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Abstract

Background and Objectives: The efficacy and safety of a lower target dose of sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) for treating heart failure with reduced ejection fraction (HFrEF) in Chinese patients with moderate-to-severe chronic kidney disease (CKD) remain unknown. We performed a retrospective study to compare the efficacy of ARNI with that of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with HFrEF and moderate-to-severe CKD. Methods: This retrospective study included 129 patients. An inverse probability of treatment weighting (IPTW) analysis was performed to compare the baseline characteristics and outcomes between the 2 groups. The incidence of death due to cardiovascular disease, rehospitalization due to heart failure after treatment, and improvement in cardiac function symptoms (New York Heart Association [NYHA]) were assessed after 12 months. Improvements of ejection fraction (EF), N-terminal pro-brain natriuretic peptide (NT-proBNP) level, left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) were compared. Results: Compared with the ACEI/ARB group, the ARNI group, with 90.77% (59/65) in the lower target dose group, showed a lower rate of death due to cardiovascular disease (6.6% vs 0.9% after IPTW) and a lower incidence of rehospitalization (46.5% vs 30.4% after IPTW). NYHA class, estimated glomerular filtration rate, EF, NT-ProBNP levels, LVEDD, and LVESD improved in the ARNI group. None of the patients withdrew from treatment because of adverse drug reactions. Conclusion: Our study showed that ARNI resulted in a greater improvement in heart failure than ACEIs/ARBs in patients with HFrEF and moderate-to-severe CKD.

Keywords

sacubitril/valsartan (LCZ696)heart failure angiotensin-converting enzyme inhibitors angiotensin receptor blockers chronic kidney disease

Introduction

Heart failure (HF), characterized by fatigue, expiratory dyspnea, and peripheral edema, is a common form of heart disease associated with high mortality.^1,2 It often coexists with chronic kidney disease (CKD), possibly due to pathophysiological links between CKD and HF, such as high blood pressure (BP), anemia, and hyperparathyroidism.^3-5 However, patients with HF and CKD have 15 times higher cardiovascular mortality than those without CKD.^6,7 Chronic kidney disease reduces the effects of standard therapy owing to the low utilization of renin–angiotensin–aldosterone system inhibitors and mineralocorticoid receptor antagonists.^8,9 Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits both neprilysin and angiotensin (AT1) receptors, reducing BP, cardiac hypertrophy, and fibrosis.^10,11 The PARADIGM-HF trial demonstrated that ARNI was more effective than enalapril in reducing mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF), and almost 37% of patients with a baseline estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² were included in the study. However, it did not include patients with adverse renal dysfunction (eGFR < 30 mL/min/1.73 m²).¹² The UK HARP-III trial showed that ARNI has similar effects on kidney function as irbesartan, although it has greater effects on reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with CKD (20 mL/min/1.73 m²< eGFR < 60 mL/min/1.73 m²).¹³ However, few studies have reported on the effects of ARNI in patients with HFrEF and advanced CKD.^14,15 Moreover, in China, most patients with HFrEF and CKD do not receive the recommended target dose (200 mg bid(twice a day)), and the final target dose is always moderate (100 mg bid) or low (50 mg bid). Whether a low or moderate target dose of ARNI is efficacious and safe is not conclusive. In this study, we compared the efficacy and safety of ARNI with those of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in Chinese patients with HFrEF and CKD (GFR <45 mL/min/1.73 m²).

Methods

Study Design

This single-center, real-world retrospective study was performed at our hospital and included 7 million people in the surrounding area of Southeast China. A total of 129 patients with HF, HFrEF, and CKD who were treated with ARNI or ACEIs/ARBs between January 2020 and January 2022 were enrolled via an electronic medical record system. All patients were followed up approximately every 3 months for 12 months.

Patients

The inclusion criteria were as follows: (1) age ≥18 years, men or women, (2) diagnosis of HF with left ventricular ejection fraction (LVEF) ≤ 40% and eGFR ≤ 45 mL/min/1.73 m² but not undergoing dialysis, (3) treatment with ARNI or ACEI/ARBs, and (4) HF symptoms consistent with New York Heart Association (NYHA) class II to IV. The exclusion criteria were as follows: (1) LVEF ≥ 40%, (2) HF resulting from right ventricular failure or congenital heart disease, (3) hypotension (systolic blood pressure [SBP] < 100 mm Hg), hyperkalemia (potassium concentration > 5.5 mmol/L); and (4) allergy to ARNI or ACEIs or ARBs.

Data Collection and Recording

The following clinical data were collected at baseline and 12 months after follow-up: serum creatinine, blood urea nitrogen (BUN), eGFR, NT-proBNP, ejection fraction (EF), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), serum potassium, SBP, diastolic BP (DBP), and NYHA classification. Information regarding combined medications was also collected.

The primary outcomes included the incidence of rehospitalization due to HF after treatment and the rate of death due to cardiovascular disease. Secondary outcomes included improvements in NT-proBNP, EF, LVESD, LVEDD, and NYHA classification. Safety outcomes were the rate of patients developing end-stage kidney disease (ESKD) and changes in eGFR, BUN, SBP, DBP, and serum potassium level.

Statistical Analysis

Quantitative data are expressed as means ± standard deviation for normal distribution or median (interquartile range) for skewed distribution, and categorical variables are presented as percentages. The Student t test or Mann-Whitney U test was used for comparisons between continuous data. The χ² test was used to compare categorical data. Statistical significance was defined as a 2-tailed P value of <.05. The inverse probability of treatment weighting (IPTW) was used to balance the differences in baseline characteristics between patients taking ARNI and those taking ACEIs/ARBs. The standardized mean difference (SMD) was used to assess the balance of baseline between groups; SMD <0.1 after IPTW was an acceptable balance between the 2 groups. The cumulative incidence of death caused by cardiovascular disease, rehospitalization caused by HF after treatment, and the rates of ESKD over time, was estimated using the IPTW-adjusted Kaplan-Meier method and compared between the 2 groups using the log-rank test. Kaplan-Meier survival analysis was used to plot the survival curves. All the tests were 2-sided. Missing observational data for deaths were imputed using hospitalization data prior to death. All statistical analyses were performed using R4.1.2.

Results

Baseline Patient Characteristics

A total of 129 patients were included in this study with 64 patients in the ACEI/ARB group and 65 patients in the ARNI group. The mean age of the patients was 75.76 ± 9.49 years, and 55% of the patients were men. Patients in the ARNI group had a higher proportion of diabetes (47.7% vs 42.2%) and hypertension (80% vs 73.4%) but a lower proportion of stroke (15.54% vs 20.3%), smoking (20% vs 26.2%), and drinking (18.5% vs 14.1%). Among these patients, 126 (97.7%), 102 (79.1%), and 22 (17.1%) patients also additionally took β-receptor blockers, aldosterone receptor antagonist, and nitrate esters, respectively. Serum creatinine, BUN, and NT-proBNP levels were higher in the ARNI group than in the ACEI/ARB group (153.68 ± 27.87 vs 148.91 ± 22.06, 11.54 ± 6.75 vs 10.76 ± 3.08, 4895.80 [3568.32, 6368.38] vs 4786.00 [3580.00, 7039.00], respectively). However, eGFR, EF, LVESD, DBP, and blood potassium levels in the ARNI group were lower than those in the ACEI/ARBs group (34.49 ± 7.09 vs 35.39 ± 5.24, 0.33 ± 0.05 vs 0.34 ± 0.05, 47.66 ± 5.50 vs 49.02 ± 3.50, 79.88 ± 6.04 vs 80.53 ± 5.11, 4.25 ± 0.38 vs 4.32 ± 0.44, respectively). The proportion of patients with NYHA class IV disease was higher in the ARNI group than in the ACEI/ARB group (83.1% vs 78.1%). The baseline characteristics of patients in the 2 groups after IPTW are shown in Table 1. All the parameters in the 2 groups were balanced with an absolute SMD of <0.1, indicating that the weighted balance between the 2 groups was acceptable.

Table 1.

Baseline Characteristics Between the ARB/ACEI Group and the ARNI Group After IPTW Adjustment.

			Before IPTW			After IPTW
			Overall (n = 129)	ACEI/ARB (n = 64)	ARNI (n = 65)	ACEI/ARB (n = 64)	ARNI (n = 65)	SMD	P value
Age (years)			75.76 ± 9.49	75.92 ± 9.85	75.60 ± 9.20	75.41 ± 9.86	76.33 ± 9.52	0.097	.608
Sex		Male	71 (55.0%)	36 (56.2%)	35 (53.8%)	57.4%	53.3%	0.082	.665
Sex		Female	58 (45.0%)	28 (43.8%)	30 (46.2%)	42.6%	46.7%	0.082	.665
Weight (kg)			60.33 ± 10.35	60.78 ± 7.63	59.89 ± 12.52	60.94 ± 7.72	59.33 ± 12.76	0.1	.433
Height (cm)			162.84 ± 7.97	162.55 ± 7.56	163.14 ± 8.40	162.82 ± 7.60	163.07 ± 8.80	0.03	.876
Diabetic			58 (45.0%)	27 (42.2%)	31 (47.7%)	45.6%	43.9%	0.036	.851
Myocardial infarction			32 (24.8%)	15 (23.4%)	17 (26.2%)	23.4%	23.5%	0.004	.981
Stroke			23 (17.8%)	13(20.3%)	10(15.4%)	17.6%	17.8%	0.004	.982
Smoke			30 (23.3%)	17 (26.6%)	13 (20.0%)	23.8%	22.1%	0.041	.828
Drink			21 (16.3%)	9(14.1%)	12(18.5%)	14.8%	16.2%	0.037	.844
Hypertension			99 (76.7%)	47 (73.4%)	52 (80.0%)	76.4%	76.4%	<0.001	1
β receptor blocker			126 (97.7%)	63 (98.4%)	63 (96.9%)	98.7%	98.2%	0.043	.779
Aldosterone receptor antagonist			102 (79.1%)	50(78.1%)	52(80.0%)	77.6%	79.8%	0.054	.782
Nitrate esters			22 (17.1%)	12(18.8%)	10(15.4%)	18.8%	19.7%	0.023	.912
Scr (μmol/L)			151.31 ± 25.17	148.91 ± 22.06	153.68 ± 27.87	149.95 ± 21.85	148.75 ± 28.5	0.047	.803
eGFR (mL/min/1.73 m²)			34.93 ± 6.23	35.39 ± 5.24	34.49 ± 7.09	35.19 ± 5.33	35.66 ± 7.66	0.07	.739
30 ≤ eGFR ≤ 45 (mL/min/1.73 m²)			101	51(79.7%)	50(76.92%)
eGFR ≤ 30 (mL/min/1.73 m²)			28	13(20.3%)	15(23.08%)
BUN (mmol/L)			11.15 ± 5.26	10.76 ± 3.08	11.54 ± 6.75	10.97 ± 3.58	11.15 ± 5.36	0.041	.808
NT-proBNP (pg/mL)			4852 [3570.66, 6600]	4895.80 [3568.32, 6368.38]	4786.00 [3580.00, 7039.00]
EF (%)			0.34 ± 0.05	0.34 ± 0.05	0.33 ± 0.05	0.34 ± 0.05	0.34 ± 0.05	0.002	.991
LVEDD (mm)			56.77 ± 4.28	56.56 ± 3.58	56.97 ± 4.90	56.94 ± 3.81	57.01 ± 4.69	0.017	.929
LVESD (mm)			48.33 ± 4.65	49.02 ± 3.50	47.66 ± 5.50	48.99 ± 3.59	49.14 ± 5.94	0.029	.888
SBP (mm Hg)			127.47 ± 11.57	127.34 ± 8.88	127.60 ± 13.78	127.52 ± 8.98	126.94 ± 12.79	0.053	.765
DBP (mm Hg)			80.20 ± 5.59	80.53 ± 5.11	79.88 ± 6.04	80.38 ± 5.15	80.21 ± 5.86	0.03	.873
Potassium level (mmol/L)			4.28 ± 0.41	4.32 ± 0.44	4.25 ± 0.38	4.27 ± 0.43	4.27 ± 0.37	0.003	.988
NYHA	III		48 (37.2%)	23 (35.9%)	25 (38.5%)	20.4%	19.5%	0.021	.918
NYHA	IV		81 (62.8%)	41 (64.1%)	40 (61.5%)	79.6%	80.5%	0.021	.918

Abbreviations: IPTW, inverse probability of treatment weighting; SMD, standardized mean difference; Scr, serum creatinine ; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-brain natriuretic peptide; BUN, blood urea nitrogen; EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; SBP, systolic pressure; DBP, diastolic pressure; NYHA, New York Heart Association.

Data are n (%), mean ± SD and median [IQR].

Clinical Outcomes

At baseline, 20 (30.77%) and 45 (69.23%) patients were started on 50 and 100 mg bid ARNI, respectively. After 12 months of treatment, only 6 (9.23%) patients achieved the recommended target dose (200 mg bid), and 2 (3.08%) received a lower target dose (25 mg bid), 14 (21.54%) received a low target dose (50 mg bid), and 43 (66.15%) received a moderate target dose (100 mg bid). A total of 62 (95.38%) patients experienced no titration or uptitration; however, 3 (4.62%) patients experienced downtitration due to hypotension or hyperkalemia.

After 12 months of follow-up, patients in the ARNI group showed greater improvements in EF, NT-proBNP level, LVEDD, and LVESD than those in the ACEI/ARB group (Table 2). The LVEF increased by 3% ± 6% from 33% ± 5% to 36% ± 6% in the ARNI group, whereas NT-proBNP decreased by 818 [−1642.70, 150.00] pg/mL in the ARNI group. LVEDD increased by 0.29 ± 2.56 mm in the ACEI/ARB group and decreased by 0.86 ± 2.75 mm in the ARNI group. Meanwhile, LVESD increased by 0.39 ± 2.46 mm in the ACEI/ARB group and decreased by 0.59 ± 2.41 mm in the ARNI group. The eGFR, BUN, and serum creatinine levels slightly improved, but there were no statistically significant differences between the 2 groups. Blood pressure decreased in patients treated with ARNI or ACEIs/ARB, especially in those treated with ARNI; however, the decrease in BP was tolerated. All patients in these 2 groups showed mildly increased potassium levels; however, these levels were within the normal range (Table 2). The cardiac functional class (NYHA) improved more in the ARNI group than in the ACEI/ARB group: 26.83% (11/41) of patients with NYHA class IV decreased to class III; 21.74% (5/23) of patients with NYHA class III decreased to class II in the ACEI/ARB group; 52.5% (21/40) of patients with NYHA class IV decreased to class II or III; and 32% (8/25) of patients with NYHA class III changed to NYHA class II in the ARNI group.

Table 2.

The Change of Clinical Outcomes in the ACEI/ARB and ARNI Groups After 12 Months Follow-Up.

Variables		Before IPTW			After IPTW
Variables		AECI/ARB group	ARNI group	P value	AECI/ARB group	ARNI group	P value
ΔeGFR (mL/min/1.73 m²)		0.26 ± 8.71	−0.22 ± 9.16	.76	0.54 ± 8.58	−1.42 ± 9.51	.25
ΔBUN (mmol/L)		1.38 ± 2.98	−0.26 ± 7.03	.09	1.38 ± 3.12	0.14 ± 5.71	.10
ΔNT-proBNP (pg/mL)		563.75 [−565.64, 1389.67]	−818 [−1642.70, 150.00]	<.001	417.91 [−594.84, 1382.65]	−874.43 [−1734.46, 104.56]	.001
ΔEF (%)		−1.4%±5.3%	2.5%±6%	<.001	−1%±5%	3%±6%	.001
ΔLVEDD (mm)		0.35 ± 2.58	−0.77 ± 2.78	.019	0.29 ± 2.56	−0.86 ± 2.75	.02
ΔLVESD (mm)		0.41 ± 2.4	−0.44 ± 2.24	.039	0.39 ± 2.46	−0.59 ± 2.41	.04
ΔSBP (mm Hg)		−6.77 ± 7.32	−15.03 ± 9.36	<.001	−7.26 ± 7.34	−15.83 ± 8.97	<.001
ΔDBP (mm Hg)		−4.33 ± 4.97	−9.8 ± 6.84	<.001	−4.43 ± 4.94	−10.33 ± 7.11	<.001
Δpotassium level (mmol/L)		0.43 ± 0.35	0.33 ± 0.44	.14	0.45 ± 0.35	0.35 ± 0.43	.16
NYHA	II	5 (7.8%)	12 (18.5%)	.006	9.5(7.7%)	27.7 (20.5%)	.006
	III	22 (34.4%)	33 (50.8%)		40.0 (32.5%)	65.6 (48.6%)
	IV	37 (57.8%)	20 (30.8%)		73.7(59.8%)	41.8(30.9%)

Abbreviations: ΔeGFR, the change of estimated glomerular filtration rate from baseline; ΔBUN, the change of blood urea nitrogen from baseline; ΔBNP, the change of N-terminal pro-brain natriuretic peptide from baseline; ΔEF, the change of ejection fraction from baseline; ΔLVEDD, the change of left ventricular end-diastolic diameter from baseline; ΔLVESD, the change of left ventricular end-systolic diameter from baseline; ΔSBP, the change of systolic pressure; ΔDBP, the change of diastolic pressure from baseline; NYHA, New York Heart Association.

Data are n (%), mean ± SD and median [IQR].

Death caused by cardiovascular disease occurred in 4 (6.2%) patients in the ACEI/ARB group and in one (1.5%) patient in the ARNI group. The results of the Kaplan-Meier analysis showed that the cumulative incidence of death caused by HF was lower in the ARNI group than in the AEVI/ARB group (6.6% vs 0.9%, log-rank test: P = .01 after IPTW). A total of 29 (45.3%) patients treated with ACEIs/ARBs and 20 (30.8%) patients treated with ARNI experienced rehospitalization due to HF after treatment. The cumulative incidence of rehospitalization for HF after treatment was significantly lower in the ARNI group than in the ACEI/ARB group (46.5% vs 30.4%, log-rank test: P = .08). The proportion of patients with ESKD in the ARNI group was comparable with that in the ACEI/ARB group (9.4% vs 7.7%, P_log-rank= 0.4) (Figure 1).

Figure 1.

Comparison of cumulative event rates of cardiovascular death before (A) and after (B) inverse probability of treatment weighting (IPTW), rehospitalization after treatment before (C) and after (D) IPTW, and end-stage kidney disease (ESKD) before (E) and after (F) IPTW between the angiotensin receptor neprilysin inhibitor (ARNI) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) users.

Safety and Tolerability

Elevated blood potassium levels were not significantly different between the 2 groups. However, the declines in SBP and DBP differed between the 2 groups. The decrease in BP in the ARNI group was more evident; however, the decrease was well tolerated by the patients, and none of the patients withdrew from treatment.

Discussion

Sacubitril/valsartan is recommended as a fundamental drug to reduce morbidity and mortality in patients with HFrEF and NYHA classes II to III according to the 2022 AHA/ACC/HFSA guidelines for the management of HF.¹⁶ Patients with advanced kidney disease have a higher prevalence of HF; however, patients with an eGFR below 30 mL/min/1.73 m² should use ARNI with caution due to uncertain safety and effectiveness. Some real-world studies included mostly patients with HFrEF and CKD II to III but did not include those with a less severe form of CKD or no severe CKD (CKD IV-V). Other studies included patients with HFrEF and severe CKD; however, their follow-up periods were short (<12 months).^17-20 Patients with renal function equal to or less than CKD IIIb progress more easily to ESKD and develop cardiovascular adverse events.²¹ Therefore, our study included patients with HFrEF and impaired renal function (eGFR ≤45 mL/min/1.73 m², CKD IIIb-IV), and the follow-up period was 12 months. Most patients in China receive the target dose of ARNI as 100 mg bid. This dose is lower than the recommended target dose (200 mg bid). The patients included in our study received a low (50 mg bid) or moderate (100 mg bid) target dose of ARNI, and only 6 patients received the recommended target dose (200 mg bid). The determination of whether the final lower target dose will be effective and safe in patients with HFrEF and CKD (eGFR ≤45 mL/min/1.73 m²) is clinically valuable information. We not only explored the effects of ARNI on cardiac biochemical markers, cardiac function, cardiovascular death, and rehospitalization caused by HF but also observed the safety of ARNI on kidney function in a real-world Chinese population. We deemed it important to not only explore the efficacy of a low-to-moderate target dose of ARNI on cardiac function in patients with HFrEF and CKD (eGFR ≤ 45 mL/min/1.73 m²) but also assess the effect on kidney function.

We found that the rates of cardiovascular mortality and rehospitalization after treatment for HF were lower in the ARNI group than in the ACEI/ARB group, which was in accordance with the results of the PARADIGM-HF trial: ARNI improved morbidity and mortality in patients with HFrEF more effectively than enalapril.¹² Lee et al found that patients with both HFrEF and CKD in the ARNI group showed lower all-cause mortality but not lower cardiovascular mortality, which may be due to the different cardiorenal functions of the patients enrolled in the 2 studies.¹⁹ We also found that patients in the ARNI group showed lower EF and NT-proBNP levels. Furthermore, LVEDD and LVESD after 12 months were slightly improved in the ARNI group. These results were consistent with those of the PIONEER-HF study, which revealed that initiation of ARNI therapy led to a greater reduction in NT-proBNP concentration than enalapril therapy in patients with HFrEF.²² The mechanism by which ARNI improves HF may involve reducing antifibrotic and anti-inflammatory substances such as procollagen type 1C-terminal propeptide, human cartilage glycoprotein-39, and plasma renin activity.²³ ANRI exerts cardioprotective effects by reducing the production of intracellular reactive oxygen species, associated oxidative products, and inflammatory factors.²⁴ Patients with NYHA class III and IV comprised 35.9% (23/64) and 38.46% (25/65), respectively, of the patients in the ACE/ARB group and 64.06% (41/64) and 61.53% (40/65), respectively, of the patients in the ANRI group before treatment. However, after 12 months of treatment, the proportion of patients with NYHA class IV decreased to 57.8% (37/64) and 30.8% (20/65) of the patients in the ARNI and ACEI/ARB groups, respectively. Scott et al²⁵ found that NYHA class could be better improved in patients with EF-preserved heart failure (HFpEF) treated with ARNI than in patients treated with ARB. This phenomenon is not only found in patients with HFpEF but also in patients with HFrEF.^26,27 Thus, ARNI can improve cardiac function.

We included patients with eGFR < 45 mL/min/1.73 m², and whether ARNI leads to further renal function deterioration remains meaningful information. ARNI could reportedly better improve renal function and histology by attenuating most of the molecular markers of oxidative stress, inflammation, and fibrosis such as MCP-1 and NF-κB, which may explain why ARNIs delay the progression of kidney disease.²⁸ Thus far, the UK HARP-III trial, which was a randomized double-blind trial, observed that the patients with eGFR of 20 to 60 mL/min/1.73 m² showed a similar effect on eGFR and the urinary albumin:creatinine ratio in both the ARNI group (97/103 mg twice daily) and irbesartan group (300 mg once daily).²⁹ However, some real-world studies have found that the decline in eGFR in the ARNI group was slower than that in the ACEI/ARB group. Others have found that ARNI and ACEI/ARB users have a comparable risk of progression to dialysis.^14,18 These contradictory results may be due to different sample sizes, follow-up periods, and target doses of ARNI. Our study found that the improved eGFR and rates of progression to ESKD were similar between the ARNI and ACEI/ARB groups. This implies that a low or moderate target dose of ARNI is expected to improve HF without deteriorating renal function in patients with eGFR <45 mL/min/1.73 m². In our study, patients with HFrEF in the ARNI group had lower SBP and DBP at 12 months of follow-up. Fortunately, all patients tolerated the decreased BP. We also found that all patients in the 2 groups had increased blood potassium levels compared with baseline levels, but these levels were still within the normal range. These results suggest that ARNI is safe in patients with HFrEF and severe renal impairment.

Our study has some limitations. First, the number of patients in the study was small. Second, the follow-up period was only 12 months, and a longer follow-up period is needed. Third, the study was retrospective in nature, and some follow-up data were missing and were therefore substituted using hospitalization data prior to death. Finally, it was impossible to perform a stratified analysis of eGFR owing to the small sample size.

Conclusion

Angiotensin receptor neprilysin inhibitor reduced the occurrence of cardiovascular death and rehospitalization due to HF. The EF and NT-proBNP levels in patients with moderate-to-severe impairment of renal function improved more in the ARNI group than in the ACEI/ARB group. The number of patients with ESKD and the eGFR, BP, and blood potassium levels after 12 months of follow-up were comparable between the 2 groups. Low and moderate target doses of ARNI may be effective and safe for treating patients with HFrEF and moderate-to-severe CKD.

Footnotes

Acknowledgements

The authors would like to thank Guoquan Chen for providing guidance on the statistical methods.

Authors’ Contribution

Zhaowei Zhang and Shenjue Chen planned the study, collected data, and wrote the manuscript. Jian Huang and Xuchun Xu were the attending doctors. Qun Shi and Guang Wen Luo performed the statistical analyses. All the authors have reviewed the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This study was approved by the Affiliated JinhHua Hospital, Zhejiang University School of Medicine Ethics Committee on 15 June 2023 (number 173). Informed consent was not required owing to the retrospective nature of the study.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Jinhua Science and Technology Project (2023-3-068).

ORCID iD

Zhaowei Zhang

Data Availability Statement

Supplementary data for this article can be found online at .

References

Groenewegen

Rutten

Mosterd

Hoes

. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342-1356.

Kuhn

Gathright

Dolansky

Gunstad

Josephson

Hughes

. Health literacy, cognitive function, and mortality in patients with heart failure. J Cardiovasc Nurs. 2022;37(1):50-55.

Jankowski

Floege

Fliser

Böhm

Marx

. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation. 2021;143(11):1157-1172.

Haynes

Zhu

Judge

Herrington

Kalra

Baigent

. Chronic kidney disease, heart failure and neprilysin inhibition. Nephrol Dial Transpl. 2020;35(4):558-564.

Tuegel

Bansal

. Heart failure in patients with kidney disease. Heart. 2017;103(23):1848-1853.

Granata

Clementi

Virzì

, et al. Cardiorenal syndrome type 4: from chronic kidney disease to cardiovascular impairment. Eur J Intern Med. 2016;30:1-6.

Silverberg

Wexler

Blum

Schwartz

Iaina

. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens. 2004;13(2):163-170.

Pontremoli

Borghi

Filardi

. Renal protection in chronic heart failure: focus on sacubitril/valsartan. Eur Heart J Cardiovasc Pharmacother. 2021;7(5):445-452.

Ames

Atkins

Pitt

. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med. 2018;33(2):363-382.

10.

Kuang

Huang

Zhou

Cheng

. Sacubitril/valsartan in chronic kidney disease: from pharmacological mechanism to clinical application. Eur J Pharmacol. 2021;907:174288.

11.

Kario

. The sacubitril/valsartan, a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI): potential uses in hypertension, heart failure, and beyond. Curr Cardiol Rep. 2018;20(1):5.

12.

McMurray

Packer

Desai

, et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825.

13.

UK HARP-III Collaborative Group. Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)-III-rationale, trial design, and baseline data. Nephrol Dial Transpl. 2017;32(12):2043-2051.

14.

Martínez-Esteban

Vázquez-Sánchez

Pozo-álvarez

, et al. Cardiorenal benefits of sacubitril/valsartan in patients with advanced chronic kidney disease: experience in daily clinical practice. BMC Nephrol. 2022;23(1):293.

15.

Chang

Feng

Fong

, et al. Sacubitril/valsartan in heart failure with reduced ejection fraction patients: real world experience on advanced chronic kidney disease, hypotension, and dose escalation. J Cardiol. 2019;74(4):372-380.

16.

Heidenreich

Bozkurt

Aguilar

, et al. 2022 AHA/ACC/HFSA guidelines for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e876-e894.

17.

Hsiao

Lin

Tung

Y-C

Chu

P-H

. Angiotensin receptor-neprilysin inhibitors in patients with heart failure with reduced ejection fraction and advanced chronic kidney disease: a retrospective multi-institutional study. Front Cardiovasc Med. 2022;9:794707.

18.

Jia

Zhang

, et al. Effect of sacubitril/valsartan on renal function in patients with chronic kidney disease and heart failure with preserved ejection fraction: a real-world 12-week study. Eur J Pharmacol. 2022;928:175053.

19.

Lee

Liao

Chen

, et al. Sacubitril/valsartan improves all-cause mortality in heart failure patients with reduced ejection fraction and chronic kidney disease. Cardiovasc Drugs Ther. 2024;38(3):505-515.

20.

Chang

Wang

Hsiao

, et al. Sacubitril/valsartan vs. angiotensin receptor inhibition in heart failure: a real-world study in Taiwan. ESC Heart Fail. 2020;7(5):3003-3012.

21.

Baek

Kim

, et al. Does stage III chronic kidney disease always progress to end-stage renal disease? A ten-year follow-up study. Scand J Urol Nephrol. 2012;46(3):232-238.

22.

Velazquez

Morrow

Devore

, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548.

23.

Bolla

Fedele

Faggiano

Sala

Santangelo

Carugo

. Effects of sacubitril/valsartan on biomarkers of fibrosis and inflammation in patients with heart failure with reduced ejection fraction. BMC Cardiovasc Disord. 2022;22(1):217.

24.

Imran

Hassan

Akhtar

Rahman

Akhtar

Najmi

. Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in Wistar rats. Clin Exp Hypertens. 2018;41(1):62-69.

25.

Solomon

Zile

Pieske

, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387-1395.

26.

Maggioni

Clark

Barrios

, et al. Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: the ARIADNE registry. ESC Heart Fail. 2022;9(6):4209-4218.

27.

Mann

Greene

Givertz

, et al. Sacubitril/valsartan in advanced heart failure with reduced ejection fraction: rationale and design of the LIFE trial. JACC Heart Fail. 2020;8(10):789-799.

28.

Jing

Vaziri

Nunes

, et al. LCZ696 (sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD. Am J Transl Res. 2017;9(12):5473-5484.

29.