Mid-term patency of iliac venous stenting for Non-Thrombotic May-Thurner Syndrome: a systematic review with meta-analysis

2020/2021 Ana Teresa MelandaAlves Patência a médio prazo do stent ilíaco venoso no síndrome de MayThurner Não Trombótico: revisão sistemática com meta-análise Mid-term patency of iliac venous stenting for Non-Thrombotic MayThurner Syndrome: a systematic review with meta-analysis MARÇO, 2021 Mestrado Integrado em Medicina Área: ciências médicas e da saúde Tipologia: Dissertação Trabalho efetuado sob a Orientação de: Doutor Armando Amílcar Pires Mansilha Rodrigues de Almeida E sob a Coorientação de: Dr. José Pedro Oliveira Pinto Trabalho organizado de acordo com as normas da revista: International Angiology Ana Teresa MelandaAlves Patência a médio prazo do stent ilíaco venoso no síndrome de MayThurner Não Trombótico: revisão sistemática com meta-análise Mid-term patency of iliac venous stenting for Non-Thrombotic MayThurner Syndrome: a systematic review with meta-analysis MARÇO, 2021 DEDICATÓRIA Aos meus pais e irmã pelo apoio incondicional. Ao Rúben pela força e dedicação. À Anabela e ao Manuel António pelo carinho e apoio. 1 Mid-term patency of iliac venous stenting for Non-Thrombotic May-Thurner Syndrome: a systematic review with meta-analysis Teresa ALVES 1 *, José OLIVEIRA-PINTO 1,2 *, Armando MANSILHA 1,2 1University of Porto, Faculty of Medicine, Porto, Portugal; 2Department of Angiology and Vascular Surgery, Hospital São João, Porto, Portugal * These authors have equally contributed for this manuscript Corresponding author: Teresa Alves, University of Porto, Faculty of Medicine, Al. Prof. Hernâni Monteiro 4200, 319, Porto, Portugal. E-mail: anateresam[email protected] 2 WHAT THIS PAPER ADDS Iliac venous stenting has become a proeminent therapeutic choice for patients with symptomatic May-Thurner Syndrome (MTS), either as post-thrombotic syndrome or in its non-thrombotic form (NIVL). This systematic review evaluates long-term performance of venous stenting on NIVL. Among eligible studies, very good patency rates at 36 months were found, with low associated complications rate. Additionally, a significant clinical improvement was registered since an important patients` proportion reported symptoms relief before and after iliac venous stenting. This meta-analysis shows that iliac venous stenting may be a secure and durable technique for NIVL treatment, although more research is needed. 3 ABSTRACT INTRODUCTION: May-Thurner syndrome (MTS) consists in a compression of the left common iliac vein by the right common iliac artery. Iliac venous stenting represents one of the landmark treatments for symptomatic Non-Thrombotic iliac vein lesion (NIVL). The aim of this systematic review is to evaluate the mid-term patency of iliac venous stenting and assess the symptomatic relief before and after stenting. EVIDENCE ACQUISITION: Two databases were searched: Medline and Scopus. The last analysis was performed in September 2020. The articles were independently reviewed through their titles and abstracts. All studies that reported patients with NIVL submitted to iliac stenting were included. EVIDENCE SYNTHESIS: Twelve articles were included in the analysis, totaling 1053 patients with NIVL submitted to iliac stenting, with a proportion of 95.2%. Among twelve articles, six reported primary stent patency after 12 months, with a combined proportion of 94.8%, and three studies evaluated the primary patency after 36 months reporting 96.8%. Four studies reported secondary patency, ranging from 100% to 91% during a follow-up of 18 months and 36 months respectively. Finally, some studies reported a clinical improvement, but only one of them quantified the global clinic improvement of 95.7% after endovascular treatment. Relatively to specific symptoms one study reported 58.5% of edema relief and other an edema cure rate over than 90% and an ulcer healing of 85.0%. CONCLUSIONS: Iliac venous stenting is a safe and durable treatment in patients with NIVL, with a reduced rates of stent thrombosis and an important incidence of symptoms relief. Key words: May-Thurner syndrome; Non-Thrombotic iliac vein lesions; stent; iliac vein 4 INTRODUCTION May-Thurner syndrome (MTS) is a vascular condition in which the left common iliac vein is compressed by the right common iliac artery, occurring mostly on the left side due to iliac vein course (1, 2). It presents itself in two major forms: thrombotic, also known as post-thrombotic syndrome, and non-thrombotic (NIVL). The exact prevalence and incidence of MTS are unknown since only a small percentage of patients develop symptoms (3). It is estimated that 2-5% of acute lower venous disorders are caused by MTS and, according to Kibbe et al, 24% patients with more than 50% of left common iliac vein stenosis do not have symptoms (1, 4). The progression of venous outflow obstruction with symptoms of chronic venous hypertension is possible with or without thrombosis, but in fact iliofemoral thrombosis increases the severity of the symptoms and the risk of post-thrombotic syndrome (5). Clinical features of MTS include acute pain, asymmetric swelling, venous claudication and symptoms/signs of venous insufficiency, such as edema, skin hyperpigmentation and ulcers (6, 7). Management of MTS has progressed through the years mainly due to the increased awareness of the disease and technological developments (8). Nowadays, endovascular techniques are preferred over conservative treatment, targeting symptoms’ relief, the recovery of venous flow and preventing post-thrombotic syndrome (9). Iliocava stenting has been increasingly applied, however, there is still controversy regarding primary stenting in this cohort of patients (9, 10). The aim of this study is to assess mid-term patency of venous iliac stenting for NIVL along with symptomatic improvement. 11 90% (13) in patients diagnosed with NIVL. In the future, prospective studies comparing stenting efficacy in symptomatic improvement with conservative treatment is warranted. Limitations of the study Limitations can be associated with this systematic review that affect these conclusions. Firstly, only two databases were used which could have led to unnoticed data. Furthermore, only a small number of studies was eligible for the meta-analysis process, hindering all conclusions on the impact of the endovascular procedure in patients diagnosed with NIVL. Finally, only a restrict number of studies described the characteristics of patients diagnosed with NIVL and submitted to stent procedures. Due to these major limitations, heterogeneity can be high in the present study and could have increased the risk of potential bias in the review process. Conclusion In conclusion, iliac venous stenting can be considered safe and durable in midterm treatment of patients with NIVL, reporting a low proportion of thrombosis and a significant improvement of clinical symptoms. Yet, larger studies with longer follow-up is required to ascertain procedural durability. 12 REFERENCES 1. Bondarev S, Keller EJ, Han T, Young VA, Gupta S, Vogelzang RL, et al. Predictors of Disease Recurrence after Venoplasty and Stent Placement for May–Thurner Syndrome. J Vasc Interv Radiol. 2019;30(10):1549-54. 2. Aldag M, Bademci MS, Kocaaslan C, Oztekin A, Aydin E. Clinical outcomes of pharmacomechanical thrombectomy and iliac venous stenting in iliac vein thrombosis with May-Thurner Syndrome. International Angiology. 2019;38(1):76-7. 3. Liu Z, Gao N, Shen L, Yang J, Zhu Y, Li Z, et al. Endovascular treatment for symptomatic iliac vein compression syndrome: A prospective consecutive series of 48 patients. Annals of Vascular Surgery. 2014;28(3):695-704. 4. 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Endovascular treatment for iliac vein compression syndrome with or without lower extremity deep vein thrombosis: A retrospective study on mid-term in-stent patency from a single center. European Journal of Radiology. 2016;85(1):7-14. 19. Derubertis BG, Alktaifi A, Jimenez JC, Rigberg D, Gelabert H, Lawrence PF. Endovascular management of nonmalignant iliocaval venous lesions. Annals of Vascular Surgery. 2013;27(5):577-86. 20. Xu J, Liu Y, Zhou W. Mid-and long-term efficacy of endovascular-based procedures for Cockett syndrome. Scientific Reports. 2018;8(1). 21. Zhang X, Jing Y, Sang H, Chen Z, Sun Y, Li X. Long-term follow-up of the stenting across the iliocaval confluence in patients with iliac venous lesions. Journal of Thrombosis and Thrombolysis. 2019;47(1):134-9. 22. Seager MJ, Busuttil A, Dharmarajah B, Davies AH. Editor's Choice - A Systematic Review of Endovenous Stenting in Chronic Venous Disease Secondary to Iliac Vein Obstruction. European Journal of Vascular and Endovascular Surgery. 2016;51(1):100-20. 14 23. Raju S. Best management options for chronic iliac vein stenosis and occlusion. Journal of Vascular Surgery. 2013;57(4):1163-9. 24. Black SA, Alvi A, Baker SJ, Beckett D, Breen K, Burfitt NJ, et al. Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus. Int Angiol. 2020;39(1):3-16. 15 Conflicts of interest. - The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Funding. - The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. Authors’ contributions. – Teresa Alves and José Oliveira-Pinto equally contributed to this manuscript. All authors read and approved the final version of the manuscript. 16 TABLES Table I: Quality assessment employing the Newcastle-Ottowa Quality Assessment Scale (NOS) Author Year Type of Study n Selection Comparability Outcome Lou(12) 2009 Retrospective Study 38 3 1 2 Meng(13) 2011 Retrospective Study 272 3 0 3 Hager(14) 2013 Retrospective Multi Centre Study 19 3 0 3 DeRubertis(19) 2013 Retrospective analysis 7 3 0 2 Liu(3) 2014 Prospective Cohort Study 36 3 0 3 Rollo(15) 2015 Retrospective Study 18 3 1 3 Shi(18) 2016 Retrospective Case Series Study 66 3 0 3 Ahmed(17) 2016 Retrospective Single Centre Study 23 3 0 2 Jayaraj(16) 2018 Retrospective Study 202 3 0 3 Xu(20) 2018 Retrospective Single Centre Study 151 2 0 2 Attaran(11) 2019 Retrospective Single Centre Study 45 3 0 3 Zhang(21) 2019 Retrospective Multi Centre Study 177 3 0 3 17 Table II: Study characteristics and patients with NIVL submitted to stent. Study Year No. patients with NIVL Patients with NIVL submitted to stent No. % Lou(12) 2009 39 38 97.4% Meng(13) 2011 296 272 91.9% Hager(14) 2012 19 19 100.0% DeRubertis(19) 2013 11 7 63.6% Liu(3) 2014 42 35 83.3% Rollo(15) 2015 32 18 56.3% Shi(18) 2016 66 66 100.0% Ahmed(17) 2016 34 23 67.6% Jayaraj ≤60%(16) 2018 55 55 100.0% Jayaraj 61-89%(16) 2018 87 87 100.0% Jayaraj ≥90% (16) 2018 60 60 100.0% Xu(20) 2018 181 151 83.4% Attaran(11) 2019 45 45 100.0% Zhang(21) 2019 177 177 100.0% 18 Table III: Patient demographic characteristics. NR: Non reported Author Year Female Gender (%) Mean Age (years) Mean time of follow-up (months) Clinical symptoms Pain (%) Swelling (%) Lou(12) 2009 NR NR 10.2 NR NR Meng(13) 2011 160/296 (54.1) 43 46 NR 98/296 (32.4) Hager(14) 2013 14/19 (73.7) 52.8 22.4 NR NR DeRubertis(19) 2013 NR NR 9.6 11/11 (100.0) 11/11 (100.0) Liu(3) 2014 24/36 (66.7) 39.4 12 15/36 (41.7) 17/36 (47.2) Rollo(15) 2015 24/32 (75.0) 46 24 25/32 (78.1) 32/32 (100.0) Shi(18) 2016 NR NR 72 NR NR Ahmed(17) 2016 NR NR 21.3 NR NR Jayaraj ≤60%(16) 2018 46/55 (83.6) 57 94 NR NR Jayaraj 61-89%(16) 73/87 (83.9) 55 NR NR Jayaraj ≥90%(16) 46/60 (76.7) 54 NR NR Xu(20) 2018 100/181 (55.2) 44 26.4 NR NR Attaran(11) 2019 32/45 (71.1) 53.9 18 NR NR Zhang(21) 2019 NR NR 62 NR NR 19 Table IV: Patient demographic characteristics – continued. NR: Non reported Author Diabetes Mellitus (%) Hypertension (%) Hypercoagulable state (%) Lou(12) NR NR NR Meng(13) NR NR NR Hager(14) 3/19 (15.8) 7/19 (36.8) 0 (0.0) DeRubertis(19) NR NR NR Liu(3) NR NR NR Rollo(15) NR NR 7/32 (31.8) Shi(18) NR NR NR Ahmed(17) NR NR NR Jayaraj ≤60%(16) NR NR 20/55 (36.4) Jayaraj 6189%(16) NR NR 38/87 (43.7) Jayaraj ≥90%(16) NR NR 31/60 (51.7) Xu(20) NR NR NR Attaran(11) NR NR 1/45 (2.2) Zhang(21) NR NR NR 20 Table V: Procedural details. Author Device (stent) Anticoagulation protocol Lou(12) Luminexx stent LMWH 3-5 days + Warfarin 1-6 months Meng(13) NR NR Hager(14) Protegè stent Heparin bolus intraprocedure AAS + Clopidogrel 3 months + compression stockings DeRubertis(19) Protegè stent or Wallstent Heparin intraprocedure + AAS+Clopidogrel 3 months + Strict compression therapy Liu(3) Wallstent LMWH 4,000IU 12-12h 3 days + warfarin 6 months + compression stockings 3 months Rollo(15) Self-expanding stainless steel stents LMWH intraoperative + AAS+Clopidogrel 3months Shi(18) Luminexx stent LMWH initially + warfarin ≥6months + elastic stockings ≥1y Ahmed(17) S.M.A.R.T stent or Wallstent LMWH before + enoxaparin 2x/d 14days + compression stockings Jayaraj ≤60%(16) Wallstent-Z stent +/- Cook Gianturco Z stent Perioperative LMWH 40mg + Bivalirudina intraoperative + Oral anticoagulants ≥ 3 months + aspirin 81mg+cilostazol 50mg 2x/d ≥ 6 weeks Jayaraj 61-89%(16) Jayaraj ≥90%(16) Xu(20) COOK 1880 Z stent; Wallstent; Luminexx stent; Optimed sinus stent or Protegè stent Warfarin 6-12 months + elastic stockings 6m-1y Attaran(11) Wallstent endoprothesis Intravenous heparin during intervention Anticoagulation after procedure Zhang(21) Luminexx stent or Sinus XL stent LMWH 5-7 days + Anticoagulation or antiplatelet + compression stockings 27 Figure 5 - Forest plot representing the pooled proportion of Stent Thrombosis. A fixed effects model was used for meta-analysis. Study 95% Study Weight Proportion CI Heterogeneity: I2=44.75%; Q=7.24; p=0.124 AGRADECIMENTOS Esta importante jornada da minha vida termina para dar lugar a outra que espero que seja recheada de vitórias e muitas alegrias. Contudo, nada teria sido possível sem um conjunto de pessoas: Ao Professor Doutor Armando Mansilha pela disponibilidade em aceitar ser meu tutor na tese final. Ao Professor José Pedro Pinto pela co-orientação, por ter estado sempre disponível para me auxiliar na elaboração deste trabalho e por ter esclarecido sempre as minhas dúvidas. Por fim, à minha família e ao meu namorado por terem estado sempre disponíveis para me ouvir e por contribuírem ativamente na minha vida académica. Sem eles esta longa jornada teria sido muito mais difícil. Aos meus pais e irmã que mesmo longe todos os dias me davam força e ânimo para ultrapassar as adversidades. Ao Rúben Calaia por ser um “porto seguro”. ANEXOS Anexo I - PRISMA Statement - Checklist of items that should be included in systematic review and meta-analysis. Section/topic # Checklist item Reported on page and paragraph/ table # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. - MANDATÓRIO Page 1: “Mid-term patency of iliac venous stenting for Non-Thrombotic May-Thurner Syndrome: a systematic review with meta-analysis” ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. – SEGUIR RECOMENDAÇÕES DA REVISTA Page 3: “INTRODUCTION: May-Thurner syndrome (MTS) consists in a compression of the left common iliac vein by the right common iliac artery. Iliac venous stenting represents one of the landmark treatments for symptomatic Non-Thrombotic iliac vein lesion (NIVL). The aim of this systematic review is to evaluate the mid-term patency of iliac venous stenting and assess the symptomatic relief before and after stenting. EVIDENCE ACQUISITION: Two databases were searched: Medline and SCOPUS. The last analysis was performed in September 2020. The articles were independently reviewed through their titles and abstracts. All studies that reported patients with NIVL submitted to iliac stenting were included. EVIDENCE SYNTHESIS: Twelve articles were included in the analysis, totaling 1053 patients with NIVL submitted to iliac stenting, with a proportion of 95.2%. Among twelve articles, six reported primary stent patency after 12 months, with a combined proportion of 94.8%, and three studies evaluated the primary patency after 36 months reporting 96.8%. Four studies reported secondary patency, ranging from 100% to 91% during a follow-up of 18 months and 36 months respectively. Finally, some studies reported a clinical improvement, but only one of them quantified the global clinic improvement of 95.7% after endovascular treatment. Relatively to specific symptoms one study reported 58.5% of edema relief and other an edema cure rate over than 90% and an ulcer healing of 85.0%. CONCLUSIONS: Iliac venous stenting is a safe and durable treatment in patients with (NIVL), with a reduced rates of stent thrombosis and an important incidence of symptoms relief.” INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. – MANDATÓRIO O rationale corresponde à justificação da importância da revisão sistemática Page 4: “Iliocava stenting has been increasingly applied, however, there is still controversy regarding primary stenting in this cohort of patients.” Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). - MANDATÓRIO Page 4: “The aim of this study is to assess mid-term patency of venous iliac stenting for NIVL along with symptomatic improvement.” METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. – FACULTATIVO NA Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. – MANDATÓRIO É altamente recomendado, de acordo com as boas práticas da Cochrane, que não sejam aplicados critérios de exclusão baseados na língua e/ou data de publicação dos estudos. Page 5: “The eligibility criteria for study selection were determined in advance. Inclusion criteria consisted of publications reporting iliac venous stenting for Non-Thrombotic iliac vein lesions (NIVL) subtype of MTS. Exclusion criteria were determined as following: articles published before 2000; reports in non-English languages; non-human studies; systematic reviews and meta-analysis; case reports with less than 10 patients; articles reporting iliac venous stenting after post-thrombotic syndrome; articles reporting MTS with thrombosis.” Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. – MANDATÓRIO Em consonância com as boas práticas da Cochrane, é mandatório que se verifique pesquisa em pelo menos duas bases de pesquisa bibliográfica (idealmente, deverão ser pesquisadas duas bases generalistas e uma específica da área). No caso de revisões sistemáticas de estudos experimentais/ensaios clínicos aleatorizados, é altamente recomendado que uma das bases pesquisadas corresponda à CENTRAL ou a bases de ensaios clínicos como a ClinicalTrials.gov. Page 5: “…a systematic review was performed in compliance with PRISMA Statement framework and focusing on Medline and Scopus databases.”, “…last search for reports was performed on September 8, 2020.” Estudos de revisão da literatura em que a pesquisa decorra numa única base de dados não serão classificados como revisões sistemáticas. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. – MANDATÓRIO A query de pesquisa deve ser obrigatoriamente disponibilizada. A utilização de filtros de pesquisa da InterTASC é altamente recomendada (https://sites.google.com/a/york.ac.uk/issg-search-filtersresource/home) Page 5: “Medline: (((((stent[MeSH Terms]) OR (stent[MeSH Terms])) OR (Venous stent)) OR (Venous stenting) OR (Endovascular Procedures[MeSH Terms] ) AND (((((May-Thurner Syndrome[MeSH Terms]) OR (Chronic venous insufficiency)) OR (iliac vein stenosis)) OR (iliac vein compression syndrome)) OR (non thrombotic iliac vein lesions))) AND ((((((vein[MeSH Terms]) OR (vein)) OR (venous[MeSH Terms])) OR (venous)) OR (iliac vein[MeSH Terms])) OR (iliac vein)); - Scopus: (ALL (iliac AND vein)) AND (ALL (may-thurner AND syndrome) OR ALL (nonthrombotic AND iliac AND vein AND lesions)) AND (ALL (venous AND stent) OR AND (venous AND stenting)).” Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the metaanalysis). – MANDATÓRIO As fases de selecção dos estudos primários devem ser descritas. Em consonância com as boas práticas da Cochrane, é mandatório que o processo de selecção envolva duas fases (fase de rastreio, em que os registos são seleccionados por título e abstract, e fase de inclusão, na qual se procede à leitura integral dos full texts). Em cada uma destas fases, o processo de selecção deve mandatoriamente envolver dois investigadores actuando de forma independente. Figure 1 Page 5: “The eligibility criteria for study selection were determined in advance. Inclusion criteria consisted of publications reporting iliac venous stenting for Non-Thrombotic iliac vein lesions (NIVL) subtype of MTS.” Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. – MANDATÓRIO Trata-se de descrever de que forma se procedeu à extracção de dados dos estudos primários. Em consonância com as boas práticas da Cochrane, tal processo deverá envolver dois investigadores de forma independente. Page 6: “The two reviewers (TA and JOP) working independently determined each study’s eligibility. After this initial process, the articles were further analyzed and the reviewers extracted descriptive, methodological data and results from each study. Disagreements were discussed with a third reviewer (AM), as stated in the “Study Selection” section.” Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. – MANDATÓRIO Trata-se de descrever as variáveis para as quais foi obtida informação. Page 6: “…year of publication; number of patients with NIVL; number of stents in NIVL group; primary patency of the stent after 12 and/or 36 months; secondary patency of the stent; number of stent thrombosis; signs and symptoms relief after procedure; and procedural details as implanted device and anticoagulation protocol. When available, the demographic characteristics of patients were also collected… Risk of bias in individual studies / Risk of bias across studies 12/ 15 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. – MANDATÓRIO Em todas as revisões sistemáticas, deverá existir um processo de avaliação da qualidade dos estudos primários. No caso de revisões sistemáticas de estudos experimentais/ensaios clínicos aleatorizados, a aplicação dos critérios de risco de viés (Risk of Bias) da Cochrane é altamente recomendada. No caso de revisões sistemáticas de estudos observacionais, poderão ser seguidos os critérios ROBINS ou os critérios dos National Institutes of Health (https://www.nhlbi.nih.gov/health-topics/study-quality-assessmenttools). Page 6: “Newcastle-Ottowa Quality Assessment Scale (NOS) was used to assess studies for their risk of bias.” Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). – FACULTATIVO. APENAS NECESSÁRIO SE FOR FEITA META-ANÁLISE Page 6: “Combined proportion was used to calculate the percentage of patients with NIVL submitted to iliac venous stenting and to calculate the mid-term patency of the stent. The number of stent thrombosis was also evaluated by combined proportion.” Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each metaanalysis. – FACULTATIVO. APENAS NECESSÁRIO SE FOR FEITA META-ANÁLISE Page 7: “In this meta-analysis, it was determined that if I2 exceeded 50% a random effects model would be applied, otherwise a fixed effect model was to be used.” Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. – FACULTATIVO. APLICÁVEL APENAS SE FOR FEITA META-ANÁLISE NA RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. – MANDATÓRIO Figure 1 Page 8: “The PRISMA flow diagram represented in Figure 1 shows the research progress.” Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. – MANDATÓRIO Tables III, IV and V. Page 8: “The characteristics of the studies and patients are presented in Table III and IV. The type and combination of implanted stents varied in each study. Twelve articles included in this systematic review referred to the intraprocedural and/or post-procedural anticoagulation protocol with an average duration of 3-6 months. The procedural details are presented in Table V.” Risk of bias within and across studies 19/ 22 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). – MANDATÓRIO Table I: “Quality assessment employing the Newcastle-Ottowa Quality Assessment Scale (NOS)” Page 6: “Newcastle-Ottowa Quality Assessment Scale (NOS) was used to assess studies for their risk of bias. This scale evaluated all studies on three categories: patient selection method, comparability of the study group and evaluation of relevant outcomes.” Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. – FACULTATIVO. APLICÁVEL APENAS SE FOR FEITA META-ANÁLISE Figures 2, 3, 4 and 5. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. – FACULTATIVO. MANDATÓRIO APENAS SE FOR FEITA META-ANÁLISE Page 9: “…pooled proportion for this outcome was 94.8% (95% CI 0.92; 0.98; I2 = 64.56%)…”; “…combined proportion of stent patency was 96.8% (95% CI 0.95; 0.98; I2 = 0.00%)…”; “…combined proportion obtained in the meta-analysis was 2.24% (95% CI 0.01; 0.03; I2 = 44.75%)…” Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). – FACULTATIVO. APLICÁVEL APENAS SE FOR FEITA META-ANÁLISE NA DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). – MANDATÓRIO Page 10: “The present review reports excellent mid-term patency of iliac venous stenting for treatment of NIVL, with low thrombosis stent rate along with a significant symptomatic improvement.” Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). – MANDATÓRIO Page 11: “Limitations can be associated with this systematic review that affect these conclusions. Firstly, only two databases were used which could have led to unnoticed data. Furthermore, only a small number of studies was eligible for the meta-analysis process, hindering all conclusions on the impact of the endovascular procedure in patients diagnosed with NIVL. Finally, only a restrict number of studies described the characteristics of patients diagnosed with NIVL and submitted to stent procedures. Due to these major limitations, heterogeneity can be high in the present study and could have increased the risk of potential bias in the review process.” Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. – MANDATÓRIO Page 11: “In conclusion, iliac venous stenting can be considered safe and durable in mid-term treatment of patients with NIVL, reporting a low proportion of thrombosis and the significant improvement of clinical symptoms. Yet, larger studies with longer follow-up is required to ascertain procedural durability.” FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. – SEGUIR RECOMENDAÇÕES DA REVISTA Page 15: “Funding. - The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.” From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 Legend: NA – Not applicable AUTHORS Authors must meet the criteria for authorship established by the Uniform Requirements for Manuscripts Submitted to Biomedical Editors by the International Committee of Medical Journal Editors (ICJME). Author’s name must be written in full, middle name’s initial in capital letters and surname. 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