MANAGING CONGESTIVE HEART
FAILUREAnnual Conference of the Lebanese Society of Annual Conference of the Lebanese Society of
Family MedicineFamily Medicine
Antoine Sarkis, MDAntoine Sarkis, MDAssociate Professor of Associate Professor of
CardiologyCardiologyHotel Dieu de France Hotel Dieu de France
HospitalHospital
GuidelinesGuidelines ESCESC HFSAHFSA CCSCCS ACC/AHAACC/AHA
NYHA Classification
Four stage classification
2005
2006
2006
2005
Heart diseaseHeart disease(any)(any)
HypertensionHypertensionDiabetes, Hyperchol.Diabetes, Hyperchol.
Family HxFamily HxCardiotoxinsCardiotoxins
AsymptomaticAsymptomaticLV dysfunctionLV dysfunction
SystolicSystolic / / DiastolicDiastolic
Marked symptomsMarked symptomsat rest despiteat rest despitemax. therapymax. therapy
Dyspnea, FatigueDyspnea, FatigueReduced exerciseReduced exercise
Tolerance (current or past)Tolerance (current or past)
Stages in the EvolutionStages in the Evolutionof Heart Failure.of Heart Failure.
Clinical CharacteristicsClinical CharacteristicsAA
BB
CC
DD
AHA / ACC HF guidelines 2001AHA / ACC HF guidelines 2001
Classification of Classification of RecommendationRecommendation
Class I: General agreement or evidence Class I: General agreement or evidence that a therapy is beneficial that a therapy is beneficial ►►(therapy is recommended)(therapy is recommended)
Class II: Conflicting evidenceClass II: Conflicting evidence IIa: evidence in favor of efficacy IIa: evidence in favor of efficacy
►►( therapy should be considered)( therapy should be considered) IIb: evidence less well established IIb: evidence less well established
►►( therapy may be considered)( therapy may be considered) Class III: Not recommended, may be Class III: Not recommended, may be
harmfulharmful
Level of evidenceLevel of evidence
Level A:Level A: multiple randomized multiple randomized clinical trials or meta-analysisclinical trials or meta-analysis
Level B:Level B: single randomized trial, or single randomized trial, or non randomized studiesnon randomized studies
Level C:Level C: Consensus opinion of Consensus opinion of experts experts
Treatment ObjectivesTreatment Objectives Mainly decrease symptoms and prolong Mainly decrease symptoms and prolong
lifelife But also:But also:
Decrease morbidity (hospital admissions, Decrease morbidity (hospital admissions, embolism…)embolism…)
Increase exercise capacity and improve Increase exercise capacity and improve quality of lifequality of life
Control neurohormonal changesControl neurohormonal changes Retard progression of CHFRetard progression of CHF
• Control of risk factors• Life style• Treat etiologic cause / aggravating factors• Drug therapy
• Revascularization• ICD (Implantable Cardiac Defibrillator)• Ventricular resynchronization (CRT)• Ventricular assist devices• Heart transplant• Artificial heart• Neoangiogenesis, Gene therapy
AllAll
Sele
cted
pat
ient
sSe
lect
ed p
atie
nts
Treatment of CHFTreatment of CHF
Correction of reversible Correction of reversible causescauses
IschaemiaIschaemia Valvular heart diseaseValvular heart disease Thyrotoxicosis and other high output statusThyrotoxicosis and other high output status ShuntsShunts ArrhythmiaArrhythmia
Atrial fibrillation, flutter, Atrial fibrillation, flutter, Medications Medications
Ca channel blockers, some antiarrhythmics Ca channel blockers, some antiarrhythmics
Pharmacologic Therapy Diuretics ACE inhibitors Beta Blockers ARBs Digitalis Spironolactone Other
Symptomatic HF, with fluid retention• Peripheral edema• Dyspnea/ Pulmonary edema (Xray)• Jugular distension• Hepatomegaly
AHA / ACC HF guidelines 2005 AHA / ACC HF guidelines 2005 ESC HF guidelines 2005ESC HF guidelines 2005
Diuretics. IndicationsDiuretics. Indications
• K+, Mg+ (15 - 60%) (sudden death ???)
• Na+
• Hyperuricemia (15 - 40%)
• Stimulation of neurohormonal activity
• Hypotension. Pre-renal azotemia, Ototoxicity, Gastrointestinal, Metabolic Alkalosis.
• Skin rashes, Neutropenia, Thrombocytopenia
Adverse Effects of Diuretics. Adverse Effects of Diuretics.
Inhibitors of renin-angiotensin- aldosterone
system
Renin-angiotensin-aldosterone Renin-angiotensin-aldosterone systemsystem is activated early in the is activated early in the course of heart failure and course of heart failure and plays an important roleplays an important role in the in the progression of the syndromeprogression of the syndrome
RAAS Blockade
Angiotensin Converting
Enzyme Inhibitors
(ACE-I)
Angiotensin Receptor Blockers
(ARB)
• Improve symptoms• Reduce remodeling / progression• Reduce hospitalization• Improve survival
ACE-I. Clinical Effects in CHF
Placebo
Enalapril
12111098765
Probability ofDeath
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
43210
ACE-IACE-I
253 patients
NYHA IV31 %
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
N = 2589 CHF - NYHA II-III- EF < 35 %
ACE-IACE-I
Mortality %
4
SAVEN Engl J Med 1992;327:669
Years
30
20
10
01 2 3
Placebo
Captopril
0
n=1115
n=1116
p=0.019² -19%
Asymptomatic ventriculardysfunction post MI
ACE-IACE-I
N = 22313 - 16 days post AMIEF < 40 %12.5 --- 150 mg / day
MonthsMonths
303024241212 181800 66
1010
3030
2020
00
PlaceboPlacebo
RamiprilRamipril
p = 0.002p = 0.002
Mortality %Mortality %
AIRELancet 1993;342:821Lancet 1993;342:821ACE-IACE-I
N = 2006N = 2006HF after AMIHF after AMI
ACE-I IndicationsACE-I Indications
Symptomatic heart failure Symptomatic heart failure (stage C)(stage C) Asymptomatic ventricular dysfunctionAsymptomatic ventricular dysfunction
LVEF <35-40 % LVEF <35-40 % (stage B)(stage B) Patients with recent or remote history Patients with recent or remote history
of MI regardless of EF or presence of of MI regardless of EF or presence of HF HF (stage B)(stage B)
Class I recommendationLevel of evidence A
AHA / ACC HF guidelinesAHA / ACC HF guidelinesESC HF guidelinesESC HF guidelines
Start with very low dose Renal function & serum K+ after 1-2 w In the absence of fluid retention, ACE-I should be given first / In the presence of fluid retention together with diuretics
Dose NOT determined by symptoms. ACE-I should be up-titrated to dosages shown to be effective in clinical trials
ACE-I. Practical Use
• Hypotension (1st dose effect)Hypotension (1st dose effect)• Worsening renal function, Worsening renal function,
HyperkalemiaHyperkalemia• CoughCough• AngioedemaAngioedema• Rash, ageusia, neutropenia, …Rash, ageusia, neutropenia, …• Pregnancy is a contra Pregnancy is a contra
indicationindication
ACE-I. Adverse EffectsACE-I. Adverse Effects
Substitute or adjunctive therapy to ACE
inhibitors ?
Angiotensin Receptor Angiotensin Receptor
Blockers (ARBs) in Blockers (ARBs) in Heart FailureHeart Failure
• ARBs more effective than ACE-I due to: - Better RAAS Blockade- Absence of angiotensin II escape - Placebo like side effects
Potential advantages of Potential advantages of ARBsARBs
(Reprinted with permission from Pitt B, et al. Lancet. 2000)
All-cause mortality
Prob
abili
ty
of S
urvi
val 1.0
0.80.60.40.20.0
All-cause mortality or hospital admission
Even
t-fre
e Pr
obab
ility
Sudden death or resuscitated arrest
Even
t-fre
e Pr
obab
ility
1.00.80.60.40.2
0
1.00.80.60.40.2
0
0 100 200 400300 500 600 700Follow-up (days)
P P = .16= .16
P P = .08= .08
P P = .18= .18
LosartanCaptopril
ELITE II: Endpoint ResultsELITE II: Endpoint Results
Val-HeFT: Val-HeFT: Study Design and Inclusion CriteriaStudy Design and Inclusion Criteria
Randomized to
Receiving background therapy
5010 patients EF < 40%; NYHA II - IV
ACEIs (93%), diuretics (86%),digoxin (67%), beta-blockers (35%)
Valsartan 40 mg bid titrated to 160 mg bid Placebo
(Cohn JN, et al. N Engl J Med. 2001)
1.0
0.9
0.8
0.613% risk reduction p= 0.009
0
Even
t-fre
e pr
obab
ility
Placebo
Valsartan
3 6 9 12 211815 24 27Time since randomisation (months)
0.7
1.0
0.9
0.8
0.7
Time since randomisation
(months)
p = 0.80
Surv
ival
pro
babi
lity
(%)
0 3 6 9 12 211815 24 27
All-cause mortality and morbidity All-cause mortality
Cohn et al. NEJM 2001;345:1667
Effect of Valsartan on Combined Mortality and Morbidity End Point* in Overall
Population
CHARM Added
CHARMPreserved
CHARM ProgramCHARM Program3 component trials comparing Candesartan
to placebo in patients with symptomatic heart failure
CHARMAlternative
n=2028 LVEF 40%
ACE inhibitor intolerant
n=2548LVEF 40%
ACE inhibitor treated
n=3025LVEF >40%
ACE inhibitor treated/not treated
CHARM ProgramCHARM Program Mortality and morbidityMortality and morbidity
0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2
All Cause MortalityCV Death or
CHF Hospitalisation
Hazard ratio Hazard ratio
p heterogeneity=0.43
Alternative
Added
Preserved
Overall
p heterogeneity=0.37
p=0.0004
p=0.055
p=0.011
p=0.118
p<0.0001
0.77
0.85
0.89
0.840.91
ARB Indications in CHF Patients intolerant to ACE-Inhibitors:
(Class I recommendation in stage C) On top of ACE I and B Blockers in patients who
remain symptomatic: optional (discrepancy in guidelines):Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)
Use of ARB instead of ACE-I is a Class IIa recommendation (reasonable, should be considered) in stage C heart failure
Aldactone
Placebo
SurvivalSurvival
1.0
0.9
0.8
0.7
0.6
0.5
0 6 12 18 24 30 36
months
p < 0.0001
Annual MortalityAldactone 18%; Placebo 23%
N = 1663N = 1663NYHA III-IVNYHA III-IV
Mean follow-up 2 yMean follow-up 2 y
RALESRALESNEJM 1999;341:709NEJM 1999;341:709SpironolactoneSpironolactone
Spironolactone. Indications
Moderate-severe Moderate-severe symptoms/advanced heart failuresymptoms/advanced heart failure
Class I recommendation, level of Class I recommendation, level of evidence Bevidence B
Routine combination of ACE-I, Routine combination of ACE-I, ARB and aldosterone antagonist ARB and aldosterone antagonist is not recommended is not recommended (Class III)(Class III)
Do not use if hyperkalemia, renal insuficieny Monitor serum K+ at “frequent intervals” Start ACE-i first Start with 25 mg / 24h
Spironolactone. Practical Spironolactone. Practical useuse
ß-Blockers
Has been traditionally Has been traditionally contraindicated in pts with CHFcontraindicated in pts with CHF
Now they are a corner stone in Now they are a corner stone in treatment of CHFtreatment of CHF
• Density of ß1 receptors • Inhibit cardiotoxicity of catecholamines• Neurohormonal activation• HR• Anti-ischemic• Anti-hypertensive• Anti-arrhythmic
ß-Adrenergic BlockersMechanism of action
• Improve symptoms (only long term)• Reduce remodeling / progression• Reduce hospitalization• Reduce sudden death• Improve survival
ß-Adrenergic BlockersClinical Effects in CHF
US Carvedilol HFUS Carvedilol HFNEJM 1996; 334: 1349-55NEJM 1996; 334: 1349-55
CarvedilolCarvedilol(n=696)(n=696)
PlaceboPlacebo(n=398)(n=398)
Risk reduction = 65%Risk reduction = 65%
pp<0.001<0.001
00 5050 100100 150150 200200 250250 300300 350350 400400
1.0
0.9
0.8
0.7
0.60.6
ß-Adrenergic Blockersß-Adrenergic Blockers
0.70.7
0.80.8
0.90.9
1.01.0
Survival %Survival %
DaysDays
I-II NYHAI-II NYHAHFHF
P< 0.00005P< 0.00005
Annual Mortality: bisoprolol=8.2%; placebo=12%Annual Mortality: bisoprolol=8.2%; placebo=12%Mean Follow-up 1.4 yearsMean Follow-up 1.4 years
DaysDays
BisoprololBisoprolol11.8%11.8%
PlaceboPlacebo17.3%17.3%
11
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
SurvivalSurvival
NYHA III-IVNYHA III-IVn=2647n=2647
00 800800400400 600600200200
CIBIS-IICIBIS-IILancet 1999;353:9Lancet 1999;353:9
ß-Adrenergic Blockersß-Adrenergic Blockers
1515
1010
55
MERIT-HFMERIT-HFLancet 1999; 353: 2001Lancet 1999; 353: 2001
MonthsMonths
Mortality % Mortality %
00 33 66 99 1212 1515 1818 212100
PlaceboPlacebo
MetoprololMetoprololpp=0.0062=0.0062
RiskRiskReduction 34%Reduction 34%
ß-Adrenergic Blockersß-Adrenergic Blockers
NYHA II-IVNYHA II-IVN=3991N=3991
100100
9090
8080
6060
7070
5050242400 2020161612128844 2828
PlaceboPlacebo
CarvedilolCarvedilol
MonthsMonths
N = 2289III-IV NYHA
COPERNICUSCOPERNICUSNEJM 2001;344:1651NEJM 2001;344:1651
Survival%Survival%
ß-Adrenergic Blockersß-Adrenergic Blockers
pp=0.00014=0.0001435% RR 35% RR
11
SurvivalSurvival
YearsYears
0.90.9
0.850.85
0.70.7
0.750.75
0.80.8
0.950.95
00 0.50.5 11 1.51.5 22 2.52.5
CarvedilolCarvedilol116 / 975 (12%)116 / 975 (12%)
PlaceboPlacebo151 / 984 (15%)151 / 984 (15%)
HR 0.77 (0.60 - 0.98) p<0.031HR 0.77 (0.60 - 0.98) p<0.031
CAPRICORNCAPRICORNLancet 2001;357:1385Lancet 2001;357:1385 ß-Adrenergic Blockersß-Adrenergic Blockers
LVD / HFLVD / HFPost AMIPost AMI
• Symptomatic heart failure (stage C)
• Asymptomatic ventricular dysfunction- LVEF < 35 - 40 % (stage B)
• After AMI
AHA / ACC HF guidelines 2005 AHA / ACC HF guidelines 2005 ESC HF guidelines 2005ESC HF guidelines 2005
ß-Adrenergic Blockersß-Adrenergic BlockersIndicationsIndications
Class I recommendation
• Patient stablePatient stable• No physical evidence of fluid retentionNo physical evidence of fluid retention• No need for I.V. inotropic drugsNo need for I.V. inotropic drugs
• Start ACE-I / diuretic firstStart ACE-I / diuretic first
• Start Low, Increase SlowlyStart Low, Increase Slowly
• Increase the dose every 2 - 4 weeksIncrease the dose every 2 - 4 weeks
ß-Adrenergic Blockersß-Adrenergic BlockersWhen to start ?When to start ?
InitialInitial TargetTarget
BisoprololBisoprolol 1.25 / 24h1.25 / 24h 10 / 24h 10 / 24h
CarvedilolCarvedilol 3.125 / 12h3.125 / 12h 25 / 12h25 / 12h
Metoprolol Metoprolol succinnatesuccinnate 12,5-25 / 24h12,5-25 / 24h 200 / 24h200 / 24h
Nebivolol Nebivolol (ESC, elderly) 1.25/24h 10 mg/24h(ESC, elderly) 1.25/24h 10 mg/24h
ß-Adrenergic Blockersß-Adrenergic BlockersDrugs and Dose (mg)Drugs and Dose (mg)
• HypotensionHypotension• Fluid retention / worsening heart failureFluid retention / worsening heart failure• FatigueFatigue• Bradycardia / heart blockBradycardia / heart block
• Review treatment (+/-diuretics, other drugs)Review treatment (+/-diuretics, other drugs)• Reduce doseReduce dose• Consider cardiac pacingConsider cardiac pacing• Discontinue beta blocker only in severe casesDiscontinue beta blocker only in severe cases
ß-Adrenergic BlockersAdverse Effects
Digitalis Glycosides
The role of digitalis has declined somewhat because of safety concern
Recent studies have shown that digitals does not affect mortality in CHF patients but causes significant Reduction in hospitalization Reduction in symptoms of HF
50
40
30
20
10
0
Placebon=3403
Digoxinn=3397
480 12 24 36
Mortality %
DIGN Engl J Med 1997;336:525
Months
p = 0.8
Digitalis
N=6800NYHA II-III
• • Sinus rythm: When no adequate Sinus rythm: When no adequate response to ACE-i + diuretics + beta-response to ACE-i + diuretics + beta-blockersblockers
• • Atrial Fibrillation: to slow AV Atrial Fibrillation: to slow AV conductionconduction
Dose 0.125 to 0.250 mg / dayDose 0.125 to 0.250 mg / day
Digitalis. IndicationsDigitalis. Indications
Narrow therapeutic to toxic ratio !!
• Inotropics: refractory HF• Nitrates: ischemia, angina, pulmonary congestion
• Antiarrhythmics: (only amiodarone) H risk arrhyth.
• Anticoagulants: High risk of embolism e.g Atrial Fibr.
• Ca channel blockers (only amlodipine): ischemia, hypertension
Other Drugs. (only in selected patients)
DevicesDevices
Cardiac Resynchronization Therapy (CRT)
Implantable Cardiac Implantable Cardiac Defibrillator (ICD)Defibrillator (ICD)
Cardiac Resynchronization Therapy for Heart Failure
(CRT) Ventricular Dysynchrony
Electrical: Inter- or Intraventricular conduction delays typically manifested as left bundle branch block
Mechanical: Regional wall motion abnormalities compromising ventricular mechanics
Cardiac Resynchronization Modification of interventricular,
intraventricular, and atrio-ventricular activation sequences
Tavazzi L. Tavazzi L. Eur HeartEur Heart J 2000;21:1211-1214 J 2000;21:1211-1214
Cleland JG. NEJM 2005; 352: 1539-1549
Primary and secondary outcomes in Primary and secondary outcomes in CARE-HF: 409 CRT-treated patients CARE-HF: 409 CRT-treated patients
as compared with 404 control as compared with 404 control patientspatients
OutcomesOutcomes Hazard Hazard ratio (95% ratio (95% CI)CI)
pp
All-cause mortalityAll-cause mortality 0.640.64(0.48-(0.48-0.85)0.85)
0.00190.0019
All-cause mortality/HF All-cause mortality/HF hospitalizationhospitalization
0.540.54(0.43-(0.43-0.68)0.68)
<0.000<0.00011
Cardiac Resynchronization Cardiac Resynchronization Therapy (CRT)Therapy (CRT)
NYHA class III or IV, LVEF < 0.35 NYHA class III or IV, LVEF < 0.35 and dyssynchrony (QRS >= 120 ms)and dyssynchrony (QRS >= 120 ms)
Class I recommendation, Level AClass I recommendation, Level A
Intra Cardiac Defibrillator. Intra Cardiac Defibrillator. Indications in Secondary Indications in Secondary
PreventionPrevention
Patients with Patients with sustained VT or SCD sustained VT or SCD →→ ICD ICD
Bardy GH et al. N Engl J Med 2005; 352:225-237.
Intracardiac DefibrillatorMortality outcomes over five years in SCD-
HeFT (Sudden Cardiac Death in Heart Failure Trial)
Parameter Parameter ICD,ICD,n=829n=829
Amiodarone, Amiodarone, n=845n=845
Placebo, Placebo, n=847 n=847
All-cause All-cause mortality (%) mortality (%)
2222 2828 2929
Mortality risk Mortality risk vs placebo, vs placebo, HR (97.5% CI)HR (97.5% CI)
0.770.77(0.62-0.96), (0.62-0.96), p=0.007p=0.007
1.061.06(0.86-1.30), (0.86-1.30), p=0.53p=0.53
——
* randomized 2521 patients with NYHA class 2-3 HF and an LVEF <35%
ICD indicationsICD indicationsPrimary preventionPrimary prevention
NYHA class II or III and LVEF <= NYHA class II or III and LVEF <= 30 %30 %
With a reasonable life expectancy With a reasonable life expectancy > 1 year> 1 year
Class I recommendationClass I recommendation However may be indicated even in However may be indicated even in
stage B (NYHA class I) especially in stage B (NYHA class I) especially in ischemic aetiologyischemic aetiology
• Refractory cardiogenic shockRefractory cardiogenic shock• Documented dependence on IV inotropic support Documented dependence on IV inotropic support
• Severe symptoms of ischemia not amenable to Severe symptoms of ischemia not amenable to revascularizationrevascularization
• Recurrent symptomatic ventricular arrhythmias Recurrent symptomatic ventricular arrhythmias refractory to all therapeutic modalitiesrefractory to all therapeutic modalities
Heart Transplant. Heart Transplant. IndicationsIndications
ACE-I, ARB,-Blockers in appropriate pts. ICD in selected pts.
Treat risk factors. ACE-I (or ARB) in appropriate pts for vascular disease or diabetes
CRTMech. Assist device
Heart Transplant
Routine: ACE-I, blockers, Diuretics In selected pts: aldost antag, ARB, Digitalis, nitratesICD, CRT
Stages in the EvolutionStages in the Evolutionof Heart Failure.of Heart Failure.
TreatmentTreatmentAA
BBCC
DD
AHA / ACC HF guidelines 2005AHA / ACC HF guidelines 2005
(Asymptomatic LV Systolic Dysfunction)
(Symptomatic LV Systolic Dysfunction)
(Refractory End-Stage (Refractory End-Stage HF)HF)