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 Conc ept of Heart Failure 1 950 to 2000

Aetiology Hypertens ion Valv heart dis S lowly progres s ive

1 950

CHD Hypertens ion Dilated CMP S lowly progres s ive or unpredic table and rapid ( c oronary event ) Neurohormonal model S udden death Pump failure Ventric ular
Improve quality of life + reduc e mortality + reduc e hos pitalization

2000

Natural Cours e (remodeling) Unders tanding Common c aus e of death Arrhythmia Treatment goal

Hemodynamic model Pulmonary infec tion Atrial Control edema

Framingham Heart Study

Annual incidence of new cases heart failure

Averages annual incidence/1000 people

35 30 25 20 15 10 5 0 45-54 55-64 65-74 75-84 85-94 Female Male

Age (years)

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.

Mild

III.

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 Mortality of Heart Failure

80 70 60 50 5 years 40 mortality (% ) 30 20 10 0 I II NYHA III IV

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

Noradrenalin

ACE-I

-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

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.

CONSENSUS

Enal

IV

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

SOLVD-T

Enal

II-III

SOLVD-P

Enal

I-II

SAVE

Capt

LV dysf. post M I

AIRE

Rena

HF post MI

confirmed the results 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 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 Survival 1.0 Mortality % 20 Days Packer et al (1996)

CIBIS-II
Bisoprolol

MERIT-HF
Placebo

15 Metoprolol CR/XL

0.8 10

Risk reduction = 34%

0.6 p<0.0001 0

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)

11.1% 13.2% 11.0% 16.6%

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

COPERNICUS Carvedilol

2289 (100)

18.5%

TERIMA KASIH