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Received: 6 July 2022    Revised: 9 September 2022    Accepted: 14 September 2022

DOI: 10.1002/phar.2730

REVIEW OF THERAPEUTICS

Evaluating the evidence for sacubitril/valsartan across the

continuum of heart failure

Preston T. Skersick1,2 | Darrian Proco2 | Preetika Sharma-­Huynh3 |

Courtney A. Montepara4  | Jo E. Rodgers1

1
UNC Eshelman School of Pharmacy,
University of North Carolina, Chapel Hill, Abstract
North Carolina, USA
Since initial publication of the PARADIGM-­HF trial in 2014, sacubitril/valsartan has
2
GlaxoSmithKline, Research Triangle Park,
Durham, North Carolina, USA
been investigated in various settings to establish optimal use, further expanding its
3
PPD, Morrisville, North Carolina, USA indications in patients with heart failure (HF). Although numerous studies have been
4
Duquesne University School of published, until recently these have primarily involved post hoc analyses from the
Pharmacy, Duquesne University,
PARADIGM-­HF study itself with a consistent focus on use of sacubitril/valsartan in
Pittsburgh, Pennsylvania, USA
patients with HF with reduced ejection fraction (HFrEF). This has led to a gap in the
Correspondence
literature regarding utility of sacubitril/valsartan in other HF subpopulations. The
Jo E. Rodgers, Campus Box 7569, 3215
Kerr Hall, 301 Pharmacy Lane, Chapel Hill, aim of this review is to provide a summary of recent clinical trials further expanding
NC 27599-­7569, USA.
use and guideline recommendations for sacubitril/valsartan. The findings of 15 stud-
Email: jerodgers@unc.edu
ies, including clinical trials and post hoc analyses, are summarized and describe the
use of sacubitril/valsartan in additional HF subpopulations, such as HFrEF following
hospitalization for acute decompensated HF and advanced HF, HF with preserved
ejection fraction (HFpEF), and HF postmyocardial infarction. In addition, three stud-
ies investigating timing of initiation, dose titration regimens, and cost-­effectiveness
are examined. Select ongoing trials are also reviewed to demonstrate the continued
commitment to further advance care of patients with HF. This comprehensive review
serves as a resource for health care providers who pursue optimal utilization of sacu-
bitril/valsartan in their respective clinical practices.

KEYWORDS
heart failure, HFpEF, HFrEF, postmyocardial infarction, sacubitril/valsartan

1  |  I NTRO D U C TI O N significant strides have been made in regard to our understanding of

Heart failure (HF), a chronic condition in which structural damage
to the myocardium has led to impaired ventricular filling or ejection
of blood, imposes a significant burden on the quality of life (QOL)
of patients living with the disease.1 From 2010 to 2019, the preva-
lence of HF in the United States increased almost 20%—­now affect-
2,3
ing approximately 6.2 million adults across the country.
HF pathophysiology and treatment, the total percentage of the US
population living with the disease continues to rise and is expected
to reach 3% (roughly 8 million people) by the year 2030. Additionally,
HF has posed a substantial economic strain on the US health care
system and its payers with an estimated total expenditure of $30.7
billion in 2012 when including factors such as health care services,
Although medications, and days of work lost.4 The rising prevalence and

At the time of the writing of this paper, Dr. Proco and Dr. Sharma-­Huynh were fellows at UNC.

© 2022 Pharmacotherapy Publications, Inc.     837

Pharmacotherapy. 2022;42:837–848. wileyonlinelibrary.com/journal/phar |
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838      SKERSICK et al.
associated health care-­related costs of HF have continued to esca-
late despite several new targeted therapies.
The United States Food and Drug Administration (FDA) approval
of sacubitril/valsartan (Entresto®) in 2015 provided the HF popula-
tion with an advanced treatment option following the publication of
the PARADIGM-­HF trial, which indicated that treatment with sacu-
bitril/valsartan reduced morbidity and mortality in patients with HF
with reduced ejection fraction (HFrEF).5 Subsequently, sacubitril/
valsartan was established as an essential medication in guideline-­
directed medical therapy (GDMT) for this disease.6 Only recently has
another HF therapy, the sodium-­glucose cotransporter-­2 (SGLT2)
inhibitors, demonstrated similar magnitude of benefit and breadth
of population impacted.7–­8 With additional evidence supporting use
in patients regardless of left ventricular ejection fraction (LVEF),
sacubitril/valsartan received an extended label in early 2021 for the
treatment of patients with both HFrEF and HF with preserved ejec-
tion fraction (HFpEF).5,9–­10
Until recently, gaps in evidence guiding use of sacubitril/valsar-
tan persisted, particularly among various HF subpopulations. The
medication's potential role in advanced HF, HFpEF, and HF postmyo-
cardial infarction had only previously been hypothesized until this
new literature emerged. This review summarizes new insights pro-
vided by recent clinical trials assessing sacubitril/valsartan in these
distinct HF subpopulations and additional secondary analyses of the
PARADIGM-­HF trial. Additionally, ongoing, prospective studies are
outlined. A total of 15 studies are included in this review, with the
overall aim of adding to the safety and efficacy profile of sacubitril/
valsartan in populations with prominent representation in the real-­
world setting.
2  |  U N D E R S TA N D I N G M EC H A N I S TI C
PRO PE RTI E S
Adverse cardiac remodeling is a hallmark feature of HFrEF, often
leading to progressive left ventricular (LV) dilation and reduced
contractile function. Several neurohormonal antagonists, including
angiotensin-­converting enzyme inhibitors (ACEi) and beta-­adrenergic
receptor blockers, help to attenuate or reverse the remodeling pro-
cess, thereby improving survival of patients with HFrEF.11 Although
the PARADIGM-­HF trial demonstrated the clinical benefits of long-­
term therapy with sacubitril/valsartan, the pathophysiologic mecha-
nism of benefit of angiotensin II receptor/neprilysin inhibitor (ARNI)
therapy was not fully understood. Ventricular dysfunction may be
manifested through several mechanisms, including alterations in car-
diac geometry and aortic stiffness. These may be demonstrated by
measuring the change in cardiac volume and function through LV
end-­diastolic and LV end-­systolic volumes indexed by body surface
area, known as LVEDVI and LVESVI, respectively.12 Furthermore,
LVEDVI and LVESVI are strong prognostic indicators of mortality,
while increased central aortic stiffening is associated with the de-
velopment of HF and can be measured through aortic characteristic
13
impedance. In combination, these measures provide insight into
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the underlying mechanism of sacubitril/valsartan, specifically its
effects on reverse remodeling. Several studies, most notably the
PROVE-­HF and EVALUATE-­HF trials, have been conducted to de-
lineate the mechanisms by which the ARNI, sacubitril/valsartan, im-
proves outcomes in patients with HFrEF (Table 1).14,15 Although both
the PROVE-­HF and EVALUATE-­HF trials attempted to elucidate the
mechanism by which an ARNI improves outcomes in patients with
HFrEF, trial designs varied considerably.
The PROVE-­HF trial14 was an open-­label, single-­arm study of
794 patients with HFrEF treated with sacubitril/valsartan over
1 year. This trial was designed to correlate changes in N-­terminal pro-­
B-­t ype natriuretic peptide (NT-­proBNP) with changes in measures of
cardiac volume and function, specifically LVEF, LVEDVI, LVESVI, left
atrial volume index (LAVI), and ratio of early transmitral Doppler ve-
locity/early diastolic annular velocity (E/e') at 12 months. Although
the PROVE-­HF trial demonstrated that reduction in NT-­proBNP was
significantly correlated with signs of reverse cardiac remodeling at
1 year, these improvements were modest. Initiation and titration
of sacubitril/valsartan led to a 37% reduction in NT-­proBNP from
the baseline median of 816 pg/mL to 455 pg/mL at 12  months (in-
terquartile range [IQR], 153–­1090; change from baseline, p < 0.001)
(Table  1). Significant correlations were also observed between
change in NT-­
proBNP and change in LVEF (r  = −0.381), LVEDVI
(r = 0.320), LVESVI (r = 0.405), LAVI (r = 0.263), and E/e' (r = 0.269)
at 12 months, all with p < 0.001. Mean LVEF increase was 9.4%, with
25% of study participants experiencing an absolute LVEF increase
of more than 13%. Although improvements in cardiac function were
more evident at 12 months, these benefits could be seen as early as
6 months. Additionally, these results were consistent in patients with
new-­onset HF and patients not receiving target sacubitril/valsartan
doses. Despite these findings, it may be unclear whether these re-
sults are due to ARNI usage given the lack of a control group.
The EVALUATE-­HF trial15 was a randomized, multicenter, double-­
blind study of sacubitril/valsartan compared to enalapril conducted
over 12 weeks in 464 patients. Patients were randomized only up to
12 weeks due to ethical concerns of withholding sacubitril/valsar-
tan in patients with HFrEF. The trial examined similar cardiac volume
and function end points as the PROVE-­HF trial but focused primarily
on measures of central aortic stiffness as evaluated by the change
from baseline to week 12 in aortic characteristic impedance. This
study demonstrated complementary overall results and improve-
ment in ventricular volumes at week 12. Compared with enalapril,
patients in the sacubitril/valsartan group had significantly greater
reductions from baseline in LVEDVI, LVESVI, LAVI, and mitral E/e'
ratio, further demonstrating benefit in measures of cardiac remodel-
ing and diastolic function (Table 1). This trial also found the benefits
of sacubitril/valsartan in patients with HFrEF are unlikely related to
changes in central aortic stiffness or pulsatile load. The primary end
point of aortic characteristic impedance decreased from 223.8 to
218.9 dyne x s/cm5 in the sacubitril/valsartan group, compared to
an increase in the enalapril group from 213.2 to 214.4 dyne x s/cm5
(between-­group difference, −2.2 dyne x s/cm5; 95% confidence in-
terval [CI]: −17.6 to 13.2 dyne x s/cm5; p = 0.78) (Table 1), suggesting
 TA B L E 1  Comparison of studies analyzing the mechanistic properties of sacubitril/valsartan in HFrEF
SKERSICK et al.

Total Treatment Results of primary efficacy end point and select

Trial abbreviation patients Key inclusion criteria Study intervention duration Primary efficacy end point secondary end points

PROVE-­HF14 794 • Age ≥18 years Sacubitril/valsartan 52 weeks Correlation between changes Significant reduction of NT-­proBNP seen with use of
(NCT02887183) • LVEF ≤40% within the in the concentration of sacubitril/valsartan, which was correlated with
preceding 6 months NT-­proBNP and cardiac measures associated with reverse remodeling
• NYHA class II, III, IV remodeling, assessed by Statistically significant correlations were observed
• Stable dose of loop diuretic change in LVEDVI, LVESVI, between the change in log2–­NT-­proBNP
for the 2 weeks preceding LVEF, LAVI, and E/e' concentration and:
study start • LVEF (r = −0.381 [IQR, −0.448 to −0.310];
• Patients with HFrEF who p < 0.001)
are candidates for on-­label • LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; p < 0.001)
treatment with sacubitril/ • LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; p < 0.001)
valsartan • LAVI (r = 0.263 [IQR, 0.186 to 0.338]; p < 0.001)
• E/e' (r = 0.269 [IQR, 0.182 to 0.353]; p < 0.001)
Additionally, at 12 months,
• Baseline median NT-­proBNP decreased from 816 to
455 pg/ml (p < 0.001)
• Mean LVEF increased from 28.2% to 37.8%
(p < 0.001)
EVALUATE-­HF15 464 • Age ≥50 years Sacubitril/valsartan 12 weeks Between-­group differences Change in aortic characteristic impedance was not
(NCT02874794) • LVEF ≤40% vs. Enalapril in change in aortic significant, however, significant improvements in
• NYHA class I, II, or III characteristic impedance some measures of diastolic function were seen
• Treatment with stable doses from baseline to week 12 Primary outcome:
of GDMT other than ACEi/ Change in aortic impedance from baseline to 12 weeks
ARB was −2.9 in the sacubitril/valsartan group
• SBP ≥105 mm Hg compared to −0.7 in the enalapril group (p = 0.78)
Secondary outcomes:
• Change in LVEDVI: treatment difference, −2.0 ml/
m2 [95% CI, −3.7 to 0.3 ml/m2]; p = 0.02
• Change in LVESVI: treatment difference, −1.6 ml/
m2 [95% CI, −3.1 to −0.03 ml/m2]; p = 0.045
• Change in LAVI: treatment difference, −2.8 ml/m2
[95% CI, −4.0 to −1.6 ml/m2]; p < 0.001
• Change in mitral E/e': treatment difference, −1.8
[95% CI, −2.8 to −0.8]; p = 0.001

Abbreviations: ACEi, angiotensin-­converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; E/e', ratio of early mitral inflow velocity/early diastolic mitral annular velocity;
GDMT, guideline-­directed medical therapy; HFrEF, heart failure with reduced ejection fraction; IQR, interquartile range; LAVI, left atrial volume index; LVEDVI, left ventricular end-­diastolic volume index;
LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-­systolic volume index; m, meters; mL, milliliters; mm Hg, millimeters of mercury; NT-­proBNP, N-­terminal pro-­brain natriuretic peptide;
NYHA, New York Heart Association; pg, picograms; SBP, systolic blood pressure.
|       839

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840      SKERSICK et al.
the mechanism of ARNI benefit may not be through aortic remod-
eling. A possible explanation for this finding could be due to lower
than anticipated impedance at baseline and higher initial levels of
ACEi and ARB usage, which may have already facilitated prior aor-
tic remodeling. Lastly, there were also no appreciable differences
between the two groups in terms of LVEF improvement. Although
the longer duration of follow-­up in the PROVE-­HF trial may have al-
lowed for more demonstrated additional benefits on cardiac remod-
eling, both studies suggest that ARNI therapy can promote cardiac
reverse remodeling in patients with HFrEF.
3  |  A DVA N C E D H Fr E F A N D ACU TE
D ECO M PE N SATE D H E A RT FA I LU R E
The PARADIGM-­HF trial was a significant milestone in the HF land-
scape, leading to expedited approval of sacubitril/valsartan by the
16
FDA along with subsequent changes to guideline recommenda-
tions for HF management.17,18 However, less than 1% of study par-
ticipants had a diagnosis of New York Heart Association (NYHA)
class IV HF in PARADIGM-­HF,19 providing limited data regarding
the use of sacubitril/valsartan in patients with advanced HFrEF.
Additionally, the role of this therapy in patients hospitalized with
acute decompensated heart failure (ADHF) had not been assessed.
Since completion of PARADIGM-­HF, additional trials have been con-
ducted in these patient populations (Table 2).
The LIFE trial was a randomized, multicenter, double-­
blind,
double-­dummy study of sacubitril/valsartan compared to valsartan
in 335 patients with advanced HFrEF, defined as an LVEF ≤35%,
NYHA class IV HF, and a minimum of 3 months on GDMT for HF or
intolerance to GDMT. 20 Valsartan was chosen as the active compar-
ator in the LIFE trial so as to specifically investigate the incremen-
tal effects of a neprilysin inhibitor in patients with HFrEF. The trial
enrolled patients during either an index hospitalization for HF or in
the outpatient setting. The primary end point was the proportional
change in area under the curve (AUC) of NT-­proBNP from baseline at
24 weeks. 21 Unfortunately, enrollment for the LIFE trial was stopped
early in March of 2020 due to the COVID-­19 pandemic, leading to
a smaller than anticipated study population. This trial demonstrated
no significant difference in the proportional change in NT-­proBNP
AUC compared to baseline. Moreover, neither group in the study
was found to have a reduction in NT-­proBNP levels below baseline
at week 24. Although symptomatic hypotension did not differ be-
tween groups, a higher percentage of patients experienced hyper-
kalemia in the sacubitril/valsartan arm of the trial. The impact of low
enrollment into the LIFE trial due to the pandemic likely played a
significant role in the outcome of this trial. 22
The PIONEER-­HF trial23 was a randomized, multicenter, double-­
blind study that assessed the impact of sacubitril/valsartan on NT-­
proBNP in 881 patients with HFrEF and ADHF. Patients in the trial
were hospitalized for ADHF at the time of enrollment. Similar to the
PARADIGM-­HF trial, the PIONEER-­HF trial utilized enalapril as the
comparator. Notably, a large percentage of patients enrolled were
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NYHA class II (25.2%) or class III (62.7%), with only 75 (8.5%) partic-
ipants diagnosed as NYHA class IV. The primary efficacy end point
was the time-­
averaged proportional change in NT-­
proBNP from
baseline at 8 weeks. In contrast to the LIFE trial, treatment with
sacubitril/valsartan led to a significant reduction of time-­averaged
NT-­proBNP levels compared to enalapril. The change in NT-­proBNP
was evident as early as week 1. At week 8, the sacubitril/valsartan
group had approximately double the NT-­proBNP level reduction
that was observed in the enalapril treatment arm. In addition, two
exploratory outcomes demonstrated significant differences be-
tween the groups—­a lower rate of rehospitalization for HF (8.0% vs.
13.8%; hazard ratio [HR] 0.56; 95% confidence CI: 0.37–­0.84) and
a lower rate of serious clinical events, which was a composite end
point of rehospitalization due to HF, implantation of a LV assist de-
vice, inclusion of patient to a list for heart transplantation, and death
(9.3% vs. 16.8%; HR 0.54; 95% CI: 0.37–­0.79) with sacubitril/valsar-
tan compared to enalapril, respectively. No significant differences
in key safety outcomes, including rates of hyperkalemia, symptom-
atic hypotension, or worsening renal function were observed. These
findings provided evidence for the safe and effective use of sacubi-
tril/valsartan in patients hospitalized for ADHF.
Following initial diagnosis, the first 3 months after hospitaliza-
tion for ADHF have been termed the “vulnerable phase,”24 in which
studies have found patients have a greater risk of death and read-
mission. 25 Similar to the PIONEER-­HF trial, the TRANSITION trial26
was conducted in patients with HFrEF and hospitalized for ADHF.
Patients with either ADHF due to a HF exacerbation or de novo HF
could be enrolled. The aim of the study was to assess the tolera-
bility and optimal timing of sacubitril/valsartan initiation, during or
shortly after hospitalization for ADHF in stabilized patients. Patients
were randomized in a 1:1 manner to begin sacubitril/valsartan ther-
apy predischarge (up to 12 hours before, n = 493) or postdischarge
(between days 1–­14, n = 489) with a target dose of 97/103 mg twice
daily. A comparable percentage of patients in the pre-­and postdis-
charge groups achieved and maintained sacubitril/valsartan use at
any dose for ≥2 weeks leading up to week 10. At week 10, there was
no significant difference in the primary end point, percentage of pa-
tients achieving the target dose, between the two treatment groups.
In addition, there was no difference in discontinued use of sacubi-
tril/valsartan due to adverse events in the pre-­and postdischarge
groups. These results indicate the initiation and uptitration of sacu-
bitril/valsartan is feasible in patients recently stabilized following
ADHF regardless of timing.
The recent 2022 American Heart Association, American College
of Cardiology, and Heart Failure Society of America (AHA/ACC/
HFSA) Guideline for the Management of Heart Failure provide
a Class 2b recommendation that, in patients with HFrEF, GDMT
should be initiated during hospitalization after clinical stability is
achieved. In addition, the guidelines recommend that if discontin-
uation of GDMT is necessary during hospitalization, it should be
reinitiated and further optimized as soon as possible. This guideline
recommendation cites various trials for different GDMT. For sacubi-
tril/valsartan, the PIONEER-­HF trial was cited, including the use of
 TA B L E 2  Comparison of studies analyzing the utilization of sacubitril/valsartan in advanced heart failure and acute decompensated heart failure

Trial Total Treatment Results of primary efficacy end point and select
SKERSICK et al.

abbreviation patients Key inclusion criteria Study interventions duration Primary efficacy end point secondary end points

LIFE20–­22 335 • Age ≥18 years Sacubitril/valsartan vs. Valsartan 24 weeks NT-­proBNP values and No significant difference detected for primary end
(NCT02816736) and ≤85 years proportional change point from baseline to week 24 between two
• NT-­proBNP ≥800 pg/ml from baseline AUC at 2, groups (p = 0.45)
OR BNP ≥250 pg/ml 4, 8, 12, and 24 weeks Neither sacubitril/valsartan group nor valsartan
• SBP ≥90 mm Hg group had reduction in NT-­proBNP levels
• Advanced HFrEFa below baseline
• Objective findings
indicative of advanced
HFb
PIONEER-­HF23 881 • Age ≥18 years Sacubitril/valsartan vs. Enalapril 8 weeks NT-­proBNP values and Sacubitril/valsartan group had greater significant
(NCT02554890) • LVEF ≤40% time-­averaged change time-­averaged reduction in NT-­proBNP
• NT-­proBNP ≥1600 pg/ml from baseline at 4 and concentration vs. enalapril group
OR BNP ≥400 pg/ml 8 weeks Change in time-­averaged NT-­proBNP concentrations
• Primary diagnosis of at 4 and 8 weeks:
ADHF with s/sx of fluid −46.7% vs. −25.3% in sacubitril/valsartan and
overload enalapril groups, respectively
Ratio of change with sacubitril/valsartan vs. enalapril:
0.71 (95% CI: 0.63–­0.81)
As early as week 1, the greater reduction in
NT-­proBNP with sacubitril/valsartan group
was evident (ratio of change = 0.76; 95% CI:
0.69–­0.85)
TRANSITION26 982 • Age ≥18 years Predischarge initiation of sacubitril/ 10 weeks Percentage of patients Patients achieving primary end point:
(NCT02661217) • Hospitalized for ADHF valsartan vs. Postdischarge achieving the sacubitril/ 45.4% pre-­vs. 50.7% postdischarge groups (RR
(de novo or exacerbation) initiation of sacubitril/valsartan valsartan target dose 0.90; 95% CI: 0.79–­1.02)
• NYHA class II-­IV of 97/103 mg twice Patients achieving and maintaining dose of 49/51
• BP ≥100 mm Hg daily at 10 weeks or 97/103 mg twice daily for ≥2 weeks leading to
• LVEF ≤40% postrandomization week 10:
62.1% pre-­vs. 68.5% postdischarge groups (RR
0.91; 95% CI: 0.83–­0.99)
Patients achieving and maintaining any dose for
≥2 weeks leading to week 10:
86.0% pre-­vs. 89.6% postdischarge groups (RR
0.96; 95% CI: 0.92–­1.01)

Abbreviations: ADHF, acute decompensated heart failure; AUC, area under curve; BNP, brain natriuretic peptide; BP, blood pressure; CI, confidence interval; GDMT, guideline-­directed medical therapy; HF,
heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; mL, milliliters; mm Hg, millimeters of mercury; NT-­proBNP, N-­terminal pro-­brain natriuretic peptide;
NYHA, New York Heart Association; pg, picograms; RR, risk ratio; s/sx, signs and symptoms; SBP, systolic blood pressure.
a
Advanced heart failure was defined as the following: LVEF <35%, NYHA class IV, and a minimum of 3 months of GDMT for HF and/or intolerance to GDMT.
b
Any one or more of the following objective findings of advanced HF including current inotropic therapy or use of inotropes in past 6 months, ≥1 hospitalization for HF in past 6 months, LVEF ≤25% within
|

past 12 months, peak VO2 <55% predicted or peak VO2 ≤16% for men or ≤14% for women, or 6-­minute walk test distance <300 m within past 3 months.
      841

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842      SKERSICK et al.
an ARNI being associated with reduced NT-­proBNP levels in patients
27
with ADHF without increased rates of adverse events.
4  |  E X PA N D I N G I N D I C ATI O N B E YO N D
H Fr E F
Despite a continued rise in the prevalence of HFpEF, treatment op-
tions remain limited. To-­date, there have been three studies inves-
tigating the effects of sacubitril/valsartan in patients with HFpEF
(Table  3). The PARAMOUNT trial28 was a phase 2, multicenter,
double-­blind, parallel-­group study of 301 patients randomized to
receive either sacubitril/valsartan at a target dose of 97/103 mg
twice daily (n = 149) or valsartan at a target dose of 160 mg twice
daily (n = 152). Prior to randomization, patients underwent a 2-­week,
single-­blind, placebo run-­in period. The vast majority of patients
were NYHA class II (81%) followed by class III (19%) at randomi-
zation, and the mean LVEF was 58 ± 7.3% (all data from sacubitril/
valsartan arm). The primary outcome, change in NT-­proBNP from
baseline to 12 weeks, was significantly reduced with sacubitril/val-
sartan compared with valsartan, but no difference was observed at
weeks 4 or 36. After 12 weeks, systolic blood pressure was signifi-
cantly lower with sacubitril/valsartan, and this reduction remained
significant at 36 weeks. Although left atrial volume/dimension was
also significantly reduced with sacubitril/valsartan, there were
no changes in LVEF, ventricular volumes, or diastolic function be-
tween the groups at 36 weeks. There was no significant change in
NYHA class at 12 weeks as well, but improvement was noted with
sacubitril/valsartan at 36 weeks (p  = 0.05). Lastly, the Kansas City
Cardiomyopathy Questionnaire (KCCQ) score did not differ between
the groups at 12 or 36 weeks. Regarding safety, no differences were
observed between the groups.
The PARAGON-­HF trial9 was a multicenter, double-­blind, active-­
controlled study of 4796 patients with HFpEF randomized to re-
ceive either sacubitril/valsartan at a target dose of 97/103 mg twice
daily (n = 2407) or valsartan at a target dose of 160 mg twice daily
(n = 2389) following a single-­blind run-­in screening period. The ma-
jority of patients were NYHA class II (77.5%) followed by class III
(19%) at randomization, with a mean LVEF of 57.6 ± 7.8% (all data
from sacubitril/valsartan arm). The primary composite outcome of
total (first and recurrent) hospitalizations for HF and death from
cardiovascular causes was not significantly different between sacu-
bitril/valsartan and valsartan alone (RR 0.87, 95% CI: 0.75–­1.01;
p = 0.06). Given this difference did not meet the predetermined level
of statistical significance, subsequent analyses were considered to
be exploratory. The total number of hospitalizations for HF was
reduced to a similar magnitude between sacubitril/valsartan and
valsartan alone (RR 0.85, 95% CI: 0.72–­1.00). In a prespecified sub-
group analysis, it was suggested that there was a possible benefit in
the primary outcome for women and in patients with a lower EF (me-
dian ≤ 57%). At 8 months, NYHA class improved in 15% of patients
on sacubitril/valsartan compared with 12.6% of patients on valsar-
tan (odds ratio, 1.45; 95% CI: 1.13–­1.86), and the reduction in KCCQ
18759114, 2022, 11, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2730 by kk yy - Tongji University , Wiley Online Library on [23/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
score (between-­group difference, 1.0 point; 95% CI: 0.0–­2.1) was
less with sacubitril/valsartan (higher scores suggest fewer symp-
toms and physical limitations). Neither cardiovascular death nor all-­
cause mortality were different between groups. Sacubitril/valsartan
was associated with higher rates of hypotension, with systolic blood
pressure < 100 mm Hg (15.5% vs. 10.8%, p < 0.001), and angioedema
(0.6% vs. 0.2%, p = 0.02), but lower rates of serum creatinine ≥2 mg/
dl (10.8% vs. 13.7%, p  = 0.002), potassium >5.5 mEq/L (13.2% vs.
15.3%, p = 0.048), and potassium >6 mEq/L (3.1% vs. 4.3%, p = 0.04)
compared with valsartan alone, respectively.
Similarly, the PARALLAX trial29 also assessed sacubitril/valsar-
tan in patients with HFpEF. In this multicenter, double-­blind, parallel-­
group trial, 2566 patients with HFpEF were evaluated to determine
the effect of sacubitril/valsartan on the co-­primary outcomes of NT-­
proBNP at 12 weeks and 6-­minute walk distance at 24 weeks, as well
as QOL at 24 weeks as one of several secondary end points. Patients
were randomized to receive either sacubitril/valsartan at a target
dose of 97/103 mg twice daily, a background medication-­based com-
parator with enalapril at a target dose of 10 mg twice daily or valsar-
tan at a target dose of 160 mg twice daily, or placebo. Most patients
were NYHA class II (67%) followed by class III (32.5%) at random-
ization, with a mean LVEF of 56.7% ± 8.3% (all data from sacubitril/
valsartan arm). Notably, 20% of patients had HF with a mildly re-
duced EF (HFmrEF) of 41%–­49%. After 12 weeks, NT-­proBNP lev-
els were significantly reduced with sacubitril/valsartan versus the
comparator medications. No differences were observed in 6-­minute
walk distance, KCCQ score, or NYHA class between the groups after
24 weeks. Therefore, despite the significant lowering of NT-­proBNP
levels, sacubitril/valsartan did not reduce symptoms enough to have
a positive effect on exercise capacity or QOL. Of note, it has been
suggested that the 6-­minute walk distance and KCCQ measures may
not be particularly sensitive to changes in exercise performance,
symptoms, and QOL in the HFpEF population.30 Consistent with
PARAGON-­HF, a higher incidence of medication-­related adverse
events were reported with sacubitril/valsartan versus the compara-
tor medication arm (30.5% vs. 22.6%, p < 0.001, respectively).
The expanded FDA indication for sacubitril/valsartan's use in
patients with chronic HF and a LVEF below normal31 was primarily
due to the benefit observed in patients with a median LVEF ≤57% in
the PARAGON-­HF trial in addition to data from the adjacent popu-
lation in the PARADIGM-­HF trial.32 Of note, the estimated absolute
benefits (primary composite events and HF hospitalizations pre-
vented) in the lower LVEF population in PARAGON-­HF were simi-
lar to that observed in the PARADIGM-­HF population (Figure 1).32
Importantly, the new label also mentions that LVEF is a variable
measure and clinical judgment should be used in deciding whom to
treat.31 This expanded labeling now gives a treatment option for pa-
tients with HFmrEF and HFpEF, increasing the number of potentially
eligible patients for treatment by up to 1.8 million individuals, which
could equate to preventing or delaying up to 180,000 worsening HF
events.33
The recent 2022 AHA/ACC/HFSA Guideline for the Management
of Heart Failure provides a Class 2b recommendation for the use of
 TA B L E 3  Comparison of studies analyzing the utilization of sacubitril/valsartan in HFpEF

Total Treatment Results of primary efficacy end point and select

SKERSICK et al.

Trial abbreviation patients Key inclusion criteria Study interventions duration Primary efficacy end point secondary end points

PARAMOUNT28 301 • Age ≥40 years Sacubitril/valsartan vs. Valsartan 36 weeks Change in NT-­proBNP from Change in NT-­proBNP was significantly reduced
(NCT00887588) • LVEF ≥45% baseline to 12 weeks with sacubitril/valsartan compared to
• NYHA II to III HF valsartan at 12 weeks
• On diuretic therapy Ratio of change with sacubitril/valsartan vs.
• NT-­proBNP >400 pg/ml valsartan: 0.77 (95% CI: 0.64–­0.92)
• SBP <140 mm Hg Systolic blood pressure was significantly lowered
or ≤160 mm Hg if on ≥3 with sacubitril/valsartan compared to
antihypertensive valsartan at 12 weeks (−9.3 vs. −2.9 mm Hg,
• eGFR ≥30 ml/min/1.73 p = 0.001, respectively)
m2
• Potassium ≤5.2 mEq/L
PARAGON-­HF9 4796 • Age ≥50 years Sacubitril/valsartan vs. Valsartan 35 months Total (first and recurrent) Primary outcome was not significantly different
(NCT01920711) • LVEF ≥45% hospitalizations for between sacubitril/valsartan and valsartan
• NYHA class II to IV HF heart failure and death alone (894 vs. 1009 events; RR 0.87, 95% CI:
• On diuretic therapy from cardiovascular 0.75–­1.01, respectively)
• Elevated NT-­proBNP causes At 8 months, NYHA class improved in 15% of
depending on patients on sacubitril/valsartan compared to
recent heart failure 12.6% of patients on valsartan (OR 1.45, 95%
hospitalization and CI: 1.13–­1.86)
presence of atrial No significant difference in all-­c ause mortality
fibrillation or flutter between the groups (14.2% sacubitril/
• Structural heart disease valsartan vs. 14.6% valsartan alone; HR 0.97,
95% CI: 0.84–­1.13)
PARALLAX 29 2566 • Age ≥45 years Sacubitril/valsartan vs. Enalapril 24 weeks Change from baseline in After 12 weeks, NT-­proBNP levels were
(NCT03066804) • LVEF >40% or Valsartan plasma NT-­proBNP significantly lower with sacubitril/valsartan
• NYHA class II to IV HF level at week 12 and in versus the comparator medications
• On diuretic therapy 6-­minute walk distance Adjusted geometric mean ratio with sacubitril/
• Elevated NT-­proBNP at week 24 valsartan vs. background medication-­based
>220 pg/ml for patients comparator: 0.84 (95% CI: 0.80–­0.88)
in sinus rhythm After 24 weeks, there was no difference in
and >600 pg/mL for 6-­minute walk distance, KCCQ score, or
patients with atrial NYHA class between the groups
fibrillation or flutter
• Structural heart disease
• Impaired KCCQ score
• History of hypertension
if on ACEi or ARB

Abbreviations: ACEi, angiotensin-­converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, heart failure; KCCQ, Kansas
City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; mL, milliliters; mm Hg, millimeters of mercury; NT-­proBNP, N-­terminal pro-­brain natriuretic peptide; NYHA, New York Heart
|

Association; OR, odds ratio; pg, picogram; RR, risk ratio; SBP, systolic blood pressure.
      843

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 |
844      SKERSICK et al.
sacubitril/valsartan to reduce hospitalizations in selected patients
with HFpEF (defined as LVEF ≥50%), predominantly those with an
LVEF on the lower end of the range or “spectrum.” For the classifi-
cation of HFmrEF (defined as LVEF 41–­49%), the guidelines state it
may be reasonable to consider the use of sacubitril/valsartan among
patients with an LVEF on the lower end of the spectrum (Class 2b
recommendation). The guidelines suggest that patients with HFmrEF
appear to respond to GDMT similar to patients with HFrEF based on
post hoc and subgroup analyses of previous HF trials. Of note, there
have been no prospective randomized controlled trials of patients
with HFmrEF to-­date. Accordingly, the guidelines acknowledge that
future prospective studies are necessary to further clarify treatment
recommendations in patients with HFmrEF. 27
5  |  H E A RT FA I LU R E FO LLOW I N G ACU TE
M YO C A R D I A L I N FA RC TI O N
Heart failure following acute myocardial infarction (AMI) has
been another potential area of interest for use of sacubitril/val-
sartan; however, study findings have been disappointing. The
34
RECOVER-­LV trial was a multicenter, double-­blind, randomized,
active-­controlled study comparing sacubitril/valsartan to valsartan
in patients ≥3 months following an AMI with a LVEF ≤40% who were
taking an ACEi equivalent to ramipril ≥2.5 mg twice daily and a beta
blocker unless contraindicated or previously intolerant. Patients in
NYHA ≥ class II or with signs and symptoms of HF were excluded. In
total, 93 patients were randomized to receive either sacubitril/vals-
artan at a target dose of 97/103 mg twice daily (n = 47) or valsartan
at a target dose of 160 mg twice daily (n = 46). The primary outcome
was change from baseline to 52 weeks in LVESVI measured by car-
diac magnetic resonance imaging. LVESVI decreased by 4.0 ± 6.6 ml/
m2 from baseline through 52 weeks in the sacubitril/valsartan group
and by 2.0 ± 7.3 ml/m2 in the valsartan group, resulting in an adjusted
between-­group difference of −1.9  ml/m2 (95% CI: −4.8-­1.0  ml/m2;
p = 0.19). There were also no significant differences in the secondary
outcomes of change in NT-­proBNP and high-­sensitivity cardiac tro-
ponin I at 52 weeks. Although LVEDVI, LAVI, and LV mass index were
numerically lower with sacubitril/valsartan compared to valsartan
monotherapy, these outcomes were not statistically significant. No
differences were observed in LVEF and patient wellbeing between
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F I G U R E 1  Time to first
cardiovascular death or HF hospitalization
of sacubitril/valsartan versus enalapril in
PARADIGM-­HF and versus valsartan in
PARAGON-­HF, respectively. (Reproduced
with permission from Reference 32)
the groups. Seven (15%) patients had symptomatic hypotension on
sacubitril/valsartan compared to one (2%) patient on valsartan; how-
ever, this did not lead to study discontinuation. Tests for statistical
significance were not performed for the safety outcomes due to the
small number of events.
The PARADISE-­MI trial35,36 was a multinational, double-­blind,
active-­controlled study assessing the efficacy and safety of sacu-
bitril/valsartan compared to ramipril in patients 0.5 to 7 days after
AMI and a newly reduced LVEF ≤40%. A total of 5661 patients were
randomized to receive either sacubitril/valsartan at a target dose
of 97/103 mg twice daily (n = 2830) or ramipril at a target dose of
5 mg twice daily (n = 2831). After a median follow-­up of 23 months,
no significant differences were detected in the primary composite
outcome of cardiovascular death, first HF hospitalization, or outpa-
tient development of HF between sacubitril/valsartan and ramipril
(11.9% vs. 13.2%; HR 0.90, 95% CI: 0.78–­1.04). Secondary outcomes
were also not different, including a composite of cardiovascular
death, nonfatal MI, or nonfatal stroke, hospitalization for HF or out-
patient HF, and all-­c ause death. Rates of hypotension were signifi-
cantly higher with sacubitril/valsartan (28.3% vs. 21.9%), whereas
cough (9.0% vs. 13.1%) and liver abnormalities (4.7% vs. 5.9%) were
significantly lower compared to ramipril (all p < 0.05), respectively.
6  |  E A R LY D OS E O P TI M IZ ATI O N A N D
E A R LY I N ITI ATI O N
Although sacubitril/valsartan had been evaluated in multiple clini-
cal trials, its impact in a real-­world HF population was unknown.
The PARADIGM-­HF trial enrolled patients receiving optimal ACEi
doses; however, despite guideline recommendations, many pa-
tients treated for HFrEF receive suboptimal dosing. The intent of
the TITRATION trial37 was to address this gap in a phase II, mul-
ticenter, randomized clinical study assessing two uptitration regi-
mens for sacubitril/valsartan, “condensed” and “conservative.” In
addition, the study enrolled a broader range of patients than pre-
viously studied, including hospitalized and ambulatory patients,
patients naïve to or with varying levels of previous exposure to
ACEi/ARB therapy, and patients with or without elevated levels of
natriuretic peptides before entry to the study. Overall, investiga-
tors aimed to capture a patient population more representative
 |

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SKERSICK et al.       845

TA B L E 4  Select ongoing clinical trials with sacubitril/valsartan

Treatment Expected
Trial abbreviation Key inclusion criteria Comparator duration Primary efficacy end point completion date

PANORAMA-­HF39 • NYHA classification II-­IV Enalapril Up to 52 weeks Part 1: PK/PD January 2022
(NCT02678312) (age 6 to <18 years) or Part 2: Percentage of
Phase II/III Ross CHF classification patients falling into each
II-­IV (age <6 years) category based on global
• Chronic HF resulting rankinga
from left ventricular
systolic dysfunction and
receiving chronic HF
therapy (if not newly
diagnosed)
• LVEF ≤40% or fractional
shortening ≤20%
PERSPECTIVE40 • Age ≥60 years Valsartan 3 years Change from baseline in March 2022
(NCT02884206) • Chronic HF with current the CogState Global
Phase III symptoms NYHA class Cognitive Composite
II-­IV Score (GCCS)b
• LVEF >40%
• NT-­pro BNP ≥125 pg/ml
at screening visit
• Patients with evidence
of adequate functioning
to complete study
assessments
PARAGLIDE-­HF41 • Age ≥40 years Valsartan Up to 20 months Proportional change in NT-­ October 2022
(NCT03988634) • HFpEF with most recent proBNP from baseline
Phase III LVEF >40% to the average of weeks
• Currently hospitalized 4 and 8
for HFpEF admissionc
or within 30 days of
discharge
• Elevated NT-­proBNP or
BNP
• Not taken ACEi for
36 hours prior to
randomization
PARACHUTE-­HF42 • Age ≥18 years Enalapril 12 weeks Time to CV death, time to December 2022
(NCT04023227) • NYHA class II-­IV HFrEF: first HF hospitalization,
Phase IV 1. LVEF ≤40% within relative change in NT-­
12 months prior to proBNP from baseline to
visit 1 AND week 12
2. NT-­proBNP ≥600 pg/
ml (or BNP ≥150 pg/
ml) at visit 1 OR
3. NT-­proBNP ≥400 pg/
ml (or BNP ≥100 pg/
ml) at visit 1 and a
hospitalization for HF
within last 12 months
• Chagas' disease
diagnoses confirmed
by at least 2 serological
tests for anti-­
Trypanosoma cruzi

Abbreviations: ACEi, angiotensin-­converting enzyme inhibitor; BNP, brain natriuretic peptide; CV, cardiovascular; HF, heart failure; HFpEF, heart
failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT-­proBNP, N-­
terminal pro-­brain natriuretic peptide; NYHA, New York Heart Association; PD, pharmacodynamics; pg, picograms; PK, pharmacokinetics.
a
Global ranking is based on clinical events, such as death, listing for urgent heart transplant, mechanical life support requirement at end of study,
worsening HF, NYHA, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory (PedsQL) physical functioning domain.
b
Change in cognition is assessed as a change in a Global Cognitive Composite Z score. The cognitive composite comprises cognitive domains
including attention, memory, and execution function. A negative change from baseline will indicate worsening performance.
c
Patients with a diagnosis of acute HF had to have symptoms and signs of fluid overload (i.e., jugular venous distension, edema, or rales on
auscultation or pulmonary congestion on X-­ray).
 |
846      SKERSICK et al.
of daily clinical practice. In total, 498 patients were randomized
to either the “condensed” treatment arm (n  = 247) with uptitra-
tion to sacubitril/valsartan 97/103 mg twice daily over 3 weeks
or the “conservative” arm (n = 251) with uptitration to 97/103 mg
twice daily over 6 weeks. Almost 90% of patients were from the
outpatient setting. The primary objective of the study was to de-
termine the tolerability of the two outlined uptitration regimens
through assessment of various adverse effects. Over 12 weeks,
no difference was observed in the two titration schemes (“con-
densed” vs. “conservative”) with regards to hypotension (9.7% vs.
8.4%; p  = 0.57), renal dysfunction (7.3% vs. 7.6%; p  = 0.99), hy-
perkalemia (7.7% vs. 4.4%; p = 0.114), and angioedema (0.0% vs.
0.8%), respectively. Approximately 76% of all patients (n  = 378)
achieved and maintained the target dose of sacubitril/valsartan
throughout the 12 weeks without study interruption or down-­
titration needed (77.8% in “condensed” vs. 84.3% in “conserva-
tive”; p = 0.078). Although these rates were not different in those
on high-­d ose ACEi/ARB between the “condensed” and “conserva-
tive” uptitration groups (82.6% vs. 83.8%, p = 0.783), target dose
attainment was found to be greater in those on low-­d ose ACEi/
ARB in the “conservative” uptitration group (73.6% vs. 84.9%,
p  = 0.03), respectively. Even though a larger percentage of pa-
tients in the “conservative” titration regimen achieved the target
dose, the results from this study indicate that uptitrating sacubi-
tril/valsartan over 3 or 6 weeks did not differ significantly in terms
of patient tolerability.
Until recently, another largely unknown aspect of sacubitril/
valsartan has been the impact on outcomes and cost-­effectiveness
based upon timing of initiation. One recent study was conducted to
estimate the outcomes and associated cost-­effectiveness of sacu-
bitril/valsartan initiated in the hospital compared to enalapril with
no initiation of sacubitril/valsartan or initiation posthospitalization
in stabilized HFrEF patients. 38 Utilizing US patient data from the
PARADIGM-­HF and PIONEER-­HF trials, the authors performed an
evaluation aimed at characterizing sacubitril/valsartan's economic
impact in three different subgroups: (1) sacubitril/valsartan initi-
ated during hospitalization and continued throughout the analysis,
(2) enalapril received during the inpatient stay and continued for
2 months, then switched to sacubitril/valsartan, and (3) enalapril
continued indefinitely. Inpatient initiation of sacubitril/valsartan
was found to result in 62 fewer HF-­related admissions per 1000
patients when compared to outpatient initiation and 116 fewer
HF-­related admissions compared to indefinite enalapril treatment.
The total yearly cost of sacubitril/valsartan initiated during hospi-
talization was estimated at $5628; however, these patients saved
$452 per year compared with indefinite enalapril treatment and
$811 per year compared to patients initiated 2 months posthospi-
talization. Additionally, the observed cost-­effectiveness of start-
ing sacubitril/valsartan therapy in the hospital was sustained over
time, with the study investigators concluding that estimated sav-
ings per patient for 1 year was $449 and for 5 years was $2550
compared to continuing enalapril therapy. These findings indicate
that the initiation of sacubitril/valsartan in patients hospitalized
18759114, 2022, 11, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2730 by kk yy - Tongji University , Wiley Online Library on [23/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
for HFrEF is associated with reduced HF-­related hospital admis-
sions, larger cost savings, and increased quality-­a djusted life ex-
pectancy when compared to no initiation of sacubitril/valsartan
or initiation after discharge.
7  |  S E LEC T O N G O I N G C LI N I C A L TR I A L S
Moving forward, the manufacturer of sacubitril/valsartan con-
tinues to invest in assessing sacubitril/valsartan's efficacy,
safety, and impact on QOL for various HF subpopulations.
Table  4 outlines select ongoing phase II, III, and IV clinical tri-
als. The ongoing PANORAMA-­H F study is a pivotal phase II/
III pharmacokinetic trial in which the FDA approved sacubitril/
valsartan for the treatment of symptomatic HF with LV systolic
dysfunction in pediatric patients ≥1 year of age. 39 This trial con-
tinues with the intent to generate further evidence from the full
study population to assess the benefit of sacubitril/valsartan
in participants over the duration of 52 weeks. Other phase III
and IV studies include the PERSPECTIVE, PARAGLIDE-­H F, and
PARACHUTE-­H F trials. 40,41,42 The PERSPECTIVE trial will exam-
ine the effect of sacubitril/valsartan versus valsartan on cogni-
tive function in patients with HFpEF. 40 The PARAGLIDE-­H F trial
will assess the impact of sacubitril/valsartan versus valsartan
on changes in NT-­p roBNP in patients with acute decompen-
sated HFpEF. 41 Lastly, the PARACHUTE-­H F trial will evaluate
the effect of sacubitril/valsartan versus enalapril in patients
with HFrEF caused by Chagas' disease, becoming the first dedi-
cated study to examine the use of sacubitril/valsartan in this
population. 42
8  |  CO N C LU S I O N
The approval of sacubitril/valsartan led to a shift in the landscape
of HF management. Recent clinical trials have further expanded in-
dications and guideline recommendations for the use of sacubitril/
valsartan to include treatment of patients with HFrEF hospitalized
with ADHF or advanced HF, as well as selected patients with HFpEF,
predominantly those with an LVEF on the lower end of the range.
Studies have also addressed time to initiation, optimal titration
schemes, and cost-­effectiveness of sacubitril/valsartan. This article
provides an overview of the primary literature supporting these new
recommendations. The results of ongoing studies and studies utiliz-
ing real-­world data are needed to further strengthen the evidence
supporting these recommendations.
C O N FL I C T O F I N T E R E S T
The authors have no conflicts to disclose.
ORCID
Courtney A. Montepara  https://orcid.org/0000-0002-9839-2510
Jo E. Rodgers  https://orcid.org/0000-0001-6016-0469

SKERSICK et al.
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How to cite this article: Skersick PT, Proco D,
Sharma-Huynh P, Montepara CA, Rodgers JE. Evaluating the
evidence for sacubitril/valsartan across the continuum of
heart failure. Pharmacotherapy. 2022;42:837-848.
doi: 10.1002/phar.2730