Efficacy and safety of clopidogrel versus prasugrel and ticagrelor for coronary artery disease treatment in patients with CYP2C19 LoF alleles: a systemic review and meta‐analysis

Yoon, Hee; Lee, Nari; Seong, Jong-Mi; Gwak, Hye Sun

doi:10.1111/bcp.14317

Cited by 19 publications

(10 citation statements)

References 40 publications

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“…33 However, antiplatelet medications such as ticagrelor and prasugrel are not dependent on CYP2C19 metabolism and reportedly have better clinical outcomes in LoF carriers compared with clopidogrel. 34 A recent meta-analysis of 16 studies (8 RCTs and 8 cohorts) concluded that genotype-guided antiplatelet treatment (primarily based on CYP2C19 LoF alleles) improved patient outcomes for major cardiovascular events (eg, RR for MI 0.45, 95% CI 0.35 to 0.58, p<0.00001), with decreased risk of major bleeding. 29 Treatment strategy in the different metaboliser groups varied between individual studies, but included use of higher doses of clopidogrel (150 mg/day instead of the usual 75 mg/day), or prescribing of prasugrel or ticagrelor, or a combination.…”

Section: Discussionmentioning

confidence: 99%

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

Pilling

Türkmen

et al. 2021

BMJ Open

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ObjectiveTo determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel.DesignRetrospective cohort analysis.SettingPrimary care practices in the UK from January 1999 to September 2017.Participants7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36–79 years at time of first clopidogrel prescription.InterventionsClopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years).Main outcome measureHospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel.Results28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79.ConclusionsA substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.

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Section: Discussionmentioning

confidence: 99%

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

Pilling

Türkmen

et al. 2021

BMJ Open

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“…Particularly, data for ticagrelor or prasugrel as DAT or TAT seem discouraging due to the high bleeding rate compared with that observed with clopidogrel (ticagrelor: relative risk [RR] 1.36; 95% CI, 1.18–1.57 and prasugrel: RR 2.11; 95% CI, 1.34–3.30) ( 36 ), which suggests that powerful P2Y12 inhibitors may not be the first-line choice for use with OAC in AF patients after PCI. Because clopidogrel is characterized as providing less potent and variable platelet inhibition ( 37 ), more individualized and comprehensive antithrombotic strategies could be evaluated in future studies.…”

Section: Critical Discussion Of Key Scientific Datamentioning

confidence: 99%

Antithrombotic Management for Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention or With Acute Coronary Syndrome: An Evidence-Based Update

Zhao

Hong

Cai

et al. 2021

Front. Cardiovasc. Med.

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Combined antithrombotic regimens for atrial fibrillation (AF) patients with coronary artery disease, particularly for those who have acute coronary syndrome (ACS) and/or are undergoing percutaneous coronary intervention (PCI), presents a great challenge in the real-world clinical scenario. Conventionally, a triple antithrombotic therapy (TAT), which consists of combined oral anticoagulant therapy to prevent systemic embolism or stroke along with dual antiplatelet therapy to prevent coronary arterial thrombosis (CAT), is used. However, TAT has been associated with a significantly increased risk of bleeding. With the emergence of non-vitamin K antagonist oral anticoagulants (NOACs), randomized controlled trials have demonstrated a better risk-to-benefit ratio of dual antithrombotic therapy (DAT) in combination of a NOAC and with a P2Y12 inhibitor than vitamin K antagonist-based TAT. The results of these studies have impacted the recommendations of current international guidelines, which favor a DAT with a NOAC and P2Y12 inhibitor (especially clopidogrel) in this clinical setting. Additionally, aspirin can be administered during the periprocedural period, while the treatment duration of TAT should be as short as possible. In this article, we summarize the up-to-date evidence regarding antithrombotic regimens for AF patients with PCI or ACS, with a specific focus on the optimal approach and critical discussions of key scientific data and future developments for antithrombotic management in these patients.

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“…Clopidogrel is a recommended antiplatelet medication for the prevention of stroke in the USA (2) and is the currently recommended antiplatelet medication for prevention of stroke or TIA in the UK (31). However, antiplatelet medications such as ticagrelor and prasugrel are not dependent on CYP2C19 metabolism and reportedly have better clinical outcomes in LoF carriers compared to clopidogrel (32). A recent meta-analysis of 16 studies (8 RCTs and 8 cohorts) concluded that genotype-guided antiplatelet treatment (primarily based on CYP2C19 LoF alleles) improved patient outcomes for major cardiovascular events (e.g.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

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Türkmen

et al. 2021

Preprint

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Background The antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related interventions. Little is known about the magnitude of impact of LoF variants in family practice, especially over long periods of exposure. We aimed to determine whether CYP2C19 LoF alleles increase risk of ischemic stroke and MI in primary care patients prescribed clopidogrel for up to 18 years. Methods Retrospective cohort analysis of 7,483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36 to 79 years at first clopidogrel prescription. We examined CYP2C19 LoF variant (*2-*8) associations with incident hospital-diagnosed ischemic stroke and MI in patients prescribed clopidogrel for at least 2 months using time-to-event models, with secondary analysis of the *17 gain of function variant. Results 28.7% (n=2,144/7,483) of included subjects (mean age 63 years at first clopidogrel prescription) carried at least one CYP2C19 intermediate or low metabolizer LoF variant. 1.9% of LoF variant carriers had an incident ischemic stroke whilst prescribed clopidogrel (mean 2.6 years, range 2 months to 18 years), versus 1.3% without the variants (0.6% absolute excess: Hazard Ratio 1.53: 95% CI 1.04 to 2.26, p=0.031). Additionally, 26.4% of CYP2C19 LoF variant carriers had an incident MI versus 24.1% (HR 1.14: 1.04 to 1.26, p=0.008). Adjustment for aspirin co-prescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischemic stroke by age 79 (the oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers: the absolute excess stroke incidence with LoF variants was 7.1% by age 79. Conclusion In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischemic events. Genotype-guided (or routine) prescription of antiplatelet medications unaffected by CYP2C19 variants may improve outcomes in patients for whom clopidogrel is currently indicated.

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Efficacy and safety of clopidogrel versus prasugrel and ticagrelor for coronary artery disease treatment in patients with CYP2C19 LoF alleles: a systemic review and meta‐analysis

Cited by 19 publications

References 40 publications

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

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

Antithrombotic Management for Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention or With Acute Coronary Syndrome: An Evidence-Based Update

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

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