CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis

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The association between the CYP2C19 loss of function (LOF) gene and the prevalence of ISR after coronary stenting remains controversial. Previous studies have produced conflicting results and have been limited by their small population sizes. We conducted this systematic review and meta-analysis to determine the association between the presence of the CYP2C19 LOF gene and the prevalence of ISR. Methods A systematic online database search was performed until April 2021. The primary outcome was ISR and assessed using OR with 95% CI. Quality of the study was assessed using the Newcastle Ottawa Scale. I2 was applied to examine heterogeneities among the studies. Results A total of 284 patients (four non-randomized controlled trial studies) were included in this study. Two hundred and six patients had wild-type genotypes, while 78 patients had the LOF genotype. Among the 78 patients with the LOF gene, 38 patients had an ISR. Meanwhile, of the 206 patients with a wild-type gene, 69 patients had an ISR. LOF gene was associated with a higher risk of ISR (OR 95% CI = 2.71 [1.42–5.16], P = 0.003). However, study-specific variability should be considered when applying these findings clinically. Conclusions Patients with LOF genes, regardless of the allele variation, treated with clopidogrel, had a higher likelihood of ISR after coronary stenting. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/11-346", "name": "CYP2C19 polymorphism and coronary in-stent restenosis:A systematic..." } } ] } Home Browse CYP2C19 polymorphism and coronary in-stent restenosis:A systematic... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Pintaningrum Y, . V, Dewi IP et al. CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.12688/f1000research.109321.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] Yusra Pintaningrum https://orcid.org/0000-0002-8843-4684 1 , Vitriyaturrida . 2 , Ivana Purnama Dewi https://orcid.org/0000-0002-1602-3384 3,4 , [...] Hendy Bhaskara Perdana Putra https://orcid.org/0000-0002-4231-1013 5 , Idar Mappangara 6 , Muzakkir Amir https://orcid.org/0000-0002-4914-3542 6 , Irawan Yusuf 7 , Agussalim Bukhari 8 Yusra Pintaningrum https://orcid.org/0000-0002-8843-4684 1 , Vitriyaturrida . 2 , [...] Ivana Purnama Dewi https://orcid.org/0000-0002-1602-3384 3,4 , Hendy Bhaskara Perdana Putra https://orcid.org/0000-0002-4231-1013 5 , Idar Mappangara 6 , Muzakkir Amir https://orcid.org/0000-0002-4914-3542 6 , Irawan Yusuf 7 , Agussalim Bukhari 8 PUBLISHED 15 Jan 2025 Author details Author details 1 Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Mataram, Mataram, West Nusa Tenggara, 83126, Indonesia 2 Department of Cardiology and Vascular Medicine, Slamet Martodirdjo General Hospital, Pamekasan, Madura, 69317, Indonesia 3 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University - Dr Soetomo General Hospital, Surabaya, East Java, 60132, Indonesia 4 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, Special Region of Yogyakarta, 55224, Indonesia 5 Emergency Department, dr. Ramelan Navy Hospital, Surabaya, East Java, 60244, Indonesia 6 Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makasar, South Sulawesi, 90245, Indonesia 7 Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, South Sulawesi, 90245, Indonesia 8 Department of Nutrition, Faculty of Medicine, University of Hasanuddin, Makassar, South Sulawesi, 90245, Indonesia Yusra Pintaningrum Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Methodology, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Vitriyaturrida . Roles: Data Curation, Formal Analysis, Investigation, Validation, Writing – Review & Editing Ivana Purnama Dewi Roles: Methodology, Software, Validation, Writing – Review & Editing Hendy Bhaskara Perdana Putra Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation Idar Mappangara Roles: Methodology, Resources, Software, Writing – Review & Editing Muzakkir Amir Roles: Project Administration, Supervision, Validation Irawan Yusuf Roles: Supervision, Validation, Visualization Agussalim Bukhari Roles: Supervision, Visualization OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background In-stent restenosis (ISR) remains a major drawback in coronary stenting. The association between the CYP2C19 loss of function (LOF) gene and the prevalence of ISR after coronary stenting remains controversial. Previous studies have produced conflicting results and have been limited by their small population sizes. We conducted this systematic review and meta-analysis to determine the association between the presence of the CYP2C19 LOF gene and the prevalence of ISR. Methods A systematic online database search was performed until April 2021. The primary outcome was ISR and assessed using OR with 95% CI. Quality of the study was assessed using the Newcastle Ottawa Scale. I 2 was applied to examine heterogeneities among the studies. Results A total of 284 patients (four non-randomized controlled trial studies) were included in this study. Two hundred and six patients had wild-type genotypes, while 78 patients had the LOF genotype. Among the 78 patients with the LOF gene, 38 patients had an ISR. Meanwhile, of the 206 patients with a wild-type gene, 69 patients had an ISR. LOF gene was associated with a higher risk of ISR (OR 95% CI = 2.71 [1.42–5.16], P = 0.003). However, study-specific variability should be considered when applying these findings clinically. Conclusions Patients with LOF genes, regardless of the allele variation, treated with clopidogrel, had a higher likelihood of ISR after coronary stenting. READ ALL READ LESS Keywords CYP2C19, polymorphism, coronary in-stent restenosis, systematic review, clopidogrel Corresponding Author(s) Yusra Pintaningrum ( [email protected] ) Close Corresponding author: Yusra Pintaningrum Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Pintaningrum Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Pintaningrum Y, . V, Dewi IP et al. CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.12688/f1000research.109321.3 ) First published: 22 Mar 2022, 11 :346 ( https://doi.org/10.12688/f1000research.109321.1 ) Latest published: 15 Jan 2025, 11 :346 ( https://doi.org/10.12688/f1000research.109321.3 ) Revised Amendments from Version 2 This version of the article includes corrections for typographical errors identified in the previous version and incorporates revisions based on the reviewers' suggestions. These changes aim to enhance the clarity and accuracy of the content while addressing feedback provided during the review process. No major alterations to the study design, methodology, or primary findings have been made. This version of the article includes corrections for typographical errors identified in the previous version and incorporates revisions based on the reviewers' suggestions. These changes aim to enhance the clarity and accuracy of the content while addressing feedback provided during the review process. No major alterations to the study design, methodology, or primary findings have been made. See the authors' detailed response to the review by Dyana Sarvasti See the authors' detailed response to the review by Fazli Rabbi Awan READ REVIEWER RESPONSES Introduction Despite the fact that the prevalence of in-stent restenosis (ISR) has decreased gradually, consistent with stent evolution, ISR remains a major drawback in coronary stenting. 1 ISR is defined as stenosis with a diameter > 50% at the stent segment or its edges. In the stent era, ISR is primarily a result of neointimal hyperplasia. Stent implantation causes injury to endothelial cells and induces several complex biological responses, including the activation, proliferation, and migration of smooth muscle cells (SMC) into the endovascular lumen. Vascular smooth muscle cells (VSMCs) play a crucial role in the pathogenesis of vascular diseases, including vascular inflammation and restenosis following angioplasty. 2 Stent implantation also stimulates the release of thrombogenic and vasoactive cytokines. 3 An animal study conducted by Niu et al . revealed that expression of the P2Y12 receptor in the vessel wall promoted atherogenesis and VSMC migration from media to intima. Direct activation of P2Y12 also mediates VSMC proliferation. 4 Furthermore, thrombin-induced P2Y12 is known to enhance mitogenesis in human SMC. 5 Clopidogrel has long been used as a P2Y12 inhibitor. Clopidogrel is converted to an active metabolite by the enzyme CYP2C19. The genes encoding the CYP enzyme are polymorphic, and several variants have been related to increased or decreased activity of the drug. Based on the genetic polymorphism of CYP2C19, wild-type homozygote CYP2C19*1*1 is a powerful metabolizer. However, carriers of CYP2C19 loss of function (LOF) alleles (*2, *3, *4, *5) are poorer metabolizers. 6 Several studies have been conducted to assess the association between ISR events and CYP2C19 polymorphism. 7 – 10 However, the results are conflicting. Therefore, this study aims to conduct a meta-analysis regarding the association between CYP2C19 LOF genes and ISR events. Methods This study was conducted following Cochrane’s methodology and PRISMA guidelines. 11 It is registered in the PROSPERO database, registration number: 293424. Search strategy We performed a systematic search of several online databases (Scopus, PubMed, Cochrane Central Register of Controlled Trials [CENTRAL], ScienceDirect, and ResearchGate) for all studies on CYP2C19 polymorphism and in-stent restenosis published between January 2012 and December 2021. We used the terms “coronary restenosis” AND “in-stent restenosis” AND “gene polymorphism” AND “CYP2C19” AND “genotype”. Eligibility criteria The criteria included were observational studies or randomized controlled trials (RCTs), which examined the association between gene polymorphism and coronary restenosis after stent implantation. Exclusion criteria included case reports, case series, studies in languages other than English, and non-human studies. Two reviewers (V. and HBPP) independently screened the search results according to the inclusion and exclusion criteria. Any discrepancies were settled through discussion with a third investigator (YP) until a consensus was reached. Quality and publication bias assessment The studies were evaluated based on Cochrane methodological criteria. However, the quality of observational studies was evaluated using the Newcastle – Ottawa Scale. 12 Funnel plot was used to assess the potential for publication bias. Endpoint The primary endpoint was in-stent restenosis after stent implantation regardless of the type of previous stent. Statistical analysis Statistical analysis was carried out using RevMan 5.4 software (RRID:SCR_003581). All outcomes were analyzed using a random-effects model and presented as odds ratios (OR) with 95% confidence intervals (CI). A P-value equal to or less than 0.05 was considered statistically significant. I 2 assessed heterogeneity. I 2 values less than 25% were defined as low heterogeneity; I 2 values between 25% and 50% were defined as moderate heterogeneity, and I 2 values greater than 50% were defined as high heterogeneity. Results The initial search identified a total of 43 studies. Of these 43 studies, one article did not contain full text, and 13 studies were duplicates, leaving 29 studies. Of the remaining studies, 20 were excluded due to irrelevant titles or abstracts. Furthermore, five full-text articles were categorized as case reports, reviews, letters to the editor, or did not provide data for calculation. Finally, four observational studies were included in the qualitative synthesis ( Figure 1 ). A total of 284 patients were included in the study. Two hundred and six patients had wild-type genotypes, while 78 patients had a LOF genotype. The quality of the four observational studies is shown in Table 1 . The funnel plot appears symmetrical distribution of studies suggesting that the results are likely robust and not significantly influenced by selective reporting. Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram of study selection. Table 1. Newcastle – Ottawa scale indicating the quality of each included study. Selection Comparability Outcome Total score Overall grade Da Costa et al . (2020) 7 * 0 ** 3 Poor Zhang et al . (2020) 8 ** * ** 5 Fair Wirth et al . (2018) 9 ** * *** 6 Fair Nozari et al . (2015) 10 ** * *** 6 Fair Patient characteristics The patients included in the studies had similar characteristics; they were predominantly male (62–72%) ( Table 2 ), with a mean age range of 60–66 years, except for the study by Da Costa et al ., which did not report their patients’ characteristics. 7 The patients in the Wirth et al . study had the highest proportion of diabetes and hypertension compared to the other studies. 9 Table 2. Included studies and baseline characteristics. Author (year) Da Costa et al . (2020) 7 Zhang et al . (2020) 8 Wirth et al . (2018) 9 Nozari et al . (2015) 10 Study type Cross-sectional Retrospective cohort Retrospective cohort Case match study Sample size (n) 24 78 82 100 Wild gene (%) 6 (25.0) 51 (65.4) 60 (73.2) 89 (89) LOF gene (%) 18 (75.0) 27 (34.6) 22 (26.8) 11 (11) LOF gene type *1*2/ *2*2 alelle *2 or *3 alelle *2 *1*2 Stent type Not clear DES BMS & DES BMS & DES Clopidogrel dose Not clear 75 mg/day Not clear 75 mg/day Total ISR event 13 17 29 50 BMS – ISR Not clear N/A 4 30 DES – ISR Not clear 17 25 20 Age (mean ± SD, years) N/A 66.69 ± 6.2 64.58 ± 9.2 60.09 ± 10.29 Male (%) N/A 49 (62.8) 65 (79.2) 72 (72) Diabetes mellitus (%) N/A 25 (32.0) 49 (59.8) 26 (26) Hypertension (%) N/A 54 (69.2) 74 (90.2) 51 (51) Dyslipidemia (%) N/A N/A 76 (92.7) 62 (62) Smoking (%) 24 (100) 32 (41.0) 20 (24.4) 20 (20) Genotype characteristics In most of the studies examined, the wild gene (*1*1) was dominant (in 65%–89% of patients) ( Table 2 ). Only in the study by Da Costa et al . was the wild gene the minority (in only 25% of patients). 7 The four selected studies examined different LOF genes. The study by Nozari et al . showed the heterozygote *1*2 LOF gene. 10 In contrast, the study by Da Costa et al . examined LOF heterozygote *1*2 and homozygote *2*2 genes without clearly specifying the percentage. 7 The study by Zhang et al . only mentioned that the LOF gene has a *2 or *3 allele. 8 The study by Wirth et al . stated that the LOF gene has a *2 allele. 9 Stent characteristics Da Costa et al . did not state clearly the stent type used in their study. 7 However, Zhang et al . only used drug-eluting stents (DES). 8 Meanwhile, Wirth et al . and Nozari et al . used bare-metal stents (BMS) and DES in their studies without clearly stating the percentages ( Table 2 ). 9 , 10 Reported outcomes From all of the studies, the only incidence of ISR can be calculated quantitatively. However, regardless of the time of presentation from the stent implantation to ISR detection, it is known that there were 38 incidents of ISR in the 78 patients with LOF genes and 69 incidents of ISR in the 206 patients with a wild gene. Furthermore, our analysis shows a statistically significant association between the LOF gene and higher ISR incidence (OR 95% CI = 2.71 [1.42–5.16], P = 0.003) ( Figure 2 ). Figure 2. Pooled analysis shows a statistically significant association between the LOF gene and higher ISR incidence. Discussion The response to clopidogrel differs from person to person. Many investigations have been conducted to determine the biological components involved in this variance. Polymorphisms in the liver cytochrome isozyme P450 (CYP2C19, CYP3A4, and CYP3A5), as well as the P2Y12 receptor itself, seem to be the major cause of variation. 13 , 14 The ability of the LOF gene to reduce the clopidogrel response in platelets was the first to be revealed, as seen by enhanced platelet aggregation in terms of CYP2C19 polymorphisms. 13 Numerous studies have found that CYP2C19 polymorphisms vary greatly among ethnic groups. In comparison to the white population (25%–35%) and the black population (35%–45%), the Asian population (55–70%) exhibited a greater prevalence rate of the LOF CYP2C19 allele variation (CYP2C19 *2 and *3). In comparison to the white population (18%), the Asian population (4%) exhibited a lower frequency of the CYP2C19 GOF variant allele (CYP2C19 *17). 14 A study by Mega et al . involving 1,477 acute coronary syndrome patients, with primary outcomes characterized by death from nonfatal myocardial infarct (MI), nonfatal stroke, and other cardiovascular causes, showed a significantly higher rate of LOF polymorphism (12.1% vs 8%; P = 0.01) than wild-type CYP2C19. 15 For 450 days after clopidogrel therapy, similar results were reported for the rate of stent thrombosis (2.6% vs 0.8%; P = 0.02). Another study of 259 patients using clopidogrel medication for one month after their first MI found that individuals with CYP2C19 polymorphisms had considerably poorer five-year survival (HR = 3.69; 95% CI = 1.69–8.5; P = 0.0005), which was linked to considerably poorer clinical outcomes following coronary stenting. 16 In another study, 552 individuals were revealed to have the wild-type CYP2C19 allele, and 245 had at least one of two alleles. Patients who were homozygous for the wild-type gene had considerably lower platelet aggregation levels than those with two alleles (11% vs 23%; P < 0.0001). 17 This meta-analysis is the first to provide a comprehensive review of the existing evidence from observational studies, which assesses the association between CYP2C19 LOF gene polymorphisms and the risk of ISR. The study offers a novel pooled estimate of this relationship, showing a significant association between ISR and the LOF gene. The odds of ISR were found to be 2.71 times higher in the LOF gene compared to the wild gene. The wild gene can metabolize clopidogrel more effectively than the LOF gene. Zhang et al . and Nozari et al . stated that they used clopidogrel 75 mg in their study. 8 , 10 Moreover, Zhang et al . also had a third group of patients with the LOF gene who were administered a double dose of clopidogrel (150 mg). There were no significant differences in this group compared to patients with the wild gene who were given a normal dose of clopidogrel (75 mg). 8 The first choice for a clopidogrel resistance management strategy is to increase the dose of clopidogrel, with the current loading dose for clopidogrel being 300 mg. A larger loading dosage of 600 mg was compared to a lower loading dosage of 300 mg in two studies. Cuisset et al . randomly selected 292 patients undergoing stenting for non-ST elevation myocardial infarction (STEMI) to receive a loading dose of either 300 mg or 600 mg 12 hours before percutaneous coronary intervention (PCI). One month after the intervention, all patients were administered aspirin 160 mg and clopidogrel 75 mg daily. The 600 mg loading dosage group demonstrated reduced adenosine diphosphate (ADP) induced platelet aggregation and P-selection expression compared to the 300 mg loading dosage group. Furthermore, there were fewer cardiovascular incidents in the 600 mg loading dosage group after one month (7 vs 18 events; P = 0.02). 18 One hundred and forty-eight patients undergoing elective PCI were randomly assigned to three groups in a study conducted by L’Allier et al . Group A patients were administered 75 mg clopidogrel on the morning of the procedure and 300 mg clopidogrel a day (≥15 hours) before the procedure. Group B patients were administered 600 mg clopidogrel in the morning (≥2 hours) of the procedure. Meanwhile, group C patients were administered 600 mg clopidogrel on the morning of the procedure and 600 mg clopidogrel a day before the procedure. Group C revealed substantially higher relative inhibition of peak and final ADP-stimulated platelet aggregation than groups A and B. Thus, it appears that a successive 600 mg/dose of clopidogrel bolus resulted in more substantial platelet inhibition than a single loading dosage. 19 The effectiveness of a daily maintenance dosage of clopidogrel 150 mg in patients undergoing elective PCI was examined in a study by Angiolillo et al . Both groups of patients continued medication for 30 days before returning to the regular dose. ADP-induced platelet aggregation (20 μM) was higher in 75 mg clopidogrel/day patients than in 150 mg clopidogrel/day individuals (64% vs 52.1%; P < 0.001). 20 The VerifyNow test evaluated relative platelet aggregation in response to 5 μM ADP (45.1% vs 65.3%; P < 0.001), and platelet function inhibition (60 vs 117; P = 0.004) was substantially improved in patients who received clopidogrel 150 mg compared to those given 75 mg. 20 A larger trial of 153 individuals with a low clopidogrel response (platelet reactivity index 69%) to 75 mg/day or 150 mg/day (n = 95 or n = 58) clopidogrel found similar results. After two weeks of therapy, clopidogrel 150 mg/day was linked with a considerably lower platelet reactivity index than 75 mg/day (43.9% vs 58.6%; P < 0.001). After switching to clopidogrel 150 mg/day for two weeks, 20 out of 31 patients in the 75 mg/day group were responsive (platelet reactivity was 69%). 21 Overall, the outcomes of this study point to the possibility of employing higher clopidogrel bolus and maintenance dosages. Other alternative drugs include prasugrel, ticagrelor and cilostazol. Although there is limited evidence to suggest that using prasugrel interacts with proton pump inhibitors (PPIs) via cytochrome P450, a study of TRITON-TIMI 38 and PRINCIPLES 44 showed that PPIs did not affect the efficacy of prasugrel. Thus, the use of PPIs with prasugrel is preferable. Ticagrelor is a new platelet aggregation inhibitor. Ticagrelor, like clopidogrel, binds to P2Y12, which acts as an antagonist to the ADP receptor on platelets, preventing platelet aggregation. Unlike clopidogrel, ticagrelor reversibly binds to P2Y12 and does not displace ADP from the receptor, allowing it to target 2-MeS-ADP-induced signalling. Furthermore, because ticagrelor does not need hepatic enzymatic activation, it is more consistent in reducing platelet aggregation. It has a lower risk of medication interactions and is not affected by CYP polymorphisms. 22 Cilostazol suppresses cAMP degradation in platelets by inhibiting platelet aggregation via phosphodiesterase-3-blockers. As a result, cilostazol may be an option for people who are resistant to clopidogrel. In patients receiving contemporary stent-based percutaneous procedures, using cilostazol in combination with clopidogrel and aspirin may minimize restenosis cerebral and cardiac side effects. 23 As a result, cilostazol is more beneficial than clopidogrel at high maintenance dosages. However, cilostazol was terminated more often in this trial due to the adverse effects. Shim et al . randomly categorized 400 patients who underwent successful PCI with DES into triple antiplatelet therapy (clopidogrel, cilostazol, and aspirin) and dual antiplatelet therapy (clopidogrel and aspirin) groups. They reported a significant decrease in clopidogrel resistance in the triple antiplatelet group (19.7% vs 40%, P < 0.001). As a result, the rate of clopidogrel resistance in patients undergoing PCI with DES can be reduced. 24 Several trials compared the effectiveness and safety of using cilostazol with aspirin and clopidogrel in dual antiplatelet therapy (DAPT). Cilostazol combination therapy has significant advantages in major cardiac side effects, death from any cause, cardiac death, target lesion revascularization, and in-segment restenosis. Benefits are reported in patients with clopidogrel resistance. 23 Several limitations were evident in the present study. First, regarding the association between the LOF gene and ISR, there were limited studies with small sample sizes, which may have limited statistical power. Second, none of the studies included were RCTs. Third, varying types of LOF genes were included in the studies, and some studies did not state clearly whether they were examining homozygote LOF genes or heterozygote LOF genes. Fourth, the studies utilized different stent types and did not clearly state the percentage of BMS and DES used in their studies, as we know that BMS have a higher tendency to form ISR. Fifth, none of the studies used intracoronary imaging. Furthermore, individual patient-level data were not available. Conclusions In conclusion, the present study supports the theory that, in patients who have undergone coronary stenting and been treated with clopidogrel, the presence of the LOF gene increases their likelihood of ISR. Furthermore, larger-scale studies are required to examine appropriate strategies in patients with the LOF gene who have undergone coronary stenting. Data availability Underlying data All data underlying the results are available as part of the article and no additional source data are required. Reporting guidelines Figshare: PRISMA checklist and Funnel plot for ‘CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.19312115 . 11 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0) References 1. Shlofmitz E, Iantorno M, Waksman R: Restenosis of Drug-Eluting Stents: A New Classification System Based on Disease Mechanism to Guide Treatment and State-of-the-Art Review. Circ. Cardiovasc. Interv. 2019; 12 : e007023. PubMed Abstract | Publisher Full Text 2. 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L’Allier PL, Ducrocq G, Pranno N, et al. : Clopidogrel 600-mg Double Loading Dose Achieves Stronger Platelet Inhibition than Conventional Regimens: Results From The PREPAIR Randomized Study. J. Am. Coll. Cardiol. 2008; 51 : 1066–1072. PubMed Abstract | Publisher Full Text 20. Angiolillo DJ, Capranzano P, Goto S, et al. : A Randomized Study Assessing The Impact of Cilostazol on Platelet Function Profiles in Patients with Diabetes Mellitus and Coronary Artery Disease on Dual Antiplatelet Therapy: Results of The OPTIMUS-2 Study. Eur. Heart J. 2008; 29 : 2202–2211. PubMed Abstract | Publisher Full Text 21. Aleil B, Jacquemin L, De Poli F, et al. : Clopidogrel 150 mg/day to Overcome Low Responsiveness in Patients Undergoing Elective Percutaneous Coronary Intervention: Results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) Randomized Study. JACC Cardiovasc. Interv. 2008; 1 : 631–638. PubMed Abstract | Publisher Full Text 22. 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PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 22 Mar 2022 ADD YOUR COMMENT Comment Author details Author details 1 Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Mataram, Mataram, West Nusa Tenggara, 83126, Indonesia 2 Department of Cardiology and Vascular Medicine, Slamet Martodirdjo General Hospital, Pamekasan, Madura, 69317, Indonesia 3 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University - Dr Soetomo General Hospital, Surabaya, East Java, 60132, Indonesia 4 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, Special Region of Yogyakarta, 55224, Indonesia 5 Emergency Department, dr. Ramelan Navy Hospital, Surabaya, East Java, 60244, Indonesia 6 Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makasar, South Sulawesi, 90245, Indonesia 7 Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, South Sulawesi, 90245, Indonesia 8 Department of Nutrition, Faculty of Medicine, University of Hasanuddin, Makassar, South Sulawesi, 90245, Indonesia Yusra Pintaningrum Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Methodology, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Vitriyaturrida . Roles: Data Curation, Formal Analysis, Investigation, Validation, Writing – Review & Editing Ivana Purnama Dewi Roles: Methodology, Software, Validation, Writing – Review & Editing Hendy Bhaskara Perdana Putra Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation Idar Mappangara Roles: Methodology, Resources, Software, Writing – Review & Editing Muzakkir Amir Roles: Project Administration, Supervision, Validation Irawan Yusuf Roles: Supervision, Validation, Visualization Agussalim Bukhari Roles: Supervision, Visualization Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 15 Jan 2025, 11:346 https://doi.org/10.12688/f1000research.109321.3 version 2 Revised Published: 12 Aug 2022, 11:346 https://doi.org/10.12688/f1000research.109321.2 version 1 Published: 22 Mar 2022, 11:346 https://doi.org/10.12688/f1000research.109321.1 Copyright © 2025 Pintaningrum Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Pintaningrum Y, . V, Dewi IP et al. CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.12688/f1000research.109321.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 12 Aug 2022 Revised Views 0 Cite How to cite this report: Awan FR. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249958 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249958 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 06 May 2024 Fazli Rabbi Awan , Diabetes and Cardio-Metabolic Disorders Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan; Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan Approved VIEWS 0 https://doi.org/10.5256/f1000research.134740.r249958 I have read this article with great interest. It is well written study. Though, the sample size (number of papers used in this meta-analysis) was small as less literature has been available, authors were careful to draw any generalized conclusions. ... Continue reading READ ALL I have read this article with great interest. It is well written study. Though, the sample size (number of papers used in this meta-analysis) was small as less literature has been available, authors were careful to draw any generalized conclusions. They have hinted towards ISR correlatoin with the risk (loss of function) genotype of the investigated gene. Overall, it is a good read. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Genetics of Metabolic and Cardiovascular Disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Awan FR. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249958 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249958 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 15 Jan 2025 Ivana Purnama Dewi , Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia 15 Jan 2025 Author Response Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be ... Continue reading Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Authors response: The typo "P-selection" has been corrected to "P-selectin." We sincerely apologize for this oversight. Additionally, we have carefully reviewed the manuscript and ensured that "vs" is used consistently throughout the text. Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Authors response: The typo "P-selection" has been corrected to "P-selectin." We sincerely apologize for this oversight. Additionally, we have carefully reviewed the manuscript and ensured that "vs" is used consistently throughout the text. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 15 Jan 2025 Ivana Purnama Dewi , Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia 15 Jan 2025 Author Response Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be ... Continue reading Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Authors response: The typo "P-selection" has been corrected to "P-selectin." We sincerely apologize for this oversight. Additionally, we have carefully reviewed the manuscript and ensured that "vs" is used consistently throughout the text. Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Authors response: The typo "P-selection" has been corrected to "P-selectin." We sincerely apologize for this oversight. Additionally, we have carefully reviewed the manuscript and ensured that "vs" is used consistently throughout the text. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Lesauskaitė V and Paukstaitiene R. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249956 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249956 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Mar 2024 Vaiva Lesauskaitė , Laboratory of Molecular Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania Renata Paukstaitiene , Department of Physics, Mathematics and Biophysics, Lithuanian University of Health Sciences, Kaunas, Lithuania Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.134740.r249956 1. There is no information from which year publications were searched for systematics literature review in the search strategy. 2. Authors chose odds ratio as the effect size. But they use the terms “correlation” and “risk” in the results ... Continue reading READ ALL 1. There is no information from which year publications were searched for systematics literature review in the search strategy. 2. Authors chose odds ratio as the effect size. But they use the terms “correlation” and “risk” in the results sections. No statistical methods were used to calculate correlation or risk. Terms must be corrected according to used statistical methods. 3. Two models (Fixed effect model and random effect model) are mentioned in the Methods chapter, but only the results of fixed effect are presented in the Results chapter. Why random effect model was not included in the results?. 4. The use of the fixed-effect model for the analysis is not acceptable because the analyzed results are gained from different types of studies, and studies are taken from different countries. Authors indicated that choice of fixed- effect model was based on the absence of heterogeneity. But only four studies are included in the meta- analysis, thus the power of the test of heterogeneity is low. Thus, authors don’t give sufficient evidence that the studies really represent a single population, and all studies measure the same effect, which is different due to sampling error. 5. To edit Fig.5. It is not clear which group is assigned as a treatment group in the research. Usually, the same side for treatment and control group is used in the table and in the Forest plot. Authors changed these sides, and it is not clear if the conclusion is correct. 6. Newcastle – Ottawa Scale is used to assess the quality of the publication in the systematic literature review, but it is not suitable for estimation of the publication bias for the meta-analysis as it is indicated in the abstract of the review. At least Funnel plot has to be presented to show that there is no publication bias. 6. Table 2 line Age - it is not clear what numerical characteristics are presented “?±?” mean±SD?, SE? 7. The statement "The odds of ISR were 2.8% higher in the LOF gene compared to the wild gene" is not correct. OR 2,8 means increase in 2,8 folds or 280 percents. 8.The novelty and significance of meta analysis results are not disclosed in Discussion Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? No Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cardiovascular pathology, pharmacogenomics;, We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Lesauskaitė V and Paukstaitiene R. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249956 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249956 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 22 Mar 2022 Views 0 Cite How to cite this report: Sarvasti D. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.120809.r128371 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v1#referee-response-128371 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Apr 2022 Dyana Sarvasti , Department of Internal Medicine, Faculty of Medicine, Widya Mandala Catholic University, Surabaya, Indonesia Approved VIEWS 0 https://doi.org/10.5256/f1000research.120809.r128371 This meta-analysis study is interesting and useful, although it only involves four non-randomized controlled trials. It can be used as additional knowledge about the management of antiplatelet therapy use in patients undergoing PCI who are suspected of having the presence ... Continue reading READ ALL This meta-analysis study is interesting and useful, although it only involves four non-randomized controlled trials. It can be used as additional knowledge about the management of antiplatelet therapy use in patients undergoing PCI who are suspected of having the presence of the CYP2C19 LOF gene. Unfortunately, the research objectives related to the use of antiplatelets are not fully described in the abstract, even though in the discussion and conclusions there are many mentions of the relationship between LOF genes, ISR, and various types of antiplatelets, especially clopidogrel. If possible, the association of the CYP2C19 LOF gene with antiplatelet use (clopidogrel) should also be addressed in the research objectives in the abstract. In addition, there are some mistypes that need to be corrected. Here are some points related to this: In table 2, it appears that “ Cross sectional” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “ bare metal ” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “ drug eluting ” is missing a hyphen. Consider adding the hyphen(s). There is an inconsistency in writing the title of the bibliography in the reference list. Sometimes it is written in lower case, sometimes in upper case. Consider making corrections. Thank you for your kind attention. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cardiovascular Prevention and Rehabilitation I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sarvasti D. Reviewer Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.120809.r128371 ) The direct URL for this report is: https://f1000research.com/articles/11-346/v1#referee-response-128371 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 07 Jun 2022 Ivana Purnama Dewi , Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia 07 Jun 2022 Author Response Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Competing Interests: No competing interests were disclosed. Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 07 Jun 2022 Ivana Purnama Dewi , Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia 07 Jun 2022 Author Response Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Competing Interests: No competing interests were disclosed. Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 22 Mar 2022 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 3 (revision) 15 Jan 25 Version 2 (revision) 12 Aug 22 read read Version 1 22 Mar 22 read Dyana Sarvasti , Widya Mandala Catholic University, Surabaya, Indonesia Vaiva Lesauskaitė , Laboratory of Molecular Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania Renata Paukstaitiene , Lithuanian University of Health Sciences, Kaunas, Lithuania Fazli Rabbi Awan , Diabetes and Cardio-Metabolic Disorders Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan; Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Awan F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 May 2024 | for Version 2 Fazli Rabbi Awan , Diabetes and Cardio-Metabolic Disorders Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan; Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan 0 Views copyright © 2024 Awan F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have read this article with great interest. It is well written study. Though, the sample size (number of papers used in this meta-analysis) was small as less literature has been available, authors were careful to draw any generalized conclusions. They have hinted towards ISR correlatoin with the risk (loss of function) genotype of the investigated gene. Overall, it is a good read. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Genetics of Metabolic and Cardiovascular Disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 15 Jan 2025 Ivana Purnama Dewi, Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia Thank you for your thorough review and valuable feedback on our manuscript. We appreciate your positive comments and constructive suggestions. I only found one typing mistake: P-selection should be P-selectin and either use, vs or verses throughout. Authors response: The typo "P-selection" has been corrected to "P-selectin." We sincerely apologize for this oversight. Additionally, we have carefully reviewed the manuscript and ensured that "vs" is used consistently throughout the text. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Awan FR. Peer Review Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249958) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249958 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Lesauskaitė V et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Mar 2024 | for Version 2 Vaiva Lesauskaitė , Laboratory of Molecular Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania Renata Paukstaitiene , Department of Physics, Mathematics and Biophysics, Lithuanian University of Health Sciences, Kaunas, Lithuania 0 Views copyright © 2024 Lesauskaitė V et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1. There is no information from which year publications were searched for systematics literature review in the search strategy. 2. Authors chose odds ratio as the effect size. But they use the terms “correlation” and “risk” in the results sections. No statistical methods were used to calculate correlation or risk. Terms must be corrected according to used statistical methods. 3. Two models (Fixed effect model and random effect model) are mentioned in the Methods chapter, but only the results of fixed effect are presented in the Results chapter. Why random effect model was not included in the results?. 4. The use of the fixed-effect model for the analysis is not acceptable because the analyzed results are gained from different types of studies, and studies are taken from different countries. Authors indicated that choice of fixed- effect model was based on the absence of heterogeneity. But only four studies are included in the meta- analysis, thus the power of the test of heterogeneity is low. Thus, authors don’t give sufficient evidence that the studies really represent a single population, and all studies measure the same effect, which is different due to sampling error. 5. To edit Fig.5. It is not clear which group is assigned as a treatment group in the research. Usually, the same side for treatment and control group is used in the table and in the Forest plot. Authors changed these sides, and it is not clear if the conclusion is correct. 6. Newcastle – Ottawa Scale is used to assess the quality of the publication in the systematic literature review, but it is not suitable for estimation of the publication bias for the meta-analysis as it is indicated in the abstract of the review. At least Funnel plot has to be presented to show that there is no publication bias. 6. Table 2 line Age - it is not clear what numerical characteristics are presented “?±?” mean±SD?, SE? 7. The statement "The odds of ISR were 2.8% higher in the LOF gene compared to the wild gene" is not correct. OR 2,8 means increase in 2,8 folds or 280 percents. 8.The novelty and significance of meta analysis results are not disclosed in Discussion Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? No Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Cardiovascular pathology, pharmacogenomics;, We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. reply Respond to this report Responses (0) Lesauskaitė V and Paukstaitiene R. Peer Review Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.134740.r249956) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-346/v2#referee-response-249956 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2022 Sarvasti D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Apr 2022 | for Version 1 Dyana Sarvasti , Department of Internal Medicine, Faculty of Medicine, Widya Mandala Catholic University, Surabaya, Indonesia 0 Views copyright © 2022 Sarvasti D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This meta-analysis study is interesting and useful, although it only involves four non-randomized controlled trials. It can be used as additional knowledge about the management of antiplatelet therapy use in patients undergoing PCI who are suspected of having the presence of the CYP2C19 LOF gene. Unfortunately, the research objectives related to the use of antiplatelets are not fully described in the abstract, even though in the discussion and conclusions there are many mentions of the relationship between LOF genes, ISR, and various types of antiplatelets, especially clopidogrel. If possible, the association of the CYP2C19 LOF gene with antiplatelet use (clopidogrel) should also be addressed in the research objectives in the abstract. In addition, there are some mistypes that need to be corrected. Here are some points related to this: In table 2, it appears that “ Cross sectional” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “ bare metal ” is missing a hyphen. Consider adding the hyphen(s). In abbreviations in table 2, It appears that “ drug eluting ” is missing a hyphen. Consider adding the hyphen(s). There is an inconsistency in writing the title of the bibliography in the reference list. Sometimes it is written in lower case, sometimes in upper case. Consider making corrections. Thank you for your kind attention. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Cardiovascular Prevention and Rehabilitation I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 07 Jun 2022 Ivana Purnama Dewi, Department of Cardiology and Vascular Medicine, Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, 55224, Indonesia Dear Dyana Sarvasti, M.D Thank you for your kind review We will make some corrections regarding your suggestions Best regards, Yusra Pintaningrum, M.D View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sarvasti D. Peer Review Report For: CYP2C19 polymorphism and coronary in-stent restenosis: A systematic review and meta-analysis [version 3; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 11 :346 ( https://doi.org/10.5256/f1000research.120809.r128371) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-346/v1#referee-response-128371 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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