Cardiorenal trade-off of sacubitril/valsartan in heart failure with reduced ejection fraction and advanced chronic kidney disease: a propensity-weighted multicentre analysis

Background Patients with heart failure with reduced ejection fraction (HFrEF) frequently have coexisting chronic kidney disease (CKD). Although angiotensin receptor–neprilysin inhibitors (ARNi) improve cardiovascular outcomes in HFrEF, evidence in advanced CKD is limited, particularly regarding progression to dialysis. Purpose To evaluate the cardiovascular and renal outcomes associated with ARNi therapy across the spectrum of kidney function, with a prespecified focus on severe CKD (sCKD; estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²). Methods In this multicentre retrospective cohort study (2013–2021), 6,161 adults with HFrEF initiating ARNi (n=2,676) or renin–angiotensin system inhibitors (RASi; n=3,485) were analysed after excluding baseline dialysis. Inverse probability of treatment weighting balanced 12 baseline covariates. The primary endpoint was cardiovascular (CV) death or heart failure hospitalisation (hHF). Incident haemodialysis was evaluated as a key renal outcome. Secondary endpoints included all-cause mortality and CV death over 3 years. Effect modification by sCKD and nonlinear associations across eGFR were examined using interaction testing and restricted cubic splines. Results ARNi was associated with lower risk of CV death or hHF (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.72–0.87; P<0.001), all-cause mortality (HR 0.61; 95% CI 0.53–0.70; P<0.001), and CV death (HR 0.53; 95% CI 0.45–0.63; P<0.001). Treatment benefit was greater in sCKD for CV death or hHF (HR 0.63; 95% CI 0.52–0.78; P-interaction=0.006). However, ARNi showed a non-significant trend toward increased haemodialysis initiation in sCKD (HR 1.46; 95% CI 0.96–2.21; P=0.076). Restricted cubic spline analysis identified an eGFR inflection near 16.9 mL/min/1.73 m², below which dialysis risk increased while CV and mortality benefits were preserved. Conclusions In HFrEF patients with advanced CKD, ARNi therapy confers substantial cardiovascular and survival benefits but may accelerate progression to dialysis at very low eGFR levels. These findings highlight a clinically relevant cardiorenal trade-off and support individualized decision-making in this high-risk population.