JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. -, NO.

-, 2023
ª 2023 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Angiotensin-Neprilysin Inhibition
in Patients With Mildly Reduced
or Preserved Ejection Fraction
and Worsening Heart Failure
Robert J. Mentz, MD,a Jonathan H. Ward, PHARMD,b Adrian F. Hernandez, MD, MHS,a Serge Lepage, MD,c
David A. Morrow, MD, MPH,d Samiha Sarwat, PHD,b Kavita Sharma, MD,e Randall C. Starling, MD, MPH,f
Eric J. Velazquez, MD,g Kristin M. Williamson, PHARMD,b Akshay S. Desai, MD, MPH,d Shelley Zieroth, MD,h
Scott D. Solomon, MD,d Eugene Braunwald, MD,d on behalf of the PARAGLIDE-HF Investigators

ABSTRACT

BACKGROUND U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly
reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart
failure (WHF) event is unknown.

OBJECTIVES PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompen-
sated HFpEF) assessed sacubitril-valsartan vs valsartan in EF >40% following a recent WHF event.

METHODS PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients

with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in
amino terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary
hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and
4) change in NT-proBNP.

RESULTS In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was
greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P ¼ 0.049). The hierarchical outcome
favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P ¼ 0.16).
Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic
hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with
EF #60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95%
CI: 1.09-1.95).

CONCLUSIONS Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater
reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone,
despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In
DEcompensated HFpEF; NCT03988634) (J Am Coll Cardiol 2023;-:-–-) © 2023 The Authors. Published by Elsevier on
behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

From the aDuke Clinical Research Institute, Durham, North Carolina, USA; bNovartis Pharmaceuticals Corporation, East Hanover,
New Jersey, USA; cDepartment of Cardiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada; dCardiovascular Division,
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; eDivision of
Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA; fDepartment of Cardiovascular Medicine, Cleveland
Clinic, Cleveland, Ohio, USA; gDepartment of Internal Medicine, Section of Cardiovascular Medicine, Yale School of Medicine, New
Haven, Connecticut, USA; and the hSection of Cardiology, Max Rady College of Medicine, University of Manitoba, Winnipeg,
Manitoba, Canada.

ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2023.04.019

2 Mentz et al
ARNI in Worsening Heart Failure
T
ABBREVIATIONS he PARAGON-HF trial suggested ef-
AND ACRONYMS ficacy of sacubitril/valsartan (Sac/
Val) vs valsartan (Val) in patients
HFpEF = heart failure with
preserved ejection fraction
with heart failure (HF) and ejection fraction
(EF) $45%, 1 but benefits were most apparent
NT-proBNP = amino terminal
pro–B-type natriuretic peptide in those with mildly reduced EF or patients
Sac/Val = sacubitril/valsartan with heart failure with preserved ejection
Val = valsartan
(HFpEF) with EF below normal (#60%). Re-
sidual uncertainty about how best to utilize
WHF = worsening heart failure
Sac/Val in patients with HF and EF >40%
has fueled disparate clinical recommendations. 2-5 In
this context, additional data regarding the efficacy
of Sac/Val in HFpEF are needed, particularly in popu-
lations not well-represented in PARAGON-HF,
including Black patients and those with newly diag-
nosed HF, severe obesity, and higher EF.
In addition, a post hoc analysis of PARAGON-HF
noted a signal for greater benefit with Sac/Val in pa-
tients recently hospitalized for HF. 6 Because this
period following a worsening heart failure (WHF)
event is recognized as a high-risk interval for cardiac
events,7,8 additional data to validate this finding
would be of clinical importance. The PARAGLIDE-HF
(Prospective comparison of ARNI with ARB Given
following stabiLization In DEcompensated HFpEF)
trial was designed to assess the efficacy, safety, and
tolerability of Sac/Val vs Val in a diverse population of
patients with EF >40% and a recent WHF event.
METHODS
TRIAL DESIGN AND OVERSIGHT. The trial design and
baseline characteristics have been previously re-
ported.9 Briefly, PARAGLIDE-HF was a multicenter,
double-blind, randomized controlled trial that inves-
tigated the effect of Sac/Val vs Val on changes in NT-
proBNP, safety, and tolerability in patients with HF
with mildly reduced EF or HFpEF following stabiliza-
tion from a WHF event. The trial was performed at 100
centers in the United States and Canada. The ethics
committee at each trial center approved the trial, and
all patients provided written informed consent. The
Supplemental Appendix includes a complete list of
site investigators and members of the Steering Com-
mittee and Data and Safety Monitoring Board.
The trial was led by an academic Steering Com-
mittee in collaboration with the sponsor, Novartis.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received March 27, 2023; revised manuscript received April 19, 2023, accepted April 20, 2023.
JACC VOL. -, NO. -, 2023
-, 2023:-–-
Overall responsibility for the oversight and manage-
ment of the trial was with the Steering Committee
comprised of independent academic investigators as
well as representatives from the sponsor. A Data and
Safety Monitoring Board included specialists in HF
and an independent statistician responsible for sur-
veillance of safety data including adverse events. The
statistical analyses were performed by the sponsor
and were replicated and verified independently by
the Duke Clinical Research Institute.
PARTICIPANTS. Stable patients age $18 years with a
diagnosis of HF, an EF >40%, and an elevated
NT-proBNP or B-type natriuretic peptide were eligible
for participation during a current hospitalization for
WHF or within 30 days of a WHF event (defined as HF
hospitalization, emergency department visit, or out-
of-hospital urgent HF visit, all requiring intravenous
diuretic agents). Patients with Sac/Val use within the
past 60 days, serum potassium >5.2 mEq/L, estimated
glomerular filtration rate (eGFR) <20 mL/min/1.73 m 2,
isolated right HF, or hypersensitivity to the study
drugs were not eligible. Following management of the
acute WHF episode, all patients were required to be
medically stabilized as defined by a systolic blood
pressure >100 mm Hg for the preceding 6 hours, no
increase in intravenous diuretic agents or use of
intravenous vasodilators within the last 6 hours, and
no intravenous inotropes for 24 hours before
randomization. Detailed inclusion and exclusion
criteria are provided in the Supplemental Appendix.
TRIAL PROCEDURES. Patients were randomly
assigned 1:1 to Sac/Val titrated to a target dose of 97/
103 mg twice daily vs Val titrated to 160 mg twice
daily as detailed previously.9 Screening occurred
during the index hospitalization or within 30 days of
a WHF event. Following randomization and baseline
assessment, study visits were to occur at day 7
(Week 1) followed by day 28 (Week 4), day 56
(Week 8), and then approximately every 112 days
(16 weeks). Patients were followed for prespecified
outcomes for the duration of the trial, regardless of
whether they were adherent to the trial regimen or
procedures. The planned maximum duration of
treatment was up to approximately 20 months of
double-blind treatment, and the last patient ran-
domized was followed for a minimum of 8 weeks.
JACC VOL. -, NO. -, 2023
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F I G U R E 1 Consort Diagram
586 Patients Screened
466 Randomized and Treated
233 Assigned to Sacubitril/Valsartan
173 (73.9%) Completed Protocol Alive
61 (26.1%) Early Study Discontinuation
18 (7.7%) Died
6 (2.6%) Lost to Follow-Up
24 (10.3%) Participant Decision to Discontinue Study
9 (3.8%) Physician Decision to Discontinue Study
4 (1.7%) Adverse Event
233 Included in Analysis
The flow of participants throughout the study is shown, including the number screened, excluded, randomized, prematurely discontinued, and completed in this
randomized, controlled clinical trial.
TRIAL OUTCOMES. The primary efficacy endpoint
was the time-averaged proportional change in
NT-proBNP from baseline to Weeks 4 and 8 as in
PIONEER-HF (Comparison of Sacubitril/Valsartan
Versus Enalapril on Effect on NT-proBNP [N-terminal
pro-B type natriuretic peptide] in Patients Stabilized
From an Acute HF Episode),10 and detailed in the
Statistical Analysis Plan (Supplemental Appendix). In
brief, this was calculated as the average of the geo-
metric means of NT-proBNP at Weeks 4 and 8 divided
by the geometric mean of NT-proBNP at baseline in a
natural logarithmic scale (ie, ratio of geometric
means) and summarized as the difference between
treatment groups in the ratio of the geometric means.
Secondary endpoints included a win-ratio–based
composite hierarchical outcome consisting of: 1) time
to cardiovascular death; 2) number and timing of HF
hospitalizations during follow-up; 3) number and
timing of urgent HF visits during follow-up; and
4) time-averaged proportional change in NT-proBNP
(from baseline to Weeks 4 and 8). Additional sec-
ondary clinical outcomes included the cumulative
number of recurrent cardiovascular composite
events, ie, the total number of HF hospitalizations,
urgent HF visits, and cardiovascular death; and the
Mentz et al 3
ARNI in Worsening Heart Failure
119 Excluded
• 110 Screen Failure
• 3 Physician Decision
• 5 Patient Decision
• 1 Technical Issue
233 Assigned to Valsartan
182 (78.1%) Completed Protocol Alive
51 (21.9%) Early Study Discontinuation
26 (11.2%) Died
7 (3.0%) Lost to Follow-Up
13 (5.6%) Participant Decision to Discontinue Study
5 (2.1%) Physician Decision to Discontinue Study
0 (0.0%) Adverse Event
233 Included in Analysis
incidences of a composite endpoint of worsening
renal function, defined as renal death, reaching end-
stage renal disease or $50% decline in eGFR relative
to baseline. The incidence of the following adverse
events of special interest during treatment were
assessed: symptomatic hypotension (investigator-re-
ported), hyperkalemia (potassium >5.5 mEq/L),
angioedema, and worsening renal function (ie, in-
crease in serum creatinine of $0.5 mg/dL and wors-
ening of the eGFR by $25% from baseline). All deaths,
all hospitalizations, and urgent HF visits were adju-
dicated by an independent, blinded committee at the
Brigham and Women’s Hospital. A complete list of
endpoints is provided in the Supplemental Appendix.
STATISTICAL ANALYSIS. The primary null hypothe-
sis was that the ratio of the average of the geometric
means of NT-proBNP at Weeks 4 and 8 to the baseline
NT-proBNP would be equal for the Sac/Val and Val
groups. The time-averaged proportional change from
baseline in a natural logarithmic scale was analyzed
using an analysis of covariance model using data
averaged from Weeks 4 and 8 with treatment (ie, the
mean of the Week 4 and/or Week 8, as available), in-
hospital/out-of-hospital randomization, sex, and
baseline left ventricular EF (#median, >median) as
4 Mentz et al JACC VOL. -, NO. -, 2023
ARNI in Worsening Heart Failure -, 2023:-–-

Supplemental Appendix, including EF below normal

T A B L E 1 Characteristics of the Patients at Baseline
(#60%). The primary analysis was performed based
Sacubitril/Valsartan Valsartan on all available data. Missing values caused by une-
(n ¼ 233) (n ¼ 233)
valuable samples or early study discontinuations
Age, y 71.0 (61.0-78.0) 72.0 (62.0-79.0)
were not imputed. Patients with missing baseline
Sex
Female 121 (51.9) 121 (51.9) NT-proBNP and/or missing both of Weeks 4 and 8
Male 112 (48.1) 112 (48.1) were not included in the primary analysis. All efficacy
Race analyses were performed according to the intention-
White 176 (75.5) 176 (75.5) to-treat principle, with the use of all available data.
Black or African American 50 (21.5) 52 (22.3) A sample size of approximately 450 patients provided
Asian 3 (1.3) 3 (1.3)
85% power to detect a 23% reduction in the time-
Native Hawaiian or other Pacific Islander 1 (0.4) 1 (0.4)
averaged proportional change in NT-proBNP from
American Indian or Alaska Native 3 (1.3) 1 (0.4)
Ethnicity
baseline to Weeks 4 and 8 for the Sac/Val treatment
Hispanic or Latino 18 (7.7) 9 (3.9) group. The power was estimated assuming a 2-sided
Not Hispanic or Latino 215 (92.3) 222 (95.3) significance level of 0.05, a common SD of 0.85 for
Unknown 0 (0.0) 2 (0.9) change in log transformed NT-proBNP, and a 15% rate
Clinical features of HF of missingness in NT-proBNP at both Weeks 4 and 8.
History of HF prior to the qualifying event 155 (66.5) 158 (67.8)
As detailed in the SAP, the composite hierarchical
Ischemic etiology 44 (18.9) 38 (16.3)
outcome was analyzed by estimating the win ratio by
Prior HF hospitalization 84 (36.1) 98 (42.1)
pairwise comparison of every participant in the Sac/
NYHA functional class
I 8 (3.4) 9 (3.9) Val group to every participant in the Val group
II 102 (43.8) 101 (43.3) sequentially at each level of the hierarchy to deter-
III 117 (50.2) 112 (48.1) mine a winner. For instance, the patient with the later
IV 4 (1.7) 10 (4.3) time to cardiovascular death was the winner; if
Not assessed 2 (0.9) 1 (0.4) neither patient died, then the patient with fewer WHF
Screening NT-proBNP, pg/mL—local lab 2,307 (1,496-3,980) 1,903 (1,248-3,651)
events was the winner (comparing hospitalizations
n 134 127
first and then urgent visits); if the number of WHF
Screening BNP, pg/mL 491 (305-809) 536 (383-903)
n 96 105
events was common, then the patient with the later
Baseline NT-proBNP, pg/mL—central lab 1,629 (886-2,875) 1,542 (712-2,941) time of the event was the winner; for NT-proBNP, the
n 226 224 patient with the larger decrease or smaller increase in
LVEF, % the proportional change was considered the winner.
Mean 55.2  8.06 55.7  8.07 To support clinically significant biomarker values, if
Median 55.0 55.0
the ratio of the proportional changes from 2 patients
Q1, Q3 (IQR) 50.0, 60.0 (10) 50.0, 60.0 (10)
was between 0.75 and 1/0.75 (ie, 1.33), then the pair-
Min, max 41.0, 75.0 41.0, 80.0
wise comparison of the change in NT-proBNP was
LVEF category
41%-49% 56 (24.0) 51 (21.9) considered tied. For comparisons, only those events
50%-60% 122 (52.4) 128 (54.9) that occurred in the time at risk that were common for
>60% 55 (23.6) 54 (23.2) both patients in the pair was used for analysis to
Medical history define a win or tie. Further details regarding the rules
Hypertension 228 (97.9) 219 (94.0) with unequal follow-up are detailed in the SAP. The
Diabetes mellitus 107 (45.9) 119 (51.1)
estimated win ratio (the total number of wins in the
History of atrial fibrillation/atrial flutter 140 (60.1) 133 (57.1)
Sac/Val arm divided by the total number of wins in
Ongoing atrial fibrillation/atrial flutter 120 (51.5) 120 (51.5)
Stroke 25 (10.7) 23 (9.9)
the Val arm) was calculated with corresponding 2-
Myocardial infarction 12 (5.2) 15 (6.4) sided 95% CIs. 11
Continued on the next page The cumulative number of composite cardiovas-
cular events was calculated with the time to these
recurrent events analyzed using the semiparametric
proportional rates model (abbreviated as LWYY).12
fixed effect factors and both age and the logarithmic For the renal composite, the total number of com-
baseline NT-proBNP as covariates. The estimated posite events was performed using a negative bino-
treatment effect in terms of ratios of geometric means mial regression model. Incidences of other events of
was based on the least-squares means from the interest were analyzed using a logistic regression
model, and the corresponding 2-sided 95% CIs are model with treatment and in-hospital/out-of-hospital
presented. Prespecified subgroups are noted in the randomization as fixed factors to estimate the OR for
JACC VOL. -, NO. -, 2023 Mentz et al 5
-, 2023:-–- ARNI in Worsening Heart Failure

treatment and its 95% CIs. Events were assessed

T A B L E 1 Continued
throughout the duration of follow-up. All statistical
tests were conducted against a 2-sided alternative Sacubitril/Valsartan Valsartan
(n ¼ 233) (n ¼ 233)
hypothesis, employing a significance level of 0.05. All
Examination and laboratory values
analyses were performed with SAS software version
Systolic blood pressure, mm Hg 127 (116-142) 129(117-145)
9.4 (SAS Institute). Heart rate, beats/min 75 (65-89) 72 (65-85)
BMI, kg/m2 33.3 (27.3-41.3) 32.7 (27.0-39.5)
RESULTS
Serum creatinine, mg/dL 1.3 (1.0-1.6) 1.2 (1.0-1.5)
eGFR, mL/min/1.73 m2 47.4 (36.4-62.2) 51.1 (39.4-64.8)
PATIENTS. From June 2019 through October 2022, a Serum potassium, mmol/L 4.3 (4.0-4.6) 4.3 (3.9-4.5)
total of 466 patients were randomized to receive Prior medications
either Sac/Val (n ¼ 233) or Val (n ¼ 233) (Figure 1). The ACE inhibitor or ARB 177 (76.0) 182 (78.1)
baseline characteristics of the patients in the 2 groups MRA 75 (32.2) 60 (25.8)

were similar (Table 1). Overall, 52% were women, 22% BB 185 (79.4) 169 (72.5)
SGLT2i 27 (11.6) 29 (12.4)
were Black, the mean age was 70  12 years, median
Loop diuretic 232 (99.6) 233 (100.0)
EF was 55% (IQR: 50%-60%), 33% had de novo HF,
Randomization location
69.5% were enrolled in the hospital, and median
In-hospital 162 (69.5) 162 (69.5)
screening NT-proBNP was 2,009 pg/mL (IQR: 1,291- Out of hospital 71 (30.5) 71 (30.5)
3,813 pg/mL).
End-of-study visits occurred by December 14, 2022, Values are median (IQR), n (%), or mean  SD, unless otherwise indicated.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; BB ¼ beta-blocker; BMI ¼ body
which was also the final date for follow-up data mass index; BNP ¼ B-type natriuretic peptide; eGFR ¼ estimated glomerular filtration rate; HF ¼ heart failure;
collection. Database lock occurred on February 24, LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal
pro-brain natriuretic peptide; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure;
2023. Figure 1 and Supplemental Figure 1 provide the SGLT2i ¼ sodium-glucose cotransporter-2 inhibitor.

consort diagram for patient follow-up for clinical

outcomes and biomarker assessment, respectively. A
total of 68 patients discontinued follow-up in the trial
(for reasons other than death) before study comple-
tion (43 [18.4%] in the Sac/Val group and 25 [10.7%] in
the Val group) (Figure 1). Among those, there were 13
patients lost to follow-up (6 [2.6%] in the Sac/Val
group and 7 [3.0%] in the Val group). Overall, 385
patients (83%) started on the low dose of study drug
(dose level 1) following randomization (84% in Sac/
Val, 82% in Val) and 81 patients (17%) on the middle
dose (dose level 2). Study drug was stopped prema-
turely in 105 (44.9%) patients in the Sac/Val and 90
(38.6%) patients in the Val group. Reasons for treat-
ment discontinuation are reported in Supplemental
Table 1. During follow-up, the percentage of patients
who received dose level 1, 2, and 3 as the maximum
dose was 39%, 21%, and 40%, respectively, and was
similar in the 2 groups (Supplemental Table 2). The
mean  SD and median duration of follow-up were 7.9
 6.3 months and 5.9 months (IQR: 2.8-13.9 months),
respectively. Recruitment was slower than antici-
pated in the context of the COVID-19 pandemic, but
there were few COVID-19–related serious adverse
events (discussed in the following text).
PRIMARY OUTCOME. Overall, 89 patients (19.1%) did
not contribute to the primary endpoint because of
missing baseline or missing both of Weeks 4 and 8 (53
[22.7%] in the Sac/Val group and 36 [15.5%] in the Val
group), as detailed in Supplemental Figure 1. The
time-averaged reduction in the NT-proBNP was
greater in the Sac/Val group than the Val group; the
ratio of the geometric means obtained at Weeks 4 and
8 to the baseline value was 0.72 in the Sac/Val group
compared with 0.84 in the Val group (ratio of change:
0.85; 95% CI: 0.73-0.999; P ¼ 0.049) (Table 2, Central
Illustration). Supplemental Table 3 shows NT-proBNP
geometric mean values by visit. The greater reduction
in the NT-proBNP concentration with Sac/Val than
with Val was evident as early as Week 1. The effect of
Sac/Val was generally consistent across prespecified
subgroups including in those with worsening of
chronic HF vs de novo HF as well as by baseline sys-
tolic blood pressure (<110 mm Hg vs $110 mm Hg)
(Figure 2). However, there was evidence of a pattern
of a larger treatment effect in the subgroup with EF
below normal (#60%) (P for interaction ¼ 0.033).
Specifically, the ratio of change was 0.78 (95% CI:
0.65-0.93) in the group with EF #60% and 1.17
(95% CI: 0.86-1.59) in the group with EF >60%
(Supplemental Figure 2).
SECONDARY OUTCOMES. The win ratio for the hi-
erarchical outcome numerically favored patients
treated with Sac/Val compared with Val but was not
statistically significant (unmatched win ratio: 1.19;
95% CI: 0.93-1.52; P ¼ 0.16) (Table 2, Central
Illustration). In the prespecified subgroup with
EF #60%, we observed an unmatched win ratio of
1.46 (95% CI: 1.09-1.95) (Figure 3). For the recurrent
6 Mentz et al JACC VOL. -, NO. -, 2023
ARNI in Worsening Heart Failure -, 2023:-–-

T A B L E 2 Primary and Secondary Outcomes a

Sacubitril/Valsartan (n ¼ 233) Valsartan (n ¼ 233) P Value

Primary Endpoint

Ratio of the Geometric Mean at Ratio of the Geometric Mean at Ratio of Change
Follow-Up to the Baseline Value Follow-Up to the Baseline Value With Sac/Val vs
(95% CI) (95% CI) Val (95% CI)

Change in NT-proBNP at Weeks 4 0.72 (0.64-0.81) n ¼ 180 0.84 (0.76-0.94) n ¼ 197 0.85 (0.73-0.999) 0.049
and 8
Geometric means for NT-proBNP
Baseline 1,536 (1,328-1,776) 1,397 (1,205-1,619)
Week 4 965 (809-1,150) 1,243 (1,068-1,447)
Week 8 975 (805-1,181) 1,075 (906-1,274)

Secondary Endpoints
Hierarchical Composite of CV Death, % Wins % Wins Win Ratio (95% CI)
HF Hospitalizations, Urgent HF
Visits, Change in NT-proBNP
(wk 4, 8)
Overall 36.9 31.0 1.19 (0.93-1.52) 0.16
Recurrent CV Composite Events of Events/(n patients) Exposure-Adjusted Events/(n patients) Exposure-Adjusted RR (95% CI)
HF Hospitalizations, Urgent HF Rate per 100 pt-y Rate per 100 pt-y
Visits and CV Death (95% CI) (95% CI)
Total events 94/59 63.5 (51.3-77.7) 117/71 76.2 (63.0-91.3) 0.83 (0.57-1.23)
CV death 10/10 6.8 (3.2-12.4) 18/18 11.7 (6.9-18.5)
HF hospitalizations 71/48 48.0 (37.5-60.5) 81/55 52.7 (41.9-65.6)
Urgent HF visits 13/7 8.8 (4.7-15.0) 18/12 11.7 (6.9-18.5)
Worsening Renal Function Events/(n patients) Estimated Rate Events/(n patients) Estimated Rate RR (95% CI)
Composite Endpoint of Renal (95% CI) per-pt/y (95% CI) per-pt/y
Death, ESRD, or ‡50% Decline
in eGFR
Overall 34/27 0.75 (0.37-1.51) 46/35 1.19 (0.62-2.29) 0.62 (0.25-1.56)
Renal death 0 2/2
ESRD 20/20 22/22
$50% decline eGFR 14/14 22/22
Adverse Events of Special Interest n (%) n (%) OR (95% CI)
Symptomatic hypotension 56 (24.0) 36 (15.5) 1.73 (1.09-2.76)
Hyperkalemia 45 (19.3) 43 (18.5) 1.06 (0.66-1.68)
Worsening renal function 50 (21.5) 72 (30.9) 0.61 (0.40-0.93)
Angioedema 0 (0.0) 1 (0.4) —

Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and 8 visits. The change from baseline to averages of Week 4 and 8 is the log transformed NT-proBNP calculated as ln(average post dose
value) – ln(baseline value). The change from baseline in logarithmic scale is analyzed using an analysis of covariance model with treatment, in-hospital/out-of-hospital randomization, sex, and baseline LVEF
(# median, >median) as fixed effect factors, with age and the logarithmic baseline NT-proBNP as covariates. Recurrent cardiovascular (CV) composite endpoint (ie, HF hospitalizations, urgent HF visits and CV
death) was analyzed using the proportional rates model (LWYY) with treatment and in-hospital/out-of- hospital randomization as fixed-effect factor and with robust (sandwich) variance estimate. CV death is
analyzed using Cox’s proportional hazard model with treatment and in-hospital/out-of-hospital as fixed-effect factor. Worsening renal function composite (renal death, ESRD, or $50% decline in eGFR) was
analyzed using a negative binomial regression model, adjusted for treatment, in-hospital/out-of-hospital randomization as fixed-effect factors. Log(follow-up duration, study exposure) is the offset variable.
Incidence of adverse events of special interest was analyzed using a logistic regression model with treatment and in-hospital/out-of- hospital randomization as fixed factors. Hyperkalemia was defined as
potassium $5.5 mEq/L. Worsening renal function adverse event was defined as increase in serum creatinine of $0.5mg/dL AND worsening of the eGFR by at least 25%. aPrimary endpoint: Geometric
mean ¼ exponentially back transformed from LS means based on the analysis of covariance model. The same transformation is applied to the 95% CI. P values and treatment comparisons were evaluated
using an analysis of covariance model.
ESRD ¼ end-stage renal disease; other abbreviations as in Table 1.

composite cardiovascular endpoint, there were 94
events in the Sac/Val group and 117 events in the Val
group resulting in a rate ratio of 0.83 (95% CI: 0.57-
1.23). For the subgroup with EF #60%, the rate ratio
for the recurrent composite cardiovascular endpoint
was 0.61 (95% CI: 0.37-1.01). For the worsening renal
function clinical endpoint, there were 34 events in
the Sac/Val group and 46 events in the Val group
resulting in a rate ratio of 0.62 (95% CI: 0.25-1.56).
SAFETY. Compared with Val, Sac/Val had less wors-
ening renal function (OR: 0.61; 95% CI: 0.40-0.93) and
more symptomatic hypotension (OR: 1.73; 95% CI:
1.09-2.76) (Table 2). There was 1 case of angioedema,
which occurred in the valsartan group. Hyperkalemia
events were similar between groups. The exposure
adjusted incidence rate of serious adverse events was
103 (122.2 per 100 patient treatment year) for the Sac/
Val group and 103 (122.2 per 100 patient treatment
JACC VOL. -, NO. -, 2023 Mentz et al 7
-, 2023:-–- ARNI in Worsening Heart Failure

C ENTR AL I LL USTRA T I ON Changes in N-Terminal Pro–B-Type Natriuretic Peptide and the

Win-Ratio Clinical Endpoint

Primary Endpoint
% Change in NT-proBNP
15% greater reduction with Sac/Val; 95% CI: 0%-27%; P = 0.049

1,750
Geometric Mean NTproBNP (pg/mL)

1,500

1,250

1,000

750

500

250

Baseline Week 1 Week 4 Week 8

Visit Week
226 185 172 155
224 201 194 172
Sacubitril/Valsartan Valsartan

Secondary Outcome
Hierarchical composite outcome of: a) time to cardiovascular death;
b) HF hospitalizations; c) urgent HF visits; and d) change in NT-proBNP
Unmatched win ratio = 1.19; 95% CI: 0.93-1.52; P = 0.16

36.9%
Overall 31%
32.1%

4%
CV Death
2.8%

13.8%
HF Hospitalizations
12.6%

2.5%
Urgent HF Visits
1.5%

27.9%
Change in NT-proBNP
23.3%

Ties 32.1%

Sacubitril + Valsartan Winner Valsartan Winner Ties

Mentz RJ, et al. J Am Coll Cardiol. 2023;-(-):-–-.

The time-averaged reduction in the N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration was significantly greater in the
sacubitril/valsartan (Sac/Val) group than in the valsartan (Val) group; the ratio of the geometric means obtained at Weeks 4 and 8 to the
baseline value was 0.72 in the Sac/Val group compared with 0.84 in the Val group (ratio of change: 0.85; 95% CI: 0.73-0.999; P ¼ 0.049).
The composite hierarchical outcome of cardiovascular death, heart failure (HF) hospitalizations, urgent HF visits, and change in NT-proBNP
was analyzed by estimating the unmatched win ratio by comparing every participant in the Sac/Val group to every participant in the Val
group to determine a winner. The estimated win ratio (the total number of wins in the Sac/Val arm divided by the total number of wins in the
Val arm) was calculated with corresponding 95% CIs.
8 Mentz et al JACC VOL. -, NO. -, 2023
ARNI in Worsening Heart Failure -, 2023:-–-

F I G U R E 2 Analyses of Change in the NT-proBNP Concentration in Prespecified Subgroups

Subgroup Sacubitril/Valsartan Valsartan Favors Interaction

n/N (%) n/N (%) Sacubitril/Valsartan Favors Valsartan Rate Ratio (95% CI) P Value

Overall 180/180 (100.0) 197/197 (100.0) 0.855 (0.731-0.999)

Age, y 0.032
<65 59/180 (32.8) 58/197 (29.4) 0.655 (0.479-0.896)
≥65 121/180 (67.2) 139/197 (70.6) 0.952 (0.794-1.142)
Age, y 0.140
<75 121/180 (67.2) 115/197 (58.4) 0.783 (0.631-0.971)
≥75 59/180 (32.8) 82/197 (41.6) 0.997 (0.794-1.252)
Sex 0.908
Female 91/180 (50.6) 101/197 (51.3) 0.860 (0.689-1.074)
Male 89/180 (49.4) 95/197 (48.7) 0.838 (0.670-1.049)

Race 0.014
Black or African American 33/180 (18.3) 40/197 (20.3) 0.527 (0.351-0.793)
White 142/180 (78.9) 153/197 (77.7) 0.966 (O.813-1.147)
Other 5/180 (2.8) 4/197 (2.0) 1.807 (0.004-894.825)

Ethnicity 0.084
Not Hispanic or Latino 165/180 (91.7) 189/197 (95.9) 0.821 (0.700-0.963)
Hispanic or Latino 15/180 (8.3) 7/197 (3.6) 1.738 (0.676-4.470)
Prior history of HF 0.567
Yes 117/180 (65.0) 134/197 (68.0) O.882 (0.734-1.060)
No 62/180 (34.4) 62/197 (31.5) 0.805 (0.599-1.082)

NYHA functional class at randomization 0.382

I 5/180 (2.8) 8/197 (4.1) 2.771 (0.193-39.83O)
II 86/180 (47.8) 85/197 (43.1) 0.794 (0.640-0.985)
III 83/180 (46.1) 95/197 (48.7) 0.904 (0.713-1.145)

4 groups defined by the baseline quartiles of NT-proBNP 0.183

Baseline NT-proBNP Q1 45/180 (25.0) 51/197 (25.9) 0.744 (0.527-1.050)
Baseline NT-proBNP Q2 47/180 (26.1) 46/197 (23.4) 0.697 (0.504-0.965)
Baseline NT-proBNP Q3 51/180 (28.3) 49/197 (24.9) 0.963 (0.702-1.321)
Baseline NT-proBNP Q4 37/180 (20.6) 51/197 (25.9) 1.039 (0.757-1.427)

LVEF categories prior to randomization 0.082

≤Median 104/180 (57.8) 111/197 (56.3) 0.760 (0.618-0.935)
>Median 76/180 (42.2) 86/197 (43.7) 1.003 (0.789-1.276)
LVEF categories prior to randomization 0.033
>40 to ≤60% 136/180 (75.6) 151/197 (76.6) 0.775 (0.646-0.930)
>60% 44/180 (24.4) 46/197 (23.4) 1.169 (0.857-1.594)

Atrial fibrillation/atrial flutter 0.593

Yes 105/180 (58.3) 116/197 (58.9) 0.883 (0.736-1.060)
No 75/180 (41.7) 81/197 (41.1) 0.799 (0.602-1.061)

SBP at randomization, mm Hg 0.862

<110 25/180 (13.9) 25/197 (12.7) 0.840 (0.580-1.218)
≥110 154/180 (85.6) 168/197 (85.3) 0.864 (0.728-1.026)
Body mass index, kg/m2 0.437
<30 54/180 (30.0) 75/197 (38.1) 0.940 (0.701-1.260)
≥30 126/180 (70.0) 122/197 (61.9) 0.820 (0.679-0.991)

Baseline eGFR, mL/min/1.73 m2 0.096

<45 79/180 (43.9) 74/197 (37.6) 1.017 (0.810-1.277)
45 to <60 40/180 (22.2) 61/197 (31.0) 0.818 (0.592-1.129)
≥60 57/180 (31.7) 61/197 (31.0) 0.682 (0.507-0.917)

ACE inhibitor or ARB at screening 0.523

Yes 143/180 (79.4) 155/197 (78.7) 0.883 (0.745-1.048)
No 37/180 (20.6) 42/197 (21.3) 0.759 (0.508-1.133)
In-hospital randomization or out-of-hospital randomization 0.991
Randomized in hospital 119/180 (66.1) 130/197 (66.0) 0.857 (0.697-1.053)
Randomized out of hospital 61/180 (33.9) 67/197 (34.0) 0.870 (0.695-1.088)

0.125 0.25 0.5 1 2 4 10

Rate Ratio

Continued on the next page

JACC VOL. -, NO. -, 2023
-, 2023:-–-
years) for the Val group. The most frequent serious
adverse events and treatment-related adverse events
are summarized in Supplemental Tables 4 and 5,
respectively. There were numerically
hypertensive-related SAEs (eg, hypertensive urgency
and emergency) in the Sac/Val group vs Val (1 vs 7)
and more treatment-related hypotensive adverse
events (eg, orthostatic hypotension and hypotension)
in the Sac/Val group vs Val (45 vs 26). There were
18 deaths in the Sac/Val group (10 cardiovascular) and
26 deaths in the Val group (18 cardiovascular).
DISCUSSION
Among a diverse population of patients with EF
>40% stabilized after a recent episode of WHF,
treatment with Sac/Val led to a greater reduction in
NT-proBNP than treatment with Val through 8 weeks.
Analysis of the hierarchical composite outcome also
appeared to favor Sac/Val over Val, particularly in the
prespecified subgroup with EF below normal (#60%).
Patients treated with Sac/Val in this study experi-
enced higher rates of symptomatic hypotension but
no increase in rates of hyperkalemia, and fewer renal
events. In light of similar findings from PARAGON-
HF, we believe these data provide additional sup-
port for the clinical benefits of combined angiotensin-
receptor neprilysin inhibition in patients with HFpEF,
particularly among those with EF below normal.
PRIMARY ENDPOINT: NT-proBNP CHANGE. The trial
met its primary endpoint of a significantly greater
reduction in NT-proBNP with Sac/Val than Val. The
benefit occurred early with biomarker
diverging at 1 week. The NT-proBNP reduction in this
study of patients with recent WHF and EF >40% was
consistent with the effect of Sac/Val on NT-proBNP in
lower-risk patients with chronic HFpEF enrolled in
PARAGON-HF and PARAMOUNT. 13,14 This finding is
important, because it validates the incremental effect
of concomitant neprilysin inhibition over angiotensin
inhibition alone in patients with HF and EF >40%.
Moreover, these observations extend those from prior
studies because the population enrolled
PARAGLIDE-HF included a number of patients under-
represented in PARAGON-HF (eg, severely obese).
Compared with earlier studies with Sac/Val, the
F I G U R E 2 Continued
Shown are data on the time-averaged proportional change in the amino terminal pro–B-type natriuretic peptide (NT-proBNP) concentration, from the baseline value to
the geometric mean of values obtained at Weeks 4 and 8, with each treatment according to subgroup. Information on race was reported by the patient.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; eGFR ¼ estimated glomerular filtration rate; HF ¼ heart failure; LVEF ¼ left ventricular
ejection fraction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure.
Mentz et al 9
ARNI in Worsening Heart Failure
PARAGLIDE-HF population had a higher body mass
index (BMI), more atrial fibrillation, and worse renal
function, which each affect natriuretic peptide levels.
fewer Study participants had the highest BMI of any of
the major trials of Sac/Val (mean BMI 35 kg/m 2 vs
30 kg/m 2 in PARAGON-HF) and a high prevalence of
AF (history of AF in 59% vs 32% in PARAGON-HF).
The trial also had 22% Black individuals and prior
studies have shown that Black patients with HF may
have distinct natriuretic peptide profiles. 15,16 Thus,
these data provide important insights regarding the
effect of Sac/Val in diverse populations not histori-
cally represented well in clinical trials.
CLINICAL OUTCOMES. Although PARAGLIDE-HF was
not powered to detect a reduction in clinical events,
the secondary clinical endpoints trended toward fa-
voring Sac/Val, even if they did not formally meet the
criteria for statistical significance. This trend was
consistent with findings from PARAGON-HF, in which
there was a numerical reduction in HF hospitaliza-
tions and renal events. 1,17 Similarly, in PARAGLIDE-
HF, there were numerically lower rates of the
hierarchical composite outcome as well as the recur-
rent composite cardiovascular endpoint and renal
events in patients assigned to Sac/Val. The magnitude
of these potential benefits was consistent and com-
parable to those seen in PARAGON-HF despite
enrollment of a higher-risk population with WHF in
PARAGLIDE-HF. As in PARAGON-HF, results were
most compelling in the population with EF #60%.
Together, these data suggest that combined angio-
tensin receptor neprilysin inhibition is likely more
values effective than angiotensin receptor blockade alone in
treatment of patients with HF and EF >40%, regard-
less of the care setting (hospital or clinic), in which
they are encountered with a larger benefit when EF is
below normal.
PARAGLIDE-HF complements the PARAGON-HF
trial data by specifically focusing on patients stabi-
lized after a WHF event with EF >40% similar to the
manner in which PIONEER-HF complemented
PARADIGM-HF (Prospective Comparison of ARNI with
in ACEI to Determine Impact on Global Mortality and
Morbidity in Heart Failure) in patients with reduced
EF. Specifically, PARAGON-HF included a run-in
period and focused on patients with chronic HFpEF
10 Mentz et al JACC VOL. -, NO. -, 2023
ARNI in Worsening Heart Failure -, 2023:-–-

F I G U R E 3 Win Ratio in the Subgroup With EF Below Normal (#60%)

37.9%
Overall 26%
36.1%

Time to CV Death 3.3%

Win Ratio: 1.459 (95% CI: 1.092-1.948)
(Adjudication) 2.3%

Recurrent Events of HF
Hospitalization 12.9%
(Confirmed) 8.9%
(Adjudication)

Recurrent Events of 2.4%

Urgent Heart Failure
(Adjudication) 1.3%

29%
Change in NT-proBNP
20.2%

Ties 36.1%

Sacubitril + Valsartan Winner Valsartan Winner Ties

The composite hierarchical outcome of cardiovascular (CV) death, HF hospitalizations, urgent HF visits, and change in NT-proBNP was analyzed by estimating the
unmatched win ratio by comparing every participant in the sacubitril/valsartan group to every participant in the valsartan group to determine a winner. The estimated
win ratio (the total number of wins in the sacubitril/valsartan arm divided by the total number of wins in the valsartan arm) was calculated with corresponding CIs.
Abbreviations as in Figure 2.

who had been on a loop diuretic for at least 30 days included in PARAGLIDE-HF supports the generaliz-
with specific echocardiographic abnormalities (eg, ability of these data to similar patients seen in routine
left atrial enlargement or left ventricular hypertro- practice.
phy) and excluded those with improved/recovered EF SAFETY: SYMPTOMATIC HYPOTENSION. In PARAGLIDE-
(ie, prior EF <40%) or current decompensation. HF, Sac/Val increased risk for symptomatic hypoten-
PARAGLIDE-HF had no run-in period, included those sion compared with Val (73% higher risk). The blood
with newly diagnosed HF, was broadly inclusive of pressure–lowering effects of Sac/Val are well estab-
those with a clinical diagnosis of acute HF (without lished. In PIONEER-HF, which had similar stabiliza-
specific echocardiographic requirements), and tion criteria to PARAGLIDE-HF but enrolled patients
allowed improved EF. Moreover, PARAGLIDE-HF with HF with reduced EF, there was an 18% numerical
included those with GFR down to 20 mL/ increase in symptomatic hypotension with Sac/Val
min/1.73 m2 and systolic blood pressure as low as compared with enalapril (nonsignificant).10 In
100 mm Hg without a BMI exclusion (vs exclusions of PARAGON-HF, hypotension occurred in 15.8% of the
30 mL/min/1.73 m 2, 110 mm Hg, and >40 kg/m 2, Sac/Val group compared with 10.8% of the Val group.1
respectively, in PARAGON-HF). The broad population Potential reasons for the increased risk of
JACC VOL. -, NO. -, 2023
-, 2023:-–-
symptomatic hypotension in PARAGLIDE-HF may
relate to more significant fluctuations in volume sta-
tus as well as autonomic dysfunction around the time
of a WHF event in those with EF >40%. 18 Notably, in
PARAGON-HF, the differential effect of Sac/Val on
blood pressure compared with Val did not impact the
potential treatment benefit. 1
Early study discontinuation (caused by either
physician or participant decision) was higher in the
Sac/Val group than the Val group (33 vs 18), and more
patients in the Sac/Val group than the Val group did
not contribute to the primary endpoint (53 vs 36).
This difference may have been related in part to more
symptomatic hypotension with Sac/Val or potentially
caused by chance. However, these observations
should also be interpreted in the context of fewer
deaths in the Sac/Val group in a trial that enrolled a
relatively ill and older age population.
STUDY LIMITATIONS. The sample size was relatively
modest, and the study was not powered for clinical
events. The follow-up duration was also fairly short
compared with PARAGON-HF but extended further
into the postevent period than PIONEER-HF. In
addition, approximately 19% of patients did not
contribute to the primary endpoint given the lack of
NT-proBNP data. Nonetheless, this was only slightly
greater than the 15% rate of missingness anticipated
from similarly designed prior trials. 10 Finally, rela-
tively few patients were being treated with a sodium-
glucose cotransporter-2 inhibitor, which is now
recommended in this patient population.2-5 There-
fore, future studies will need to explore concomitant
treatment with Sac/Val and sodium-glucose cotrans-
porter-2 inhibitors in HFpEF, particularly in the early
period following a WHF event.
CONCLUSIONS
Among a diverse population of patients with heart
failure with EF >40% and stabilized WHF, Sac/Val led
to a greater reduction in NT-proBNP and a potential
clinical benefit compared with Val, with numerically
fewer cardiovascular and renal events but more
symptomatic hypotension. In a prespecified subgroup
with EF below normal, the effect on natriuretic pep-
tide level and clinical outcomes appeared larger.
These data add to the evidence supporting a potential
treatment benefit of Sac/Val in those with EF >40%
(particularly in those with EF below normal), and may
influence future guidance for use of Sac/Val in this
population, regardless of treatment setting (hospital
Mentz et al 11
ARNI in Worsening Heart Failure
vs clinic) or HF chronicity (acute on chronic vs de
novo HF).
ACKNOWLEDGMENTS The PARAGLIDE-HF leader-
ship recognizes the contributions of the CardioNerds
who partnered with the trial investigators to enhance
recruitment and pair equitable trial enrollment with
trainee development. A complete list of the
PARAGLIDE-HF trial investigators is provided in the
Supplemental Appendix.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
PARAGLIDE-HF was funded by Novartis Pharmaceuticals Corpora-
tion. Dr Mentz has received research support and/or honoraria from
Novartis, Abbott, American Regent, Amgen, AstraZeneca, Bayer,
Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast
BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck,
Novo Nordisk, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi,
Vifor, Windtree Therapeutics, and Zoll. Drs Ward, Sarwat, and Wil-
liamson are employees of Novartis. Dr Hernandez has received
research grants from American Regent, Amgen, AstraZeneca, Bayer,
Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Somo-
logic, and Verily; and has served as a consultant for Amgen, Astra-
Zeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston
Scientific, Cytokinetics, Merck, Novartis, and Novo Nordisk. Dr
Morrow is a member of the TIMI Study Group, which has received
institutional research grant support through Brigham and Women’s
Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA
Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals,
Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc,
Janssen Research and Development, LLC, Merck, Novartis, Pfizer,
Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche,
Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, and
Zora Biosciences; and has received consulting fees from Abbott
Laboratories, ARCA Biopharma, Inflammatix, Merck and Co, Novar-
tis, and Roche Diagnostics. Dr Sharma serves as an advisory board
member and/or consultant to AstraZeneca, Alleviant, Bayer, Boeh-
ringer Ingelheim, Imbria, Novartis, Novo Nordisk, RIVUS, and ViC-
ardia; and receives grant funding from Amgen and the American
Heart Association. Dr Starling serves on the steering committee for
the PARAGLIDE trial sponsored by Novartis. Dr Velazquez has
received grants from Novartis, Amgen, Phillips, and the National
Heart, Lung, and Blood Institute/National Institutes of Health. Dr
Desai has received research grants (to BWH) from Abbott, Alnylam,
AstraZeneca, Bayer, and Novartis; and has received personal
consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Bio-
pharma, Axon Therapeutics, Bayer, Biofourmis, Cytokinetics, Glax-
oSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel,
Regeneron, River2Renal, Roche, Verily, and Veristat. Dr Zieroth has
received research grant support, served on advisory boards for, or
has had speaker engagements with Abbott, Akcea AstraZeneca,
Amgen, Alnylam, Bayer, Bristol Myers Squibb, Boehringer Ingel-
heim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Novo
Nordisk, Otsuka, Pfizer, Roche, Servier and Vifor Pharma; and serves
on a clinical trial committee or as a national lead for studies spon-
sored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis
and Pfizer. Dr Solomon has received research grants from Alnylam,
AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cytokinetics,
Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes
of Health/National Heart, Lung, and Blood Institute, Novartis, Novo
Nordisk, Respicardia, Sanofi Pasteur, Theracos, Actelion, Amgen,
Bellerophon, Celladon, Gilead, Mesoblast, Neurotronik, and US2;
and has consulted for Abbott, Action, Akros, Alnylam, Amgen,
12 Mentz et al JACC VOL. -, NO. -, 2023
ARNI in Worsening Heart Failure -, 2023:-–-

Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers

PERSPECTIVES
Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo,
GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Ther-
acos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions,
COMPETENCY IN PATIENT CARE AND
Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna,
American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr PROCEDURAL SKILLS: Among patients with left
Braunwald has received grant support to his institution from ventricular EF >40% stabilized after a period of WHF,
Novartis for the conduct of the PIONEER-HF trial, for serving on the treatment with sacubitril/valsartan was associated
Executive Committee of the PARADISE-MI trial and the Steering
with greater reduction in plasma NT-proBNP levels
Committee of the PARAGLIDE-HF trial, and for participation in an
Advisory Board Meeting. Dr Lepage has reported that he has no and clinical benefit compared with valsartan alone,
relationships relevant to the contents of this paper to disclose. despite more symptomatic hypotension.

TRANSLATIONAL OUTLOOK: Future studies

ADDRESS FOR CORRESPONDENCE: Dr Robert J.
should explore concomitant treatment with sacubitril/
Mentz, Division of Cardiology, Department of
valsartan plus sodium-glucose cotransporter-2 inhib-
Medicine, Duke Clinical Research Institute, Duke
itors in patients with heart failure and relatively pre-
University Medical Center, 2301 Erwin Road, Durham,
served EF, particularly early after a period of WHF.
North Carolina 27710, USA. E-mail: robert.mentz@
duke.edu. Twitter: @robmentz.

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KEY WORDS acute decompensated HFpEF,
clinical outcomes, HFmrEF, natriuretic
peptides, sacubitril/valsartan
A PPE NDI X For an expanded Methods section
as well as supplemental tables and figures,
please see the online version of this paper.