Time Course for Benefit and Risk With Ticagrelor and Aspirin in Individuals With Acute Ischemic Stroke or Transient Ischemic Attack Who Carry <i>CYP2C19</i> Loss-of-Function Alleles

Pan, Yuesong; Meng, Xia; Jin, Aoming; Li, Hao; Bath, Philip M; Xie, Xuewei; Jing, Jing; Lin, Jinxi; Wang, Yilong; Wang, Wenjuan; Li, Zixiao; Jiang, Yong; Liu, Liping; Yang, Hongqin; Cheng, Jiwei; Wang, Zhimin; Wang, Yongjun

doi:10.1001/jamaneurol.2022.1457

Cited by 13 publications

(7 citation statements)

References 30 publications

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“…The CHANCE-2 trial, a randomized controlled trial among patients with minor IS or TIA who were carriers of CYP2C19 LOF variants, showed patients with CYP2C19 LOF variants may benefit from ticagrelor instead of clopidogrel [18]. The beneficial effect of ticagrelor was predominantly visible in the first week of treatment [19]. However, the study is performed among Chinese patients, and generalizability to non-Asian patients is limited [18, 19].…”

Section: Discussionmentioning

confidence: 99%

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The Frequency of CYP2C19 Loss-of-Function Variants in Patients with Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack in the Dutch Population

Heuvel¹,

Vermeer²,

Kerkhoff³

et al. 2023

Cerebrovasc Dis

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Introduction: The CYP2C19 enzyme converts clopidogrel into an active metabolite. Carriers of CYP2C19 loss-of-function (LOF) variants with a history of ischemic stroke or transient ischemic attack (TIA) using clopidogrel may have a higher risk of recurrent stroke. To study the implications of genetic CYP2C19 heterogeneity in treatment of cerebral ischemia, knowledge about the prevalence of CYP2C19 LOF variants within the population is important. We investigated the frequency of CYP2C19 LOF variants in patients with non-cardioembolic ischemic stroke or TIA in the Dutch population. Methods: We performed a single-centre observational study with a cross-sectional design in a Dutch thrombectomy-capable stroke center. We included all patients presenting with non-cardioembolic ischemic stroke or TIA. We determined the frequency of CYP2C19 LOF variants in the full cohort. Additionally, we compared the frequency of CYP2C19 LOF variants in two subgroups: patients with first-ever non-cardioembolic ischemic stroke or TIA versus patients with recurrent ischemic stroke or TIA using clopidogrel because of a history of ischemic stroke or TIA. Results: We enrolled 410 patients between 1 January 2021 and 1 July 2021. 109 (26.6%) patients were carriers of CYP2C19 LOF variants. We found no difference in the frequency of CYP2C19 LOF variants between patients with first-ever ischemic stroke or TIA versus patients with recurrent ischemic stroke or TIA using clopidogrel (25.9% versus 31.9% respectively, p = 0.31). Discussion and conclusion: About a quarter of patients with non-cardioembolic ischemic stroke or TIA in the Dutch population carry a CYP2C19 LOF variant. This is lower than estimates found in studies with Asian populations, but similar to estimates found among Caucasian patients in other parts of the world.

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Section: Discussionmentioning

confidence: 99%

“…The beneficial effect of ticagrelor was predominantly visible in the first week of treatment [19]. However, the study is performed among Chinese patients, and generalizability to non-Asian patients is limited [18, 19]. Further research on Caucasian patients is needed.…”

Section: Discussionmentioning

confidence: 99%

The Frequency of CYP2C19 Loss-of-Function Variants in Patients with Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack in the Dutch Population

Heuvel¹,

Vermeer²,

Kerkhoff³

et al. 2023

Cerebrovasc Dis

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“… 1 2 3 4 An estimate suggests that two thirds of recurrences of stroke within three months occurred within seven days of symptom onset. 5 6 More importantly, the three month high risk period accounts for approximately 70% of subsequent strokes within one year and 40% within five years. 7 8 Exploration of novel treatments are needed to reduce the early recurrent risk of stroke and the overall burden of stroke.…”

Section: Introductionmentioning

confidence: 99%

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial

Li,

Meng,

Shi

et al. 2024

BMJ

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Objectives To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3). Design Multicentre, double blind, randomised, placebo controlled trial. Setting 244 hospitals in China between 11 August 2022 and 13 April 2023. Participants 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled. Interventions Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days. Main outcome measures The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. Results 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83). Conclusions The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L. Trial registration ClinicalTrials.gov, NCT05439356 .

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“…In regard of genetics, study on AR is mainly concentrated on single nucleotide polymorphisms (SNPs). SNPs in platelet receptor genes (GP IIIa, 13 GP IV, 14 GP Ibα, 15 PEAR1, 16 P2Y12, and P2Y1 17 ), platelet activation‐related genes (HO‐1, 18 TXB2, 19 COX‐1 and COX‐2 20 ), drug absorption and metabolism genes (CYP2C19, 21,22 ABCB1, 23 UGT1A6 24 ), and lipid metabolism genes (ApoE 25 ) have been proven to be associated with AR. Accordingly, the interactions between gene SNPs is also a factor that cannot be ignored.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profile in the whole blood of acute coronary syndrome patients with aspirin resistance

Yang

Wang

et al. 2022

Clinical Laboratory Analysis

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Background Aspirin resistance (AR) results in major adverse cardiovascular events, and DNA methylation might participate in the regulation of this pathological process. Methods In present study, a sum of 35 patients with AR and 35 non‐AR (NAR) controls were enrolled. Samples from 5 AR and 5 NAR were evaluated in an 850 BeadChip DNA methylation assay, and another 30 AR versus 30 NAR were evaluated to validate the differentially methylated CpG loci (DML). Then, qRT‐PCR was used to investigate the target mRNA expression of genes at CpG loci. Finally, Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to reveal the enriched pathways. Results The AR and NAR groups displayed significant differences in DNA methylation at 7707 positions, with 270 hypermethylated sites (e.g., cg09555818 located in APOC2) and 7437 sites hypomethylated sites (e.g., cg26828689 located in SLC12A5). Six DML were validated by pyrosequencing, and it was confirmed that DNA methylation (cg16391727, cg21008208, cg21293749, and cg13945576) was related to the increasing risk of AR. The relative mRNA expression of the ROR1 gene was also associated with AR (p = 0.007), suggesting that the change of cg21293749 in DNA methylation might lead to differential ROR1 mRNA expression, ultimately resulting in AR. Furthermore, the identified differentially methylated sites were associated with the molecular pathways such as circadian rhythms and insulin secretion. Conclusion Hence, the distinct DNA methylation might play a vital role in the biological regulation of AR through the pathways such as circadian rhythms.

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Time Course for Benefit and Risk With Ticagrelor and Aspirin in Individuals With Acute Ischemic Stroke or Transient Ischemic Attack Who Carry CYP2C19 Loss-of-Function Alleles

Cited by 13 publications

References 30 publications

The Frequency of CYP2C19 Loss-of-Function Variants in Patients with Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack in the Dutch Population

The Frequency of CYP2C19 Loss-of-Function Variants in Patients with Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack in the Dutch Population

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial

DNA methylation profile in the whole blood of acute coronary syndrome patients with aspirin resistance

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