Breaking barriers: Neprilysin inhibition in chronic cardiorenal syndrome

Table 1 Studies exploring the impact of sacubitril/valsartan in concomitant heart failure with reduced ejection fraction and chronic kidney disease or end-stage kidney disease treated with hemodialysis

Year	Ref.	Study design	eGFR	Total number of participants	Duration of follow-up	Main findings for ARNI vs RAASi	Comments
2018	Haynes et al[26]	HARP-III trial	20-60 (mean eGFR 34)	414 (207 in ARNI, 207 in control group)	12 months	No significant difference in eGFR at 3, 6, 9, or 12 months or proteinuria	No difference in incidence of serios adverse effects or nonserious adverse reactions
2024	Chatur et al[28]	Post-hoc parallel trial analysis of PARADIGM-HF and PARAGON-HF	eGFR < 30	691 in PARADIGM-HF and 613 in PARAGON-HF		A trend towards decreased HF hospitalizations and CV death (RR = 0.81; 95%CI: 0.58-1.15)	No incremental increase in adverse events
2022	Hsiao et al[29]	Retrospective multi-institutional cohort	eGFR < 30	1105 (206 in ARNI, 833 in RAASi) group	7.3 months	Similar risk of composite of mortality, HF hospitalizations and progression to ESKD	Subgroup analysis of 14% of patients who progressed to ESKD had a trend towards increased HF hospitalizations in ARNI group
2024	Le et al[8]	Retrospective, 1:1 propensity score-matched comparative effectiveness study	ESKD	2868 (1434 in ARNI and 1434 in RAASi group)	10.8 months	ARNI was associated with 18% lower all-cause mortality and 14% lower all-cause hospitalizations, but no difference in CV mortality or HF hospitalizations	No increase in hyperkalemia or hypotension
2024	Lin et al[9]	Retrospective cohort	ESKD	178 (61 in ARNI and 117 in RAASi group)	9 months	ARNI was associated with 54% lower mortality but had a non-significant trend for increased all-cause hospitalizations	High variability in reported LVEF
2021	Feng et al[20]	Prospective cohort	ESKD	11 (before and after ARNI)	18 months	ARNI concentrations remained in safe range
2021	Lihua et al[30]	Prospective single center cohort	ESKD	110 (before and after ARNI)	12 months	LVEF increase from 35.1% to 49.8%, P < 0.001	Improvement in NYHA symptom severity
2022	Niu et al[31]	Case-control study	ESKD	49 (26 in ARNI, 23 in RAASi group)	12 months	LVEF increase from 31.3% to 45.1%, P < 0.0001	No increase in hyperkalemia or hypotension

eGFR: Estimated glomerular filtration rate; ARNI: Angiotensin receptor-neprilysin inhibitor; RAASi: Renin-angiotensin-aldosterone system inhibitor; HARP-III: Heart and Renal Protection-III; PARADIGM-HF: Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON-HF: Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in Heart Failure with Preserved Ejection Fraction; CV: Cardiovascular; RR: Relative risk; CI: Confidence interval; ESKD: End-stage-kidney disease; HF: Heart failure; NYHA: New York Heart Association; LVEF: Left ventricular ejection fraction.