Analysis of<i>CYP2C19</i>genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study

Pilling, Luke C.; Türkmen, Deniz; H, Fullalove; Atkins, Janice L.; Delgado, João; Kuo, Chia‐Ling; Kuchel, George A.; Ferrucci, Luigi; Bowden, Jack; Masoli, Jane; Melzer, David

doi:10.1136/bmjopen-2021-053905

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…After correction for potential confounders, including prior stroke events, there remained a significant association between CYP2C19 LoF variant carriage and more frequent ischemic stroke events. A retrospective study conducted in the UK Biobank also showed a persistent effect of pharmacogenetic associations during long‐term treatment (> 1 year) with clopidogrel 35 . Together, these findings highlight the potential value of genetic testing in reducing stroke risk, even when patients return to the primary care setting.…”

Section: Discussionmentioning

confidence: 80%

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CYP2C19 Loss‐of‐Function Variants Associated With Long‐Term Ischemic Stroke Events During Clopidogrel Treatment in the Chinese Population

Wu,

Liu,

Tian

et al. 2023

Clin Pharma and Therapeutics

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This study aims to determine whether CYP2C19 loss‐of‐function (LoF) variants were associated with long‐term ischemic stroke risk in Chinese primary care patients treated with clopidogrel. Patients treated with clopidogrel were ascertained from Chinese electronic medical records linked with a biobank for a retrospective cohort study. Their medical information was examined for the period from January 2018 to December 2021. Two CYP2C19 major loss of function variants (*2:rs4244285 and *3: rs4986893) were genotyped. The clinical outcome was ischemic stroke event. Cox regression analysis was used to evaluate the association between the occurrence of ischemic stroke events and CYP2C19 LoF variants. Covariates included age, gender, body mass index, prior ischemic stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipoidemia, smoke status, aspirin use, proton‐pump inhibitor use, and statin use. Of the 1,141 patients included in the clopidogrel therapy cohort, 61.9% carried at least one CYP2C19 LoF variant. During a median follow‐up period of 12 months, 103 patients (9.0%) had an ischemic stroke. After adjusting for other risk factors, carriers of CYP2C19 LoF variants had significantly higher risk of ischemic stroke compared with non‐carriers (hazard ratio: 1.64, 95% confidence interval: 1.06–2.53, P = 0.025). This pharmacogenetic study of clopidogrel provides novel insights into the association between the CYP2C19 LoF variant and long‐term stroke risk. We established that there is still a need for CYP2C19 genotype‐guided personalized antiplatelet therapy in those who have returned to the primary care setting for clopidogrel prescription.

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Section: Discussionmentioning

confidence: 80%

“…A retrospective study conducted in the UK Biobank also showed a persistent effect of pharmacogenetic associations during long-term treatment (> 1 year) with clopidogrel. 35 Together, these findings highlight the potential value of genetic testing in reducing stroke risk, even when patients return to the primary care setting.…”

Section: Articlementioning

confidence: 87%

CYP2C19 Loss‐of‐Function Variants Associated With Long‐Term Ischemic Stroke Events During Clopidogrel Treatment in the Chinese Population

Wu,

Liu,

Tian

et al. 2023

Clin Pharma and Therapeutics

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“…[HR 0.49; 95% CI 0.12–1.95] Lv et al (2021) [ 52 ] Cohort China IS Clopidogrel or Aspirin 485 Composite Vascular Outcome Bleeding Yes [HR 2.05; 95% CI 1.30–3.25 P = 0.002] Lin et al (2021) [ 53 ] Cohort China First IS Clopidogrel 122 Recurrent Stroke Bleeding Yes [HR: 7.56; 95% CI 1.35–42.78, P = 0.022]. Pilling et al (2021) [ 78 ] Cohort UK Patients in UK-Biobank Prescribed Clopidogrel Clopidogrel 7483 IS MI, Composite Vascular Outcome Yes. [HR 1.53; 95% CI 1.04–2.26 CHANCE-2 (2021) [ 68 ] RCT China Minor Stroke or High-Risk TIA and LoFA carriers [Ticagrelor + Aspirin] vs [Clopidogrel + Aspirin] 6412 Recurrent Stroke Bleeding Unable to assess.…”

Section: The Evidence For Cyp2c19 Genotyping After Stroke or Tiamentioning

confidence: 99%

“…Existing data repositories have also been leveraged on a larger scale to investigate the impact of CYP2C19 genotype status on clinical outcomes following IS. Pilling et al assessed the records and genetic information of 7,477 UK Biobank (UKB) participants and identified 110 individuals who had been treated with clopidogrel after an incident stroke who also had CYP2C19 genotype data available [ 78 ]. Analysis suggested that CYP2C19 LoFA carriers were more likely to have an IS whilst taking clopidogrel than non-carriers (HR 1.53, 95% CI 1.04–2.26).…”

Section: The Evidence For Cyp2c19 Genotyping After Stroke or Tiamentioning

confidence: 99%

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

McDermott

Leach

Sen

et al. 2022

Expert Review of Clinical Pharmacology

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Introduction Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. Areas covered A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. Expert opinion There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

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“…One of the most extensively studied pharmacogenetic interactions is the impact of CYP2C19 genotype on clopidogrel outcomes. This association is well supported by evidence and is endorsed by the US Food and Drug Administration and the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines [3–14]. The latest guidance from the National Institute of Health Care Excellence now recommends CYP2C19 genotyping for patients who have an acute indication for clopidogrel.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics at scale in real-world bioresources: CYP2C19 and clopidogrel outcomes in UK Biobank

Bedair,

Smith,

Palmer

et al. 2023

Pharmacogenetics and Genomics

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Objective The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date. Methods Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients. Results Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE [incidence rate ratios (IRR), 1.094; 1.044–1.146], but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903–0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction. Conclusion The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.

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Analysis ofCYP2C19genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study

Cited by 9 publications

References 33 publications

CYP2C19 Loss‐of‐Function Variants Associated With Long‐Term Ischemic Stroke Events During Clopidogrel Treatment in the Chinese Population

CYP2C19 Loss‐of‐Function Variants Associated With Long‐Term Ischemic Stroke Events During Clopidogrel Treatment in the Chinese Population

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

Pharmacogenetics at scale in real-world bioresources: CYP2C19 and clopidogrel outcomes in UK Biobank

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