Pharmacotherapy of Heart Failure:

Fantastic Four Drug and Diuretics

Oleh:
Halim P. Jaya
 Heart Anatomy

SA node

AV node Common bundle

Bundle branches

Purkinje fibers

Servier Medical Art de Servier est mis à disposition selon les termes de la licence Creative Commons Attribution 3.0 France
Heart Contraction
Heart Circulation
Cross Section of The Heart
Heart Chamber Pressure
What is heart failure?
Gagal Jantung
 Adanya kelainan struktur atau fungsi pada jantung pada saat pengisian
atau pemompaan yang mengakibatkan penurunann volume darah yang
dipompa ke seluruh tubuh (Normal 4.0 – 8,0 L/Menit)
 Gejala
 Dyspnea
 Kelemahan
 Penurunan kemampuan fisik
 Kongesti paru
 Kongesti splanik
 Edema perifer
Gagal Jantung Sistolik dan Diastolik
Normal Heart Volume

 End Systolic Volume = 50 mL

 End Diastolic Volume = 120 mL
 Stroke Volume = 70 mL
 Heart rate = 70-90 bpm
 Cardiac output = 5-7 L/minute
AHA Classification of Heart Failure
Stage Patient Description
High risk for • Hypertension
A developing heart •
•
CAD
Diabetes mellitus
failure (HF) • Family history of cardiomyopathy
Asymptomatic HF • Previous MI
B •
•
LV systolic dysfunction
Asymptomatic valvular disease
Symptomatic HF • Known structural heart disease
C •
•
Shortness of breath and fatigue
Reduced exercise tolerance
Refractory • Marked symptoms at rest despite
D end-stage HF maximal medical therapy (eg, those who
are recurrently hospitalized or cannot be
safely discharged from the hospital
without specialized interventions)
Hunt SA et al. J Am Coll Cardiol 2001;38:2101–2113.
 Konsekuensi Klinis Gagal Jantung
Aktivasi sistem renin angiotensin
Aktivasi sistem saraf simpatis
aldosterone (RAAS)

Peningkatan mekanisme
kompensasi oleh jantung

Remodelling pada otot

jantung

Progresivitas Gagal
Jantung

Kematian
Heart Failure and Symphathetic Nerve Stimulation
Clinical Concequences
Renin Angiotensin Aldosterone System
Farmakoterapi Gagal Jantung
 Stage A
 Terapi Hipertensi
 Terapi gangguan lipid
 Memperbaiki obesitas
 Kontrol DM
 Stop merokok
 Menghindari obat kardiotoksik
Farmakoterapi Gagal Jantung Stage B
dan C
Medical Therapy of Heart Failure in 1984

Vasodilators

Diuretics
Restriction of Na+ Intake
Digitalis
Restriction of
Physical Activity
Functional Class
Brauwnwald E. Management of heart failure. Heart Disease 2nd ed. 1984; 503-550.
Diuretik
Diuretik Pada Gagal Jantung
 Diuretik akan mengurangi gejala kongesti pada pasien gagal
jantung mengurangi alir balik vena1
 Secara umum, diuretik tidak meningkatkan keberlangsungan
hidup pasien (kecuali spironolakton)
 Pasien yang resisten terhadap diuretik dapat disebabkan oleh
 Konsumsi natrium yang terlalu tinggi2
 Penggunaan obat yang menghambat efek diuresis(e.g. NSAIDs)1
 Adanya gangguan ginjal atau low output syndrome1
 Pada pasien yang mengalami kongesti paru akut
 Diberikan diuretik secara intravena2
 Kombinasi diuretik (Diuretik loop + MRA)
1RavnanSL et al. Congest Heart Fail. 2002;8:80-85
2 Brater DC. Drugs. 1985;30:427-443.
Location of Diuretic Action

Proximal Tubule
Carbonic anhydrase inhibitors

Distal Tubule
Thiazide diuretics

Collecting Duct
Vasopressin antagonists
Aldosterone antagonists
Ascending limb of Loop of Henle
Loop diuretics
Digoxin
Digitalis and the Treatment of Cardiac Dropsy

Dr. William Withering 17th Century patient Foxglove

1741 - 1799 with severe dropsy (Digitalis purpurea)

Withering W “An account of the foxglove and some of its medical uses;
with practical remarks on the dropsy, and some other diseases,” 1785
Effect of Digoxin Upon Clinical
Outcomes in Subjects with Heart Failure
All Cause Mortality Death or Hospitalization Due to HF

Placebo
Placebo RR = 0.99
(0.91-1.07)
RR = 0.85
p = 0.80
Digoxin (0.79-0.91)
Digoxin p < 0.001

The Digitalis Investigator Group. N Eng J Med 1997; 336: 525-33.

ACE Inhibitor dan ARB
ACE Inhibitor
ACE Inhibition Improves Survival
SOLVD Treatment Trial SAVE
50 30
Chronic HF Acute MI
NYLVEF<35%
Placebo Asymptomatic
Placebo
(n=1284) (n=1116)
40 HA II-III LV dysfunction

20
% Mortality

30
Enalapril Captopril
(n=1115)
20 (n=1285)
10

10 p=0.019
P=0.0036

0 0
0 12 24 36 48 0 1 2 3 4
Months Years
SOLVD Investigators. N Engl J Med 1991;325:293-302. Pfeffer MA et al. N Engl J Med 1992;327:669-77.
 ACEI is Superior to Vasodilator Therapy
VHeFT II
in Chronic Heart Failure

0.75

0.54 Isosorbide +
0.46 Hydralazine
0.5 0.48
Mortality

0.36 0.42 Enalapril

0.25 0.31
0.25
0.13 0.18 RR = 28%
p = 0.016
0 0.09
0 0
0 12 24 36 48 60
Months

Cohn JN et al. N Engl J Med 1991;325:303-10.

ARB Improves Outcomes
in ACEI Intolerant Patients
CV death or CHF hospitalisation %
50
Placebo (n = 1013) (40.0%)
40 (33.0%)
30
Candesartan (n = 1015)
20

10 HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001
0
0 1 2 3 3.5 years

Granger CB et al. Lancet 2003;362:772-6.

ARNI (Angiotensin Receptor Blocker and Nephrilysin Inhibitor)
Mechanism Of Action
ARNI (Angiotensin Receptor Blocker and Nephrilysin Inhibitor)
All Event Rate Outcome
ARNI (Angiotensin Receptor Blocker and Nephrilysin Inhibitor)
All Death Only
Beta Blocker
Beta-Blockade Improves Survival

Advanced Heart Failure Post Myocardial Infarction

Copernicus (n = 2289) Capricorn (n= 1959)
100
1

90 0.95 RR=23%
Carvedilol P=.031
% Survival

0.9
80

Placebo 0.85 Carvedilol

70
0.8
35%  in risk Placebo
60
P=.00013 (unadjusted) 0.75
P=.0014 (adjusted)
0 0.7
0 3 6 9 12 15 18 21 0 0.5 1 1.5 2 2.5
Months Years
Packer M et al. N Engl J Med 2001;344:1651-8. CAPRICORN Investigators. Lancet 2001;357:1385–90.
Major Trials of -Blockade in Heart Failure
Trial Drug Mortality Reduction
US Carvedilol Program* carvedilol  65% (P<0.001)
1094 patients (Class II–IV)

CIBIS-II Trial HF2 bisoprolol  34% (P<0.0001)

2647 patients (Class III–IV)

MERIT-HF metoprolol  34% (P=0.0062)

3991 patients (Class II–IV) succinate

BEST bucindolol  10% (P=0.109)

2708 patients (Class III–IV)

COPERNICUS carvediolol  35% (P=0.00014)

2289 patients (Class III-IV)

SENIORS* nebivolol  12% (P=0.21)

2128 patients (Class II-IV)

*Mortality not the primary efficacy endpoint in these trials

Effects of Metoprolol Tartrate and COMET
Carvedilol on Mortality in Heart Failure
40
Metoprolol ( n = 1511)
30

20 Carvedilol (n = 1518)

10
Hazard ratio 0.83,
95% CI 0.74-0.93, P = 0.0017
0
0 1 2 3 4 5
Time (years)

Poole-Wilson PA et al. Lancet 2003;362:7-13.

Mineralocorticoid Receptor Antagonist (MRA)/
Aldosterone antagonist
Aldosterone Antagonists Improve Survival

Advanced Heart Failure Post Myocardial Infarction

1.00
RALES EPHESUS
0.95
0.90
RR = 0.85 (0.75-0.96)
0.85
P = 0.008
0.80
0.75 Placebo
0.70
Spironolactone
0.65
0.60
0.55
Eplerenone
Placebo
0.50 RR = 0.70 (0.60-0.82)
P < 0.001
0.45

0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months Follow-up Months Follow-up

Pitt B et al. N Engl J Med. 1999;341:709–717. Pitt B et al. N Engl J Med 2003;348:1309-21.
SGLT-2 Inhibitor
Site of Action SGLT-2 Inhibitor
SGLT2 inhibitors have been shown to improve CV risk
factors in patients with Type 2 Diabetes Mellitus

SGLT2 inhibitor on top of Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin

metformin 10 mg1 100 mg2 10 mg3 5 mg4

HbA1c, % -0.70* -0.73† -0.84‡ -0.7§

Weight, kg -2.08* -3.3† -2.9‡ -3.0§

Systolic blood
pressure, mmHg
-4.5* -3.5† -5.1¶ -4.4§

Diastolic blood
pressure, mmHg
-2.0* -1.8† -1.8¶ -1.6§

Comparison of studies should be interpreted with caution due to differences in study design, populations and
methodology
*Adjusted mean change from baseline at Week 24; †Least squares mean change from baseline at Week 52; ‡Adjusted
mean change from baseline at Week 24; §Least squares mean change from baseline at Week 26; ¶Mean change from
baseline at Week 24
1. Häring H-U et al. Diabetes Care 2014;37:1650; 2. Lavalle-Gonzalez FJ et al. Diabetologia 2013;56:2582; 3. Bailey
CJ et al. Lancet 2010;375:2223;
4. Rosenstock J et al. Diabetes Obes Metab 2018;20:520
In CVOTs, SGLT2 inhibitors have demonstrated multiple
CV benefits in patients with T2D and high CV risk and eCVD

EMPA-REG OUTCOME1 CANVAS Program2 DECLARE-TIMI 583

VERTIS CV4
(empagliflozin) (canagliflozin) (dapagliflozin)

HR 0.65 HR 0.67 HR 0.73 HR 0.70

HHF (95% CI 0.50, 0.85) (95% CI 0.52, 0.87)† (95% CI 0.61, 0.88)† (95% CI 0.54, 0.90)†
p=0.002*

HR 0.62 HR 0.87 HR 0.98 HR 0.92

CV
(95% CI 0.49, 0.77) (95% CI 0.72, 1.06)† (95% CI 0.82, 1.17)† (95.8% CI 0.77, 1.11)†
death
p<0.001*

HR 0.97
HR 0.86 HR 0.86 HR 0.93
3P- (95.6% CI 0.85, 1.11)
(95% CI 0.74, 0.99) (95% CI 0.75, 0.97) (95% CI 0.84, 1.03)
MACE p<0.001 for non-
p=0.04 p=0.02‡ p=0.17
inferiority

Comparison of studies should be interpreted with caution due to differences in study design, populations and methodology
p-values are for superiority except for the primary outcome of VERTIS CV, where p-values are for non-inferiority
*Nominal p-value; †Exploratory outcome, no p-value is reported – only nominal effect estimate is given; ‡Testing for superiority for
3P-MACE was part of the statistical analysis plan but was not part of the hierarchical testing strategy
eCVD, established cardiovascular disease; HHF, hospitalisation for heart failure; T2D, type 2 diabetes.
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Neal B et al. N Engl J Med 2017;377:644; 3. Wiviott S et al. N Engl J Med
2019;380:347; 4. Cannon CP et al. N Engl J Med 2020;383:1425
Kesimpulan
 Telah banyak pengobatan berbasis bukti pada pasien gagal
jantung yang telah banyak diteliti sejak tahun 1984
 Obat yang mampu menurunkan gejala gagal jantung pada
pasien
 Diuretik
 Vasodilator
 Obat yang telah terbukti meningkatkan keberlangsungan hidup
pasien
 ACEI/ARB atau ARNI
 Beta Blocker
 Aldosterone antagonist
 SGLT-2 Inhibitor
Keterbatasan Terapi Obat Pada Gagal
Jantung
 Beberapa pasien belum memperoleh obat
yang telah terbukti meningkatkan
keberlangsungan hidup pasien
 Manajemen intake cairan susah dilakukan
pada pasien rawat jalan
 Pasien dapat meninggal tiba tiba karena
aritmia
 Progresivitas gagal jantung akan tetap
terjadi sekalipun pasien telah memperoleh
obat secara optimal