Angiotensin‐Neprilysin Inhibition and Renal Outcome in Men and Women With Heart Failure

Abstract

Background

Sacubitril/valsartan is known to reduce adverse renal outcomes and slow the decline in estimated glomerular filtration rate (eGFR) compared with renin‐angiotensin system (RAS) inhibitors across the entire spectrum of heart failure. However, whether these renoprotective effects differ by sex has not been elucidated. Thus, we aimed to evaluate whether the treatment effect of sacubitril/valsartan versus RAS inhibitors on renal outcomes differs by sex.

Methods

Data sets from the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; ejection fraction ≤40%, n=8399) and PARAGON‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; ejection fraction ≥45%, n=4796) trials were integrated in a prespecified pooled analysis. We evaluated the treatment effect (sacubitril/valsartan versus RAS inhibitors) on the prespecified renal composite outcome (death from renal failure, end‐stage renal disease, or ≥50% reduction in eGFR) and changes in eGFR slope in female (n=4311) and male (n=8884) patients to determine whether sex modified the effect of sacubitril/valsartan on renal outcomes.

Results

At baseline, women exhibited lower eGFR values than men (67.2±19.7 versus 72.6±20.4 mL/min/1.73 m², P<0.001). Compared with RAS inhibitors, sacubitril/valsartan reduced the renal composite outcome similarly in women (1.1% versus 2.2%, hazard ratio [HR], 0.51 [95% CI, 0.31–0.83]) and in men (1.0% versus 1.7%, HR, 0.60 [95% CI, 0.41–0.86]; P for interaction=0.60). Sacubitril/valsartan attenuated the decline in eGFR compared with RAS inhibitors similarly in women (−1.8 versus −2.2 mL/min/1.73 m² per year, P=0.006) and men (−1.6 versus −2.3 mL/min/1.73 m² per year, P<0.001) (P for interaction for difference in eGFR slopes=0.19).

Conclusions

Sacubitril/valsartan significantly reduces the incidence of renal composite outcome and decelerates the decline in eGFR compared with RAS inhibitors. The renoprotective effects of this drug are uniformly observed in both women and men.

Nonstandard Abbreviations and Acronyms

ARNI

angiotensin receptor‐neprilysin inhibitor

HHF

hospitalization for heart failure

PARADIGM‐HF

Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure

PARAGON‐HF

Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction

RAS

renin‐angiotensin system

Clinical Perspective.

What Is New?

• This post hoc pooled analysis of the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trials demonstrates that treatment with sacubitril/valsartan is associated with a consistent reduction in renal composite outcomes and a slower annual decline in estimated glomerular filtration rate compared with renin–angiotensin system inhibitors in both women and men, across baseline levels of left ventricular ejection fraction, estimated glomerular filtration rate, N‐terminal pro‐B‐type natriuretic peptide, and systolic blood pressure.

What Are the Clinical Implications?

• In contrast to the sex‐based heterogeneity previously observed for cardiovascular death and heart failure hospitalization—particularly in heart failure with preserved ejection fraction—the renoprotective benefits of sacubitril/valsartan appear consistent across the entire heart failure spectrum, irrespective of sex.

• These findings provide reassurance that sacubitril/valsartan confers uniform renal protection and supports renal risk reduction in both women and men.

In the landmark PARADIGM‐HF (Prospective Comparison of ARNI [Angiotensin Receptor‐Neprilysin Inhibitor] With ACE [Angiotensin‐Converting Enzyme] Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, sacubitril/valsartan, an ARNI, was shown to reduce the risk of all‐cause death and hospitalization for heart failure (HHF) compared with renin‐angiotensin system (RAS) inhibition with enalapril in patients with heart failure (HF) with reduced ejection fraction. ¹ However, in the PARAGON‐HF (Prospective Comparison of ARNI With ARB [Angiotensin Receptor Blocker] Global Outcomes in HF With Preserved Ejection Fraction) trial, sacubitril/valsartan did not significantly reduce cardiovascular death and total HHF in HF with preserved ejection fraction (EF) compared with valsartan. ² Notably, unlike what was seen in PARADIGM‐HF, sex was found to influence the efficacy of sacubitril/valsartan in PARAGON‐HF, with women experiencing a more pronounced benefit in the primary composite outcome compared with men. ² , ³ , ⁴

Chronic kidney disease (CKD) is a common and important comorbidity that is present in an estimated 30% to 60% of patients with HF across the spectrum of left ventricular EF (LVEF). ⁵ , ⁶ , ⁷ , ⁸ When present, CKD is associated with increased risk for adverse cardiovascular events in HF. ⁷ , ⁹ , ¹⁰ Furthermore, the risk of rapid renal function decline is significantly higher in patients with HF than in those without. ¹¹

Analysis of data from the PARADIGM‐HF and PARAGON‐HF trials showed renoprotective benefits of sacubitril/valsartan, demonstrating its efficacy in reducing adverse renal outcomes and decelerating the decline in estimated glomerular filtration rate (eGFR) across the entire spectrum of HF, compared with RAS inhibition alone. ¹² , ¹³ , ¹⁴ However, whether these benefits might vary by sex has not been fully elucidated. Notably, the PARAGON‐HF trial suggested a potential sex‐specific response, with sacubitril/valsartan appearing to reduce cardiovascular death and HHF more effectively in women than in men. ² , ³ In light of these observations, this post hoc analysis was designed to assess the impact of sacubitril/valsartan versus RAS inhibitors on renal outcomes by sex, using the pooled data from the PARADIGM‐HF and PARAGON‐HF trials.

METHODS

Data Availability Statement

The sponsor of the study, Novartis, emphasizes its commitment to the sharing of patient‐level data and pertinent clinical documents from eligible studies with credible external researchers. Requests for access are subject to a thorough evaluation and approval process conducted by an independent review panel, which judges the scientific merit of each proposal. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. Trial data are available according to the criteria and process described. ¹⁵ For this study, the data were uploaded to a secure cloud server, providing the research team with access for comprehensive analysis without the need to export the original data sets. To verify data completeness and analysis accuracy, investigators successfully replicated the original outcomes from the PARADIGM‐HF and PARAGON‐HF study.

Study Populations

We integrated the data sets from the PARADIGM‐HF and PARAGON‐HF studies, both of which were randomized, double‐blind, active comparator trials. These studies evaluated the efficacy of sacubitril/valsartan against a RAS inhibitor among patients with symptomatic HF. The design and primary results of both studies have been reported previously. ¹ , ² , ¹⁶ , ¹⁷ In brief, the PARADIGM‐HF study compared the impact of sacubitril/valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) with that of enalapril (target dose, 10 mg twice daily) in 8399 patients with HF and LVEF ≤40% and New York Heart Association functional classes II to IV. The primary outcome was time to first occurrence of cardiovascular death or HHF during a median follow‐up of 27 months. The PARAGON‐HF study compared the efficacy and safety of sacubitril/valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) with valsartan (target dose, 160 mg twice daily) in 4796 patients with HF with preserved EF aged ≥50 years, New York Heart Association functional classes II to IV, LVEF ≥45%, evidence of structural heart disease, elevated natriuretic peptides, and diuretic therapy. The primary outcome was a composite of cardiovascular deaths and total HHF during a median follow‐up of 35 months. The exclusion criteria regarding kidney function were consistent across both studies. Patients were excluded if they presented with an eGFR of <30 mL/min/1.73 m² at the time of screening or <25 mL/min/1.73 m² at the time of randomization. Additionally, individuals showing a decline of >35% in eGFR between the screening and randomization phases were also excluded.

All patients provided written informed consent to participate in each of the trials, and study protocols were approved by local institutional review boards. The institutional review board of Seoul National University Bundang Hospital (institutional review board No B‐2208‐777‐005) approved the study protocol. This study complied with the Declaration of Helsinki principles.

Definition of Outcomes

In this study, we assessed the impact of sacubitril/valsartan on renal outcomes in contrast to RAS inhibitors (either enalapril or valsartan), across the entire spectrum of LVEF according to sex. The prespecified renal end point for the original PARADIGM‐HF was time to first occurrence of any of the following: (1) a 50% decline in eGFR relative to baseline, (2) >30 mL/min/1.73 m² decline in eGFR relative to baseline to <60 mL/min/1.73 m², or (3) reaching end‐stage renal disease. ¹ , ¹⁶ For the purpose of the current pooled analysis, the renal composite outcome from PARAGON‐HF was considered, ² , ¹⁷ defined as either (1) death from renal failure, (2) development of end‐stage renal disease, or (3) a decrease in eGFR of ≥50% from baseline (ie, worsening renal function) (Table S1). Additionally, we conducted an analysis of the effects of sacubitril/valsartan (versus RAS inhibitors) on each individual component of the composite renal outcomes according to sex. As prespecified subgroup analyses, the differential effect of sacubitril/valsartan on the composite renal outcome according to baseline LVEF, eGFR, natriuretic peptide (NP) levels, and systolic blood pressure (SBP) was evaluated.

Further analyses were performed to evaluate whether sex modified the effect of sacubitril/valsartan on changes in eGFR slope during the follow‐up period. When assessing the renal composite outcome, the Modification of Diet in Renal Disease formula ¹⁸ was used for calculating eGFR, consistent with the original PARADIGM‐HF and PARAGON‐HF trials, where worsening renal function was identified programmatically by the sponsor. For evaluating change in eGFR slope during the follow‐up period, the most recent equation of the 2021 Chronic Kidney Disease Epidemiology Collaboration (2021 equation) ¹⁹ was used, similar to previous studies. ¹³ , ¹⁴

Statistical Analysis

Categorical variables are reported as frequencies (percentages) and were compared using Pearson's chi‐square test. Continuous variables were tested for normality using the Shapiro–Wilk normality test. Continuous variables with normal distribution are expressed as means±SD and were compared using Student's t test. Nonnormally distributed continuous variables are presented as medians with interquartile ranges and were compared using the Mann–Whitney U test.

The analyses were performed according to the intention‐to‐treat principle and included data from all patients who had undergone a valid randomization. For the assessment of the renal outcomes, we used Cox proportional hazards models to calculate hazard ratios (HRs) with 95% CIs. The proportional hazards assumption was tested using Schoenfeld residuals. These models were stratified by sex and the specific study (either PARADIGM‐HF or PARAGON‐HF) to account for potential variations in these factors. We investigated the interaction between the treatment effect of sacubitril/valsartan and sex with respect to composite renal outcomes by computing interaction terms. The effect modification of sacubitril/valsartan on the composite renal outcome, which was considered as a continuous function of LVEF, baseline eGFR, NT‐proBNP (N‐terminal pro‐B‐type NP) level, and SBP, was examined using restricted cubic splines, offering a more nuanced view of how they may influence treatment outcomes. Further, we assessed the relationship between LVEF, eGFR, NT‐proBNP, and SBP and the efficacy of sacubitril/valsartan in both men and women by calculating 3‐way interaction terms due to the observed effect modification by sex in the PARAGON‐HF trial.

The analysis of eGFR changes over time was conducted using repeated measures mixed‐effects models, incorporating data collected at randomization and at subsequent follow‐ups at 4, 16, 32, 48, 96, and 144 weeks with no imputation for missing data. These models were adjusted for treatment assignment, time of the trial visit, and the interaction between treatment assignment and visit time, allowing for the individualization of eGFR trajectories over the study period. This approach, which included patient and time as random effects, permitted the modeling of varying intercepts and slopes over time for each participant, providing a comprehensive assessment of renal function dynamics under the influence of sacubitril/valsartan compared with RAS inhibitors. To assess whether treatment effects on eGFR changes over time varied between women and men, interaction testing was performed.

All tests were 2 tailed, and a P value <0.05 was considered statistically significant. Statistical analyses were performed using R programming version 4.3.2 (The R Foundation for Statistical Computing, Vienna, Austria) and Python version 3.10 (Python Software Foundation, Beaverton, OR, USA).

RESULTS

Patient Characteristics

Data from 8399 patients in the PARADIGM‐HF study and 4796 patients from the PARAGON‐HF study were combined, resulting in a total of 13 195 patients. These patients were then stratified by sex, with 67.3% being male and 32.7% female. Baseline characteristics stratified according to sex are displayed in Table 1. Overall, female patients were older and had higher BP and body mass index compared with their male counterparts. They had a less frequent ischemic cause and a higher mean LVEF and lower median NT‐proBNP level than men. Furthermore, they received mineralocorticoid receptor antagonists and beta blockers less frequently at randomization than men. Comparisons according to the parent study are reported in Table S2.

Table 1.

Baseline Characteristics According to Sex

Characteristics	Women (n=4311)	Men (n=8884)	P value
Age, y	70.0±10.6	65.6±11.3	<0.001
Race, n (%)			<0.001
White	3168 (73.5)	6283 (70.7)
Black	194 (4.5)	336 (3.8)
Asian	579 (13.4)	1537 (17)
Other	370 (8.6)	728 (8)
Geographic region, n (%)			0.009
North America	368 (8.5)	793 (8.9)
Latin America	613 (14.2)	1190 (13.4)
Western Europe	1118 (25.9)	2322 (26.1)
Central Europe	1541 (35.7)	3000 (33.8)
Asia‐Pacific or other	671 (15.6)	1578 (17.8)
Systolic blood pressure, mm Hg	127.6±16.3	123.3±15.7	<0.001
Heart rate, bpm	71.8±12.0	71.6±12.2	0.56
Body mass index, kg/m2	29.6±5.8	28.6±5.2	<0.001
Serum creatinine, mg/dL	0.97±0.26	1.18±0.30	<0.001
eGFR*, mL/min/1.73m2	62.3±19.8	67.6±19.8	<0.001
eGFR†, mL/min/1.73m2	67.2±19.7	72.6±20.4	<0.001
Clinical features of heart failure
Ischemic cause, n (%)	1640 (38.0)	5119 (57.6)	<0.001
Left ventricular ejection fraction, %	46.6±16.0	36.3±13.5	<0.001
N‐terminal pro‐B‐type natriuretic peptide, pg/mL	1132 [585–2115]	1395 [764–2721]	<0.001
New York Heart Association class, n (%)			<0.001
I	116 (2.7)	410 (4.6)
II	3077 (71.4)	6548 (73.7)
III	1083 (25.1)	1867 (21.0)
IV	34 (0.8)	45 (0.5)
Missing data	1 (0.0)	14 (0.2)
Medical history, n (%)
Hypertension	3751 (87.0)	6773 (76.2)	<0.001
Diabetes	1614 (37.4)	3355 (37.8)	0.74
Atrial fibrillation or flutter	1352 (31.4)	3291 (37.0)	<0.001
Stroke	411 (9.5)	822 (9.3)	0.63
Myocardial infarction	984 (22.8)	3733 (42.0)	<0.001
Hospitalization for heart failure	2221 (51.5)	5359 (60.3)	<0.001
Treatment, n (%)
Diuretic at randomization	3829 (88.8)	7494 (84.4)	<0.001
Angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker at screening	3977 (92.3)	8561 (96.4)	<0.001
Mineralocorticoid receptor antagonist at randomization	1616 (37.4)	4294 (48.3)	<0.001
Beta blocker at randomization	3676 (85.3)	7956 (89.6)	<0.001
Sacubitril/valsartan	2120 (49.2)	4474 (50.4)	0.21

Values are expressed as number (%), mean±SD, or median [interquartile range]. eGFR indicates estimated glomerular filtration rate.

^*eGFR estimated according to the Modification of Diet in Renal Disease formula.

^† eGFR estimated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration.

Composite Renal Outcomes According to Sex

At baseline, women exhibited lower eGFR values by 2021 Chronic Kidney Disease Epidemiology Collaboration equation than men (67.2±19.7 versus 72.6±20.4 mL/min/1.73 m², P<0.001). The renal composite outcomes were observed in 1.7% (72 of 4311) among women and 1.4% (121 of 8884) among men, with no significant difference. Over the 4‐year follow‐up period, both male and female patients receiving sacubitril/valsartan experienced fewer composite renal end points compared with those receiving RAS inhibitors, as depicted in Figure 1. Compared with RAS inhibitors, sacubitril/valsartan similarly reduced the renal composite end point in both women (1.1% versus 2.2%, HR, 0.51 [95% CI, 0.31–0.83]) and men (1.0% versus 1.7%, HR, 0.60 [95% CI, 0.41–0.86]), with no significant sex‐based interaction (P for interaction=0.60), as detailed in Table 2.

Figure 1. Kaplan–Meier analysis of composite renal outcome by sex.

Estimates are shown for the probability of a first occurrence of the composite renal outcome, defined as a ≥50% reduction in estimated glomerular filtration rate from baseline, development of end‐stage renal disease, or death due to renal failure, in (A) all patients, (B) the PARADIGM‐HF trial, and (C) the PARAGON‐HF trial. ARNI indicates angiotensin receptor‐neprilysin inhibitor; HR, hazard ratio; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RAS, renin‐angiotensin system.

Table 2.

Effects of Sacubitril/Valsartan on Renal Outcomes Stratified by Sex

	Women				Men				Interaction P value
	All	Sacubitril/valsartan	RAS inhibitor	Hazard ratio (95% CI)	All	Sacubitril/valsartan	RAS inhibitor	Hazard ratio (95% CI)
Combined (n=13 194)
Renal composite end point	72/4311 (1.7%)	24/2120 (1.1%)	48/2191 (2.2%)	0.51 (0.31–0.83)	121/8884 (1.4%)	46/4474 (1.0%)	75/4410 (1.7%)	0.60 (0.41–0.86)	0.60
Worsening renal function	62/4311 (1.4%)	20/2120 (0.9%)	42/2191 (1.9%)	0.48 (0.28–0.82)	99/8884 (1.1%)	39/4474 (0.9%)	60/4410 (1.4%)	0.63 (0.42–0.94)	0.42
End‐stage renal disease	13/4311 (0.3%)	5/2120 (0.2%)	8/2191 (0.4%)	0.64 (0.21–1.97)	30/8884 (0.3%)	10/4474 (0.2%)	20/4410 (0.4%)	0.48 (0.23–1.03)	0.70
Renal death	2/4311 (0.1%)	1/2120 (0.1%)	1/2191 (0.1%)	1.02 (0.06–16.32)	2/8884 (0.02%)	1/4474 (0.02%)	1/4410 (0.02%)	0.98 (0.06–15.62)	0.98
PARADIGM‐HF (n=8399)
Renal composite end point	24/1832 (1.3%)	8/879 (0.9%)	16/953 (1.7%)	0.55 (0.23–1.28)	72/6567 (1.1%)	29/3308 (0.9%)	43/3259 (1.3%)	0.66 (0.41–1.06)	0.72
Worsening renal function	20/1832 (1.1%)	7/879 (0.8%)	13/953 (1.4%)	0.59 (0.24–1.48)	54/6567 (0.8%)	25/3308 (0.8%)	29/3259 (0.9%)	0.85 (0.50–1.44)	0.52
End‐stage renal disease	5/1832 (0.3%)	2/879 (0.2%)	3/953 (0.3%)	0.73 (0.12–4.38)	19/6567 (0.3%)	6/3308 (0.2%)	13/3259 (0.4%)	0.45 (0.17–1.18)	0.65
Renal death	0/1832 (0%)	0/879 (0%)	0/953 (0%)	…	2/6567 (0.03%)	1/3308 (0.03%)	1/3259 (0.03%)	0.98 (0.06–15.64)	…
PARAGON‐HF (n=4795)
Renal composite end point	48/2479 (1.9%)	16/1241 (1.3%)	32/1238 (2.6%)	0.50 (0.27–0.91)	49/2317 (2.1%)	17/1166 (1.5%)	32/1151 (2.8%)	0.51 (0.28–0.92)	0.92
Worsening renal function	42/2479 (1.7%)	13/1241 (1.0%)	29/1238 (2.3%)	0.45 (0.23–0.86)	45/2317 (1.9%)	14/1166 (1.2%)	31/1151 (2.7%)	0.43 (0.23–0.81)	0.97
End‐stage renal disease	8/2479 (0.3%)	3/1241 (0.2%)	5/1238 (0.4%)	0.61 (0.14–2.54)	11/2317 (0.5%)	4/1166 (0.3%)	7/1151 (0.6%)	0.54 (0.16–1.86)	0.94
Renal death	2/2479 (0.1%)	1/1241 (0.1%)	1/1238 (0.1%)	0.99 (0.06–15.89)	0/2317 (0%)	0/1166 (0%)	0/1151 (0%)	…	…

PARADIGM‐HF indicates Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RAS renin‐angiotensin system; and RAS, renin‐angiotensin system.

Regarding the individual renal end point, the majority of events within the renal composite outcome were attributed to declines in eGFR of ≥50% relative to baseline. A similar treatment effect was observed in both women (HR, 0.48 [95% CI, 0.28–0.82]) and men (HR, 0.63 [95% CI, 0.42–0.94]; P for interaction=0.42). Additionally, rates of progression to end‐stage renal disease were similarly reduced by sacubitril/valsartan compared with RAS inhibitors in both women (HR, 0.64 [95% CI, 0.21–1.97]) and men (HR, 0.48 [95% CI, 0.23–1.03]; P for interaction=0.70). There were 2 renal deaths in women (1 in each randomized treatment arm) and 2 renal deaths in men (1 in each randomized treatment arm).

Change in Estimated Glomerular Filtration Rate Over Time in Men and Women

During the follow‐up period from randomization to trial completion, the mean decline in eGFR for all patients was −2.0 mL/min/1.73 m² per year, with a 95% CI of −2.1 to −1.9 mL/min/1.73 m² per year (Table 3). Patients receiving sacubitril/valsartan experienced a slower decline in eGFR compared with those treated with RAS inhibitors (−1.7 versus −2.3 mL/min/1.73 m² per year, P<0.001). Sacubitril/valsartan attenuated the decline in eGFR compared with RAS inhibitors similarly in women (−1.8 versus −2.2 mL/min/1.73 m² per year, P=0.006) and men (−1.6 versus −2.3 mL/min/1.73 m² per year, P<0.001) (P‐interaction for difference in eGFR slopes=0.19) (Figure 2).

Table 3.

Change From Baseline in eGFR

	All patients	Women	Men
Combined (n=13 194)
All patients	−2.0 (−2.1 to −1.9)	−2.0 (−2.2 to −1.8)	−1.9 (−2.1 to −1.8)
Sacubitril/valsartan	−1.7 (−1.8 to −1.6)	−1.8 (−2.0 to −1.6)	−1.6 (−1.8 to −1.4)
RAS inhibitor	−2.3 (−2.4 to −2.2)	−2.2 (−2.4 to −2.0)	−2.3 (−2.5 to −2.1)
Mean difference (95% CI; P value)	0.6 (0.4 to 0.8; P<0.001)	0.5 (0.1 to 0.8; P=0.006)*	0.7 (0.4 to 0.9; P<0.001)*
PARADIGM‐HF (n=8399)
All patients	−1.3 (−1.5 to −1.2)	−1.3 (−1.7 to −1.0)	−1.3 (−1.5 to −1.2)
Sacubitril/valsartan	−1.1 (−1.3 to −0.9)	−1.0 (−1.5 to −0.5)	−1.1 (−1.3 to −0.9)
RAS inhibitor	−1.5 (−1.7 to −1.3)	−1.6 (−2.1 to −1.1)	−1.5 (−1.8 to −1.2)
Mean difference (95% CI; P value)	0.4 (0.1 to 0.7; P=0.007)	0.6 (−0.1 to 1.3; P=0.086)	0.4 (0.0 to 0.7; P=0.031)
PARAGON‐HF (n=4795)
All patients	−2.3 (−2.5 to −2.2)	−2.2 (−2.4 to −2.0)	−2.5 (−2.7 to −2.3)
Sacubitril/valsartan	−2.0 (−2.2 to −1.8)	−2.0 (−2.3 to −1.7)	−2.1 (−2.4 to −1.8)
RAS inhibitor	−2.7 (−2.9 to −2.5)	−2.4 (−2.7 to −2.1)	−2.9 (−3.2 to −2.6)
Mean difference (95% CI; P value)	0.6 (0.4 to 0.9; P<0.001)	0.5 (0.1 to 0.8; P=0.017)	0.9 (0.5 to 1.2; P<0.001)

Data are presented as mean change in eGFR (mL/min/1.73 m² per year) with 95% CIs. P values are reported for differences in eGFR change between patients treated with sacubitril/valsartan and with RAS inhibitor. eGFR indicates estimated glomerular filtration rate; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RAS renin‐angiotensin system.

^* P for interaction was 0.19, assessing whether the treatment effects of sacubitril/valsartan (vs RAS inhibitor) on eGFR changes over time between female and men.

Figure 2. Change in eGFR over time in female and male.

The eGFR was calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. Error bars indicate 95% CIs. Estimates are shown for (A) all patients, (B) the PARADIGM‐HF trial, and (C) the PARAGON‐HF trial. *P ‐values are reported for differences in eGFR change between patients treated with ARNI and those treated with RASi. †P for interaction are reported to assess whether the treatment effects of sacubitril/valsartan (compared with RASi) on eGFR changes over time varied between women and men. ARNI indicates angiotensin receptor‐neprilysin inhibitor; eGFR, estimated glomerular filtration rate; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RASi, renin‐angiotensin system inhibitor.

Similar patterns were noted when patients were stratified according to their original study cohorts, PARADIGM‐HF versus PARAGON‐HF. Upon further stratification by the originating study, the PARADIGM‐HF study demonstrated fewer renal composite end points in comparison to those noted in the PARAGON‐HF study (1.1% versus 2.0%; P<0.001). Nevertheless, the efficacy of sacubitril/valsartan in improving renal outcomes was consistent across both studies and irrespective of sex, as delineated in Figure 1 and Table 2. Particularly within the PARAGON‐HF study cohort, where the impact of sacubitril/valsartan on the composite end point of cardiovascular death and total HHF showed a less pronounced effect in men, marked by a significant interaction, the renoprotective effect of sacubitril/valsartan exhibited no variation between women (HR, 0.50 [95% CI, 0.27–0.91]) and men (HR, 0.51 [95% CI, 0.28–0.92]) (P for interaction=0.92).

Subgroup Analysis According to LVEF, eGFR, NT‐proBNP Levels, and SBP at Baseline

Next, we evaluated whether the effects of sacubitril/valsartan (compared with RAS inhibitors) on renal composite outcomes by sex were consistent across baseline levels of LVEF, eGFR, NT‐proBNP, and SBP.

Regarding LVEF, the renal benefit seems to diminish in patients with LVEF <25%, with a trend observed similarly in both men and women. The effect modification by LVEF on the efficacy of sacubitril/valsartan was similar in both men and women (3‐way interaction P=0.81; Figure 3A). By contrast, the renoprotective effect of sacubitril/valsartan remained consistent irrespective of baseline eGFR, NT‐proBNP levels, and SBP (Figure 3B–D). Additionally, the modification of effect by eGFR, NT‐proBNP levels, and SBP on the efficacy of sacubitril/valsartan was consistent in both men and women (3‐way interaction P>0.10 for all).

Figure 3. Continuous treatment effect of sacubitril/valsartan versus RAS inhibitors on the renal composite outcome according to LVEF, eGFR, NT‐proBNP levels, and SBP.

Estimated hazard ratios and 95% CIs are displayed for men (blue) and women (red) separately, according to (A) LVEF, (B) eGFR, (C) NT‐proBNP levels, and (D) SBP. eGFR indicates estimated glomerular filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; RAS, renin‐angiotensin system; and SBP, systolic blood pressure.

Sensitivity Analyses

Sensitivity analyses using alternative eGFR equations (the 2009 Chronic Kidney Disease Epidemiology Collaboration equation) to estimate longitudinal eGFR slopes, as well as a Fine–Gray competing risk regression for the renal composite outcome with all‐cause death treated as a competing event, yielded consistent results (Tables S3 and S4).

DISCUSSION

This post hoc pooled analysis of the PARADIGM‐HF and PARAGON‐HF trials revealed that despite significant baseline differences between male and female participants (notably, women were older, had higher LVEF, and lower eGFR at the baseline), treatment with sacubitril/valsartan led to a uniform reduction in the incidence of renal composite outcomes compared with RAS inhibitors in both sexes. In addition, sacubitril/valsartan attenuated the decline of eGFR compared with RAS inhibitors similarly in men and women. Such consistency suggests that the drug's renal benefits transcend sex. Moreover, this contrasts with the observed variability in cardiovascular death and HHF outcomes among patients with HF with preserved ejection fraction based on sex. ² , ³ This distinction underlines the potential for sacubitril/valsartan to provide a universally effective renal protective strategy in HF, for both female and male patients.

The Differential Effect of Sacubitril/Valsartan According to Sex and HF Category

In the initial findings of the PARAGON‐HF trial, sacubitril/valsartan did not achieve a significant reduction in the primary composite end point of cardiovascular death and total HHF (HR, 0.95 [95% CI, 0.79–1.16, P=0.06]). ² Intriguingly, a prespecified subgroup analysis uncovered a significant interaction between the drug's effectiveness and both LVEF and sex. ³ , ²⁰ This analysis suggested efficacy in women, but not in men, and among participants with an LVEF below the median of 57%. The specific reasons for this variation, influenced by both LVEF and sex, remain elusive, fueling ongoing clinical interest. These previous results, however, raise the question of whether sacubitril/valsartan's impact on renal outcomes also varies by sex, a question underscored by the drug's anticipated renoprotective advantages. Although a few studies have briefly addressed this issue, in‐depth investigations have been lacking. ¹² , ¹³ , ¹⁴ In our investigation, the renoprotective effects of sacubitril/valsartan were found to be consistent across sexes throughout the HF spectrum.

This finding is clinically meaningful, as preservation of renal function is a key determinant of long‐term prognosis, treatment tolerability, and the ability to implement disease‐modifying therapies across the heart failure spectrum. Moreover, in the contemporary context of cardiovascular‐kidney‐metabolic syndrome ²¹ —where multiple pharmacologic classes have demonstrated renal benefits—our results provide reassurance that ARNI confers consistent renal protection in both women and men. Although elucidating the mechanisms underlying sex‐specific cardiovascular responses remains an important research priority, the present findings underscore that such heterogeneity does not extend to renal outcomes and highlight the complementary role of sacubitril/valsartan in renal risk mitigation irrespective of sex.

Decline in eGFR

Women often have lower baseline eGFR compared with men, and in this pooled trial cohort, eGFRs were indeed lower in the female patients compared with in their male counterparts. The presence of reduced eGFR at baseline raises concerns about potential declines in eGFR following HF medication. However, our study has demonstrated that the effect of sacubitril/valsartan in slowing the decline of eGFR compared with RAS inhibitors does not differ between men and women. Because dynamic changes in eGFR are associated with subsequent renal outcomes, ²² our findings support the premise that preserving the eGFR trajectory is a key driver of the drug's renoprotective effect and suggest that sacubitril/valsartan provides multifaceted renal benefits.

RAS inhibition alone caused vasodilation of efferent arterioles and often results in a decrease in eGFR. ²³ In contrast, neprilysin inhibition increases NP levels in the kidney and attenuates the constrictive tubuloglomerular feedback on the afferent arteriole by increasing cyclic guanosine monophosphate levels. ²⁴ , ²⁵ These effects result in dilation of afferent arterioles, an increase in intraglomerular pressure, and consequently, an increase in GFR. ²⁶ The comparison between sacubitril/valsartan and RAS inhibition alone on renal function in the pooled trial data indicates the superiority of combined neprilysin/angiotensin inhibition and demonstrates that this effect is independent of sex.

Although women had lower baseline eGFR values than men at baseline, this difference did not translate into a higher risk of the composite renal end point or into differential renoprotective effects of sacubitril/valsartan. Several factors may explain this observation. First, the renal composite outcome was driven predominantly by a relative decline in renal function (≥50% reduction in eGFR from baseline), such that modest baseline differences in eGFR within the preserved‐to‐moderate impairment range would not be expected to result in substantially different event rates. Second, both PARADIGM‐HF and PARAGON‐HF excluded patients with advanced kidney disease, thereby limiting baseline renal risk and minimizing extreme separation of renal vulnerability between women and men. Third, creatinine‐based eGFR reflects, in part, sex‐related differences in muscle mass and creatinine generation; consequently, lower baseline eGFR in women does not necessarily indicate more severe intrinsic renal disease.

Prespecified Subgroup Analysis According to Baseline LVEF, NT‐proBNP Level, and SBP

Our study provides evidence that the renoprotective efficacy of sacubitril/valsartan is unaffected by LVEF. This consistency is particularly significant given the LVEF‐dependent benefits for HF outcomes demonstrated in the PARAGON‐HF study ² , ²⁰ and indicates the superiority of combined neprilysin/angiotensin inhibition over RAS inhibition across the spectrum of LVEF. Considering the crucial role that natriuretic peptides play in renal natriuresis, it was essential to investigate whether its efficacy is compromised in patients with elevated NT‐proBNP levels. Elevated baseline NT‐proBNP typically indicates an already heightened NP activity in patients. Our results confirm that sacubitril/valsartan maintains its renoprotective benefits regardless of NT‐proBNP concentrations in both men and women. In the PARAGON‐HF study, sacubitril/valsartan lowered BP to a greater extent than valsartan and was associated with a higher frequency of hypotensive events. ² Similar findings were observed in the PARADIGM‐HF study. ¹ However, the occurrence of adverse renal events was lower in the sacubitril/valsartan group compared with the RAS inhibitors group across the entire spectrum of baseline SBP. These findings suggest that potential adverse effects of BP reduction with sacubitril/valsartan on renal function were not sufficient to outweigh the renoprotective effects of this therapy. In addition, the influence of LVEF, eGFR, NT‐proBNP level, and SBP on the efficacy of sacubitril/valsartan was consistent across both men and women. This detailed subgroup analysis reinforces the robustness of sacubitril/valsartan's renoprotective effects, advocating for its essential role in the HF treatment strategies focused on preserving renal function.

Study Limitations

This study has several limitations. First, although the renal composite outcome was a prespecified secondary end point in both PARADIGM‐HF and PARAGON‐HF trials, these studies were not specifically powered to assess individual renal components or to precisely evaluate differences in eGFR decline. Consequently, the relatively small number of observed renal composite events and the potential for residual confounding renders these findings exploratory in nature, and our posthoc analyses should be treated with caution and considered only as hypothesis generating. Second, the exclusion of patients with advanced kidney disease (eGFR <30 mL/min/1.73 m²) and the modest representation of women and non‐White populations in both PARADIGM‐HF and PARAGON‐HF trials may restrict the broader applicability of our conclusions. Third, due to the design of the original trials, data on patients with an LVEF in the 41% to 45% range are scarce, which could limit insights into this specific subgroup. Fourth, the use of a unified definition for the composite renal outcome across both trials for comparative analysis poses an additional challenge, given that PARADIGM‐HF and PARAGON‐HF initially employed differing criteria for defining renal composite end points. ¹⁶ , ¹⁷ Fifth, PARADIGM‐HF and PARAGON‐HF used different RAS inhibitor comparators (enalapril versus valsartan). However, prior evidence suggests that ACE inhibitors and ARBs provide broadly comparable renal protection in large active‐comparator randomized data (eg, telmisartan versus ramipril in ONTARGET [Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint] ²⁷ ), and contemporary CKD guidelines consider either ACEi or ARB as standard renoprotective RAS inhibition. ²⁸

CONCLUSIONS

In conclusion, our post hoc analysis of the PARADIGM‐HF and PARAGON‐HF trials demonstrates that sacubitril/valsartan significantly reduces the incidence of renal composite outcomes and decelerates the decline in eGFR compared with enalapril or valsartan, with this renoprotective benefit being uniformly observed in both women and men. These findings underscore the essential role of sacubitril/valsartan in HF treatment including renal function preservation for both sexes.

Sources of Funding

This work was supported by Novartis Pharma AG, Basel, Switzerland. It was also supported by National Science Foundation of Korea Grant RS‐2022‐00165404 and RS‐2024‐00463402. Additional funding was provided by Institute of Information & communications Technology Planning & Evaluation grant funded by the Korean government (Ministry of Science and ICT) [NO. RS‐2021‐II211343], and a grant (no. 02‐2025‐0025) from Seoul National University Bundang Hospital Research Fund.

Disclosures

None.

Supporting information

Tables S1–S4

CONSORT Checklist