Heart Failure

Final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction Cardinal manifestations of heart failure include dyspnea, fatigue and fluid retention Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 30-40% annually in patients with advanced disease

Main causes
Coronary artery disease Hypertension Valvular heart disease Cardiomyopathy Cor pulmonale

Compensatory changes in heart failure

Activation of SNS Activation of RAS Increased heart rate Release of ADH Release of atrial natriuretic peptide Chamber enlargement Myocardial hypertrophy

NYHA Classification of heart failure

Class I: No limitation of physical activity Class II: Slight limitation of physical activity Class III: Marked limitation of physical activity Class IV: Unable to carry out physical activity without discomfort

New classification of heart failure

Stage A: Asymptomatic with no heart damage but have risk factors for heart failure Stage B: Asymptomatic but have signs of structural heart damage Stage C: Have symptoms and heart damage Stage D: Endstage disease
ACC/AHA guidelines, 2001

Types of heart failure

Diastolic dysfunction or diastolic heart failure Systolic dysfunction or systolic heart failure

Factors aggravating heart failure

Myocardial ischemia or infarct Dietary sodium excess Excess fluid intake Medication noncompliance Arrhythmias Intercurrent illness (eg infection) Conditions associated with increased metabolic demand (eg pregnancy, thyrotoxicosis, excessive physical activity) Administration of drug with negative inotropic properties or fluid retaining properties (e. NSAIDs, corticosteroids) Alcohol

Goals of treatment
To improve symptoms and quality of life To decrease likelihood of disease progression To reduce the risk of death and need for hospitalisation

Approach to the Patient with Heart Failure

Assessment of LV function (echocardiogram, radionuclide ventriculogram) EF < 40% Assessment of volume status Signs and symptoms of fluid retention Diuretic (titrate to euvolemic state) No signs and symptoms of fluid retention ACE Inhibitor

b-blocker

Digoxin

Relation between plasma noradrenaline and mortality in patients with heart failure
Cumulative mortality (%) 100 80 60 40 Noradrenaline < 600 pg/ml 20 0 0 12 24 36 48 60 Months
NEJM 1984; 311: 819-823
Overall p<0.0001

Noradrenaline > 900 pg/ml

Noradrenaline > 600 pg/ml and < 900 pg/ml

Effects of SNS Activation in Heart Failure

Dysfunction/death of cardiac myocytes Provokes myocardial ischemia Provokes arrhythmias Impairs cardiac performance

These effects are mediated via stimulation

of b and a1 receptors
Am J Hypertens 1998; 11: 23S-37S

Receptor densities in human left ventricular myocardium

70
Normal myocardium

60
Receptor density (fmol/mg)

Idiopathic dilated cardiomyopathy

50 40 30 20 10 0 b 1 b

*p < 0.05

Scand Cardiovasc J 1998; Suppl 47:45-55

Carvedilol in Heart Failure

Effective receptor-blockade approach to heart

failure

Negative inotropic effect counteracted by vasodilation

Provides anti-proliferative, anti-arrhythmic activity and inhibition of apoptosis

Prevents renin secretion

Drugs of Today 1998; 34 (Suppl B): 1-23.

US Multicenter Program
Placebo (n=398) All-cause 31 mortality (7.8%) Death due to progressive 13 heart failure (3.3%) Sudden death 15 (3.8%) Risk of hospitalization for cardiovascular reasons Combined risk of mortality & hospitalization
NEJM 1996; 334:1349-1355

Carvedilol (n=696) 22 (3.2%) 5 (0.7%) 12 (1.7%) 78 (14.1%) 110 (16%)

% Risk Reduction 65%

78 (19.6%) 98 (25%)

27% 38%

ANZ Multicentre Heart Failure Trial

Placebo (n=208) All-cause mortality Risk of hospitalization for cardiovascular reasons Combined risk of mortality & hospitalization
Lancet 1997; 349: 375-380.

Carvedilol (n=207) 20 (10%) 64 (31%) 74 (36%)

% Risk Reduction 24% 28% 29%

26 (12.5%) 84 (40%) 97 (47%)

Effect of carvedilol on progression of congestive heart failure

All randomized patients Endpoint Primary endpoint Death due to CHF Placebo (n=134) 28 (21%) 4 (3%) Carvedilol (n=232) 25 (11%)* 0 (0%)

Hospitalization due to worsening CHF

Increase in CHF medication
* Placebo vs. carvedilol, p = 0.008
Drugs of Today 1998; 34 (Suppl B): 1-23.

8 (6%)
16 (12%)

9 (4%)
16 (7%)

COPERNICUS: Effect on Mortality

20 18 16

18.5%

Mortality (%)

14 12 10 8 6 4 2 0

11.4%

35%

Carvedilol (n=1156)

Placebo (n=1133)

22nd Congress of European Society of Cardiology, August 2000

COPERNICUS: Mortality reduction in special patient groups with carvedilol

EF < 15%, hospitalised 3 or more times during prior year for worsening heart failure

EF<20%, hospitalised for heart failure in year prior to study entry

Mortality reduction (%)

-10 -20 -30 -40

36% 42%

-50 -60

22nd Congress of European Society of Cardiology, August 2000

Carvedilol vs. Metoprolol

12

Change in LVEF (%) from baseline

10 8 6 4 2 0

18.5%

11.4%

Metoprolol

Carvedilol
Circulation 2000; 102: 546-551

Dosage guidelines for Carvedilol in heart failure

Patient selection Stable on background medications (diuretics, digoxin and/or ACE inhibitors) Not in a fluid-overload state Not hypotensive

3.125 mg bid

2 weeks

Doubled every 2 weeks

Max dose 25 mg bid (<85 kg); 50 mg bid (>85 kg)

After each new dose initiation Observe for signs of dizziness or light headedness for one hour

Before dose increase Evaluate for Worsening heart failure Vasodilation Bradycardia

Management of Complications
Transient worsening of heart failure (e.g. increasing dyspnea,

decreasing exercise capacity)

Increase dose of diuretic and/or ACE inhibitor If necessary, reduce carvedilol dose and/or prolong titration interval Search for other possible causes (e.g. thyroid malfunction, infection, non-compliant drug intake, excessive liquid intake, etc.)

Vasodilatory Symptoms (dizziness, light headedness, symptomatic hypotension)

Decrease diuretic dose and, if necessary, ACE inhibitor dose If the cessation of both is not successful, reduce carvedilol dose and/or prolong titration interval

Management of Complications (Contd.)

Bradycardia (Pulse rate below 55 beats/min)

Check and eventually reduce digitalis dose If necessary, reduce carvedilol dose and/or prolong titration interval Withdraw carvedilol only in the event that hemodynamics are affected

Symptoms of Bronchial obstruction

Search for other possible causes (e.g., concurrent infection, subacute pulmonary edema) Reduce dose of, or withdraw, carvedilol only after possible causes for symptoms have been ruled out

The role of angiotensin II in the progression of heart failure

Coronary artery disease Cardiomyopathy Cardiac overload

Left ventricular dysfunction

Arterial blood pressure Renin release Angiotensin II Aldosterone release Vasoconstriction Peripheral organ blood flow Cardiac remodelling Skeletal muscle blood flow Renal blood flow Left ventricular dilation & hypertrophy

Na+ and water retention

Inotropy and hypertrophy of vascular and cardiac cells

Exercise intolerance

Oedema

Pump failure

ACE Inhibitors: physiologic benefits

Arteriovenous Vasodilatation
pulmonary arterial diastolic pressure pulmonary capillary wedge pressure left ventricular end-diastolic pressure systemic vascular resistance systemic blood pressure maximal oxygen uptake (MVO2)

ACE Inhibitors: physiologic benefits

LV function and cardiac output renal, coronary, cerebral blood flow No change in heart rate or myocardial contractility no neurohormonal activation resultant diuresis and natriuresis

ACE Inhibitors: clinical benefits

Increases exercise capacity improves functional class attenuation of LV remodeling post MI decrease in the progression of chronic HF decreased hospitalization enhanced quality of life improved survival

Asymptomatic Patients
Enalapril
SOLVD Prevention Trial EF<35% HF progression, hospitalization

Captopril
SAVE, GISSI-3, ISIS-4 Post MI, EF <40% overall mortality, re-infarction hospitalization, HF progression

Symptomatic Patients
Hydralazine + Isosorbide dinitrate
VHeFT-I mortality, improved functional class as compared with use of digoxin and diuretics VHeFT-II proved less effective than enalapril

Dosage of ACE inhibitors: ATLAS study

Low-dose High-dose (2.5-5 mg) (32.5-35mg)
Cardiovascular 44.9% mortality All-cause mortality + hospitalisation for 83.8% cardiovascular reason All-cause mortality + hospitalisation for 60.4% heart failure 42.5%

79.7%

55.1%

Circulation 1999;100:2312-18

AIRE
AIRE Study demonstrated efficacy of ramipril on mortality and morbidity in CHF post-MI NYHA class I-III patients 2006 patients enrolled in a double-blind,randomized, placebo-controlled study 27% reduction in the risk of death 23% decrease in progression to severe / resistant heart failure

Lancet. 1993; 342:821-828

Guidelines to ACE Inhibitor Therapy

Contraindications Renal artery stenosis Renal insufficiency (relative) Hyperkalemia Arterial hypotension Cough Angioedema Alternatives Hydralazine + ISDN, AT-II inhibitor

Guidelines to ACE Inhibitor Therapy

All patients with symptomatic heart failure and those in functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless contraindicated or not tolerated ACE inhibitors should be continued indefinitely It is important to titrate to the dosage regimen used in the clinical trials in the absence of symptoms or adverse effects on end-organ perfusion In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac output

ACE Inhibitor Therapy in Heart Failure Patients

(Ejection Fraction < 0.40)

Systolic Blood Pressure

<100 mmHg (or elevated creatinine) Lowest Dose, Short-Acting

100-139 mmHg (or recent intense diuresis) Usual Starting Dose, Longor Short-Acting Follow-Up Every 1-2 Weeks

>140 mmHg

Intermediate Dose, Long- or Short-Acting

Stable BP and Creatinine Level

Stop ACE Inhibitor Therapy Increase ACE Inhibitor Dose; Follow-Up Every 1-2 Weeks
Y

Symptomatic Low BP or Rising Creatinine Level

Residual Excess Fluid?
N

Refer to specialist

Stop Diuretic and ACE Inhibitor Therapy

N Y

Target Dose Resume ACE Inhibitor Titration Return to Baseline BP and Creatinine Level ?

Diuretics
Indicated in patients with symptoms of heart failure who have evidence of fluid retention Enhance response to other drugs in heart failure such as beta-blockers and ACE inhibitors Therapy initiated with low doses followed by increments in dosage until urine output increases and weight decreases by 0.5-1kg daily

Digoxin
Enhances LV function, normalizes baroreceptor-mediated reflexes and increases cardiac output at rest and during exercise Recommended to improve clinical status of patients with heart failure due to LV dysfunction and should be used in conjunction with diuretics, ACE inhibitors and beta-blockers Also recommended in patients with heart failure who have atrial fibrillation Digoxin initiated and maintained at a dose of 0.25 mg daily Adverse effects include cardiac arrhythmias, GI symptoms and neurological complaints (eg. visual disturbances, confusion)

Summary of drug treatment for CHF

Asymptomatic LV dysfunction ACE inhibitor Beta blocker Mild to moderate CHF Digoxin Diuretics ACE inhibitor Beta blocker Moderate to severe CHF Digoxin Diuretics ACE inhibitor Beta blocker Spironolactone