Up-date

Manajemen Terapi
Gagal Jantung

Hasanah Mumpuni
KSM Jantung / Dep. Kardiologi dann Kedokteran Vaskular
RSUP Dr. Sardjito / FK-KMK UGM

HISFARSI - Maret 2022

ISI
• Pendahuluan Isi
• Diagnosis Gagal Jantung
• Tata laksana Gagal Jantung
- Tujuan
- Strategi
- Up date terapi Gagal Jantung
• Study pendukung
 HF patients are at very high risk of death and hospitalisation
Nearly one-third of patients Each hHF increases
with HFrEF are at high risk the risk of mortality further 3,b
of hospitalisation or CV death,
including those who appear stable2

9 10 out of
PATIENTS
32% of
patients

are symptomatic,
even with current
HF SoC1,a
Patients with hHF/CV death
Patients event free

Based on NYHA classification over

a 4-year period, from the 2004 CHARM study
• aBased on a prospective observational study of 3494 US outpatients with chronic HFrEF in the CHAMP-HF registry; bBased on a retrospective analysis of 51,286 patients from a US Military Data Repository admitted to a healthcare facility for the f irst time for heart failure. During the 7-year study period (2007–2013),
patients were assessed for subsequent hHF, comorbidities, and mortality data. No distinction was made between patients with reduced or preserved ejection fraction

• CV, cardiovascular; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hHF, hospitalisation for heart failure; NYHA, New York Heart Association; SoC, standard of care
1. Khariton Y, et al. JACC Heart Fail 2018:6;465–473; 2. Young JB, et al. Circulation 2004;110:26182626; 3. Lin AH, et al. Mil Med 2017;182:e1932–e1937
 Pendahuluan
Heart failure leads
HF merupakan salah to
satufrequent hospitalizations
terbanyak yang dirawat di RS pada usia >65 years (
diikuti pneumonia, cancer, cerebro vascular disease, dan CAD) 1

• Di Eropa hampir 44% pasien HF readmisi dalam 1 th

• Di USA, re-admissionrates >25% dalam 30 hari 2
• Di Eropa , re-admission rates 24% dalam 12 mgg 2

• Length of stay perawatan HF  5–10 hari

• Registry HF RS Sardjito (2019), Dari 1493 psn:

 42 % ( > 60 th); Kematian pasien rawat inap 8.8 % ; Rehospitalisasi 44 %
• Registry POKJA HF PERKI (2019):
 Kematian di RS th 17,2%, Rehospitalisasi 17 %, kematian dlm 1 th 11,3 %

HF, heart failure 1. Bui et al. Nat Rev Cardiol 2011;8:30–41; 2. Powie et al. ESC Heart Failure 2014; 1: 110–145;
4
Re-hospitalization Risk Among Patients Hospitalized For
Heart Failure
Stabilization
Chronic
Heart failure and post-
heart
hospitalization discharge
failure
period
Re-admission rate

Transition
phase
Approximately 25% of patients will
Plateau be readmitted to hospital within
phase
30 days after discharge1

Median time from hospital discharge

• Red indicates period of highest risk for readmission: Mortality during this 30-day period can
immediately after discharge and just before death reach up to 10%1
• Yellow indicates lower risk (plateau phase)
Picture from: Desai AS and Stevenson LW. Circulation 2012;126(4):501-6
• Green indicates baseline (unavoidable readmission) 1. Greene et al. Nat Rev Cardiol 2015;12:220–29
 Referensi Protocol HF di Indonesian

2021 Update to the 2017

Expert Consensus Decision Pedoman Tatalaksana Gagal
ESC HFA CONSENSUS UPDATE Pathway - ACC Jantung PERKI 2020
2021
 Definisi - HF
• Perubahan dari struktur atau fungsi jantung yang menyebabkan kegagalan
dari jantung untuk mendistribusikan oksigen ke seluruh tubuh.

Gejala Tanda
Tipikal Spesifik
Breathlessness Elevated jugular venous pressure
Orthopnea Hepatojugular reflux
Paroxysmal nocturnal dyspnoea Third heart sound (gallop rhythm)
Reduced exercise tolerance Laterally displaced apical impulse
Fatigue, tiredness, increased time to recover after
exercise
Ankle swelling
Gejala dan Tanda Gejala Tanda
lain – Kurang Kurang tipikal Kurang spesifik
spesifik Nocturnal cough Weight gain (>2kg/week) Cheyne-Stokes
respiration
Wheezing Weight loss (in advanced HF) Hepatomegaly
Bloated feeling Tissue wasting (cachexia) Ascites
Loss of appetite Cardiac murmur Cold extremities
Confusion ( in the Peripheral oedema (ankle, Oliguria
elderly) sacral, scrotal)
Depression Pulmonary crepitations Narrow pulse
pressure
Palpitation Pleural effusion
Dizziness Tachycardia
Syncope Irregular pulse
Bendopnea Tachyopnea
Pemeriksaan
Penunjang
Diagnosis
Pembagian HF
 Klasifikasi HF
ACCF/AHA Stages of HF NYHA Functional Classification
At high risk for HF but without structural
A None
heart disease or symptoms of HF.
Structural heart disease but without No limitation of physical activity. Ordinary physical
B I
signs or symptoms of HF. activity does not cause symptoms of HF.
No limitation of physical activity. Ordinary physical
I
activity does not cause symptoms of HF.
Structural heart disease with prior or
C Slight limitation of physical activity. Comfortable at
current symptoms of HF.
II rest, but ordinary physical activity results in
symptoms of HF.
Marked limitation of physical activity. Comfortable
Refractory HF requiring specialized III at rest, but less than ordinary activity causes
D interventions. symptoms of HF.
. Unable to carry on any physical activity without
IV
symptoms of HF, or symptoms of HF at rest.
 

Tujuan 
Managemen 
HF 
Non-Pharmacological Management

LOW SALT WEIGHT EXERCISE DAILY WEIGHT

INTAKE REDUCTION

EDUCATION SELF- NURSE ADVICE

MANAGEMENT
Pharmacological
Management

Prognosis Symptoms
• ACE Inhibitors • Diuretics
• B Blockers • Mineralcorticoid
• Mineralcorticoid Receptor Antagonists (MRA) • Digoxin
• AIIRB • Hydralazine / Nitrates
• ARNI • Ivabradin
• SGL2 Inhibitor
 Device / Surgical Management
Devices Surgery
• Simple Pacemakers • Valve repair /replacement
• Biventricular Pacemakers • Revascularisation
• Defibrillators • Volume reduction
• Balloon pumps • surgery
• LV assist devices • Transplantation
 Pharmacological treatment of HF in Asian Countries
Pharmacological treatment of HF in some countries or Pharmacological treatment shows mortality
region1 reduction in HF patient2

Pharmacological treatment of HF Indonesia Malaysia Singapore Europe

RAAS inhibitor 78% 67% 74% 89%

β – blocker 32% 72% 65% 87%

Calcium channel blocker - 17% - 10%

Ivabradine - - - -

Diuretic 78% 99% 87% 83%

Digoxin 21% 44% 27% 21%

Lipid-lowering agent - 76% 72% 54%

Anticoagulant - 25% 12% 43%

may leads to
Suboptimal treatment Clinical Inertia

• 1. Reyes, E. B., Ha, J. W., Firdaus, I., Ghazi, A. M., Phrommintikul, A., Sim, D., Vu, Q. N., Siu, C. W., Yin, W. H., & Cowie, M. R. (2016). Heart failure across Asia: Same healthcare burden but differences in organization of care. International
journal of cardiology, 223, 163–167. https://doi.org/10.1016/j.ijcard.2016.07.256 ; 2. R.R.Baliga, William T.Abraham. Color Atlas and Synopsis of Heart Failure. McGraw-Hill Education
Patofisiologi & Pengaruh Obat obatan pada HF

RAAS

Sympatetic NS
RENIN
activation
 ARNI: Angiotensin-Receptor blockade and Neprilysin Inhibition
β-blockers
SNS
Epinephrine α 1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
Vasodilation
RAAS inhibitors
Blood pressure
(ACEI, ARB, MRA)
Sympathetic tone
Natriuresis/diuresis
RAAS
Vasopressin
Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
ARNI Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
ARNI simultaneously enhances the beneficial effects of NP system, while suppress negative effects of RAAS
• 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; SN=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
Management

ESC 2021
Rekomendasi Farmakologi HFrEF
ESC 2021
 2021 ESC HF Guidelines recommendations for
the management of patients with HF

Management of patients with HF 1

• Sacubitril/valsartan is recommended as the first-line pharmacological treatment for all patients with HFrEF to reduce mortality and the risk
for HF hospitalization including patients previously not treated with ACEi/ARB (i.e. de novo HF) and to replace ACEi in patients who remain
symptomatic
– Initiation of sacubitril/valsartan in recently hospitalized stable patients with HFrEF is safe and may be considered

• SGLT2i, dapagliflozin or empagliflozin, are recommended as add-on therapy for all patients with HFrEF already treated with an ACEi/ARNI,
a BB, and an MRA to reduce the risk of CV death and worsening HF, regardless of whether or not they have diabetes

• ARB is recommended in symptomatic patients who are unable to tolerate an ACEi/ARNI (patients should also receive a BB and an MRA)

• In addition, sacubitril/valsartan is recognized as a treatment option in HFmrEF patients (LVEF 41–49%) and mentioned as a potential option
for HFpEF patients, although without a formal recommendation

• Diuretics are recommended in patients with HF and congestion (Class I recommendation for HFrEF, HFmrEF and HFpEF)

• Other new drugs that may be considered in selected patients with HFrEF: vericiguat and omecamtiv mecarbil (currently not licensed)

• Tailored treatment for patients with HFrEF based on their phenotypes: QRS duration and morphology, etiology (ischemic/not ischemic),
cardiac rhythm, valvular heart disease, diabetes, iron deficiency, electrolyte abnormalities (hyperkalemia), cancer, amyloidosis and other
2 cardiomyopathies
24 ACEi, angiotensin converting enzyme inhibitors; ARNI, angiotensin receptor blocker neprilysin inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; MRA, mineralocorticoid receptor
4
antagonist; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left-ventricular ejection fraction; QRS, Q, R, and S waves (on a 12-lead electrocardiogram); SGLT2i, sodium-
glucose cotransporter 2 inhibitors
 Algoritma GDMT – ACC Guideline
Untuk pasien dengan kelebihan volume
yang terus menerus, Titrasi Diuretik
NYHA Kelas II-IV

HFrEF Stage C Untuk pasien dg eGFR ≥ 30 mL / menit /

Treatment 1,73 m2, atau kreatinin ≤2.5 mg / dL pada pria antagosis Aldosterone
atau ≤ 2.0 mg / dL pada wanita, atau K+ ≤ 5.0mEq / L, Tambahkan
NYHA Kelas II-IV

ARNI/ACEi/ARB
(ARNI lebih di sarankan)*, Untuk pasien dengan kriteria eGFR yang
DAN beta-blocker berdasarkan † sesuai, atau Tambahkan SGLT2i
bukti ilmiah dengan diuretik sesuai NYHA kelas II-IV
kebutuhan
Untuk pasien kulit hitam bergejala persisten
meskipun ARNI / beta blocker / antagonis aldosteron Hidralazine +
/ SGLT2i, Tambahkan isosorbide dinitrate
NYHA Kelas II-IV

Untuk pasien dengan HR ≥ 70, pada dosis beta

blocker yang dapat ditoleransi secara maksimal Tambahkan Ivabradine
dalam ritme sinus, NYHA Kelas II-III

On the far right column: blue color identifies a Class I therapy from clinical practice guidelines, w hereas orange color indic ates a Class II therapy.
eGFR=estimated glomerular filtration rate; GDMT=Guideline-Directed Medical Therapy; HR=heart rate; NYHA=New York Heart Association; SGLT2i=sodium-glucose cotransporter-2 inhibitor.
*ACEi/ARB should only be considered in patients w ith contraindications, intolerability, or inaccessibility to ARNI.
†Carvedilol, metoprolol succinate, or bisoprolol.

Reference: Maddox TM, Januzzi JL Jr, Allen LA, et al. J Am Coll Cardiol. doi:10.1016/j.jacc.2020.11.022.
 ARNI’s Position as 1st Line Treatment in The 2021 Main International Guideline

2021 ACC ECDP11 2021 ESC HF Guidelines1

ARNI preferred as HFrEF therapy than Recommend ARNI as the cornerstone therapy for HFrEF, either as a substitute
ACEi/ARB for ACEi or in patients without a history of ACEi treatment (naive)

26 ARNI/ACEi/ARB + BB + Diuretics (ACEi/ARNI + BB + MRA) + SGLT2i

 ✓
ESC 2021

✓
 Exercise Rehabilitation

Exercise to Improve :  I A
• Exercise Capacity
• QOL
• Reduce rehospitalization
Multi-professional Diseases Management
HF cardiologist
Perawat HF – klinik / ruangan
Farmasi
Klinik HF
Nutrisionis
Di RS
Cardiac Rehabilitasion
Dokter spesialis lain
Lainnya
Layanan HF di RS Dr. Sardjito

Tim HF Klinik HF Pendukung

• Dr. SpJP • Poli klinik dr spesialis • Registry HF RS
• Perawat • Konsultasi Gizi • “ORION HF” –
Bangsal/poli/intensif • Konsultasi Farmasi aplikasi – jejaring
• Nutrisionis • Rehabilitasi DIY dan sekitarnya
• Farmasi (telemonitor) • Buku Saku
• Rehabilitasi • Konsultasi - WA • Penelitian / publikasi
• Sp. lain
Clinical Trials
ARNI
• PARADIGM-HF trial
• PIONEER-HF and TRANSITION

Ivabradin
• SHIFT (Systolic Heart failure treatment with the I(f) inhibitor
ivabradine Trial)

SGL2 Inhibitor
• Dapaglifozin ( DAPA -HF)
• Implaglifozin (EMPEROR-Reduced trial )
 2021 ESC HF Guidelines recommend sacubitril/valsartan as first-line therapy for all Home

patients with HFrEF Recommendation includes ACEi naive (i.e. de novo) patients with HFrEF References

The guidelines recommend the use of ARNI as a replacement for ACEi in suitable patients who remain symptomatic on ACEi, BB, and
MRA therapies; however, an ARNI may be considered as a first-line therapy instead of an ACEi1

Ambulatory patient with HFrEF Hospitalized stable patient with HFrEF

• The ESC HF guidelines recommend that an ACEi is replaced by ARNI • Evidence based pharmacotherapy should be initiated pre-discharge,
in ambulatory patients with HFrEF, who remain symptomatic and re-evaluated for further optimization 1-2 weeks after discharge
despite optimal treatment. Initiation of ARNI in ACEi-naïve (i.e. de • Initiation of ARNI in recently hospitalized stable patients with
novo) patients with HFrEF may be considered1 HFrEF, including those who are ACEi/ARB naïve, is safe and may be
– In the PARADIGM-HF trial, sacubitril/valsartan (ARNI) was considered in this setting1
shown to be superior to enalapril (ACEi) in reducing HF
– Two studies, PIONEER-HF and TRANSITION, have examined the
hospitalizations, CV mortality, and all-cause mortality in
use of ARNI in hospitalized patients, some of whom had not
patients with ambulatory HFrEF14
been previously treated with ACEi 13,32,33
– Additional benefits of sacubitril/valsartan included an
improvement in symptoms and QOL,14 a reduction in the – Initiation in this setting is safe and reduces subsequent CV
incidence of diabetes requiring insulin treatment,29 and a death or HF hospitalizations by 42% compared to enalapril
reduction in the decline in eGFR, rate of hyperkalemia and (ACEi)13,32,33
loop diuretic requirement16,30,31
32 ACEi, angiotensin converting enzyme inhibitors; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta blocker; CV, cardiovascular; eGFR,
estimated glomerular filtration rate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal pro−B-type
Confidential. For Internal use only natriuretic peptide; QOL, quality of life
 PARADIGM-HF: Executive Summary
Study code CLCZ696B2314
To evaluate the efficacy and safety of sacubitril/valsartan compared with
Aim
ACE inhibitor enalapril on morbidity and mortality in patients with HFrEF

Patients population
8,442 patients with chronic HF NYHA class II–IV and LVEF ≤40% (changed
to ≤35%)
Study design Multicenter, randomized, double-blind, parallel-group, active-controlled study (Phase III)
Follow-up Median: 27 months
Participating countries 985 sites in 47 countries worldwide
Primary endpoint Time to first occurrence of either CV death or HF hospitalization
Key secondary endpoints Effect on CV death, HF hospitalization, all-cause death, and change in KCCQ scores
Sacubitril/valsartan was superior to enalapril in reducing the risk of composite outcome (CV
Result summary
death or HF hospitalization)
Status Completed and results published
NCT01035255
FPFV (or Start of data collection): December 8, 2009
LPLV (or End of data collection): May 21, 2014
Milestones
McMurray et al., Eur J Heart Fail. 2013;15(9):1062-73; ACE=angiotensin-converting enzyme; CV=cardiovascular; FPFV= first patient

http://www.accessdata.fda.gov/drugsatfda_docs/nda/201
Study
McMurray et al., N Engl J Med. 2014;371:993-1004; first visit; HF= heart failure; HFrEF= heart report:
failure with October
reduced ejection
KCCQ= Kansas City Cardiomyopathy Questionnaire; LPLV=last patient last
fraction; 31, 2014
5/207620Orig1s000MedR.pdf; Clinicaltrials.gov: visit; LVEF= left Study publication: August 30, 2014
ventricular ejection
NYHA=New York Heart Association
fraction;
NCT01035255, accessed Nov 2021
 PARADIGM-HF core study results

Primary endpoint Composite primary endpoint

Sacubitril/valsartan secara signifikan mengurangi Sacubitril/valsartan secara signifikan mengurangi kematian Cardiovaskular atau
hospitalisasi pertama akibat HF*
Kematian Cardiovaskular* NNT NNT
0.4 Enalapril‡ (N=4,212)
Enalapril‡ (N=4,212)
0.3
3
X2X Sacubitril/valsartan (N=4,187)
**§* Sacubitril/valsartan (N=4,187)
21 §

Cumulative probability
Cumulative probability

0.3

0.2
0.2

0.1
p<0.001 RELATIVE RISK REDUCTION OF 0.1 p<0.0001 RELATIVE RISK REDUCTION
HR: 0.80 CARDIOVASCULAR MORTALITY HR: 0.80 OF PRIMARY ENDPOINT
(95 % CI: 0.71–0.89) (95 % CI: 0.73–0.87)
ARR: 3.2 % ARR: 4.7 %

0 0
6 12 18 24 30 36 42 6 12 18 24 30 36 42
No. at risk No. at risk
Sacubitril/ Months since randomization Sacubitril/ Months since randomization
valsartan 4,187 4,056 3,891 3,282 2,478 1,716 1,005 280 valsartan 4,187 3,922 3,663 3,018 2,257 1,544 896 249
Enalapril 4,212 4,051 3,860 3,231 2,410 1,726 994 279 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
*Time to cardiovascular 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 in the PARADIGM-HF study (in addition of standard therapy). § 27 months since randomization (median)
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;
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; CV=cardiovascular; HR=hazard ratio NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004 McMurray et al. N Engl J Med 2014;371:993–1004
 Sacubitril/valsartan lebih superior secara signifikan vs. enalapril* dalam
menurunkan mortalitas dan morbiditas

Summary of primary and secondary endpoints of the PARADIGM-HF study

Sacubitril/
Enalapril HR RRR
valsartan p-value NNT
(N=4,212) (95% CI) (%)
(N=4,187)

Primary composite endpoint N (%)

Death from CV causes or first 0.8

914 (21.8) 1,117 (26.5) 20% <0.001 21
hospitalization for worsening of HF (0.73–0.87)

0.8
Death from CV causes 558 (13.3) 693 (16.5) 20% <0.001 31
(0.71–0.89)

0.79
First hospitalization for worsening of HF 537 (12.8) 658 (15.6) 21% <0.001 36
(0.71–0.89)

Secondary endpoints N (%)

0.84
All-cause mortality 711 (17.0) 835 (19.8) 16% <0.001 36
(0.76–0.93)

Change in KCCQ clinical summary score at 1.64

–2.99 ±0.36 –4.65 ±0.36 – 0.001 –
8 months, mean ± SD‡ (0.63–2.65)
0.97
New onset atrial fibrillation§ 84 (3.1) 83 (3.1) – 0.83 –
(0.72–1.31)
0.86
Decline in renal function¶ 94 (2.2) 108 (2.6) – 0.28 –
(0.65–1.13)
*Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy); ‡KCCQ scores range from 0 to 100 –
higher scores indicate fewer symptoms and physical limitations associated with HF; §2,670 patients in the sacubitril/valsartan and 2,638 in the enalapril group who did not have atrial
fibrillation at randomization were evaluated; ¶Defined as: (a) ≥ 50% decline in eGFR from randomization; (b) > 30 mL/min/1.73 m 2 decline in eGFR from randomization or to a value
of <60 ml/min/1.73 m 2, or (c) progression to end-stage renal disease.
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; CV=cardiovascular; eGFR=estimated glomerular filtration rate; HF=heart failure;
HR=Hazard Ratio; KCCQ=Kansas City Cardiomyopathy Questionnaire; RRR=relative risk reduction; SD=standard deviation
McMurray et al. N Engl J Med 2014;371:993–1004
 TRANSITION: Executive Summary
Study code CLCZ696B2401
To explore two modalities of treatment initiation (Pre-discharge, and Post-discharge) with sacubitril/valsartan in patients with
Aim HFrEF following stabilization after an ADHF episode
Randomized 1,002 hospitalized patients with HFrEF (LVEF ≤40%) NYHA class II–IV, stabilized after ADHF
Patients population
episode, including de novo HF and naïve to or on different doses of ACEIs/ARBs at baseline
Study design Multicenter, randomized, open-label, parallel-group, Phase IV study
Follow-up 26 weeks (10 weeks Treatment initiation + 16 weeks follow up)
Participating countries 159 sites in 19 countries worldwide
Proportion of patients in the pre- and post-discharge treatment initiation groups achieving the target dose of sacubitril/valsartan
Primary endpoint 97/103 mg bid at the end of the Week 10 after randomization, regardless of previous temporary dose interruption or down-
titration
• The proportion of patients who achieved and maintained either the dose of 49/51 mg and/or 97/103 mg sacubitril/valsartan
bid for at least last 2 weeks from 10 weeks after randomization, regardless of previous temporary dose interruption or down -
titration
Key secondary endpoints • The proportion of patients who achieved and maintained any dose of sacubitril/valsartan for at least last 2 weeks from 10
weeks after randomization, regardless of previous temporary dose interruption or down-titration
• The proportion of patients permanently discontinued from the study drug, due to AEs, during the 10-week treatment epoch

Initiation of sacubitril/valsartan in a wide range of HFrEF patients, early after ADHF event in-
Results summary
hospital or shortly after discharge, was feasible and overall well tolerated
Status Completed and results published
FPFV (or Start of data collection): February 12, 2016 NCT02661217
LPLV (or End of data collection): June 20, 2018
Milestones Study report: April 3, 2019
ACEI= angiotensin-converting enzyme inhibitor; ADHF= acute decompensated Pascual-Figal et al., ESC Heart Fail. 2018;5(2):327-
Studyreceptor
heart failure; AE=adverse event; ARB= angiotensin publications: May 368;
blocker; bid=twice 27,Wachter
2019et al., Eur J Heart Fail. 2019;21(8):998-
daily; FPFV= first patient first visit; h= hour; HF=heart failure; HFrEF=heart 1007; Clinicaltrials.gov: NCT02661217, accessed Nov
failure with reduced ejection fraction; LPLV=last patient last visit; LVEF=left 2021
ventricular ejection fraction; NYHA=New York Heart Association
 PIONEER-HF: Executive Summary
Study code CLCZ696BUS01

To assess the effect of in-hospital initiation of sacubitril/valsartan versus enalapril on time averaged proportional change in NT-proBNP levels in
Aim patients with HFrEF hospitalized for ADHF who achieved stability

Patients population Enrolled 887 patients with HFrEF (LVEF<40%) hospitalized for ADHF and stable* for ≥24 hours
Study design Multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study (Phase IIIb/IV)

Follow-up 8 weeks followed by 4 weeks open-label treatment with sacubitril/valsartan

Participating country United States (180 sites)
Primary endpoint Time-averaged proportional change of NT-proBNP levels at Weeks 4 and 8

Incidence of symptomatic hypotension, hyperkalemia (potassium level >5.5 mEq/L) and angioedema during 8 weeks of treatment; change in hs-
Key secondary endpoints troponin, urinary cGMP and BNP:NT-proBNP ratio from baseline to Weeks 4 and 8; proportional change in NT-proBNP from baseline to week 8

The initiation of sacubitril/valsartan led to a greater reduction in the NT-proBNP concentration than enalapril. Rates of worsening renal function,
hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. Exploratory clinic al outcome
Results summary (composite of clinical events) did not differ between the two groups; however, in-hospital initiation of sacubitril/valsartan was associated with lower
rate of HF re-hospitalization and serious clinical composite events (death, HF re-hospitalization, implantation of LVAD, and inclusion in the list of
patients eligible for transplantation)

Status Completed and results published

FPFV (or Start of data collection): April 29, 2016
LPLV (or End of data collection): June 29, 2018
Milestones Study report: March 2019
NCT02554890
Study publication: November 11, 2018
* Defined as SBP ≥110 mmHg for preceding 6 h, no increase in i.v.
diuretic dose for 6 h prior to randomization and did not receive i.v.
ADHF=acute decompensated heart failure; BNP= B-type natriuretic peptide; Velazquez et al., N Engl J Med. 2019;380(6):539-548; inotropic drugs for 24 h prior or i.v. vasodilators including nitrates for
Velazquez et al., Am Heart J. 2018;198:145-151;
cGMP= cyclic guanosine monophosphate; ; FPFV= first patient first visit; HFrEF= Clinicaltrials.gov: NCT02554890, accessed Dec 2018 6 h prior to randomization
heart failure with reduced ejection fraction; h=hours; hs= high sensitivity; i.v.=
intravenous; LPLV= last patient last visit; LVEF= left ventricular ejection fraction;
NT-proBNP= N-terminal pro-BNP; SBP=systolic blood pressure; Q= quarter
 Insiden kematian kardiovaskuler atau rehospitalisasi
pada de novo HF & ACEi/ARB - naive

de Novo vs perburukan HF kronik Riwayat pemberian ACEi/ARB

20
Persentase pasien dengan
Komposit endpoint klinis

20
Log-rank p value < 0.0001

Persentase pasien dengan

Komposit endpoint klinis
Log-rank p value = 0.1151

10
10

0 0
0 7 14 21 28 35 42 49 56 0 7 14 21 28 35 42 49 56
Time since randomization (Days) Time since randomization (Days)

Worsening chronic HF (n = 578) De novo HF (n = 303) ACEi/ARB–Yes (n = 422) ACEi/ARB–No (n = 459)

ACEi, angiotensin-converting enzyme inhibitor;

Ambrosy ARB,
A etangiotensin receptor
al, J Am Coll Cardiolblocker; CV
cardiovascular;
2020;76(9):1034–48. 38
HF, heart failure.
 Benefit sac/val kematian kardiovaskuler atau rehospitalisasi
terbukti pada subgroup yg di analisis
De novo HF perburukan HF kronik
20
Persentase pasien dengan
Komposit endpoint klinis

20
Log-rank p value = 0.0496

Persentase pasien dengan

Komposit endpoint klinis
Log-rank p value = 0.0195

10
10

0 0
0 7 14 21 28 35 42 49 56 0 7 14 21 28 35 42 49 56
Time since randomization (Days) Time since randomization (Days)

Sac/val (n = 141) Enalapril (n = 162) Sac/val (n = 298) Enalapril (n = 278)

• Kelompok pasien sac/val secara signifikan lebih rendah insiden komposit endpoint klinis (baik pada pasien de novo maupun
perburukan HF kronik), dibandingkan kelompok enalapril

Ambrosy A et al, J Am Coll Cardiol

2020;76(9):1034–48.
ACEi, angiotensin converting enzyme inhibitor; CV, cardiovascular; HF, heart failure; 39
sac/val, sacubitril/valsartan.
 Life-saving efficacy by reducing the risk of CV death
and worsening of HF*

DAPA-HF PRIMARY ENDPOINT: COMPOSITE OF CV DEATH OR WORSENING OF HF1*

30
HR 0.74 (95% CI, 0.65, 0.85)
P <0.001
Studied in 4744
Placebo
25
% patients with HFrEF

26
Cumulative Incidence (%)

on 2016 guideline-directed
20 RRR therapy (including
beta blockers, diuretics,
MRA, and RAASi), with
15
Dapaglifozin 10 mg
4.9 %
(21.2% vs 16.3%)
ARR
eGFR ≥30 mL/min/1.73 m2

10

5
Efficacy
Observed 0
As soon as
28 days2† 0 3 6 9 12 15 18 21 24

Months from Randomisation NNT=21

Median follow-up of 18.2 months
Number at Risk
Dapaglifozin 10 mg2373 2305 2221 2147 2002 1560 1146 612 210
Placebo 2371 2258 2163 2075 1917 1478 1096 593 210
Adapted from McMurray et al (2019).
2 † 1
*Worsening of HF is defined as hHF or urgent HF visit requiring initiation or intensification of treatment specifically for HF ; Post hoc exploratory analysis of the primary endpoint.

ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; DAPA-HF, Dapagliflozin And Prevention of Adverse outcomes in Heart Failure; eGFR, estimated glomerular filtration rate;
HF, heart f ailure; HFrEF, heart failure with reduced ejection fraction; hHF, hospitalisation for heart failure; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; NNT, number needed to treat; RAASi, renin-angiotensin-aldosterone system inhibitor; RRR,
relativ e risk reduction

References: 1. McMurray JJV, et al. N Engl J Med. 2019;381(21):1995–2008. 2. Berg DD, et al. JAMA Cardiol. 2021;6(5):499–507.
 …AND SECONDARY OUTCOMES

Secondary outcomes by eGFR

P for
Dapaglifozin Placebo HR (95% CI)
interaction
CV death
eGFR <60 mL/min/1.73 m 2 12.4% 13.9% 0.88 (0.69, 1.13)
0.41
eGFR ≥60 mL/min/1.73 m 2 7.7% 9.9% 0.76 (0.59, 0.98)

hHF or urgent HF visit

eGFR <60 mL/min/1.73 m 2 12.5% 18.0% 0.66 (0.51, 0.82)

0.46
eGFR ≥60 mL/min/1.73 m 2 8.3% 10.9% 0.75 (0.59, 0.95)

Death from any cause

eGFR <60 mL/min/1.73 m 2 14.9% 17.9% 0.85 (0.68, 1.06)
0.76
eGFR ≥60 mL/min/1.73 m 2 9.4% 11.5% 0.81 (0.64, 1.02)

Pre-specified sub-group analysis

0.4 0.6 0.8 1.0 1.2
All of the above were exploratory endpoints
Dapaglifozin better Placebo better
Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 mL/min. Patients with a GFR < 30 mL/min were excluded from DAPA-HF.
In patients treated with FORXIGA for both heart failure and type 2 diabetes mellitus, additional glucose-lowering treatment should be considered if GFR falls persistently below 45 mL/min.

CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; hHF, hospitalization for heart failure; HR, hazard ratio
Solomon SD, et al. Presented at American Society of Nephrology Kidney Week 2019; November 5th–10th, 2019; Washington, DC, USA.
Simpulan
• Gagal jantung merupakan masalah kesehatan yang progresif
dengan angka mortalitas dan morbiditas yang tinggi.
• Gagal jantung merupakan sindroma klinik yang bersifat
kompleks, diikuti perkembangan dalam diagnosis dan terapi
– farmakologi, sehingga update terhadap pedoman /guideline
sangat dibutuhkan .
• Penatalaksanaan HF yang komprehensif dan multidisiplin
sangat penting dengan tujuan utama; menurunkan mortalitas,
rehospitalisasi dan meningkatkan kualitas hidup penderita.
Alhamdulillah