IJCS | Volume 31, Nº3, May/ June 2018

292 Martucheli et al. Cystatin C and acute coronary syndromes International Journal of Cardiovascular Sciences. 2018;31(3)290-307 Review Article Results In the initial search, 640 articles were identified, and 17 were included in this systematic review (Figure 1). The studies that met the eligibility criteria were published between 2004 and 2015; characteristics of these studies are described in Table 1. The studies included patients with ACS, 29.4% (n = 5) of them included STEMI patients only, 17.7% (n = 3) evaluated only patients with NSTEMI, 23.5% (n = 4) analyzed patients with unstable angina, STEMI andNSTEMI, and 17.7% (n = 3) examined patients with unstable angina and NSTEMI, and 11.7% (n = 2) evaluated patients with NSTEMI and STEMI. Among the studies evaluated, 35.3% (n = 6) used the recommended diagnostic criteria, 14 whereas 41.2% (n = 7) did not use these criteria; 23.5% (n = 4) did not report the criteria used. Sample size of these studies varied from 71 to 16,401 patients; it was greater than 1,000 in 23.5% of the studies (n = 4); 2 between 200 and 1,000 in 52.9% (n = 8) of the studies, and lower than 200 in 29.4% (n = 5) of the studies. Age of the study groups ranged from 31 to 82 years. Mean follow-up period was 15 months, varying from 1 month to 5 years. Patients were followed for 1-6 months in 35.3% (n = 6) of the studies and for more than 6 months in 64.7% (n = 11). In 52.9% (n = 9) of the studies, outcome measures were all-cause mortality and non-fatal cardiovascular events; 41.2% (n = 7) of them evaluated cardiovascular death and non-fatal cardiovascular events, and one study (5.9%) 3 analyzed all-cause mortality only. The methods for cystatin C measurement were immunonephelometry(41.2%[n=7]),immunoturbidimetry (41.2% [n = 7]), immunofluorimetry (5.9% [n = 1]) and immunoenzymatic assay (5.9% [n = 1]), and one study (5.9%) did not report the method used. In 88.2% (n = 15) of the studies, patients with normal and altered kidney function were included, whereas 11.8% (n = 2) of the studies included patients with normal kidney function only. Kidney function was assessed mostly by GFR (82.4% [n = 14]), followed by serum creatinine (17.6% [n = 3]). Classification criteria of patients, the variables included in the multivariate analysis and results of each study are described in Table 2. In 14 (82.3%) studies, patients were classified by cystatin levels, in 7 (41.2%) by quartiles, in 3 (17.6%) by tertiles. Two studies (11.8%) adopted the cutoff point to prevent cardiovascular events, one (5.9%) study used themedian values of cystatin C levels, another study used the reference value of the cystatin C measurement method (immunonephelometry), whereas 3 (17.6%) studies did not make this classification. Most studies (88.2%, n = 15) performed multivariate analysis; 58.8% (n = 10) of them included, among other variables, GFR or serum creatinine in this analysis. On the other hand, five studies (29.4%) included other variables than GFR or serum creatinine. All studies included in this systematic review assessed the association between increased cystatinC and outcome measures using odds ratio or relative risk and found a significant association between them. A significant association was found of increased cystatin C with cardiovascular events or all-causemortality in 47.1%(n= 8) of the studies, with cardiovascular events or cardiovascular mortality in 17.6% (n = 3), with cardiovascular events in 17.6% (n = 3) and with cardiovascular death or all-cause mortality in 17.6% (n = 3). In addition, 35.3% (n = 6) of the studies compared the proportion of patientswith increased cystatinC levelswho had outcomes with those who did not. This proportion was significantly greater for cardiovascular events in 2 (11.8%) studies, for cardiovascular events or all-cause mortality in two (11.8%), and for cardiovascular events or cardiovascular death in one study (5.9%). Only one (5.9%) study did not report a statistically significant difference between the proportions of patients with increased cystatin C levels who developed cardiovascular events or cardiovascular death in comparison with those with lower cystatin C levels who developed these outcomes. Analysis of the methodological quality of the studies is described in Table 3, with the criteria for assignment of the stars described in detail in the legend. Four (23.5%) studies showed good methodological quality and 13 (76.5%) showed excellent methodological quality. Only 5 studies compared the fourth and the first quartile of cystatinC and performedmultivariate analysis, including GFR and serum creatinine in this analysis. Of these, only 2 evaluated similar outcomes (cardiovascular death, non-fatal myocardial death), and thereby were included in the meta-analysis (Figure 2). Since the studies were heterogeneous (I2 < 0,001 e p = 0,621), the odds ratio was calculated using the random effect model. Results of the meta-analysis (OR = 1.65 [1.464 – 1.861], p < 0.001) indicate a significant association between increased levels of cystatin C and the risk of cardiovascular death or non- fatal myocardial infarction in ACS patients.