WHAT IS THE NEW

GUIDELINE SAYS ABOUT

HEART FAILURE

For Healthcare Professional Only

PNP no : NVS/SLID/102016/0087
 Epidemiology, aetiology and natural
history of heart failure

 1–2% of the adult population in developed

countries, rising to ≥10% among people > 70
years of age

 Among people > 65 years of age presenting to

primary care with breathlessness on exertion,
one in six will have unrecognized HF (mainly
HFpEF)

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 Heart failure definition

• ESC 2016: HF is a clinical syndrome

characterized by typical symptoms that
may be accompanied by signs caused
by a structural and/or functional cardiac
abnormality, resulting in a reduced
Left
atrium
cardiac output and/ or elevated
Right
intracardiac pressures at rest or during atrium
Left
stress1 ventricle

Right
• ACCF/AHA 2013: HF is a complex ventricle

clinical syndrome that results from any

structural or functional impairment of
ventricular filling or ejection of blood2

ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation
1. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200; 2. Yancy et al. JACC 2013;62:e147–239
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 The pathophysiology of chronic HF

Damage to cardiac myocytes and extracellular matrix leads to

changes in the size, shape and function of the heart
(remodeling) and cardiac wall stress

These changes lead to systemic neurohormonal imbalance

This may lead to fibrosis, apoptosis, hypertension,

hypertrophy, cellular and molecular alterations, myotoxicity

Remodeling and
Hemodynamic alterations,
progressive worsening of
salt and water retention
LV function

Morbidity and mortality HF symptoms

arrhythmias, pump failure dyspnea, edema, fatigue

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
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 Terminology related to left ventricular
ejection fraction
Heart failure definition

Diastole
ventricles relaxing

Systole
ventricles contracting

Amount of blood
pumped out of
the ventricle
= Ejection fraction (%)
Total amount of
blood in
the ventricle

McMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442
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HFrEF and HFpEF
Heart failure definition

Systolic dysfunction Diastolic dysfunction

HFpEF

HFrEF HFmrEF HFpEF

LVEF≤ 40% LVEF 40-49% LVEF ≥ 50%
Echocardiography is a useful method for evaluating left ventricular ejection fraction
* Ponikowski et al. EHJ.2016;37:2129-200
** McMurray et al. EHJ.2012;33:1787–847;
*** Dickstein et al. EHJ.2008;29:2388–442
 Most common causes of Heart Failure
Etiology

• Coronary heart disease • Congenital heart disease

• Hypertension • Pericardial disease
• Valvular disease • Hyperkinetic states
• Anemia
• Cardiomyopathy
• Arterio-venous fistula
• Idiopathic cardiomyopathy
• Beriberi
• Alcoholic cardiomyopathy
• Toxin-related cardiomyopathy
e.g. adriamycin
• Post-partum cardiomyopathy
• Hypertrophic obstructive
cardiomyopathy
• Tachyarrhythmia-induced
cardiomyopathy

• Infiltrative disorders (e.g.

amyloidosis)
*Others: Including hypertension, diabetes, exposure to
cardiotoxic agents, peripartum cardiomyopathy, etc.

Krum and Gilbert. Lancet 2003;362:147–58; Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008;
Dickstein et al. Eur Heart J 2008;29:2388–442
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 A range of risk factors and co-morbidities
contribute to the development of heart failure

Progression of hypertension to LVH and heart failure.*

Obesity Diastolic
LVH LV dilatation
dysfunction
Diabetes

HYPERTENSION
CHF Death

Smoking
Systolic
Dyslipidemia MI LV damage
dysfunction
Diabetes

Subclinical
Left ventricular Overt heart
left ventricular
remodelling failure
dysfunction
Time (decades) Time (months)
* Vasan, RS, et al. Arch Intern Med.1996:156;1789-96

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 Patterns of ventricular remodeling are
different for HFrEF and HFpEF

Left ventricle
normal

HFpEF HFrEF
HFpEF – a condition of HFrEF – a condition of
Pressure Volume
pressure overload volume overload
overload overload
• characterized by • characterized by
concentric hypertrophic Increased Increased eccentric hypertrophy
systolic pressure diastolic pressure
growth • results in thinning of
• results in normal sized Increased Increased the LV walls, decreased
LV cavity with thickened systolic wall stress diastolic wall stress systolic function and
−
walls and preserved Parallel addition Series addition of new enlarged LV volume
−
systolic function of new myofibrils sarcomeres
Wall Chamber
thickening enlargement
Concentric Eccentric Left ventricle
Left ventricle hypertrophy hypertrophy volume
pressure overload
overload
* Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer.2008
** Grossman W, et al. Perspectives in Cardiovascular Research; Myocardial Hypertrophy and Failure. Vol 7. Raven Press.1993
 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

SNS RAAS NP system

Activated in response to reduced cardiac output1 Release of NPs in

response to cardiac stress2
Short-term effects are beneficial in early HF1
Opposes the actions of the
Long-term activation exerts unfavourable effects1,3 RAAS2 and SNS4,5

NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system;SNS=sympathetic nervous system

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
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 The SNS and RAAS are overactivated in heart failure and are
responsible for many of the pathophysiological responses that
contribute to disease progression

SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Vasoconstriction
RAAS activity 
Vasopressin 
HF SYMPTOMS Heart rate 
& PROGRESSION Contractility 

RAAS
Ang II AT1R
Vasoconstriction
Blood pressure 
Sympathetic tone 
Aldosterone 
Hypertrophy 
Fibrosis 
Sodium and water retention 
ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors;
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; Kemp & Conte. Cardiovascular Pathology 2012;365–371;
Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85
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 Secretion of natriuretic peptides results in a number of responses
that act to reduce the symptoms and progression of heart failure

NP system HF SYMPTOMS
& PROGRESSION
NPRs NPs
Vasodilation
 Blood pressure
 Sympathetic tone
 Natriuresis/diuresis
 Vasopressin
Inactive
 Aldosterone
fragments
 Fibrosis
 Hypertrophy

NP=natriuretic peptide; NPRs=natriuretic peptide receptors

Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte.
Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85;
Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30;
Brewster et al. Am J Med Sci 2003;326:15–24
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 As heart failure advances, the RAAS and SNS become the
predominantly activated neurohormonal systems

SNS
Epinephrine α1, β1, β2
Norepinephrine receptors

Vasoconstriction
RAAS activity 
Vasopressin 
NP system HF SYMPTOMS Heart rate 
& PROGRESSION
Contractility 
NPRs NPs

Vasodilation
 Blood pressure
 Sympathetic tone RAAS
 Natriuresis/diuresis
 Vasopressin Ang II AT1R
Inactive
 Aldosterone fragments
Vasoconstriction
 Fibrosis
Blood pressure 
 Hypertrophy
Sympathetic tone 
Aldosterone 
Hypertrophy 
Fibrosis 
ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; Sodium and water retention 
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; Kemp & Conte.
Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85;
Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30;
Brewster et al. Am J Med Sci 2003;326:15–24
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 Natriuretic peptides have potential for
protection of the heart, vessels and kidneys

NPs are released in response to cardiac wall stress and act in the brain,
adrenal gland, kidney, vasculature and heart

Sympatho-inhibitory

Inhibition of
RAAS

ANP Lusitropic
Enhanced endothelial function Attenuation of cardiac remodeling
Endothelin inhibition BNP (LVH) and fibrosis
Vasodilation
Aldosterone suppression

Antiproliferative effect:
reverse vascular remodeling Renin inhibition
(arterial stiffness) Improved renal hemodynamics
Increased natriuresis and diuresis
Attenuation of renal fibrosis

ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; LVH=left ventricular hypertrophy; NPs=natriuretic peptides;
RAAS=renin-angiotensin-aldosterone system
Figure reproduced with permission from Boerrigter G, Burnett JC Jr. Expert Opin Investig Drugs 2004;13(6):643–52. Copyright © 2004.
Informa Healthcare; Rubattu et al. Am J Hypertens 2008;21:733–41; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52
14
 Natriuretic peptides inhibit the activity of the RAAS and
counterbalance the sympathetic nervous system

ANP and BNP inhibit the RAAS ANP interacts with baroreflex control
via actions in the kidneys of the circulation to inhibit the
and the adrenal glands1 activity of the SNS2

ANP/BNP ANP

Modulation of
arterial and
cardiopulmonary
baroreceptors

Inhibition of renin Inhibition of aldosterone

secretion secretion Decrease in SNS outflow

Decrease in BP Decrease in BP

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; BP=blood pressure; NPs=natriuretic peptides;
RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
1. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; 2. Rubattu et al. Am J Hypertens 2008;21:733–41
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 Symptoms and Signs
Clinical manifestations
Tiredness
• Main symptoms Shortness of breath

• Breathlessness Pumping action Coughing

of the heart
• Orthopnea grows weaker Fluid retention
• Paroxysmal Nocturnal Dyspnea
• Reduced exercise tolerance
Pleural effusion
• Fatigue
• Ankle swelling

• Main signs
• Elevated jugular venous pressure Swelling of feet,
• Hepato-jugular reflux ankles, abdomen
and lower back
• Third heart sound area

• Laterally displaced apical impulse

• Cardiac murmur
Pulmonary edema

Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200 McMurray et al. Eur Heart J 2012;33:1787–847
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Pharmacological Treatment

19
 HFrEF management

 Survival rates in chronic HF have improved with the introduction of new therapies 1

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

 However, significant mortality remains – ~50% of patients die within 5 years of diagnosis 6–7
*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%
• ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor  1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med
blocker; HF=heart failure; ARR=absolute risk reduction; HFrEF=heart 1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J
failure with reduced ejection fraction; LVEF=left ventricular ejection Med 1999;341:709-17; 5. Granger et al. Lancet 2003;362:772–66. 6. Yancy et al. Circulation
fraction; MRA=mineralocorticoid receptor antagonist 2013;128:e240–327; 7. Levy et al. N Engl J Med 2002;347:1397–402
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 Landmark trials in patients with HFrEF

SOLVD-T1 (1991) CHARM-Alternative3 (2003) SHIFT5 (2010) PARADIGM-HF7 (2014)

2,569 patients 2,028 patients 6,558 patients 8,442 patients
Key benefits of enalapril (ACEI) Key benefits of candesartan Key benefits of ivabradine Key benefits of (ARNI) vs
vs placebo: (ARB) vs placebo: (If inhibitor) vs placebo: enalapril:
• 16%  all-cause mortality • 23%  CV mortality or HF • 18%  CV death or HF • 20%  CV mortality or
hospitalization hospitalization HF hospitalization

1990s 2000s 2010s

CIBIS-II2 (1999) CHARM-Added4 (2003) EMPHASIS-HF6 (2011)

2,647 patients 2,548 patients 2,737 patients
Key benefits of bisoprolol (BB) Key benefits of Key benefits of eplerenone
vs placebo: candesartan (ARB) vs (MRA) vs placebo:
• 34%  all-cause mortality placebo: • 37%  CV mortality or HF
• 15%  CV mortality or HF hospitalization
hospitalization

Percentages are relative risk reductions vs comparator

ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker;
ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular;
21HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
1. SOLVD Investigators. N Engl J Med 1991;325:293–302
2. CIBIS-II Investigators. Lancet 1999;353:9–13; 3. Granger et al. Lancet 2003;362:772−6
4. McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85
6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–
1004
 Evolution of pharmacologic approaches in HF:
ARNI as a new alternative to an ACEI or ARBs in patients
with HFrEF1
β-blockers
SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
Heart rate
NP system HF SYMPTOMS &
PROGRESSION Contractility
NPRs NPs

Vasodilation RAAS inhibitors

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

 ARNI: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression
ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin;
ARB=angiotensin
receptor blocker; AT 1R=angiotensin II type 1 receptor; HF=heart failure;
HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid
22 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
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
Schrier & Abraham. N Engl J Med 2009;341:577–85
 ARNI Clinical Study :
PARADIGM-HF
Primary objective : to evaluate the effect of LCZ696 200 mg BID compared with enalapril 10 mg BID, in
addition to conventional HFrEF treatment, in delaying time to first occurrence of either CV death or HF
hospitalization1

Chronic HF NYHA FC II–IV with LVEF ≤40%

Randomization
SBP ≥ 100 mmHg at screening
Double-blind
n=8442
Treatment period
Single-blind active
run-in period

LCZ696 200 mg BID‡

Enalapril LCZ696 LCZ696
10 mg BID* 100 mg BID† 200 mg BID‡

Enalapril 10 mg BID§

2 Weeks 1–2 Weeks 2–4 Weeks Median of 27 months’ follow-up

On top of standard HFrEF therapy (excluding ACEIs and ARBs)

*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated
with ARBs or with a low dose of ACEI; †200 mg TDD; ‡400 mg TDD; §20 mg TDD.
23 McMurray et al. Eur J Heart Fail. 2013;15:1062–73; McMurray et al. Eur J Heart Fail. 2014;16:817–25;
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Disclaimer : LCZ696 has not yet been marketed in Indonesia
Recommended by Guidelines
as Part of Standard of Care1,2

ACE inhibitor
and β blocker
Ivabradine
MR antagonist Symptomatic
LVEF ≤ 35%
Symptomatic
sinus rhythm*
LVEF ≤ 35%

*HR≥70 bpm

1. Ponikowski P et al. Eur Heart J. 2016; 37, 2129–2200. 2. Yancy CW et al. J Am Coll Cardiol. 2016;68(13):1476-1488.
  Ivabradine
• Specific Inhibitor of the If current in the Sinoatrial Node

• Decreases resting heart rate

• Unlike β-Blockers, no other channels are affected (decreased risk of side effects)

27
 RAPIDLY Reduces
rehospitalizations1
Cumulative Incidence of all cause hospitalization following
first hospitalization for heart failure

Standard Therapy
(ß-blocker + ACE inhibitor + MR antagonist)

+ Ivabradine

28
1. Komajda M et al. Eur J Heart Fail. 2016. doi: 10.1002/ejhf.582.
(Ponikowski P. et al, EHJ 2016)
 2016 ESC Guideline
Therapy for HFpEF (preserved EF)

No treatment has yet been

shown, convincingly, to
reduce morbidity or mortality in
patients with HFpEF or HFmrEF.

However, since these patients

are often elderly and highly
symptomatic, and often have a
poor quality of life, an important
aim of therapy may be to
alleviate symptoms and
improve well-being.
. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200

31
2016 ACC/AHA/HFSA Focused Update on New
Pharmacological Therapy for Heart Failure (1)

Recommendations for Renin-Angiotensin System Inhibition

With ACEi / ARB / ARNI
COR LOE Recomendation
I ACEi : A The use of ACE inhibitors is beneficial for patients with prior or current
symptoms of chronic HFrEF to reduce morbidity and mortality
I ARB : A The use of ARBs to reduce morbidity and mortality is recommended in patients
with prior or current symptoms of chronic HFrEF who are intolerant to ACE
inhibitors because of cough or angioedema
I ARNI : B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an
ACE inhibitor or ARB, replacement by an ARNI is recommended to further
reduce morbidity and mortality
Notes • ARNI should not be administered concomitantly with ACE inhibitors or within
36 hours of the last dose of an ACE inhibitor (III : Harm, B-R)
• ARNI should not be administered to patients with a history of angioedema (III
Harm, C-EO)

Yancy et al. Circulation 2016;134(13): e282–293 34

2016 ACC/AHA/HFSA Focused Update on New
Pharmacological Therapy for Heart Failure (2)

Recommendation for Ivabradine

COR LOE Recomendation
IIa Ivabradine : B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with
symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who
are receiving GDEM, including a beta blocker at maximum tolerated
dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater
at rest

Yancy et al. Circulation 2016;134(13): e282–293 35

 Chronic Heart Failure

Optimize HF treatment
(DIURETIC, ACE-I/ARB, B-BLOCKER,
MRA)
Toleransi ACE-I/ARB  replace
ARNI
Symptomatic, EF ≤ 35% :
Clinical judgement SR, QRSd ≥ 130 ms  +/- CRT

SR, HR ≥ 70 ms  +IVABRADINE
Summary
• HF has a complex pathophysiology involving activation of two key
neurohormonal systems:
• Renin–angiotensin–aldosterone system
• Sympathetic nervous system

• Secretion of NPs results in a number of physiological responses that act to

reduce the symptoms and progression of HF via inhibition of the RAAS
and SNS activation
• As HF advances, excessive activation of the SNS and the RAAS occurs
leading to cardiac stress and overcomes any benefits of NPs, leading to
a neurohormonal imbalance
• Natriuretic peptides counteract the detrimental effects of RAAS and SNS
activation.
• Multiple pharmacological agent are useful in improving mortality and
morbidity.
• Among them, ARNI was superior to ACEi in reducing the risks of death
and of hospitalization for heart failure
37
NEW HOPE FOR HEART FAILURE TREATMENT

ARNI
Angiotensi Receptor Neprylisin Inhibitor

38
THANK YOU
Case Discussion

• Laki2 umur 46 th, riwayat ACS dan PCI 2stent th

2015.
• Sejak awal 2016 r.inap berulang 7kali dlm
setahun sd awal 2017.
• EKG : SR,rate 96/mnt,LVH (+)
• Xfoto CTR 65%, tanda bendungan (+)
• Th/ Ramipril 5mg,Furosemide 2x1 tab,
Spironolactone 25mg,Bisoprolol 1,25mg

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Case Discussion

• Saran anda:

a. Tambah ISDN x5mg

b. Optimalkan dosis obat yg sdh ada
c. Ganti Ramipril dg ARNI
d. Tambah Ivabradine
e. Tambah digoxin

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3bln kemudian ps masuk lagi dg gejala kongesti dan
debar2
Ternyata AF disertai kongesti

• Pilihan obatnya:
a. Bisoprolol ganti digoxin
b. Tambahkan Ivabradine
c. Ramipril ganti dg ARNI
d. Kirim untuk pasang CRT

42