CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with

CHRONIC CONGESTIVEHEART FAILUREAmerican Heart Associationin collaboration with

Sociedad Española de Cardiologia

June, 1999

Chronic Congestive Heart FailureChronic Congestive Heart Failure

Committee on Post Graduate Education,Council on Clinical Cardiology,American Heart Association

Developed in collaboration with the Sociedad Española de Cardiologia

Prepared by:Ann F. Bolger, MDJosé Lopez Sendón, MD

The content of these slides is current as of June, 1999. (Slide #62 updated 9/00)

Future revisions will be posted on the American Heart Association website (www.americanheart.org).


DEFINITION“The situation when the heart is incapable of maintaining a cardiac output adequate to accommodatemetabolic requirements and the venous return."

E. Braunwald

EVOLUTION OF CLINICAL STAGES

NORMAL

Asymptomatic LV Dysfunction

CompensatedCHF

DecompensatedCHF

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptoms ExerciseAbnormal LV fxn

Symptoms ExerciseAbnormal LV fxn

RefractoryCHF

Symptoms not controlled with treatment



DETERMINANTS OF VENTRICULAR FUNCTION

STROKE VOLUME

PRELOAD

CONTRACTILITY

CARDIAC OUTPUT

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOAD


SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms

TREATMENT OBJECTIVES


TREATMENTCorrection of aggravating factors

MEDICATIONS

EndocarditisObesityHypertensionPhysical activityDietary excess

PregnancyArrhythmias (AF)InfectionsHyperthyroidismThromboembolism


TREATMENTPHARMACOLOGIC THERAPYDIURETICSINOTROPESVASODILATORSNEUROHORMONAL ANTAGONISTSOTHERS (Anticoagulants, antiarrhythmics, etc)

Chronic Congestive Heart FailureChronic Congestive Heart Failure DRUGS

HEMODYNAMIC EFFECTS

AI

A + V

VD

Ventricular Filling Pressure

StrokeVolume

Normal

CHF


PHARMACOLOGIC THERAPY

DIURETICS

Improved symptoms

Decreasedmortality

Preventionof CHF

yes ? ?

Vasodil.(Nitrates) yes yes ?

DIGOXIN yes = minimal

INOTROPES yes mort. ?

Other neurohormonal control drugs yes + / - ?

ACEI yes YES yes

NeurohormonalControl

NO

yes

no

no

YES

YES


TREATMENTNormalAsymptomaticLV dysfunctionEF <40%

Symptomatic CHFNYHA II

InotropesSpecialized therapyTransplant

Symptomatic CHFNYHA - IV

Symptomatic CHFNYHA - III

Secondary preventionModification of physical activity

ACEI Diuretics mildNeurohormonal inhibitors Digoxin?

Loop Diuretics


Cortex

Medulla

ThiazidesInhibit active exchange of Cl-Na

in the cortical diluting segment of the ascending loop of Henle

K-sparingInhibit reabsorption of Na in the

distal convoluted and collecting tubule

Loop diuretics Inhibit exchange of Cl-Na-K in

the thick segment of the ascending loop of Henle

Loop of HenleCollecting tubule

DIURETICS


THIAZIDESMECHANISM OF ACTION

Excrete 5 - 10% of filtered Na+

Elimination of K and MgInhibit carbonic anhydrase: increase elimination of HCO3

Reabsorption of uric acidNo dose - effect relationship


LOOP DIURETICSMECHANISM OF ACTION

Excrete 15 - 20% of filtered Na+

Elimination of K+, Ca+ and Mg++

Resistance of afferent arterioles-Cortical flow and GFR- Release renal PGs- NSAIDs may antagonize diuresis


K-SPARING DIURETICS MECHANISM OF ACTION

Eliminate < 5% of filtered Na+

Inhibit exchange of Na+ for K+ or H+

Spironolactone = competitive antagonist for the aldosterone receptor

Amiloride and triamterene block Na+ channels controlled by aldosterone


Volume and preloadImprove symptoms of congestion

No direct effect on CO, butexcessive preload reduction may Improves arterial distensibilityNeurohormonal activation

Levels of NA, Ang II and ARP Exception: with spironolactone

DIURETIC EFFECTS


Na+

K+

K+

Na+

Na+ Ca++

Ca++

Na-K ATPase Na-Ca Exchange

Myofilaments

DIGOXIN

CONTRACTILITY


DIGOXIN PHARMACOKINETIC PROPERTIES

Oral absorption (%)Protein binding (%)Volume of distribution (l/Kg)Half lifeEliminationOnset (min)

i.v.oral

Maximal effect (h)i.v.oral

DurationTherapeutic level (ng/ml)

60 - 7525

6 (3-9)36 (26-46) h

Renal

5 - 3030 - 90

2 - 43 - 6

2 - 6 days0.5 - 2


DIGOXINDIGITALIZATION STRATEGIES

(mg)

0.125-0.5 / d

0.25 / d

i.v

0.5 + 0.25 / 4 h

ILD: 0.75-1

oral 12-24 h

0.75 + 0.25 / 6 h

1.25-1.5

oral 2-5 d

0.25 / 6-12 h

1.5-1.75

Loading dose (mg) Maintenance Dose

ILD = average INITIAL dose required for digoxin loading


DIGOXINHEMODYNAMIC EFFECTSCardiac outputLVejection fractionLVEDPExercisetolerance

NatriuresisNeurohormonalactivation


DIGOXIN NEUROHORMONAL EFFECTS

Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone

Normalizes arterial baroreceptors


%WORSENING

OF CHFp = 0.001DIGOXIN: 0.125 - 0.5 mg /d

(0.7 - 2.0 ng/ml)EF < 35%Class I-III (digoxin+diuretic+ACEI)Also significantly decreased exercisetime and LVEF.

DIGOXIN EFFECT ON CHF PROGRESSION

RADIANCEN Engl J Med 1993;329:1

Placebo n=93DIGOXIN Withdrawal

DIGOXIN n=85

30

10

0

20

10080200 40 60Days


50

40

30

20

10

0

Placebon=3403

DIGOXINn=3397

480 12 24 36

OVERALL MORTALITY

%

DIGN Engl J Med 1997;336:525 Months

p = 0.8


DIGOXIN LONG TERM EFFECTS

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions


DIGOXIN CLINICAL USES

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs


CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

MilrinonePiroximone

POSITIVE INOTROPES


ß-ADRENERGIC STIMULANTSCLASSIFICATION

B1 StimulantsIncrease contractility

Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol

B2 StimulantsProduce arterial vasodilatation and reduce SVR

PirbuterolCarbuterol

RimiterolFenoterol

TretoquinolSalbutamol

TerbutalineSalmefamol

SoterenolQuinterenol

MixedDopamine


DOPAMINE AND DOBUTAMINEEFFECTS

ReceptorsContractilityHeart RateArterial Press.Renal perfusionArrhythmia

DA (µg / Kg / min) Dobutamine< 2

DA1 / DA2

±±±

++-

2 - 5ß1

+++++±

> 5ß1 +

++++++±

++

ß1

++±

+++±


POSITIVE INOTROPES CONCLUSIONS

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy


CO

PRELOAD AFTERLOAD

Normal Contractility

Diminished Contractility

Normal Contractility

DiminishedContractility

VV AV

VASODILATOR DRUGSPRINCIPLES


Venous Vasodilatation

MIXEDCalcium antagonists -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

VENOUSNitrates

Molsidomine

ARTERIALMinoxidil

Hydralazine

VASODILATORSCLASSIFICATION

Arterial Vasodilatation


1- VENOUS VASODILATATION Preload

2- Coronary vasodilatation Myocardial perfusion3- Arterial vasodilatation Afterload

4- Others

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

• Cardiac output• Blood pressure


20 mg / 8h

4weeks

100

200

300

400

EXERCISE TIME,

ISOSORBIDE 5 - MONONITRATEJansen W et alMed Welt 1982;33:1756

NITRATES FUNCTIONAL CAPACITY

Control 1ST

dose

seconds

267

384 392

** **n=24


0.6

PROBABILITYOFDEATH

0

Placebo (273)Prazosin (183)Hz + ISDN (186)

MONTHS

0.7

0.5

0.3

0.4

0.2

0.1

VHefT-1N Engl J Med 1986;314:1547

NITRATESSURVIVAL

0 6 12 18 24 30 36 42


" Decrease in the effect of a drugwhen administered in a long-acting form"

NITRATESTOLERANCE

Develops with all nitratesIs dose-dependentDisappears in 24 h. after stopping the drugTolerance can be avoided

- Using the least effective dose- Creating discontinuous plasma levels


NITRATESTOLERANCE

Can be avoided or minimized- Intermittent administration- Use the lowest possible dose- Intersperse a nitrate-free interval

Allow peaks and valleys in plasma levels- Vascular smooth muscle recovers its nitrate sensitivity during the nadirs- Patches: remove after 8-10 h


NITRATES CLINICAL USES

Pulmonary congestionOrthopnea and paroxysmal nocturnal dyspneaCHF with myocardial ischemiaIn acute CHF and pulmonary edema: NTG s.l. or i.v.


VASOCONSTRICTION VASODILATATION

Kininogen

Kallikrein

Inactive Fragments

Angiotensinogen

Angiotensin IRENIN

Kininase IIInhibitor

ALDOSTERONE

SYMPATHETICVASOPRESSIN

PROSTAGLANDINStPA

ANGIOTENSIN II

BRADYKININ

ACEIMECHANISM OF ACTION

A.C.E.


ACEIHEMODYNAMIC EFFECTS

Arteriovenous Vasodilatation- PAD, PCWP and LVEDP- SVR and BP- CO and exercise tolerance

No change in HR / contractilityMVO2

Renal, coronary and cerebral flowDiuresis and natriuresis


75

95No Additional TreatmentNecessary(%)

Quinapril Heart Failure TrialJACC 1993;22:1557

ACEIFUNCTIONAL CAPACITY

Quinaprilcontinuedn=114

QuinaprilstoppedPlacebon=110

p<0.001

100

90

85

80

Weeks

Class II-III

161262 104 8 18 2014


ACEIADVANTAGES

Inhibit LV remodeling post-MIModify the progression of chronic CHF

- Survival- Hospitalizations- Improve the quality of life

In contrast to others vasodilators, do not produce neurohormonal activationor reflex tachycardiaTolerance to its effects does not develop


Placebo

Enalapril

12111098765

PROBABILITYOFDEATH

MONTHS

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6p< 0.001

p< 0.002

CONSENSUSN Engl J Med 1987;316:1429

ACEI SURVIVAL

43210


50

40

30

20

10

0

Months0 6 12

p = 0.30

2418 30 36 42 48

Enalapriln=2111

Placebon=2117

SOLVD (Prevention)N Engl J Med 1992;327:685

%MORTALITY

ACEI SURVIVAL

n = 4228No CHF symptomsEF < 35


50

40

30

20

10

0

Months0 6 12

p = 0.0036

%MORTALITY

2418 30 36 42 48

Enalapriln=1285

Placebon=1284

SOLVD (Treatment)N Engl J M 1991;325:293

ACEI SURVIVAL

n = 2589CHF - NYHA II-III- EF < 35


Mortality,%

4SAVEN Engl J Med 1992;327:669 Years

30

20

10

01 2 3

Placebo

Captopril

0

n=1115

n=1116

p=0.019² -19%

ACEI SURVIVAL

n = 22313 - 16 days post AMIEF < 4012.5 --- 150 mg / day

Asymptomatic ventriculardysfunction post MI


ACEIINDICATIONS

Clinical cardiac insufficiency- All patients

Asymptomatic ventricular dysfunction

- LVEF < 35 %


ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION

RENIN

Angiotensinogen Angiotensin I

ANGIOTENSIN II

ACEOther paths

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT2

AT1 RECEPTOR BLOCKERS

RECEPTORS


AT1 RECEPTOR BLOCKERSDRUGS

LosartanValsartanIrbersartanCandersartan

Competitive and selective blocking of AT1 receptors


ALDOSTERONE

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Collagen deposition

Fibrosis - myocardium

- vessels

Spironolactone

Edema

Arrhythmias

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

ALDOSTERONE INHIBITORS


ALDOSTERONE INHIBITORSINDICATIONS

FOR DIURETIC EFFECT• Pulmonary congestion (dyspnea)• Systemic congestion (edema)

FOR ELECTROLYTE EFFECTS• Hypo K+, Hypo Mg+

• Arrhythmias• Better than K+ supplementsFOR NEUROHORMONAL EFFECTS• Please see RALES results, N Engl J Med 1999:341:709-717


• Hyperkalemia

• Severe renal insufficiency

• Metabolic acidosis

ALDOSTERONE INHIBITORSCONTRAINDICATIONS


ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

Density of ß1 receptors Inhibit cardiotoxicity of catecholaminesNeurohormonalactivationHRAntihypertensive and antianginalAntiarrhythmicAntioxidantAntiproliferative


50

40

30

20

10

0

LV EJECTION FRACTION< 30% 30-40% > 40%

%

ß Blocker Placebo

BHATJACC 1990;16:1327

ß BLOCKERSSURVIVAL


ACEI

ß BLOCKER

Yes

No

n=2231 YES No

13.3%

19.5%

24.3%

27.7%

ß BLOCKERSMortality

SAVECirculation 1995;92:3132


ß BLOCKERSCARVEDILOL

4 studies in U.S.; 1 in Australia/New Zealand

U.S. studies with control groupMortality with Placebo 8.2%Mortality with Carvedilol 2.9%

Initial low doses, progressive

p < 0.0001


ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION

Not clearly established

Begin with very low doses

Slow augmentation of dose

Slow withdrawal ?


ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina


ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Clinical instability

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency


CALCIUM ANTAGONISTSPOTENTIAL EFFECTS

Antiischemic

Peripheral Vasodilatation

Inotropy


CALCIUM ANTAGONISTSPOSSIBLE UTILITY

Diltiazem contraindicatedVerapamil and Nifedipine not recommended

Vasoselective (amlodipine, nisoldipine),may be useful in ischemia + CHF

Amlodipine may be useful in nonischemic CHF


ANTICOAGULANTSPREVIOUS EMBOLIC EPISODEATRIAL FIBRILLATIONIdentified thrombusLV Aneurysm (3-6 mo post MI)Class III-IV in the presence of:

- EF < 30- Aneurysm or very dilated LV

PhlebitisProlonged bed rest


ANTIARRHYTHMICSSustained VT, with/without symptoms

- ß Blockers- Amiodarone

Sudden death from VF- Consider implantable defibrillator


ANTIARRHYTHMICSMORTALITY

EMIATAm Coll Cardiol 1996

13.6 13.7

Placebo Amiodarone0

5

10

15

101 / 743 102 / 743

MORTALITYAT 2 YEARS

%n=14865-21d post MIAmiodarone 200 mg/dFollow up 1 - 4 years

ns


American Heart Associationin collaboration withSociedad Española de Cardiologia

CHRONIC CONGESTIVE

HEART FAILURE

The content of these slides is current as of June, 1999.Future revisions will be posted on the American Heart Association website (www.americanheart.org)

CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with

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