The Difference Between Cystatin C- and Creatinine-Based eGFR in Heart Failure With Reduced Ejection Fraction: Insights From PARADIGM-HF.

RATIONALE & OBJECTIVE The clinical implications of the discrepancy between cystatin C (cysC)- and serum creatinine (sCr)-estimated glomerular filtration rate (eGFR) in patients with heart failure and reduced ejection fraction (HFrEF) are unknown. STUDY DESIGN Post-hoc analysis of randomized trial data. SETTING & PARTICIPANTS 1,970 patients with HFrEF enrolled in PARADIGM-HF with available baseline cysC and sCr. EXPOSURE Intra-individual differences between eGFRcysC and eGFRsCr (eGFRdiffcysC-sCr). OUTCOMES Clinical outcomes included the PARADIGM-HF primary endpoint (composite of cardiovascular [CV] mortality or HF hospitalization), CV mortality, all-cause mortality, and worsening kidney function. We also examined poor health-related quality of life (HRQoL), frailty, and worsening HF (WHF), defined as HF hospitalization, emergency department visit, or outpatient intensification of therapy between baseline and 8-month follow-up. ANALYTICAL APPROACH Fine-Gray sub-distribution hazard models and Cox proportional hazard models regressed clinical outcomes on baseline eGFRdiffcysC-sCr. Logistic regression investigated the association of baseline eGFRdiffcysC-sCr with poor HRQoL and frailty. Linear regression models assessed the association of WHF with eGFRcysC, eGFRsCr, and eGFRdiffcysC-sCr at an 8-month follow-up. RESULTS Baseline eGFRdiffcysC-sCr was >+10 and <-10 ml/min/1.73 m2 in 13.0% and 35.7% of the patients, respectively. More negative values of eGFRdiffcysC-sCr were associated with worse outcomes ([sub]-hazard ratio per standard deviation [SD]: PARADIGM-HF primary endpoint: 1.18, p=0.008; CV mortality: 1.34, p=0.001; all-cause mortality 1.39, p<0.001; worsening kidney function: 1.31, p=0.05). For 1-SD decrease in eGFRdiffcysC-sCr, the prevalence of poor HRQoL and frailty increased by 29% and 17%, respectively (p ≤0.008). WHF was associated with a more pronounced decline in eGFRcysC than in eGFRsCr, resulting in a change in 8-month eGFRdiffcysC-sCr of -4.67 ml/min/1.73 m2 (p<0.001). LIMITATIONS Lack of gold-standard assessment of kidney function. CONCLUSIONS In patients with HFrEF, discrepancies between eGFRcysC and eGFRsCr are common and are associated with clinical outcomes, HRQoL, and frailty. The decline in kidney function associated with WHF is more marked when assessed with eGFRcysC than with eGFRsCr.