A brief review on resistance to P2Y12 receptor antagonism in coronary artery disease

Warlo, Ellen Mathea Kirsch; Arnesen, Harald; Seljeflot, Ingebjørg

doi:10.1186/s12959-019-0197-5

Cited by 55 publications

(56 citation statements)

References 49 publications

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“…The THEMIS trial conducted by Steg et al in 2019 demonstrated that patients with stable CAD and diabetes benefited from taking ticagrelor in combination with ASA, compared to ASA and a placebo [ 23 ]. Ticagrelor also has significantly lower rates of non-sensitivity, as low as 0–3%, compared to ASA and clopidogrel, which may have rates as high as 65% [ 13 , 44 ]. As we demonstrated here in our study, 100% of our ASA non-sensitive patients were sensitive to ticagrelor.…”

Section: Discussionmentioning

confidence: 99%

“…Ticagrelor is a fast-acting antiplatelet, as it is an active drug, unlike its counterpart clopidogrel, which is a pro-drug requiring activation by hepatic enzymes, specifically the cytochrome P450 isoenzymes (CYPs) [ 45 , 46 ]. It is hypothesized that clopidogrel resistance is higher compared to ticagrelor as there are several single nucleotide polymorphisms in the CYP genes that can affect the conversion of clopidogrel into its active form [ 44 ]. The Study of Platelet Inhibition and Patient Outcomes (PLATO) compared outcomes in patients on ticagrelor or clopidogrel and noted a 16% relative risk reduction of death due to vascular causes, MI, and stroke, and a 22% relative risk reduction in overall mortality in patients taking ticagrelor; however, patients taking ticagrelor had an increase in minor, non-procedure-related bleeds when compared to patients taking clopidogrel [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

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Ticagrelor as an Alternative Antiplatelet Therapy in Cardiac Patients Non-Sensitive to Aspirin

et al. 2020

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Background and Objectives: Aspirin (acetylsalicylic acid—ASA) is a first-line antiplatelet therapy provided to patients with coronary artery disease (CAD). However, it has been demonstrated that 20–30% of these patients are non-sensitive to their ASA therapy. ASA non-sensitivity is a phenomenon where low-dose ASA (81–325 mg) does not completely inhibit arachidonic-acid-induced platelet aggregation, putting patients at risk of adverse cardio-thrombotic events. Ticagrelor is a P2Y12 receptor inhibitor and alternative antiplatelet that has been approved to reduce the risk of stroke, myocardial infarction, and overall cardiovascular-related death. In this study, we aimed to identify ASA non-sensitive patients and evaluate if they would be sensitive to ticagrelor. Materials and Methods: For this pilot study, thirty-eight patients with CAD taking 81 mg ASA were recruited. Blood samples were collected from each patient and platelet rich plasma (PRP) from each sample was isolated. Light-transmission aggregometry (LTA) was used to determine baseline ASA sensitivity in each patient using 0.5 mg/mL arachidonic acid as a platelet agonist. Patients with ≥20% maximal platelet aggregation after activation were considered ASA non-sensitive. Fresh PRP samples from all patients were then spiked with a clinical dosage of ticagrelor (3 μM—approximately equivalent to a loading dose of 180 mg ticagrelor). Sensitivity was determined using LTA and 5 μM ADP as a platelet agonist. Patients with ≥46% maximal platelet aggregation were considered ticagrelor non-sensitive. Results: Of the 38 CAD patients taking 81 mg ASA, 32% (12/38) were non-sensitive to their 81 mg ASA therapy. All 38 of the recruited patients (100%) were sensitive to ticagrelor ex vivo. In conclusion, we were able to identify ASA non-sensitivity using LTA and determine that ASA non-sensitive patients were sensitive to ticagrelor. Conclusions: Our results suggest that ticagrelor is a promising alternative therapy for patients who are non-sensitive to ASA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ticagrelor as an Alternative Antiplatelet Therapy in Cardiac Patients Non-Sensitive to Aspirin

et al. 2020

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“…High percentage of individuals usually experiences antiplatelet therapy resistance that impairs successful prevention of cardiovascular events, and some determinants of resistance to antiplatelet therapy are gender responsive [141][142][143][144][145][146]. A prospective study on 160 patients with stable coronary heart disease (118 men and 42 women, aged 65:2 ± 7:8 years), indeed, showed a sex-related response to long-term double antiplatelet therapy (75 mg/day aspirin and clopidogrel for three months): female gender was more predisposed to resistance to both aspirin and clopidogrel compared to men [19].…”

Section: Dietary Factors Experimental Protocol Main Findings Refsmentioning

confidence: 99%

Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions

Gasperi

Catani

Savini

2020

Cardiovascular Therapeutics

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Cardiovascular diseases (CVD) represent one of the biggest causes of death globally, and their prevalence, aetiology, and outcome are related to genetic, metabolic, and environmental factors, among which sex- and age-dependent differences may play a key role. Among CVD risk factors, platelet hyperactivity deserves particular mention, as it is involved in the pathophysiology of main cardiovascular events (including stroke, myocardial infarction, and peripheral vascular injury) and is closely related to sex/age differences. Several determinants (e.g., hormonal status and traditional cardiovascular risk factors), together with platelet-related factors (e.g., plasma membrane composition, receptor signaling, and platelet-derived microparticles) can elucidate sex-related disparity in platelet functionality and CVD onset and outcome, especially in relation to efficacy of current primary and secondary interventional strategies. Here, we examined the state of the art concerning sex differences in platelet biology and their relationship with specific cardiovascular events and responses to common antiplatelet therapies. Moreover, as healthy nutrition is widely recognized to play a key role in CVD, we also focused our attention on specific dietary components (especially polyunsaturated fatty acids and flavonoids) and patterns (such as Mediterranean diet), which also emerged to impact platelet functions in a sex-dependent manner. These results highlight that full understanding of gender-related differences will be useful for designing personalized strategies, in order to prevent and/or treat platelet-mediated vascular damage.

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“…The pathological mechanism of CR has been investigated in many analyses in recent years; clinical factors, drug-drug interactions and genetic factors have been assessed ( Thomas and Storey, 2016 ; Warlo et al, 2019 ). Different clinical features, such as diabetes, gender, obesity, and hypercholesterolemia, contribute to a low clopidogrel response as well ( D’ascenzo et al, 2014 ; Franchi and Angiolillo, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Clopidogrel Resistance Is Associated With DNA Methylation of Genes From Whole Blood of Humans

Yang

Xu³

et al. 2021

Front. Genet.

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Antiplatelet therapy has become a cornerstone in the treatment of coronary heart disease (CHD). However, due to high-residual-platelet-reactivity, clopidogrel resistance (CR) is a common phenomenon, and it is rarely known about the relationship between CR and epigenetic changes. This study compared the whole genomic methylation patterns of blood samples from patients with CR (n = 6) and non-CR (n = 6) with the Human Methylation 850K BeadChip assay. We explored differentially methylated CpG sites, genes, and pathways using bioinformatics profiling. The CR and control groups showed significantly different DNA methylation at 7,098 sites, with 979 sites showing hypermethylation and 6,119 sites showing hypomethylation. The pyrosequencing method was used to validate four differentially methylated CpG loci (cg23371584, cg15971518, cg04481923, cg22507406), confirming that DNA methylation was associated with the risk of CR (30 CR vs. 30 non-CR). The relative mRNA expression of the four genes (BTG2, PRG2, VTRNA2-1, PER3) corresponding to the loci above was also associated with CR, suggesting that alterations in DNA methylation may affect the expression of these four genes, eventually resulting in CR. Additionally, differentially methylated sites are partially related to genes and pathways that play key roles in process of circadian entrainment, insulin secretion, and so on. Hence, the mechanism and biological regulation of CR might be reflected through these epigenetic alterations, but future research will need to address the causal relationships.

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A brief review on resistance to P2Y12 receptor antagonism in coronary artery disease

Cited by 55 publications

References 49 publications

Ticagrelor as an Alternative Antiplatelet Therapy in Cardiac Patients Non-Sensitive to Aspirin

Ticagrelor as an Alternative Antiplatelet Therapy in Cardiac Patients Non-Sensitive to Aspirin

Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions

Clopidogrel Resistance Is Associated With DNA Methylation of Genes From Whole Blood of Humans

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