CARDIAC FAILURE

PROF H duT THERON2010

MANAGEMENT OF HEARTFAILUREOVERVIEW• Heart failure

• Resulting from

• Compensatory mechanisms

* Complex syndrome* Easily recognized* difficult to define

* Left ventricular disfunction¤ systolic¤ diastolic

* Inadequate* Non specific* Worsening cycle of events

HEALTH CARE IMPACT• 0,5 to 2% population• 200 000 to 800 000 in RSA• Adverse prognosis

• Economic impact

* 40% five year survival* Class 4 NYHA and IHD

¤ 43% one year survival¤ 18% three year survival

* Hospitalization¤ Reduce hospitalization¤ length of stay

* Pharmacotherapy ¤ ACE inhibitors - expensive¤ AIIRB - expensive¤ Loop diuretics - expensive

DEFINITION

• Haemodynamic: Cardiac failure will result when the heart is unable to effectively manage the volume of blood

delivered to the heart.

• Pathophysiologic: Heart failure occurs when an abnormality of cardiac function causes the heart to fail to

pump blood at a rate required by the metabolizing tissues or when the heart can do so only with elevased filling pressures. This inability may be due to insufficient or defective cardiac filling and or impaired contraction.

• Clinical: Congestive heart failure represents a complex clinical syndrome characterized by

abnormalities of LV function and neurohormonal regulation, which are accompanied by effort intolerance, fluid retention and longevity.

COMPENSATORY MECHANISMS

Chamber function adaptive response

VOLUME

PRES

SUR

E

Figure 1: Relationship between end diastolic pressure and end diastolic volumeNOTE: An increase in end diastolic volume will be accompaniedby an increase in end diastolic pressure

Figure 2: Starlings cardiac output curveNOTE: An increase in end diastolic pressure will lead to anincreased cardiac output.

END DIASTOLIC PRESSURE

CA

RD

IAC

OU

TPU

T

Figure 3: Guyton’s cardiac pump function curveEND DIASTOLIC PRESSURE

CA

RD

IAC

OU

TPU

THYPER EFFECTIVE

NORMAL

HYPO EFFECTIVE

The 3 figures show the following• Increased end diastolic volume Almost linear related increase in end diastolic pressure• Increased end diastolic pressure ( increased end diastolic volume ) Increase in cardiac output• Starling “ Within physiological limits, the larger the volume of the heart the greater are the energy of

its contraction and the amount of chemical change at each contraction.” The mechanism is effective only up to a certain point: when cardiac end diastolic volume

exceeds a critical level further increases in volume will lead to a reduction in cardiac output. In the failing heart this mechanism ultimately fails to improve myocardial contractility.

VENTRICULAR REMODELLINGRegionally ischemic ventricle

Ischemic

Normal

Infarcted

After remodeling

Normal

IschemicInfarcted

VENTRICULAR REMODELLING

VENTRICULAR REMODELLING

• Left ventricular dilatation• Hypertrophy may occur• Fibrosis of infarcted tissue

• Cardiomegaly• Maintain stroke volume

• Increase in wall stress• Increase in myocardial oxygen demand

RESULT

COST

REFLEX CONTROL MECHANISMS

* Sympathetic nervous system* Renin angiotensin* Aldosterone* Vasopressin (ADH)

PERCEIVED THREAT TO CIRCULATORY HOMEOSTASIS

HypovolemiaHeart failure

Decrease in cardiac output

Reduction peripheral perfusion

Response

Hypovolemia Reduced cardiac output

THUS: The adaptive response of reduced peripheral perfusion secondary to decrease in cardiac output or hypovolemia are similar, leading to worsening cardiac failure.

ABNORMALITIES OF THE SYMPATHETIC NERVOUS SYSTEM

Cardiac output Peripheral perfusion Activation sympathetic nervous system

* peripheral resistance* afterload* metabolic cardiac demand* cardiac output

VISIOUS CYCLE OF EVENTS

RENIN ANGIOTENSIN ALDOSTERONE SYSTEM

Cardiac output

Peripheral perfusion

Renal perfusion

Angiotensinogen

Renin

Angiotensin

CONVERTING ENZYME

Angiotensin

Aldosterone secretionVasoconstriction

Increase afterload Salt & water retention

INCREASE CARDIAC WORKLOAD

WORSENING IN CARDIAC FAILURE

VASOPRESSIN

Cardiac output

Baroreceptor pressure Hypothalamic blood flow

Angiotensin

Vasopressin

Arteriolar vasoconstriction Sodium & water retention

Increase afterload Volume overload

Cardiac workload

Cardiac output

ENDOTHELIN

Endothelin levels increased

Aldosterone ANF Renin

Atrial natriuretic factor (ANF)

Cardiac output

Volume overload

Atrial dilatation

ANF

Aldosterone Vasodilatation

Neuro endocrine activation

EFFECTIVE COUNTER REGULATORY MECHANISMANF - degradation via neutral endopeptidase

Neutral endopeptidase inhibitors ANF - RX.CCF

ALDOSTERONE

Cardiac output

Renin angiotensin aldosterone

Aldosterone levels Hypercoagulation?

Na+ retention

Fluid retention

Myocardial fibrosis

LV Hypertrophy

K+

Arrythmia

Vasoconstrition

Afterload

WORSENING CARDIAC FAILURE

Important implication in pharmacological relevance for treatment of heart failure

NEW

RESULT OF REFLEX CONTROL MECHANISMS

• Increase vascular resistance ( afterload)• Salt & water retention ( preload)

Myocardial wall stress Myocardial oxygen demand

CARDIAC FAILURE BEGETS CARDIAC FAILURE

TREATMENT OF CARDIAC FAILURE

• Are presenting symptoms and signs related to cardiac failure

• What is the ethiology• Are there precipitating factors• Evaluation needed diagnosis: systolic/diastolic• How severe is the heart failure syndrome• How should the patient be treated acutely• How should the patient be treated chronically• Medication - ? Detrimental• Life style adjustment• Surgery

Questions

PRESIPITATING FACTORS• Acute myocardial ischemia• Superimposed infections• Onset of atrial fibrillation• Alcohol abuse• Poorly controlled

• Excessive dietary sodium intake• Non compliance with drug therapy• Anemia

* diabetes* hypertension* hypothyroidism

ROLE OF ANEMIAANEMIA

TACHICARDIA INCREASE MYOCARDIAL WORL LOAD WORSENING HEART FAILURE

ACTIVATION RAS WORSENING HEART FAILURE

CARDIAC FAILURE RENAL PERFUSION

RAS ACTIVATION ERITHROPOITIN WORSENING CF ANEMIA

CARDIAC FAILURE CAN PRESIPITATE ANEMIA AND ANEMIA CAN PRESIPITATE CARDIAC FAILURE

THEN

VISCIOUS CIRCLE OF EVENTS

CARDIAC FAILUREAS A RESULT OF

SYSTOLIC DYSFUNCTION

MEDICATIONS COMMONLY USED IN HEART FAILURE TREATMENT PROTOCOLS

DRUG

THIAZIDE DIURETICSHydrochlorothiazide

Clorthalidone

THIAZIDE RELATED AGENTSMetolazone

LOOP DIURETICSFurosemide

POTASSIUM-SPARINGDIURETICS

SpironolactoneTriamtereneAmiloride

RECOMMENDEDMAX DOSE (MG)

50 qd50 qd

10 bid

240 bid

100 bid100 bid40 bid

MAJOR ADVERSEREACTIONS

Postural hypotensionHypokalemia,hyperglycemica,

rash; rare severe reactionincludes pancreatitis, bone

marrow supression, andanaphylaxis

Same as thiazide diuretics

Same as thiazide diuretics

Hyperkalemia, gynecomastia(spironolactone only)

MEDICATIONS COMMONLY USED IN HEART FAILURE TREATMENT PROTOCOLS

DRUG

SELECT ACE INHIBITORSEnalaprilCaptoprilLisinoprilQuinapril

ANGIOTENSIN II RECEPTOR BLOCKERLosartan Valsartan

Candasartan

BETA BLOCKERS

DIGOXIN

HYDRALAZINE

ISOSORBIDE DINITRATE(Isordil)

ISOSORBIDE MONONITRATE(Imdur)(Ismo)

RECOMMENDEDMAX DOSE (MG)

20 bid100 mg tid

40 qd40 qd

100 mg qd

As needed

100 tid

80 tid

240 mg qd40 mg qd

MAJOR ADVERSEREACTIONS

Hypotension, hyperkalemia, renal insufficiency, cough, skin rash,

angioedema, neutropenia, nausea,dysgeusia

Diarrhea, dyspepsia, orthostatic dizziness

Cardiotoxicity, confusion, nausea,anorexia, visual disturbances

Headache, nausea, dizziness,tachycardia, lupuslike syndrome

Headache, hypotension, flushing

Same as isosorbide dinitrateSame as isosorbide dinatrate

POSITIVE INOTROPIC AGENTS

ControversyDigitalis trial

Indications

* Neutral effect on mortality* Reduction in hospitalization

* Atrial fibrillation & CHF* Symptomatic CHF despite ACE inhibitors & diuretics* Sinus tachycardia related CHF* Pregnancy and CHF

Digitalis

MILD HEART FAILURE & SINUS RHYTHM

No AF or tachycardia

Digoxin

Not necessary

INTRAVENOUS INOTROPIC THERAPY

• Adrenalin

• Dobutamine

• Dopamine

• Milrinone

• Amrinone

DiureticsMainstay treatmentRelieve volume overload

Mild volume overload

Severe volume overload

Marked volume overload / pulmonary oedema

* peripheral oedema* preload mycardial wall stress myocardial oxygen demand cardiac mechanics cardiac output

* thiazide diuretic

* loop diuretics

* intravenous furosamide

DIRECT ACTING VASODILATORS

Venodilatation

Preload

Myocardialwall stress

Peripheral art. dilatation

Afterload

Impedance ventricular emptying

CARDIAC WORK LOAD

MYOCARDIAL OXYGEN DEMAND

IMPROVE CARDIAC OUTPUT

V Heft I

V Heft II

CONSENSUS

SOLVD

SAVE

AIRE

IsosorhideHydralazin

Conventionaltherapy

Enalapril Hydralazin

Enalapril

Enalapril

Captopril

Ramipril Acute MI

STUDIES

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 20-25% (p<0.001)

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

ANGIOTESIN CONVERTING ENZYME INHIBITORS (ACEI)

Cardiac output

Renal perfusion

Inactive renin

renin

Renin substrate (angiotensinogen)

Angiotensin IAngiotensin

converting Enzyme ACE inhibitors

Angiotensin II

Pressor effect

Sympathetic stimulation

Aldosterone secretion

Renal action

ACE INHIBITORS

Preload Afterload Sympathetic outflow Aldosterone secretion

Unless contra indicated or tolerated all patients withsymptomatic heart failure should be treated with anACE Inhibitor.

Escape later

CONTRA INDICATIONS TO ACE TREATMENT

Absolute

Relative

* Cardiogenic shock* Angioneurotic oedema* Persistantly elevated potasium level* Bilateral renal artery stenosis* Pregnancy

* Hypotension - systolic BP < 90 mmHg* Impaired renal function* Hypertrophic obstructive cardiomyopathy* Tight AS or MS

ACE INHIBITORS (CONTD)

Adverse events

Predictable in the presence of

* Hyponatremia* Orthostatic hypotension* Low BP* Renal dysfunction

ACE INHIBITORS (CONTD)

General principles* Favorable effects are class related* Usually well tolerated* Avoid excessive diuresis - lower diuretics* Start low dosage* Titrate slowly upwards over weeks

AIM : minimize diuretics dosage maximize ACE inhibitors dosage

Alternatives : Nitrates & Hydralazine

US Consensus Recommendations (1996)US Consensus Recommendations (1996)

ACE inhibitors in heart failure

Consensus recommendations

All patients with heart failure due to left ventricular systolic dysfunction should receive an ACE inhibitor unless they have a contraindication to its use or cannot tolerate treatment with the drug

Effects = ACE inhibitors

Data supports use of Losartan / Valsartan /CandesartanIndication

No need to replace ACE for ARII without adequate reason

ACE Inhibitor intolerance

ANGIOTENSIN II RECEPTOR BLOCKERS

Possibly no aldosterone escape

ANGIOTENSIN II RECEPTOR BLOCKERS

ELITE 1 • LOSARTAN : CAPTOPRIL• ? REDUCTION IN MORTALITY

ELITE 2• NO DIFFERENCE IN MORTALITY

VALHeFT • VALSARTAN : PLACEBO• MORTALITY UNAFFECTED• REDUCTION IN HOSPITALIZATION• IMPROVEMENT IN EJECTION FRACTION

CHARM• ALTERNATIVE • ADDED• PRESERVED

CHARM PROGRAMME 3 Component trials comparing candasartan to placebo

in patients with symptomatic heart failure

CHARM Alternative

n = 2028 LVEF ≤ 40% ACE Inhibitor intolerant

CHARM Added

n = 2548 LVEF ≤ 40% ACE Inhibitor treated

CHARM Preserved

N = 3025 LVEF > 40% ACE InhibitorTreated / not treated

Primary outcome for each trial: CV death or CHF hospitalisationPrimary outcome for Overall Programme: All-cause death

CHARM Programme

All Cause Mortality CV Death or CHF Hospitalisation

Mortality and morbidity

Alternative

Added

Preserved

Overall0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2

0.91P = 0.005

0.77

0.85

0.89

0.84

P = 0.0004

P = 0.011

P = 0.118

P < 0.0001

Hazard Ratiop heterogeneity = 0.37

Hazard Ratiop heterogeneity = 0.43

INDICATIONS

ACE INTOLERANCE ? COMBINATION WITH ACE INHIBITORS ISCHAEMIC HEART DISEASE IMPORTANT

SYSTOLIC HEART FAILURE (IMPAIRED FX )

DIASTOLIC HEART FAILURE (PRESERVED FX)

NO INDICATION

NO INDICATION TO REPLACE ACE INHIBITORS WITH AR BLOCKERS

CALCIUM CHANNEL ANTAGONISTS

ArteriodilatorsNegative inotropic effects

* Nifedepine* Diltiazim* Verapamil

Amlodipine well tolerated

General : Caution in their use Limited role

BETA ADRENERGIC BLOCKING AGENTSDecrease sympathetic outflow

Negative chronotropic effect

Negative Inotropic effect

Beneficial

Beneficial Harmfull

In acute myocardial -

Non ischaemic heart failure - * Metoprolol* Bisoprlol* Carvedelol

CAUTION IN THEIR USE

Benefit proven

Low dosagesTitrate slowly

benefit

?

11 receptors receptors 22 receptors receptors

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

11 receptors receptors

CardiacCardiacsympathetic activitysympathetic activity

SympatheticSympatheticactivity to kidneysactivity to kidneys& blood vessels& blood vessels

VasoconstrictionVasoconstrictionSodium retentionSodium retention

CNS sympatheticCNS sympatheticoutflowoutflow

Packer, AHA 2000Packer, AHA 2000

ADRENERGIC ACTIVATION

11 receptors receptors 11 receptors receptors

CARDIOTOXICITYCARDIOTOXICITY

22 receptors receptors

Sympathetic activationSympathetic activation

BisoprololBisoprololMetoproloMetoprolollPropranololPropranolol

CarvedilolCarvedilol

Antiadrenergic therapy by blockade

Packer, AHA 2000Packer, AHA 2000

Over 13,000 patients evaluated in placebo-controlled clinical trials

Consistent improvement in cardiac function, symptoms and clinical status

Decrease in all-cause mortality by 30– 35% (p<0.0001)

Decrease in combined risk of death and hospitalisation by 25–30% (p<0.0001)

BLOCKERS

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%Risk reduction = 65%p<0.001

Packer et al (1996)

Lancet (1999)0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction = 34%Risk reduction = 34%

The MERIT-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=0.0062Risk reduction = 34%Risk reduction = 34%

US Carvedilol StudyUS Carvedilol Study

blockers in blockers in heart failure -heart failure -

all-cause mortalityall-cause mortality

CIBIS-IICIBIS-II MERIT-HFMERIT-HF

MERIT-HFMERIT-HF

CIBIS IICIBIS II

BESTBEST

Favours treatmentFavours treatment Favours placeboFavours placebo0.50.50.250.25 0.750.75 1.51.5 2.02.01.01.0

Survival effects of blockers in class IV heart failure

Packer, AHA 2000Packer, AHA 2000

Carvedilol provides comprehensive Carvedilol provides comprehensive adrenergic blockade adrenergic blockade

Adapted from M PackerAdapted from M Packer

blockadeblockade

blockadeblockadeblockadeblockade

Cardiac Cardiac outputoutput

Renal Renal blood flowblood flow

Worsening Worsening heart failureheart failure

Sodium Sodium retentionretention

CCarvedilarvedilooll PProsprospeective ctive RRaanndomdomiizedzedCCumumuulative Survival Triallative Survival Trial

COPERNICUS

Objectives and design

To determine the effect of carvedilol compared with placebo on all-cause mortality in patients with severe chronic heart failure

Randomised, placebo-controlled, parallel- group multicenter study in patients with ischaemic or non-ischaemic cardiomyopathy

DSMB recommendations (14 March 2000)

• Highly significant effect on mortality

• Exceeded predefined criteria for early termination

• Consistent across all predefined subgroups

• Serious adverse events more common on placebo

• Unanimous recommendation for early termination

• All patients should be offered open-label carvedilol

COPERNICUS

MonthsMonths

100100

8080

6060

4040

202033 9900 66 2121181815151212

% S

urvi

val

% S

urvi

val

CarvedilolCarvedilol

PlaceboPlacebo

All-cause mortalityAll-cause mortality(recent or recurrent decompensation)(recent or recurrent decompensation)

COPERNICUS

Risk reduction 34%Risk reduction 34%PP=0.00013=0.00013

All patientsAll patients

Recent or Recent or recurrentrecurrentdecompensationdecompensation

Death or anyDeath or anyhospitalisationshospitalisations

Death or Death or cardiovascularcardiovascularhospitalisationshospitalisations

Death or CHFDeath or CHFhospitalisationshospitalisations

Effect of carvedilol on morbidity and mortalityEffect of carvedilol on morbidity and mortality

0.50.50.250.25 0.750.75 1.251.251.01.000Favours treatmentFavours treatment Favours placeboFavours placebo

Packer, AHA 2000Packer, AHA 2000

COPERNICUS

CAPRICORN

Study characteristics• 1958 patients with acute myocardial infarction within

21 days• LV ejection fraction <40%, receiving an ACE

inhibitor• Randomized to placebo or carvedilol (target 25 mg

BID)• Endpoints: combined risk of death or cardiovascular

hospitalisations, all-cause mortality• Data analysis ongoing

Carvedilol Post Infarct Survival Controlin Left Ventricular Dysfunction

Packer, AHA 2000Packer, AHA 2000

SCAN

CARMENLEFT VENTRICULAR DYSFUNCTION AND REMODELLING

CARVEDILOL CARVEDILOL AND ENALAPRIL ENALAPRIL

CARVEDILOL AND ENALAPRIL MORE EFFECTIVE THAN

CARVEDILOL MORE EFFECTIVE THAN

ENALAPRIL

COMET STUDYCARVEDILOL OR METOPROLOL EUROPEAN TRIAL

0

20

30

40

10

0 1 2 3 4 5

Time (years)

Mor

talit

y (%

)

All-cause mortality

MetoprololCarvedilol

Number at riskCarvedilol 1511 1366 1259 1155 1002383Metoprolol 1518 1359 1234 1105933 352

Implications for public healthLives saved by treating1000 patients for 1 yearHOPE (ramipril) <1SOLVD Prevention (enalapril) 7SOLVD Treatment (enalapril) 17MERIT-HF (metoprolol) 38CIBIS-II (bisoprolol) 42RALES (spironolactone) 52

COPERNICUS (carvedilol) 70

Packer, AHA 2000Packer, AHA 2000

COPERNICUS

IMPLICATIONS FOR PUBLLIC HEALTH

If 1000 patients are treated per year

approximately 70 lives would be saved

Packer, AHA 2000Packer, AHA 2000

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

Why are the recommendations more restrictive than for ACE inhibitors despite the available evidence?

BLOCKERS IN HEART FAILURE

ALDOSTERONE ANTAGONISTS

RALES STUDY (Spironolactone)• 30% reduction

• Class III & IV NYHA CCF• Probably a new “old” cornerstone in pharmacological

treatment of CCF• Reason for benefit

* Mortality* Hospitalizations

* Salt & water retention* LVHT & myocardial fibrosis* Arrythmia* Afterload* Counter act aldosterone escape with ACEI

• Eplirinone * Ephesis study * Emphysis study

• Side effect profile * gynecomastia

ALDOSTERONE RECEPTOR

ANTAGONISTS

• Anemia: CCF

• DAL Heart Study – ongoing

ERITHROPOETIN ANALOGS

• Assynchronic right and left ventricular systolic function

• Right and left ventricular pacing

• Grade 4 cardiac failure

• ECG criteria

CARDIAC RESYNCHRONIZATION THERAPY

NON PHARMACOLOGICAL MANAGEMENT

• Avoidance of risk factors• Daily fluid allowance• Daily salt allowance• Rest and activity recommendations

* Initial bed rest* Late supervised / unsupervised training programs

SURGICAL MANAGEMENT

According to

Operations

* Ethiology* Left ventricular function

* Coronary bypass* Valve repair* Valve replacement* Congenital lesion surgery* Cardiac transplant

CARDIAC FAILURE AS A RESULT OF DIASTOLIC DYSFUNCTION

• Diastoly as important as systoly• Incomplete ventricular relaxation• Impaired ventricular filling• Pulmonary congestion• Attempted maintenance cardiac output

Supernormal ventricular systolic function

ETIOLOGY• Hypertrophic heart disease

• Ischemic heart disease

• Old age

• Infiltrative diseases of the myocardium

* Hypertension* Aortic stenosis* Hypertrophic obstructive cardiomyopathy

* Diffuse low / high grade

* Myofibrosis

CLINICAL PROFILE

Diastolic dysfunction

Ventricular relaxation

Impaired filling

Pulmonary congestionDyspnea

HEAVING APEX

LV HYPERTROPHY

Systolic dysfunction

Ventricular contraction

Impaired emptying

Dyspnea

APEX DISPLACED

LV DILATATION

MANAGEMENT

Ventricular contraction is normal No indication

Inotropic drugs Arteriolar dilators

Negative inotropics Negative chronotropics

Time ventricular filling Ventricular relaxation

Diuretics Pulmonary congestion

PHARMACOTHERAPYB BLOCKERSCa BLOCKERSDIURETICS

GENERAL SYSTOLIC : DIASTOLIC FAILURE

• Similar symptoms• Sometimes similar ethiology• Different mechanism of failure• Different pharmacotherapy

HOW TO DISTINGUISH

Index of suspicionClinical profile uncertainEchocardiography certain

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