1. A Case report of Heart Failure 2. Discussion on Heart Failure 3. Role of Peptides in Heart Failure 4. Importance of 30 days in heart failure 5. Role of ENTRESTO in Stable Heart Failure patient (PARADIGM-HF study)(HFrEF) 6. Biomarkers in Heart Failure 7. Role of ARNI in Hospitalized Heart Failure patient (PIONEER-HF study) 8. Role of ARNI in HFpEF (PARAMOUNT Trial) 9. Safety and usefulness of ACEI/ARB/ARNI 10. Role of SGPL2 inhibitors in HF with/without DM

1. Professor Dr Md Toufiqur Rahman
Professor & Head of Cardiology, CMMC,
Manikganj
Ex Professor of cardiology,
NICVD
Heart Failure Management
- The Role of ARNI

2. Scope of Discussion
1. A Case report of Heart Failure
2. Discussion on Heart Failure
3. Role of Peptides in Heart Failure
4. Importance of 30 days in heart failure
5. Role of ENTRESTO in Stable Heart Failure patient (PARADIGM-HF study)(HFrEF)
6. Biomarkers in Heart Failure
7. Role of ARNI in Hospitalized Heart
Failure patient (PIONEER-HF study)
8. Role of ARNI in HFpEF (PARAMOUNT Trial)
9. Safety and usefulness of ACEI/ARB/ARNI
10. Role of SGPL2 inhibitors in HF with/without DM

8. Newer Classification of Heart Failure
Steinberg et. al. 2012:65-75
Heart Failure
with Reduced EF
EF<40%
Heart Failure
with Preserve EF
EF ≥ 50%
 Echocardiography is a useful method for evaluating left ventricular
ejection fraction
Heart Failure with
Mid-Range EF
EF 40-49%
Definite HFpEF
(LVEF ≥50%)4
Definite HFrEF
(LVEF <40%)4
HFmrEF
(40% ≤LVEF <50%)4
14%
50% 36%

10. 10
HF is a common clinical condition
HF=heart failure
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Yancy et al. JACC 2013;62:e147–239
3. Townsend et al. 2012 Coronary heart disease statistics 2012 edition.
Available at: https://www.bhf.org.uk/publications/statistics/coronary-heart-disease-statistics-2012
4.Roger et al. JAMA 2004;292:344–50; 5. Levy et al. NEJM 2002;347:1397–402
Prevalence
Incidence
Mortality

11. 1. Lloyd-Jones DM et al. Circulation 2002;106(24):3068–72; 2. McCullough et al. J Am Coll Cardiol 2002;39:60–9
Incident cases of HF in men and
women by age2
29,686 patients of all ages in the Henry Ford Hospital, Detroit (USA) met the definition of HF (at least two outpatient encounters or one hospitalization for
HF) between 1989 and 1999 in the Resource Utilization Among Congestive Heart Failure (REACH) study.
*p<0.0000001 for all inter-group comparisons.
<65 66–74 75–84 >85
Age group (years)
*
*
*
*
Incidence
rate/1,000
health
system
patients
60
50
40
30
20
10
0
Women
Men
Increasing incidence with age
Epidemiology
In the USA, HF is the leading cause of hospitalization for people aged 65 years and over1

12. 1. National Cancer Institute. Cancer stat fact sheets. Available at: http://seer.cancer.gov/statfacts. Accessed 31 May 2016;
2. Roger et al. JAMA 2004;292:344–50
0
10
20
30
40
50
Breast cancer Hodgkin's
lymphoma
Non-Hodgkin's
lymphoma
Colon and
rectum cancer
Leukemia Heart failure
5-YEAR DEATH RATES
Percentage
10%1
14%1
29%1
34%1
40%1
48%2
HF is deadlier than many cancers

16. 16
Symptoms and signs of HFpEF are similar
to those of HFrEF
*Assessed via auscultation with a stethoscope; may be confirmed by echocardiography
HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced
ejection fraction
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Bhatia et al. N Engl J Med
2006;355:260–9; 3. Asher et al. Cardiac Physical Examination. In: Griffin et al, editors. The
Cleveland Clinic Cardiology Board Review. 2nd ed, 2012;p10
.
Edema Hepatomegaly
Pulmonary congestion
 Rales
 Wheezing
 Chest pain
 Dyspnea
 Orthopnea
Third heart
sound (gallop
rhythm)*
Symptoms and signs of HFpEF/HFrEF1–3

17. 17
Morbidity and mortality:
arrhythmias, pump failure
HF symptoms:
dyspnea, edema, fatigue
The pathophysiology of HFrEF
HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LV=left
ventricular
McMurray. N Engl J Med 2010;362:228–38
Francis et al. Ann Intern Med 1984;101:370–7
Krum, Abraham. Lancet 2009;373:941–55
Maladaptive remodeling and
progressive worsening
of LV function
Hemodynamic alterations,
salt and water retention
Systemic neurohormonal overactivation
Damage to cardiac myocytes and extracellular matrix leads to changes in
the size, shape and function of the
heart and cardiac wall stress
Vasoconstriction, fibrosis, apoptosis, hypertrophy,
cellular and molecular alterations, myotoxicity

18. Due to the progressive nature of HF,
patients cannot be perceived as ‘stable’
Mortality
Cardiac
function
and
Quality
of life Decompensation/
hospitalization
Chronic decline1
Disease progression
1. Adapted from Gheorghiade et al. Am J Cardiol 2005;96:11G–17G; 2. Ahmed et al. Am Heart J 2006;151:444–50; 3. Gheorghiade and Pang. J Am Coll Cardiol 2009;53:557–73; 4.
Holland et al. J Card Fail 2010;16:150–6; 5. Muntwyler et al. Eur Heart J 2002;23:1861–6
Frequency of decompensation and risk of mortality increase,1–5 with acute
events and sudden death occurring at any time

19. Cardiac dysfunction triggers the activation of three
compensatory neurohormonal systems
Cardiac structure/function abnormality
Activation of compensatory mechanisms to maintain
cardiac output and organ perfusion1
Activated in response to reduced cardiac output1
Short-term effects are beneficial in early HF1
Long-term activation exerts unfavourable effects1,3
1. Francis et al. Ann Intern Med 1984;101:370–7; 2. Clerico et al. Am J Physiol Heart Circ Physiol 2011;301:H12–H20;
3. Von Lueder et al. Circ Heart Fail 2013;6:594–605 4. Luchner & Schunkert. Cardiovasc Res 2004;63:443–9;
5. Thysgesen et al. Eur Heart J 2012;33:2001–6
Release of NPs in
response to cardiac stress2
Opposes the actions of the
RAAS2 and SNS4,5
SNS RAAS NP system

20. But, neprilysin rapidly degrade natriuretic
peptide and turns them into inactive fragments
• ACEI=angiotensin-convertingenzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker;
AT1R= angiotensin II type 1 receptor; HF=heart failure; MRA=mineralocorticoid receptor antagonist;
NP=natriureticpeptide; NPRs=natriureticpeptide receptors; RAAS=renin-angiotensin-aldosterone
system; SNS=sympatheticnervous system
• 1. McMurrayet al. Eur J Heart Fail 2013;15:1062–73
• Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy2002;22:27–42; Kemp & Conte. CardiovascularPathology 2012;365–71;
Schrier & Abraham N Engl J Med 2009;341:577–85
SNS
RAAS
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II AT1R
HFSYMPTOMS&
PROGRESSION
INACTIVE
FRAGMENTS
NP system
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility

21. *Studies ongoing; not approved for treatment of HF
ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme inhibitor;
ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; MRA=mineralocorticoid receptor
Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier and Abraham. N Engl J Med
1999;341:577–85; Brewster et al. Am J Med Sci 2003;326:15–24; Schmieder. Am J
Hypertens 2005;18:720–30; McMurray et al. Eur Heart J 2012;33:1787–847 Francis et
al. Ann Intern Med 1984;101:370–7;
Von Lueder et al. Circ Heart Fail 2013;6:594–605.
RAAS: Initially compensatory and
subsequently pathological in HF
Angiotensinogen
Ang I
Ang II
ACE
Renin
AT1 receptor
Biological actions
Signalling
cascade
Direct renin
inhibitors*
ACEIs
ARBs
Hypertrophy
Fibrosis
Vasoconstriction
hypertrophy
Aldosterone
secretion
Na+/H2O
retention
ADH
Secretion
Norepinephrine release
Sympathetic tone
Cardiac remodeling
Myocyte necrosis
Blood
Pressure
Blood volume Heart rate
Contractility
MRAs

22. ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic
peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine triphosphate;
NPR=neprilysin receptor
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension
2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP,
1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur.
Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N
Engl J Med 1998;339;321–8.
Effects of the natriuretic peptide system: NPs mediate a wide
range of physiological effects via NP receptors
NPR-A
GTP
ANP and BNP
NPR-C
Internalization
Degradation
of NPs7
Receptor
recycling
Cardiomyocytes1
cGMP
 Vasodilation1,2
 Antihypertrophy1,2
 Antiproliferation2
 Vascular regeneration3
 Myocardial relaxation4,5
 Diuresis, natriuresis1,2
 Antiapoptosis6
 Anti-aldosterone1,2
 Renin secretion inhibition7
 Reduced sympathetic tone8
 Lipolysis7
NPR-B
CNP
Endothelial cells1
GTP
cGMP
 Vasodilation1,2
 Antihypertrophy1,2
 Antiproliferation2
 Vascular regeneration1
 Venodilation1
 Antifibrosis1
Natriuretic peptide
degradation and clearance

24. ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor
blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with
reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic
peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system;
SNS=sympathetic nervous system
1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Minguet et al., Exp.
Opin.Pharamacother, 2015, 16:435-46;,
Figure references: Levin et al. N Engl J Med 1998;339:321–8
Sacubitril/valsartan: Neprilysin inhibition combined with RAAS
blockade is an alternative to an ACEI or ARB in patients with HFrEF 1
SNS
RAAS
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II AT1R
HFSYMPTOMS&
PROGRESSION
INACTIVE
FRAGMENTS
NP system
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
Neprilysin
inhibitors
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
Sacubitril/valsartan

27. 27
Neprilysin inhibition must be accompanied by
simultaneous RAAS blockade
ACE=angiotensin-converting enzyme; AT1=angiotensin II type 1;
Ang=angiotensin; H20=water; Na=sodium;
RAAS=renin-angiotensin- aldosterone system
1. Von Lueder et al. Circ Heart Fail 2013;6:594–605
2. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Angiotensinogen
Ang I
Ang II
AT1 receptor
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction
Hypertrophy
Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
 Neprilysin metabolizes Ang I and Ang II via several
pathways1,2
 Inhibition of neprilysin alone is insufficient as it associated
with an increase in Ang II levels, counteracting the
potential benefits of neprilysin inhibition2
 Neprilysin inhibition must be accompanied by
simultaneous RAAS blockade (e.g. AT1 receptor blockade)2
Signaling
cascade
Ang-(1–7)
Renin
ACE
Inactive
fragments
Neprilysin
inhibitor
Neprilysin
inhibitor
Neprilysin
Neprilysin

28. 28
Vasorelaxation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
Inactive
fragments
ANP, BNP, CNP, other
vasoactive peptides*
AT1 receptor
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
Angiotensinogen
(liver secretion)
Ang I
Ang II
RAAS
LCZ696 simultaneously inhibits neprilysin (via
LBQ657) and blocks AT1 receptors (via valsartan)
*Neprilysin substrates listed in order of relative affinityfor neprilysin: ANP, CNP, Ang II, Ang I, adrenomedullin,
substance P, bradykinin, endothelin-1, BNP
Ang=angiotensin; ANP=atrial natriureticpeptide; AT1=angiotensin II type 1; BNP=B-type natriureticpeptide; CNP=C-
type natriureticpeptide; NEP=neprilysin; RAAS=renin-angiotensin-aldosteronesystem
Levin et al. N Engl J Med 1998;339:321–8
Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Schrier & Abraham. N Engl J Med 2009;341:577–85
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Feng et al. Tetrahedron Letters 2012;53:275–6
LCZ696
Sacubitril
(AHU377; pro-drug)
Inhibiting
Enhancing
LBQ657
(NEP inhibitor)
OH
O
HN
O
HO
O
Valsartan
N
NH
N
N
N
O
OH
O

29. 29
Simultaneous inhibition of neprilysin and suppression of the
RAAS with LCZ696 has complementary effects
cGMP=cyclic guanosine monophosphate; RAAS=renin-angiotensin-
aldosterone system; SNS=sympathetic nervous system
Levin et al. N Engl J Med 1998;339:321–8
Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Schrier & Abraham. N Engl J Med 2009;341:577–85
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
LCZ696
Enhancing cGMP-mediated effects of
natriuretic peptides
 Vasodilation
 Natriuretic and diuretic effects
 Proliferation
 Hypertrophy
 SNS outflow/sympathetic tone
 Aldosterone secretion
 Detrimental effects of vascular
remodeling
Suppressing RAAS-mediated effects
 Vasoconstriction
 Sodium and water retention
 Ventricular hypertrophy/remodeling
 Aldosterone secretion
 Cardiac fibrosis
 Sympathetic tone
 Systemic vascular resistance

30. 30
A number of diagnostic assessments
support the presence of HF
BNP=B-type natriuretic peptide; BP=blood pressure; ECG=echocardiograph; HF=heart
failure; MI=myocardial infarction; NT-proBNP=N-terminal pro-B-type natriuretic peptide Dickstein et al. Eur Heart J 2008;29:2388–442
Assessment of
symptoms
Compatible symptoms include breathlessness, fatigue, angina, palpitations or
syncope
Assessment
of signs
Compatible signs should include appearance, pulse, BP, fluid overload,
respiratory and heart rate
ECG ECG changes are common (e.g. presence of new Q waves reflecting a MI;
wave abnormalities reflecting ischemia, or an arrhythmia). If the ECG is
completely normal, HF, especially with systolic dysfunction, is unlikely (<10%)
Laboratory
analyses
Elevated BNP/NT-proBNP, hyponatremia, renal dysfunction, mild elevations of
troponin
Chest X-ray Permits assessment of pulmonary congestion and may demonstrate important
pulmonary or thoracic causes of dyspnea
Echocardiography Provides extensive information on cardiac anatomy, wall motion and valvular
and ventricular function; used to confirm HF diagnosis

31. 31
BNP and NT-proBNP measurement is useful
for the diagnosis of HFrEF
BNP=B-type natriuretic peptide; ECG=electrocardiograph;
HF=heart failure; HFrEF=heart failure with reduced ejection fraction; NT-proBNP=N-terminal
pro-B-type natriuretic peptide
Dickstein et al. Eur Heart J 2008;29:2388–442
Melanson, Lewandrowski. Am J Clin PathoI 2005;124:S122–8
Clinical examination, ECG,
chest X-ray, echocardiography
Chronic HF unlikely Chronic HF likely
Uncertain diagnosis
Natriuretic peptides
BNP >400 pg/mL
NT-proBNP >2,000 pg/mL
BNP 100–400 pg/mL
NT-proBNP 400–2,000 pg/mL
BNP <100 pg/mL
NT-proBNP <400 pg/mL
 Clinical usefulness of BNP and NT-proBNP testing in patients with chronic HF:
• diagnosis of chronic HF in patients with dyspnea
• prognosis and risk stratification
• screening for chronic HF in high-risk populations
• monitoring and guiding treatment
• treatment with recombinant BNP

32. 32
Treatment algorithm as per ESC 2016
guidelines
Ponikowski P et al. Eur Heart J. 21 May 2016.
doi:10.1093/eurheartj/ehw128

33. 33
Guidelines recommend several core
therapies for patients with HFrEF
*Patients in NYHA classes II, III or IV have mild, moderate or severe symptoms of HF, respectively. ACEI=angiotensin-
converting enzyme inhibitor; ARB=angiotensin-receptor blocker; HF=heart failure; LVEF=left ventricular ejection
fraction; NYHA=New York Heart Association; RAAS=renin-angiotensin-aldosterone system McMurray et al. Eur Heart J 2012;33:1787–847
Therapy Recommendation
ACEIs
LVEF ≤40% to reduce risk of mortality and HF hospitalization (unless contraindicated or not
tolerated)
β-blockers LVEF ≤40% to reduce risk of mortality and HF hospitalization
Aldosterone
antagonists
Persisting symptoms (NYHA class II–IV*) and LVEF ≤35%, despite treatment with an ACEI
(or ARB if an ACEI is not tolerated) and a β-blocker, to reduce risk of mortality and HF
hospitalization
ARBs
LVEF ≤40% unable to tolerate ACEI therapy to reduce risk of mortality and HF
hospitalization
Persisting symptoms (NYHA class II–IV*) and LVEF ≤40%, despite treatment with an ACEI
and a β-blocker, who are unable to tolerate aldosterone antagonist therapy
Diuretics
As needed to relieve signs and symptoms of congestion (have not been shown to reduce
risk of mortality and HF hospitalization)
 Most patients with chronic HF should be routinely managed with a combination of a RAAS
inhibitor, a β-blocker and a diuretic

34. 34

35. Heart failure leads to frequent
hospitalisations
• HF is one of the most common causes of hospitalisation for
patients aged >65 years in developed countries1
• Nearly 44% of patients with all types of HF are readmitted
for any cause within 1 year after discharge2
• Length of stay for HF hospitalisation ranges between
5 and 10 days3
• In the US, 30-day readmission rates are >25%4
• In Europe, readmission rates are ~24% at 12 weeks5
3
5
HF=heart failure.
References: 1. Bui AL, et al. Nat Rev Cardiol. 2011;8(1):30-41. 2. Maggioni AP, et al. Eur J Heart Fail. 2013;15:808-817.
3. Ponikowski P, et al. ESC Heart Fail. 2014;1(1):4-25. 4. Kociol RD, et al. Am Heart J. 2013;165(6):987-994.e1. 5. Cleland JG, et al. Eur Heart J.
2003;24(5):442-463.

36. Mortality during this 30-day
period can approach 10%2
HF hospitalisation2
Stabilisation and
postdischarge
period2
Chronic HF2
Approximately 25% of patients
will be readmitted to the hospital
within 30 days after discharge2
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.
3
6
Vulnerable phase after hospitalisation for ADHF1

37. HFrEF is characterized by frequent
hospitalization and linked to higher mortality
5
Year
1
Year
60
Days
~40–50%
Mortality rate
after 5 years4,5
~20–30%
Mortality rate
after 1 year3,4
30–50%
Mortality or
hospitalization rate
60 days after
admission2
4%
Mortality rate
in hospital1*
~50% of heart failure deaths occur suddenly6
*Study data based on 105.388 US patients, hospitalized between 1997 and 2004 because of heart failure in the Acute Decompensated Heart Failure National Registry
HFrEF=heart failure with reduced ejection fraction
1. Adams et al. Am Heart J 2005;149:209–16; 2. Dickstein et al. Eur Heart J 2008;29:2388–42; 3. Chen et al. JAMA 2011;306:1669–78;
4. Loehr et al. Am J Cardiol 2008;101:1016–22; 5. Roger et al. Circulation 2012;125:e2–220; 6. McMurray et al.. Eur Heart J 2012;33:1787–847

38. Hospitalisation provides an opportunity to
optimise chronic HF therapy*
44.5
49.5
12.6
6.9
42
91.2
94.1
27.2
18.9
56.4
0
10
20
30
40
50
60
70
80
90
100
ACEI/ARB Beta blocker Aldosterone
antagonist
H‐ISDN Anticoagulant
Patients
with
prescription%
†
Use at admission
Prescribed at discharge
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; H‐ISDN=hydralazine‐isosore dinitrate;
LVEF=left ventricular ejection fraction.
*Data from 158,922 patients with HF discharged from 271 hospitals participating in the Get With the Guidelines®‐Heart Failure quality
improvement initiative between 1 April 2008 and 30 June 2013. Among patients eligible for specific therapy; includes continuing prescription
(with use prior to admission) and newly prescribed ACEi/ARB indicates angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.
†Approximately half of patients presenting with symptoms of HF have reduced LVEF (<40%).
Reference: Allen LA, et al. Circulation. 2015;132(14):1347-1353.
3
8

40. Primary outcome: To demonstrate superiority of ENTRESTO over enalapril in reducing composite of CV death or a 1st
hospitalisation for HF (N=8442 patients with chronic HF, NYHA Class II–IV and LVEF ≤40% and elevated BNP)1
PARADIGM-HF study design
2 weeks Median duration of follow-up: 27 months
Randomisation
Enalapril 10 mg BID
ENTRESTO 97/103 mg BID
ENTRESTO‡
97/103 mg BID
On top of standard HF therapy,
excluding ACEis and ARBs3
Testing tolerability to target doses of enalapril and ENTRESTO2
ENTRESTO‡
49/51 mg BID
Enalapril†
10 mg BID
1–2 weeks 2–4 weeks
Single-blind run-in period
Double-blind randomised treatment period
• 36 hour washout was required between enalapril and ENTRESTO run-in and prior to randomisation1
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; BID=twice daily; BNP=B-type natriuretic peptide; CV=cardiovascular;
HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association.
*Enalapril 5 mg BID for 1–2 weeks, followed by enalapril 10 mg BID, was an optional starting run-in dose for patients treated with ARBs or with a low dose of
ACEi.
†Dosing in clinical trials was based on the total amount of both components of sacubitril/valsartan; 24/26 mg, 49/51 mg, and 97/103 mg were referred to as
50 mg, 100 mg, and 200 mg, respectively. ENTRESTO was formerly known as LCZ696 in clinical trials.
References: 1. ENTRESTO Core Data Sheet, Version 1.2. Novartis Pharmaceuticals, July 2017. 2. McMurray JJ, et al. Eur J Heart Fail. 2014;16(7):817-825. 3.
McMurray JJ, et al. N Engl J Med. 2014;371(11):993-1004.
40

41. 41
NYHA I–IV, LVEF ≤35%, standard therapy
 SOLVD-T showed enalapril benefit in NYHA class IIV HFrEF2
 Enalapril* significantly reduced the risk of mortality vs placebo in this broad spectrum of
patients with HFrEF2
Enalapril*
2.5–20 mg QD
n=1,285
Placebo*
n=1,284
Primary endpoint:
All-cause mortality at follow-up
Randomization
SOLVD-T trial2
Placebo
Enalapril
Mortality
from
all-causes
(%) Months
0 6 12 18 24 30 36 42 48
10
20
30
40
50
0
16% relative risk reduction
over 48 months
p=0.0036
Enalapril was chosen as the comparator to LCZ696 as the only
ACEI shown to reduce mortality in a broad spectrum of HFrEF patients1
*On top of standard therapy for HF
ACEI=angiotensin-convertingenzyme inhibitor; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction;
NYHA=New York Heart Association; QD=once daily; SOLVD=Studies of Left VentricularDysfunction
1. McMurray et al. Eur J Heart Fail 2014;16:817–25
2. SOLVD Investigators. N Engl J Med 1991;325:293–302

42. Outcome, n %
ENTRESTO
(n=4187)
Enalapril
(n=4212)
Hazard ratio*
(95% CI)
P value†
Primary composite outcome:
CV death or HF hospitalisation1 914 (21.8) 1117 (26.5) 0.80 (0.73, 0.87) <0.0001
• CV death as first event2 377 (9.0) 459 (10.9)
• HF hospitalisation as first event1 537 (12.8) 658 (15.6)
Number of patients with events‡:
• Death from CV causes1§ 558 (13.3) 693 (16.5) 0.80 (0.71, 0.89)
• HF hospitalisation1 537 (12.8) 658 (15.6) 0.79 (0.71, 0.89)
CI=confidence interval; CV=cardiovascular; HF=heart failure.
*Calculated with the use of stratified Cox proportional hazard models.
†Two-sided P values calculated by means of a stratified logrank test without adjustment for multiple comparisons.
‡Analyses of the components of the primary composite end point were not prospectively planned to be adjusted for multiplicity.
§Includes subjects who had heart failure hospitalisation prior to death.
References: 1. ENTRESTO Core Data Sheet, Version 1.2. Novartis Pharmaceuticals, July 2017. 2. ENTRESTO [prescribing information]. East Hanover,
NJ: Novartis Pharmaceuticals Corp; November 2017.
Study outcomes
42

43. ENTRESTO vs enalapril (primary end point)1
ARR=absolute risk reduction; CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard ratio; KM=Kaplan-Meier; NNT=number needed to treat;
RRR=relative risk reduction.
References: 1. ENTRESTO Core Data Sheet, Version 1.2. Novartis Pharmaceuticals, July 2017. 2. McMurray JJ, et al. N Engl J Med. 2014;371(11):993-1004.
43

44. ARR=absolute risk reduction; CV=cardiovascular; HF=heart failure; NNT=number needed to treat; RRR=relative risk reduction.
*Component of the primary end point.
References: 1. ENTRESTO Core Data Sheet, Version 1.2. Novartis Pharmaceuticals, July 2017. 2. Cook RJ, et al. BMJ. 1995;310(6977):452-454. 3.
McMurray JJ, et al. N Engl J Med. 2014;371(11):993-1004.
ENTRESTO vs enalapril―HF hospitalisation
and CV death
44

45. CI=confidence interval; HF=heart failure; OR=odds ratio; RRR=relative risk reduction.
*The primary unit of analysis was hospitalisations, including repeat hospitalisations, rather than patients.
†Among patients hospitalised at least once for HF, patient characteristics were similar at baseline between treatment groups.
‡Data are from a PARADIGM-HF post hoc analysis (hospital readmission rate was not a primary end point).
Reference: Desai AS, et al. J Am Coll Cardiol. 2016;68(3):241-248.
PARADIGM-HF: ENTRESTO reduced 30-day
HF readmissions vs enalapril (post hoc analysis)*†
45

46. 46

47. • BNP and NT-proBNP are the gold standard biomarkers for diagnosis and
prognosis in patients with HF1
• These biomarkers:
o Increase in response to myocardial wall stress and cardiac congestion2
o Are modified by HF therapy3
o Are endorsed by HF clinical guidelines4,5
o Can be used to predict future outcomes and guide HF therapy3,6
• High BNP and NT-proBNP levels are readouts of cardiac congestion and
anticipate CV risk (mortality and HF worsening)1,7
• Small increases in hs-TnT can reflect an increased risk of disease
progression in HF8
BNP=B-type natriuretic peptide; CV=cardiovascular; HF=heart failure; hs-TnT=high-sensitivity troponin T; NT-proBNP=N-terminal pro–b-type natriuretic peptide.
References: 1. Gaggin HK, et al. Biochim Biophys Acta. 2013;1832(12):2442-2450. 2. Iqbal N, et al. Cardiovasc Diagn Ther. 2012;2(2):147-164.
3. Jaffe AS, et al. Clin Chem. 2017;63(5):954-957. 4. Ponikowski P, et al. Eur Heart J. 2016;37(27):2129-2200. 5. Yancy CW, et al. Circulation. 2016;134(13):e282-293. 6.
Troughton R, et al. Eur Heart J. 2014;35(1):16-24. 7. McMurray JJ, et al. Eur J Heart Fail. 2014;16(7):817-825.
8. Perna ER, et al. Circulation. 2004;110(16):2376-2382.
NT-proBNP and hs-TnT are established
biomarkers in HF
47

48. • Reduction in NT-proBNP following HF treatment is associated with reduction in CV death
and HF hospitalisation*
Achieved NT-proBNP <1000
HR=0.41 (0.29,0.58)
P<0.001
Years
Achieving levels of NT-proBNP <1000 as early as 1 month after randomisation to HF therapy
was associated with a significant reduction in risk of CV death or first HF hospitalisation
Risk
of
Primary
End
Point
After
1
Month
Did not achieve NT-proBNP <1000
CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio; NT-proBNP=N-terminal
pro–b-type natriuretic peptide.
*This was a post hoc analysis of PARADIGM-HF Study. Analytic variability (imprecision of the test) and biological variability (expected
variability within the subject over time) may influence the accuracy of a predictive value of a change in biomarkers. The change from baseline
data should therefore be interpreted in light of the influence of the biological variability known to be present in patients with HFrEF.
Reference: Zile MR, et al. J Am Coll Cardiol. 2016;68(22):2425–2436.
Relationship of NT-proBNP and CV events
48
Risk of CV death or first HF hospitalisation

49. NT-proBNP=N-terminal pro–b-type natriuretic peptide.
Reference: Metra M, et al. J Am Coll Cardiol. 2013;61(2):196-206.
All-cause mortality
Significance of lowering NT-proBNP
49
Cumulative
risk
Study day

50. BNP=B-type natriuretic peptide; NT-proBNP=N-terminal pro-B-type natriuretic peptide; sac/val=sacubitril/valsartan; V=visit.
References: 1. Zile MR, et al. J Am Coll Cardiol. 2016;68:2425-2436. 2. Packer M, et al. Circulation. 2014; DOI: 10.1161/CIRCULATIONAHA.114.013748.
ENTRESTO significantly reduced NT-proBNP vs
enalapril
• Consistently lower levels
of NT-proBNP were observed in
ENTRESTO group compared
with enalapril group1
• Unlike BNP, NT-proBNP
is not a substrate
for neprilysin1
• Levels of NT-proBNP reflect the
effects ENTRESTO has on cardiac
wall stress2
50

51. 51

52. HF=heart failure; LVAD=left ventricular assist device; NT-proBNP=N-terminal pro–b-type natriuretic peptide.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
Study end points
Primary end point
• Time-averaged proportional change in NT-proBNP concentration from baseline
through
Weeks 4 and 8
Safety
• Incidents of worsening renal function
• Hyperkalaemia
• Symptomatic hypotension
• Angioedema
Exploratory clinical outcomes
• Serious clinical composite: Death, rehospitalisation for HF, LVAD, or listing for
cardiac transplant
A more complete list of PIONEER study end
points has been previously published in
Velazquez, et al. Am Heart J 198 (2018) 145-
151.
52

53. ENTRESTO
97/103 mg twice daily*
Enalapril
10 mg twice daily*
vs
In-hospital initiation
Hospitalised with acute decompensated
HF with reduced EF
Stabilised
Study drug for 8 weeks
Evaluate biomarker surrogates of efficacy
Evaluate safety and tolerability
Explore clinical outcomes
EF=ejection fraction; HF=heart failure.
*Target dose.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
Study design
53

54. ADHF=acute decompensated heart failure; BNP=b-type natriuretic peptide; h=hours; IV=intravenous; LVEF=left ventricular ejection fraction;
NT-proBNP=N-terminal pro–b-type natriuretic peptide; SBP=systolic blood pressure.
*At screening.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
• Hospitalised for ADHF
• LVEF ≤40% within the last 6 months
• NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL*
• Stabilised while hospitalised
o SBP ≥100 mmHg in prior 6h; no symptomatic hypotension
o No increase in IV diuretics in prior 6h
o No IV vasodilators in prior 6h
o No IV inotropes in prior 24h
A complete list of inclusion and exclusion criteria has been published in Velazquez, et al. Am
Heart J. 2018.
Key entry criteria
54

55. ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; HF=heart failure; SBP=systolic blood pressure.
References: 1. Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851. 2. Data on file. PIONEER-HF Protocol, Novartis Pharmaceuticals Corp; October 2018.
3. Velazquez EJ, et al. Am Heart J. 2018;198:145-151.
• Starting dose level based on SBP algorithm
o If 100 ≤ SBP < 120 mmHg: sacubitril/valsartan 24/26 mg BID or enalapril 2.5
mg twice daily1
o If SBP ≥ 120 mmHg: sacubitril/valsartan 49/51 mg BID or enalapril 5 mg
twice daily1
 At Week 1, dose titrated upwards if SBP ≥ 110 mmHg1
 At Week 2, 4, 6, dose titrated upwards if SBP ≥ 100 mmHg1
• Target dose
o Sacubitril/valsartan 97/103 mg BID or enalapril 10 mg twice daily2,3
 Clinical assessment and judgment permitted2
Study dose titration
Patients taking low-dose or no ACEi/ARB at randomisation were initiated on ENTRESTO 49/51 mg if their SBP was
≥ 120 mmHg. Similarly, patients were up-titrated as early as Week 1 and again at Week 2 based on their blood pressure. Follow
label dosing recommendations.2
55

56. Randomisation
Enalapril
n=444
Analysed
n=441 (100%)
Excluded due to
inappropriate randomisation n=3
Never dosed
n=5
Safety cohort
n=436 (98.2%)
ENTRESTO
n=443
Analysed
n=440 (100%)
Excluded due to
inappropriate randomisation n=3
Safety cohort
n=439 (99.1%)
Final safety set
77 patients failed screening
• 7 investigator decision
• 8 subject/guardian decision
• 59 screen failure
• 2 technical problems
• 1 death
Evaluable
n=379 (85.6%)
Evaluable
n=374 (84.2%)
Evaluable for
NT-proBNP
Full analysis set
964 patients screened
887 patients enrolled
Never dosed
n=1
NT-proBNP=N-terminal pro–b-type natriuretic peptide.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
Patient disposition
56

57. All patients randomised to ENTRESTO require a 36-hour washout period prior to starting active
study treatment, due to potential increased risk of angioedema in patients who receive both an
ACEi and ENTRESTO
36-hour washout for ENTRESTO
treatment arm
Enalapril
ENTRESTO
6-hour observation
Screening
Last dose of
previous ACEi
Randomisation
(0 hrs)
1st dose
placebo
24 hrs post-
randomisation
3rd dose
active drug
12 hrs post-
randomisation
2nd dose
placebo
24 hrs post
randomisation
3rd dose
active drug
12 hrs post
randomisation
2nd dose
active drug
Randomisation (0
hrs)
1st dose
active drug
Last dose of
previous ACEi
ACEi=angiotensin-converting enzyme inhibitor; hrs=hours
Reference: Velazquez EJ, et al. Am Heart J. 2018;198:145-151.
36-hour washout requirement
57

58. Demographics
ENTRESTO
(n=440)
Enalapril
(n=441)
Age, median (25th, 75th) years 61 (51, 71) 63 (54, 72)
Women, median, % 25 30
Black, % 40 36
Prior HF diagnosis, % 68 63
LVEF, median (25th, 75th) % 0.24 (18, 30) 0.25 (20, 30)
Systolic pressure, median (25th, 75th)
mmHg
118 (110, 133) 118 (109, 132)
NT-proBNP median (25th, 75th) pg/mL
at randomisation
2883 (1610, 5403) 2536 (1363, 4917)
ACEi/ARB therapy, % 47 49
Beta-adrenergic blockers, % 60 60
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; HF=heart failure; LVEF=left ventricular ejection fraction; NT-
proBNP=N-terminal pro–b-type natriuretic peptide.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
Baseline characteristics
58

59. 10
0
- 10
- 20
Percent
change
from
baseline
- 30
- 40
- 50
- 60
- 70
Week since randomisation
Baseline Week 1 Week 2 Week 4 Week 8
HR 0.71 (95% CI 0.63, 0.80); P<0.001
Enalapril
ENTRESTO
Time-averaged proportional change of NT-proBNP from baseline*
CI=confidence interval; HR=hazard ratio; NT-proBNP=N-terminal pro–b-type natriuretic peptide.
*Percentage (%) change from baseline to mean of Weeks 4 and 8.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
397 355 363 365 349
394 359 351 350 348
No. of patients
ENTRESTO
Enalapril
Primary end point
59
29%

60. 20
KM
estimate
of
event
rate
(%)
10
0
0 7
ENTRESTO
n=440
Enalapril
n=441
14 21 28 35 42 49 56
Days since randomisation
CI=confidence interval; HF=heart failure; HR=hazard ratio; KM=Kaplan-Meier; LVAD=left ventricular assist device; NNT=number needed to treat.
*Exploratory serious clinical composite end point was driven by the reduction of risk of death and HF rehospitalisations.
References: 1. Data on file. Velazquez EJ, et al. Late Breaker AHA 2018. Chicago, IL, USA; November 10-12, 2018. 2. Data on file.
PIONEER-HF Protocol, Novartis Pharmaceuticals Corp; October 2018.
HR 0.54 (95% 0.63, 0.80) P=0.001
NNT=13
Exploratory serious clinical composite end point
60
Composite of death, HF rehospitalisation, LVAD, listing for transplant1*
440 434 421 416 381
441 429 418 408 352
No. of patients2
ENTRESTO
Enalapril
405
394
398
367
388
367
385
357
46%

61. ENTRESTO
(n=440)
Enalapril
(n=441)
ENTRESTO vs enalapril Hazard
ratio (95% CI)*
Serious Composite, % 9.3 16.8 0.54
Death, % 2.3 3.4 0.66
Rehospitalisation for HF, % 8.0 13.8 0.56
Requirement of LVAD, % 0.2 0.2 0.99
Cardiac Transplant, % 0 0 -
HF=heart failure; LVAD=left ventricular assist device.
*Hazard ratios and associated 95% confidence intervals were calculated with a Cox proportional hazards model. Confidence intervals have not been adjusted for
multiple comparisons, and therefore, inferences drawn from these intervals may not be reproducible.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
Additional clinical end points
61

62. All Patients
Prior HF
No
Yes
Prior ACEi/ARB
No
Yes
Subgroup
Change in NT-proBNP
0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9
Favours
ENTRESTO
Favours
enalapril
sacubitril/valsartan
vs enalapril mean
(95% CI)
0.71 (0.63, 0.81)
0.65 (0.53, 0.81)
0.72 (0.63, 0.83)
0.72 (0.60, 0.86)
0.72 (0.61, 0.85)
P value (interaction) = NS
Favours
enalapril
Serious Composite End Point
0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9
Favours
ENTRESTO
0.54 (0.37, 0.79)
0.37 (0.12, 1.15)
0.53 (0.35, 0.80)
0.52 (0.29, 0.95)
0.56 (0.34, 0.92)
Hazard Ratio
(95% CI)
All Patients
Prior HF
No
Yes
Prior ACEi/ARB
No
Yes
Subgroup
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CI=confidence interval; HF=heart failure; NS=not significant; NT-
proBNP= N-terminal pro–b-type natriuretic peptide.
Reference: Data on file. Velazquez EJ, et al. Late Breaker AHA 2018. Chicago, IL, USA; November 10-12, 2018.
62
Key subgroup analyses

63. Open-label Extension of the PIONEER-HF Trial
63
Changes in NT-proBNP from baseline over 12 weeks
DeVore AD, Braunwald E, Morrow DA, et al. Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure
Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial. JAMA Cardiol. doi:10.1001/jamacardio.2019.4665; E1-E6

64. 64
Effect of Sacubitril/Valsartan on Clinical Outcomes Over 12 Weeks
DeVore AD, Braunwald E, Morrow DA, et al. Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure Secondary Analysis of
the Open-label Extension of the PIONEER-HF Trial. JAMA Cardiol. doi:10.1001/jamacardio.2019.4665; E1-E6
Open-label Extension of the PIONEER-HF Trial

65. Safety events
ENTRESTO
(n=440)
Enalapril
(n=441)
ENTRESTO vs enalapril
Relative risk (95% CI)
Worsening renal function, %* 13.6 14.7 0.93 (0.67 to 1.28)
Hyperkalaemia, % 11.6 9.3 1.25 (0.84 to 1.84)
Symptomatic hypotension, % 15.0 12.7 1.18 (0.85 to 1.64)
Angioedema events, %†
0.2 1.4 0.17 (0.02 to 1.38)
Safety
CI=confidence interval; RR=relative risk; SCr=serum creatinine.
*Worsening renal function was defined by an increase in the SCr of 0.5 mg per deciliter or more (≥44 μmol per liter) and a decrease in the eGFR rate
of 25% or more.
†Positively adjudicated angioedema cases.
Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851.
65

66. Conclusions for PIONEER-HF
• PIONEER-HF reconfirms the superiority of ENTRESTO over ACEi as shown in PARADIGM-HF,
now demonstrated in the hospital setting in a wide range of patients with HFrEF who have
been haemodynamically stabilised after an acute decompensated HF event, including
ACEi/ARB-naïve and newly diagnosed (de novo) patients1-3
• In-hospital initiating of ENTRESTO compared with enalapril leads to:
o Significantly greater and more rapid reductions in NT-proBNP, an established biomarker for HF
severity and prognosis1
o Significantly greater reduction of the risk of serious clinical outcomes soon after discharge: In a
prespecified, exploratory, serious clinical composite end point, risk of death, HF rehospitalisation,
LVAD implantation, or listing for cardiac transplant was reduced by 46% compared with enalapril over
8 weeks. The risk reduction was driven by the reduction of risk of death and HF rehospitalisations1
• PIONEER-HF reconfirms that in-hospital initiation of ENTRESTO shortly after haemodynamic
stabilisation has safety comparable to enalapril1
PIONEER-HF reconfirms the superiority of ENTRESTO
over ACEi in the hospital setting1
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVAD=left
ventricular assist device; NT-proBNP=N-terminal pro–b-type natriuretic peptide.
References: 1. Reference: Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851. 2. ENTRESTO Core Data Sheet, Version
1.2. Novartis Pharmaceuticals, July 2017; 3. Velazquez EJ, et al.
Am Heart J. 2018;198:145-151.

67. Prospective comparison of ARNI with ARB on Management Of heart
failUre with preserved ejectioN fraction
 Comparing ARNI (200mg bd) with Valsaratan (160mg bd)
 261 & 241 patients at 12 & 36 weeks follow-up
NT-proBNP was significantly reduced at 12
weeks in the ARNI group compared with the
valsartan group
Lancet, Vol 380; October 20, 2012
HFpEF: PARAMOUNT Trial

68. COVID-19 &
Management of Chronic Heart Failure

69. 5x* increase mortality risk in CVD patients with COVID-19
“The first reported death was a 61-year-old male, with a long
history of smoking, who succumbed to acute respiratory
distress, heart failure, and cardiac arrest” 2
Overall the case mortality rate remains low at 2.3%1,2; however,
the mortality rate jumps to 6% in hypertensives, 7.3% in
diabetics, 10.5% in patients with cardiovascular disease2, and
14.8% for patients ≥ 80 years of age
Case mortality rate for underlying cardiovascular disease (10.5%)
is greater than in patients with underlying chronic respiratory disease2(6.3%)
*interpret from AVE death 2.3% in average from all age t o10.5% in cardiac patients
1.Melvin Sanicas et al, Epidemiological Characteristics of an Outbreak of COVID-19 in China (2020). https://www.linkedin.com/pulse/epidemiological-
characteristics-outbreak-covid-19-china-sanicas. Access Mar3, 2020
2 Mohammad Madjid, Scott D Solomon, Orly Vardeny. ACC Clinical Bulletin Cardiac Implications of Novel Wuhan Coronavirus (COVID-19). American
College of Cardiology (ACC). Published online Feb 12, 2020.https://www.acc.org/~/media/665AFA1E710B4B3293138D14BE8D1213.pdf.
Accessed Feb 20, 2020.

70. Comorbidities of COVID 19
• Data about the commonly seen comorbidities are consistent among different studies,
patients with cardiovascular disease that contract COVID
• These are common comorbidities seen in HF patients.
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases
(COVID-19) — China, 2020. China CDC Weekly, 2020, 2(8): 113–122.

71. Outcomes
• Sepsis was the most frequently observed complication, followed by respiratory
failure, ARDS, heart failure, and septic shock
Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China:
a retrospective cohort study. The Lancet. Published online March 19, 2020. https://doi.org/10.1016/S0140-
6736(20)30566-3

72. Why is cardiovascular disease (CVD) so
prevalent in those who died with COVID-19?
• Most acute viral infections have three short-term effects on the
CV system:
 Increase the risk of acute coronary syndromes due to the inflammatory
response
 Depression of the myocardium leading to worsening heart failure
 The inflammatory process can unmask heart arrhythmias
University of Oxford, Centre for Evidence Based Medicine, March 23rd,2020

73. International professional societies’ recommendations on
current treatment continuation with RAAS Blockers
All strongly encouraged/
recommended the
continuation of
ACEi/ARBs

74. What does this mean for patients on Entresto?
Most of the international societies recommend that, patients should stay on
ACEi/ARB for the treatment of heart failure & hypertension.

75. 75
Covid-19 and ACEI/ARB

76. 76
Covid-19 and ACEI/ARB

77. Covid-19 and ACEI/ARB

78. Covid-19 and ACEI/ARB

79. • Angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-
receptor blockers (ARBs) have physiologic effects that could be either
beneficial or harmful in patients with COVID-19 (NEJM JW Cardiol May
2020 and N Engl J Med 2020; 382:1653). In three retrospective studies,
researchers have addressed this issue.
• In a single-center Chinese study that involved 362 hospitalized COVID-19
patients with histories of hypertension, 32% were taking ACE inhibitors
or ARBs on admission; the drugs were continued if possible.
Researchers found no difference in severity of COVID-19 or mortality in
users of ACE inhibitors or ARBs compared with nonusers. Statistical
adjustment for potentially confounding factors was not conducted.
Covid-19 and ACEI/ARB

80. In a multicenter Chinese study of 1128 hospitalized COVID-19 patients with histories of
hypertension, 17% were taking ACE inhibitors or ARBs; the drugs were continued during
hospitalization in two thirds of these patients. Mortality was significantly lower in ACE
inhibitor or ARB users than in nonusers (3.7% vs. 9.8%). In a propensity-score matched
analysis to adjust for potential confounders, mortality remained significantly lower in ACE
inhibitor or ARB users (adjusted hazard ratio, 0.37).
• Finally, U.K. researchers have posted a “preprint” report of 205 COVID-19 patients, 37
of whom who took ACE inhibitors within 7 days before symptom onset or during
hospitalization. The proportion of patients who died or required critical care support
was lower in ACE inhibitor recipients than in other patients (14% vs. 29%); the
difference was significant after adjustment for multiple confounding variables (adjusted
odds ratio, 0.29). Because only 9 patients were taking ARBs, outcomes with ARBs were
not examined.
Covid-19 and ACEI/ARB

81. Covid-19 and ACEI/ARB
• Mehra et al.conducted a database study involving patients who had been hospitalized
in 11 countries on three continents.
• The study included 8910 patients who had received a diagnosis of Covid-19, who had
been admitted to the hospital between December 20, 2019, and March 15, 2020, and who
had either died in the hospital or survived to hospital discharge.
• In multivariate logistic-regression analysis, an age greater than 65 years, coronary
artery disease, congestive heart failure, history of cardiac arrhythmia, chronic
obstructive pulmonary disease, and current smoking were associated with an
increased risk of in-hospital death.
• Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs
were associated with an increased risk of in-hospital death.
• A secondary analysis that was restricted to patients with hypertension (those for whom
an ACE inhibitor or ARB would be indicated) also did not show harm

82. Mancia et al. conducted a case–control study involving patients with confirmed
Covid-19 in the Lombardy region of Italy, which has been severely affected by the
pandemic.
In this analysis, 6272 people with confirmed SARS-CoV-2 infection that had been
diagnosed between February 21 and March 11, 2020, were compared with 30,759
controls who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors
nor ARBs were associated with the likelihood of SARS-CoV-2 infection. An
additional analysis comparing patients with severe or fatal infections with
matched controls also did not show an association between these drugs and
severe Covid-19.
82
Covid-19 and ACEI/ARB

83. • Reynolds et al. conducted a study based on data from the electronic health records of 12,594
patients in the New York University (NYU) Langone Health system who were tested for Covid-19
between March 1 and April 15, 2020. A total of 5894 patients had a positive test, among whom
1002 had severe illness (defined as admission to the intensive care unit, mechanical ventilation,
or death).
• Propensity-score matching was performed among all tested patients and among patients with
hypertension (to assess whether the likelihood of a positive test result was associated with each
of several antihypertensive drug classes), as well as among Covid-19–positive patients and all
such patients with hypertension (to assess whether the likelihood of severe illness among those
with a positive test was associated with the same drug classes).
• The investigators’ Bayesian analysis showed no positive association for any of the analyzed
drug classes, including ACE inhibitors and ARBs, for either a positive test result or severe
illness.
Covid-19 and ACEI/ARB

84. Mehra et al. found that use of either ACE inhibitors or statins
may be associated with a lower risk of in-hospital death than
nonuse, but neither of the other two studies estimated a lower
risk of Covid-19 or the likelihood of a positive test among
patients treated with these agents.
The unexpected result in the study by Mehra et al. may be due to
unmeasured confounding and, in the absence of a randomized
trial, should not be regarded as evidence to prescribe these
drugs in patients with Covid-19.
84
Covid-19 and ACEI/ARB

85. 85

86. 5

87. Patients at baseline Hospitalised post-ADHF Ambulatory chronic HF
TITRATION
Study
LCZ696BUS01
PIONEER-HF1
LCZ696B2314
PARADIGM-HF3
LCZ696B2228
TITRATION4
No. of patients N=887 N=8442 N=498
Primary end point Effects of ENTRESTO vs
enalapril on changes in NT-
proBNP levels
Morbidity and mortality
vs enalapril
Safety and tolerability
3-week vs
6-week up-titration ENTRESTO
Treatment duration 12 wks 27 mos 11 wks
Outpatients; n (%) 0 8442 (100%) 442 (89%)
Inpatients; n (%) 887 (100%) 0 56 (11%)
ACEi/ARB naïve; n (%) 459 (52%) 0 33 (7%)
De novo; n (%) 303 (34%) 0 0
ACEi=angiotensin-converting enzyme inhibitor; ADHF=acute decompensated heart failure; ARB=angiotensin II receptor blocker; f/u=follow-up; HFrEF=
heart failure with reduced ejection fraction; HF=heart failure; NT-proBNP=N-terminal pro–b-type natriuretic peptide; mos=months; wks=weeks.
References: 1. Velazquez EJ, et al. N Engl J Med. doi:10.1056/NEJMoa1812851. 2. Wachter R, et al. Poster presented at: ESC Congress 2018;
August 25-28, 2018; Munich, Germany. 3. ENTRESTO Core Data Sheet, Version 1.2. Novartis Pharmaceuticals, July 2017. 4. Senni M, et al.
Eur J Heart Fail. 2016;18(9):1193-1202.
PIONEER-HF is complementary with other ENTRESTO
studies in patients with HFrEF
87

88. Conclusions
88
• PIONEER-HF reconfirms the superiority of ENTRESTO over ACEi as shown in
PARADIGM-HF, now demonstrated in the hospital setting in a wide range of
patients with HFrEF who have been haemodynamically stabilised after an
acute decompensated HF event, including ACEi/ARB naïve and newly
diagnosed (de novo) patients1,2
• Complementary evidence from PIONEER-HF reconfirms that in-hospital
initiation of ENTRESTO shortly after haemodynamic stabilisation is safe and
well tolerated1,3
• Building on PARADIGM-HF and PIONEER-HF establish ENTRESTO as standard
of care for patients with HFrEF after an acute decompensated HF event,
irrespective of prior ACEi/ARB use or HF diagnosis1-3
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; HF=heart failure; HFrEF=heart failure with reduced
ejection fraction.
References: 1. Velazquez EJ, et al. N Engl J Med. doi:10.1056/ NEJMoa1812851. 2. ENTRESTO Core Data Sheet, Version 1.2. Novartis
Pharmaceuticals, July 2017. 3. Wachter R, et al. Poster presented at: ESC Congress 2018; August 25-28, 2018; Munich, Germany. 4. Velazquez
EJ, et al. Am Heart J. 2018;198:145-151.
Start ENTRESTO prior to discharge or soon after stabilisation to help keep your patients with HFrEF home and better
protected1-3

89. Role of SGLT2 receptor blockers in
management of heart failure

90. 90

91. 91

92. 92

93. 93

94. 94

95. Comments
• SGLT-2 inhibitors have emerged as a potential
effective class of drug for the prevention of HF in
patients with T2D.
• Mounting mechanistic evidence indicates that these
drugs may also induce combined cardiac and renal
beneficial effects and hold promise for the treatment
of HF in patients with and without diabetes mellitus, as
well as in both HFpEF and HFrEF.