Cystatin C for Risk Stratification in Patients After an Acute Coronary Syndrome

Abstract

Background Cystatin C (Cys-C) is a marker of renal function that has shown prognostic value for cardiovascular risk stratification across different patient populations. The incremental value of Cys-C beyond established cardiac and renal biomarkers remains incompletely explored. Methods and Results SOLID - TIMI 52 (Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52; www.clinicaltrials.gov , NCT01000727) randomized patients ≤30 days post-acute coronary syndrome were treated with darapladib or placebo. The association between Cys-C and long-term risk (median follow-up 2.5 years) was assessed in 4965 individuals with adjustments made for clinical variables and other risk markers (eg, estimated glomerular filtration rate, high-sensitivity troponin I, brain-type natriuretic peptide, and fibroblast growth factor-23). The prespecified outcome of interest was cardiovascular death (CVD) or heart failure hospitalization. Cys-C was strongly correlated with creatinine ( r=0.60) and estimated glomerular filtration rate ( r=-0.68), moderately correlated with fibroblast growth factor-23 ( r=0.39), and weakly correlated with brain-type natriuretic peptide ( r=0.28) and high-sensitivity troponin I ( r=0.06) (all P<0.0001). After multivariate adjustment, increasing concentration of Cys-C (per SD of log-transformed Cys-C) was significantly associated with a 28% higher hazard of CVD or heart failure hospitalization (hazard ratio [ HR ] 1.28, 95% confidence interval [ CI ] 1.12-1.46, P<0.001), including CVD ( HR 1.24, 95% CI 1.04-1.47, P=0.01) and heart failure hospitalization ( HR 1.42, 95% CI 1.19-1.69, P<0.001). Cys-C was also associated with a higher hazard of CVD, myocardial infarction, or stroke ( HR 1.15, 95% CI 1.04-1.28, P<0.01), including myocardial infarction ( HR 1.17, 95% CI 1.02-1.33, P=0.02). The addition of Cys-C to a fully adjusted model without estimated glomerular filtration rate improved the C-statistic from 0.80 to 0.81 ( P=0.03) for CVD or heart failure hospitalization. In contrast, the addition of estimated glomerular filtration rate to a fully adjusted model without Cys-C failed to improve model discrimination ( P=0.17). Conclusions Cys-C is associated with the risk of adverse outcomes in patients after acute coronary syndrome. This relationship is independent of established and novel biomarkers of the cardiorenal axis.

Keywords: acute coronary syndrome; biomarker; cystatin C; prognosis.

Figures

Figure 1

Cumulative incidence curves by cystatin‐C quartile through long‐term follow‐up for the composite end point of cardiovascular death or heart failure hospitalization (A) and MACE (B). CV indicates cardiovascular; HF, heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; Q1‐Q4, quartiles 1‐4.

Figure 2

The 3‐year Kaplan‐Meier event rates of various prespecified outcomes by quartile of baseline cystatin‐C. CV indicates cardiovascular; HF, heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction.

Figure 3

Adjusted risk of outcomes for cystatin‐C and eGFR when both are modeled as dichotomous variables and included simultaneously in a model with other risk predictors. Variables included in the model are age (quartiles), sex, BMI (<18.5, 18.5 to <25, 25 to <30, ≥30), history of HF, diabetes mellitus, hypertension, hyperlipidemia, prior MI, current smoker, region (North America and Western Europe vs other regions), race (white vs nonwhite), index diagnosis (STEMI vs non‐STE ACS), catheterization for qualifying event, baseline LDL cholesterol (quartiles), days from qualifying event (≤14 days), randomized treatment arm, hsTnI (<26 mg/dL), BNP (<80 pg/mL). BMI, body mass index; BNP, brain‐type natriuretic peptide; CI, confidence interval; CV, cardiovascular; Cys‐C, cystatin‐C; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; hsTnI, high‐sensitivity troponin I; LDL, low‐density lipoprotein; MACE, major adverse cardiovascular events; MI, myocardial infarction; non‐STE ACS, non–ST‐elevation acute coronary syndrome; STEMI, ST‐elevation MI.