CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants

Máchal, Jan; Hlinomaz, Ota; Kostolanská, Katarína; Peš, Ondřej; Máchalová, Alena; Šplíchal, Zbyněk; Moťovská, Zuzana; Juřica, Jan

doi:10.1080/00498254.2020.1731625

Cited by 4 publications

(5 citation statements)

References 45 publications

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“…For the third screening, studies that reported other interventions (n = 81), only including pharmacokinetic study (n = 6), did not report available data (n = 13), or were review articles (n = 29) and repeated studies (n = 28) were further excluded. Eight studies were finally included into this systematic review [ 11 – 14 , 25 – 28 ]. A manual search of the reference lists of these studies did not yield any new eligible studies.…”

Section: Resultsmentioning

confidence: 99%

“…Yu et al found bleeding complications were higher in patients carrying no CYP2C19 LOF allele after PCI with coronary heart disease, while there was no difference in MACEs [ 12 ]. Machal et al revealed that the ADP-induced platelet reactivity didn't differ among different CYP2C19 genotype in ticagrelor-treated patients [ 28 ]. Finally, an ambispective single-center observational study conducted by Zhang et al showed there was no significant difference in MACEs and bleeding between CYP2C19 LOF group and non-LOF group of Chinese ACS patients after PCI [ 13 ].…”

Section: Resultsmentioning

confidence: 99%

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Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

Xie

Xiang

Liu

et al. 2022

BMC Cardiovasc Disord

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Background Studies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying. Methods This systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes. Results Eight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22–0.75; P = 0.004). Furthermore, any LOF allele carriers didn’t yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76–1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99–2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17–4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27–1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30–2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33–2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required. Conclusions This qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

Xie

Xiang

Liu

et al. 2022

BMC Cardiovasc Disord

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“…Ticagrelor is a potent platelet inhibitor that binds reversibly to P2Y12, an ADP receptor. ADP-induced platelet aggregation is a good indicator of ticagrelor pharmacodynamics [ 9 ], which may explain the lack of a significant difference in the ADP-induced platelet aggregation rate observed between the 2 groups. However, the variation in the pharmacodynamics of aspirin is greater than the variation in that of ticagrelor, which is correlated with aspirin metabolism-associated SNPs such as PEAR1 and GP1BA SNPs [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Lower Platelet Aggregation Is a Risk Factor for Dual Antiplatelet Therapy-Associated Bleeding: A Preliminary Retrospective Study with Genotype Analysis

et al. 2020

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Background The purpose of this study was to investigate factors influencing bleeding in patients with acute coronary syndrome (ACS) who are on aspirin and ticagrelor as dual antiplatelet therapy. Material/Methods This retrospective case-control study included 50 patients with ACS (25 with reported bleeding events and 25 without) on aspirin and ticagrelor. Adenosine diphosphate (ADP)- and arachidonic acid (ACA)-induced platelet aggregation rates were measured using light transmission aggregometry. Single-nucleotide polymorphisms (SNPs) in PEAR1 , GP1BA , and GSTP1 were genotyped. Results ACA-induced platelet aggregation rates were obviously lower in patients with bleeding events than in those without (13.28±8.46% vs. 24.93±9.89%, P<0.001). No significant differences in ADP-induced platelet aggregation rates were observed between the 2 groups (16.17±9.74% vs. 16.88±12.69%, P>0.05). Among those with bleeding events and among controls, 70% and 80% had an ACA-induced platelet aggregation rate of 0–18% and 18–50%, respectively. Mutation rates of rs6065 in GP1BA and rs1695, rs4891, and rs8191439 in GSTP1 also differed significantly between the 2 groups. Conclusions Lower ACA-induced platelet aggregation rates are associated with increased risk of bleeding in patients with ACS who are on aspirin and ticagrelor. An ACA-induced platelet aggregation rate of 18% may be considered the cutoff point for identifying high risk of aspirin-associated bleeding events in patients with ACS. SNP genotyping may also help predict the risk of bleeding in patients with ACS.

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“…Some researchers claim that the polymorphisms of CYP2C19, ABCB1, CYP3A4, and other genes do not have any impact on the pharmacodynamic effects of ticagrelor. [15][16][17] Studies on healthy volunteers have shown that ABCB1 genetic polymorphism is not related to ticagrelor efficacy. 7 Meanwhile, other studies have reported a possible impact of the CYP2C19 genetic polymorphism on the metabolism of ticagrelor or its active metabolite M8.…”

Section: Introductionmentioning

confidence: 99%

“…Up to date, research on the impact of the ABCB1 rs1045642 genetic polymorphism in patients using P2Y 12 receptor inhibitors has not confirmed any significant relationship between the pharmacodynamic or pharmacokinetic effects of ticagrelor and polymorphisms of this or other genes. [15][16][17] Literature data on the ABCB1 rs1045442 genetic polymorphism are mostly linked to a reduced activity of transmembrane P-glycoprotein (P-gp) and worse renal function, and this in turn can have an impact on the elimination of ticagrelor and its active metabolites and can increase drug antiplatelet activity as well as the frequency of ticagrelor-related adverse events. 21,22,27 It is known that P-gp is encoded by the ABCB1 gene; therefore, the polymorphisms of this gene can influence P-gp expression and properties.…”

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confidence: 99%

The Effect of Platelet Activity, ABCB1 Genetic Polymorphism, and Renal Function on the Development of Ticagrelor-Related Dyspnea in Patients with Acute Coronary Syndrome

Tamakauskas,

Žaliūnas,

Lesauskaitė

et al. 2024

DDDT

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Purpose The aim of this study was to determine the effect of ABCB1 genetic polymorphism and renal function on the occurrence of ticagrelor-related dyspnea. Patients and Methods A total of 299 patients with acute with type 1, 2, or 3 myocardial infarction (with and without ST-segment elevation), who underwent coronary angiography and PTCA with stent implantation and were treated with antiplatelet drugs (ticagrelor and aspirin), were enrolled in this prospective study. For all enrolled patient’s platelet aggregation (induction with high-sensitivity adenosine diphosphate, ADP HS) testing was performed using a MULTIPLATE ® analyzer. Venous blood was also collected for genotyping. Results Patients experiencing ticagrelor-related dyspnea had lower ADP HS value (ADP HS ≤ 19.5 U; OR = 2.254; P = 0.009), higher creatinine concentration (>90 µmol/l; OR = 3.414; P = 0.019), and lower GFR value (<60 mL/min/1.73 m 2 ; OR = 2.211; P = 0.035). ABCB1 T allele was associated with ticagrelor-related dyspnea (OR = 2.550; P = 0.04). Conclusion Ticagrelor-related dyspnea was found to be related to low platelet aggregation, increased plasma creatinine concentration, decreased GFR, and ABCB1 T allele. Carriers of the ABCB1 T allele had a higher plasma creatinine concentration that could be associated with an inhibitory effect of ticagrelor on P-glycoprotein function.

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CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants

Cited by 4 publications

References 45 publications

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

Lower Platelet Aggregation Is a Risk Factor for Dual Antiplatelet Therapy-Associated Bleeding: A Preliminary Retrospective Study with Genotype Analysis

The Effect of Platelet Activity, ABCB1 Genetic Polymorphism, and Renal Function on the Development of Ticagrelor-Related Dyspnea in Patients with Acute Coronary Syndrome

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