Heart Failure Liviu Klein MD, MS .

Heart Failure

Liviu Klein MD, MS

http://www.cardiologyfellows.northwestern.edu/cculectures

Outline• Definition

• Pathophysiology

• Epidemiology (prevalence, incidence, trends)

• Epidemiology (mortality and associated morbidity)

• Risk factors

• Heart failure stages and treatment

• Advanced heart failure and transplant

Definition

Heart Failure Definition• A complex clinical syndrome that can result from any

structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.

• Cardinal manifestations are dyspnea and fatigue (which may limit exercise tolerance), and fluid retention (which may lead to pulmonary congestion and peripheral edema).

• Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they do not necessarily dominate the clinical picture at the same time.

Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.

• Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema and report few symptoms of dyspnea or fatigue.

• Because not all patients have volume overload at the time of initial or subsequent evaluation, the term “heart failure” is preferred over the older term “congestive heart failure.”

• One line definition: LV EDP > 12 mmHg

Heart Failure Definition



• Pathophysiology



• Risk factors



Pathophysiology

Heart Failure Pathophysiology

NecrosisApoptosis

Cell death

Altered gene expression

Growth and remodeling

Ischemia and energy depletion

Activation of RAS, SNS, and cytokines

Increased loadReduced systemic perfusion

Direct toxicity

Cardiac injury

Progression of Heart Failure

Coronary artery disease

Hypertension Diabetes

Atrial Fibrillation

Death

PathologicRemodeling

Low ejectionfraction

Left ventricularinjury

Cardiomyopathic factors

Valvular disease

Heart Failure Clinical Stages

Symptoms not controlled with treatment

NORMAL

Asymptomatic LV Dysfunction

Compensated

Decompensated

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptoms ExerciseAbnormal LV fxn

Symptoms ExerciseAbnormal LV fxn

Refractory


• Pathophysiology



• Risk factors



Epidemiology (prevalence, incidence, trends)

Prevalence of Heart Failure

Source: CDC/NCHS and NHLBI.

Absolute Numbers(millions patients)

Rate(per thousand)

Western Europe 5.3 14Eastern Europe 1.3 13Former Soviet Union 5.6 19North America 5.2 18Japan 2.4 19South America ? ?Asia ? ?

Prevalence of Heart Failure

Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Geneva: World Health Organization; 1996.

Sys/Diastolic Dysfunction Prevalence

Redfield MM et al. JAMA. 2003; 289: 194-202.

Systolic Dysfunction Prevalence

Wang TJ et al. Ann Intern Med. 2003; 138: 907-916. 4%

Temporal Changes in Incidence

Roger VL et al. JAMA. 2004; 292: 344-351.


• Pathophysiology



• Risk factors



Epidemiology (mortality and associated morbidity)

Cardiovascular Deaths

300,000 death/yr

Survival according to NYHA Class

NYHA Class I–II(SOLVD Prevention Trial)

0 6 12 18 24 30 36 42 480

102030405060708090

100

Mor

talit

y (%

)

Placebo

Months

NYHA Class IV (CONSENSUS)

Conventional therapies (diuretics, digoxin)

NYHA Class II–III(SOLVD Treatment Trial)

CONSENUS Trial Study Group. N Engl J Med. 1987; 316: 1429-1435.The SOLVD Investigators. N Engl J Med. 1991; 325: 293-298.The SOLVD Investigators. N Engl J Med. 1992; 327: 685-690.

Trends in Heart Failure Mortality

Roger VL et al. JAMA. 2004; 292: 344-351.

Mode of Death by NYHA Class

NYHA II NYHA III NYHA IV

HF26%HF

26%

Other 15%Other 15%

SD59%SD59% HF

56%HF

56%

Other 11%Other 11%

SD33%SD33%

MERIT-HF Study Group. Lancet. 1999; 353: 2001-2007.

HF12%HF

12%

SD64%SD64%

Other 24%Other 24%

Source: CDC/NCHS.

Heart Failure Hospitalizations

Heart Failure Hospitalizations

Rosamond W et al. Circulation. 2008; 115: e2-e122.

Hos

pita

lizat

ions

/100

,000

Pop

ulat

ion

19700

50

100

150

200

250

1975 1980 1985 1990 1995

Year

65+ years

45-64 years

1 mil hospitalizations/ year

Estimated Direct and Indirect Costs

254.8

142.1

56.8 59.727.9

393.5

050

100150200250300350400450

Hea

rtD

isea

se

Cor

onar

yH

eart

Dis

ease

Str

oke

Hyp

erte

nsiv

eD

isea

se

Con

gest

ive

Hea

rt F

ailu

re

Tot

al C

VD

*

Bil

lio

ns

of

Do

llar

s


Heart Failure Direct Costs

Home Health ($3.0 billion) 10%

Drugs/Medical Durables

($3 billion) 10%

Physicians/Other Providers

($2 billion) 7%

Hospital/Nursing Home ($21 billion) 73%

Total Expenditure (direct costs) = $29 billion



• Pathophysiology



• Risk factors



Risk factors


• Pathophysiology



• Risk factors



Heart failure stages and treatment

New Classification of Heart Failure


• Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Refractory end-stage HFD

• Known structural heart disease• Shortness of breath and fatigue• Reduced exercise tolerance

Symptomatic HFC

• Previous MI• LV systolic dysfunction• Asymptomatic valvular disease

Asymptomatic HFB

• Hypertension• CAD • Diabetes mellitus• Family history of cardiomyopathy

High risk for developing heart failure (HF)A

Patient DescriptionStage

Management of Chronic HF• Establish diagnosis (BNP, echo)• Determine etiology• Define syndrome (e.g. systolic vs. diastolic)• Correct precipitating factors (NSAIDS, COX2, etc.)• Evaluate and correct ischemia• Initiate chronic therapy

• Nonpharmacologic (e.g. exercise, tx. of sleep apnea, etc)• Pharmacologic (ACE - I, b - Blockers, ARB, diuretics, digoxin, etc.)• Electrical• Surgical

• Assess response to therapy

Stage C: Symptomatic HFClass I• Level A evidence

– Diuretics in patients with fluid retention

– ACE inhibition, unless contraindicated

– Beta blockade in stable patients, unless contraindicated

– Digitalis, unless contraindicated

• Level B evidence– Withdrawal of drugs known to adversely affect the clinical status of patients

All Class I recommendations for Stages A and B


Diuretics• Loop diuretics in pts. with CrCl < 30• Torsemide ↓ hospitalizations compared to furosemide• Have to be given bid to avoid rebound Na reabsorbtion• May use thiazides if CrCl > 30• Use combination (e.g. furosemide + thiazide), iv bolus

or iv drips• Metolazone in refractory HF or in pts. with renal

failure. Should not be used daily.• Add spironolactone if Cr < 2.5 and K < 5.


Trial ACEI Placebo RR (95% CI)

Mortality

CONSENSUS I

SOLVD (T)

SOLVD (P)

Post-MI

SAVE

TRACE

AIRE

39% 54% 0.56 (0.34-0.91)

40%35% 0.82 (0.70-0.97)

15% 16% 0.92 (0.79-1.08)

25%20% 0.81 (0.68-0.97)

17% 23% 0.73 (0.60-0.89)

SMILE 5% 6.5% 0.75 (0.40-1.11)

Totals

0.78 (0.67-0.91)35% 42%

21% 25%

Enalapril (18.4 mg)

Drug (mean dose)

Enalapril (11.2 mg)

Enalapril (12.7 mg)

Captopril (150 mg)*

Ramipril (1.25-5 mg)†

Trandolapril (1-4 mg)†

Zofenopril (7.5-30 mg)†

* No mean given; target dose † No mean given; dose range

ACE - I and Mortality in HF

Chronic HF

0.84

ACE Inhibitors• Most pts. tolerate ACE - I.• ACE - I improve symptoms immediately (days).• Pts. should not be “too dry” (no orthostatic ↓ BP).• If ↓ BP, check for orthostatic changes. If none, ACE - I OK.• Low BP and CRF are not CI for ACE - I.• If BUN/ Cr are raising, adjust the diuretic dose.• Low BP, low Na, renal dysfunction: low dose, short acting

ACE - I, titrate to target dose or the highest dose tolerated.• Low vs. high dose ACE - I: difference in outcomes.


1 CIBIS II Investigators and Committees. Lancet. 1999; 353: 9-17.2 MERIT - HF Study Group. Lancet. 1999; 353: 2001-2007.3 Packer M et al. N Engl J Med. 2001; 344: 1651-1658.

Study All - cause All - cause mortality hospitalizations

CIBIS II 1 (bisoprolol) 34% 20% 2647 pts. NYHA III - IV (p < 0.0001) (p = 0.0006)

MERIT – HF 2 (metoprolol XL) 34% 8.6% 3991 pts. NYHA II - IV (p = 0.0062) (p = 0.005)

COPERNICUS 3 (carvedilol) 35% 15% 2289 pts. NYHA IV (p = 0.0014) (p = 0.0029)

Beta - Blockers in HF

1 BEST Investigators. N Engl J Med. 2001; 344: 1659-1667. * All-cause mortality/ CV hospitalizations2 Flather MD et al.Eur Heart J . 2005; 26: 215-221.

Study All - cause All - cause mortality hospitalizations

BEST1 (bucindolol) 10% 8% 2708 pts. NYHA III - IV (p < 0.1) (p = 0.08)

SENIORS2 (nebivolol) 12% 4%* 2135 pts. NYHA II - III (p = 0.21) (p = 0.47)

Beta-Blockers: Not Created Equal

Beta-Blockers: Not Created Equal ?

COMET: Metoprolol vs. Carvedilol

Time (years)

Mor

talit

y (%

)

0

10

20

30

40

0 1 2 3 4 5

Metoprolol IR 50 mg bid

Carvedilol 25 mg bid

HR 0.83 (0.74 - 0.93)p = 0.0017

Poole-Wilson PA et al. Lancet. 2003; 362: 7-16.

Beta - Blockers• Only bisoprolol, carvedilol and metoprolol succinate.• Start at low doses, increase every 2 weeks to target dose or the

highest tolerated dose.• Intermediate vs. high dose: no difference in outcomes.• Do not start in pts. dependent of inotropic support.• Can start before hospital discharge in pts. not fluid overloaded.• Do not stop BB in hospitalized pts. who are on chronic BB

therapy (may worsen HF).• BB will take 3-6 months to improve symptoms.• Low BP and severe HF are not CI for BB.


Time Course of Changes in LV EF

0.20

0.25

0.30

0.35

0.40

Baseline Day 1 1 Mo 3 Mo Baseline Day 1 1 Mo 3 Mo

Ejec

tion

Frac

tion p < 0.0001

p < 0.05

p = 0.013 for metoprolol vs. standard therapy

Standard Therapy Metoprolol

Hall SA et al. J Am Coll Cardiol. 1995; 25: 1154-1160.

Which First: ACE or BB?

Willenheimer R et al. Circulation.. 2005; 112: 2426-2430.

Death/Hospitalization All-cause mortality

SCD/All-cause Mortality with First Bisoprolol Compared with EnalaprilEnd point HR (95% CI) pSudden death Monotherapy phase 0.50 (0.21-1.16) 0.10712 months 0.54 (0.29-1.00) 0.049End of study 0.84 (0.51-1.38) 0.487

All-cause mortality Monotherapy phase 0.72 (0.42-1.24) 0.2412 months 0.69 (0.46-1.02) 0.06End of study 0.88 (0.63-1.22) 0.44

Willenheimer R. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain.

Beta - Blockers

• Combination ARB + ACE - I + Beta - Blockers is safe.

• No mortality benefit when ARB is added to ACE - I.

• ARB are useful in pts. who are ACE intolerant.

• ARB could be added to ACE - I for symptomatic improvement.

• Triple RAAS blockade (ACE - I, ARB, aldosterone blockers) should not be used (Hyper K).

Angiotensin Receptor Blockers

CHARM- Added

CHARM-Preserved

CHARM Program3 component trials comparing candesartan to

placebo in patients with symptomatic HF

CHARM-Alternative

n=2028

LVEF < 40%ACE inhibitor

intolerant

n=2548LVEF < 40%ACE inhibitor

treated

n=3025LVEF > 40%ACE inhibitor

treated/not treated

Primary outcome for overall program: All-cause deathPrimary outcome for each trial: CV death or HF hospitalization

Pfeffer MA et al. Lancet. 2003; 362: 759-767.

Effect of Candesartan on Mortality and HF Hospitalizations


All-cause mortalityCardiovascular death/

HF hospitalizations

Alternative

Added

Preserved

Overall

0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.9 1.0 1.1 1.20.8

Aldosterone Antagonists: Spironolactone

1.00

Placebo

Months

Mor

tality

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 < 0.001

30% Relative risk reduction

Pitt B et al. N Engl J Med. 1999; 341; 709-715.

Months Since Randomization

Cumulative Incidence (%)

22

0

2

20

16

18

14

12

10

8

6

4

RR = 0.85 (95% CI, 0.75–0.96) P = 0.008

Placebo

Eplerenone

3633302724211815129630

Eplerenone post MI: MortalityEplerenone post MI: Mortality

Pitt B et al. N Engl J Med. 2003; 348: 1309-1315.

Months Since Randomization

Cum

ulat

ive

Inci

denc

e (%

)

3 6 9 12

15

18

21

24

27

30

33

36

10

9

8

7

6

5

4

3

2

1

0

0

RR = 0.79 (95% CI, 0.64–0.97)P = 0.03

Eplerenone

Placebo

All Patients

3633302724211815129630

0

2

4

6

8

10

12

14

16

RR = 0.67 (95% CI, 0.50–0.91)P = 0.009

Placebo

Eplerenone

Patients with Baseline Ejection Fraction 30%

Eplerenone and SCD post MI

Pitt B et al. N Engl J Med. 2003; 348: 1309-1315.

Sudden Death Post MI in VALIANT

Solomon SD et al. N Engl J Med. 2005; 352: 2581-2588.

Eplerenone and SCD Post MI

Pitt B et al. J Am Coll Cardiol. 2005; 46: 425-430.

Risk of Death and Serum Digoxin

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Hazard Ratio(Dig versus Placebo)

2.01.81.61.41.21.00.80.5

Serum Digoxin Concentration (ng/ml)

Undetectable

< 0.5

1.04

WomenAllMen

Adams KF et al. J Am Coll Cardiol. 2005; 46: 505-510.

Digoxin: Mortality/ Hospitalizations

Total mortality/ hospitalization

HF mortality/ hospitalizations

All pts. EF< 45% 0.94 (0.88 - 1.00) 0.69 (0.63 - 0.76)

EF < 25% 0.84 (0.76 - 0.93) 0.84 (0.76 - 0.93)

EF 25 - 45% 0.99 (0.91 - 1.07) 0.74 (0.66 - 0.84)

EF > 45% 1.04 (0.88 - 1.23) 0.72 (0.53 - 0.99)

NYHA I/ II 0.96 (0.89 - 1.04) 0.70 (0.62 - 0.80)

NYHA III/ IV 0.88 (0.80 - 0.97) 0.65 (0.57 - 0.75)

CTR ≤ 55% 0.98 (0.91 - 1.06) 0.71 (0.63 - 0.81)CTR > 55% 0.85 (0.77 - 0.94) 0.65 (0.57 - 0.75)

DIG Investigators. N Engl J Med. 1997; 336: 525-532. * At 24 months

ISDN – Hy in African Americans

Taylor AL et al. N Engl J Med. 2004; 351: 2049-2057.

McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005; Boca Raton, FL.

Hy – ISDN and NO Genotype

NOS3 exon 7 genotype

GRACE whites

GRACE blacks

A-HeFT

Asp-Asp (%) 14 2 1

Asp-Glu (%) 45 31 20

Glu-Glu (%) 41 67 79

Primary End-point in A-HeFTParameter Placebo ISDN-

hydralazinep

Genotype subset (treatment impact on composite score)

Glu-Glu -0.22 0.18 0.051

Heterozygous or Asp-Asp 0.29 0.38 0.82

Genotype subset (treatment impact on composite's QOL component)

Glu-Glu -0.08 0.43 0.046

Heterozygous or Asp-Asp 0.58 0.61 0.93

McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005; Boca Raton, FL.

ICD for Primary Prevention

• Patients with heart failure due to severe LV systolic dysfunction (EF < 30%) with class II and III symptoms, with survival > 12 months.

• At least 40 days post MI, > 3 months for NICM.

SCD-HeFT Trial: Survival

HR 97.5% Cl P

Amiodarone vs Placebo

1.06 0.86-1.30 0.53

ICD vs Placebo 0.77 0.62-0.96 .007

Months of Follow-Up

Mor

talit

y

0 6 12 18 24 30 36 42 48 54 600

.1

.2

.3

.4

Amiodarone

ICD TherapyPlacebo

†17%

†22%

Bardy GH et al. N Engl J Med. 2005; 352: 225-231.

CRT: Who Should Get It?

• Patients with heart failure due to severe LV systolic dysfunction (EF < 35%) with class III and IV symptoms, in spite of adequate and maximum medical therapy.

• QRS duration of 120 ms.

• Responders?

CARE-HF: All-cause Mortality or Unplanned CVD Hospitalizations

0 500 1000 15000.00

0.25

0.50

0.75

1.00HR 0.63 (95% CI 0.51 to 0.77)

Even

t-fre

e Su

rviv

al

Days

P < .0001

CRT

Medical Therapy

Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549.

CARE-HF: All-Cause Mortality

0 500 1000 15000.00

0.25

0.50

0.75

1.00

Even

t-fre

e Su

rviv

al

Days

Medical Therapy

HR 0.64 (95% CI 0.48 to 0.85)

P = .0019CRT

Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549.

Recommendation for Diastolic HF• Control of systolic and diastolic BP.

• Control ventricular rate in pts. with A Fib.

• Diuretics to control pulmonary and peripheral edema.

• Anticoagulation in pts. with A Fib.

• Coronary revascularization in pts. with CAD and ischemia.

• Restoration of sinus rhythm in pts. with A Fib.

• Addition of Beta - Blockers, ACE - I, ARB, or CCB to control HTN.

• ACE –Inhibitors, ARBs, digoxin to minimize HF symptoms.


Perindopril for Diastolic HF

Cleland JGF et al. Eur Heart J. 2006; 27: 2338-2346.

Digoxin for Diastolic HF?

Ahmed A et al. Circulation. 2006; 114: 397-404.

Candesartan For Diastolic HF


All-cause mortalityCardiovascular death/

HF hospitalizations

Alternative

Added

Preserved

Overall

0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.9 1.0 1.1 1.20.8

Stage D: End-stage HF

Class I• Level A evidence

– Refer patient to specialist in HF management

• Level B evidence

– Closely watch for and control fluid retention

– Refer eligible patients for cardiac transplantation, LVAD

All Class I recommendations for Stages A- C


LVADs as Destination Therapy

Lietz K et al. Circulation. 2007; 116: 497-505.

Heart Transplants Reported by Year

Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879.

Adult Heart Transplant SurvivalSu

rviva

l (%

)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12Years

1982-1988 (N=9,071)1989-1993 (N=17,685)1994-1998 (N=18,758)1999-6/2004 (N=16,227)

Average: 1982-1988: 8.2 years; 1989-1993: 9.7 years; 1994-1998: 10.2 years

Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879.

CONCLUSIONS: Chronic HF• STAGE A (HTN, CAD or DM):

– Routine: ACE-I/ARB; selected pts. BB, statin, antiplatelets

• STAGE B (Asymptomatic structural heart disease):– Routine: ACE-I/ARB, BB; selected pts. statin, antiplatelets

• STAGE C (Symptomatic HF and low EF):– Routine: ACE-I/ARB, BB, Aldo blockers, diuretics, digoxin– Selected pts. CRT, ICD, Hy-ISDN

• STAGE C (Symptomatic HF and preserved EF):– Consider ACE-I/ARB, digoxin ?, BB, CCB, Aldo blockers.

• STAGE D (End-stage HF):– Referral to HF program for LVAD, OHT.

Paradigm for Management of HF

Diuretics

ACE – I /ARB

DigoxinARB

Treat Congestion:

Slow Disease Progression:

Treat Residual Symptoms:

BB Aldo bloc.

ICDSudden Death: BB Aldo bloc.

Cardiac Resynchronization Therapy (CRT)

Advanced Disease: LVAD OHT

Heart Failure

The future is here….

Heart Failure Liviu Klein MD, MS .

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