Optimizing endovascular therapy for large vessel occlusion using CYP2C19 genotype-guided antiplatelet therapy: a case report

Introduction

CYP2C19 belongs to the superfamily of cytochrome P450 enzymes that are crucial for hepatic metabolism of drugs such as conversion of clopidogrel into its active metabolite. Several variants of the CYP2C19 gene, which encodes CYP2C19, result in either loss-of-function (LOF) or increased function alleles, yielding eight distinct phenotypes: ultrarapid, rapid, normal, likely intermediate, intermediate, likely poor, poor, and indeterminate metabolizers (1). The frequency of the CYP2C19 alleles vary across populations. For example, approximately 60% of East Asians carry LOF alleles and are refractory to clopidogrel treatment, with a higher rate of recurrent ischemic stroke than non-carriers (2). Therefore, it is preferable to administer antiplatelet drugs appropriately based on the detected variants for best therapeutic outcomes.

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is effective for acute coronary syndrome (3). Additionally, the CHANCE2 study demonstrated the efficacy of CYP2C19 genotype-guided antiplatelet therapy for minor ischemic stroke or transient ischemic attack (4). However, the effectiveness of such individualized treatment in patients with large vessel occlusion (LVO) during endovascular therapy (EVT) remains unclear. We describe the case of a patient with LVO who received CYP2C19 genotype-guided antiplatelet therapy during EVT. We present this article in accordance with the CARE reporting checklist (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-86/rc).

Case presentation

An 80-year-old male with right vertebral artery (VA) occlusion and severe left VA stenosis (Figure 1A) presented to our hospital with dysarthria, left hemianopia, hemiparesis, and somatosensory deficits; his National Institute of Health Stroke Scale (NIHSS) score was 8. Diffusion-weighted magnetic resonance (MR) imaging revealed high signal intensity in the right thalamus (Figure 1B). MR angiography revealed an occlusion of the right posterior cerebral artery (PCA) P2 trunk (Figure 1C). The patient was diagnosed with large artery atherosclerosis (LAA), attributed to an artery-to-artery embolism of the right P2 caused by the left VA stenosis. Aspirin and clopidogrel were administered before EVT, and concurrent genotyping for CYP2C19 variants was performed using real-time polymerase chain reaction (LightCycler 96; Roche, Basel, Switzerland) after obtaining written informed consent with detailed explanation.

Figure 1 Previous and current MR images. (A) A MR angiography scan obtained 6 years before stroke onset showed occlusion of the right vertebral artery and stenosis of the left vertebral artery. (B) Diffusion-weighted MR imaging revealed high signal intensity in the right thalamus. (C) MR angiography showed occlusion of the right posterior cerebral artery P2 trunk. MR, magnetic resonance.

A 6 Fr aspiration catheter was guided distal to the left VA stenosis, and reperfusion was achieved after two passes of the stent retriever. This resulted in an Extended Thrombolysis in a Cerebral Infarction grade of 3 (Figure 2A,2B). However, the lesion promptly developed stenosis again following withdrawal of the aspiration catheter proximal to the left VA stenosis (Figure 2C). The percent stenosis measured using the diameter of the proximal normal artery as a reference was 80%. Repeat angioplasty was performed on the stenotic lesion, which yielded temporary improvement but continued restenosis. We considered that the repeated restenosis could be caused not only by the organic cause of the vascular stenosis but also by thrombogenic factors.

Figure 2 Angiographical findings and rapid genotyping for CYP2C19 variants during endovascular therapy. (A) Angiography from a catheter advanced distally to the left vertebral artery stenosis revealed occlusion of the right posterior cerebral artery P2 trunk. (B) Successful reperfusion was achieved after two passes of the stent retriever. (C) Angiography from a catheter moved proximally to the left VA stenosis showed restenosis. (D) A real-time polymerase chain reaction instrument measures the fluorescence emitted during each polymerase chain reaction cycle, and the data is presented as amplification curves. The steep rise of the solid line, dotted line, and both lines indicate wild-type, homozygous, and heterozygous, respectively. Based on the amplification curves, the patient is heterozygous for CYP2C19*2 (G681A). (E) According to the amplification curves, the patient is heterozygous for CYP2C19*3 (G636A). The patient is, therefore, compound heterozygous (*2/*3). (F) After prasugrel administration and rescue stenting, the final angiography confirmed sufficient patency.

The genotyping results for CYP2C19 variants revealed two deficient alleles (*2/*3), which indicated that the patient was a poor metabolizer of clopidogrel (Figure 2D,2E). The patient was started on prasugrel, and angioplasty was done to prevent restenosis with rescue stenting for the stenotic lesion in the left VA (Figure 2F). The patient’s neurological symptoms improved to NIHSS score of 5 without neuroradiological complications. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The current article demonstrates a case with posterior circulation tandem occlusion due to LAA managed by CYP2C19 genotype-guided antiplatelet therapy during EVT, leading to a successful outcome.

Recent advances in EVT have dramatically improved outcomes in patients with LVO (5). However, approximately 5% of patients with LAA who achieve successful recanalization experience reocclusion within 7 days of undergoing the procedure (6). Moreover, patients with LAA who are refractory to clopidogrel are prone to unfavorable outcomes after cerebral angioplasty with or without stenting (7). This indicates the importance of appropriate antiplatelet therapy during revascularization in patients with LAA.

Various platelet function assays are used to guide antiplatelet therapy; however, they have specific reliability and reproducibility issues (8). These limitations may be overcome through CYP2C19 genotyping. In our case, rapid genotyping of CYP2C19 confirmed clopidogrel resistance during EVT. Accordingly, replacing clopidogrel with prasugrel effectively prevented restenosis following angioplasty and stent placement.

Compared with clopidogrel, prasugrel has a more potent inhibitory effect on platelet aggregation (9). While this allows greater ischemic prophylaxis, it also carries a higher risk of bleeding (3). Therefore, indiscriminate administration of prasugrel to patients with acute ischemic stroke could increase the incidence of hemorrhagic events, which may sometimes be fatal. Contrastingly, antiplatelet treatment guided by CYP2C19 genotyping yields optimal benefits. Specifically, it reduces the risk of cardiovascular and cerebrovascular events and minimizes hemorrhagic adverse effects (1). Additionally, CYP2C19 genotype-guided antiplatelet therapy for ischemic stroke is highly cost-effective (10).

In East Asia, 15–25% of patients with LVO treated with EVT are diagnosed with intracranial atherosclerotic disease (11,12). The East Asian-specific RNF213 p.R4810K variant, the susceptibility gene for moyamoya disease, is commonly detected in early-onset ischemic stroke with intracranial artery stenosis (13). Since patients with LVO who carry this variant have a higher frequency of acute and early reocclusion after undergoing EVT, rapid genotyping could facilitate the prediction of the underlying etiology and prognosis (14). Therefore, genotyping of frequent variants in certain ethnic groups, including CYP2C19 and RNF213 p.R4810K variants, in patients with hyperacute stroke could inform prompt and optimal individualized therapy.

Conclusions

Genotyping of CYP2C19 variants during EVT for patients with LVO due to LAA could lead to individualized antiplatelet therapy, potentially resulting in a favorable outcome. Although ethical issues regarding genotyping must be considered, appropriate individualized therapy for acute disease is effective, as practiced in this case, and expected to become widespread in the future.

Acknowledgments

The authors would like to thank Masamitsu Shikata, Kenji Ninomiya, and Tomoko Inagaki, who are affiliated with the Diagnostics Management Department, Analytical & Instrument Division, Shimadzu Corporation, for technical assistance with the experiments.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-86/rc

Peer Review File: Available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-86/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-86/coif). T.Y. reports lecturer fees from Daiichi-Sankyo, attendance at Daiichi-Sankyo-sponsored meetings outside the submitted work, and patents owned related to RNF213 pR4810k variant (JP-A2021-185538, JP-A 2023-071164). Hirotoshi Imamura reports lecturer fees from Daiichi-Sankyo. H.K. reports honoraria for lectures from Daiichi-Sankyo. M.I. reports lecturer honoraria from Daiichi-Sankyo. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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