Angiotensin Receptor Neprilysin Inhibitor dalam

Tata Laksana Gagal Jantung

(Paradigm HF trial)

Syafrudin Tamar
 Pengertian Gagal Jantung (Heart Failure )
ESC / European Society of Cardiology (2016)
• HF adalah sindrom klinis yang ditandai dengan gejala khas ,disertai tanda-tanda yang
disebabkan oleh kelainan jantung struktural dan/atau fungsional, yang mengakibatkan
berkurangnya curah jantung dan/atau tekanan intrakardiak yang tinggi saat istirahat
atau stress

ACCF/ AHA : The American College of Cardiology Foundation / American Heart

Association (2013 )
•
HF adalah sindrom klinis kompleks yang dihasilkan dari gangguan struktural atau
fungsional pada pengisian ventrikel atau pengeluaran darah dari jantung.
 HFrEF and HFpEF

Heart failure definition

Systolic dysfunction Diastolic dysfunction

HFrEF HFmEF HFpEF

LVEF≤ 40% LVEF 40-49% LVEF ≥ 50%

Echocardiography is a useful method for evaluating left ventricular ejection fraction

HFpEF: heart failure with preserved ejection fraction, HFmEF : heart failure with mid-range ejection frection
Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200; McMurray et al. Eur Heart J 2012;33:1787–847;
Dickstein et al. Eur Heart J 2008;29:2388–442
3
Prevalensi Heart Failure
Gagal jantung (HF) di Amerika Serikat (2011)

• 37,7 juta orang secara global

• 5,7 juta orang hidup dengan HF dan 870.000 kasus baru didiagnosis setiap tahun.

Prevalensi penyakit jantung di Indonesia (2007)

• 7,2 persen atau 7 dari 100 orang menderita penyakit jantung berdasarkan diagnosis.

American Heart Association (2002 )

• 10 dari setiap 1.000 orang berusia di atas 65 tahun di Amerika Serikat menderita HF

Global Burden of Disease Study (2013)

• 17,3 juta orang meninggal karena penyebab kardiovaskular pada tahun 2013
 However, significant mortality remains ~50% of patients die within 5 years of diagnosis,
worse than cancer patients

50% of patient is dead in 5 years after diagnosis

https://www.tctmd.com/news/hf-survival-rates-worse-those-common-cancers-including-bladder-and-breast-cancer 5
 Patients with NYHA class II (so called “stable HF”) are at
high risk of sudden death

70 NYHA class II:

Mode of CV death
Death (%)

60
64 N=791
59
56
50

Other CV death *
40 28.2%

33 Sudden death
30 44.8%
26
24
20

15
10 12 11

Worsening HF
0 27.1%
NYHA II NYHA III NYHA IV

Sudden death Worsening HF Other*

*Other death includes all CV deaths not ascribed to *Other CV death includes all CV deaths not ascribed to
WHF or sudden death pump failure or sudden death
A post-hoc analysis from MERIT-HF An analysis from PARADIGM-HF
(n=3,991)1 (n=8,399)2
Mean follow up, 1 year Median follow up, 2.3 years

1. MERIT-HF Study Group. Lancet. 1999;353(9169):2001–7; 2. Desai et al. Eur Heart J. 2015;36:1990–7

6
 Penyebab Gagal Jantung
• Penyakit Arteri Koroner
• Infark miokardium
• Hipertensi
• Kerusakan katup jantung
• Cardiomiopati
• Lung Disease
• Diabetes
• Infeksi
• Alcohol
• Penyakit jantung congenital
• Obat –obatan
 Neuroendocrine Imbalance in
Heart Failure
Growth-promoting:
Sympathetic activation
NP Angiotensin (AT1 receptor)
Aldosterone
Endothelin
Arginine Vasopressin

Anti-proliferative substances:
Natriuretic peptides SNS
Bradykinin RAAS
Nitric oxide
Adrenomedullin

8
 Current HF treatment paradigm :
Restoring the balance of neurohormonal system

SNS
NP system
RAAS

9
 Difficulties in Diagnosing HF

Heart
Failure
Pulmonary Deconditioning
disease

Multiple
Normal Other
aging
 HEART FAILURE  CLINICAL SYNDROME
symptom
• breathlessness
• ankle swelling
• fatigue

sign
• elevated jugular venous pressure
• pulmonary crackles
• peripheral oedema

caused by structural and/or functional cardiac abnormality, resulting in reduced

cardiac output and/or elevated intracardiac pressures at rest or during stress

12
 Essential Initial Investigation
natriuretic peptides (NPs)
• for ruling out HF (not to establish diagnosis)
• normal B-type natriuretic peptide (BNP) : 35 pg/mL
• normal N-terminal pro-BNP (NT-proBNP) : 125 pg/mL

ECG
• depends on aetiology

Echocardiography
• chamber volumes
• ventricular systolic and diastolic function
• wall thickness
• valve function
• pulmonary hypertension 13
14
2016 ESC Guideline
Therapeutic algorithm for symptomatic HFrEF

ARNI as a new alternative to an ACEI or ARBs

in patients with HFrEF

. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin
receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT = cardiac resynchronization therapy;
HF = heart failure; HFrEF = heart failure with reduced ejection fraction; H-ISDN = hydralazine and
isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter defibrillator; LBBB = left bundle
branch block; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR =
mineralocorticoid receptor; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York
Heart Association; OMT = optimal medical therapy; VF = ventricular fibrillation; VT = ventricular
tachycardia.

15
 2016 ACC/AHA/HFSA
Focused Update on New Pharmacological Therapy for Heart Failure
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)

ARNI as replacement / substitute for ACEI or ARB in patients with HFrEF

Yancy et al. Circulation 2016;134(13): e282–293 16

 Landmark trials in patients with HFrEF
CHARM-Alternative
CHARM-Alternative33 (2003)
(2003) SHIFT
SHIFT55 (2010)
(2010) PARADIGM-HF
PARADIGM-HF77 (2014)
(2014)
SOLVD-T
SOLVD-T (1991)
11
(1991) 6,558
2,028
2,028 patients
patients 6,558 patients
patients 8,442
8,442 patients
patients
2,569
2,569 patients
patients Key
Key
Key benefits
benefits of
of candesartan
candesartan (ARB)
(ARB) vs
vs Key benefits
benefits of
of ivabradine
ivabradine Key
Key benefits
benefits of
of LCZ696
LCZ696 (ARNI)
(ARNI) vs
vs
Key
Key benefits
benefits of
of enalapril
enalapril (ACEI)
(ACEI) vs
vs (I(Iff inhibitor)
placebo:
placebo: inhibitor) vs
vs placebo:
placebo: enalapril:
enalapril:
placebo:
placebo: •• 23% •• 20%
•• 16% 23%  CV
CV mortality
mortality or
or HF
HF •• 18%18%   CV
CV mortality
mortality or
or HF
HF 20%  CV
CV mortality
mortality or
or HF
HF
16% 
 all-cause
all-cause mortality
mortality hospitalization
hospitalization hospitalization hospitalization
hospitalization
hospitalization

1990s
1990s 2000s
2000s 2010s
2010s

CIBIS-II
CIBIS-II22 (1999)
(1999)
2,647
2,647 patients
patients
CHARM-Added
CHARM-Added44 (2003)
(2003) EMPHASIS-HF
EMPHASIS-HF66 (2014)
(2014)
Key
Key benefits
benefits of
of bisoprolol
bisoprolol (BB)
(BB) vs
vs 2,548
2,548 patients
patients 2,737
2,737 patients
patients
placebo: Key
Key benefits
benefits of
of candesartan
candesartan (ARB)
(ARB) vs
vs Key
Key benefits
benefits of
of eplerenone
eplerenone (MRA)
(MRA) vs
vs
placebo:
•• 34% placebo: placebo:
34% 
 all-cause
all-cause mortality
mortality placebo: placebo:
•• 15%
15% 
 CV
CV mortality
mortality or
or HF
HF hospitalization
hospitalization •• 37%
37% 
 CV
CV mortality
mortality or
or HF
HF hospitalization
hospitalization

Percentages are relative risk reductions vs comparator ACEIs β-blockers

ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor neprilysin inhibitor; BB: beta
blocker; CV: cardiovascular; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; MRA: mineralocorticoid receptor ARBs Ivabradine
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;362:767–71; 5. Swedberg et al. Lancet 2010;376:875–85;
MRAs LCZ696
6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004
 Drugs That Reduce Mortality in Heart Failure
With Reduced Ejection Fraction
Angiotensin Mineralocorticoid
receptor ACE Beta receptor
blocker inhibitor blocker antagonist
0%
% Decrease in Mortality

10%

20%
Drugs that inhibit the renin-
30% angiotensin system have
modest effects on survival

40%
Based on results of SOLVD-Treatment, CHARM-Alternative,
COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF
 Natriuretic peptides have potential beneficial actions in HF

Release of ANP and BNP from heart and CNP in vasculature1,2

1,2

 Sympathetic outflow22
 Vasopressin22 ANP/BNP2
 Salt appetite and water intake22
CNP
(endothelium)3

Relaxation;  arterial stiffness4

 Hypertrophy2,2, 44
 Fibroblast proliferation4,4,

 Na++/H22O loss22
Vasodilation2,3,4
2,3,4

 Aldosterone22  Systemic vascular resistance44

 Renin22  Pulmonary artery pressure44
 Pulmonary capillary wedge pressure44
 Right atrial pressure55

ANP=atrial natriuretic peptide; 1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Levin et al. N Engl J Med 1998;339;321–8;
BNP=B-type natriuretic peptide; 3. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 4. Langenickel and Dole. Drug Discov Today: 5. Marcus et al.,
CNP=C-type natriuretic peptide; HF=heart failure Circulation 1996; 94: 3184-89.
 Neurohormonal Inbalance in HF
Natriuretic peptide counter overactivation of SNS and RAAS system

Renovascular pathway
CNS Pathway
+ ↑ Renal renin
↓ CNS inhibitory, vagal
↑ Intravascular ang II
↑ CNS excitatory, Sympathetic
↑ Adrenal aldosterol

+ +
Systemic vasoconstriction and increased renal NA+
reabsorption and water retention

Inactive
Neprilysin
Stimulation of synthesis and secretion of NP by
fragment atrial and ventricular cardiomyocites

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

20
 ARNI novel mechanism :
block RAAS pathway and delay NP degradation

ACEi/ARB
Beta Renovascular pathway
CNS Pathway MRA
Blocker + ↑ Renal renin
↓ CNS inhibitory, vagal
↑ Intravascular ang II
↑ CNS excitatory, Sympathetic ARNI
↑ Adrenal aldosterol

+ +
Systemic vasoconstriction and increased renal NA+
reabsorption and water retention

ARNI
Neprilysin
Inactive Stimulation of synthesis and secretion of NP by atrial and
fragment ventricular cardiomyocites

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
21
ARNI Pivotal Study : PARADIGM-HF
 PARADIGM-HF: the most geographically diverse trial in patients with HFrEF
•• 8,442
8,442 patients
patients were
were randomized
randomized at
at 985
985 sites
sites in
in 47
47 countries
countries1,2
1,2

ACEI: angiotensin-converting-enzyme inhibitor; ARNI: angiotensin receptor neprilysin inhibitor; HFrEF: heart failure with reduced ejection fraction; PARADIGM-HF: Prospective comparison of ARNI with ACEI to
Determine Impact on Global Mortality and morbidity in Heart Failure
1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. McMurray et al. Eur J Heart Fail 2013;15:1062–73
 ARNI Clinical Trial: 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
Randomization
Chronic HF NYHA FC II–IV with LVEF ≤40%
n=8442 Double-blind
SBP ≥ 100 mmHg at screening
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.
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.
 PARADIGM-HF: key inclusion criteria
• Chronic HF NYHA FC II–IV with LVEF ≤40%*

• BNP (or NT-proBNP) levels as follows:

– ≥150 (or ≥600 pg/mL), or
– ≥100 (or ≥400 pg/mL) and a hospitalization for HFrEF within the last 12 months

• ≥4 weeks’ stable treatment with an ACEI or an ARB#, and a β-blocker

• Aldosterone antagonist should be considered for all patients (with treatment with a stable
dose for ≥4 weeks, if given)

*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment; #Dosage equivalent to enalapril ≥10 mg/day
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor neprilysin inhibitor; BNP: B-type natriuretic peptide; FC: functional class; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; LVEF: left
ventricular ejection fraction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; PARADIGM-HF: Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
 PARADIGM-HF: key exclusion criteria
• History of angioedema
• eGFR <30 mL/min/1.73 m2 at screening, end of enalapril run-in or randomization, or a >35% decrease in eGFR
between screening and end of enalapril run-in or between screening and randomization
• Serum potassium >5.2 mmol/L at screening OR >5.4 mmol/L at the end of the enalapril run-in or end of the
LCZ696 run-in
• Requirement for treatment with both ACEI and ARBs
• Symptomatic hypotension, SBP <100 mmHg at screening, OR SBP <95 mmHg at end of enalapril
run-in or at randomization
• Current acute decompensated HF
• History of severe pulmonary disease
• Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major CV surgery, PCI, or
carotid angioplasty within the 3 months prior to screening

ACEI: angiotensin-converting-enzyme inhibitor; ARNI: angiotensin receptor neprilysin inhibitor; ARB: angiotensin receptor blocker; CV: cardiovascular; eGFR: estimated glomerular filtration rate; HF: heart failure;
PARADIGM-HF: Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; PCI: percutaneous coronary intervention; SBP: systolic blood pressure
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
 Sacubitril/valsartan significantly reduced composite end point :
CV death / first hospitalization for HF*

0.4
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
0.3
Cumulative probability

0.2

0.1 p 0.00000004
HR: 0.80
20
RELATIVE RISK REDUCTION
OF PRIMARY ENDPOINT
%
(95 % CI: 0.73–0.87)
ARR: 4.7 %

0
No. at risk
6 12 18 24 30 36 42
Sacubitril/ Months since randomization
valsartan
4,187 3,922 3,663 3,018 2,257 1,544 896 249
Enalapril
4,212 3,883 3,579 2,922 2,123 1,488 853 236

*Compared with enalapril, as assessed via time until cardiovascular death or first hospitalization for HF.1 ‡Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of
standard therapy). §27 months since randomization (median)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
 Sacubitril/valsartan significantly reduced all-cause mortality*

0.3
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)

16
Cumulative probability

0.2 %
RELATIVE RISK REDUCTION
OF ALL-CAUSE MORTALITY
0.1
p<0.01
HR: 0.84
(95 % CI: 0.76–0.93)
ARR: 2.8  %

0
No. at risk 6 12 18 24 30 36 42
Sacubitril/ Months since randomization
valsartan 4,187 4,056 3,891 3,282 2,478 1,716 1,005 280
Enalapril 4,212 4,051 3,860 3,231 2,410 1,726 994 279
*Time to all-cause death. ‡Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy).
§
27 months since randomization (median)
ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
 PARADIGM-HF: the largest mortality-morbidity
trial in patients with HFrEF

10,000
9,000 N=8442
8,000
Number of patients

7,000 N=6505
6,000
5,000
4,000 N=3834

3,000 N=2569 N=2548 N=2737

N=1798
2,000
1,000
0
SOLVD-T CHARM-Added HEAAL RAFT SHIFT EMPHASIS-HF PARADIGM-HF

Recruitment 1986–1989 1999–2001 2001–2005 2003–2009 2006–2009 2006–2010 2009–2013

CHARM-Added, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Added trial; EMPHASIS-HF, Eplerenone in Mild Patients
Hospitalization And Survival study in Heart Failure; HEAAL, Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan; HFrEF, heart failure with reduced
McMurray et al. Eur J Heart Fail 2014;16:817–25 ejection fraction; RAFT, Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; SHIFT, Systolic Heart Failure Treatment with the If Inhibitor Ivabradine
Trial; SOLVD-T, Studies of Left Ventricular Dysfunction Treatment trial
 Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on
Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin
System
Angiotensin Angiotensin
receptor ACE neprilysin
blocker inhibitor inhibition
0%
% Decrease in Mortality

15% 18%
10%

20%
20%
30%

40% Effect of ARB vs placebo derived from CHARM-Alternative trial

Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
Sacubitril/valsartan reduced the frequency and severity of hospitalizations compared to
enalapril*

30
FEWER VISITS
%
18
FEWER STAYS
%
12
LOWER RISK
%
TO THE EMERGENCY UNIT IN INTENSIVE CARE UNITS OF ALL-CAUSE
FOR HEART FAILURE HOSPITALIZATION

p=0.017 p=0.005 p<0.001

*Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy).
Packer et al. Circulation 2015;131:54–61
 Treatment with Sacubitril Valsartan resulted in a lower likelihood of multiple
hospitalizations for HF

HR 0.79
Sacubitril Valsartan (N=4,187)
(95% CI: 0.71–0.89)
p<0.001 Enalapril (N=4,212)

29% fewer HFrEF patients were hospitalized

Proportion of patients (%)

more than once for HF with Sacubitril Valsartan

p<0.001 than with enalapril (n=170 and n=240
respectively; p=0.001)

p<0.001

p<0.001
p<0.001

n=537 n=658 n=367 n=418 n=110 n=143 n=33 n=53 n=27 n=44
Total number of patients 1 2 3 ≥4
hospitalized for HF once
and multiple times
Number of admissions for HF

CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio
Packer et al. Circulation 2015;131:54–61
 Sacubitril Valsartan has a safety and tolerability profile comparable to that of enalapril

Four most frequently reported adverse reactions and incidence of angioedema in PARADIGM-HF

Sacubitril Valsartan (N=4,187)

p=0.15 Enalapril* (N=4,212)
20
17.3
p<0.001 16.1 p<0.001
14.3
Proportion of adverse events (%)

15 14.0
11.3
10 9.2
p=0.07

5 4.5
3.3 p=0.19
0.2 0.1
0
Cough Renal impairment‡ Hyperkalemia§ Symptomatic Angioedema¶
hypotension
*Enalapril 10 mg 2x daily as comparator vs Sacubitril Valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy);
‡
Elevated serum creatinine ≥2,5 mg/dL; §Elevated serum potassium >5,5 mmol/l; ¶Angioedema with no treatment or use of antihistamines only
McMurray et al. N Engl J Med 2014;371:993–1004
 Sacubitril Valsartan had fewer adverse events leading to permanent study drug discontinuation 1

Sacubitril Valsartan (N=4,187)

Enalapril* (N=4,212)
15 p=0.03
Therapy discontinuation (%)

12.3 Hypotension occurs, but did not make

10.7 patient stop the therapy  manageable,
10 reduce diuretic dose

5 p=0.38 p=0.002 p=0.56

0.9 0.7 0.7 1.4

0.3 0.4
0
Any adverse event Hypotension Renal impairment Hyperkalemia

76% of patients remained on the target dose of Sacubitril Valsartan (200 mg 2x daily) until the end of
the study2
*Enalapril 10 mg 2x daily as comparator vs Sacubitril Valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy)
1. McMurray et al. N Engl J Med 2014;371:993–1004; 2. Packer et al. Circulation 2015;131:54–61
Effect of ARNI on Physical and social limitations
 Sacubitril/valsartan makes you (feel) younger!
Patient QoL score after using Sacubitril Valsartan is as good as patient with 9 year old
younger
 Sacubitril Valsartan significantly improve
Quality of life vs Enalapril
Change from baseline to 8 months: Difference* between sacubitril/valsartan and
enalapril
2.5

P change score 0.59 0.15 0.10 0.029 0.027 0.042 0.007 0.001 <0.001 0.002
difference
2
Adjusted change score

1.5

0.5

0
i ps
s k ily g d s s h
ing
1 2 3 4 5 6 7 8 9 10
ing ir
blo
c in
ya
r ie r e s
e ss
wer sta 1 fa m
o gg in o bb cho
t ion
r o i n g g g / j g h ld l a
D in g e
Sh im
b
lk in
is it
ry in
r ki n in g
e ho
a l r
l a V r o Do s xu
C W Hu W o u e
H S
*All analyses were adjusted for baseline
mean score of each respective activity.
 Kesimpulan

HF mempunyai pathofisiologi yg komplek, melibatkan aktifasi 3 sistim neurohormonal: RAAS;

SNS dan NP.

Meskipun beta bloker RAAS bloker sudah digunakan secara luas, outcome dari HFrEF tetap
masih rendah, 50% penderita HF meninggal dalam 5 tahun.

Dengan meningkatkan NP, telah menjadi pendekatan terapi baru HF, dimana ARNI menjadi
pilihan yg bekerja meningkatkan kenerja NP dan menghambat RAAS yg berdampak
menurunkan mortalitas dan rawat inap berulang, sehingga ARNI direkomendasikan sebagai
class I-B untuk menggantikan ACEi/ARB pada pasien symptomatik HFrEF.

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 Kesimpulan

PARADIGM-HF dihentikan lebih awal karena temuan kuat bahwa Sacubitril Valsartan lebih unggul
dari Enalapril : Menurunkan 20% angka kematian akibat CV dan menurunkan frekuensi dan
lamanya rawat inap pasien HF serta aman dengan toleransi baik.

ARNI (Sacubitril Valsartan) menghambat degradasi NP oleh neprilisin bersamaan memblokir

AT1R, mengembalikan keseimbangan sistem neurohormonal

ACEi / ARB dan beta blocker adalah rekomendasi lini pertama untuk HFrEF.

Sacubitril Valsartan direkomendasikan (kelas I) dengan pedoman untuk menggantikan ACEi / ARB
pada pasien HFrEF simptomatik

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Terimakasih

43
Heart Failure with
Preserved Ejection
Fraction
presence of symptoms and/or signs of HF

preserved EF

• LVEF ≥50%

elevated NPs

• BNP >35 pg/mL and/or NT-proBNP >125 pg/mL)

cardiac functional and structural alterations

• left atrial volume index (LAVI) >34 mL/m 2

• left ventricular mass index (LVMI) ≥115 g/m 2 (males) and ≥95
g/m2 (females)
• E/e’ ≥13
• mean e’ septal and lateral wall <9 cm/s

stress test or invasively measured elevated LV

filling pressure
44