetic polymorphism within a subgroup of a prospective randomized trial. They attempted to evaluate the role of genetic polymorphism on the aspirin response in patients after coronary artery bypass grafting. The authors postulated that several genetic polymorphisms are common and some may affect responses to aspirin. In particular, PIA2 polymorphism seems to cause aspirin resistance. As with most genetic studies, the results were not clear-cut and statistical significance was not achieved, although trends were similar to published results. The design of this study is a major weakness for determining correlation between clinical findings and genetic polymorphisms. Basically most studies on genetic polymorphism need several populations of subjects. Several different subject populations or a highly selected group can establish a correlation between clinical findings and polymorphisms. Analytic studies that investigate the association of biochemical aspirin resistance and clinical events must quantitatively account for potential confounders (eg, age, sex, ethnicity, and clinical conditions), hematologic and biochemical factors (eg, hyperlipidemia, platelet count, and hemoglobin level), and nonadherence. The analysis in this study did not consider aspirin resistance that can be diagnosed in the laboratory by measurement of platelet thromboxane A2 production or thromboxane-dependent platelet function. Potential causes of aspirin resistance include inadequate dose, drug interactions, genetic polymorphisms involved in thromboxane biosynthesis, upregulation of nonplatelet sources of thromboxane biosynthesis, and increased platelet turnover. To prove the association between the polymorphism and clinical risk, statistical exclusion of confounders is required to reach a conclusion. Differential sensitivity to aspirin may have potential clinical implications, whereby specific antiplatelet therapy is best tailored to a patient’s PIA2 genotype. A well-designed study in a larger population is necessary to confirm the association between genetic polymorphisms and aspirin resistance. Dose-Related Efficacy of Aspirin After Coronary Surgery in Patients With PlA2 Polymorphism (NCT00262275)The Annals of Thoracic SurgeryVol. 83Issue 1PreviewTo evaluate the impact of the genetic polymorphisms affecting aspirin response using platelet aggregation and the response to different aspirin doses after cardiopulmonary bypass, we performed a subanalysis of the results from a randomized trial evaluating low- and medium-dose aspirin and clopidogrel. Full-Text PDF

Mo-P5:301 Effects of exercise on biochemical aspirin resistance

Mo-P5:301 Effects of exercise on biochemical aspirin resistance