Chronic chf

CHRONIC CONGESTIVE

HEART FAILUREAmerican Heart Association

in collaboration with

Sociedad Española de Cardiologia

June, 1999

CHRONIC CONGESTIVE

HEART FAILUREAmerican Heart Association

in 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).

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).


DEFINITIONDEFINITION

“The situation when the heart is

incapable of maintaining a cardiac

output adequate to accommodate

metabolic requirements and the

venous return."

“The situation when the heart is

incapable of maintaining a cardiac

output adequate to accommodate

metabolic requirements and the

venous return."E. BraunwaldE. Braunwald

EVOLUTION OF CLINICAL STAGES

EVOLUTION OF CLINICAL STAGES

NORMALNORMAL

Asymptomatic LV DysfunctionAsymptomatic LV Dysfunction

CompensatedCHF

CompensatedCHF

DecompensatedCHF

DecompensatedCHF

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptoms ExerciseAbnormal LV fxn

No symptoms ExerciseAbnormal LV fxn

Symptoms ExerciseAbnormal LV fxn

Symptoms ExerciseAbnormal LV fxn

RefractoryCHF

RefractoryCHF

Symptoms not controlled with treatmentSymptoms not controlled with treatment



DETERMINANTS OF VENTRICULAR FUNCTION

DETERMINANTS OF VENTRICULAR FUNCTION

STROKE VOLUMESTROKE VOLUME

PRELOADPRELOAD

CONTRACTILITYCONTRACTILITY

CARDIAC OUTPUTCARDIAC OUTPUT

HEART RATE

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOADAFTERLOAD


SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms

SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms

TREATMENT OBJECTIVESTREATMENT OBJECTIVES


TREATMENTCorrection of aggravating factors

TREATMENTCorrection of aggravating factors

MEDICATIONSMEDICATIONS

Endocarditis

Obesity

Hypertension

Physical activity

Dietary excess

Endocarditis

Obesity

Hypertension

Physical activity

Dietary excess

Pregnancy

Arrhythmias (AF)

Infections

Hyperthyroidism

Thromboembolism

Pregnancy

Arrhythmias (AF)

Infections

Hyperthyroidism

Thromboembolism


TREATMENTPHARMACOLOGIC THERAPY

TREATMENTPHARMACOLOGIC THERAPY

DIURETICS

INOTROPES

VASODILATORS

NEUROHORMONAL ANTAGONISTS

OTHERS (Anticoagulants, antiarrhythmics, etc)

DIURETICS

INOTROPES

VASODILATORS

NEUROHORMONAL ANTAGONISTS

OTHERS (Anticoagulants, antiarrhythmics, etc)

Chronic Congestive Heart FailureChronic Congestive Heart Failure DRUGS

HEMODYNAMIC EFFECTSDRUGS

HEMODYNAMIC EFFECTS

AAII

A + VA + V

VV

DD

Ventricular Filling PressureVentricular Filling Pressure

StrokeVolumeStrokeVolume

NormalNormal

CHFCHF


PHARMACOLOGIC THERAPYPHARMACOLOGIC THERAPY

DIURETICSDIURETICS

Improved symptomsImproved symptoms

Decreasedmortality

Decreasedmortality

Preventionof CHF

Preventionof CHF

yesyes ?? ??

Vasodil.(Nitrates)Vasodil.(Nitrates) yesyes yesyes ??

DIGOXINDIGOXIN yesyes == minimalminimal

INOTROPESINOTROPES yesyes mort. mort. ??

Other neurohormonal control drugsOther neurohormonal control drugs

yesyes + / -+ / - ??

ACEIACEI yesyes YESYES yesyes

NeurohumoralControl

NeurohumoralControl

NONO

yesyes

nono

nono

YESYES

YESYES


TREATMENTTREATMENTNormalNormal

AsymptomaticLV dysfunctionEF <40%

AsymptomaticLV dysfunctionEF <40%

Symptomatic CHFNYHA II

Symptomatic CHFNYHA II

InotropesSpecialized therapyTransplant

InotropesSpecialized therapyTransplant

Symptomatic CHFNYHA - IV

Symptomatic CHFNYHA - IV

Symptomatic CHFNYHA - III

Symptomatic CHFNYHA - III

Secondary preventionModification of physical activitySecondary preventionModification of physical activity

ACEIACEI

Diuretics mild

Neurohormonal inhibitors Digoxin?

Diuretics mild

Neurohormonal inhibitors Digoxin?

Loop DiureticsLoop Diuretics


CortexCortex

MedullaMedulla

ThiazidesInhibit active exchange of Cl-Na

in the cortical diluting segment of the ascending loop of Henle

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

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 diuretics Inhibit exchange of Cl-Na-K in

the thick segment of the ascending loop of Henle

Loop of HenleLoop of HenleCollecting tubuleCollecting tubule

DIURETICSDIURETICS


THIAZIDESMECHANISM OF ACTION

THIAZIDESMECHANISM OF ACTION

Excrete 5 - 10% of filtered Na+

Elimination of K

Inhibit carbonic anhydrase: increase elimination of HCO3

Excretion of uric acid, Ca and Mg

No dose - effect relationship


Elimination of K

Inhibit carbonic anhydrase: increase elimination of HCO3

Excretion of uric acid, Ca and Mg

No dose - effect relationship


LOOP DIURETICSMECHANISM OF ACTION

LOOP DIURETICSMECHANISM OF ACTION


Elimination of K+, Ca+ and Mg++

Resistance of afferent arterioles

-Cortical flow and GFR

- Release renal PGs

- NSAIDs may antagonize diuresis


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

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

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, but

excessive preload reduction may

Improves arterial distensibility

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

Volume and preloadImprove symptoms of congestion

No direct effect on CO, but

excessive preload reduction may

Improves arterial distensibility

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

DIURETIC EFFECTSDIURETIC EFFECTS


DIURETICS ADVERSE REACTIONS

Thiazide and Loop Diuretics

DIURETICS ADVERSE REACTIONS

Thiazide and Loop Diuretics Changes in electrolytes:

Volume Na+, K+, Ca++, Mg++ metabolic alkalosis

Metabolic changes: glycemia, uremia, gout LDL-C and TG

Cutaneous allergic reactions

Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis

Metabolic changes: glycemia, uremia, gout LDL-C and TG

Cutaneous allergic reactions


DIURETICSADVERSE REACTIONS


DIURETICSADVERSE REACTIONS


Idiosyncratic effects:Blood dyscrasia, cholestatic jaundice and acute pancreatitis

Gastrointestinal effectsGenitourinary effects:

Impotence and menstrual cramps

Deafness, nephrotoxicity (Loop diuretics)

Idiosyncratic effects:Blood dyscrasia, cholestatic jaundice and acute pancreatitis

Gastrointestinal effectsGenitourinary effects:

Impotence and menstrual cramps

Deafness, nephrotoxicity (Loop diuretics)


DIURETICSADVERSE REACTIONSK-SPARING DIURETICS

DIURETICSADVERSE REACTIONSK-SPARING DIURETICS

Changes in electrolytes:

Na+, K+, acidosis

Musculoskeletal:

Cramps, weakness

Cutaneous allergic reactions :

Rash, pruritis

Changes in electrolytes:

Na+, K+, acidosis

Musculoskeletal:

Cramps, weakness

Cutaneous allergic reactions :

Rash, pruritis


Na+Na+

K+K+

K+K+

Na+Na+

Na+Na+ Ca++Ca++

Ca++Ca++

Na-K ATPaseNa-K ATPase Na-Ca ExchangeNa-Ca Exchange

MyofilamentsMyofilaments

DIGOXINDIGOXIN

CONTRACTILITYCONTRACTILITY


DIGOXIN PHARMACOKINETIC PROPERTIES

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)

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

60 - 7525

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

Renal

5 - 3030 - 90

2 - 43 - 6

2 - 6 days0.5 - 2


DIGOXINDIGITALIZATION STRATEGIES

DIGOXINDIGITALIZATION STRATEGIES

(mg)

0.125-0.5 / d

0.25 / d

(mg)

0.125-0.5 / d

0.25 / d

i.v

0.5 + 0.25 / 4 h

ILD: 0.75-1

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 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

oral 2-5 d

0.25 / 6-12 h

1.5-1.75

Loading dose (mg)Loading dose (mg) Maintenance Dose

Maintenance Dose

ILD = average INITIAL dose required for digoxin loading

ILD = average INITIAL dose required for digoxin loading


DIGOXINHEMODYNAMIC EFFECTS

DIGOXINHEMODYNAMIC EFFECTS

Cardiac output

LVejection fraction

LVEDP

Exercisetolerance

Natriuresis

Neurohormonalactivation

Cardiac output

LVejection fraction

LVEDP

Exercisetolerance

Natriuresis



DIGOXIN NEUROHORMONAL EFFECTS

DIGOXIN NEUROHORMONAL EFFECTS

Plasma Noradrenaline

Peripheral nervous system activity

RAAS activity

Vagal tone

Normalizes arterial baroreceptors

Plasma Noradrenaline

Peripheral nervous system activity

RAAS activity

Vagal tone

Normalizes arterial baroreceptors


%WORSENING

OF CHF

%WORSENING

OF CHFp = 0.001p = 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: 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

DIGOXIN EFFECT ON CHF PROGRESSION

RADIANCEN Engl J Med 1993;329:1RADIANCEN Engl J Med 1993;329:1

Placebo n=93DIGOXIN Withdrawal

Placebo n=93DIGOXIN Withdrawal

DIGOXIN n=85DIGOXIN n=85

3030

1010

00

2020

1001008080202000 4040 6060DaysDays


5050

4040

3030

2020

1010

00

Placebon=3403Placebon=3403

DIGOXINn=3397DIGOXINn=3397

484800 1212 2424 3636

OVERALL MORTALITY OVERALL MORTALITY

%%

DIGN Engl J Med 1997;336:525

DIGN Engl J Med 1997;336:525 MonthsMonths

p = 0.8p = 0.8


DIGOXIN LONG TERM EFFECTS

DIGOXIN LONG TERM EFFECTS

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions


DIGOXIN CLINICAL USES

DIGOXIN CLINICAL USES

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs


DIGOXINCONTRAINDICATIONS

DIGOXINCONTRAINDICATIONS

ABSOLUTE:- Digoxin toxicity

RELATIVE- Advanced A-V block without pacemaker- Bradycardia or sick sinus without PM- PVC’s and TV- Marked hypokalemia- W-P-W with atrial fibrillation

ABSOLUTE:- Digoxin toxicity

RELATIVE- Advanced A-V block without pacemaker- Bradycardia or sick sinus without PM- PVC’s and TV- Marked hypokalemia- W-P-W with atrial fibrillation


DIGOXIN TOXICITYCARDIAC MANIFESTATIONS

DIGOXIN TOXICITYCARDIAC MANIFESTATIONS

ARRHYTHMIAS :- Ventricular (PVCs, TV, VF)- Supraventricular (PACs, SVT)

BLOCKS:- S-A and A-V blocks

CHF EXACERBATION

ARRHYTHMIAS :- Ventricular (PVCs, TV, VF)- Supraventricular (PACs, SVT)

BLOCKS:- S-A and A-V blocks

CHF EXACERBATION


DIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONSDIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONS

GASTROINTESTINAL:- Nausea, vomiting, diarrhea

NERVOUS:- Depression, disorientation, paresthesias

VISUAL:- Blurred vision, scotomas and yellow-green

vision HYPERESTROGENISM:

- Gynecomastia, galactorrhea

GASTROINTESTINAL:- Nausea, vomiting, diarrhea

NERVOUS:- Depression, disorientation, paresthesias

VISUAL:- Blurred vision, scotomas and yellow-green

vision HYPERESTROGENISM:

- Gynecomastia, galactorrhea


CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

MilrinonePiroximoneMilrinonePiroximone

POSITIVE INOTROPESPOSITIVE INOTROPES


ß-ADRENERGIC STIMULANTS

CLASSIFICATION

ß-ADRENERGIC STIMULANTS

CLASSIFICATION

B1 StimulantsIncrease contractility

Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol

B1 StimulantsIncrease contractility

Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol

B2 StimulantsProduce arterial vasodilatation and reduce SVR

B2 StimulantsProduce arterial vasodilatation and reduce SVR

PirbuterolCarbuterolPirbuterolCarbuterol

RimiterolFenoterolRimiterolFenoterol

TretoquinolSalbutamolTretoquinolSalbutamol

TerbutalineSalmefamolTerbutalineSalmefamol

SoterenolQuinterenolSoterenolQuinterenol

MixedMixedDopamineDopamine


DOPAMINE AND DOBUTAMINEEFFECTS

DOPAMINE AND DOBUTAMINEEFFECTS

ReceptorsReceptors

ContractilityContractility

Heart RateHeart Rate

Arterial Press.Arterial Press.

Renal perfusionRenal perfusion

ArrhythmiaArrhythmia

DA (µg / Kg / min)DA (µg / Kg / min) DobutamineDobutamine

< 2< 2DA1 / DA2DA1 / DA2

±±

±±

±±

++++

--

2 - 52 - 5ß1ß1

++++

++

++

++

±±

> 5> 5ß1 + ß1 +

++++

++++

++++

±±

++++

ß1ß1

++++

±±

++++

++

±±


POSITIVE INOTROPES CONCLUSIONS

POSITIVE INOTROPES CONCLUSIONS

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy


COCO

PRELOADPRELOAD AFTERLOADAFTERLOAD

Normal ContractilityNormal Contractility

Diminished Contractility Diminished Contractility

Normal ContractilityNormal Contractility

DiminishedContractility DiminishedContractility

VVVV AVAV

VASODILATOR DRUGSPRINCIPLES

VASODILATOR DRUGSPRINCIPLES


Venous Vasodilatation

Venous Vasodilatation

MIXEDCalcium antagonists -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

MIXEDCalcium antagonists -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

VENOUSNitrates

Molsidomine

VENOUSNitrates

Molsidomine

ARTERIALMinoxidil

Hydralazine

ARTERIALMinoxidil

Hydralazine

VASODILATORSCLASSIFICATIONVASODILATORSCLASSIFICATION

Arterial Vasodilatation

Arterial Vasodilatation


1- VENOUS VASODILATATION Preload

2- Coronary vasodilatation Myocardial perfusion

3- Arterial vasodilatation Afterload

4- Others

1- VENOUS VASODILATATION Preload

2- Coronary vasodilatation Myocardial perfusion

3- Arterial vasodilatation Afterload

4- Others

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

NITRATESHEMODYNAMIC EFFECTS

• Cardiac output

• Blood pressure

• Cardiac output

• Blood pressure


20 mg / 8h20 mg / 8h

4weeks

4weeks

100100

200200

300300

400400

EXERCISE TIME, EXERCISE TIME,

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

NITRATES FUNCTIONAL CAPACITY

NITRATES FUNCTIONAL CAPACITY

ControlControl 1ST

dose1ST

dose

secondsseconds

267

384 392

**** ****n=24n=24


0.60.6

PROBABILITYOFDEATH

PROBABILITYOFDEATH

00

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

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

MONTHSMONTHS

0.70.7

0.50.5

0.30.3

0.40.4

0.20.2

0.10.1

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

NITRATESSURVIVALNITRATESSURVIVAL

00 66 1212 1818 2424 3030 3636 4242


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

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

NITRATESTOLERANCE

NITRATESTOLERANCE

Develops with all nitrates

Is dose-dependent

Disappears in 24 h. after stopping the drug

Tolerance can be avoided- Using the least effective dose- Creating discontinuous plasma levels

Develops with all nitrates

Is dose-dependent

Disappears in 24 h. after stopping the drug

Tolerance can be avoided- Using the least effective dose- Creating discontinuous plasma levels


NITRATESTOLERANCE

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

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


s.l. NTG

ISDN

I 5-MN

Percutaneous NTG

s.l. NTG

ISDN

I 5-MN

Percutaneous NTG

TOLERANCE

TOLERANCE

HALF

LIFE

HALF

LIFE

NITRATESTOLERANCE

NITRATESTOLERANCE


NITRATESCONTRAINDICATIONS

NITRATESCONTRAINDICATIONS

Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

WITH CAUTION:WITH CAUTION:� Constrictive pericarditis� Intracranial hypertension� Hypertrophic cardiomyopathy

� Constrictive pericarditis� Intracranial hypertension� Hypertrophic cardiomyopathy


NITRATES CLINICAL USES

NITRATES CLINICAL USES

Pulmonary congestion

Orthopnea and paroxysmal nocturnal

dyspnea

CHF with myocardial ischemia

In acute CHF and pulmonary edema:

NTG s.l. or i.v.

Pulmonary congestion

Orthopnea and paroxysmal nocturnal

dyspnea

CHF with myocardial ischemia

In acute CHF and pulmonary edema:

NTG s.l. or i.v.


VASOCONSTRICTIONVASOCONSTRICTION VASODILATATION VASODILATATION

KininogenKininogen

KallikreinKallikrein

Inactive FragmentsInactive Fragments

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

RENINRENIN

Kininase IIKininase IIInhibitorInhibitor

ALDOSTERONEALDOSTERONE

SYMPATHETICSYMPATHETICVASOPRESSINVASOPRESSIN

PROSTAGLANDINSPROSTAGLANDINS

tPAtPA

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

ACEIMECHANISM OF ACTION

ACEIMECHANISM OF ACTION

A.C.E.A.C.E.


ACEIHEMODYNAMIC EFFECTS

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

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


7575

9595No Additional TreatmentNecessary(%)

No Additional TreatmentNecessary(%)

Quinapril Heart Failure TrialJACC 1993;22:1557Quinapril Heart Failure TrialJACC 1993;22:1557

ACEIFUNCTIONAL CAPACITY

ACEIFUNCTIONAL CAPACITY

Quinaprilcontinuedn=114

Quinaprilcontinuedn=114

QuinaprilstoppedPlacebon=110

QuinaprilstoppedPlacebon=110

p<0.001p<0.001

100100

9090

8585

8080

WeeksWeeks

Class II-IIIClass II-III

161612126622 101044 88 1818 20201414


ACEIADVANTAGES

ACEIADVANTAGES

Inhibit LV remodeling post-MI

Modify the progression of chronic CHF

- Survival

- Hospitalizations

- Improve the quality of life

In contrast to others vasodilators, do not produce neurohormonal activationor reflex tachycardia

Tolerance to its effects does not develop

Inhibit LV remodeling post-MI

Modify the progression of chronic CHF

- Survival

- Hospitalizations

- Improve the quality of life

In contrast to others vasodilators, do not produce neurohormonal activationor reflex tachycardia

Tolerance to its effects does not develop


PlaceboPlacebo

EnalaprilEnalapril

1212111110109988776655

PROBABILITYOFDEATH

PROBABILITYOFDEATH

MONTHSMONTHS

0.10.1

0.80.8

00

0.20.2

0.30.3

0.70.7

0.40.4

0.50.5

0.60.6p< 0.001p< 0.001

p< 0.002p< 0.002

CONSENSUSN Engl J Med 1987;316:1429CONSENSUSN Engl J Med 1987;316:1429

ACEI SURVIVALACEI SURVIVAL

4433221100


5050

4040

3030

2020

1010

00

MonthsMonths00 66 1212

p = 0.30p = 0.30

24241818 3030 3636 4242 4848

Enalapriln=2111Enalapriln=2111


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

%MORTALITY

%MORTALITY


n = 4228No CHF symptomsEF < 35

n = 4228No CHF symptomsEF < 35


5050

4040

3030

2020

1010

00

MonthsMonths00 66 1212

p = 0.0036p = 0.0036

%MORTALITY

%MORTALITY

24241818 3030 3636 4242 4848

Enalapriln=1285Enalapriln=1285


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


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

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


Mortality,%

Mortality,%

44SAVEN Engl J Med 1992;327:669

SAVEN Engl J Med 1992;327:669

YearsYears

3030

2020

1010

0011 22 33

PlaceboPlacebo

CaptoprilCaptopril

00

n=1115n=1115

n=1116n=1116

p=0.019p=0.019² -19%² -19%


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

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

Asymptomatic ventriculardysfunction post MI

Asymptomatic ventriculardysfunction post MI


ISIS-4ISIS-4

GISSI-3GISSI-3

SAVESAVE

SMILESMILE

AIREAIRE

ACEIACEI BenefitBenefit Pt SelectionPt Selection

CaptoprilCaptopril

LisinoprilLisinopril

CaptoprilCaptopril

ZofenoprilZofenopril

RamiprilRamipril

0.5 / 5 wk0.5 / 5 wk

0.8 / 6 wk0.8 / 6 wk

4.2 / 3.5 yr4.2 / 3.5 yr

4.1 / 1 yr4.1 / 1 yr

6 / 1 yr6 / 1 yr

All with AMIAll with AMI

All with AMIAll with AMI

EF < 40asymptomatic

EF < 40asymptomatic

Ant. AMI, No TRLAnt. AMI, No TRL

Clinical CHFClinical CHF

TRACETRACE TrandolaprilTrandolapril 7.6 / 3 yr7.6 / 3 yr Vent Dysfx / Clinical CHFEF < 35

Vent Dysfx / Clinical CHFEF < 35

ACEISURVIVAL POST MI

ACEISURVIVAL POST MI


ACEIINDICATIONS

ACEIINDICATIONS

Clinical cardiac insufficiency- All patients

Asymptomatic ventricular dysfunction

- LVEF < 35 %

Clinical cardiac insufficiency- All patients

Asymptomatic ventricular dysfunction

- LVEF < 35 %


ACEIUNDESIRABLE EFFECTS

ACEIUNDESIRABLE EFFECTS

Inherent in their mechanism of action- Hypotension- Hyperkalemia- Angioneurotic edema

Due to their chemical structure- Cutaneous eruptions- Neutropenia,

thrombocytopenia- Digestive upset

Inherent in their mechanism of action- Hypotension- Hyperkalemia- Angioneurotic edema

Due to their chemical structure- Cutaneous eruptions- Neutropenia,

thrombocytopenia- Digestive upset

- Dry cough- Renal Insuff.- Dry cough- Renal Insuff.

- Dysgeusia- Proteinuria- Dysgeusia- Proteinuria


ACEICONTRAINDICATIONS

ACEICONTRAINDICATIONS

Renal artery stenosis

Renal insufficiency

Hyperkalemia

Arterial hypotension

Intolerance (due to side effects)

Renal artery stenosis

Renal insufficiency

Hyperkalemia

Arterial hypotension

Intolerance (due to side effects)


ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION

ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION

RENINRENIN

AngiotensinogenAngiotensinogen Angiotensin I

ANGIOTENSIN II

Angiotensin I

ANGIOTENSIN II

ACEACEOther pathsOther paths

VasoconstrictionVasoconstriction Proliferative Action

Proliferative Action

VasodilatationVasodilatation Antiproliferative Action

Antiproliferative Action

AT1 AT1 AT2AT2

AT1 RECEPTOR BLOCKERS

AT1 RECEPTOR BLOCKERS

RECEPTORSRECEPTORS


AT1 RECEPTOR BLOCKERSDRUGS

AT1 RECEPTOR BLOCKERSDRUGS

Losartan

Valsartan

Irbersartan

Candersartan

Losartan

Valsartan

Irbersartan

Candersartan

Competitive and selective

blocking of AT1 receptors

Competitive and selective

blocking of AT1 receptors


ALDOSTERONEALDOSTERONE

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Collagen

deposition

Fibrosis - myocardium

- vessels

SpironolactoneSpironolactone

Edema Edema

Arrhythmias Arrhythmias

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

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

ALDOSTERONE INHIBITORSALDOSTERONE INHIBITORS


ALDOSTERONE INHIBITORSINDICATIONSALDOSTERONE 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

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

• Hyperkalemia

• Severe renal insufficiency

• Metabolic acidosis

ALDOSTERONE INHIBITORSCONTRAINDICATIONSALDOSTERONE INHIBITORSCONTRAINDICATIONS


ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines


HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines


HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative


5050

4040

3030

2020

1010

00

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

%%

ß Blockerß Blocker Placebo Placebo

BHATJACC 1990;16:1327BHATJACC 1990;16:1327

ß BLOCKERSSURVIVAL

ß BLOCKERSSURVIVAL


ACEIACEI

ß BLOCKERß BLOCKER

YesYes

NoNo

n=2231n=2231 YESYES NoNo

13.3%13.3%

19.5%19.5%

24.3%24.3%

27.7%27.7%

ß BLOCKERSMortality

ß BLOCKERSMortality

SAVECirculation 1995;92:3132

SAVECirculation 1995;92:3132


ß BLOCKERSCARVEDILOLß BLOCKERSCARVEDILOL

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

U.S. studies with control group

Mortality with Placebo 8.2%

Mortality with Carvedilol 2.9%

Initial low doses, progressive

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

U.S. studies with control group

Mortality with Placebo 8.2%

Mortality with Carvedilol 2.9%

Initial low doses, progressive

p < 0.0001p < 0.0001


ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATIONß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION

Not clearly established

Begin with very low doses

Slow augmentation of dose

Slow withdrawal ?

Not clearly established

Begin with very low doses

Slow augmentation of dose

Slow withdrawal ?


ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?

ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina


ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS

ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Clinical instability

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Clinical instability

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency


CALCIUM ANTAGONISTSPOTENTIAL EFFECTS

CALCIUM ANTAGONISTSPOTENTIAL EFFECTS

Antiischemic

Peripheral Vasodilatation

Inotropy

Antiischemic

Peripheral Vasodilatation

Inotropy


CALCIUM ANTAGONISTSPOSSIBLE UTILITY

CALCIUM ANTAGONISTSPOSSIBLE UTILITY

Diltiazem contraindicated

Verapamil and Nifedipine not recommended

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

Amlodipine may be useful in nonischemic CHF

Diltiazem contraindicated

Verapamil and Nifedipine not recommended

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

Amlodipine may be useful in nonischemic CHF


ANTICOAGULANTSANTICOAGULANTSPREVIOUS 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

PREVIOUS 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


ANTIARRHYTHMICSANTIARRHYTHMICS

Sustained VT, with/without symptoms- ß Blockers- Amiodarone

Sudden death from VF- Consider implantable defibrillator

Sustained VT, with/without symptoms- ß Blockers- Amiodarone

Sudden death from VF- Consider implantable defibrillator


ANTIARRHYTHMICSMORTALITY

ANTIARRHYTHMICSMORTALITY

EMIATAm Coll Cardiol 1996EMIATAm Coll Cardiol 1996

13.613.6 13.713.7

PlaceboPlacebo AmiodaroneAmiodarone00

55

1010

1515

101 / 743 102 / 743

MORTALITYAT 2 YEARS

%

MORTALITYAT 2 YEARS

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

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

nsns


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)

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 chf

Health & Medicine

Transcript of Chronic chf