HEART FAILURE, THE CLINICAL EVIDENCE

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

Gatot Soebroto Military Hospital Dept. of Cardiology, FKUPNV 2010

Evolution of the Concept of Heart Failure 1950 to 2000 1950

Aetiology Hypertension Valv heart dis Slowly progressive

2000
CHD Hypertension Dilated CMP Slowly progressive or unpredictable and rapid ( coronary event ) Neurohormonal model

Natural Course (remodeling) Understanding Common cause of death Arrhythmia Treatment goal

Hemodynamic model

Pulmonary infection Sudden death Pump failure Atrial Control edema Ventricular
Improve quality of life +reduce mortality +reduce hospitalization

35 30 25 20 15 10 5 0 45-54 55-64

Annual incidence
65-74 75-84 85-94

Framingha
Female Male

Heart Failure Classification N Y H A

Class I. Definition Patients with cardiac disease but without resulting limitation of physical activity Patients with cardiac disease resulting in slight limitation of physical activity Patient with cardiac disease resulting in marked limitation of physical activity Patient with cardiac disease resulting in ability to carry on any physical activity without discomfort Terminology Asymptomatic

II. III.

Mild Moderate

IV.

Severe

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 70 Mortality of Heart Failure 60

5 years mortality (%) 50 40 30 20 10 0 I II NYHA III IV

80

Coronary artery disease Hypertension Cardiomyopathy Valvular disease

catecholamine RAAS endothelin natriuretic peptide cytokine growth factor
Cohn, N Engl J Med, 1996;335

Arrhythmia

Left ventricular dysfunction

Remodeling

Low ejection fraction

Death
Pump failure

Noncardiac factors

Symptoms

Chronic Heart failure

Activation and Blockade of Neurohumoral System in CHF

RAA System SNS System

Angiotensin II
ACE-I

Noradrenalin
-Blocker

Hypertrophy, apoptosis, ischaemia, arrhythmia, remodeling, fibrosis

Renin Angiotensin Aldosteron System

ANGIOTENSINOGEN
(LIVER)

RENIN INHIBITOR BRADYKININ PEPTIDES

Other enzymes e.g. CHYMASE

ANGIOTENSIN I ACE INHIBITOR ANGIOTENSIN II

AT1 RECEPTOR BLOCKER

AT1

AT2

RAS: SCIENTIFIC RATIONALE

EFFECTS OF ANGIOTENSIN II ON AT1 AND AT2 RECEPTORS

ANGIOTENSIN II
AT1 AT2

(-) effects :
INCREASED VASCULAR TONE VASCULAR PROLIFERATION NA+ RETENTION ALDOSTERONE SECRETION CARDIAC MYOCYTE PROLIFERATION INCREASED SYMPATHETIC TONE

(+) effects :
NO VASODILATION GROWTH INHIBITION APOPTOSIS

ACE Inhibitors in Heart Failure

TRIALS Captopril MC DRUGS Capt NYHA II-III OUTCOME improved exercise tolerance improved survival improved survival better for onset CHF better for survival & onset CHF improved survival COMMENTS first MCT to show improvement in excerc. first CT to show improvement in survival first large simple CT in CHF first CT to show prevention of CHF first CT to test the remodelling hypothesis confirmed the results of SAVE

CONSENSUS SOLVD-T SOLVD-P SAVE

Enal Enal Enal Capt

IV II-III I-II LV dysf. post M I HF post MI

AIRE

Rena

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 2025% (p<0.001) Decrease in combined risk of death and hospitalisation by 20-25% (p<0.001)

Adrenergic Activation
CNS sympathetic outflow

Cardiac sympathetic activity

Sympathetic activity to kidneys & blood vessels

1 receptors

2 receptors

1 receptors

Myocyte hypertrophy & death, dilatation, ischaemia & arrhythmia's

Vasoconstriction Sodium retention

Packer, AHA 2000

Mortality in Long-term -Blocker Trials

Trial No of Death/Pts Control Norwegian (Timolol) BHAT (Propanolol) 152/939 188/1921 62/697 -Blocker 98/945 138/1916 40/698 102/1520 64/873 568/7024 Reduction (%) 36 26 36 20 18 10

Gteborg (Metoprolol)

Multicenter (Proctolol) 127/1520 US (Sotalol) 52/583 584/6482

All Others (18 studies)

Sudden Deaths in -Blocker Trials

Trial

No of Death/Pts Control -Blocker

Reduction (%) 51 28 41 -7 30

Norwegian (Timolol) BHAT (Propanolol)

95/939 89/1921

47/945 64/1916 62/2753 41/873 113/3102

All Metoprolol (5 studies) 104/2721 UK (Sotalol) 27/583 156/2968

All Others (7 studies)

US Carvedilol Study
Survival

-Blockers in Heart Failure All-cause Mortality

1.0 0.9 0.8 0.7 0.6 0.5

Carvedilol (n=696)

Placebo (n=398)

Risk reduction = 65%

p<0.001

0 50 100 150 200 250 300 350 400 Days Packer et al (1996)

Survival 1.0

CIBIS-II
Bisoprolol

Mortality % 20

MERIT-HF
Placebo

15 Metoprolol CR/XL

0.8 10

Risk reduction = 34%

0.6 p<0.0001

Placebo 5

Risk reduction = 34%

p=0.0062

0 0 200 400 Time after inclusion (days) 600 800 Lancet (1999) 0 3 6 9 12 15 Months of follow-up 18 21

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 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 Class IV HF N (%) Overall placebo mortality rate Effect on mortality in NYHA IV patients

US Carvedilol CIBIS II MERIT-HF BEST

Carvedilol Bisoprolol Metoprolol Bucindolol

32 (2.9) 445 (16.8) 145 (3.6) 216 (8.0) 2289 (100)

11.1% 13.2% 11.0% 16.6% 18.5%

N/S N/S N/S Possible AEs 35% risk reduction (p < 0.0002)

COPERNICUS Carvedilol

TERIMA KASIH