Definition Of Aspirin Resistance Research Articles

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.

Definition of aspirin resistance using whole blood impedance aggregometry in patients undergoing coronary artery surgery: methodological challenges and outcome improvement opportunities

Methods Prospective observational trial at University Hospital Center Zagreb enrolled 131 patients scheduled for CABG, and divided them into 4 groups with respect to preoperative antiplatelet therapy (APT). Group 1 received 100 mg ASA per day, Group 2 100 mg ASA + 75 mg clopidogrel per day, Group 3 75 mg clopidogrel per day, and Group 4 did not receive any APT. MEA with ASPI test (sensitive to ASA) and ADP test (sensitive to clopidogrel) was performed prior to surgery. In Group 1, patients were characterized as ASA resistant if their ASPI test value exceeded the 75th percentile distribution. Results Study enrolled 131 patients. Significant differences both in the ASPI (p<0.001) and the ADP test (p=0.038) were observed between patients in different APT groups. In Group (1) ASPI test value of 30 AUC presented 75th percentile of distribution, thus indicating ASA resistance. Group 2 patients had slightly lower ADP test values, but no significant difference occurred (mean 60.05 vs. 63.32 AUC, p=0.469). In Group 1 and 2, significant correlations between the ADP test and both, platelet count (r=0.347, p<0.001) and fibrinogen level (r=0.364, p<0.001) were observed.

TRUE RESISTANCE AND PSEUDORESISTANCE TO ASPIRIN

Low dose aspirin reduces the secondary incidence of myocardial infarction and stroke. Drug resistance to aspirin might result in treatment failure. Despite this concern, no clear definition of aspirin resistance has emerged, and estimates of its incidence have varied remarkably. Researchers from university of Pennsylvania (Philadelphia, the USA), led by Dr. Tilo Grosser, aimed to determine the specific phenotype of true pharmacological resistance to aspirin — such as might be explained by genetic causes. However the study failed to identify a single case of true drug resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric coated but not immediate release aspirin administration.

Aspirin Resistance or Variable Response or Both?

Numerous clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. However, a constellation of clinical and laboratory evidence exists that demonstrates diminished or absent response to aspirin in some patients. This has led to the concept of "aspirin resistance," which is a poorly defined, somewhat misleading term. The mechanism for aspirin resistance has not been fully established, but it is almost certainly due to a combination of clinical, biological, and genetic properties affecting platelet function. There are no criteria for distinguishing true resistance from treatment failure, and there is no consensus on whether the definition of aspirin resistance should be based on clinical outcomes, laboratory evidence, or both. Studies in large populations are needed to define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes. One such prospective randomized trial is completed, and 2 others are under way: the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention, and the Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented coronary artery disease. The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y(12) Receptor Resistance (RESISTOR) trial is investigating whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance.

Aspirin “resistance”

A variable responsiveness to antiplatelet drugs is a clinical phenomenon that does not principally differ from other drug treatments in other therapeutic fields. The pharmacological part is to clarify whether a “true” resistance exists in pharmacological terms, i.e., a reduced potency of the compound to work as suggested and to find out the underlying cellular mechanism(s). Two principally different methods of laboratory control for platelet sensitivity to aspirin (ASA) are available: measurement of platelet function (ex vivo) or measurement of inhibition of thromboxane formation. Both methods have limitations and did not yet result in a generally accepted definition of a pharmacological ASA “resistance”. The new typological approach of Weber et al. [A.A. Weber, B. Przytulski, A. Schanz, et al., Towards a definition of aspirin resistance: a typological approach. Platelets 13 (2002) 37. [1]] helps to identify different subtypes of ASA resistance in pharmacological terms by combining in vitro aggregometry with thromboxane measurement. Using this method, a “true” pharmacological resistance, associated with a reduced antiplatelet response to ASA and reduced inhibition of thromboxane formation, was found in patients undergoing coronary artery bypass surgery. Platelets of these patients expressed a hitherto unknown isoform of COX-2-COX-2a which might generate a different gene product. In this context, it is interesting that CABG patients express transiently an immunoreactive COX-2 protein with lower molecular weight. Studies on the significance of this finding for ASA resistance are in progress.

Aspirin Resistance - A Comparison of Platelet Functions and 11-Dehydro Thromboxane B2 and 8-epi Prostaglandin F2α Plasma Concentration.

Introduction. Laboratory tests do not reveal any changes due to administration of aspirin (75 – 150 mg/d) in about 25% of patients. The definition of aspirin resistance and parameters of different laboratory tests for its identification have not yet been established.Aim. The aim of our study was to compare the results of platelet aggregation studies, the closure times in PFA-100, the plasma concentrations of 11-dehydro thromboxane B2 (11-d TxB2) and 8-epi prostaglandin F2α (8-epi PgF2α) in patients receiving aspirin chronically.Material. The study group consisted of 22 patients taking aspirin for the secondary prevention of ischemic stroke (IS). All patients were at least 6 months after the acute onset, and had a diminished intraplatelet concentration of malonyldialdehyde due to aspirin ingestion.Methods. Following parameters have been evaluated:Platelet aggregation induced by either ADP (3,5 and 5,0 μM), collagen (2 μg/ml) or arachidonic acid (AA) (0,6 mM);Closure time in PFA-100 (collagen/epinephrine and collagen/ADP cartridges);Plasma 11-d TxB2 and 8-epi PgF2α concentration measured by ELISA method (Cayman Chemicals).Aspirin resistance has been determined by the following criteria: the intensity of ADP induced platelet aggregation ≥ 60%, collagen induced aggregation ≥ 70%, AA induced aggregation ≥ 20%, PFA-100 closure time ≤ 165 s, 11-d TxB2 concentration ≥ mean of the control group ± 2 SD.Results.The frequency of aspirin resistance in patients after ischaemic strokeAggregationADP 3,5 μMADP 5,0 μMCollagenArachidonic acidPFA-10011-d TxB263,6%45,5%18,2%13,6%54,5%50,0%Statistically significant correlations have been found between the plasma concentration of 11-d TxB2 and PFA-100 (Col/Epi) closure times and between plasma concentration of 8-epi PgF2α and PFA-100 (Col/Epi) closure times. There was no difference in mean plasma concentration of 8-epi PgF2α between the group of patients and controls.Conclusions.The most valid laboratory method of aspirin resistance identification in ischemic stroke patients (besides a mesurement of 11-dehydro thromboxane B2) seems to be PFA-100 closure time.Our PFA-100 studies reveal a much higher percentage of aspirin resistance as compared to former studies.The plasma concentration of 8-epi prostaglandin F2α remains in the normal range in patients taking aspirin for the secondary prevention of ischemic stroke.

Towards a definition of aspirin resistance: a typological approach

'Aspirin resistance' is a poorly defined term to describe the inability of aspirin to protect individuals from thrombotic complications and there are conflicting reports on incidence rates and clinical relevance of this phenomenon. Using collagen (1 w g/ml)-induced platelet aggregation and thromboxane formation (measured as thromboxane B 2 ) in citrated platelet-rich plasma, this study demonstrates that aspirin resistance can be classified into three distinct types. In aspirin responders, both, collagen-induced platelet aggregation and thromboxane formation was completely (>95%) inhibited by oral aspirin treatment (100 mg/day). In type I resistance (pharmacokinetic type), oral treatment with aspirin was ineffective but addition of aspirin (100 w M) in vitro resulted in a complete inhibition of collagen-induced platelet aggregation and thromboxane formation. In type II resistance (pharmacodynamic type), neither oral treatment with aspirin nor addition of aspirin in vitro inhibited collagen-induced platelet aggregation and thromboxane formation. In type III resistance (pseudo-resistance), platelet aggregation was induced by a low concentration of collagen (1 w g/ml) despite of a complete inhibition of thromboxane formation by oral aspirin treatment. This typology of aspirin resistance should help to clarify the mechanisms, the actual rate, and the possible clinical consequences of this phenomenon.