Prognostic Impact of Sustained Reduction of N-Terminal Pro-B-Type Natriuretic Peptide After Initiating Sacubitril/Valsartan　― Insights From the REVIEW-HF Registry ―

Abstract

Background: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values after initiating sacubitril/valsartan (Sac/Val) are considered a favorable prognostic factor in patients with heart failure (HF). However the relationship between the trajectory of repeated NT-proBNP measurements and cardiovascular events after Sac/Val remains uncertain.

Methods and Results: A Japanese nationwide multicenter study enrolled 995 patients who were prescribed Sac/Val from August 2020 to August 2021. Of them, 434 patients who had a complete set of NT-proBNP measurements were divided into 3 groups: sustained-responder group (n=129), with ≥10% reduction in NT-proBNP at 1 month and further ≥10% reduction at 3 months; transient-responder group (n=161), with ≥10% reduction at 1 month but not at 3 months; and non-responder group (n=144), without ≥10% reduction at 1 month. There were no significant differences in the mean Sac/Val dose at each measurement point among the 3 groups. During a median follow-up of 456 (interquartile range: 371–549) days, the primary endpoint, which was either cardiovascular death or hospitalization for HF, occurred in 78 patients. Kaplan-Meier analysis revealed that the sustained-responder group had a significantly higher event-free survival rate among the 3 groups (Log-rank P<0.001).

Conclusions: Repeated NT-proBNP monitoring and the pattern of the NT-proBNP trajectory after Sac/Val may be helpful in optimizing HF therapy and understanding the prognosis of HF.

The prevalence of heart failure (HF) in the adult population generally ranges between 1% and 3%,¹ escalating with age.² Despite significant advances in pharmacological therapy, patients with HF still have a poor prognosis.^3,4 N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a crucial biomarker for managing volume status and hemodynamics in patients with HF,⁵ and its levels are widely used for prognostication and risk stratification in routine HF clinical practice.^6–8 Previous studies have demonstrated that sacubitril/valsartan (Sac/Val) decreases cardiovascular mortality rates, particularly in HF patients with reduced left ventricular ejection fraction (LVEF), and reduces NT-proBNP values in HF patients regardless of LVEF.^9,10 Additionally, NT-proBNP values at 1 month after initiating Sac/Val, along with changes in those values from baseline, have been found to predict cardiovascular events in HF patients.^10,11 However, in clinical practice, there are instances where NT-proBNP values initially decrease after initiating Sac/Val but then increase during the clinical course. Although a relationship between changes in NT-proBNP values before and after initiating Sac/Val and prognosis has been demonstrated, the relationship between the trajectory of repeated NT-proBNP values measurements and cardiovascular events remains uncertain. In this study, we investigated the prognostic impact of the NT-proBNP trajectory after initiating Sac/Val on the risk of cardiovascular events.

Methods

Study Design and Patient Population

The REVIEW-HF (Real-world evidence of Angiotensin Receptor-Neprilysin Inhibitor in Patients with Heart Failure) registry was a nationwide multicenter retrospective cohort study in Japan that was conducted to evaluate the efficacy and safety of newly prescribed Sac/Val in patients aged ≥20 years with HF at 17 facilities in Japan from August 2020 to August 2021.¹² In Japan, the indication of Sac/Val was approved for HF management regardless of LVEF, and serial assessment of HF condition was required during this period under the Japanese insurance system. Both the initiation and the maintenance dose of Sac/Val was at the doctor’s discretion. Patients were divided into 3 groups based on the NT-proBNP trajectory from baseline to 3 months: sustained-responder group (reduction of NT-proBNP by ≥10% at 1 month and a further reduction of ≥10% at 3 months); transient-responder group (≥10% reduction at 1 month but not at 3 months); and non-responder group (did not achieve ≥10% reduction at 1 month) (Figure 1). Patients who lacked the required data were excluded from the study, which encompassed cases managed by BNP, not NT-proBNP assessments. The study adhered to the principles of the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Toho University Omori Medical Center (no. M21257). Informed consent was waived for each participating hospital due to the retrospective nature of the study and the opt-out method of inclusion. Study information, including the objectives, inclusion and exclusion criteria, and the names of participating hospitals were published in the publicly available University Hospital Information Network Clinical Trial Registry (UMIN-ID: UMIN000047636).

Figure 1.

Study flowchart. Non-responder group, patients without ≥10% reduction of NT-proBNP at 1 month; sustained-responder group, patients with 10% reduction of NT-proBNP at 1 month and with further 10% reduction of NT-proBNP at 3 months; transient-responder group, patients without 10% reduction of NT-proBNP at 3 months although with 10% reduction of NT-proBNP at 1 month.

Data Collection and Study Outcomes

Utilizing an electronic data capture system, we collected patients’ data, including medical history, physical examination, pre-Sac/Val prescription therapy, blood pressure (BP) measurement, laboratory data, electrocardiography, and echocardiography. Patients were followed up, and longitudinal data, including laboratory data and Sac/Val dose, were collected at 2 weeks, 1 month, and 3 months. The primary endpoint was defined as a composite of cardiovascular death (CVD) and first hospitalization for HF (HHF). The secondary endpoints included evaluating changes in daily Sac/Val dosage, systolic BP (sBP), and the relationship between the trajectory of NT-proBNP values and prognosis in subgroups created based on LVEF. Additionally, we analyzed the change of echocardiographic parameters (LVEF and LV end-diastolic diameter [LVDd]) from baseline in the patients with LVEF <50%.

Statistical Analysis

All data were analyzed using the JMP Pro ver.17.0.0 (SAS Institute, Cary, NC, USA).

Categorical variables are expressed as numbers (percentages) and continuous variables as mean±standard deviation (SD) or the median and interquartile range (IQR). Baseline and follow-up data were compared in the 3 groups, using ANOVA or Kruskal-Wallis test for continuous variables and Chi-square test for categorical variables. If there were significant differences among the groups, we used Bonferroni correction to assess the sustained-responder group data compared with the transient-responder group or the non-responder group, respectively. Event-free survival curves of the 3 groups were created using the Kaplan-Meier method, and comparison between curves was performed using the log-rank test. We plotted the event-free survival curves between the sustained-responder group and the transient-responder group using the landmark method and defined the landmark time as 3 months after initiating Sac/Val. Cox proportional hazard analysis was performed to assess the hazard ratio for the primary endpoint within the subgroup stratified by LVEF <40%, 40≤LVEF<50%, or LVEF ≥50% and group interaction was assessed. To predict “sustained-responder” status after initiating Sac/Val, we performed logistic regression univariate and multivariate analysis of initial responders at 1 month. In the multivariate analysis, we included variables that demonstrated a P value <0.200 in the univariate analysis. P<0.050 was considered statistically significant.

Results

Baseline Characteristics

A total of 995 patients were enrolled, and of them 559 patients without NT-proBNP measurement at baseline, 1 month, or 3 months, and 2 patients without LVEF data at baseline were excluded. Finally, 434 patients met the inclusion criteria for this study (Figure 1). Baseline clinical characteristics for each of the subgroup are described in Table 1. In this study, 290 of 434 patients (67%) experienced ≥10% reduction of NT-proBNP at 1 month, and of them, 129 (44%) experienced a sustained ≥10% reduction of NT-proBNP from 1 month to 3 months. The mean age was 68±14 years, but significantly younger in the sustained-responder group, with females comprising 29%. The initial Sac/Val dose was 98.3±34.2 mg/dL, and 38% of patients began using Sac/Val during hospitalization. The majority of those patients were classified as New York Heart Association (NYHA) functional class II or III. The median NT-proBNP value at baseline was 1,833 [792, 3,566]. Significant differences were noted among the 3 groups concerning age, heart rate, estimated glomerular filtration rate, the number of patients whose time since diagnosis of HF was ≥1.5 years, NT-proBNP values, and LVEF. In particular, the number of patients whose time since diagnosis of HF was ≥1.5 years was significantly lower in the sustained-responder group. There were no significant differences in the mean sBP, mean initial Sac/Val dose, the number of patients initiated Sac/Val treatment during hospitalization, the prevalence of NYHA functional class, and medication among the 3 groups.

Table 1.

Baseline Characteristics of the Study Patients

	Available for analysis (N)	All patients	Sustained- responder (n=129)	Transient- responder (n=161)	Non- responder (n=144)	P value
Age (years)	434	68±14	63±16*,†	71±13	69±15	<0.001
Female, n (%)	434	125 (29)	32 (25)	51 (32)	42 (29)	0.436
sBP (mmHg)	437	115.3±19.2	115.8±19.0	116.7±19.5	113.2±18.9	0.267
Heart rate (beats/min)	411	74±14	76±14*	73±13	73±15	0.047
Initial Sac/Val dose (mg/day)	434	98.3±34.2	96.1±23.1	99.5±40.5	99.0±34.7	0.684
Initiation of Sac/Val during hospitalization, n (%)	434	167 (38)	59 (46)	55 (34)	53 (37)	0.116
Ischemic etiology, n (%)	434	154 (35)	45 (35)	56 (35)	53 (37)	0.921
Previous HF hospitalization, n (%)	433	299 (69)	81 (63)	116 (72)	102 (71)	0.184
Time since diagnosis of HF ≥1.5 years, n (%)	433	242 (56)	52 (40)*,†	100 (63)	90 (63)	<0.001
Cardiac resynchronization therapy, n (%)	434	63 (15)	13 (10)	24 (15)	26 (18)	0.172
Implantable cardioverter defibrillator, n (%)	434	39 (9)	10 (8)	14 (9)	15 (10)	0.735
NYHA functional class	432					0.369
I, n (%)		57 (13)	18 (14)	18 (11)	21 (15)
II, n (%)		234 (54)	66 (52)	92 (57)	76 (53)
III, n (%)		119 (28)	33 (26)	42 (26)	44 (31)
IV, n (%)		22 (5)	10 (8)	9 (6)	3 (2)
Laboratory data
Hemoglobin (g/dL)	434	13.0±2.1	13.3±2.3	12.6±2.1	13.1±2.0	0.009
Creatinine (mg/mL)	434	1.3±0.5	1.2±0.5	1.3±0.6	1.3±0.6	0.179
eGFR (mL/min/1.73 m2)	434	49.2±19.6	53.8±20.0	46.8±18.6	47.9±20.3	0.006
Sodium (mEq/L)	434	140±3	140±3	140±3	139±3	0.006
NT-proBNP (pg/mL)	434	1,833 [792, 3,566]	2,019 [1,047, 4,220]†	1,843 [961, 3,567]	1,595 [549, 2,996]	0.022
Medications
ACEI or ARB, n (%)	434	416 (96)	124 (96)	154 (96)	138 (96)	0.980
β-blocker, n (%)	434	386 (89)	111 (86)	142 (88)	133 (92)	0.234
MRA, n (%)	434	302 (70)	88 (68)	108 (67)	106 (74)	0.429
SGLT2 inhibitor, n (%)	434	152 (35)	48 (37)	55 (34)	49 (34)	0.824
ACEI/ARB + β-blocker + MRA + SGLT2i, n (%)	434	109 (25)	31 (24)	39 (24)	39 (27)	0.800
Loop diuretics, n (%)	434	329 (76)	101 (78)	119 (74)	109 (76)	0.687
Daily loop diuretics dose furosemide equivalent dose (mg/day)	434	29.5±18.8	27.6±17.6	28.7±21.3	31.9±16.7	0.221
Echocardiography
LVEF (%)	434	37.3±14.6	33.5±13.0*,†	40.0±15.5	37.6±14.8	<0.001
LVEF <50%, n (%)	434	347 (80)	115 (89)*,†	120 (75)	112 (78)	0.006
LV end-diastolic diameter (mm)	434	58.3±10.6	58.9±10.0	57.8±10.2	58.2±11.3	0.666
E/e′	382	15.4±9.0	15.4±8.1	14.9±8.3	15.9±10.3	0.666
≥ moderate MR, n (%)	434	141 (32)	40 (31)	56 (35)	45 (31)	0.735
TRPG (mmHg)	365	27.0±10.3	27.8±10.8	26.2±9.3	27.2±10.9	0.468
TAPSE (mm)	225	16.2±4.5	16.3±4.5	16.0±4.4	16.2±4.8	0.907
Electrocardiography
Sinus rhythm, n (%)	433	241 (56)	82 (64)	87 (54)	72 (50)	0.079
Atrial fibrillation, n (%)	433	105 (24)	28 (22)	41 (25)	36 (25)	0.722
QRS duration (ms)	434	120.2±30.2	117.6±29.1	119.8±29.4	123.0±32.1	0.322

Values are expressed as mean±standard deviation or median for continuous measures and n (%) for categorical measures. *P<0.0125, compared with transient-responder group; ^†P<0.0125, compared with non-responder group. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MRA, mineral corticoid antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association functional classification; Sac/Val, sacubitril/valsartan; sBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter-2; TAPSE, tricuspid annular plane systolic excursion; TRPG, tricuspid regurgitant pressure gradient.

NT-proBNP Trajectory Subtypes and Sac/Val Dose During Follow-up

In this study, the mean reduction of NT-proBNP at 1 month from baseline was 41%, and both the sustained-responder group (30%) and the transient-responder group (37%) experienced ≥10% reduction of NT-proBNP at 1 month. However, NT-proBNP values at 3 months were significantly higher in the transient-responder group (sustained-responder group: 560 [287, 1,040] pg/mL, transient-responder group: 1,170 [579, 2,769] pg/mL, P<0.001) (Table 2). The mean dose of Sac/Val was significantly uptitrated at 3 months (baseline: 98.3±34.2 mg/day, 3 months: 207.9±138.3 mg/day). However, there were no significant differences in the mean dose of Sac/Val at baseline, 1 month, and 3 months among the 3 groups (Figure 2). At 3 months after initiating Sac/Val, 127 of 434 patients (32%) achieved the target dose of Sac/Val (97/103 mg twice daily), and 256 of 434 patients (65%) had achieved ≥50% of the target dose. There were no significant differences in these rates of Sac/Val target dose achievement among the 3 groups. There was a significant change in mean sBP in each group from baseline to 1 month, but no significant change from 1 month to 3 months (Supplementary Figure 1). During 3 months, 49 patients (11%) discontinued Sac/Val, and the discontinuation rate was significantly higher in the non-responder group (19%). However, no significant difference was observed in the discontinuation rate between the sustained-responder group and the transient-responder group (5% vs. 9%, P=0.214).

Table 2.

NT-proBNP Values (pg/mL) at Baseline, 1 Month, and 3 Months After Sacubitril/Valsartan

NT-proBNP values	All patients (n=434)	Sustained-responder (n=129)	Transient-responder (n=161)	Non-responder (n=144)	P value
Baseline	1,833 [792, 3,566]	2,019 [1,047, 4,220]†	1,843 [961, 3,567]	1,595 [549, 2,996]	0.022
1 month	1,086 [502, 2,687]	959 [410, 1,923]†	834 [443, 1,974]	2,082 [685, 3,869]	<0.001
3 months	918 [386, 2,522]	560 [287, 1,040]*,†	1,170 [579, 2,769]	1,450 [494, 3,737]	<0.001

*P<0.0125, compared with transient-responder group; ^†P<0.0125, compared with non-responder group. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 2.

Sacubitril/valsartan daily dose in each subgroup at baseline, 1 month, and 3 months. Baseline: sustained-responder group 96.1±23.1 mg/day, transient-responder group 99.5±40.5 mg/day, non-responder group 99.0±34.7 mg/day, P=0.684; 1 month: sustained-responder 171.2±92.1 mg/day, transient-responder 182.4±110.5 mg/day, non-responder group 158.5±92.1 mg/day, P=0.135; 3 months: sustained-responder 217.4±128.8 mg/day, transient-responder group 215.2±139.3 mg/day, non-responder group 191.3±145.1 mg/day, P=0.211. There were no significant differences in the sacubitril/valsartan dose among the 3 groups at each time point.

Study Outcomes

During the follow-up period (median: 456, [371, 549] days), CVD or HHF (the primary endpoint) occurred in 78 of 434 patients (18%). Kaplan-Meier analysis showed a significant difference among the 3 groups. Notably, the sustained-responder group had the lowest event rate compared with both the transient-responder and non-responder groups, regarding the primary and component endpoint of HHF (Figure 3). The sustained-responder group was observed to have a better prognosis in a subgroup with LVEF <40%, but not in patients with LVEF ≥40% (Figure 4). We used landmark analysis to evaluate the primary endpoint and the component endpoints of HHF between the sustained-responder group and the transient-responder group, and defined the landmark time as 3 months after initiating Sac/Val. The event-free survival curves according to the landmark method showed that the sustained-responder group had a significantly lower rate of the primary endpoint (Figure 5). The results of univariate and multivariate logistic regression analysis for the clinical variables associated with the sustained reduction of NT-proBNP from baseline to 3 months are summarized in Table 3. Older age and time since diagnosis of HF ≥1.5 years were negative predictors of “sustained-responder”. In the patients with LVEF <50%, follow-up echocardiography showed significant improvement of LVEF and LVDd in the sustained-responder group among the 3 groups (Supplementary Table).

Figure 3.

Kaplan-Meier survival curves for composite events (A) and hospitalization for heart failure (B). Among the 3 groups, the sustained-responder group had the lowest event rate compared with both the transient-responder group and the non-responder group for the composite event and for hospitalization for heart failure.

Figure 4.

Subgroup analysis for the composite event in the sustained-responder group compared with the transient-responder or non-responder group. Only in patients with LVEF <40% was sustained-responder associated with a lower rate of the composite event compared with transient-responders (A) and non-responders (B). A significant interaction was observed between LVEF <40% or not. CI, confidence interval; LVEF, left ventricular ejection fraction.

Figure 5.

Event-free survival curves for the composite event (A) and hospitalization for heart failure (B) using the landmark analysis. The landmark analysis defined the landmark time as 3 months after initiating sacubitril/valsartan. The sustained-responder group had a significantly lower rate of the primary endpoint.

Table 3.

Logistic Analysis for “Sustained Responder” in the Sustained-Responder and Transient-Responder Groups

Variable	Univariate		Multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Age (per 1 year)	0.96 (0.95, 0.98)	<0.001	0.98 (0.95, 0.99)	0.042
Sex, female	0.71 (0.42, 1.20)	0.199	0.78 (0.43, 1.40)	0.399
NYHA functional class	1.03 (0.76, 1.39)	0.870
Time since diagnosis of HF ≥1.5 years	0.41 (0.25, 0.65)	<0.001	0.41 (0.24, 0.69)	<0.001
Ischemic etiology	1.00 (0.62, 1.63)	0.986
Heart rate at baseline (per 1 beat/min)	1.02 (1.00, 1.04)	0.018	1.01 (0.99, 1.03)	0.430
sBP at baseline (per 1 mmHg)	1.00 (0.99, 1.01)	0.690
Hemoglobin (per 1 g/dL)	1.16 (1.04, 1.29)	0.006	1.08 (0.94, 1.23)	0.290
Sodium (per 1 mEq/L)	0.96 (0.90, 1.04)	0.341
Log NT-proBNP at baseline (per 1 pg/mL)	1.15 (0.95, 1.40)	0.157	1.27 (0.98, 1.65)	0.073
eGFR (per 1 mL/min/1.73 m2)	1.02 (1.01, 1.03)	0.002	1.01 (0.99, 1.03)	0.230
LVEF at baseline (per 1%)	0.97 (0.95, 0.99)	<0.001	0.99 (0.97, 1.01)	0.331
Atrial fibrillation at baseline	0.81 (0.48, 1.40)	0.455
QRS duration (per 1 ms)	1.00 (0.99, 1.01)	0.514
Initial Sac/Val dose (per 1 mg/day)	1.00 (0.99, 1.00)	0.395
Achieved the maximum dose of Sac/Val	0.84 (0.50, 1.41)	0.516

Abbreviations as in Table 1.

Discussion

Major Findings

In this multicenter retrospective cohort study evaluating the efficacy and safety of newly prescribed Sac/Val in Japan, the key findings were: (1) sustained reduction of NT-proBNP from baseline to 3 months after initiating Sac/Val was recognized in 129 of 434 patients (30%), which is less than half of the patients with a ≥10% NT-proBNP reduction at 1 month; (2) among the 3 groups, there were no significant differences in the mean dose of Sac/Val at any time point, or the rates of achieving the maximum and ≥50% of the target daily dose of Sac/Val; (3) patients in the sustained-responder group had a significantly lower risk of CVD or HHF compared with the transient-responder and non-responder groups; (4) 175 of 434 patients (40%) had LVEF ≥40%. In this LVEF phenotype, the prognostic implication of a sustained reduction in NT-proBNP values for the primary endpoint was not established. Notably, these are the first reported findings on the prognostic implication and clinical significance of NT-proBNP trajectory evaluation.

NT-proBNP Trajectory Evaluation

In HF with reduced EF (HFrEF) patients, previous trials have demonstrated that Sac/Val significantly reduced cardiovascular mortality rates, and the reduction in NT-proBNP at 1 month after initiating Sac/Val was a predictor of cardiovascular events.^13,14 Moreover, a reduction ≥10% in NT-proBNP values 1 month after initiating Sac/Val was identified as a favorable predictor for CVD or HHF.¹¹ However, in clinical practice, we sometimes have patients with NT-proBNP re-elevation after a transient early NT-proBNP reduction, and thus the importance and prognostic impact of evaluating the NT-proBNP trajectory after initiating Sac/Val remain uncertain. Previous studies have shown that repeated NT-proBNP measurements can inform about future changes in cardiac remodeling and predict adverse outcomes in HFrEF patients.^15,16 In the subanalysis of the PROVE-HF study, HFrEF patients were divided by patterns of change in NT-proBNP concentrations following 12 months of therapy with Sac/Val, and the analysis demonstrated that those groups with sustained NT-proBNP reduction had more favorable reverse remodeling and improvement in health status compared with those with NT-proBNP re-elevation despite transient early NT-proBNP reduction; however, the prognostic impact of the NT-proBNP trajectory was not addressed.¹⁷ The present study results revealed that the risk of the composite endpoint was significantly lower in the sustained-responder group among 3 groups, and that repeated evaluation of NT-proBNP values after initiating Sac/Val may be a prognostic indicator for HF. This trend was particularly observed in the group with high baseline NT-proBNP values (Supplementary Figure 2). Also, guideline-directed medical therapy (GDMT), including Sac/Val, recommends uptitration to the target dose, but we often experience difficulties in achieving GDMT in daily clinical practice for reasons such as hypotension.¹⁸ In the PARADIGM-HF trial, 42% of patients reduced the Sac/Val dose after randomization, and those who had any dose reduction had a higher risk of CVD or HHF compared with those who remained on the full dose.¹⁹ However, some reports suggest that the maintenance dose of Sac/Val is not associated with improvements in NT-proBNP levels, improvements of echocardiographic, or a reduced risk of cardiovascular events.^20,21 There are no consistent opinions for the uptitrated dose of Sac/Val. In this study, there were no significant differences in the mean dose of Sac/Val at baseline, 1 month, and 3 months among the 3 groups, nor in the number of patients who achieved the maximum or half dose of Sac/Val.

Sustained-Responder Group vs. Transient-Responder Group

Previous trials have shown that Sac/Val reduced NT-proBNP in patients with HF. However, there is a lack of data on whether patients who experienced a reduction in NT-proBNP shortly after initiating Sac/Val had a sustained reduction in NT-proBNP. In this study, 129 patients had a sustained NT-proBNP reduction from baseline to 3 months, and more than half of the patients did not have a sustained NT-proBNP reduction. Sac/Val improves the hemodynamics in patients with HF by inhibiting neprilysin (NEP), increasing not only natriuretic peptide but also other substrates such as bradykinin and adrenomedullin.²² In this study, sBP significantly decreased in the sustained-responder and transient-responder groups at 1 month after initiating Sac/Val. However, no significant changes in sBP were observed from 1 month to 3 months. Additionally, among patients with LVEF <50%, those in the sustained-responder group showed significant improvement in the LVEF and LVDd compared with the transient-responder group. Previous studies have shown that the reduction in NT-proBNP values following Sac/Val occurred in the early phase before LVEF improvement, and there was a correlation between NT-proBNP changes at 12 months and LVEF improvement.²³ In the present study, the early NT-proBNP reduction observed in both groups following Sac/Val was possibly due to NEP inhibition-induced hemodynamic effects. Furthermore, the sustained NT-proBNP reduction observed subsequently might be attributable to improvements in cardiac function as a result of hemodynamic improvement. Logistic regression analysis was performed to distinguish between the sustained-responder and transient-responder groups. Multivariate logistic regression analysis revealed that older age and time ≥1.5 years from HF diagnosis to Sac/Val initiation were independent negative predictors of “sustained responder”. It is known that age and longer time since HF diagnosis are poor prognostic factors,^24–26 which suggests that early prescription of Sac/Val after HF diagnosis may have a better effect. Furthermore, this study showed that assessing the NT-proBNP trajectory is valid in patients with LVEF <40%, but is challenging to apply in patients with LVEF ≥40%. Similarly, a previous study reported that the effect of Sac/Val was modified by LVEF, and benefit appeared to be present primarily for individuals with EF below the normal range.²⁷ Additionally, Sac/Val has been reported to reduce NT-proBNP values in patients with LVEF ≥40%,^10,28,29 but there is insufficient evidence to support a reduction in cardiovascular risk.³⁰ This finding may be related to the limited sustained reduction in NT-proBNP values in patients with LVEF ≥40%. The etiologies of HF with mildly reduced EF (HFmrEF) and preserved EF (HFpEF) are known to be multifactorial and complex. In addition, these patients have many comorbidities, such as aging, obesity, chronic kidney disease (CKD), and diabetes, and it is known that patients with atrial fibrillation and CKD often have higher NT-proBNP levels than expected for the severity of HF.^31,32 In such patients, their comorbidities may contribute to the lack of a favorable reduction in NT-proBNP.

Clinical Implications

Sustained NT-proBNP reduction following 3 months after initiating Sac/Val was a prognostic factor, but initiating Sac/Val for older patients or those with a long duration of HF did not lead to sustained NT-proBNP reduction in this study. In patients without a sustained NT-proBNP reduction, physicians should consider other pharmacotherapy for HF, but the repeated evaluation of the NT-proBNP trajectory may highlight early optimization of HF therapy.

Study Limitations

Several limitations needed to be acknowledged. First, this was a retrospective observational study without a control group and more than half of the enrolled patients were excluded due to missing NT-proBNP data. The study was conducted early after Sac/Val became available in Japan, and many of the excluded patients had initial or follow-up measurements performed of BNP instead of NT-proBNP. Also, we did not follow the pharmacotherapeutic change other than diuretics. Second, we included patients who were newly initiated on Sac/Val for HF therapy. Not all patients underwent detailed diagnostic evaluation, such as cardiovascular magnetic resonance imaging or pathology. Therefore, patients with reversible causes of HF may have been included. Third, in the early part of the study period, sodium-glucose cotransporter-2 (SGLT2) inhibitors were not yet approved for the treatment of HF in Japan. Therefore, their use was low, and the incidence of the primary endpoint of this study (CVD or HHF) might have been lower if these drugs had been used. Fourth, the patients were required to undergo serial evaluation of HF status under the Japanese insurance system, and optimal HF therapies, including diuretic dose, were adjusted every 2 weeks by cardiologists. These factors may have caused selection bias and caution should be exercised when interpreting our results.

Conclusions

Among the patients prescribed Sac/Val, a sustained reduction in NT-proBNP levels was observed in 30% of them, associated with a reduced risk of CVD or HHF. This result suggests that repeated NT-proBNP measurements, along with monitoring of the NT-proBNP pattern during treatment with Sac/Val, may be helpful in optimizing HF therapy and understanding the prognosis of HF.

Acknowledgments

We thank all investigators for their efforts in conducting the REVIEW-HF (Real-world evidence of Angiotensin Receptor-Neprilysin Inhibitor in Patients with Heart Failure) Registry.

Sources of Funding

None.

Disclosures

S.I. received speaker’s honorarium from Novartis Japan and Otsuka Pharmaceutical Co., Ltd.; K. Kanaoka received speaker’s honoraria from Eli Lilly Japan and Otsuka Pharmaceutical Co., Ltd.; N.K. is affiliated with a department endowed by grants from Paramount Bed Co., Ltd., received research grants from EchoNous. Inc. and AMI Inc., and received honoraria from Novartis Japan, Otsuka Pharma, Eli Lilly, and Nippon Boehringer Ingelheim outside the submitted work. J.A. is a member of Circulation Reports’ Editorial Team. The remaining authors have no disclosures to report.

IRB Information

The study protocol was approved by the Ethics Committee of Toho University Omori Medical Center (approval no. M21257).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0029

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