This multicenter, retrospective cohort study was conducted at seven hospitals belonging to the Tokai-Hokuriku Group of the National Hospital Organization (Mie Chuo Medical Center, Shizuoka Medical Center, Toyohashi Medical Center, Nagoya Medical Center, Kanazawa Medical Center, Nagara Medical Center, and National Center for Geriatrics and Gerontology).

Data on adult patients with HF receiving ARBs, ARNIs, and hANPs at the seven hospitals from September 1, 2020, to March 31, 2023, were collected. The exclusion criteria were as follows: (1) receipt of concomitant therapy for only 1 day, (2) unavailability of IN-volume (fluid intake and infusion volume) or OUT-volume (urinary output) measurements; (3) unknown ARB, ARNI, or hANP dosage; and (4) use of dialysis. Clinical data on patient characteristics (sex, age, weight, height, body surface area, clinical laboratory data, New York Heart Association [NYHA] classification, medical history, and concomitant medications); ARB, ARNI, and hANP dosages; ARB, ARNI, and hANP initiation dates; discharge and death dates; IN-volume; and OUT-volume were collected from electronic medical records. The data on concomitant medications were evaluated immediately prior to the initiation of combination therapy with ARB/ARNI and hANP. Adjusted fluid balance was calculated using the following formulae:

$$\text\ (\text/\text/\upmu\text) = \text - \text\ (\text/\text)-\text-\text\ (\text/\text)/\text(\upmu\text)$$

The design scheme used in this study is illustrated in Fig. 1. The start date of combination therapy with ARB/ARNI and hANP was defined as day 0. As the accurate time for conducting this combination therapy was unknown, and the diuretic may exert a maximal effect on day 1 [10], the fluid balance data were collected on day 1. The primary endpoint was the adjusted fluid balance. ARNIs increase endogenous ANP levels mediated by neprilysin inhibition, which leads to an increase in urinary output, without concomitant use of hANP [9, 11]. Whereas a diuretic effect of ARNIs was observed on the first day, this phenomenon was not observed on the fifth day [12]. Therefore, we evaluated the adjusted fluid balance in patients who received ARBs or ARNIs for more than 5 days, at the time of combination therapy with ARB/ARNI and hANP as sub-group analysis.

Schematic illustrating the study procedures. ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; hANP, human atrial natriuretic peptide; PS, propensity score

As continuous variables were abnormally distributed, the Mann–Whitney U test was used. The chi-square test was used to compare categorical variables. To remove the influence of confounding factors, 1:1 propensity score (PS) matching was performed between the ARB + hANP and ARNI + hANP groups. The PS was calculated using the following variables: age; body mass index (BMI); creatinine clearance; medical history (atrial fibrillation, hypertension, diabetes, hyperlipidemia, and myocardial infarction); NYHA classification; and concomitant drugs such as loop diuretics, thiazide diuretics, tolvaptan, mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nitrates. The ARB + hANP and ARNI + hANP pairs were matched 1:1 with a caliper of 0.2 of the standard deviation of the logit of the PS. After PS matching, the respective baseline patient characteristics were evaluated and standardized differences were calculated. All statistical analyses were performed using SPSS version 28 (IBM Japan, Tokyo, Japan), and statistical significance was set at p < 0.05.