HEART FAILURE,

THE CLINICAL EVIDENCE

Prof.DR.dr. Zainal Musthafa, SpJP, MSi, FS, FIHA

Gatot Soebroto Military Hospital
Dept. of Cardiology, FK’UPNV’
2013
 Evolution of the Conc ept of Heart Failure 1 950 to 2000

1 950 2000
Aetiology Hypertens ion CHD
Valv heart dis Hypertens ion
Dilated CMP

Natural Cours e S lowly progres s ive S lowly progres s ive

(remodeling) or unpredic table and rapid
( c oronary event )

Unders tanding Hemodynamic model Neurohormonal model

Common c aus e Pulmonary infec tion S udden death

of death Pump failure

Arrhythmia Atrial Ventric ular

Treatment goal Control edema Improve quality of life

+ reduc e mortality
+ reduc e hos pitalization
 Framingham Heart Study
Annual incidence of new cases heart failure

35
Averages annual incidence/1000 people

30

25

20 Female
15 Male

10

0
45-54 55-64 65-74 75-84 85-94

Age (years)
Heart Failure Classification N Y H A
Class Definition Terminology
I. Patients with cardiac disease Asymptomatic
but without resulting
limitation of physical
activity
II. Patients with cardiac disease Mild
resulting in slight limitation
of physical activity
III. Patient with cardiac disease Moderate
resulting in marked
limitation of physical
activity
IV. Patient with cardiac disease Severe
resulting in ability to carry
on any physical activity
without discomfort
 Treatment of Heart Failure:
Objectives

 Identify and, if possible correct the

underlying cause

 Correct aggravating factors:

Hypertension, arrhytmia, severe anemia

 Correct salt and water overload

 Correct major symptoms:

Dyspnoea, fatigue and edema

 Improve prognosis
 Framingham Study 5 Year
Mortality of Heart Failure

80
70
60
50
5 years
40
mortality (% )
30
20
10
0
I II III IV
NYHA
Coronary artery
disease Arrhythmia
Left
Hypertension Low
ventricular Remodeling Death
ejection
dysfunction
fraction
Cardiomyopathy Pump
failure
Valvular disease

catecholamine
RAAS Non- Chronic
endothelin cardiac Symptoms Heart
natriuretic peptide factors failure
cytokine
growth factor
Cohn, N Engl J Med, 1996;335
Activation and Blockade of Neurohumoral
System in CHF

RAA System SNS System

Angiotensin II Noradrenalin

ACE-I ß-Blocker

Hypertrophy, apoptosis, ischaemia,

arrhythmia, remodeling, fibrosis
 Renin Angiotensin Aldosteron System

ANGIOTENSINOGEN
(LIVER) Other enzymes
e.g.CHYMASE
RENIN
INHIBITOR
ANGIOTENSIN I
BRADYKININ
ACE
PEPTIDES INHIBITOR
ANGIOTENSIN II
AT1 RECEPTOR BLOCKER

AT1 AT2
 ACE Inhibitors in Heart Failure
TRIALS DRUGS NYHA OUTCOME COMMENTS

Captopril MC Capt II-III improved first MCT to show im-

exercise provement in excerc.
tolerance

CONSENSUS Enal IV improved first CT to show im-

survival provement in survival

SOLVD-T Enal II-III improved first large simple CT

survival in CHF

SOLVD-P Enal I-II better for first CT to show pre-

onset CHF vention of CHF

SAVE Capt LV dysf. better for first CT to test the re-

post M I survival & modelling hypothesis
onset CHF

AIRE Rena HF post improved confirmed the results

MI survival of SAVE
ACE inhibitors in heart failure

• Approximately 7,000 patients evaluated

in placebo-controlled clinical trials

• Consistent improvement in cardiac

function, symptoms and clinical status

• Decrease in all-cause mortality by 20-

25% (p<0.001)

• Decrease in combined risk of death and

hospitalisation by 20-25% (p<0.001)
 Adrenergic Activation
CNS sympathetic
outflow

Cardiac Sympathetic
sympathetic activity activity to kidneys
& blood vessels

1 receptors 2 receptors 1 receptors

Myocyte hypertrophy & death, Vasoconstriction

dilatation, ischaemia & arrhythmia's Sodium retention
Packer, AHA 2000
 Mortality in Long-term
-Blocker Trials
Trial No of Death/Pts Reduction
Control ß-Blocker (%)

Norwegian (Timolol) 152/939 98/945 36

BHAT (Propanolol) 188/1921 138/1916 26

Göteborg (Metoprolol) 62/697 40/698 36

Multicenter (Proctolol) 127/1520 102/1520 20

US (Sotalol) 52/583 64/873 18

All Others (18 studies) 584/6482 568/7024 10

 Sudden Deaths in -Blocker Trials

Trial No of Death/Pts Reduction

Control ß-Blocker (%)

Norwegian (Timolol) 95/939 47/945 51

BHAT (Propanolol) 89/1921 64/1916 28

All Metoprolol (5 studies) 104/2721 62/2753 41

UK (Sotalol) 27/583 41/873 -7

All Others (7 studies) 156/2968 113/3102 30

 US Carvedilol Study
Survival
Carvedilol
1.0
(n=696)

-Blockers in 0.9

Heart Failure - 0.8

Placebo
(n=398)

All-cause Mortality 0.7 Risk reduction = 65%

p<0.001
0.6

0.5
0 50 100 150 200 250 300 350 400
Days Packer et al (1996)
Survival Mortality %
1.0 CIBIS-II 20
MERIT-HF
Placebo
Bisoprolol 15
0.8
Metoprolol CR/XL
10
Placebo
Risk reduction = 34% Risk reduction = 34%
0.6 5
p=0.0062
p<0.0001

0
0 0 200 400 600 800 0 3 6 9 12 15 18 21
Lancet (1999) Months of follow-up
Time after inclusion (days)
The MERIT-HF Study Group (1999)
 Beta-Blockade in
Heart Failure

Consensus recommendations

All patients with stable class II or III

heart failure due to left ventricular
systolic dysfunction should receive a ß-
blocker
(in addition to an ACE inhibitor) unless
they have a contraindication to its use or
cannot tolerate treatment with the drug
 -Blockade in Patients with Severe HF
Trials Agent Pts with NYHA Overall placebo Effect on mor-
Class IV HF mortality rate tality in NYHA
N (%) IV patients

US Carvedilol Carvedilol 32 (2.9) 11.1% N/S

CIBIS II Bisoprolol 445 (16.8) 13.2% N/S

MERIT-HF Metoprolol 145 (3.6) 11.0% N/S

BEST Bucindolol 216 (8.0) 16.6% Possible

AEs

COPERNICUS Carvedilol 2289 (100) 18.5% 35% risk

reduction
(p < 0.0002)
TERIMA KASIH