What question did this study set out to answer?

To evaluate how CYP2C19 gene polymorphisms influence the timing of ischemic and bleeding risks in patients prescribed clopidogrel after percutaneous coronary intervention.

May 28, 2021Open Access

Clinical Outcomes after Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms: Evidence from a Chinese Cohort

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Percutaneous coronary intervention (PCI) (n=1341). Intervention: CYP2C19 poor metabolizer phenotype (two loss-of-function alleles) vs. CYP2C19 non-loss-of-function metabolizer phenotype. Primary outcome: Composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke and stent thrombosis at 90 days (HR 2.944, 95% CI 1.184-7.321, p=0.020).

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Key result

Carriers of two CYP2C19 loss-of-function alleles prescribed clopidogrel after PCI had a significantly higher risk of ischemic events at 3 months compared to noncarriers (HR 2.944).

Why the study?

To investigate the association between CYP2C19 gene polymorphism and ischemic and bleeding risks over different time periods after PCI among patients receiving clopidogrel.

Does CYP2C19 poor metabolizer status increase the risk of ischemic events in patients receiving clopidogrel after PCI?

Key Points

To evaluate how CYP2C19 gene polymorphisms influence the timing of ischemic and bleeding risks in patients prescribed clopidogrel after percutaneous coronary intervention.
Conducted an observational cohort study of 1,341 post-PCI patients in China genotyped for CYP2C19 and treated with clopidogrel between October 2015 and January 2017.
Categorized patients by phenotype into non-loss-of-function metabolizers (559/1,341 [41.7%]), intermediate metabolizers with one LOF allele (621/1,341 [46.3%]), and poor metabolizers with two LOF alleles (161/1,341 [12.0%]).
Evaluated a composite primary endpoint (all-cause mortality, nonfatal MI, nonfatal ischemic stroke, and stent thrombosis) alongside bleeding outcomes using landmark analyses at 90 days and 1 year.
At 3 months post-PCI, primary ischemic events occurred in 5.6% of carriers with two LOF alleles versus 1.8% of noncarriers (adjusted HR 2.944, 95% CI 1.184–7.321, p = 0.020).
Among patients with acute coronary syndrome at index PCI, two LOF alleles similarly elevated 3-month ischemic risk (adjusted HR 3.046, 95% CI 1.237–7.501, p = 0.015), but differences did not persist between months 3 and 12 across all cohorts.
Bleeding outcome rates remained comparable across all CYP2C19 metabolizer phenotypes throughout the entire 1-year follow-up.

Study Design

Type

Cohort (n=1,341)

Multicenter

Structured PICO

Does CYP2C19 poor metabolizer status increase the risk of ischemic events in patients receiving clopidogrel after PCI?

Population

1,341 patients aged 18 years and older who underwent CYP2C19 genotyping and received clopidogrel after percutaneous coronary intervention, followed for 12 months.

Exposure

Clopidogrel (75 mg daily) and aspirin (100 mg daily) for at least one year after a 300-mg aspirin and 600-mg clopidogrel loading dose prior to PCI, specifically in patients with CYP2C19 loss-of-function alleles (intermediate metabolizers with 1 LOF allele and poor metabolizers with 2 LOF alleles).

Comparator

Patients with no CYP2C19 loss-of-function alleles (non-loss-of-function metabolizers) receiving the exact same clopidogrel and aspirin regimen.

Outcome

Composite of death from any cause, the first occurrence of nonfatal myocardial infarction, nonfatal ischemic stroke and stent thrombosis occurring during exposure to clopidogrel.composite

Main Result

Hazard Ratio: 2.944 (95% CI 1.184–7.321)

Absolute Event Rate: 5.6% vs 1.8%

p-value: p=0.020

Patients with two CYP2C19 loss-of-function alleles have a significantly higher risk of ischemic events during the first 3 months of clopidogrel therapy after PCI, highlighting the potential need for early alternative antiplatelet strategies in this subgroup.

Limitations

Retrospective single-center design with potential selection bias for genotyping
Did not analyze other genetic polymorphisms like ABCB1 and PON1
Did not independently analyze carriers of the gain-of-function CYP2C19 allele (*17)
Used all-cause mortality instead of cardiovascular mortality
Limited power to detect significant differences in bleeding events due to small number of events

Implication

CYP2C19 status may stratify timed ischemic and bleeding risks on clopidogrel post-PCI; leaves open whether genotyping should guide therapy.

Abstract

Purpose： To investigate the association between CYP2C19 gene polymorphism and the risk of ischemic and bleeding complications in the different period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Methods： Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated clopidogrel after PCI were enrolled this observational cohort study. Included patients were categorized as non-loss-of-function metabolizers (NLOFMs), intermediate metabolizers (IMs) and poor metabolizers (PMs) based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1-year post-PCI. Results： Of 1,341 patients, 161 (12.0%) had two copy of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of two LOF alleles (5.6%) than in noncarriers (1.8%) (adjusted HR 2.944, 95% CI 1.184-7.321, p = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% CI 1.237-7.501, p = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all-comers or subjects with ACS. The incidences of bleeding outcome events were similar among CYP2C19 phenotypes throughout the follow-up period. Conclusion： These data demonstrate a higher risk for ischemic events in patients with two CYP2C19 LOF alleles who are prescribed clopidogrel, previously seen at 3 months following PCI, that is not sustained for 12 months. These ﬁndings emphasize the need to place greater weight on a PM result during early antiplatelet therapy de-escalating decisions.

Discussion

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Cite This Study

Zhang et al. (2021) conducted a cohort in Percutaneous coronary intervention (PCI) (n=1,341). CYP2C19 poor metabolizer phenotype (two loss-of-function alleles) vs. CYP2C19 non-loss-of-function metabolizer phenotype was evaluated on Composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke and stent thrombosis at 90 days (HR 2.944, 95% CI 1.184-7.321, p=0.020). Carriers of two CYP2C19 loss-of-function alleles prescribed clopidogrel after PCI had a significantly higher risk of ischemic events at 3 months compared to noncarriers (HR 2.944).

synapsesocial.com/papers/6a778921576efb0ddaf76ccd https://doi.org/10.21203/rs.3.rs-503780/v1

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Implication

CYP2C19 status may stratify timed ischemic and bleeding risks on clopidogrel post-PCI; leaves open whether genotyping should guide therapy.

Clinical Outcomes after Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms: Evidence from a Chinese Cohort

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Clinical Outcomes after Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms: Evidence from a Chinese Cohort

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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