
==== Front
J Pharm Health Care Sci
J Pharm Health Care Sci
Journal of Pharmaceutical Health Care and Sciences
2055-0294
BioMed Central London

379
10.1186/s40780-024-00379-1
Short Report
Changes in urinary output due to concomitant administration of sacubitril/valsartan and atrial natriuretic peptide in patients with heart failure: a multicenter retrospective cohort study
Yanagawa Tatsuki 1
http://orcid.org/0000-0002-1933-8592
Asai Yuki yuki0715asai@gmail.com

12
Zakoji Nobuyuki 3
Hosoe Shingo 4
Kondo Yoshihiro 5
Ootsuki Shinnosuke 6
Kato Hidekazu 7
Aoki Maria 8
Yamamoto Yoshiaki 9
Yamamoto Takanori 10
Takahashi Masaaki 1
1 https://ror.org/039kky066 grid.505758.a 0000 0004 0621 7286 National Hospital Organization Mie Chuo Medical Center, Tsu, Mie 514-1101 Japan
2 grid.412075.5 0000 0004 1769 2015 Department of Pharmacy, Mie University Hospital, Faculty of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507 Japan
3 grid.415810.9 0000 0004 0466 9158 National Hospital Organization Shizuoka Medical Center, 762-1 Nagasawa, Shimizu, Shizuoka, Sunto-gun 411-8611 Japan
4 https://ror.org/03ntccx93 grid.416698.4 National Hospital Organization Toyohashi Medical Center, 50 Hamamichigami, Imure-cho, Toyohashi, Aichi 440-8510 Japan
5 grid.410840.9 0000 0004 0378 7902 National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-Ku, Nagoya, Aichi 460-0001 Japan
6 grid.414958.5 0000 0004 0569 1891 National Hospital Organization Kanazawa Medical Center, 1-1 Shimoishibiki, Kanazawa, Ishikawa 920-8650 Japan
7 https://ror.org/03vmdsx94 grid.416389.1 0000 0004 0643 0917 National Hospital Organization Nagara Medical Center, 1300-7 Nagara, Gifu, 502-8558 Japan
8 https://ror.org/05h0rw812 grid.419257.c 0000 0004 1791 9005 National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511 Japan
9 https://ror.org/00garhy75 grid.419174.e 0000 0004 0618 9684 Department of Clinical Research, National Hospital Organization Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka, 420-8688 Japan
10 https://ror.org/0045e2c31 grid.459861.7 National Hospital Organization Mie National Hospital, 357 Osatokubota, Tsu, Mie 514-0125 Japan
16 9 2024
16 9 2024
2024
10 5617 2 2024
10 9 2024
© The Author(s) 2024
2024
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Background

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure.

Methods

In this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg).

Results

Ninety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026).

Conclusions

These findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40780-024-00379-1.

Keywords

Sacubitril/valsartan
Natriuretic peptide
Heart failure
Multicenter retrospective cohort study
issue-copyright-statement© Japanese Society of Pharmaceutical Health Care and Sciences and BioMed Central Ltd. 2024
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pmcBackground

Renin–angiotensin–aldosterone inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been used for treating patients with heart failure (HF) with reduced ejection fraction (HFrEF) [1]. Furthermore, sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has been reported to reduce the risk of hospitalization and death associated with HF compared with those related to enalapril [2].Therefore, sacubitril/valsartan has been recommended for reducing morbidity and mortality in patients with HFrEF in the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guideline [3].

Sacubitril/valsartan is decomposed into sacubitril and valsartan in the body [4]. While valsartan inhibits angiotensin II receptor-mediated vasoconstriction, leading to myocardial hypertrophy and fibrosis, and water and sodium reabsorption [5], sacubitril is further metabolized to the active neprilysin inhibitor. Neprilysin is a membrane-bound protease distributed in a wide range of tissues in the body and is responsible for the degradation of natriuretic peptides [6]. Atrial natriuretic peptides (ANPs) are known to contribute to a decrease in vascular tone, increase renally mediated excretion of electrolytes and water, and have antifibrotic and antihypertrophic effects in the heart [7].

In Japan, human ANPs (hANPs) have been administered intravenously to patients with acute HF to ensure urinary output [8]. Nougue et al. [9] reported that switching from an ACEI/ARB to an ARNI may increase blood ANP levels. Considering this evidence [9] and the pharmacological mechanism of ARNIs, neprilysin inhibition by sacubitril may elevate hANP concentrations in the body; however, the underlying mechanisms remain unknown.

Hence, this multicenter study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANPs based on the urinary output in patients with HF.

Methods

Study design

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 collection and exclusion criteria

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:

Adjusted fluid balance(mL/day/μg hANP)=IN-volume(mL/day)-OUT-volume(mL/day)/daily hANP dosage(μg)

Outcome

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.Fig. 1 Schematic illustrating the study procedures. ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; hANP, human atrial natriuretic peptide; PS, propensity score

Statistical analysis

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.

Results

From September 2020 to March 2023, 125 patients received ARBs and hANPs, and 83 patients received ARNIs and hANPs (Fig. 2). Based on the exclusion criteria, 92 and 62 patients in the ARB + hANP and ARNI + hANP groups, were eligible for the present study, respectively. The characteristics of patients in the ARB + hANP and ARNI + hANP groups are listed in Table 1. There were no significant differences in basic characteristics, such as sex, age, and clinical laboratory data, between the two groups. A higher percentage of patients in the ARB + hANP group had hypertension. A gap was observed between the NYHA classification (p < 0.001). Whereas the value of diastolic blood pressure was significantly lower in the ARB + hANP group compared to the ARNI + hANP group (p < 0.001), no significant differences were observed in systolic blood pressure. Regarding concomitant drugs, the ARNI + hANP group was more likely to use MRAs and SGLT2 inhibitors. The differences in tolvaptan and loop diuretics dosage between the ARB + hANP and ARNI + hANP groups were not significant.Fig. 2 Flow diagram illustrating the patient recruitment process. ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; hANP, human atrial natriuretic peptide; PS, propensity score

Table 1 Baseline characteristics of the eligible patients

Factors	ARB + hANP	ARNI + hANP	P value	
n = 92	n = 62	
Basic property	
 Sex (Male/Female)	56/36	41/21	0.507a	
 Age (years)	84 (77, 88)	82 (72, 88)c	0.263b	
 Body Weight (kg)	55.9 (48.2, 68.8)	57.3 (48.0, 68.5)c	0.897b	
 Height (m)	1.56 (1.47, 1.65)	1.61 (1.48, 1.67)c	0.110b	
 Body Mass Index (kg/m2)	23.2 (20.6, 26.6)	22.5 (19.4, 25.2)c	0.239b	
 Body surface area (m2)	1.54 (1.34, 1.72)	1.59 (1.40, 1.73)c	0.392b	
Clinical laboratory data	
 Na (mEq/L)	140 (136, 143)	140 (137, 143)c	0.601b	
 K (mEq/L)	4.3 (3.7, 4.7)	4.4 (3.8, 4.7)c	0.625b	
 Blood urea nitrogen (mg/dL)	26.7 (19.7, 38.0)	27.9 (20.0, 40.0)c	0.609b	
 Serum creatinine (mg/dL)	1.31 (0.93, 1.83)	1.39 (1.11, 1.79)c	0.202b	
 Creatinine clearance (mL/min)	30.5 (20.3, 46.1)	28.3 (22.1, 41.0)c	0.614b	
Medical history	
 Atrial fibrillation, n (%)	31 (34)	29 (47)	0.103a	
 Hypertension, n (%)	81 (88)	40 (65)	 < 0.001a	
 Diabetes, n (%)	29 (32)	22 (35)	0.608a	
 Hyperlipidemia, n (%)	29 (32)	19 (31)	0.908a	
 Myocardial infarction, n (%)	14 (15)	12 (19)	0.501a	
 Valve replacement /Valvuloplasty, n (%)	5 (5)	2 (3)	0.519a	
 CABG, n (%)	5 (5)	1 (2)	0.402a	
 PCI, n (%)	10 (11)	7 (11)	0.935a	
 PMI, n (%)	5 (5)	5 (8)	0.516a	
NYHA Classification	
 Class I, n (%)	4 (4)	2 (3)	 < 0.001a	
 Class II, n (%)	43 (47)	8 (13)	-	
 Class III, n (%)	31 (34)	37 (60)	-	
 Class IV, n (%)	6 (7)	9 (15)	-	
 Unknown, n (%)	8 (9)	6 (10)	-	
Blood pressure	
 Systolic blood pressure (mmHg)	120 (105, 133)	124 (108, 140)	0.051b	
 Diastolic blood pressure (mmHg)	62 (55, 72)	71 (65, 78)	 < 0.001b	
Oral medication	
 Loop diuretic, n (%)	60 (65)	38 (61)	0.619a	
 Azosemide dosage (mg)	30 (30, 30)	30 (15, 30)	0.805b	
 Furosemide dosage (mg)	20 (20, 40)	20 (20, 40)	0.941b	
 Torasemide dosage (mg)	6 (4, 8)	8 (4, 8)	0.683b	
 Thiazide diuretic, n (%)	6 (7)	3 (5)	0.741a	
 Indapamide dosage (mg)	1 (0.75, 1)	1 (1, 1)	1.000b	
 Hydrochlorothiazide dosage (mg)	9.38 (7.81, 10.9)	-	-	
 Trichloromethiazide dosage (mg)	1 (1, 1)	1 (1, 1)	1.000b	
 Tolvaptan, n (%)	32 (35)	31 (50)	0.060a	
 Tolvaptan dosage (mg)	7.5 (3.75, 7.5)	7.5 (7.5, 15)	0.153b	
 MRA, n (%)	26 (28)	29 (47)	0.019a	
 Spironolactone dosage (mg)	25 (12.5, 25)	25 (25, 25)	0.435b	
 Eplerenone dosage (mg)	50 (50, 50)	50 (50, 50)	0.857b	
 Esaxerenone dosage (mg)	1.25 (1.25, 1.25)	1.25 (1.25, 1.25)	1.000b	
 β blocker, n (%)	37 (40)	31 (50)	0.231a	
 SGLT2 inhibitor, n (%)	10 (11)	22 (35)	 < 0.001a	
 Empagliflozin dosage (mg)	10 (10, 10)	10 (10, 13.8)	0.494b	
 Dapagliflozin dosage (mg)	10 (10, 10)	10 (10, 10)	0.424b	
 Canagliflozin dosage (mg)	100 (100, 100)	100 (100, 100)	1.000b	
 Nitrate medicine, n (%)	4 (4)	4 (6)	0.715a	
 Number of internal medicine	8 (6, 11)	9 (7, 12)c	0.363b	
Intravascular medication	
 Catecholamine, n (%)	5 (5)	5 (8)	0.525a	
ARB Angiotensin II receptor blocker, ARNI Angiotensin receptor neprilysin inhibitor, CABG Coronary artery bypass grafting, hANP human atrial natriuretic peptide, MRA Mineralocorticoid receptor antagonist, NYHA New York Heart Association, PCI Percutaneous coronary intervention, PMI Pacemaker implantation, SGLT2 Sodium glucose cotransporter 2

aChi–square test

bMann–Whitney U test

cEach value represents the median (25th, 75th percentile)

The adjusted fluid balance is shown in Fig. 3A. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). In patients who received ARBs or ARNIs for more than 5 days, the adjusted fluid balance in the hANP + ARNI group also decreased on day 1 (p = 0.023) (Supplementary Fig. 1). In the sensitivity analysis, we compared the adjusted fluid balance after PS matching. After 1:1 PS matching, both ARB + hANP and ARNI + hANP groups included 27 patients each. Data on the basic characteristics of the patients after PS matching are shown in Table 2. There were no significant intergroup differences, and the standardized difference was less than 0.1, except for the BMI. A significant decrease in the adjusted fluid balance was observed in the ARNI + hANP group compared with that in the ARB + hANP group (p = 0.026) (Fig. 3B).Fig. 3 Fluid balance in the ARB + hANP and ARNI + hANP groups. A Adjusted fluid balance in the ARB + hANP and ARNI + hANP groups before PS matching. B Adjusted fluid balance in the ARB + hANP and ARNI + hANP groups after PS matching. Adjusted fluid balance was calculated as follows: In-volume (mL/day) – OUT-volume (mL/day) /daily hANP dosage. ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; hANP, human atrial natriuretic peptide; PS, propensity score

Table 2 Baseline characteristics after propensity score matching

Factors	ARB + hANP	ARNI + hANP	P value	Std diff	
n = 27	n = 27	
Basic property	
 Age (years)	84 (78, 88)	84 (78, 90)c	0.749b	0.011	
 Body Mass Index (kg/m2)	23.5 (20.6, 269)	22.5 (20.0, 24.0)c	0.539b	0.120	
Clinical laboratory data	
 Creatinine clearance (mL/min)	30.1 (17.8, 41.0)	28.2 (23.2, 37.0)c	0.789b	0.049	
Medical history	
 Atrial fibrillation, n (%)	16 (59)	13 (48)	0.413a	0.043	
 Hypertension, n (%)	22 (81)	22 (81)	1.000a	0.000	
 Diabetes, n (%)	5 (19)	6 (22)	0.735a	0.021	
 Hyperlipidemia, n (%)	4 (15)	9 (33)	0.111a	0.086	
 Myocardial infarction, n (%)	5 (19)	5 (19)	1.000a	0.000	
NYHA Classification	
 Class I, n (%)	1 (4)	2 (7)	0.673a	0.036	
 Class II, n (%)	10 (37)	7 (26)	-	0.058	
 Class III, n (%)	14 (52)	14 (52)	-	0.000	
 Class IV, n (%)	2 (7)	4 (15)	-	0.052	
Oral medication	
 Loop diuretic, n (%)	21 (78)	20 (74)	0.750a	0.012	
 Thiazide diuretic, n (%)	1 (4)	2 (7)	1.000a	0.036	
 Tolvaptan, n (%)	14 (52)	14 (52)	1.000a	0.000	
 MRA, n (%)	12 (44)	11 (41)	0.783a	0.015	
 β blocker, n (%)	15 (56)	13 (48)	0.586a	0.029	
 SGLT2 blocker, n (%)	5 (19)	5 (19)	1.000a	0.000	
 Nitrate medicine, n (%)	1 (4)	1 (4)	1.000a	0.000	
ARB Angiotensin II receptor blocker, ARNI Angiotensin receptor neprilysin inhibitor, hANP human atrial natriuretic peptide, MRA Mineralocorticoid receptor antagonist, NYHA New York Heart Association, SGLT2 Sodium glucose cotransporter 2, Std diff Standardized difference

aChi–square test. 

bMann–Whitney U test

cEach value represents the median (25th, 75th percentile)

Discussion

To the best of our knowledge, this is the first study to demonstrate that concomitant use of ARNIs may increase urinary output compared to that of ARBs in patients treated with hANP. Moreover, the sensitivity analysis showed a decrease in the adjusted fluid balance, suggesting that the results of this study are highly reliable.

The ratio of hypertension, NYHA classification, diastolic blood pressure, MRA, and SGLT2 inhibitor were significantly different between the two groups (Table 1). The diuretic effect of MRA is relatively weak, and the beneficial effect of MRAs on HF has been attributed to non-diuretic effects [13]. On the other hand, SGLT2 inhibitors can increase urine output in HF patients [14]. Owing to these differences, we implemented PS matching to adjust for confounding factors, and differences in fluid levels were observed (Fig. 3B), suggesting that ARNI may potentially enhance the diuretic effect of hANP more effectively than ARB. In addition, this study included a large number of elderly patients (over the age of 80 years) compared with previous studies that investigated the background of patients with HF in Japan [15], indicating the efficacy of the ARNI and hANP combination in elderly patients with HF.

In sub-group analysis, we compared 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 to exclude the diuretic effect of ARNI alone. The adjusted fluid balance was lower in the ARNI + hANP group than in the ARB + hANP group, even after 5 days (Supplementary Fig. 1). Since hANP has an intramolecular neprilysin degradation site in its molecular structure [16, 17], it has been suggested that the suppression of hANP degradation by sacubitril results in an increased urinary output.

The present study has several limitations. First, the severity data of HF, such as clinical scenarios, serum ANPs, serum brain natriuretic peptides concentration, and ejection fraction data could not be elucidated because there are many missing values or descriptions. Second, although there were no significant differences in diuretic dosages among groups, the possibility that the combined effect of the diuretics influenced the fluid balance cannot be denied. Considering these limitations, future studies with larger sample sizes and greater statistical power should be conducted. Despite these limitations, the strength of this study was that it was a multicenter study, which minimized the scientific rigor and external validity biases.

Conclusions

This study indicates that ARNIs may potentiate the action of hANPs and that the combination of ARNIs and hANPs may be useful in the treatment of HF.

Supplementary Information

Supplementary Material 1: Fig. 1. Adjusted fluid balance in patients in whom the concomitant therapy was administered for more than 5 days. Adjusted fluid balance was calculated as follows: In-volume (mL/day) – OUT-volume (mL/day) /daily hANP dosage. ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; hANP, human atrial natriuretic peptide; PS, propensity score.

Abbreviations

ACEI Angiotensin-converting enzyme inhibitors

ANP Atrial natriuretic peptide

ARB Angiotensin II receptor blockers

ARNI Angiotensin receptor neprilysin inhibitor

BMI Body mass index

CABG Coronary artery bypass grafting

hANP Human atrial natriuretic peptide

HF Heart failure

HFrEF HF with reduced ejection fraction

MRA Mineralocorticoid receptor antagonist

NYHA New York Heart Association

PCI Percutaneous coronary intervention

PMI Pacemaker implantation

PS Propensity score

SGLT2 Sodium-glucose cotransporter 2

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Authors’ contributions

Conceived of designed the study: TY, YA, YY, TY, and MT. Performed research: TY, NZ, SH, YK, SO, HK, and MA. Analyzed data: TY and YA. Wrote the paper: TY and YA. All authors read and approved the final manuscript.

Funding

The present study was funded by Grants from the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) (Grant No. 22K15331).

Availability of data and materials

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with ethical guidelines for medical and health research involving human subjects. The study design was approved by Mie Chuo Medical Center (approval ref. MCERB-202252), Shizuoka Medical Center (approval ref. 2022-R33), Toyohashi Medical Center (approval ref. 4–21), Nagoya Medical Center (approval ref. 2022–055), Kanazawa Medical Center (approval ref. R04-066), Nagara Medical Center (approval ref. 2022–9), and the National Center for Geriatrics and Gerontology (approval ref. 22TB37). Owing to the retrospective study design, consent was obtained from each patient using an opt-out document posted on the website of the respective hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare that there are no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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