“Neprilysin-inhibition: Beyond Heart Failure”

Kyaw Soe Win

Consultant Cardiologist
Department of Cardiovascular Medicine
Mandalay General Hospital
10th March 2024
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
Overactivation of the RAAS and SNS in HFrEF

SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Vasoconstriction
Natriuretic peptide RAAS activity
Vasopressin
system Heart rate
HFrEF
SYMPTOMS & Contractility
PROGRESSION
NPRs NPs

Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone RAAS
(ACEI, ARB, MRA)
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone
Fibrosis Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1
 Benefits of β-blockers indicate that the SNS also plays a key role1

1. McMurray et al. Eur Heart J 2012;33:1787–847

Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy
2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71
See notes for abbreviation definitions Schrier & Abraham. N Engl J Med 1999;341:577–85
RAAS Inhibition in CHF
 HFrEF Pharmacologic Treatment:
Foundational Therapies

RAS
BB MRA
Blockers

Ponikowski P, et al. Eur Heart J. 2016;37:2129-2200; Yancy C, et al. Circulation. 2017;136:e137-e161.

Beta Blockers in Heart Rate to Improve Mortality in HFrEF:
Targeting
Heart Failure
Sinus Rhythm and AF
Beta Blockers
BBs Are in the Most Evidence-Based Therapy in HF
Heart Failure
 Effect of ACE Inhibition in Patients With
ACEIs in Heart
Failure
CHF: CONSENSUS Trial

CONSENSUS Trial Study Group. N Engl J Med. 1987;316(23):1429-1435

 SOLVD Treatment Trial: Effect of ACEI
ACEIs in Heart
Failure
on Survival In Patients With HFrEF
 An ARB Is An Alternative In Patients
ARBs in Heart
Failure
Intolerant of an ACEI Due to Cough
 ARBs: No Better Than ACE Inhibitors But
ARBs in Heart
Failure
Probably AS GOOD AS
 Effect of MRAs On Morbidity and
MRAs in Heart
Failure
Mortality In Patients With HFrEF
MRAs MRAs
in Heartin HF
Failure
ATMOSPHERE: Would Dual Blockade of the RAS With
Evidence-Based Background Therapy Be Superior to Single-
Agent RAS Inhibition?

McMurray JJ, et al. N Engl J Med. 2016;374:1521-1532 *89% 10mg twice daily † target dose ( titrated from 150mg once daily)
ATMOSPHERE: Direct Renin Inhibition and ACE Inhibition
Similar: DUAL Inhibition NO BETTER and Produced More
Side Effects

McMurray JJ, et al. N Engl J Med. 2016;374:1521-1532

 Death rate in Heart failure remains high despite the
introduction of new therapies that improve survival
 Survival rates in chronic HF have improved with the introduction of new therapies1

ACEI* β-blocker* MRA* ARB*

Reduction in relative risk of
mortality vs placebo

16% 17%
(4.5% ARR; (3.0% ARR;
mean follow up median follow up
of 41.4 months) of 33.7 months)
SOLVD1,2 CHARM-
30%
34% (11.0% ARR; Alternative5
mean follow up
(5.5% ARR; of 24 months)
mean follow up
of 1.3 years) RALES4
CIBIS-II3

 However, significant mortality remains – ~50% of patients die within 5 years of diagnosis 6–8
*On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such
relative risk reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized
Aldactone Evaluation Study) enrolled chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity)
enrolled chronic HF patients with LVEF≤40%
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
What is Neprilysin?
Adverse Neurohormonal Activation in HF Has Formed the Basis for
Evidence-Based Pharmacologic Therapy

Cohn JN. Cardiology. 1997;88:2-6

Neurohormonal Activation:
Good and Bad

Von Lueder TG, et al. Pharmacol Ther. 2014;144:41-49

NP System: Endogenous Compensatory Mechanisms in HF Counteract
Some Deleterious Effects of RAAS Activation
Action and Clearance of NPs

Mangiafico S, et al. Eur Heart J. 2012;34:1-11

Overactivation of the RAAS and SNS in HFrEF

SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Vasoconstriction
RAAS activity
Natriuretic peptide Vasopressin
Heart rate
system HFrEF
SYMPTOMS & Contractility
PROGRESSION
NPRs NPs

Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone RAAS (ACEI, ARB, MRA)
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone
Fibrosis Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1
 Benefits of β-blockers indicate that the SNS also plays a key role1
1. McMurray et al. Eur Heart J 2012;33:1787–847
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy
2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71
See notes for abbreviation definitions Schrier & Abraham. N Engl J Med 1999;341:577–85
 Evolution of pharmacologic approaches in HF:
Neprilysin inhibition as a new therapeutic strategy 1
SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
Ne
Vasodilation pr
ily
Blood pressure sin
RAAS inhibitors
Sympathetic tone
Natriuresis/diuresis
RAAS (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73 Blood pressure
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–71; Sympathetic tone
Schrier & Abraham N Engl J Med 2009;341:577–85
Aldosterone
Hypertrophy
Fibrosis

 Neprilysin inhibitors: natriuretic and other vasoactive peptides enhancement

ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker;
AT1R = angiotensin II type 1 receptor; HF=heart failure; MRA=mineralocorticoid receptor antagonist;
25 NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone
system; SNS=sympathetic nervous system
Neurohormonal Pathways in HFrEF
 Rationale for Neprilysin inhibition

Preventing the breakdown of natriuretic peptides

to potentially protect the body
from pressure and volume overload

Expert faculty opinion

 Evolution of pharmacologic approaches in HF:
Neprilysin inhibition as a new therapeutic strategy 1
SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
Ne
Vasodilation pr
ily
Blood pressure sin
RAAS inhibitors
Sympathetic tone
Natriuresis/diuresis
RAAS (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73 Blood pressure
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–71; Sympathetic tone
Schrier & Abraham N Engl J Med 2009;341:577–85
Aldosterone
Hypertrophy
Fibrosis

 Neprilysin inhibitors: natriuretic and other vasoactive peptides enhancement

ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker;
AT1R = angiotensin II type 1 receptor; HF=heart failure; MRA=mineralocorticoid receptor antagonist;
28 NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone
system; SNS=sympathetic nervous system
Rationale for Neprilysin inhibition
(Angiotensin Receptor Antagonist+ Neprilysin Inhibitor)
ARNI: Simultaneously inhibits RAAS and Augments Vasoactive Peptides
SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
N
Vasodilation ep
ril
Blood pressure y si
n
RAAS RAAS inhibitors
Sympathetic tone
Natriuresis/diuresis (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Sacubitril/Valsartan Aldosterone
Hypertrophy
Fibrosis

 LCZ696: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression

ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73
receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert.
reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; Pharmacotherapy 2002;22:27–42
NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; Kemp & Conte. Cardiovascular Pathology 2012;365–71
SNS=sympathetic nervous system Schrier & Abraham. N Engl J Med 2009;341:577–85
Mechanism of action of Sacubitril/ Valsartan
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
 ARNI in patients with HFrEF
PARADIGM-HF: Study
Design

McMurray JJ, et al. N Engl J Med. 2014;371:993-1004

 ARNI in patients with HFrEF
PARADIGM-HF: Key
Results
PARADIGM-HF Primary Results: Significant Reduction in
Primary Endpoints, CV Death, and All-Cause Mortality

McMurray JJ, et al. N Engl J Med. 2014;371:993-1004

PARADIGM-HF: Early Benefit of Sacubitril/Valsartan

Packer M, et al. Circulation. 2015;131:54-61

Influence of Sacubitril/Valsartan on 30-Day
Readmission After HF Hospitalization

Desai AS, et al. J Am Coll Cardiol. 2016;68:241-248

Estimated Long-term Benefit of 1.5-2 Years Using Actuarial Methods:
Based on PARADIGM-HF

Claggett B, et al. N Engl J Med. 2015;373:2289-2290

Sacubitril/Valsartan Was Effective Across the Spectrum of EF:
PARADIGM-HF Enrolled >2000 Patients With EF Between
35% and 40%

Solomom SD, Claggett B, Desai AS et al. Circ Heart fail.2016

NT-proBNP and BNP

Mair J et al. Clin Chem Lab. 2001;39:571-588

PARADIGM-HF: Measurement of
NT-proBNP and BNP

Packer M, et al. Circilation. 2015;131:54061

Summary
• Sacubitril/valsartan inhibits the RAS and enhances endogenous
compensatory vasodilators (including the biologically active NPs)
• In PARADIGM-HF, sacubitril/valsartan was shown to significantly
reduce CV death, HF hospitalization, and all-cause mortality
• The role of this agent for other indications, such as HFpEF and post-
MI
ARNI in patients with HFpEF
PARAMOUNT study
PARAMOUNT: Designed in Parallel With PARADIGM-HF
to Provide Pilot Data for Sacubitril/Valsartan in HFpEF

Solomon SD, et al. Lancet. 2012;380:1387-1395

PARAMOUNT: Significant Reduction in NT-proBNP
With Sacubitril/Valsartan at 12 Weeks

Solomon SD, et al. Lancet. 2012;380:1387-1395

PARAMOUNT: Improvement in Left Atrial Size and NYHA Class With
Sacubitril/Valsartan at 36 Weeks

Solomon SD, et al. Lancet. 2012;380:1387-1395

ARNI in patients with HFpEF
PARAGON-HF: study design
ARNI in patients with HFpEF
PARAGON-HF: Primary Endpoint and Key
Findings
PARADISE-MI: Trial Design

ClinicalTrials.gov. NCT0294727
Results:Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311).
Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn
accelerometer device, respectively. After 12weeks, 6MWT improved by 35.09m with sacubitril/valsartan and by 26.11m with enalapril. Mean daily
non-sedentary daytime activity decreased by 27min with sacubitril/valsartan and by 21 min with enalapril after 12weeks. 6MWT improved by
≥30m in 51% of patients in the sacubitril/valsartan group vs. 44% of patients treated with enalapril. At Week 4, non-sedentary daytime activity increased
by ≥10% in 58% of patients treated with sacubitril/valsartan vs. 64% with enalapril; 58% of patients treated with sacubitril/valsartan reported improved
HF symptoms as assessed by patient global assessment vs. 43% with enalapril. However, these differences did not persist at Week 12.

Conclusion After 12weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or daytime physical activity measured
by actigraphy compared with enalapril
 ESC Virtual Congress 2020 – Clinical Trials Hotline Session I August 30, 2020

Angiotensin receptor neprilysin inhibition

compared with individualized medical therapy for

comorbidities in patients with heart failure and

preserved ejection fraction - the PARALLAX trial
Burkert Pieske, MD.
Charité University Medicine & German Heart Center, Berlin, Germany
Sanjiv J. Shah1, Rolf Wachter2, Scott Solomon3, Peter Szecsöedy4, Ghionul Ibram5, Victor Shi5,
Ziqiang Zhao6, Martin Cowie7
On behalf of the PARALLAX Investigators
1
Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2University Hospital Leipzig, Germany; 3Brigham and Women’s Hospital, Boston, Massachusetts,
USA; 4Formerly Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals, East Hanover, USA; 6Novartis Pharma Co. Ltd., Shanghai, China; 7Imperial College,
London, UK
Background:
• Heart failure with preserved or mid-range ejection fraction (HFpEF, HFmrEF) accounts for more than
half of all heart failure cases and is associated with substantial morbidity and mortality 1

• No specific therapies that improve outcome are available for this relevant patient population

• PARAGON-HF recently demonstrated a potential benefit of sacubitril/valsartan (S/V) on outcomes

in patients with HFpEF

• Heart Failure Guidelines recommend diuretics for symptom control and the individualized
management of comorbidities in these patients

1. Redfield MM, et al. N Engl J Med 2017;376:89; 2. Solomon SD et al. N Engl J Med 2019; 381:1609-20
6MWD, 6-minute walk distance; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide
PARALLAX rationale
• To test the effects of sacubitril/valsartan (S/V) compared to individual medical therapy (IMT) for
comorbidities

• To use a marker of disease severity and prognosis, NTproBNP, as a component of the primary
endpoint

• To test the effects of S/V vs. IMT on exercise capacity (6MWD) and quality of life (KCCQ)

• To assess the effects of S/V vs IMT on tolerability and safety

1. Redfield MM, et al. N Engl J Med 2017;376:89; 2. Solomon SD et al. N Engl J Med 2019; 381:1609-20
6MWD, 6-minute walk distance; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide
PARALLAX: Trial design
A prospective 24-week, randomised,
active-controlled, parallel-group trial Randomisation

NYHA II-IV, LVEF >40%

Evidence of LVH or LAE

Elevated NTproBNP

Optimized treatment of comorbidities

2572 patients randomized (1:1)

Follow-up, 24 weeks

*Patients in the ACEi or ARB strata must have a history of hypertension

PARALLAX Study design: Wachter R et al., ESC Heart Fail. 2020; 3: 856-64
 Baseline demographics (1/2)
S/V IMT
N=1281 N=1285
Age (years) – mean (SD) 73 (8.4) 72 (8.6)
Sex Female 50% 51%
Race White 87% 87%
North America 5% 5%
Latin and Central America 14% 14%
Region Europe 76% 75%
Asia/Pacific/other 69% 70%
Baseline LVEF (%) – mean (SD) 57 (8.3) 56 (8.0)
Baseline NT-proBNP (pg/mL) – median (Q1–Q3) 786 (415–1401) 760 (380–1398)
Baseline KCCQ clinical summary score – mean (SD) 53 (16.7) 53 (16.9)
Baseline 6MWD – mean, metres (SD) 301 (107.4) 306 (103.3)
100–450 m 90% 90%
NYHA class at randomisation, Class I / II / III / IV, (%) 0.1 / 67 / 32 / 0.4 0.3 / 68 / 31 / 0.3
Baseline systolic/diastolic BP at randomisation – mean (SD) 133 (14.0) / 77.0 (10.3) 134 (14.5) / 77 (10.2)
Body mass index – mean (SD) 31 (5.0) 31 (4.8)

6MWD, 6-minute walk distance; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection
fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; SD, standard deviation
 Baseline demographics (2/2)
S/V IMT
N=1281 N=1285
Hypertension 97% 97%
Diabetes mellitus 39% 41%
Medical history AF at screening ECG 39% 37%
AF at any time in the past 55% 54%
Hospitalisation for HF 35% 36%
ACEi 41% 42%
ARB 46% 46%
Medications Diuretics
Prior to randomisation 100% 100%
MRAs 33% 31%
Beta-blockers 84% 83%

ACEi, angiotensin converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; MRA,
mineralocorticoid receptor antagonist
 PARALLAX: Primary outcomes
NT-proBNP – change from baseline 6MWD – change from baseline at Week 24*
Adjusted mean difference (95% CI) (S/V−IMT):
900
−2.50 (−8.53, 3.53) m; P=0.42
(geometric mean [95% CI])

Adjusted geometric mean ratio at Week 12 (S/V vs

IMT): Adjusted mean change from baseline (95% CI)
NT-proBNP, pg/mL

800
0.84 (0.80, 0.88); P<0.0001 9.7 (5.4, 14.0) m 12.2 (7.9, 16.5) m
IMT 400
700

Mean (SD) 6MWD, metres

350
600 S/V
300

500
Baseline Week 4 Week 12 Week 24 250
Weeks since randomisation
200

292.2 309.8 296.6 315.2

150
Baseline Week 24 Baseline Week 24
S/V IMT
(n=1082) (n=1075)
*In patients with baseline 6MWD 100–450 metres
6MWD, 6-minute walk distance; CI, confidence interval; GMR, geometric mean ratio; NT-proBNP, N-terminal pro B-
type natriuretic peptide, IMT, individualized medical therapy
PARALLAX: Secondary outcomes
KCCQ-CSS at Week 24 NYHA class– change from
baseline at Week 24*
LSM of difference (95% CI) (S/V vs IMT):
0.52 (−0.93, 1.97); P=0.48 Odds ratio (95% CI) (S/V vs IMT):
1.01 (0.75, 1.37); P=0.93
LSM change from baseline (95% CI)
80 12.3 (11.3, 13.4) 11.8 (10.8, 12.8) 100 4.2 4.3

Proportion (%) of patients

Mean (SD) KCCQ-CSS score

70
80
60
50 60 72.2 71.7
40
40
30
20 20
10 23.6 24
52.7 66.7 53.3 66.2
0 0
Baseline Week 24 Baseline Week 24 S/V IMT
S/V (n=1228) (n=1229)
IMT
(n-1207) (n=1210) Improved Unchanged Worsened
*Due to the pre-defined sequentially rejective multiple
testing procedure, NYHA was not formally tested

CI, confidence interval; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score; LSM, least
square means; NYHA, New York Heart Association; SD, standard deviation, IMT, individualized medical therapy
 Cardiac failure events leading to death or
hospitalization*
Composite of time to death due to cardiac failure
First hospitalization due to HF
or HF hospitalization
5 HR (95% CI): 0.49 (0.30, 0.81) IMT
5.0
P=0.005 HR (95% CI): 0.64 (0.42, 0.97)
Cumulative probability (%)

IMT P=0.034

Cumulative probability (%)

4
4.0

3
3.0

2
2.0
S/V
S/V
1
1.0

0
0.0

0 15 30 60 90 120 150 180 0 15 30 60 90 120 150 180

Time from randomization (days) Time from randomization (days)
No. at risk No. at risk
S/V 1281 1277 1272 1258 1247 1232 1219 128 S/V 1281 1277 1272 1258 1245 1232 1219 128
IMT 1285 1281 1260 1238 1229 1216 1198 118 IMT 1285 1281 1260 1238 1229 1216 1198 118
*Post-hoc analysis of cardiac failure events leading to hospitalization and/or death that were documented as adverse events and were not adjudicated

S/V, sacubitril/valsartan, IMT, individualized medical therapy

 Conclusions: Sacubitril/Valsartan vs. IMT

• PARALLAX demonstrated a significant reduction in NT-proBNP with S/V

• S/V had no additional benefits on 6MWD and NYHA class
• QoL (KCCQ-CSS) was significantly improved after 4, but no longer after 24 weeks
• S/V was well tolerated, reduced HF hospitalization SAEs, and slowed the decline in renal
function compared with IMT

• These results are consistent with the findings from PARAGON-HF (LVEF ≥45%) and
provide further evidence for the potential benefits of S/V in patients with HF and mid-
range or preserved ejection fraction
 PANORAMA-
HF

Methods: PANORAMA-HF is a multicenter, Phase II/III study using an adaptive, seamless, 2-part design. The study
aimed to evaluate the pharmacokinetics and pharmacodynamics of single doses of sacubitril/valsartan(Part 1), and the
efficacy and safety of sacubitril/valsartan versus enalapril administered twice daily for 52weeks (Part 2) in pediatric
patients with HF due to left ventricular systolic dysfunction with biventricular heart physiology. An innovative trial
design using a novel global rank assessment of severity was employed. For analysis, eligible patients were stratified into
3 age groups (Group 1, 6 to <18 years; Group 2a, 2 to <6 years; and Group 3a, 1 month to <2 years) and functional
classification (New York Heart Association/Ross class I/II and III/IV).
https://www.ahajournals.org/doi/epub/10.1161/CIRCHEARTFAILURE.122.009816
 PANORAMA-
HF
Results: 375 pediatric patients randomized to receive the study medication. The mean age for patients
in Groups 1, 2a, and 3a was 12.2, 3.2,and 1.3 years, respectively. About 70% of patients had a prior
HF hospitalization, 85% had New York Heart Association/Ross class I/II HF, and ≈8% were
angiotensin-converting enzyme inhibitor/angiotensin receptor blocker naïve.
Conclusions: Compared to other pediatric HF studies, PANORAMA-HF recruited a relatively
homogeneous pediatric HF population across 3 age groups, enabling a more robust evaluation of
pharmacokinetics/pharmacodynamics and efficacy/safety of sacubitril/valsartan. Most patients had
mildly symptomatic HF at baseline. Results from the PANORAMA-HF study will help determine
whether sacubitril/valsartan offers greater clinical benefit compared to enalapril in pediatric patients
with HF. Future prospective studies involving a homogenous pediatric population are warranted to
provide a strong evidence-base for the management of pediatric HF.

https://www.ahajournals.org/doi/epub/10.1161/CIRCHEARTFAILURE.122.009816
 ARNI in patients Hospitalized with HF
PIONEER-HF
Vulnerable phase after hospitalisation for ADHF1

Stabilisation and
HF hospitalisation2 postdischarge Chronic HF2
period2

Approximately 25% of patients

Mortality during this 30-day
will be readmitted to the hospital
period can approach 10%2
within 30 days after discharge2

8 ADHF=acute decompensated heart failure; HF=heart failure.

References: 1. Velazquez EJ et al. N Engl J Med. 2018. doi: 10.1056/NEJMoa1812851. 2. Greene SJ, et al. Nat Rev Cardiol. 2015;12(4):220-229.
TRANSITION: Study Design
Primary and secondary end points

AE=adverse event; BID=twice daily; RRR=relative risk ratio.

28 *Safety analysis set.

Reference: Wachter R, et al. Poster presented at: ESC Congress 2018; August 25-28, 2018; Munich, Germany.
TRANSITION: Multivariate Regression for
Predictors for ARNI Dose Up-Titration
Aims: ACTIVITY-HF was a randomized, double-blind, active-controlled study, which assessed
the short-term effect of sacubitril/valsartan compared with the active comparator enalapril on
improving maximal exercise capacity in patients with heart failure with reduced ejection fraction
(HFrEF)
 ACTIVITY-HF
Methods and results: A total of 201 ambulatory patients with HFrEF (left ventricular ejection fraction≤40%, New York
Heart Association class III) across 34 centres in Germany were randomized (1:1) to receive sacubitril/valsartan 97/103 mg
bid (n = 103) or enalapril 10 mg bid (n = 98). The primary endpoint of the study was the change from baseline in peak
oxygen consumption (VO2; adjusted to body weight) after 12weeks, and the key secondary endpoint was change from
baseline in peak VO2 after 6 weeks. The study population was predominantly male (81.1%) with a mean age of 66.9 years
and a body mass index of 29.4 kg/m2. Change in peak VO2 from baseline to Week 12 was similar between
sacubitril/valsartan and enalapril groups [least squares mean difference: 0.32 mL/min/kg; 95% confidence interval (CI)
−0.21, 0.85; P = 0.2327]. Similarly, no significant differences were observed between the two treatment groups in minute
ventilation to carbon dioxide production slope, exercise capacity at first ventilatory threshold or Borg scale at either Week
6 or Week 12. Change in heart rate at first ventilatory threshold was lower in the sacubitril/valsartan group compared with
the enalapril group at Week 12 (mean −3.75 bpm; 95% CI −7.03, −0.48; P = 0.0248). The safety of sacubitril/valsartan was
comparable to enalapril.

Conclusion In patients with HFrEF, short-term treatment with sacubitril/valsartan for 12weeks did not result in significant
benefits on peak VO2 when compared with enalapril.
 PROVE-HF
OBJECTIVE To determine whether NT-proBNP changes in patients with HFrEF treated with
sacubitril-valsartan correlate with changes in measures of cardiac volume and function.
DESIGN, SETTING, AND PARTICIPANTS Prospective, 12-month, single-group, open-label
study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-
valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and
follow-up was completed on October 22, 2018.
MAIN OUTCOMES AND MEASURES The primary outcome was the correlation between
changes in log2–NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic
volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index
(LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) at
12 months.
 PROVE-HF
RESULTS Among 794 patients (mean age, 65.1 yrs; 226 women [28.5%]; mean LVEF = 28.2%),
654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816
pg/mL and 455 pg/mL at 12 months (difference, P < .001). At 12 months, LVEF increased from
28.2%to 37.8% (difference, 9.4%[95%CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased
from 86.93 to 74.15 mL/m2 (difference, −12.25 mL/m2 [IQR, −12.92 to −11.58]; P < .001) and
LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, −15.29 mL/m2 [95%CI, −16.03 to
−14.55]; P < .001). LAVI and E/e′ ratio also decreased significantly. The most frequent adverse
events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening
kidney function (12.3%).
Conclusions In this exploratory study of patients with HFrEF treated with sacubitril-valsartan,
reduction in NT-proBNP concentration was weakly yet significantly correlated with improvement
in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling
may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with
HFrEF.
 ARNI in patients Hospitalized with HF
PIONEER-HF
BACKGROUND; Myocardial fibrosis is an important pathophysiological mechanism underlying
the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we
hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular
matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered
by sacubitril/valsartan in comparison to enalapril.
OBJECTIVES; The purpose of this study was to examine the effects of sacubitril/valsartan on
biomarkers of ECM homeostasis and the association between the rate of primary composite
outcome (cardiovascular death or HF hospitalization) and these biomarkers.

J Am Coll Cardiol 2019;73:795–806

J Am Coll Cardiol 2019;73:795–806
METHODS; Biomarkers at baseline (n ¼ 2,067) and both baseline and 8 months after randomization (n ¼
1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1,
matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP),
and N-terminal propeptide of collagen III (PIIINP). The effects of sacubitril/valsartan on biomarkers were
compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to
primary outcome.

RESULTS; At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP
were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than
published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9,
PINP, and PIIINP had decreased more in the sacubitril/valsartan than enalapril group. At baseline, higher
values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from
baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes.

CONCLUSIONS; Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection
fraction, sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have
important prognostic value. These findings suggest that sacubitril/valsartan may reduce profibrotic signaling,
which may contribute to the improved outcomes. [PARADIGM-HF];

J Am Coll Cardiol 2019;73:795–806

 ARIADNE
registry
• “The ARIADNE registry provides real-world information about the efficacy of sacubitril/valsartan as administered in an
outpatient setting,” said Dr. Maggioni, who presented data on 9069 HFrEF patients followed for 12 months in 17 European
countries.

• those who received sacubitril/valsartan had lower total mortality (3.8% vs. 5.0%), lower cardiovascular mortality (1.8% vs.
2.2%) and fewer catheterization or angiography procedures (1.7% vs. 2.8%) over the course of the 12-month follow-up

• 36.2% of patients on sacubitril/valsartan achieved a clinically-meaningful improvement (≥5 points) in the Kansas City
Cardiomyopathy Questionnaire (KCCQ) score

• only 4.1% of patients discontinued sacubitril/valsartan as a result of an adverse event over the 12-month follow-up.

• Conclusion:In addition to substantiating an improvement in survival in the real-world setting, the ARIADNE registry also
documents immediate benefits to patients in the form of improved function and quality of life
OBJECTIVES: The aim of this study was to use a multicenter, observational outpatient registry of patients
with heart failure with reduced ejection fraction (HFrEF) to describe the association between changes in
patients’ medications with changes in health status.

METHODS: The association of any change in HFrEF medications with 3-month change in health status, as
measured using the 12-item Kansas City Cardiomyopathy Questionnaire Overall Summary Scale, was
determined in unadjusted and multivariate-adjusted (25 clinical characteristics, baseline health status)
models using hierarchical linear regression.
 CHAMP-HF

RESULTS; Among 3,313 outpatients with HFrEF from 140 centers, 21.9% had medication changes. Three
months later, 23.7% and 46.4% had clinically meaningfully worse ($5-point decrease) and improved ($5-
point increase) Kansas City Cardiomyopathy Questionnaire Overall Summary Scale scores. The 3-month
median change in Kansas City Cardiomyopathy Questionnaire Overall Summary Scale score for patients
whose HFrEF medications were changed was significantly larger (7.3 points; interquartile range: 3.1 to 20.8
points) than in patients whose medications were not changed (3.1 points; interquartile range: 4.7 to 12.5
points) (adjusted difference 3.0 points; 95% confidence interval: 1.4 to 4.6 points; p < 0.001). Among
patients whose medications were adjusted, 26% had very large clinical improvement ($20 points) compared
with 14% whose regimens were not changed.

CONCLUSIONS; In routine care of patients with HFrEF, changes in HFrEF medications were associated
with significant improvements in patients’ health status, suggesting that health status–based performance
measures can quantify the benefits of titrating medicines in patients with HFrEF

J Am Coll Cardiol HF 2019;7:615–25

Other effects of ARNI on the Heart
 Methods:
In this double-blind trial, we randomly assigned 118 patients with heart failure with chronic functional MR secondary to
left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan,in addition to standard medical therapy
for heart failure. The primary end point was the change in effective regurgitant orifice area of functional MR from
baseline to the 12-month follow-up. Secondary end pointsincluded changes in regurgitant volume, LV end-systolic
volume, LV end-diastolic volume, and incomplete mitral leaflet closure area.
Results:
The decrease in effective regurgitant orifice area was significantly greater in the sacubitril/valsartangroup than in the
valsartan group (–0.058±0.095 versus –0.018±0.105 cm 2; P=0.032) in an intention-to-treatanalysis including 117 (99%)
patients. Regurgitant volume was also significantly decreased in thesacubitril/valsartan group in comparison with the
valsartan group (mean difference, –7.3 mL; 95% CI, –12.6 to–1.9; P=0.009). There were no significant between-group
differences regarding the changes in incomplete mitral leaflet closure area and LV volumes, with the exception of LV
end-diastolic volume index (P=0.044). Wenoted no significant difference in the change of blood pressure between the
treatment groups, and 7 patients(12%) in the sacubitril/valsartan group and 9 (16%) in the valsartan group had ≥1 serious
adverse events(P=0.54).
Conclusions:
Among patients with secondary functional MR, sacubitril/valsartan reduced MR to a greater extent than did valsartan.
Our findings suggest that an angiotensin receptor-neprilysin inhibitor might be considered for optimal medical therapy of
patients with heart failure and functional MR.
Other effects of ARNI on the Heart
 EVALUATE-
HF

OBJECTIVE To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic
stiffness and cardiac remodeling compared with enalapril.

DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind clinical trial of 464 participants
with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016,
and June 28, 2018. Follow-up was completed on January 26, 2019.

INTERVENTIONS Randomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103mg twice

daily) vs enalapril (n = 233; target dosage, 10mg twice daily) for 12weeks.
Effect of Sac/val
compared with
enalapril Clinical
outcomes

Clinical
outcomes in
subgroups

mechanistic
outcomes
Quality of life
outcomes
Guideline Recommendation for treatment of
patients with HFrEF
Guideline Recommendation for treatment of
patients with HFrEF
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
ARNI and HbA1c in patients with T2DM and HF
PARADIGM-HF and PARAGON-HF
Evolution of RCTs in HFpEF
ARNI and Anaemia
PARADIGM-HF and PARAGON-HF
Evolution of RCTs in HFpEF
ARNI and Uric Acid
PARADIGM-HF and PARAGON-HF
Evolution of RCTs in HFpEF
ARNI and Kidney Outcomes
PARADIGM-HF and PARAGON-HF
Evolution of RCTs in HFpEF
ARNI and Kidney Outcomes
PARAGLIDE-HF and PARAGON-HF
Evolution of RCTs in HFpEF
Pascual-Figal et al., Sacubitril-Valsartan in HFrEF, November 2021 | Volume 8 | Article 754499
Abstract: The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease.
Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for
maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is
detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to
counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing
vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although
the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g.,
hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was
highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review
summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms,
providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.
The overview of calcium-
dependent signaling
cascades in ventricular
cardiomyocytes and the
beneficial effects of ARNI in
modulating cardiac
electrophysiology
Aims: Sudden death is a leading cause of mortality in heart
failure with reduced ejection fraction (HFrEF). In
PARADIGM-HF, sacubitril/valsartan reduced the incidence of
sudden death. The purpose of this post hoc study was to
analyse the effect of sacubitril/valsartan, compared to
enalapril, on the incidence of ventricular arrhythmias.
Conclusions: Sacubitril/valsartan reduced the incidence of
investigator-reported ventricular arrhythmias in patients with
HFrEF. This effect may have been greater in patients with a
non-ischaemic aetiology
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
Hypertension and heart failure, the most important CVD entities, are associated with
imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone
system, the sympathetic nervous system and the endothelin system.
Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in
hypertension and heart failure to date.
Current pharmacotherapy for hypertension and HF may slow disease progression but fails
to completely reverse the underlying pathogenetic processes.
The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering
system, and mediates a multitude of beneficial actions within cardiovascular tissues.
The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP
inhibition would increase salutary natriuretic peptide actions in CVD.

Pharmacology & Therapeutics Volume 144, Issue 1, October 2014, Pages 41-49
However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond
standard pharmacotherapy.
Combined blockers of NEP and the endothelin system demonstrated efficacy in
preclinical studies but have not been evaluated in clinical trials.
A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-
inhibitors) were promising agents for hypertension and heart failure. Despite greater
efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target
effects in some cohorts, most notably increased frequency of angioedema in hypertensive
subjects.
angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of
combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and
hopefully do so with improved clinical safety.

Pharmacology & Therapeutics Volume 144, Issue 1, October 2014, Pages 41-49
Abstract

Neprilysin is a widely expressed peptidase with broad substrate specificity that preferentially hydrolyses oligopeptide substrates, many of which
regulate the cardiovascular, nervous and immune systems. Emerging evidence suggests that neprilysin also hydrolyses peptides that play an
important role in glucose metabolism. In recent studies in humans, a dual angiotensin receptor–neprilysin inhibitor (ARNi) improved glycaemic
control and insulin sensitivity in individuals with type 2 diabetes and/or obesity. Moreover, preclinical studies have also reported that neprilysin
inhibition, alone or in combination with renin–angiotensin system blockers, elicits beneficial effects on glucose homeostasis. Since neprilysin
inhibitors have been approved for the treatment of heart failure, their repurposing for treating type 2 diabetes would provide a novel therapeutic
strategy. In this review, we evaluate existing evidence from preclinical and clinical studies in which neprilysin is deleted/inhibited, we highlight
potential mechanisms underlying the beneficial glycaemic effects of neprilysin inhibition, and discuss possible deleterious effects that may limit
the efficacy and safety of neprilysin inhibitors in the clinic. We also review the favourable impact neprilysin inhibition can have on diabetic
complications, in addition to glucose control. Finally, we conclude that neprilysin inhibitors may be a useful therapeutic option for treating type 2
diabetes; however, their combination with angiotensin II receptor blockers is needed to circumvent deleterious consequences of neprilysin
inhibition alone.
Emerging evidence suggests that neprilysin also hydrolyses peptides that play an important
role in glucose metabolism.
In recent studies in humans, a dual angiotensin receptor–neprilysin inhibitor (ARNi)
improved glycaemic control and insulin sensitivity in individuals with type 2 diabetes
and/or obesity.
This review article found the favourable impact neprilysin inhibition can have on diabetic
complications, in addition to glucose control.
Because of the action of other enzymes (e.g. DPP- 4) on neprilysin substrates, resulting in
↓ inhibitor efficacy, or the concomitant elevation of neprilysin substrates that can impair
insulin sensitivity and β cell function, the use of combination drugs is a better option than a
neprilysin inhibitor alone for treating T2DM.
a neprilysin inhibitor should necessarily be prescribed together with an ARB, which is
preferred to an ACEI to avoid angioedema.
by raising levels of several peptides
that exert beneficial effects on
glucose metabolism, such as GLP-1,
natriuretic peptides and bradykinin,
inhibition of neprilysin in conditions
of nutrient excess could be a
powerful strategy to improve
glucose homeostasis

Effects of reduced neprilysin activity in tissues modulating glucose homeostasis

The renin-angiotensin-aldosterone activation cascade
The life cycle of natriuretic peptides
The promising roles of ARNI in cardiovascular diseases
 Outlines of presentation
Neurohormonal activation in Heart Failure
What is neprilysin?
Neprilysin inhibition and heart failure
Neprilysin inhibition beyond heart failure
Potential new indications for use of neprilysin inhibitor
Safety of neprilysin inhibition
Conclusions:
The PARAGLIDE-HF trial enrolled a broad and diverse range of
patients with heart failure with mildly reduced or preserved ejection
fraction and will inform clinical practice by providing evidence
about the safety, tolerability and efficacy of Sac/Val vs Val in those
with a recent WHF event.

(J Cardiac Fail 2023;29:922930)

Safety Outcomes
PARAGLIDE-HF and PARAGON-HF
Evolution of RCTs in HFpEF
Safety Across LVEF Spectrum
PARADIGM-HF and PARAGON-HF
Evolution of RCTs in HFpEF
Safety Outcomes
TRANSITION: Safety
TRANSITION
 Long-term neprilysin inhibition:
implications for ARNIs
 By inhibiting the degradation of bradykinin and other inflammatory peptides, neprilysin inhibitor
therapy might promote angio-oedema, bronchoconstriction, and inflammation, and might promote
cancer by inhibiting the degradation of mitogenic peptides

 Neprilysin might have a role in metabolizing amyloid-β peptides and by inhibiting amyloid-β
degradation, neprilysin inhibition might predispose to diseases related to amyloid-β deposition such
as Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy

 Neprilysin inhibition might also predispose to late-onset sensorimotor axonal polyneuropathy

 Evidence suggesting potential adverse consequences of chronic neprilysin inhibition come mostly
from animal models and whether this evidence applies to humans is unknown; nevertheless, we need
to be vigilant in the use of chronic neprilysin inhibitor therapy
 Conclusion: neprilysin inhibition
 ARNI is one of the four pillars of therapy for management of patients with HFrEF, according to
current guidelines

 ARNI in patients with HFrEF reduced CV deaths and HHF, as well as all cause-mortality

 Reduction in renal events and reduction of eGFR decline was shown with ARNI across th LVEF
spectrum

 Other effects of ARNI included reversed cardiac remodeling, reduced likelihood of insulin
initiation in patients with T2DM, reduction in uric acid, less decline in Hb, and lower incidence
of new anaemia

 Safety outcomes of ARNI included increased risk of symptomatic hypotension but lower risk of
worsening renal function

 Early and timely initiation of GDMT, adherence, and close patient follow-up are all crucial
factors for improving patient outcomes
THANK YOU