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 Mainly decrease symptoms and prolong lifeprolong life

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

Sel

ecte

d p

atie

nts

Sel

ecte

d 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

1212111110109988776655

Probability ofDeath

Months

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< 0.001

p< 0.002

CONSENSUSN Engl J Med 1987;316:1429

4433221100

ACE-IACE-I

253 patients

NYHA IV31 %

50

40

30

20

10

0

Months0 6 12

p = 0.0036

% Mortality

2418 3030 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 recommendation

Level of evidence A

AHA / ACC HF guidelinesAHA / ACC HF guidelines

ESC 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

Pro

bab

ility

o

f S

urv

ival 1.0

0.80.60.40.20.0

All-cause mortality or hospital admission

Ev

ent-

fre

e

Pro

bab

ility

Sudden death or resuscitated arrest

Ev

ent-

fre

e

Pro

bab

ility

1.00.80.60.40.2

0

1.00.80.60.40.2

0

0 100 200 400300 500 600 700

Follow-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

0.6

13% 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=2548

LVEF 40%ACE inhibitor

treated

n=3025

LVEF >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-IV

n=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

MetoprololMetoprolol

pp=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=6800

NYHA 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 However may be indicated even

in stage B (NYHA class I) in stage B (NYHA class I) especially in ischemic aetiologyespecially in ischemic 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)