ABC | Volume 111, Nº6, December 2018

Original Article Einwoegerer & Domingueti Cystatin C and cardiovascular event or mortality Arq Bras Cardiol. 2018; 111(6):796-807 Methods This systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. 13 Articles Selection The articles selection was performed through the data bases Medline (PubMed) and Web of Science , using the descriptors “cystatin C”, “post-gamma-globulin”, “post‑gamma globulin”, “neuroendocrine basic polypeptide”, “basic polypeptide, neuroendocrine”, “cystatin 3”, “gamma‑trace”, “gamma trace”, combined with the descriptors “acute coronary syndrome”, “acute coronary syndromes”, “coronary syndrome, acute”, “coronary syndromes, acute”, “syndrome, acute coronary”, “syndromes, acute coronary”, “myocardial infarction”, “infarction, myocardial”, “infarctions, myocardial”, “myocardial infarctions”, “cardiovascular stroke”, “cardiovascular strokes”, “stroke, cardiovascular”, “strokes, cardiovascular”, “heart attack”, “heart attacks”, “myocardial infarct”, “infarct, myocardial”, “infarcts, myocardial”, “myocardial infarcts”, “myocardial ischemia”, “ischemia, myocardial”, “ischemias, myocardial”, “myocardial ischemias”, “ischemic heart disease”, “heart disease, ischemic”, “disease, ischemic heart”, “diseases, ischemic heart”, “heart diseases, ischemic”, “ischemic heart diseases”, using the connector “AND” between the terms. The Medical Subject Headings (MeSH) was used to define these descriptors. The selection of the articles was also performed in Scielo database, using the descriptors “cystatin C” with the Boolean operators “acute coronary syndrome”, “coronary disease”, “coronary heart disease”, “myocardial infarction”, “heart attack”, “cardiac attack”, “myocardial ischemia”, “heart disease, ischemic”, “ischemia, myocardial” and “ischemic heart disease” using AND connector between the terms. The Descriptors in Health Sciences (DeCS) was used to define these descriptors. Eligibility criteria The eligibility criteria were established according to the PRISMA recommendation, 13 and consist of prospective cohort observational studies written in English, Portuguese or Spanish evaluating the association between high levels of cystatin C, and the development of cardiovascular events or mortality in individuals with normal renal function. There was no restriction of the period of publication of articles in the research. PECOS strategy was used to elaborate the research question: 1. Population of interest: Individuals with normal renal function. 2. Exposure: High levels of cystatin C. 3. Outcome: Cardiovascular events or mortality. 4. Study Design: Prospective cohort. Extracting data from selected articles The following data were obtained from the studies that met the eligibility criteria: method used for measuring serum levels of cystatin C, patient group size, patient follow-up time, patient age range, criterion used to define normal renal function, outcome obtained in the study, outcome assessed, study population, patient classification, and parameters included in Cox proportional hazards multivariate regression analysis. Quality of the selected articles The methodological quality evaluation process of the studies included in the reviewwas carried out by two reviewers using the Newcastle-Ottawa Scale (NOS) 14 questionnaire for cohort studies, which contains the following categories of evaluation: cohort selection; comparability of the cohort and outcome. The quality of the study is indicated with a maximum of nine stars, with only one star being allowed to be assigned in the selection and outcome categories, and two stars in the comparability category. The articles reaching a score of five to six stars were considered as articles of good methodological quality, and those with seven or more stars were considered articles of excellent methodological quality. Meta-Analysis The meta-analysis included only those studies that assessed the outcome all-causemortality comparing the fourth quartile of cystatin C with the first quartile and that conducted multivariate regression analysis of Cox proportional hazards. The hazard ratio value and the 95% confidence interval adjusted by the multivariate regression analysis were used in the meta-analysis and the I 2 test was used to assess the heterogeneity among the studies. The studies were considered heterogeneous when I 2 > 50% and p < 0.10. When there was homogeneity, the hazard ratio was calculated using the fixed effect model. The distribution of the studies included in the meta-analysis was analyzed by a funnel plot. The statistical software Review Manager version 5.3 was used to perform the statistical analysis. The p value < 0.05 was considered significant. Results Literature search The initial search through the descriptors in the electronic databases resulted in a total of 647 articles. After completing the selection steps, 12 articles were included in the systematic review, and two were included in the meta-analysis. The flow chart for the selection of articles according to the eligibility criteria is presented in Figure 1. Characteristics and results of selected articles The studies that met the eligibility criteria were published between 2007 and 2016 and their characteristics are found in Table 1. Population The population of the studies analyzed consisted of patients at risk for cardiovascular events, 15 with ST-elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), 7,16 and stable coronary artery disease (CAD), 17,18 ACS, 17 patients undergoing percutaneous coronary intervention, 19 with congestive heart failure (CHF), 20,21 with 797