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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).
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DETERMINANTS OF VENTRICULAR FUNCTION
STROKE VOLUME
PRELOAD
CONTRACTILITY
CARDIAC OUTPUT
HEART RATE
- Synergistic LV contraction - LV wall integrity - Valvular competence
AFTERLOAD
Chronic Congestive Heart FailureChronic Congestive Heart Failure
SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms
TREATMENT OBJECTIVES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
TREATMENTCorrection of aggravating factors
MEDICATIONS
EndocarditisObesityHypertensionPhysical activityDietary excess
PregnancyArrhythmias (AF)InfectionsHyperthyroidismThromboembolism
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
Na+
K+
K+
Na+
Na+ Ca++
Ca++
Na-K ATPase Na-Ca Exchange
Myofilaments
DIGOXIN
CONTRACTILITY
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIGOXINHEMODYNAMIC EFFECTSCardiac outputLVejection fractionLVEDPExercisetolerance
NatriuresisNeurohormonalactivation
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIGOXIN NEUROHORMONAL EFFECTS
Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone
Normalizes arterial baroreceptors
Chronic Congestive Heart FailureChronic Congestive Heart Failure
%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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIGOXIN LONG TERM EFFECTS
Survival similar to placebo
Fewer hospital admissions
More serious arrhythmias
More myocardial infarctions
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIGOXIN CLINICAL USES
AF with rapid ventricular response
CHF refractory to other drugs
Other indications?
Can be combined with other drugs
Chronic Congestive Heart FailureChronic Congestive Heart Failure
CARDIAC GLYCOSIDES
SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists
PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone
Others
MilrinonePiroximone
POSITIVE INOTROPES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC STIMULANTSCLASSIFICATION
B1 StimulantsIncrease contractility
Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol
B2 StimulantsProduce arterial vasodilatation and reduce SVR
PirbuterolCarbuterol
RimiterolFenoterol
TretoquinolSalbutamol
TerbutalineSalmefamol
SoterenolQuinterenol
MixedDopamine
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DOPAMINE AND DOBUTAMINEEFFECTS
ReceptorsContractilityHeart RateArterial Press.Renal perfusionArrhythmia
DA (µg / Kg / min) Dobutamine< 2
DA1 / DA2
±±±
++-
2 - 5ß1
+++++±
> 5ß1 +
++++++±
++
ß1
++±
+++±
Chronic Congestive Heart FailureChronic Congestive Heart Failure
POSITIVE INOTROPES CONCLUSIONS
May increase mortality
Safer in lower doses
Use only in refractory CHF
NOT for use as chronic therapy
Chronic Congestive Heart FailureChronic Congestive Heart Failure
CO
PRELOAD AFTERLOAD
Normal Contractility
Diminished Contractility
Normal Contractility
DiminishedContractility
VV AV
VASODILATOR DRUGSPRINCIPLES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
Venous Vasodilatation
MIXEDCalcium antagonists -adrenergic Blockers
ACEIAngiotensin II inhibitors
K+ channel activatorsNitroprusside
VENOUSNitrates
Molsidomine
ARTERIALMinoxidil
Hydralazine
VASODILATORSCLASSIFICATION
Arterial Vasodilatation
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
" 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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
NITRATES CLINICAL USES
Pulmonary congestionOrthopnea and paroxysmal nocturnal dyspneaCHF with myocardial ischemiaIn acute CHF and pulmonary edema: NTG s.l. or i.v.
Chronic Congestive Heart FailureChronic Congestive Heart Failure
VASOCONSTRICTION VASODILATATION
Kininogen
Kallikrein
Inactive Fragments
Angiotensinogen
Angiotensin IRENIN
Kininase IIInhibitor
ALDOSTERONE
SYMPATHETICVASOPRESSIN
PROSTAGLANDINStPA
ANGIOTENSIN II
BRADYKININ
ACEIMECHANISM OF ACTION
A.C.E.
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ACEIINDICATIONS
Clinical cardiac insufficiency- All patients
Asymptomatic ventricular dysfunction
- LVEF < 35 %
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
AT1 RECEPTOR BLOCKERSDRUGS
LosartanValsartanIrbersartanCandersartan
Competitive and selective blocking of AT1 receptors
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
• Hyperkalemia
• Severe renal insufficiency
• Metabolic acidosis
ALDOSTERONE INHIBITORSCONTRAINDICATIONS
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS
Density of ß1 receptors Inhibit cardiotoxicity of catecholaminesNeurohormonalactivationHRAntihypertensive and antianginalAntiarrhythmicAntioxidantAntiproliferative
Chronic Congestive Heart FailureChronic Congestive Heart Failure
50
40
30
20
10
0
LV EJECTION FRACTION< 30% 30-40% > 40%
%
ß Blocker Placebo
BHATJACC 1990;16:1327
ß BLOCKERSSURVIVAL
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ACEI
ß BLOCKER
Yes
No
n=2231 YES No
13.3%
19.5%
24.3%
27.7%
ß BLOCKERSMortality
SAVECirculation 1995;92:3132
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION
Not clearly established
Begin with very low doses
Slow augmentation of dose
Slow withdrawal ?
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?
Suspected adrenergic activation
Arrhythmias
Hypertension
Angina
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS
Hypotension: BP < 100 mmHg
Bradycardia: HR < 50 bpm
Clinical instability
Chronic bronchitis, ASTHMA
Severe chronic renal insufficiency
Chronic Congestive Heart FailureChronic Congestive Heart Failure
CALCIUM ANTAGONISTSPOTENTIAL EFFECTS
Antiischemic
Peripheral Vasodilatation
Inotropy
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ANTIARRHYTHMICSSustained VT, with/without symptoms
- ß Blockers- Amiodarone
Sudden death from VF- Consider implantable defibrillator
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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)