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Heart Failure. Liviu Klein MD, MS http://www.cardiologyfellows.northwestern.edu/cculectures. Outline. Definition. Definition Pathophysiology Epidemiology (prevalence, incidence, trends) Epidemiology (mortality and associated morbidity) Risk factors Heart failure stages and treatment

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Heart failure

Heart Failure

Liviu Klein MD, MS

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


Outline
Outline

Definition

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant


Heart failure 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.


Heart failure definition1
Heart Failure Definition

  • 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

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


Outline1
Outline

Pathophysiology

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant


Heart failure pathophysiology
Heart Failure Pathophysiology

Cardiac injury

Increased load

Reduced systemic perfusion

Activation of RAS, SNS, and cytokines

Altered gene expression

Growth and remodeling

Ischemia and energy depletion

Direct toxicity

Apoptosis

Necrosis

Cell death


Progression of heart failure

PathologicRemodeling

Low ejectionfraction

Left ventricularinjury

Progression of Heart Failure

Coronary artery disease

Cardiomyopathic factors

Atrial Fibrillation

Valvular disease

Hypertension

Diabetes

Death


NORMAL

No symptoms

Normal exercise

Normal LV fxn

Asymptomatic

LV Dysfunction

No symptoms

Normal exercise

Abnormal LV fxn

Compensated

No symptoms

Exercise

Abnormal LV fxn

Decompensated

Symptoms

Exercise

Abnormal LV fxn

Refractory

Symptoms not

controlled

with treatment

Heart Failure Clinical Stages


Outline2
Outline

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant

Epidemiology (prevalence, incidence, trends)


Prevalence of Heart Failure

Source: CDC/NCHS and NHLBI.


Prevalence of heart failure
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.


Outline3
Outline

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant

Epidemiology (mortality and associated morbidity)


Cardiovascular Deaths

300,000 death/yr


Survival according to nyha class

Placebo

100

Conventional therapies (diuretics, digoxin)

90

NYHA Class IV (CONSENSUS)

80

70

60

NYHA Class II–III(SOLVD Treatment Trial)

50

Mortality (%)

40

30

20

10

0

0

6

12

18

24

30

36

42

48

Months

Survival according to NYHA Class

NYHA Class I–II(SOLVD Prevention 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
Mode of Death by NYHA Class

NYHA IV

NYHA II

NYHA III

Other 15%

Other 11%

Other 24%

SD

33%

SD

64%

SD

59%

HF

26%

HF

12%

HF

56%

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



Heart Failure Hospitalizations

250

200

150

100

50

0

1 mil hospitalizations/ year

65+ years

Hospitalizations/100,000 Population

45-64 years

1975

1980

1985

1990

1995

1970

Year

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


Estimated Direct and Indirect Costs

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


Heart failure direct costs

Physicians/Other Providers

($2 billion) 7%

Drugs/Medical Durables

($3 billion) 10%

Hospital/Nursing Home

($21 billion) 73%

Home Health

($3.0 billion) 10%

Total Expenditure (direct costs) = $29 billion

Heart Failure Direct Costs

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


Outline4
Outline

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant

Risk factors


Outline5
Outline

  • Definition

  • Pathophysiology

  • Epidemiology (prevalence, incidence, trends)

  • Epidemiology (mortality and associated morbidity)

  • Risk factors

  • Heart failure stages and treatment

  • Advanced heart failure and transplant

Heart failure stages and treatment


New classification of heart failure

Stage

Patient Description

A

High risk for developing heart failure (HF)

  • Hypertension

  • CAD

  • Diabetes mellitus

  • Family history of cardiomyopathy

B

Asymptomatic HF

  • Previous MI

  • LV systolic dysfunction

  • Asymptomatic valvular disease

C

Symptomatic HF

  • Known structural heart disease

  • Shortness of breath and fatigue

  • Reduced exercise tolerance

D

Refractory end-stage HF

  • 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)

New Classification of Heart Failure

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


Management of chronic hf
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 hf
    Stage C: Symptomatic HF

    Class 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

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


    Diuretics
    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.

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


    Ace i and mortality in hf
    ACE - I and Mortality in HF

    Mortality

    Trial

    ACEI

    Placebo

    RR (95% CI)

    Drug (mean dose)

    Chronic HF

    CONSENSUS I

    39%

    54%

    0.56 (0.34-0.91)

    Enalapril (18.4 mg)

    SOLVD (T)

    35%

    40%

    0.82 (0.70-0.97)

    Enalapril (11.2 mg)

    SOLVD (P)

    15%

    16%

    0.92 (0.79-1.08)

    Enalapril (12.7 mg)

    Post-MI

    SAVE

    20%

    25%

    0.81 (0.68-0.97)

    Captopril (150 mg)*

    AIRE

    17%

    23%

    0.73 (0.60-0.89)

    Ramipril (1.25-5 mg)†

    TRACE

    35%

    42%

    0.78 (0.67-0.91)

    Trandolapril (1-4 mg)†

    Zofenopril (7.5-30 mg)†

    SMILE

    5%

    6.5%

    0.75 (0.40-1.11)

    0.84

    Totals

    21%

    25%

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


    Ace inhibitors
    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.

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


    Beta - Blockers in HF

    Study All - cause All - cause mortality hospitalizations

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

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

    COPERNICUS 3 (carvedilol) ß 35% ß15% 2289 pts. NYHA IV (p = 0.0014) (p = 0.0029)

    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.


    Beta-Blockers: Not Created Equal

    Study All - cause All - cause mortality hospitalizations

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

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

    1 BEST Investigators. N Engl J Med. 2001; 344: 1659-1667. * All-cause mortality/ CV hospitalizations

    2 Flather MD et al.Eur Heart J . 2005; 26: 215-221.


    Beta-Blockers: Not Created Equal ?


    Comet metoprolol vs carvedilol

    40

    Metoprolol IR 50 mg bid

    30

    Carvedilol 25 mg bid

    Mortality (%)

    20

    HR 0.83 (0.74 - 0.93)

    p = 0.0017

    10

    0

    0

    1

    2

    3

    4

    5

    Time (years)

    COMET: Metoprolol vs. Carvedilol

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


    Beta blockers
    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.

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


    Time course of changes in lv ef

    0.40

    Standard Therapy

    Metoprolol

    p < 0.0001

    0.35

    p = 0.013 for metoprolol vs. standard therapy

    Ejection Fraction

    0.30

    p < 0.05

    0.25

    0.20

    Baseline

    Day 1

    1 Mo

    3 Mo

    Day 1

    1 Mo

    3 Mo

    Baseline

    Time Course of Changes in LV EF

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


    All-cause mortality

    Death/Hospitalization

    Which First: ACE or BB?

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


    Scd all cause mortality with first bisoprolol compared with enalapril
    SCD/All-cause Mortality with First Bisoprolol Compared with Enalapril

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


    Beta Enalapril - Blockers


    Angiotensin receptor blockers
    Angiotensin Receptor Blockers Enalapril

    • 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).


    Charm program
    CHARM Program Enalapril

    3 component trials comparing candesartan to

    placebo in patients with symptomatic HF

    CHARM-Alternative

    CHARM- Added

    CHARM-Preserved

    n=2028

    LVEF < 40%ACE inhibitor intolerant

    n=2548

    LVEF < 40%ACE inhibitor treated

    n=3025

    LVEF > 40%ACE inhibitor treated/not treated

    Primary outcome for each trial: CV death or HF hospitalization

    Primary outcome for overall program: All-cause death

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


    Effect of candesartan on mortality and hf hospitalizations

    Cardiovascular death/ EnalaprilHF hospitalizations

    All-cause mortality

    Alternative

    Added

    Preserved

    Overall

    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

    Effect of Candesartan on Mortality and HF Hospitalizations

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


    Aldosterone antagonists spironolactone

    1.00 Enalapril

    30% Relative risk reduction

    0.95

    0.90

    0.85

    0.80

    0.75

    Mortality

    Spironolactone

    0.70

    0.65

    0.60

    p< 0.001

    0.55

    Placebo

    0.50

    0.45

    0.00

    0

    3

    6

    9

    12

    15

    18

    21

    24

    27

    30

    33

    36

    Months

    Aldosterone Antagonists: Spironolactone

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


    Eplerenone post MI: Mortality Enalapril

    22

    20

    18

    16

    14

    Placebo

    Eplerenone

    Cumulative Incidence (%)

    12

    10

    RR = 0.85 (95% CI, 0.75–0.96)

    P = 0.008

    8

    6

    4

    2

    0

    0

    3

    6

    9

    12

    15

    18

    21

    24

    27

    30

    33

    36

    Months Since Randomization

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


    Eplerenone and scd post mi
    Eplerenone and SCD post MI Enalapril

    Patients with Baseline Ejection Fraction 30%

    All Patients

    16

    10

    9

    14

    8

    12

    7

    Placebo

    Placebo

    10

    6

    5

    Cumulative Incidence (%)

    8

    Eplerenone

    Eplerenone

    4

    6

    3

    RR = 0.67 (95% CI, 0.50–0.91)

    P = 0.009

    RR = 0.79 (95% CI, 0.64–0.97)P = 0.03

    4

    2

    2

    1

    0

    0

    0

    3

    6

    9

    12

    15

    18

    21

    24

    27

    30

    33

    36

    0

    3

    6

    9

    12

    15

    18

    21

    24

    27

    30

    33

    36

    Months Since Randomization

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


    Sudden Death Post MI in VALIANT Enalapril

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


    Eplerenone and SCD Post MI Enalapril

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


    Risk of death and serum digoxin

    Hazard Ratio Enalapril

    (Dig versus Placebo)

    1.5

    Women

    All

    1.4

    Men

    1.3

    1.2

    1.1

    1.04

    1.0

    0.9

    0.8

    0.7

    0.6

    0.5

    Undetectable

    0.5

    0.8

    1.0

    1.2

    1.4

    1.6

    1.8

    2.0

    < 0.5

    Serum Digoxin Concentration (ng/ml)

    Risk of Death and Serum Digoxin

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


    Digoxin mortality hospitalizations
    Digoxin: Mortality/ Hospitalizations Enalapril

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


    ISDN – Hy in African Americans Enalapril

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


    Hy isdn and no genotype
    Hy – ISDN and NO Genotype Enalapril

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


    Primary end point in a heft
    Primary End-point in A-HeFT Enalapril

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


    Icd for primary prevention
    ICD for Primary Prevention Enalapril

    • 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
    SCD-HeFT Trial: Survival Enalapril

    .4

    .3

    †22%

    .2

    Mortality

    †17%

    Amiodarone

    .1

    ICD Therapy

    Placebo

    0

    0

    6

    12

    18

    24

    30

    36

    42

    48

    54

    60

    Months of Follow-Up

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


    Crt who should get it
    CRT: Who Should Get It? Enalapril

    • 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

    1.00 Enalapril

    HR 0.63 (95% CI 0.51 to 0.77)

    0.75

    CRT

    0.50

    Event-free Survival

    P < .0001

    Medical Therapy

    0.25

    0.00

    0

    500

    1000

    1500

    Days

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

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


    Care hf all cause mortality
    CARE-HF: All-Cause Mortality Enalapril

    1.00

    HR 0.64 (95% CI 0.48 to 0.85)

    0.75

    CRT

    P = .0019

    0.50

    Event-free Survival

    Medical Therapy

    0.25

    0.00

    0

    500

    1000

    1500

    Days

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


    Recommendation for diastolic hf
    Recommendation for Diastolic HF Enalapril

    • 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.

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


    Perindopril for diastolic hf
    Perindopril for Diastolic HF Enalapril

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


    Digoxin for diastolic hf
    Digoxin for Diastolic HF? Enalapril

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


    Candesartan for diastolic hf
    Candesartan For Diastolic HF Enalapril

    Cardiovascular death/HF hospitalizations

    All-cause mortality

    Alternative

    Added

    Preserved

    Overall

    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

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


    Stage d end stage hf
    Stage D: End-stage HF Enalapril

    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

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


    LVADs as Destination Therapy Enalapril

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


    Heart transplants reported by year

    Heart Transplants Reported by Year Enalapril

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


    Adult heart transplant survival
    Adult Heart Transplant Survival Enalapril

    Survival (%)

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


    Conclusions chronic hf
    CONCLUSIONS: Chronic HF Enalapril

    • 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
    Paradigm for Management of HF Enalapril

    Diuretics

    Treat Congestion:

    ACE – I /ARB

    Slow Disease Progression:

    BB Aldo bloc.

    Sudden Death:

    BB Aldo bloc.

    ICD

    Treat Residual Symptoms:

    Digoxin

    ARB

    Cardiac Resynchronization Therapy (CRT)

    Advanced Disease:

    LVAD OHT


    Heart failure1

    Heart Failure Enalapril

    The future is here….


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