Exploratory Research of PCSK9 Inhibitor on Patency of Autogenous Arteriovenous Fistula After Percutaneous Transluminal Angioplasty with Paclitaxel Releasing Balloon: study protocol for a prospective, randomized, controlled trial

Exploratory Research of PCSK9 Inhibitor on Patency of Autogenous Arteriovenous Fistula After Percutaneous Transluminal Angioplasty with Paclitaxel Releasing Balloon: study protocol for a prospective, randomized, controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploratory Research of PCSK9 Inhibitor on Patency of Autogenous Arteriovenous Fistula After Percutaneous Transluminal Angioplasty with Paclitaxel Releasing Balloon: study protocol for a prospective, randomized, controlled trial yuanyuan xie, Haifen Zhang, Yijun Zhou, Yan Fang, Minxia Zhu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4433992/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Arteriovenous fistula (AVF) is the preferred type of vascular access for maintenance hemodialysis (MHD) patients. Stenosis is the main cause of AVF dysfunction. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable. However, the durability of PTA is limited. This trial aims to determine: the effect of using paclitaxel release balloons combined with PCSK9 inhibitors on improving postoperative patency of AVF and the safety of combined use. Methods This is a prospective, randomized, controlled study. It is exploratory research. The study will recruit 40 MHD patients aged from 18 to 75 years, with an intervention period of 48 weeks. Patients will be randomized into two arms: (1) The treatment group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks. (2) Control group no Intervention. The primary outcome is the main patency rate. Discussion This is an exploratory study which would be conducted to evaluate the efficacy and safety of PCSK9 inhibitors in the patency of AVF after paclitaxel release balloon surgery. Expected to improve restenosis rate and extend the service life of AVF. Trial registration The trial is approved by Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders. Clinical trials ID NCT06034691 09/10/2023 Arteriovenous fistula (AVF) percutaneous transluminal angioplasty (PTA) PCSK9 inhibitors Figures Figure 1 Figure 2 Background Arteriovenous fistula (AVF) being the preferred pathway for maintenance hemodialysis (MHD) patients is a consensus among guidelines in various countries. The main cause of AVF dysfunction is stenosis [ 1 ]. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable [ 2 ]. Nevertheless, the durability of PTA is limited [ 3 ]. Previous studies have shown that dyslipidemia is an important predictive factor for secondary loss of patency [ 4 ]. PCSK9 inhibitors are a new type of lipid-lowering drugs that can effectively reduce low-density lipoprotein (LDL) levels and improve the LDL compliance rate [ 5 ]. Studies have shown that PCSK9 inhibitors have good lipid-lowering effects in both MHD patients and non-dialysis patients, and using the same dose as non-dialysis patients is safe in MHD patients [ 6 ]. Currently, there are few studies on the use of PTA combined with PCSK9 inhibitors to improve long-term life of AVF. Therefore, we applied a prospective, randomized, and controlled study to preliminarily explore the effect of PTA combined with PCSK9 inhibitor on improving postoperative patency rate of AVF and the safety of combined application. Methods and analysis Objectives The primary objective is to determine if the use of PCSK9 inhibitors after PTA, compared to no PCSK9 inhibitors, will lead to improved target lesion and access circuit patency at one year. The secondary objectives are followed: To determine if the use of PCSK9 inhibitors after PTA will lead to decreased restenosis of the target lesion To determine if the use of PCSK9 inhibitors after PTA will lead to decreased number of interventions needed to maintain patency of AVF over 1 year To determine the safety of combined application Study design This is a prospective, randomized, and controlled exploratory research with two groups: 1) PCSK9i group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks, 2) control group no additional intervention with lipid-lowering drugs. The trial design is summarized in Fig. 1 . Inclusion criteria Agree to join this study and sign an informed consent form Age ≥ 18 years old and ≤ 75 years old, regardless of gender Maintenance hemodialysis patients using autologous arteriovenous fistula (AVF), with a dialysis frequency of three times a week AVF venous stenosis: The local stenosis rate exceeds 50% of the normal diameter of nearby blood vessels and is accompanied by at least one of the following conditions: The natural blood flow of the internal fistula is less than 500ml/min or has decreased by more than 25% compared to the previous examination result Unable to meet the required blood flow for dialysis prescription (blood flow < 200ml/min, and cannot be corrected after adjusting the puncture needle position) Decreased arterial pressure or increased venous pressure during dialysis (monitoring arterial pressure 120mmHg while maintaining 200ml/min blood flow) Difficulty in puncture: A qualified nurse who has difficulty puncturing for 3 consecutive days of hemodialysis (blood can only be drawn out after more than two punctures) Decreased dialysis adequacy [arteriovenous fistula recirculation rate (RA) > 10%, or an increase of more than 25% compared to the previous examination result] [RA=(SA-A)/(SA-V) *100, dialysis to 1 hour: SA = blood flow adjusted to 20ml/min, ultrafiltration and dialysate flow stopped, after 2 minutes, artery Blood urea nitrogen concentration A = artery Blood urea nitrogen concentration V = vein Blood urea nitrogen concentration] Abnormal signs of fistula. Patients with primary Hypercholesterolemia [LDL-C ≥ 130 mg/dl (≥ 3.4 mmol/L), and/or non-HDL-C ≥ 160 mg/dl (≥ 4.1 mmol/L)] or combine cardiovascular disease or assess patients with a high risk of cardiovascular disease Exclusion criteria MHD with AVG Breastfeeding or Pregnant Women Patients with central venous reflux obstruction Patients with AVF feeding artery disease Patients with severe Hypotension (systolic blood pressure < 90mmHg or diastolic blood pressure < 60mmHg, at least three times within one month before signing the informed consent) Left ventricular Ejection fraction less than 30% or hemodynamic instability Patients receiving immunotherapy or suspected/confirmed Vasculitis Patients with coagulation dysfunction or a history of Thrombocytopenic purpura Patients with vascular access infections or systemic active infections Patients who are known to be allergic to PCSK9 inhibitors or paclitaxel Patient's life expectancy is less than 12 months Patients who are planning kidney transplantation or switching to Peritoneal dialysis Patients participating in other intervention studies The researcher judged that the subject's condition was not suitable for participation in this study Participants The study will recruit a total of 40 patients from three branches of Renji Hospital, Shanghai Jiaotong University School of Medicine. The potential participants are patients who are scheduled for PTA of dysfunctional AVF by their primary physician. The potential participants will be screened for eligibility according to the inclusion and exclusion criteria for the study summarized above by the study team member. Eligible patients are offered enrollment. Informed consent is taken from eligible participants before the procedure. The study team members will obtain written informed consent to participate in the study from all enrolled participants. Additional informed consent for the collection and the use of participant data will also be obtained. Randomized grouping of participants using the random envelope method after the procedure. Randomization Randomization sequence will be generated by an independent data manager using SAS (V.9.3) and stored within sealed opaque envelopes. The investigator opens an envelope to obtain a number every time a patient is consented to enter the trial. Based on this number, the patient is assigned the corresponding number of medication (treatment drugs or placebos). Trial interventions Participants are randomly assigned to receive one of the following interventions: PCSK9i group (treatment group): The treatment group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks. No medication dose adjustment during the study period. Drug injections are completed by dedicated nurses after each hemodialysis session. No Intervention (control group): There was no additional intervention with lipid-lowering drugs in the control group. Study visits Study recruitment opened on 2 October 2023. An overview of the trial is provided in Fig. 2 . The researchers screen subjects according to inclusion criteria and exclusion criteria, after which the subject is randomized to the treatment or the control arm by 1:1. In the treatment arm, the subjects are treated with Ribavirin 140mg iH q2w. In the control arm, the subjects are no intervention. All subjects will be followed up at 4 weeks, 12 weeks, 24 weeks and 48 weeks (Fig. 2 ). As ultrasound is used as an imaging tool to monitor the AVF post-intervention for the study, ultrasound assessment of the AVFs will be performed by a trained operator. The diameter of vessels, volume flow rates at the mid-brachial artery and venous outflow will be recorded. The minimum diameter of each target lesion and Peak Systolic Velocity Ratio (PSVR) will be recorded. All participants will be followed up for up to 1 year. The window periods for the post-PTA visits are 1 month ± 1 week, 3 months ± 1 week, 6 months ± 4 weeks, and 12 months ± 4 weeks. During the follow-up period, ultrasound assessment will be performed in each study site’s hemodialysis unit. The Duplex ultrasonography assessment includes patency of the AVF, volume flow rates at the mid-brachial artery and venous outflow, minimum diameter of each target lesion, and any new stenosis within the AVF circuit. Observation item Demographic data of subjects at baseline will be collected. The medical history of the patients, such as the primary cause of MHD, hypertension, diabetes, cardiovascular disease, cerebrovascular disease, the date of initiate dialysis, history of AVF surgery will be collected. Dialysis data including dialysis blood flow rate, venous pressure and arterial pressure will be collected at 4 weeks, 12 weeks, 24 weeks and 48 weeks of follow-up. Laboratory examination data at baseline, 12 weeks, 24 weeks and 48 weeks of follow-up, such as white cell count, Hb, platelet, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total protein, total bilirubin, PH, HCO3–,K+, Na+, Cl–, albumin, total cholesterol, triglyceride, Low density lipoprotein (LDL), High density lipoprotein (HDL), calcium, phosphorus, iPTH, ferritin, fasting blood glucose, C reactive protein, β2-microglobulin, B natriuretic peptides, thiamine, folic acid and homocysteine will be collected. Access recirculation and dialysis adequacy (spKt/V) will be calculated. Ultrasound examination will be done at baseline, 4 weeks, 12 weeks, 24 weeks and 48 weeks of follow-up. Collect information on internal fistula re intervention and intervention methods. Data statement The case report form is filled out by the investigator on time. The investigator must properly handle all the data obtained during the clinical trial, and truthfully record all adverse events and serious adverse events during the clinical trial, so as to ensure the rights and privacy of the subjects participating in the clinical trial. Personal information of subjects will be collected, shared and maintained to protect confidentiality during and after the study. Only the project investigator will have access to the final trial data set. A data monitoring committee is composed of clinicians and biostatisticians from Clinical Centre for Investigation, Renji Hospital, School of Medicine, Shanghai Jiao Tong University who are not involved in this study for the purpose of ensuring the safety of subjects and the quality of study data. Data sharing statement No later than 3 years after the collection of the 1-year post-randomization interviews, we will deliver a completely deidentified data set to an appropriate data archive for sharing purposes. Statistical analysis technique The clinical data of this project was analyzed using SPSS statistical software. Continuous variables are represented as mean ± standard deviation or median, quartile range depends on distribution, while categorical variables are represented as absolute and relative frequencies. Use independent t-test or Wilcoxon rank sum test to test for differences between two groups of continuous variables, while categorical variables use χ 2 or Fisher's exact test. Bilateral α level of 0.05 is defined as having statistical significance. Validity analysis: main endpoint events, secondary endpoint events, adverse events, etc. were analyzed using the full analysis set and per protocol set, respectively. If there are concomitant medications, describe them in two aspects: past and during the treatment process. Statistical analysis summary: after completing the statistical analysis, write a statistical analysis report. Ethics and dissemination This trial has been approved by Shanghai Jiao Tong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A). Other participating subcenters must also obtain ethics committee approval documents prior to the start of clinical trials. The GCP19 regulations shall be strictly followed during the test implementation. Amendments to the protocol will be reviewed by ethics committees. Informed consent (2.1 20230615) will be obtained before collecting any patient data and patient information. After publication of study results, trial report will be published in peer-reviewed journals and/or in national or international conferences. All researchers involved in the design, discussion and writing of this study protocol, as the authors. Harms Each participating investigator has primary responsibility for the safety of the individual participants under their care. Throughout the clinical trial, particular attention will be given to (serious) adverse events ((S)AEs). SAEs will be collected, documented and reported from enrollment to the end-of-study event or end-of-study date for each participant. Subcutaneous injection of Ribavirin has a rare anaphylactic reaction. Safety endpoints are related directly to changes in laboratory safety indicators and incidence of adverse events between the treatment and control groups during follow-up. These endpoints will be listed according to the treatment received and recorded in detail. Participants will be followed up in detail; if any complications arise, appropriate treatment will be provided in accordance with current routine medical procedures. Discussion Arteriovenous fistula (AVF) is the preferred type of vascular access for maintenance hemodialysis (MHD) patients [ 2 ]. The main cause of AVF dysfunction is stenosis [ 1 ]. The vascular pathway intervention rate is approximately 1.9 times per patient per year [ 7 ]. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable [ 2 ]. With the development of interventional therapy recent studies have shown that the postoperative patency rate of PTA is comparable to that of open surgery [ 8 ]. Nevertheless, the durability of PTA is limited [ 3 ]. Previous studies have shown that due to the high incidence of restenosis, repeated intervention is often required after PTA surgery, with reported patency rates of 61%, 42%, and 35% at 6, 12, and 24 months, respectively [ 9 , 10 ]. To reduce the risk of dysfunction recurrence after intervention, drug-coated balloons (DCB) are used in the treatment of vascular stenosis in hemodialysis. Paclitaxel is an anti-proliferative substance that stabilizes the microtubule structure of cells and is the most commonly chosen drug for coating these balloons. A multicenter study in China shows that paclitaxel drug-coated balloons (PCB) can reduce the risk of restenosis at 6 months compared to conventional high-pressure balloon, but the target lesion and target shunt intervention-free survival was no statistically significant difference [ 11 ]. The impact of DCB mainly focuses on the target lesion itself, rather than the pathway circuit or hemodynamic changes related to angioplasty. Multiple factors limit the efficacy of DCB. In previous studies on factors related to hemodialysis pathway stenosis, it has been shown that dyslipidemia is significantly correlated with a shorter initial patency rate and an important predictive factor for secondary loss of patency [ 4 ]. The study also found that the use of statins is associated with increased primary and secondary patency rates [ 4 ]. However, there is still a lock of prospective studies on the improvement of patency rate using lipid-lowering drugs after PTA in clinical. The commonly used lipid-lowering drugs in clinical are hydroxymethylglutaryl CoA reductase inhibitors, with limited lipid-lowering effects. Previous large-scale researches have shown no significant benefits of HMG-CoA reductase inhibitors on clinical cardiovascular and mortality endpoints in MHD patients [ 12 ]. In uremic environments, the progression of calcification induced by HMG-CoA reductase inhibitors may potentially exacerbate the already severely elevated cardiovascular risk [ 12 ]. PCSK9 inhibitors are a new type of lipid-lowering drugs that can effectively reduce low-density lipoprotein (LDL) levels and improve the LDL compliance rate [ 5 ]. In cardiovascular research, it has been found that PCSK9 inhibitors can prevent vascular calcification and have certain cardiovascular protection advantages [ 13 ]. Small sample studies have been conducted using PCSK9 inhibitors in MHD patients. Studies have shown that PCSK9 inhibitors have good lipid-lowering effects in both MHD patients and non-dialysis patients, and using the same dose as non-dialysis patients is safe in MHD patients [ 6 ]. AVF is the lifeline of MHD patients. With the development of interventional therapy, PTA is easy to operate and reduces patient pain. The use of PCB can prolong the no angioplasty time for AVF undergoing PTA surgery. In order to better prolong the long-term life of AVF, increase the durability of PTA, that delaying postoperative restenosis has become one of the research focuses. MHD patients are generally associated with cardiovascular disease or have a high risk of cardiovascular disease [ 14 ]. PCSK9 inhibitors are safe and effective for MHD patients. This exploratory study would be conducted to evaluate the efficacy and safety of PCSK9 inhibitors in the patency of AVF after paclitaxel release balloon surgery. Expected to improve restenosis rate and extend the service life of AVF. Trial status The protocol version number and date: 1.1 2023.6.15 The date recruitment began: 2023.10.20 The approximate date when recruitment will be completed: 2025.12.31 Abbreviations AVF arteriovenous fistula MHD maintenance hemodialysis PTA percutaneous transluminal angioplasty LDL low-density lipoprotein RA arteriovenous fistula recirculation rate PSVR Peak Systolic Velocity Ratio DCB drug-coated balloons PCB paclitaxel drug-coated balloons. Declarations Ethics approval and consent to participate This trial has been approved by Shanghai Jiao Tong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A). Consent for publication Not applicable Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests. Funding No Authors' contributions YX, LG and RL were responsible for the design of the entire study, including the drafting, revision and submission of clinical trial protocols. HZ, YZ, YF, MZ and XZ are responsible for the discussion and revision of clinical trial protocol. YX and LG is responsible for the design of statistical methods. YX and RL is in charge of the pharmacological mechanisms and dosage selection of experimental drugs. All authors have read and approved the final manuscript. Acknowledgements Not applicable References Oh D-J, Lee JH, Kwon YE, et al. Relationship Between Arteriovenous Fistula Stenosis and Circulating Levels of Neutrophil Granule Proteins in Chronic Hemodialysis Patients. Ann Vasc Surg. 2021;77:226–35. Charmaine E, Lok TS, Huber T, Lee, et al. KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update. Am J Kidney Dis. 2020;75:S1–164. Cai C, Kilari S, Zhao C, et al. Therapeutic Effect of Adipose Derived Mesenchymal Stem Cell Transplantation in Reducing Restenosis in a Murine Angioplasty Model. J Am Soc Nephrol. 2020;31:1781–95. Kim SM, Ko HK, Noh M, et al. Factors Affecting Patency following Successful Percutaneous Intervention for Dysfunctional Hemodialysis Vascular Access. Ann Vasc Surg. 2018;47:54–61. Charles J, Ferro PB, Mark M, Kanbay, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol. 2018;14:727–49. Cara East K, Bass A, Mehta, et al. Alirocumab and Lipid Levels, Inflammatory Biomarkers, Metabolomics, and Safety in Patients Receiving Maintenance Dialysis: The ALIrocumab in DIALysis Study (A Phase 3 Trial to Evaluate the Efficacy and Safety of Biweekly Alirocumab in Patients on a Stable Dialysis Regimen). Kidney Med. 2022;4:100483. Charmaine E. Lok. Fistula Interventions: Less Is More. J Am Soc Nephrol. 2019;30:2040–2. Ulrika Hahn Lundström G, Welander JJ, Carrero, et al. Surgical versus endovascular intervention for vascular access thrombosis: a nationwide observational cohort study. Nephrol Dial Transpl. 2022;37:1742–50. Elramah M, Boujelbane L, Yevzlin AS, et al. Dialysis access venous stenosis: treatment with balloon angioplasty 30-second vs. 1-minute inflation times. Hemodial Int. 2015;19:108–14. Bountouris I, Kristmundsson T, Dias N et al. Is repeat PTA of a failing hemodialysis fistula durable? Int J Vasc Med 2014;369687. Yanqi Yin Y, Shi T, Cui, et al. Efficacy and Safety of Paclitaxel-Coated Balloon Angioplasty for Dysfunctional Arteriovenous Fistulas: A Multicenter Randomized Controlled Trial. Am J Kidney Dis. 2021;78:19–27. An S, De Vriese. Should Statins Be Banned from Dialysis? J Am Soc Nephrol. 2017;28:1675–6. Yuichi Ikegami I, Inoue K, Inoue, et al. The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. NPJ Aging Mech Dis. 2018;4:7. Cheung AK, Sarnak MJ, Yan G, et al. Atherosclerotic cardiovascular disease risk in chronic hemodialysis patients. Kidney int. 2000;58:353–62. Supplementary Files SPIRITchecklist.docx SPIRITFigure.doc Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 09 Mar, 2025 Reviewers agreed at journal 20 Jul, 2024 Reviewers invited by journal 18 Jul, 2024 Editor assigned by journal 09 Jul, 2024 First submitted to journal 29 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4433992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":328679078,"identity":"76f2e713-cd7f-49e0-946b-a1437f5019aa","order_by":0,"name":"yuanyuan 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02:31:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":40333,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4433992/v1/76d5f3b25a2ea0fc790d2644.docx"},{"id":62660102,"identity":"5c86d887-fef9-49a1-8a58-18b87e0f1e02","added_by":"auto","created_at":"2024-08-17 02:31:25","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":49664,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFigure.doc","url":"https://assets-eu.researchsquare.com/files/rs-4433992/v1/93298bc7adccfc9887e59ef3.doc"}],"financialInterests":"","formattedTitle":"Exploratory Research of PCSK9 Inhibitor on Patency of Autogenous Arteriovenous Fistula After Percutaneous Transluminal Angioplasty with Paclitaxel Releasing Balloon: study protocol for a prospective, randomized, controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003e Arteriovenous fistula (AVF) being the preferred pathway for maintenance hemodialysis (MHD) patients is a consensus among guidelines in various countries. The main cause of AVF dysfunction is stenosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nevertheless, the durability of PTA is limited [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Previous studies have shown that dyslipidemia is an important predictive factor for secondary loss of patency [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. PCSK9 inhibitors are a new type of lipid-lowering drugs that can effectively reduce low-density lipoprotein (LDL) levels and improve the LDL compliance rate [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Studies have shown that PCSK9 inhibitors have good lipid-lowering effects in both MHD patients and non-dialysis patients, and using the same dose as non-dialysis patients is safe in MHD patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Currently, there are few studies on the use of PTA combined with PCSK9 inhibitors to improve long-term life of AVF. Therefore, we applied a prospective, randomized, and controlled study to preliminarily explore the effect of PTA combined with PCSK9 inhibitor on improving postoperative patency rate of AVF and the safety of combined application.\u003c/p\u003e"},{"header":"Methods and analysis","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eObjectives\u003c/h2\u003e\n\u003cp\u003eThe primary objective is to determine if the use of PCSK9 inhibitors after PTA, compared to no PCSK9 inhibitors, will lead to improved target lesion and access circuit patency at one year.\u003c/p\u003e\n\u003cp\u003eThe secondary objectives are followed:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eTo determine if the use of PCSK9 inhibitors after PTA will lead to decreased restenosis of the target lesion\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eTo determine if the use of PCSK9 inhibitors after PTA will lead to decreased number of interventions needed to maintain patency of AVF over 1 year\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eTo determine the safety of combined application\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design\u003c/h2\u003e\n\u003cp\u003eThis is a prospective, randomized, and controlled exploratory research with two groups: 1) PCSK9i group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks, 2) control group no additional intervention with lipid-lowering drugs.\u003c/p\u003e\n\u003cp\u003eThe trial design is summarized in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eAgree to join this study and sign an informed consent form\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;18 years old and \u0026le;\u0026thinsp;75 years old, regardless of gender\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eMaintenance hemodialysis patients using autologous arteriovenous fistula (AVF), with a dialysis frequency of three times a week\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAVF venous stenosis: The local stenosis rate exceeds 50% of the normal diameter of nearby blood vessels and is accompanied by at least one of the following conditions:\u003c/p\u003e\n\u003col style=\"list-style-type: lower-alpha;\"\u003e\n\u003cli\u003e\n\u003cp\u003eThe natural blood flow of the internal fistula is less than 500ml/min or has decreased by more than 25% compared to the previous examination result\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eUnable to meet the required blood flow for dialysis prescription (blood flow\u0026thinsp;\u0026lt;\u0026thinsp;200ml/min, and cannot be corrected after adjusting the puncture needle position)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDecreased arterial pressure or increased venous pressure during dialysis (monitoring arterial pressure\u0026lt;-120mmHg for more than 2 consecutive times or monitoring venous pressure\u0026thinsp;\u0026gt;\u0026thinsp;120mmHg while maintaining 200ml/min blood flow)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDifficulty in puncture: A qualified nurse who has difficulty puncturing for 3 consecutive days of hemodialysis (blood can only be drawn out after more than two punctures)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDecreased dialysis adequacy [arteriovenous fistula recirculation rate (RA)\u0026thinsp;\u0026gt;\u0026thinsp;10%, or an increase of more than 25% compared to the previous examination result] [RA=(SA-A)/(SA-V) *100, dialysis to 1 hour: SA\u0026thinsp;=\u0026thinsp;blood flow adjusted to 20ml/min, ultrafiltration and dialysate flow stopped, after 2 minutes, artery Blood urea nitrogen concentration A\u0026thinsp;=\u0026thinsp;artery Blood urea nitrogen concentration V\u0026thinsp;=\u0026thinsp;vein Blood urea nitrogen concentration]\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAbnormal signs of fistula.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with primary Hypercholesterolemia [LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;130 mg/dl (\u0026ge;\u0026thinsp;3.4 mmol/L), and/or non-HDL-C\u0026thinsp;\u0026ge;\u0026thinsp;160 mg/dl (\u0026ge;\u0026thinsp;4.1 mmol/L)] or combine cardiovascular disease or assess patients with a high risk of cardiovascular disease\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eMHD with AVG\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eBreastfeeding or Pregnant Women\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with central venous reflux obstruction\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with AVF feeding artery disease\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with severe Hypotension (systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90mmHg or diastolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;60mmHg, at least three times within one month before signing the informed consent)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eLeft ventricular Ejection fraction less than 30% or hemodynamic instability\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients receiving immunotherapy or suspected/confirmed Vasculitis\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with coagulation dysfunction or a history of Thrombocytopenic purpura\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients with vascular access infections or systemic active infections\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients who are known to be allergic to PCSK9 inhibitors or paclitaxel\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatient's life expectancy is less than 12 months\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients who are planning kidney transplantation or switching to Peritoneal dialysis\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients participating in other intervention studies\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe researcher judged that the subject's condition was not suitable for participation in this study\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants\u003c/h2\u003e\n\u003cp\u003eThe study will recruit a total of 40 patients from three branches of Renji Hospital, Shanghai Jiaotong University School of Medicine. The potential participants are patients who are scheduled for PTA of dysfunctional AVF by their primary physician. The potential participants will be screened for eligibility according to the inclusion and exclusion criteria for the study summarized above by the study team member. Eligible patients are offered enrollment. Informed consent is taken from eligible participants before the procedure. The study team members will obtain written informed consent to participate in the study from all enrolled participants. Additional informed consent for the collection and the use of participant data will also be obtained. Randomized grouping of participants using the random envelope method after the procedure.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eRandomization\u003c/h2\u003e\n\u003cp\u003eRandomization sequence will be generated by an independent data manager using SAS (V.9.3) and stored within sealed opaque envelopes. The investigator opens an envelope to obtain a number every time a patient is consented to enter the trial. Based on this number, the patient is assigned the corresponding number of medication (treatment drugs or placebos).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eTrial interventions\u003c/h2\u003e\n\u003cp\u003eParticipants are randomly assigned to receive one of the following interventions:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003ePCSK9i group (treatment group): The treatment group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks. No medication dose adjustment during the study period.\u003c/p\u003e\n\u003cp\u003eDrug injections are completed by dedicated nurses after each hemodialysis session.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eNo Intervention (control group): There was no additional intervention with lipid-lowering drugs in the control group.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy visits\u003c/h2\u003e\n\u003cp\u003eStudy recruitment opened on 2 October 2023. An overview of the trial is provided in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The researchers screen subjects according to inclusion criteria and exclusion criteria, after which the subject is randomized to the treatment or the control arm by 1:1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the treatment arm, the subjects are treated with Ribavirin 140mg iH q2w. In the control arm, the subjects are no intervention.\u003c/p\u003e\n\u003cp\u003eAll subjects will be followed up at 4 weeks, 12 weeks, 24 weeks and 48 weeks (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAs ultrasound is used as an imaging tool to monitor the AVF post-intervention for the study, ultrasound assessment of the AVFs will be performed by a trained operator. The diameter of vessels, volume flow rates at the mid-brachial artery and venous outflow will be recorded. The minimum diameter of each target lesion and Peak Systolic Velocity Ratio (PSVR) will be recorded. All participants will be followed up for up to 1 year. The window periods for the post-PTA visits are 1 month\u0026thinsp;\u0026plusmn;\u0026thinsp;1 week, 3 months\u0026thinsp;\u0026plusmn;\u0026thinsp;1 week, 6 months\u0026thinsp;\u0026plusmn;\u0026thinsp;4 weeks, and 12 months\u0026thinsp;\u0026plusmn;\u0026thinsp;4 weeks.\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, ultrasound assessment will be performed in each study site\u0026rsquo;s hemodialysis unit. The Duplex ultrasonography assessment includes patency of the AVF, volume flow rates at the mid-brachial artery and venous outflow, minimum diameter of each target lesion, and any new stenosis within the AVF circuit.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eObservation item\u003c/h2\u003e\n\u003cp\u003eDemographic data of subjects at baseline will be collected. The medical history of the patients, such as the primary cause of MHD, hypertension, diabetes, cardiovascular disease, cerebrovascular disease, the date of initiate dialysis, history of AVF surgery will be collected.\u003c/p\u003e\n\u003cp\u003eDialysis data including dialysis blood flow rate, venous pressure and arterial pressure will be collected at 4 weeks, 12 weeks, 24 weeks and 48 weeks of follow-up.\u003c/p\u003e\n\u003cp\u003eLaboratory examination data at baseline, 12 weeks, 24 weeks and 48 weeks of follow-up, such as white cell count, Hb, platelet, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total protein, total bilirubin, PH, HCO3\u0026ndash;,K+, Na+, Cl\u0026ndash;, albumin, total cholesterol, triglyceride, Low density lipoprotein (LDL), High density lipoprotein (HDL), calcium, phosphorus, iPTH, ferritin, fasting blood glucose, C reactive protein, \u0026beta;2-microglobulin, B natriuretic peptides, thiamine, folic acid and homocysteine will be collected. Access recirculation and dialysis adequacy (spKt/V) will be calculated.\u003c/p\u003e\n\u003cp\u003eUltrasound examination will be done at baseline, 4 weeks, 12 weeks, 24 weeks and 48 weeks of follow-up.\u003c/p\u003e\n\u003cp\u003eCollect information on internal fistula re intervention and intervention methods.\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n\u003ch2\u003eData statement\u003c/h2\u003e\n\u003cp\u003eThe case report form is filled out by the investigator on time.\u003c/p\u003e\n\u003cp\u003eThe investigator must properly handle all the data obtained during the clinical trial, and truthfully record all adverse events and serious adverse events during the clinical trial, so as to ensure the rights and privacy of the subjects participating in the clinical trial. Personal information of subjects will be collected, shared and maintained to protect confidentiality during and after the study. Only the project investigator will have access to the final trial data set.\u003c/p\u003e\n\u003cp\u003eA data monitoring committee is composed of clinicians and biostatisticians from Clinical Centre for Investigation, Renji Hospital, School of Medicine, Shanghai Jiao Tong University who are not involved in this study for the purpose of ensuring the safety of subjects and the quality of study data.\u003c/p\u003e\n\u003cp\u003eData sharing statement No later than 3 years after the collection of the 1-year post-randomization interviews, we will deliver a completely deidentified data set to an appropriate data archive for sharing purposes.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis technique\u003c/h2\u003e\n\u003cp\u003eThe clinical data of this project was analyzed using SPSS statistical software. Continuous variables are represented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median, quartile range depends on distribution, while categorical variables are represented as absolute and relative frequencies. Use independent t-test or Wilcoxon rank sum test to test for differences between two groups of continuous variables, while categorical variables use \u0026chi; 2 or Fisher's exact test. Bilateral \u0026alpha; level of 0.05 is defined as having statistical significance.\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eValidity analysis: main endpoint events, secondary endpoint events, adverse events, etc. were analyzed using the full analysis set and per protocol set, respectively.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eIf there are concomitant medications, describe them in two aspects: past and during the treatment process.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eStatistical analysis summary: after completing the statistical analysis, write a statistical analysis report.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eEthics and dissemination\u003c/h2\u003e\n\u003cp\u003eThis trial has been approved by Shanghai Jiao Tong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A). Other participating subcenters must also obtain ethics committee approval documents prior to the start of clinical trials. The GCP19 regulations shall be strictly followed during the test implementation. Amendments to the protocol will be reviewed by ethics committees. Informed consent (2.1 20230615) will be obtained before collecting any patient data and patient information. After publication of study results, trial report will be published in peer-reviewed journals and/or in national or international conferences. All researchers involved in the design, discussion and writing of this study protocol, as the authors.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eHarms\u003c/h2\u003e\n\u003cp\u003eEach participating investigator has primary responsibility for the safety of the individual participants under their care. Throughout the clinical trial, particular attention will be given to (serious) adverse events ((S)AEs). SAEs will be collected, documented and reported from enrollment to the end-of-study event or end-of-study date for each participant.\u003c/p\u003e\n\u003cp\u003eSubcutaneous injection of Ribavirin has a rare anaphylactic reaction. Safety endpoints are related directly to changes in laboratory safety indicators and incidence of adverse events between the treatment and control groups during follow-up. These endpoints will be listed according to the treatment received and recorded in detail. Participants will be followed up in detail; if any complications arise, appropriate treatment will be provided in accordance with current routine medical procedures.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eArteriovenous fistula (AVF) is the preferred type of vascular access for maintenance hemodialysis (MHD) patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The main cause of AVF dysfunction is stenosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The vascular pathway intervention rate is approximately 1.9 times per patient per year [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. With the development of interventional therapy recent studies have shown that the postoperative patency rate of PTA is comparable to that of open surgery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nevertheless, the durability of PTA is limited [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Previous studies have shown that due to the high incidence of restenosis, repeated intervention is often required after PTA surgery, with reported patency rates of 61%, 42%, and 35% at 6, 12, and 24 months, respectively [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo reduce the risk of dysfunction recurrence after intervention, drug-coated balloons (DCB) are used in the treatment of vascular stenosis in hemodialysis. Paclitaxel is an anti-proliferative substance that stabilizes the microtubule structure of cells and is the most commonly chosen drug for coating these balloons. A multicenter study in China shows that paclitaxel drug-coated balloons (PCB) can reduce the risk of restenosis at 6 months compared to conventional high-pressure balloon, but the target lesion and target shunt intervention-free survival was no statistically significant difference [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The impact of DCB mainly focuses on the target lesion itself, rather than the pathway circuit or hemodynamic changes related to angioplasty. Multiple factors limit the efficacy of DCB.\u003c/p\u003e \u003cp\u003eIn previous studies on factors related to hemodialysis pathway stenosis, it has been shown that dyslipidemia is significantly correlated with a shorter initial patency rate and an important predictive factor for secondary loss of patency [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The study also found that the use of statins is associated with increased primary and secondary patency rates [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, there is still a lock of prospective studies on the improvement of patency rate using lipid-lowering drugs after PTA in clinical.\u003c/p\u003e \u003cp\u003eThe commonly used lipid-lowering drugs in clinical are hydroxymethylglutaryl CoA reductase inhibitors, with limited lipid-lowering effects. Previous large-scale researches have shown no significant benefits of HMG-CoA reductase inhibitors on clinical cardiovascular and mortality endpoints in MHD patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In uremic environments, the progression of calcification induced by HMG-CoA reductase inhibitors may potentially exacerbate the already severely elevated cardiovascular risk [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePCSK9 inhibitors are a new type of lipid-lowering drugs that can effectively reduce low-density lipoprotein (LDL) levels and improve the LDL compliance rate [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In cardiovascular research, it has been found that PCSK9 inhibitors can prevent vascular calcification and have certain cardiovascular protection advantages [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Small sample studies have been conducted using PCSK9 inhibitors in MHD patients. Studies have shown that PCSK9 inhibitors have good lipid-lowering effects in both MHD patients and non-dialysis patients, and using the same dose as non-dialysis patients is safe in MHD patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAVF is the lifeline of MHD patients. With the development of interventional therapy, PTA is easy to operate and reduces patient pain. The use of PCB can prolong the no angioplasty time for AVF undergoing PTA surgery. In order to better prolong the long-term life of AVF, increase the durability of PTA, that delaying postoperative restenosis has become one of the research focuses. MHD patients are generally associated with cardiovascular disease or have a high risk of cardiovascular disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. PCSK9 inhibitors are safe and effective for MHD patients.\u003c/p\u003e \u003cp\u003eThis exploratory study would be conducted to evaluate the efficacy and safety of PCSK9 inhibitors in the patency of AVF after paclitaxel release balloon surgery. Expected to improve restenosis rate and extend the service life of AVF.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThe protocol version number and date: 1.1 2023.6.15\u003c/p\u003e \u003cp\u003eThe date recruitment began: 2023.10.20\u003c/p\u003e \u003cp\u003eThe approximate date when recruitment will be completed: 2025.12.31\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAVF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earteriovenous fistula\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emaintenance hemodialysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercutaneous transluminal angioplasty\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow-density lipoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earteriovenous fistula recirculation rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSVR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeak Systolic Velocity Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDCB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edrug-coated balloons\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epaclitaxel drug-coated balloons.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis trial has been approved by Shanghai Jiao Tong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eYX, LG and RL were responsible for the design of the entire study, including the drafting, revision and submission of clinical trial protocols. HZ, YZ, YF, MZ and XZ are responsible for the discussion and revision of clinical trial protocol. YX and LG is responsible for the design of statistical methods. YX and RL is in charge of the pharmacological mechanisms and dosage selection of experimental drugs. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOh D-J, Lee JH, Kwon YE, et al. Relationship Between Arteriovenous Fistula Stenosis and Circulating Levels of Neutrophil Granule Proteins in Chronic Hemodialysis Patients. Ann Vasc Surg. 2021;77:226\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharmaine E, Lok TS, Huber T, Lee, et al. KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update. Am J Kidney Dis. 2020;75:S1\u0026ndash;164.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai C, Kilari S, Zhao C, et al. Therapeutic Effect of Adipose Derived Mesenchymal Stem Cell Transplantation in Reducing Restenosis in a Murine Angioplasty Model. J Am Soc Nephrol. 2020;31:1781\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim SM, Ko HK, Noh M, et al. Factors Affecting Patency following Successful Percutaneous Intervention for Dysfunctional Hemodialysis Vascular Access. Ann Vasc Surg. 2018;47:54\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharles J, Ferro PB, Mark M, Kanbay, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol. 2018;14:727\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCara East K, Bass A, Mehta, et al. Alirocumab and Lipid Levels, Inflammatory Biomarkers, Metabolomics, and Safety in Patients Receiving Maintenance Dialysis: The ALIrocumab in DIALysis Study (A Phase 3 Trial to Evaluate the Efficacy and Safety of Biweekly Alirocumab in Patients on a Stable Dialysis Regimen). Kidney Med. 2022;4:100483.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharmaine E. Lok. Fistula Interventions: Less Is More. J Am Soc Nephrol. 2019;30:2040\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUlrika Hahn Lundstr\u0026ouml;m G, Welander JJ, Carrero, et al. Surgical versus endovascular intervention for vascular access thrombosis: a nationwide observational cohort study. Nephrol Dial Transpl. 2022;37:1742\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElramah M, Boujelbane L, Yevzlin AS, et al. Dialysis access venous stenosis: treatment with balloon angioplasty 30-second vs. 1-minute inflation times. Hemodial Int. 2015;19:108\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBountouris I, Kristmundsson T, Dias N et al. Is repeat PTA of a failing hemodialysis fistula durable? Int J Vasc Med 2014;369687.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYanqi Yin Y, Shi T, Cui, et al. Efficacy and Safety of Paclitaxel-Coated Balloon Angioplasty for Dysfunctional Arteriovenous Fistulas: A Multicenter Randomized Controlled Trial. Am J Kidney Dis. 2021;78:19\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAn S, De Vriese. Should Statins Be Banned from Dialysis? J Am Soc Nephrol. 2017;28:1675\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuichi Ikegami I, Inoue K, Inoue, et al. The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. NPJ Aging Mech Dis. 2018;4:7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheung AK, Sarnak MJ, Yan G, et al. Atherosclerotic cardiovascular disease risk in chronic hemodialysis patients. Kidney int. 2000;58:353\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Arteriovenous fistula (AVF), percutaneous transluminal angioplasty (PTA), PCSK9 inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-4433992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4433992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArteriovenous fistula (AVF) is the preferred type of vascular access for maintenance hemodialysis (MHD) patients. Stenosis is the main cause of AVF dysfunction. The K/DOQI guidelines suggest that the use of percutaneous transluminal angioplasty (PTA) as the primary treatment for AVF stenosis is reasonable. However, the durability of PTA is limited. This trial aims to determine: the effect of using paclitaxel release balloons combined with PCSK9 inhibitors on improving postoperative patency of AVF and the safety of combined use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a prospective, randomized, controlled study. It is exploratory research. The study will recruit 40 MHD patients aged from 18 to 75 years, with an intervention period of 48 weeks. Patients will be randomized into two arms: (1) The treatment group received postoperative use of 140 mg of Ribavirin, subcutaneously administered every two weeks for a total of 48 weeks. (2) Control group no Intervention. The primary outcome is the main patency rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is an exploratory study which would be conducted to evaluate the efficacy and safety of PCSK9 inhibitors in the patency of AVF after paclitaxel release balloon surgery. Expected to improve restenosis rate and extend the service life of AVF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is approved by Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (LY2023-113-A). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical trials ID\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNCT06034691\u003c/p\u003e\n\u003cp\u003e09/10/2023\u003c/p\u003e","manuscriptTitle":"Exploratory Research of PCSK9 Inhibitor on Patency of Autogenous Arteriovenous Fistula After Percutaneous Transluminal Angioplasty with Paclitaxel Releasing Balloon: study protocol for a prospective, randomized, controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 02:31:20","doi":"10.21203/rs.3.rs-4433992/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-03-09T15:21:47+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-07-20T16:31:55+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-18T10:13:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-09T12:04:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-05-29T10:09:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"79407a4e-c6f9-4557-9f48-50874715fc6b","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-12T05:51:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-17 02:31:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4433992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4433992","identity":"rs-4433992","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}