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Post MI Congestive Heart failure

Dr .Badri Paudel

HIS WALK IS HISTORY

•  CCF IS A MYSTERY

“The very essence of cardiovascular practice is the recognition of early heart failure”

- Sir Thomas Lewis 1933

ALL ROADS LEAD TO CCF

Heart Failure• Final common pathway for many cardiovascular

diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction

• Prevalence: Asymptomatic- 4%. Symptomatic 2-3%, 10-20% in those

aged>75yrs.

• Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 30-40% annually in patients with advanced disease.

Epidemiologyè Most common cause of hospitalization >65 years of

age

INDEX

è 1 per 1000 Indiansè Prevalence: 18.8 million (1.76% of total population)è Incidence: 1.57 million cases per year (0.15% of total

population)è Mortality ~5-10% per year at early stages

è Up to 30-40% per year at advanced stages

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Congestive Heart Failure

“The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return”

- Eugene Braunwald

Definition• AHA/ACC defines…

A complex syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.

• ESC defines…A Clinical symptoms/ signs secondary to abnormal ventricular function.A complex clinical syndrome in which the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.

The Donkey Analogy Ventricular dysfunction limits a patient's ability to perform the routine activities of daily living…

Main causes

• Coronary artery disease - 70%• Hypertension

• Valvular heart disease – 10%• Cardiomyopathy – 10%• Others – Drugs, Toxins, Nutritional,

Infective, Infiltrative, Cor pulmonale, etc.

Risk Factorsè Coronary heart disease is the foremostè CHD as a primary cause:-

• SOLVD Trial (75% of the cases) • Hillingdon trial (36% of cases)• Framingham heart study (46% in men and 27% in

women

è Coronary artery disease and hypertension (either alone or in combination) account for cases > 90% in the Framingham study

NYHA Functional Classification of heart failure

• Class I: No limitation of physical activity

• Class II: Slight limitation of physical activity

• Class III: Marked limitation of physical activity

• Class IV: Unable to carry out physical activity without discomfort

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EVOLUTION OF CLINICAL STAGES –‘Heart Failure is a Continuum’

EVOLUTION OF CLINICAL STAGES –‘Heart Failure is a Continuum’

NORMALNORMAL

Asymptomatic LV DysfunctionAsymptomatic LV Dysfunction

CompensatedCHF

CompensatedCHFDecompensated

CHFDecompensated

CHF

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptomsExercise

Abnormal LV fxn

No symptomsExercise

Abnormal LV fxnSymptoms

ExerciseAbnormal LV fxn

SymptomsExercise

Abnormal LV fxnRefractory

CHF

Refractory

CHFSymptoms not controlled with treatmentSymptoms not controlled with treatment

DecompensatedCHF

DecompensatedCHF

Classification of HFComparison Between ACC/AHA Stage and

NYHA Functional Class

1Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.2New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al. JAMA. 2002;287:890–897.

ACC/AHA HF Stage1 NYHA Functional Class2

A At high risk for heart failure but withoutstructural heart disease or symptomsof heart failure (eg, patients withhypertension or coronary artery disease)

B Structural heart disease but withoutsymptoms of heart failure

C Structural heart disease with prior orcurrent symptoms of heart failure

D Refractory heart failure requiringspecialized interventions

I Asymptomatic

II Symptomatic with moderate exertion

IV Symptomatic at rest

III Symptomatic with minimal exertion

None

Framingham Criteria for CHF

o Major criteria- PND - CVP >16 cms of H2O- Neck vein distention - Circulation time >25sec - Rales - Hepatojugular reflux - Radiographic cardiomegaly - S3- Acute pulmonary edema- Pulmonary edema, visceral congestion or cardiomegaly at

autopsy- Weight loss > 4.5 kg in 5 days in response to Rx of CHF

oMinor Criteria- Bilateral ankle edema- Nocturnal cough- Dyspnea on ordinary exertion- Hepatomegaly- Pleural effusion- ↓ in Vital capacity by 1/3rd from

maximal value recorded- Tachycardia (>120/min)

Framingham Criteria for CHF

SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms

SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptoms

TREATMENT OBJECTIVESTREATMENT OBJECTIVESPathophysiological Mechanismso Sympathetic over activity o RAASo BNPo Vasopressin

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Adverse prognostic indicatorso Low systolic blood pressure o Poor end organ perfusiono Renal dysfunctiono Elevated catecholamineso Raised BNP, Vasopressino Low serum sodiumo Widening QRS duration on ECG

Management• Non Pharmacological:

• Pharmacological:– Diuretics, Digitalis– ACEi, ARBs– Beta Blockers– Aldosterone Antagonists– Vasodilators– others

oTherapies that improve symptoms- Diuretics- Digoxin- InotropesoTherapies that improve survival- ACEI- Beta blockers- Aldosterone antagonists- ARB

PHARMACOLOGIC THERAPYPHARMACOLOGIC THERAPYo Investigational \ Emerging Drugs- Vasopeptide inhibitors- Cytokine antagonists- Endothelin antagonists- Vasopressin receptor antagonist- Adenosine antagonists- Metabolic modulators- Statins\ Omega3 fatty acids- If channel inhibitors - Cardiac myosin activators

PHARMACOLOGIC THERAPY (Cont’d)

PHARMACOLOGIC THERAPY (Cont’d)

TREATMENT IN VARIOUS STAGESTREATMENT IN VARIOUS STAGES

NormalNormalAsymptomaticLV dysfunctionEF <40%

AsymptomaticLV dysfunctionEF <40%

Symptomatic CHFNYHA II

Symptomatic CHFNYHA II

InotropesSpecialized therapyTransplantation

InotropesSpecialized therapyTransplantation

Symptomatic CHFNYHA - IV

Symptomatic CHFNYHA - IV

Symptomatic CHFNYHA - III

Symptomatic CHFNYHA - III

Pharmacotherapy has a rolein ALL stages of Heart failure

Pharmacotherapy has a rolein ALL stages of Heart failure

ACEIACEI

Diuretics NeurohormonalantagonismDigoxin?

Diuretics NeurohormonalantagonismDigoxin?

Loop DiureticsDigoxin

Loop DiureticsDigoxin

Conventional Treatments of ADHF

Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7–S12.

Reducefluid

volume

Decreasepreloadand/or

afterload

Augmentcontrac-

tility

IV Diuretics

Loop Diuretics

Reduce Volume Overload

VasodilatorsDecrease Preload

and AfterloadNitroglycerinNitroprusside

Nesiritide

InotropesAugment

Contractility

DobutamineMilrinone

McBride BF, White M. Pharmacotherapy. 2003;23:997-1020

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VASOCONSTRICTIONVASOCONSTRICTION VASODILATATION VASODILATATION

KininogenKininogen

KallikreinKallikrein

Inactive FragmentsInactive Fragments

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin IRENINRENIN

Kininase IIKininase IIInhibitorInhibitor

ALDOSTERONEALDOSTERONE

SYMPATHETICSYMPATHETICVASOPRESSINVASOPRESSIN

PROSTAGLANDINSPROSTAGLANDINStPAtPA

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

ACEIMECHANISM OF ACTION

ACEIMECHANISM OF ACTION

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

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

ACEIs and SURVIVALACEIs and SURVIVAL

4433221100

ACEIs and SURVIVALACEIs and SURVIVAL

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

n = 4228No CHF symptomsEF < 35

n = 4228No CHF symptomsEF < 35

SAVE trial – post MI Captopril TrialTRACE trial – post MI Trandolapril

• 26% RRR in Death

• 27% RRR in Death or HF Hospitalisation

AIRE – post MIAIRE Study demonstrated efficacy of Ramipril on mortality and morbidity in CHF post-MI NYHA class I-III patients

• 2006 patients enrolled in a double-blind,randomized, placebo-controlled study

• 27% reduction in the risk of death

• 23% decrease in progression to severe / resistant heart failure

Lancet. 1993; 342:821-828

ACE Inhibitors in Heart failure • For many years, diuretics and digitalis were accepted as

standard first-line therapy for HF.

• More recently, however, large and well designed clinical studies have shown consistently that ACE inhibitors improve survival and reduce morbidity in patients with LVSD, a condition that leads to chronic HF.

• A meta-analysis of 32 randomised controlled trials in which ACE inhibitors were compared with standard therapy or placebo in 7105 patients with symptomatic HF has shown statistically significant overall reductions with ACE inhibition in both total mortality and in a combined end-point of mortality or hospitalisation*

* Garg R, Yusuf S. Overview of randomised trials of angiotensin- converting enzyme inhibitorson mortality and morbidity in patients with heart failure. JAMA 1995; 273: 1450-6

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Summary • In sum, both ACE inhibitors and ARB are

considered appropriate first-line therapy for the treatment of patients with heart failure and LVSD barring a contraindication to therapy.

• Although there is some overlap in the contraindications to their use, existing data indicates significant differences in side effect profiles and tolerability between the two classes.

SENIORS: Primary and secondary outcomes

100

90

80

70

60

50

100

90

80

70

60

500 6 12 18 24 30 0 6 12 18 24 30

HR 0.86 (0.74–0.99) P = 0.039

Time (months)

All-cause mortality or CV hospital admission

(primary outcome)

Nebivolol

Time (months)

All-cause mortality (main secondary outcome)

HR 0.88 (0.71–1.08) P = 0.214

Nebivolol 332 (31.1%)Placebo 375 (35.3%)

Placebo

Event-free

survival (%)

169 (15.8%) 192 (18.1%)

Flather MD et al. Eur Heart J. 2005;26:215-25.

No. of events:

Nebivolol

Placebo

HR = hazard ratio

Beta-Blockers in HF - New Paradigms

o Safe in mild, moderate and severe HFo May initiate early rather than late

n Start low, go slown Initiate in the hospital when euvolemic

and off inotropeso If on a BB and decompensated CHF

n Continue or reduce dosagen Rarely discontinue

o Long acting Metoprolol, Carvedilol, Bisoprolol, preferred

Major Trials of Beta Blockers in CHF

o MDCo MERIT HFo PRECISEo MOCHAo US Carvedilol heart study groupo ANZ trial Carvedilolo CIBIS IIo CAPRICONo COPERNICUSo CARMENo COMET

Mechanism of actionè Density of ß1 receptorsè Inhibit cardiotoxicity of catecholaminesè Neurohormonal activationè HRè Anti-ischemicè Anti-hypertensiveè Anti-arrhythmicè Anti-oxidant, Anti-proliferative

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Initial Target

Bisoprolol 1.25 / 24h 10 / 24h

Carvedilol 3.125 / 12h 25 / 12h

Metoprolol tartrate 6.25 / 12h 75 / 12h

Metoprolol succinnate 12.5-25 / 24h 200 / 24h

• Start Low, Increase Slowly• Increase the dose every 2 - 4 weeks

ß-Adrenergic Blockers- Dose (mg)

MSA; prototypical beta-blocker√√√√propranolol

ά, β-blocking activity√√carvedilol

Non-selective b1/b2

CommentsCHFMIArrhy.AnginaHTNClass/DrugClinical Uses

Different Classes of Beta-Blockers and Specific Drugs

MSA√√√√√metoprolol

√√√bisoprolol

√√√√atenolol

b1-selective

CommentsCHFMIArrhyAnginaHTNClass/Drug

Clinical Uses

MSA√√√√√metoprolol

√√√bisoprolol

√√√√atenolol

b1-selective

CommentsCHFMIArrhyAnginaHTNClass/Drug

Clinical Uses

Different Classes of Beta-Blockers and Specific Drugs

INDEX

Results from COMETè Carvedilol improves vascular outcomesè Carvedilol provides better protection against vascular eventsè Carvedilol significantly reduces the occurrence of all MIs by 29%è Carvedilol reduces hospitalization for unstable angina by 17%

As compared to metoprolol…è Carvedilol reduces the risk of any MI, any unstable angina or

any stroke by 19%è The effect of v on the combined end point of MI or stroke was

significant (HR 0.75) and the effect on fatal MI or fatal strokewas highly significant (HR 0.46)

Reduces Mortality, Improves Survival

Concluding Remarksè Administering carvedilol in addition to conventional

therapy reduces mortality and attenuates myocardial re-modelling in patients with left ventricular dysfunction following acute MI

è Moreover, mortality has been significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred β-blocker

INDEX

Diuretics in HF • Diuretics produce symptomatic benefits

more rapidly than any other drugs for heart failure.

• They can relieve peripheral oedema within hours or days, whereas the clinical effects of digitalis, ACE inhibitors, or beta-blockers may require weeks or months to become apparent (Hall 1995; Packer 1983)

Diuretics for heart failure (Review) 2 Copyright © 2009 The Cochrane Collaboration. Published by JohnWiley & Sons,Ltd.

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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 Henle

Collecting tubuleCollecting tubule

DIURETICSDIURETICSDiuretics

o Thiazide group loop diuretics- Hyponatremia- Hypokalemia- Reduction of GFR- Reduction of Renal blood flow

Vasopression antagonists Aquauresis Adenoreceptor antagonists Maintains renal blood

flow / GFR

èOverall incidence and prevalence increasingèAging of populationèAdvances in MI managementèMost common cause of hospitalization in age group

>65 years (US)èEdema commonly associated with CHFèLoop diuretics -- the preferred diureticsè Indicated for symptomatic treatment of CHFèRecommended by all guidelines (ESC, ACC, AHA)

CHF & Loop diureticsINDEX

Torsemide or Frusemide Torsemide or Frusemide

Torsemide in Congestive Heart Failure (TORIC)

o Efficacy of Torsemide Vs Furosemide in CHFo Fewer deaths in Torsemide group (2.2% Vs

4.5%in the Furosemide group)o Fewer episodes of hypokalemia but similar

NYHA class improvement with Torsemideo Torsemide, which has a more predictable

bioavaliability may be safer than Furosemide.

Eur J Heart Failure 2002;4:507-513

Pharmacological advantages of torsemideover frusemide (Summary)

è More potent diuresis and natriuresis

è Reduced kaliuresis

è Longer duration of action

è Greater secretion of prostacylin

è More complete and predictable bioavailability

è Alternative metabolic pathways

INDEX

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1- VENOUS VASODILATATION

Preload

2- Coronary vasodilatationMyocardial perfusion

3- Arterial vasodilatation Afterload

1- VENOUS VASODILATATION

Preload

2- Coronary vasodilatationMyocardial perfusion

3- Arterial vasodilatation Afterload

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

NITRATESHEMODYNAMIC EFFECTS

• Cardiac output• Blood pressure

• Cardiac output• Blood pressure

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

NITRATES – SURVIVAL BENEFITNITRATES – SURVIVAL BENEFIT

00 66 1212 1818 2424 3030 3636 4242

Digoxin Investigational Group Digoxin Investigational Group (DIG) Study (DIG) Study

%WORSENING

OF CHF

%WORSENING

OF CHF

p = 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

Aldosterone and Aldosterone and Aldosterone Antagonists Aldosterone Antagonists

Na & Water RetentionIncrease Preload

Potentiation of Sympathetic Activity

Role of Aldosterone in CHF

Mg Loss: Coronary Artery Spasm & Arrhythmia

Endothelial Dysfunction

Stimulate FibrosisHypertrophy

Reduction of Parasympathetic

Activity: Death

Aldosterone

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Increase Na & Water Excretion reduce

Preload

Reduce Sympathetic Activity:

Reduce Arrhythmia

Need of Aldosterone Antagonist

Retains Mg & K levels :Reduces Arrhythmias

Improved Endothelial Dysfuction

Reduce Myocardial Collagen Turnover

Increase of Parasympathetic

Activity

AldosteroneAntagonist

INDEX

N Engl J Med. 1999;341:709–717.

1.00

Placebo

Months

Prob

abili

ty o

f Sur

viva

l

Spironolactone*

0.95

0.90

0.85

0.80

0.75

0.70

0.65

0.60

0.55

0.50

0.45

0.000 3 6 9 12 15 18 21 24 27 30 33 36

P<.001

Randomized AldactoneEvaluation Study (RALES)

*NOT INDICATED TO REDUCE MORTALITY IN HF

Relative Risk of All Cause MortalityRelative Risk of All Cause Mortality

Months Since Randomization

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

22

02

20

1618

141210864

RR=0.85 (95% CI, 0.75-0.96) P=.008

3633302724211815129630

15%15%RelativeRelative

Risk Risk reductionreductionPP=.008=.008

PlaceboEplerenone

Above and

BeyondStandard Therapy

EPHESUS—All Cause Mortality

In patients with baseline LVEF ≤30%, risk of all-cause mortality was 21% lower with Eplerenon compared with placebo (P=.01)*

Endothelin Antagonistso ENCOR – ENRASENTAN à Fared

worse than placeboo REACH –1 – BOSENTAN à similar to

placeboo ENABLE 1 & 2 – BOSENTAN àLow

dose not superior to placeboo DARUSENTAN – ETA selective

antagonist - Results awaited

Remodeling and Survival Benefits by Drug Class

No BenefitNo BenefitTNFα-BAdverseAdverseIbopamine

No BenefitNo BenefitET-1-BBenefit (ACEI-neutral)Benefit (ACEI-neutral)Vasop-I

Newer TherapiesBenefitBenefitBeta-BBenefitBenefitAldo-B

Benefit (+ACEI better)Benefit (+ACEI better)ARBBenefitBenefitACE-I

Survival EffectsRemodeling EffectsEstablished Rx

Treat risk factorsAvoid toxics

ACE-I in selectedpatients

A

ACE-Iβ blockers

Diuretics / DigitalisC

Palliative therapyMechanical Assisted

Devices Heart TransplantD

Stages in the Evolution ofHF-Treatment

ACE-Iβ blockers

In selectedpatients

B

INDEX

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Despite Current Drug Therapies, Heart Failure Morbidity and Mortality Remain High

• 30% to 40% of patients are in NYHA class III or IV

• Re-hospitalization rates• 2% at 2 days • 20% at 1 month• 50% at 6 months

• 5-year mortality ranges from 15% to more than 50%• Asymptomatic LVD ≈ 15%• Mild-moderate HF ≈ 35%• Advanced HF >50%

Atrial Depolarization

Heart rateAFIB/ATACH

APACE

Ventricular Rate ResponseHeart rate

VT/VFVPACE

Patient ActivityHeart Rate VariabilityImpedance

(fluid status, respiration)

2005 ACC/AHA Heart Failure Guideline: CRT in Stage C Heart Failure

• Class I Indication: Patients with LVEF ≤35%, sinus rhythm, and NYHA functional Class III or ambulatory Class IV symptoms despite recommended optimal medical therapy and who have cardiac dysynchrony, which is currently defined as a QRS >120 msec, should receive CRT, unless contraindicated

Level of Evidence: A

Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, 2005

ACC/AHA Heart Failure Guideline:ICDs in Heart Failure

• Class I Indication: ICD therapy is recommended for primary prevention of sudden cardiac death to reduce total mortality in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-MI, a LVEF less than or equal to 35%, and NYHA functional class II or III symptoms while receiving chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 yearLevel of Evidence: A

Jessup M, Abraham WT, Casey DE, et al., Circulation and JACC 2009

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ICDs Save Lives In Heart Failure

• Second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) – 31% ↓

• Prophylactic Defibrillator Implantation in Patients with Nonischemic Dilated Cardiomyopathy (DEFINITE) trial – 30% ↓

• Sudden Cardiac Death-Heart Failure Trial (SCD-HeFT) – 23% ↓

Implantable Hemodynamic Monitors

LV Pressure Sensor

PA Pressure Sensors

RV Pressure Sensors

LA Pressure Sensor

CARDIAC TRANSPLANT CONCLUSION •  MORBIDITY & MORTALITY REMAINS HIGH IN HEART FAILURE

DEPITE CURRENT DRUG THERAPHY. •  PHARMCO THERAPHY-TREATMENT OF CHOICE- ALL STAGES

OF CCF. •  CORONARY INTERVENTIONS IN REVASCULARABLE ANATOMY. •  DEVICES & SURGERY – HAS A ROLE IN REFRACTORY

FAILURE.

•  CARDIAC TRANSPLANT IS AN OPTION .

MY TIME IS UP KINDLY WAKEUP

SMILE PLEASE

TORTURE IS OVER