Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction and Advanced Chronic Kidney Disease: A Retrospective Multi-Institutional Study

Abstract

Background: Data regarding using angiotensin receptor-neprilysin inhibitor (ARNI) in patients with both heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease (CKD) are limited.

Methods and results: Between January 2016 and December 2018, patients with HFrEF and advanced CKD (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min/1.73 m²) were identified from a multi-institutional database in Taiwan. Patients who had never been prescribed with an ARNI, angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB) were excluded. We used inverse probability of treatment weighting (IPTW) to balance baseline covariates, and compared outcomes between ARNI and ACEI/ARB users. There were 206 patients in the ARNI group and 833 patients in the ACEI/ARB group. After IPTW adjustment, the mean ages (65.1 vs. 66.6 years), male patients (68.3 vs. 67.9%), left ventricular ejection fraction (30.5 vs.31.2%), eGFR (20.9 vs. 20.3 mL/min/1.73 m²) were comparable in the ARNI and ACEI/ARB groups. Over 85% of the patients had beta-blockers prescriptions in both groups (86.2 vs. 85.5%). After IPTW adjustment, the mean follow-up durations were 7.3 months and 6.6 months in the ARNI and ACEI/ARB groups, respectively. ARNI and ACEI/ARB users had a comparable risk of the composite clinical event (all-cause mortality or heart failure hospitalization) (hazard ratio [HR], 1.31; 95% confidence interval (CI) 0.91-1.88) and progression to dialysis (HR 1.04; 95% CI 0.54-2.03). In subgroup analysis, dialysis patients who used ARNIs were associated with higher incidence of heart failure hospitalization (subdistribution HR, 1.97; 95% CI 1.36-2.85).

Conclusions: Compared with ACEIs or ARBs, ARNIs were associated with comparable clinical and renal outcomes in patients with HFrEF and advanced CKD (eGFR ≤ 30 mL/min/1.73 m²). In short-term, HF hospitalization may occur more frequently among ARNI users, especially in patients on dialysis.

Keywords: angiotensin receptor-neprilysin inhibitor; chronic kidney disease; end-stage renal disease; heart failure with reduced ejection fraction; sacubitril/valsartan.

Figure 1

Flowchart of the inclusion and exclusion criteria of the study patients.

Figure 2

Cumulative event rate of the composite of HF hospitalization and all-cause death (A), HF hospitalization (B), and progression to ESRD (C) between the ARNI and ACEI/ARB users. (A) and (B) compared with the IPTW cohort from all patients; (C) after excluding persons on dialysis at baseline then creating another IPTW cohort.

Figure 3

Subgroup analysis comparing the risk of clinical outcomes between the ARNI and ACEI/ARB users in the IPTW-adjusted cohort stratified by baseline renal function.

Figure 4

Subgroup analysis comparing the risk of clinical outcomes between the ARNI and ACEI/ARB users in the IPTW-adjusted cohort stratified by baseline DM status.