The Emergent Phenomenon of Aspirin Resistance: Insights from Genetic Association Studies

Ferreira, Mariana; Freitas-Silva, Margarida; Assis, Joana; Pinto, Ricardo; Nunes, José Pedro L.; Medeiros, Rui

doi:10.2217/pgs-2019-0133

Cited by 22 publications

(18 citation statements)

References 118 publications

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“…12 Genotyping aspirin resistance, however, has gained attention, i.e., for the genetic polymorphism of the PTGS1 gene that encodes COX-1, as specific short nucleotide polymorphisms and haplotypes dysregulate arachidonic acidinduced thromboxane production leading to inadequate aspirin responses. 13 Aspirin HPR, a risk factor for major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI), 14 is observed in up to 15% of patients undergoing neuroendovascular interventions; however, in alignment with cardiovascular studies, a consistent association of aspirin PR and clinical outcomes is not evident. However, two recent metaanalyses suggest that in DAPT, low-dose (150 mg daily) as compared to high-dose aspirin given either before or after the neuroendovascular intervention increases late (>6 months) thromboembolism by about 2.5 times without differences in hemorrhagic events.…”

Section: Resultsmentioning

confidence: 99%

P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine

et al. 2021

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Introduction Dual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors. Methods Assessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices. Results Both geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy. Conclusions The latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

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Section: Resultsmentioning

confidence: 99%

P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine

et al. 2021

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“…Между тем в других исследованиях было показано, что минорная аллель T не связана с высоким риском развития ИБС, а увеличение количества рецепторов GPIa/IIa не приводит к возрастанию тромботического риска [12]. Кроме того, сообщалось о возможном влиянии аллели Т на резистентность к АСК [13], однако в нашем исследовании это не подтвердилось.…”

Section: Gene Polymorphism and Resistance To Antiplatelet Therapy пол...unclassified

Study the Association of Nucleotide Polymorphisms in Platelet Receptor and Cytochrome P450 Genes with the Development of Resistance to Antiplatelet Drugs in Patients with Coronary Artery Disease

Semashchenko

Монгуш

Косинова

et al. 2022

Racionalʹnaâ farmakoterapiâ v kardiologii

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Aim. To study the association of nucleotide polymorphisms in platelet receptor and cytochrome P450 genes with the development of resistance to antiplatelet drugs in CHD patients.Material and Methods. The study included 243 patients diagnosed with CHD after coronary artery bypass surgery (CABG), including 140 patients in the acetylsalicylic acid (ASA) treatment group and 103 patients in the dual antiplatelet therapy (DAT) group. All patients were tested for platelet aggregation using an optical aggregometer with inducers: 5 mM ADP and 1 mM arachidonic acid (AA). DNA samples were analyzed by allele-specific PCR for the presence of polymorphisms rs2046934, rs1126643, rs5918, rs6065, rs4244285 in the platelet receptor and cytochrome P450 genes.Results. No statistically significant differences were found during comparison of the prevalence of the studied polymorphisms in the platelet receptor and cytochrome P450 genes between the groups of aspirin-sensitive and aspirin-resistant patients, as well as between the groups of clopidogrelsensitive and clopidogrel-resistant patients. No association between carriage of the minor and major alleles of the polymorphisms studied and the development of antiplatelet drug resistance was found. In the group of patients on ASA therapy, carriers of the C allele of the T1565C (rs5918) ITGB3 polymorphism had a higher rate of AA-induced platelet aggregation compared to carriers of the T allele (18,49±25,92 vs 10,43±17,34, р=0,004).Conclusion. Polymorphisms of P2RY12 (rs2046934), ITGA2 (rs1126643), ITGB3 (rs5918), GP1BA (rs6065), CYP2C19*2 (rs4244285) genes are not associated with antiplatelet drug resistance in both patients on ASC therapy and on DAT. The presence of minor alleles of the rs2046934, rs1126643, rs6065, rs4244285 polymorphisms are not associated with increased platelet aggregation activity before CABG.However, in the group of patients on ASA therapy C-allele carriers of the rs5918 polymorphism of the ITGB3 gene had a higher rate of AA-induced platelet aggregation compared to T-allele carriers.

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“…Clinically, it can be identified from the occurrence of atherothrombotic events in a patient who is under the therapeutic effect of one dose of aspirin. But this method is limited because it is mostly non-specific and can only be identified retrospectively because the events occur only after the start of the treatment ( 82 , 83 ). The laboratory monitoring of PFT is based on the platelet aggregation and presence of platelet reactivity which is mentioned above.…”

Section: Antiplatelet Resistancementioning

confidence: 99%

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review

et al. 2021

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Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.

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The Emergent Phenomenon of Aspirin Resistance: Insights from Genetic Association Studies

Cited by 22 publications

References 118 publications

P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine

P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine

Study the Association of Nucleotide Polymorphisms in Platelet Receptor and Cytochrome P450 Genes with the Development of Resistance to Antiplatelet Drugs in Patients with Coronary Artery Disease

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review

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The Emergent Phenomenon of Aspirin Resistance: Insights from Genetic Association Studies

Cited by 22 publications

References 118 publications

P2Y12inhibitors in neuroendovascular surgery: An opportunity for precision medicine

P2Y12inhibitors in neuroendovascular surgery: An opportunity for precision medicine

Study the Association of Nucleotide Polymorphisms in Platelet Receptor and Cytochrome P450 Genes with the Development of Resistance to Antiplatelet Drugs in Patients with Coronary Artery Disease

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review

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P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine

P₂Y₁₂inhibitors in neuroendovascular surgery: An opportunity for precision medicine