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).
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms
SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms
TREATMENT OBJECTIVESTREATMENT OBJECTIVES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
LOOP DIURETICSMECHANISM OF ACTION
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
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
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIURETICSADVERSE REACTIONS
Thiazide and Loop Diuretics
DIURETICSADVERSE REACTIONS
Thiazide and Loop Diuretics
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)
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
DIGOXINHEMODYNAMIC EFFECTS
DIGOXINHEMODYNAMIC EFFECTS
Cardiac output
LVejection fraction
LVEDP
Exercisetolerance
Natriuresis
Neurohormonalactivation
Cardiac output
LVejection fraction
LVEDP
Exercisetolerance
Natriuresis
Neurohormonalactivation
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
%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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
CARDIAC GLYCOSIDES
SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists
PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone
Others
CARDIAC GLYCOSIDES
SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists
PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone
Others
MilrinonePiroximoneMilrinonePiroximone
POSITIVE INOTROPESPOSITIVE INOTROPES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
++++
±±
++++
++
±±
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
COCO
PRELOADPRELOAD AFTERLOADAFTERLOAD
Normal ContractilityNormal Contractility
Diminished Contractility Diminished Contractility
Normal ContractilityNormal Contractility
DiminishedContractility DiminishedContractility
VVVV AVAV
VASODILATOR DRUGSPRINCIPLES
VASODILATOR DRUGSPRINCIPLES
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
" 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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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.
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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.
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
5050
4040
3030
2020
1010
00
MonthsMonths00 66 1212
p = 0.30p = 0.30
24241818 3030 3636 4242 4848
Enalapriln=2111Enalapriln=2111
Placebon=2117Placebon=2117
SOLVD (Prevention)N Engl J Med 1992;327:685SOLVD (Prevention)N Engl J Med 1992;327:685
%MORTALITY
%MORTALITY
ACEI SURVIVALACEI SURVIVAL
n = 4228No CHF symptomsEF < 35
n = 4228No CHF symptomsEF < 35
Chronic Congestive Heart FailureChronic Congestive Heart Failure
5050
4040
3030
2020
1010
00
MonthsMonths00 66 1212
p = 0.0036p = 0.0036
%MORTALITY
%MORTALITY
24241818 3030 3636 4242 4848
Enalapriln=1285Enalapriln=1285
Placebon=1284Placebon=1284
SOLVD (Treatment)N Engl J M 1991;325:293SOLVD (Treatment)N Engl J M 1991;325:293
ACEI SURVIVALACEI SURVIVAL
n = 2589CHF - NYHA II-III- EF < 35
n = 2589CHF - NYHA II-III- EF < 35
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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%
ACEI SURVIVALACEI SURVIVAL
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ACEIINDICATIONS
ACEIINDICATIONS
Clinical cardiac insufficiency- All patients
Asymptomatic ventricular dysfunction
- LVEF < 35 %
Clinical cardiac insufficiency- All patients
Asymptomatic ventricular dysfunction
- LVEF < 35 %
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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)
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
• Hyperkalemia
• Severe renal insufficiency
• Metabolic acidosis
• Hyperkalemia
• Severe renal insufficiency
• Metabolic acidosis
ALDOSTERONE INHIBITORSCONTRAINDICATIONSALDOSTERONE INHIBITORSCONTRAINDICATIONS
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS
ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS
Density of ß1 receptors
Inhibit cardiotoxicity of catecholamines
Neurohormonalactivation
HR
Antihypertensive and antianginal
Antiarrhythmic
Antioxidant
Antiproliferative
Density of ß1 receptors
Inhibit cardiotoxicity of catecholamines
Neurohormonalactivation
HR
Antihypertensive and antianginal
Antiarrhythmic
Antioxidant
Antiproliferative
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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 ?
Chronic Congestive Heart FailureChronic Congestive Heart Failure
ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?
ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?
Suspected adrenergic activation
Arrhythmias
Hypertension
Angina
Suspected adrenergic activation
Arrhythmias
Hypertension
Angina
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
CALCIUM ANTAGONISTSPOTENTIAL EFFECTS
CALCIUM ANTAGONISTSPOTENTIAL EFFECTS
Antiischemic
Peripheral Vasodilatation
Inotropy
Antiischemic
Peripheral Vasodilatation
Inotropy
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
Chronic Congestive Heart FailureChronic Congestive Heart Failure
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
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)
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)