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 FailureAssessment of LV function (echocardiogram,

radionuclide ventriculogram)

EF < 40%

Assessment ofvolume status

Signs and symptoms of fluid retention

No signs and symptoms offluid retention

Diuretic(titrate to euvolemic state)

ACE Inhibitor

-blockerDigoxin

NEJM 1984; 311: 819-823

C um ula tive m orta lity (% )100

80

60

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00 12 24 36 48 60

M onths

Overallp<0.0001

N oradrena line > 600 pg /m land 900 pg/m l<

N oradrena line 600 pg /m l<

N oradrena line > 900 pg /m l

Relation between plasm a noradrenaline andm ortality in patients with heart failure

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 and 1 receptorsAm J Hypertens 1998; 11: 23S-37S

*

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*p < 0.05

Idiopathic dilated cardiom yopathy

Norm al m yocardium

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60

50

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30

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

US Multicenter Program

Placebo Carvedilol % Risk(n=398) (n=696) Reduction

All-cause 31 22 65%mortality (7.8%) (3.2%)

Death due to progressive 13 5heart failure (3.3%) (0.7%)Sudden death 15 12

(3.8%) (1.7%)

Risk of hospitalization for 78 78 27%cardiovascular reasons (19.6%) (14.1%)

Combined risk of 98 110 38%mortality & hospitalization (25%) (16%)NEJM 1996; 334:1349-1355

ANZ Multicentre Heart Failure Trial

Placebo Carvedilol % Risk(n=208) (n=207) Reduction

All-cause 26 20 24%mortality (12.5%) (10%)

Risk of hospitalization for 84 64 28%cardiovascular reasons (40%) (31%)

Combined risk of 97 74 29%mortality & hospitalization (47%) (36%)

Lancet 1997; 349: 375-380.

Effect of carvedilol on progressionof congestive heart failure

All randomized patients

Endpoint Placebo Carvedilol (n=134) (n=232)

Primary endpoint 28 (21%) 25 (11%)*

Death due to CHF 4 (3%) 0 (0%)

Hospitalization due to worsening CHF 8 (6%) 9 (4%)

Increase in CHF medication 16 (12%) 16 (7%)

* Placebo vs. carvedilol, p = 0.008

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

COPERNICUS: Effect on Mortality

11.4%

18.5%

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46

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18

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Carvedilol (n=1156) Placebo (n=1133)

35%

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y (%

)

22nd Congress of European Society of Cardiology, August 2000

COPERNICUS: Mortality reduction inspecial patient groups with carvedilol

36%42%

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22nd Congress of European Society of Cardiology, August 2000

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

to study entry

EF < 15%, hospitalised3 or more times during

prior year for worsening heart failure

Carvedilol vs. Metoprolol

11.4%

18.5%

0

2

4

6

8

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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

Before dose increaseEvaluate for• Worsening heart failure• Vasodilation• Bradycardia

After each new dose initiation• Observe for signs of dizziness or

light headedness for one hour

3.125 mgbid

2 weeks Doubled every

2 weeks

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

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 Cardiac overloadCardiomyopathy

Left ventricular dysfunction

Arterial blood pressure

Angiotensin II

Peripheral organ blood flow

Skeletal muscleblood flow

Exercise intolerance

Renalblood flow

Oedema

Cardiac remodelling

Renin release

Aldosterone release

Vasoconstriction Na+ and water retention Inotropy and hypertrophy ofvascular and cardiac cells

Left ventriculardilation & hypertrophy

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

CaptoprilSAVE, 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 classas compared with use of digoxin and diuretics

VHeFT-IIproved less effective than enalapril

Dosage of ACE inhibitors: ATLAS study

Low-dose High-dose(2.5-5 mg) (32.5-35mg)

Cardiovascular 44.9% 42.5%mortalityAll-cause mortality+ hospitalisation for 83.8% 79.7% cardiovascular reasonAll-cause mortality +hospitalisation for 60.4% 55.1%heart failure

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 Therapyin Heart Failure Patients(Ejection Fraction < 0.40)

Systolic Blood Pressure

<100 mmHg (or elevated creatinine)

100-139 mmHg (or recent intense diuresis)

>140 mmHg

Lowest Dose,Short-Acting

Usual Starting Dose, Long-or Short-Acting

Intermediate Dose, Long- or Short-Acting

Follow-Up Every 1-2 Weeks

Stable BP and Creatinine Level

Symptomatic Low BP or Rising Creatinine Level

Residual Excess Fluid?

Stop Diuretic and ACE Inhibitor Therapy

Return to Baseline BP and Creatinine Level ?

Increase ACE Inhibitor Dose; Follow-Up Every 1-2

Weeks

Target DoseResume ACE

Inhibitor Titration

Refer to specialist

Stop ACE Inhibitor Therapy

Y

NY

N

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 CHFAsymptomaticMild to moderate ModerateLV dysfunction CHF to severe CHFACE inhibitor Digoxin DigoxinBeta blocker Diuretics Diuretics

ACE inhibitor ACE inhibitorBeta blocker Beta blockerSpironolactone