The Impact of
 CYP2C19
 and
 CYP4F2
 Variants and Clinical Factors on Treatment Outcomes During Antiplatelet Therapy

Tatarūnas, Vacis; Kupstytė-Krištaponė, Nora; Norvilaitė, Rita; Tamakauskas, Vytenis; Skipskis, Vilius; Veikutienė, Audronė; Jurgaitytė, Julija; Stuoka, Mantvydas; Lesauskaitė, Vaiva

doi:10.2217/pgs-2018-0178

Cited by 14 publications

(23 citation statements)

References 40 publications

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“…According to Kupstyte et al [42], the CYP4F2 AA variant is associated with early stent thrombosis. In another work, where the CYP4F2 rs3093135 polymorphism was studied, it was shown that the T allele was independently associated with bleeding during dual antiplatelet therapy [15]. Here, we also showed that the CT+TT allele variant of the CYP4F2 polymorphic marker C(Val433Met) T is associated with an increased risk of bleeding on anti-thrombotic therapy, which is consistent with the study of Kupstyte et al [42].…”

Section: Discussionsupporting

confidence: 92%

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

et al. 2022

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Introduction: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12–20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). Methods: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy – high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). Results: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. Conclusion: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

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Section: Discussionsupporting

confidence: 92%

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

et al. 2022

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“…However, among the 10 candidate SNPs, only P2Y12 (rs6787801 and rs6785930) showed a statistically significant but not clinically relevant effect on ticagrelor levels and bleeding events (Table 4), which was in agreement with the literature. [17][18][19][20] At present, several optimal potency and duration of DAPT were proposed, given the unique features of East Asian patients during antiplatelet therapy. 34,35 Notably, low-dose ticagrelor (60 mg BID) appeared to have a good safety/efficacy profile but numerically lower bleeding events than the standard dose (90 mg BID).…”

Section: F I G U R E 5 Relationship Between Ticagrelor Trough Concent...mentioning

confidence: 99%

“…18,19 Additionally, Tatarunas et al identified variants in CYP4F2, a cofactor essential for blood clotting by regulating the bioavailability of vitamins E and K, were significantly associated with bleeding events during dual antiplatelet therapy (DAPT). 20 Therefore, this study aimed to investigate the relationship between bleeding events and plasma concentrations of ticagrelor and AR-C124910XX in Chinese ACS patients with DAPT. Meanwhile, the effect of 10 SNPs on ticagrelor concentrations and bleeding events was also investigated, including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), SLCO1B1 (rs12371604 and rs113681054), PEAR1 (rs12566888, rs12041331 and rs4661012), P2Y12 (rs6785930 and rs6787801) and CYP4F2 (rs3093135).…”

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confidence: 99%

Association between ticagrelor plasma concentration and bleeding events in Chinese patients with acute coronary syndrome

Yang

et al. 2022

Brit J Clinical Pharma

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Aims:The risk of ticagrelor-related bleeding events remains a major clinical concern, especially in East Asian populations. Previous studies have reported higher ticagrelor exposure in Asian patients than in Caucasians. This prompted us to investigate the correlation between ticagrelor concentrations and bleeding events.Methods: Patients diagnosed with acute coronary syndrome and receiving dual antiplatelet therapy (aspirin and ticagrelor) were enrolled and followed up for 12 months.Trough plasma concentrations of ticagrelor and a major active metabolite were assayed, and 10 single nucleotide polymorphisms associated with ticagrelor pharmacokinetics and safety were also identified.Results: A total of 631 patients were included and 133 patients had bleeding academic research consortium type 1 or 2 bleeding event. The median ticagrelor concentration (interquartile range) was significantly higher in patients with bleeding events than that in patients without bleeding events (322.6 ng/mL [196.2-458.0 ng/mL] vs.222.1 ng/mL [140.4-341.9 ng/mL], P < .001). According to the receiver operating characteristic curve, the cut-off value for ticagrelor levels predicting bleeding events was 363.3 ng/mL (area under the curve = 0.65; P < .001, 95% Cl: 0.595-0.700).Pharmacogenomics results showed that P2Y12 (rs6787801, P = .024) and P2Y12 (rs6785930, P = .048) were statistically associated with ticagrelor levels and bleeding events, respectively. Conclusion:Ticagrelor plasma concentrations were associated with bleeding events in Chinese patients with acute coronary syndrome.

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“…Loss-of-function alleles CYP2C19*2 and CYP2C19*3 decreased activity of the metabolites by affecting functional metabolites of the enzyme, leading to a high platelet response. Patients with CYP2C19*17 [ 29 ] and CYP4F2 T alleles [ 135 ] were at higher risk of bleeding. The PLATO study found that ticagrelor was superior to clopidogrel in reducing cardiovascular composite endpoints in all CYP2C19 genotypes.…”

Section: Special Groupsmentioning

confidence: 99%

A Review of the Role of the Antiplatelet Drug Ticagrelor in the Management of Acute Coronary Syndrome, Acute Thrombotic Disease, and Other Diseases

et al. 2022

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P2Y12 inhibitors, including aspirin, are key components of dual-antiplatelet therapy (DAPT), which is the optimal therapeutic strategy for preventing arterial thrombosis in patients with acute coronary syndromes (ACS) who underwent stent implantation. Ticagrelor is a cyclopentyl-triazole pyrimidine antiplatelet drug that was the first reversible oral P2Y12 receptor antagonist. Compared with clopidogrel, ticagrelor exerts a faster onset and offset of function by reversible and selective inhibition of platelet aggregation in ACS patients, including those with coronary artery blood revascularization. Despite improvement in stent materials, stent thrombosis (ST) due to high on-treatment platelet reactivity (HPR) to clopidogrel continues to occur. In addition to antiplatelet aggregation, ticagrelor displays pleiotropic cardioprotective effects, including improving coronary blood flow, reducing myocardial necrosis after an ischemic event, and anti-inflammatory effects. The benefits of ticagrelor over clopidogrel were consistent in the PLATO results, with lower incidence of the primary endpoint. Also, in 2020, the findings from the phase 3 THALES trial (NCT03354429) showed that aspirin combined with 90 mg of ticagrelor significantly reduced the rates of stroke and death compared with aspirin alone in patients with AIS or TIA. Here, we review recent research on the superiority of ticagrelor over clopidogrel, discuss the pharmacological mechanism, and present future perspectives. This review aims to present the roles of ticagrelor in the management of acute coronary syndrome, acute thrombotic disease, and other diseases.

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The Impact of CYP2C19 and CYP4F2 Variants and Clinical Factors on Treatment Outcomes During Antiplatelet Therapy

Cited by 14 publications

References 40 publications

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

Association between ticagrelor plasma concentration and bleeding events in Chinese patients with acute coronary syndrome

A Review of the Role of the Antiplatelet Drug Ticagrelor in the Management of Acute Coronary Syndrome, Acute Thrombotic Disease, and Other Diseases

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