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Current Therapies for the Management of Chronic and Acute Heart Failure

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Title: Current Therapies for the Management of Chronic and Acute Heart Failure


1
Current Therapies for the Management of Chronic
and Acute Heart Failure
  • John L. Tan, MD, PhD
  • Heart Failure Program at the
  • North Texas Heart Center
  • Presbyterian Hospital of Dallas

2
Heart Failure The Scope
  • Prevalence 4.6 million Americans
  • Incidence 550,000 new cases/year
  • 10 per 1000 population after age 65
  • Morbidity 1,000,000 hospitalizations (2001)
  • 5 to 10 of all admissions
  • Most frequent cause of hosp in elderly
  • Mortality Contributes to ?260,000
    deaths/year
  • Up to 70 of patients die suddenly
  • Five year mortality rate 50

Adapted from AHA Heart and Stroke Facts
Statistical Update, 1999 Kannel and Belanger,
1991 Stevenson et al, 1993 OConnell and
Bristow, 1994 AHA. 2001 Heart and Stroke
Statistical Update.
3
Cost of Heart Failure
  • 38.1 billion in 1991
  • Rising to an estimated 54 billion in 1999
  • Accounting for approximately twice the cost
  • for cancer or myocardial infarction
  • 5.4 of total health care costs
  • Single largest expense for Medicare

Adapted from AHA Heart and Stroke Facts
Statistical Update, 1999 Kannel and Belanger,
1991 Stevenson et al, 1993 OConnell and
Bristow, 1994 AHA. 2001 Heart and Stroke
Statistical Update.
4
Etiology of Heart Failure (SOLVD Registry)
N6063
Valvular heart disease Congenitalheart
disease Viral Toxic Thyroid Peripartum
Bourassa et al. J Am Coll Cardiol.
19932214A-19A.
5
The 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)
Hunt SA et al. J Am Coll Cardiol.
20013821012113.
6
Symptom Relief is Not Sufficient
Heart failure is more than a symptomatic
disease Produces symptoms, limits functional
capacity, and impairs quality of life Heart
failure is a progressive disease Worsening
symptoms and clinical deterioration,
repeated hospitalization, and death Death
occurs frequently even in the presence of
minimal symptoms or the absence of progressive
symptoms Symptoms do not always correspond with
ejection fraction
7
Ventricular Remodeling
Ventricular Remodeling After Acute Infarction
Global remodeling(days to months)
Initial infarct
Expansion of infarct(hours to days)
Ventricular Remodeling in Diastolic and Systolic
HF
Normal heart
Dilated heart(systolic HF)
Hypertrophied heart(diastolic HF)
Jessup M et al. N Engl J Med. 20033482007
8
Heart Failure Pathophysiology
Myocardial Injury
Fall in LV performance
ANP BNP
Activation of RAAS, SNS, ET, and others
-
Peripheral vasoconstriction Hemodynamic
alterations
Myocardial toxicity
-
Remodeling and progressive worsening of LV
function
Heart failure symptoms
Morbidity and mortality
9
Neurohormonal Targets in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
SNS Activation
AT II
AT1 Receptors
Epinephrine Norepinephrine
Target Cells
10
ACE Inhibitors in Heart Failure
  • 7000 patients evaluated in long-term placebo-
  • controlled clinical trials
  • Improvement in cardiac function, symptoms,
  • and clinical status equivocal effects on
  • exercise tolerance
  • Decrease in all-cause mortality by 20-25
  • (Plt.001) and decrease in combined risk of
  • death and hospitalization by 30-35
  • (Plt.001)

Garg and Yusuf, 1995.
11
Mortality in Patients Receiving ACE Inhibitors
ACE inhibitor arms of CONSENSUS, V-HeFT, and
SOLVD trials. Placebo arms of PRAISE, PROMISE,
and DIG trials (all receiving ACE inhibitors).
12
Neurohormonal Targets in Heart Failure
Angiotensinogen
ACE Inhibitors
b-Blockers
Angiotensin I
SNS Activation
AT II
AT1 Receptors
Epinephrine Norepinephrine
b-Blockers
Target Cells
13
Effect of b-Blockade on All-Cause Mortality
0
0.25
0.5
0.75
1
1.25
1.5
1.75
2
Relative risk and 95 confidence intervals
14
COPERNICUS
All-cause mortality 35 decreased risk
100
90
Carvedilol (n1156)
80
Survival
70
Placebo (n1133)
60
P0.00014
50
24
0
20
16
12
8
4
28
Months
.
15
The CHF Trials in Perspective Patients Needed
to Treat for One Year to Save One Life
  • HF Stage Trial of Patients
  • A HOPE 333
  • B SOLVD-Prevention 285
  • C SOLVD-Treatment 77
  • C CIBIS-II 23
  • C MERIT-HF 25
  • D COPERNICUS 14

16
Neurohormonal Targets in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
SNS Activation
AT II
ARBs
AT1 Receptors
Epinephrine Norepinephrine
Target Cells
17
CHARM-Added Primary Endpoint
50
Placebo
538 (42.3)
40
483 (37.9)
15 risk reduction
30
CV death or HF hospitalization ()
Candesartan
20
HR 0.85 (95 CI 0.75-0.96), P0.011 Adjusted HR
0.85, P0.010
10
0
0
1
2
3
3.5
Time (years)
Number at risk Candesartan Placebo
1276 1272
1176 1136
1063 1013
948 906
457 422
HF, heart failure HR, hazard ratio CI,
confidence interval. McMurray JJV et al. Lancet.
2003362767-771.
18
A-HEFT Role of Hydralazine/Nitrates
Mortality 43 Hospitalization 33
Taylor AL, et al. N Engl J Med. 20043512049-57
19
A-HeFT Hydralazine/Nitrates
  • African-Americans (n 1050)
  • LVEF lt 35 or lt45 with increased LVEDD
  • NYHA Class III-IV
  • 70 on ACE-I, 74 on b-B
  • Baseline SBP 125 mm Hg
  • Etiology of CMP
  • 40 Hypertension
  • 23 CAD

Taylor AL, et al. N Engl J Med. 20043512049-57
20
Neurohormonal Targets in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
SNS Activation
AT II
AT1 Receptors
Epinephrine Norepinephrine
Aldosterone Receptor Blockers
Target Cells
21
RALES Aldosterone Receptor Blockade
Spironolactone n 1663 NYHA III/IV LVEF lt
40 mortality 27 hospitalization
36 (plt0.0002)
Pitt B, et al. N Engl J Med. 1999341709-717
22
Mode of Death in MERIT-HF
NYHA II
NYHA III
Other 15
Other 24
Sudden cardiac death 59
Sudden cardiac death 64
HF 26
HF 12
MERIT-HF Study Group. Lancet. 1999353(9169)2001-
2007.
23
Device Therapies in Heart Failure Implantable
Cardioverter-Defibrillators
24
MADIT II Study Design
Patients with prior MI within 30 days and LVEF lt
30 randomized in a 32 ratio 71 US centers and
5 European centers
Conventional medical therapy (n490)
Implantable defibrillator (n742)
All Cause Mortality - Average follow-up of 20
months
Stopped early by Data Safety Monitoring Board
25
MADIT II All-Cause Mortality
Death Avg. follow-up20 months
P0.016
Hazard Ratio 0.65
Conventional Therapy
ICD
26
SCD-HeFT Enrollment Scheme
DCM CAD and CHF EF lt 35 NYHA Class II or
III 6 minute walk, Holter
n2521, 111
R
Placebo
Amiodarone
ICD
Bardy G et al. NEJM 2005 3523
27
SCD-HeFT Death from Any Cause
23 RR Reduction in Death 7.2 Absolute
Reduction at 5 yrs
Bardy G et al. NEJM 2005 3523
28
SCD-HeFT Death from Any Cause in Ischemic CHF
Bardy G et al. NEJM 2005 3523
29
SCD-HeFT Death from Any Cause in Nonischemic
CHF
Bardy G et al. NEJM 2005 3523
30
SCD-HeFT Primary Conclusions
  • In class II or III CHF patients with EF lt 35 on
    good background drug therapy, the mortality rate
    for placebo-controlled patients is 7.2 per year
    over 5 years
  • Simple, single lead, shock-only ICDs decrease
    mortality by 23
  • Amiodarone, when used as a primary preventative
    agent, does not improve survival

Bardy G et al. NEJM 2005 3523
31
Mortality Benefits of HF Therapies
Absolute Annual Mortality Reduction During Trial
Absolute Reduction
32
Indications for ICDs in CHF
  • CHF for at least 3 months
  • Ejection fraction less than or equal to 35
  • NYHA Class II or III symptoms
  • Greater than 1 year life expectancy
  • Ischemic or non-ischemic cardiomyopathy
  • No QRS duration requirements

CMS Website
33
Device Therapies in Heart Failure Cardiac
Resynchronization
34
Myocardial Dyssynchrony
35
Cardiac Resynchronization in Heart Failure
  • Indications
  • EF lt35
  • NYHA III-IV
  • QRS gt130-150ms

36
Cardiac Resynchronizationin Heart Failure
60
P 0.004
P 0.003
Control
Resynchronized
P 0.005
40
Change in 6-minute Walking Distance (m)
20
0
MIRACLE Trial, N Engl J Med 20023461845-53
-20
0 1 3 6
Months after Randomization
37
Cardiac Resynchronizationin Heart Failure
0
P lt 0.001
P 0.001
-5
P lt 0.001
Control
Resynchronized
-10
Change in Quality-of-Life Score
-15
-20
MIRACLE Trial, N Engl J Med 20023461845-53
-25
0 1 3
6
Months after Randomization
38
The COMPANION Trial
  • 1520 patients (122)
  • NYHA Class III-IV
  • EF lt/35
  • QRS gt 120 ms
  • 11.9-16.5 month f/u
  • Study withdrawal
  • 26 Placebo
  • 6 Bi-V Pacemaker
  • 7 Bi-V-ICD

39
The COMPANION Trial
Bristow MR, et al. N Engl J Med. 20043502140-50
40
The COMPANION Trial
Bristow MR, et al. N Engl J Med. 20043502140-50
41
Optimal Therapy for Chronic Heart Failure
  • In Symptomatic Patients
  • Diuretics
  • Digoxin

42
Optimal Therapy for Chronic Heart Failure
  • ACE Inhibitors (or ARBII Blockers)
  • Beta-blockers
  • ARBII Blockers or Hydralazine/Nitrates
  • ICD Therapy (Class II or higher CHF)

43
Optimal Therapy for Chronic Heart Failure
  • In Persistent Class III-IV CHF
  • Spironalactone
  • Bi-ventricular pacer (Prolonged QRS)

44
MADIT II CHF
New or Worsening Heart Failure
P0.09
Conventional Therapy
ICD
45
Heart Failure Hospitalizations
The number of heart failure hospitalizations is
increasing in both men and women

AHA, 1998 Heart and Statistical Update NCHS,
National Center for Health Statistics
CDC/NCHS Hospital discharges include patients
both living and dead.
AHA Heart and Stroke Statistical Update 2001
46
Rising Hospital Admissions for Heart Failure
  • Inevitable progression of disease
  • Rising incidence of chronic heart failure
  • (population aging, improved survival with
    AMI/revascularization)
  • Incomplete treatment during hospitalization
  • Poor application of chronic heart failure
  • management guidelines
  • Noncompliance with diet and drugs

47
Emergency Department Visits for Congestive Heart
Failure
Initial Episode 21
Approximately 80 of the ED visits for CHF result
in hospitalizations
Repeat Visit 79
  • Rates of Hospital Readmission
  • 2 within 2 days 20 within 1 month
  • 50 within 6 months

Cardiology Roundtable 1998
48
Utilization of HF Medications
Patients Treated ()
Excludes patients with documented
contraindications
2300/7883 patients hospitalized with HF prior
known LV systolic dysfunction outpatient medical
regimen ADHERE Registry Report Q1 2002
(4/013/02) of 180 US Hospitals. Presented at the
HFSA Satellite Symposium, September 23, 2002
49
Causes of Hospital Readmissionfor Heart Failure
Diet Noncompliance 24
Rx Noncompliance 24
16 Inappropriate Rx
17 Other
19 Failure to Seek Care
Vinson J Am Geriatr Soc 1990381290-5
50
Heart Failure Costs
38.6Outpatient care14.7 billion(3.4
visits/year/patient)
60.6Hospitalizations23.1 billion
0.7Transplants270 million
Total 38.1 billion(5.4 of total healthcare
costs)
OConnell and Bristow. J Heart Lung Transplant.
199413S107-S112.
51
ADHF Clinical Assessment
Congestion at Rest
No
Yes
  • Signs/symptoms
  • of congestion
  • Orthopnea/PND
  • JVD
  • Ascites
  • Edema
  • Rales

Normal
Warm Wet
Warm Dry (normal)
Cardiac output/ Perfusion at Rest
Cold Wet
Cold Dry
Low
Stevenson LW. Eur J Heart Fail. 19991251
52
Risk Stratification of Patients with ADCHF
lt
gt

BUN 43

N3
2
,
324



2.68

8.98

n25,122

n7,
202

SYS BP 115

SYS BP 115

n24,933

n7,147

lt
gt
gt
lt
6.4
1


15.28

5.49

2.14

n5,102

n2,04
8
n4,099

n20,834


lt
gt
Cr 2.75

s mortality rates
n2,045

21.94


12.42


Fonarow et al. 2003
n620

n1,425

53
The ESCAPE Trial
  • Tested safety and efficacy of PA catheter
  • use in ADCHF
  • 433 patients with Class IV symptoms
  • Randomized to usual care versus PA catheter-
  • guided therapy
  • No difference in mortality or length of stay
  • However, patients felt better with the PA
    catheter

Stevenson, LW. AHA 2004
54
Therapies for Acute Decompensated Heart Failure
Congestion at Rest
Yes
No
Warm and Dry PCW and CI normal
Warm and Wet PCW elevated CI normal
No
Low Perfusion at Rest
Vasodilators Diuretics
Cold and Wet PCW elevated CI decreased
Cold and Dry PCW low/normal CI decreased
Yes
Nl SVR
High SVR
Inotropes
R. Bourge, UAB Cardiology (adapted from L.
Stevenson), Stevenson LW. Eur J Heart Failure
19991251-257
55
Parenteral Therapies for Decompensated Heart
Failure
Treatment
Limitations
Dobutamine
Heart rate, arrhythmias,

MVO2, ischemia, and tolerance
Milrinone
Heart rate, arrhythmias, hypotension
Nitroglycerin
Tolerance, side effects
Nitroprusside
Difficult administration (titration), side
effects
56
Intravenous Inotropic Agents for Decompensated
Heart Failure
Milrinone n477
Control n472
60 Day Follow-up
Days until Discharge
5.7 13
5.9 13
Adverse Events
12.6
2.1

Sustained Hypotension
10.7
3.2

Acute MI
1.5
0.4
Rehospitalized or Death
35.3
35.0
Death
2.3
3.8

Plt0.001
48-hour infusion of milrinone (0.5mcg/kg/min)
within 48 hours for worsening of CHF.
OPTIME. Gheorghiade et al. ACC Meeting 2000 Late
Breaking Trials Session
57
VMAC PCWP Through 48 Hours
0
-1
NTG
Nesiritide
-2
-3

Plt0.05 pooled nesiritide compared to
nitroglycerin
-4



-5
Mean Change (mm Hg)

-6


-7

-8
-9
-10
-11
36 h
48 h
3 h
6 h
9 h
12 h
24 h
Time
Young JB et al. AHA Meeting 2000 Late Breaking
Trials Session
58
Precedent 6 Month Survival
Log - rank Test Dobutamine vs nesiritide 0.015
?g/kg/min p0.041 Dobutamine vs nesiritide 0.030
?g/kg/min p0.445 Nes 0.015 ?g/kg/min vs nes
0.030 ?g/kg/min p0.187
Dobutamine (n141)
Nes 0.030 ?g/kg/min (n179)
35
Nes 0.015 ?g/kg/min (n187)
30
25
20
Cumulative Mortality Rate ()
15
10
5
0
0
30
60
90
120
150
180
Time from start of treatment (days)
Elkayam U. et al, J. Cardiac Failure 20006
(Suppl 2)169
59
VMAC Mortality Rates
100
Stratified Log - rank Test
90
NTG vs Nesiritide
0.01 µg/kg/min p0.616
80
NTG vs All Nesiritide doses
p0.319
NTG (n 216)
70
Nesiritide 0.01 µg/kg/min (n 211)
60
All Nesiritide (n 273)
Cumulative Mortality Rate
50
40
30
20
10
0
0
30
60
90
120
150
180
Time Observed from the Start of Treatment (days)
No increase in ischemic events in the acute
coronary syndrome patients. (AMI Events 3 NTG, 1
nesiritide)
Young JB et al. AHA Meeting 2000 Late Breaking
Trials Session
60
Pooled mortality outcomes, extracted from revised
nesiritide labeling
End point, number of studies pooled Nesiritide () Control ()
30-day mortality, 7 studies (n1717) 5.3 4.3
180-day mortality, 4 studies (n1167) 21.7 21.5
Mortality hazard-ratio confidence intervals for
nesiritide relative to control therapy include
1.00 for both pooled analyses as well as each
individual study.
Scios. Natrecor label update. Revised April 25,
2005. Available at http//www.natrecor.com/pdf/na
trecor_pi.pdf.
61
ADHF Summary
  • There are currently NO long-term mortality data
  • on ANY therapies currently in use
  • Risk stratification may be useful in guiding
    therapy
  • Best therapy may be to prevent decompensation
  • Adherence to guidelines for the
    treatment of chronic HF
  • Patient support network to
    increase compliance
  • Adequate treatment of
    signs/symptoms of HF during hosp

62
. . .The Forest for the Trees
Digoxin
ACE-I
ARB
b-Blocker
Diuretics
BNP
AldoRB
ICD
Bi-V Pacing
LVAD/Transplant
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