heart failure liviu klein md, ms
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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
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Outline• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
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
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.
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.
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
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
Rosamond W et al. Circulation. 2008; 115: e2-e122.
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
Rosamond W et al. Circulation. 2008; 115: e2-e122.
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
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
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
• 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
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
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.
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.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
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.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
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
Pfeffer MA et al. Lancet. 2003; 362: 759-767.
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.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
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
Pfeffer MA et al. Lancet. 2003; 362: 759-767.
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
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
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….