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The Clinical Pharmacology of Heart Failure

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Heart Failure

• Chronic heart failure is a syndrome characterised – by progressive cardiac dysfunction– breathlessness– tiredness– neurohormonal disturbances– sudden death

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• Chronic heart failure– affects 2-10% of the population– incidence rises with increasing age– commonly due to coronary artery disease– has a poor prognosis with a 5 year mortality of

50% rising to 80% in a year for some patients

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A prevalent condition

Prevalence of HF (per 1000 population)

Age (years)

50-59

80-89

All ages

Men

8

66

7.4

Women

8

79

7.7

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A growing burden

0

10000

20000

30000

40000

50000

1979 1985 1991 1997

HF

deat

hs

Vital Statistics of the United States, National Center for Health Statistics

Deaths from HF 1979-1997 (USA)

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Physiology

• Normal circulation and circulatory volume are maintained by means of two opposing systems– Salt and water retaining and vasoconstrictor

system– Salt and water excretion and vasodilatation

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• Salt and water retaining and vasoconstrictor system– The renin-angiotensin-aldosterone system– The sympathetic system– The endothelin system

• Salt and water excretion and vasodilatation– Natriuretic peptide system– EDRF

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• Heart failure usually occurs – following myocardial damage i.e. an MI

• Systolic Dysfunction

– Following upon sustained hypertension• Diastolic Dysfunction

• As a result cardiac output falls as does perfusion• The body registers this as a loss in circulatory

volume• The salt and water retaining systems are activated

(RAAS)• The vasoconstrictor systems are activated

(Sympathetic systems)

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• The RAAS causes the release of – angiotensin II a potent vasoconstrictor and

hypertrophogenic and fibrogenic peptide– and aldosterone a potent antinatriuretic peptide

• The result is salt and water retention, vasoconstriction and hypertrophy and fibrosis of cardiac myocytes

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• Activation of the Sympathetic System causes the release of noradrenaline and adrenaline– both are potent vasoconstrictors– both stimulate renin release – both are also hypertrophogenic

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Systolic Dysfunction• According to the Frank-Starling Law if the

muscle of a healthy heart is stretched it will contract with greater force and so pump out more blood.

• In the failing or damaged heart this relationship is lost

• As the circulatory volume increases the heart dilates, as the heart dilates the force of contraction weakens and the cardiac output drops further

• This fall in cardiac output then activates the RAAS further

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• The result is a vicious cycle in which the RAAS is activated, circulatory volume increases and cardiac performance deteriorates further

• As the heart starts to dilate the cardiac myocytes undergo hypertrophy and then fibrosis and thus the heart is further weakened

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The Final Result

• A failing heart that can not pump out sufficient blood to supply the needs of the body

• Progressive retention of salt and water which results in oedema, pulmonary oedema

• Progressive myocyte death and fibrosis

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15

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Usual treatment today has two aims

To improve symptoms• Diuretics• Digoxin• ACE inhibitors

To improve survival• ACE inhibitors Blockers• Oral nitrates plus hydralazine• Spironolactone

Aims of heart failure management

Davies et al. BMJ 2000;320:428-431

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Treatment Regimes

• Symptomatic treatment

• Inhibition of detrimental neurohormonal adaptations

• Enhancement of beneficial neurohormonal adaptations

• Enhancement of cardiac function

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Symptomatic Treatment– Loop Diuretics – the mainstay of symptomatic treatment– FRUSEMIDE or BUMETANIDE

Blocking detrimental hormonal changes

• Sympathetic activation– CARVEDILOL, BISOPROLOL and

METOPROLOL are beta blockers which are of proven benefit in the treatment of CHF

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RAAS

• Angiotensin II – Two groups of drugs available to block the

effects of angiotensin II– ACE Inhibitors (ENALAPRIL, CAPTOPRIL)– Angiotensin antagonists (LOSARTAN) but

these are not as effective (ELITE II)

• Aldosterone– Effects blocked by SPIRONOLACTONE– Produces a significant reduction in morbidity

(RALES)

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Enhancement of cardiac function

• Positive Inotropes– These drugs improve the ability of the heart to

pump and so improve cardiac status– DIGOXIN is the only drug in common use

• Vasodilators– The nitrovasodilators by reducing preload and

after load improve cardiac function (ISOSORBIDE MONO or DINITRATE

– Hydralazine an arterial dilator has also been shown to improve cardiac function

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Mortality remains high

• ACEi Risk reduction 35% (mortality and hospitalizations)

Blockers Risk reduction 38% (mortality and hospitalizations)

• Oral nitrates and hydralazineBenefit vs. placebo; inferior to enalapril (mortality)

However: 4-year mortality remains ~40%

Davies et al. BMJ 2000;320:428-431 Gibbs et al. BMJ 2000;320:495-498

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The Drugs• Loop Diuretics (FRUSEMIDE)

– The main stay of treatment– It is essential to remove excess salt and water

before introducing other agents– The loop diuretics induce profound diuresis– Act by inhibiting the NA-K-Cl transporter in

the Loop of Henle– Work at very low glomerular filtration rates– Prevent the reabsorption of 20% of filtered

sodium and water

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• In the most severely affected patients or in resistant patients they can be used in combination with thiazide diuretics

• This combination is very powerful and may induce a diuresis of 5-10 litres a day

Adverse Drug Reactions– Dehydration– Hypotension– Hypokalaemia, Hyponatraemia– Gout– Impaired glucose tolerance, diabetes

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Drug Drug Interactions

Frusemide and – aminoglycosides aural and renal toxicity– lithium renal toxicity– NSAIDs renal toxicity– antihypertensives profound hypotension– vancomycin renal toxicity

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Reducing Mortality

• Angiotensin Blockade

• Beta receptor blockade

• Aldosterone blockade

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Angiotensin I

Angiotensinogen(Liver)

AT1 AT2

Angiotensin II

ACE inhibitor

ValsartanAT1 receptor blocker

Renin inhibitor

Bradykinin

Peptides

Chymase

Local Ang II synthesis is independent of ACE

Several pathways of Ang II generation

de Gasparo et al. Pharmacol Rev 2000; 52:415

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GFRProteinuriaAldosterone releaseGlomerular sclerosis

Angiotensin-II plays a central role in organ damage

A-II AT1 receptor

Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction

LV hypertrophyFibrosisRemodellingApoptosis

Stroke

DEATH

*Preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Hypertension

Heart failureMI

Renal failure

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Angiotensin Converting Enzyme Inhibitors• ENALAPRIL, LISINOPRIL, CAPTOPRIL

– A major breakthrough in the treatment of CHF– Improve symptoms, reduce mortality, slow

down progressive deterioration in cardiac function

– Competitively block angiotensin converting enzyme

– Prevent the conversion of angiotensin I to angiotensin II

– Reduce preload and after load on the heart

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ACE Inhibitors• Conclusively demonstrated in CHF patients

to reduce– morbidity – mortality

• Post MI patients to reduce– morbidity– mortality– onset of heart failure

• Main studies CONCENSUS, SOLVD, SAVE, AIRE, ISSIS-4

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• Adverse Drug Reactions– First dose hypotension– Cough– Angioedema– Renal impairment– Renal failure– Hyperkalaemia

• Drug-Drug Interactions– NSAIDs acute renal failure– Potassium supplements hyperkalaemia– Potassium sparing diuretics hyperkalaemia

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Angiotensin Receptor Blockers

• ARBs selectively block the angiotensin II, AT1 receptor.

• They are effective in the treatment of heart failure.– NOT AS EFFECTIVE AS ACEIs

• At present recommended for use in ACEI intolerant patients.

• Some suggestion that they may have benefit when added to ACEIs.

• Major outcome studies Elite II, Charm, ValHeft Valiant

VasoconstrictionVascular proliferation Aldosterone secretionCardiac myocyte proliferationIncreased sympathetic tone

VasodilationAntiproliferationApoptosis

AT1 AT2

Angiotensin II

Different roles of AT1 and AT2 receptors

de Gasparo et al. Pharmacol Rev 2000; 52:415

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36

1.0

0.9

0.8

0.7

Kaplan-Meier analysis of probability of survival

Time since randomization (months)

p = 0.80

Surv

ival

pro

babi

lity

(%)

0 3 6 9 12 211815 24 27

Valsartan

Placebo

Cohn et al. NEJM 2001;345:1667

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1.0

0.9

0.8

0.6

13.2% risk reductionp= 0.009

Significant benefits on combined mortality / morbidity endpoint

0

Even

t-fre

e pr

obab

ility

Placebo

Valsartan

3 6 9 12 211815 24 27Time since randomization (months)

0.7

Cohn et al. NEJM 2001 345:1667

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1.0

0.8

0.6

0.4

44.5%risk reduction

p = 0.0002

Even

t-fre

e pr

obab

ility

Time since randomization (months)

3 6 9 12 211815 24 270

Valsartan (n = 185)

Placebo (n = 181)

Cohn et al. AHA Scientific Sessions 2000

Primary endpoint: greatest benefits in patients not on ACE inhibitor therapy

Combined all-cause mortality / morbidity

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Aldosterone Antagonists

• Spironolactone (RALES Study)– Potassium sparing diuretic– Inhibits the actions of aldosterone– Acts in the distal tubule– Used in combination with loop diuretics– Particularly useful in resistant oedema

• Proven to reduce mortality when used in combination with ACEIs

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SARASpironolactone (RALES trial)

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Beta Blockers• CARVEDILOL, BISOPROLOL, METOPROLOL

– The use of beta blockers in the treatment of CHF is potentially hazardous and patients must be selected carefully

– Block the actions of the sympathetic system

– May precipitate severe deterioration in CHF

– Have been demonstrated to reduce morbidity and mortality in mild/moderate and severe heart failure by 30%

– Should be used only when a patient has been stabilized and not during an acute presentation

– Specialist use only

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Carvedilol(n=696)

Placebo(n=398)

Survival

Days0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction=65%p<0.001

Packer et al (1996)Packer et al (1996)

CIBISCIBIS--II Investigators (1999)II Investigators (1999)

0 200 400 600 800

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction=34%

The MERITThe MERIT--HF Study Group (1999)HF Study Group (1999)

Months of follow-up

Mortality (%)

0 3 6 9 12 15 18 21

20

15

10

5

0

Placebo

Metoprolol CR/XL

p=0.0062

Risk reduction=34%

US Carvedilol Programme

blockers in blockers in heart failure heart failure ––

allall--cause mortalitycause mortality

CIBIS-II MERIT-HF

0.8

1.0

0.6

0

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Positive Inotropes

• DIGOXIN (The DIG Study)– Increases availability of calcium in the myocyte– Shown to reduce number of hospitalisations– No effect on mortality– Narrow therapeutic index– Arrhythmias– Nausea– Confusion

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Anticoagulants

• WARFARIN– Dilated ventricle gives rise to thrombus

formation and thrombo-embolic events– Warfarin has proven value in preventing these

events

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Therapeutic Regime

• Frusemide ± thiazide Appropriate dose

• Frusemide + pulsed metolazone

• ACE Inhibitor Appropriate dose– Angiotensin receptor blocker

• Carvedilol, Bisoprolol, Metoprolol

• Digoxin TDM

• Warfarin TDM

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Monitoring Benefit

• Symptomatic relief– SOB, tiredness, lethargy

• Clinical relief– Peripheral oedema, ascites, weight

• Monitor weight regularly– Patient performs daily weight assessment

– Increase medication according to symptoms or weight

• Patient education