Transcript Strategies for Managing Heart Failure in 2001

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
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; O’Connell and Bristow, 1994
AHA. 2001 Heart and Stroke Statistical Update.
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; O’Connell and Bristow, 1994
AHA. 2001 Heart and Stroke Statistical Update.
Etiology of Heart Failure
(SOLVD Registry)
Valvular
heart disease
Congenital
heart disease
Other
Viral 11.3%
Toxic
Thyroid
Peripartum
Idiopathic
cardiomyopathy
12.9%
N=6063
Hypertension
7.2%
Ischemic heart
disease
68.6%
Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A.
The New Classification of Heart Failure
A
B
C
D
Stage
Patient Description
High risk for
developing heart
failure (HF)
Asymptomatic HF
•
•
•
•
Symptomatic HF
• Known structural heart disease
• Shortness of breath and fatigue
• Reduced exercise tolerance
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. 2001;38:2101–2113.
Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy
• Previous MI
• LV systolic dysfunction
• Asymptomatic valvular disease
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
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. 2003;348:2007
Heart Failure Pathophysiology
Myocardial Injury
Fall in LV performance
Activation of RAAS, SNS, ET,
and others
Myocardial toxicity
Morbidity
and mortality
-
ANP
BNP
Peripheral vasoconstriction
Hemodynamic alterations
Remodeling and
progressive
worsening of
LV function
Heart failure
symptoms
Neurohormonal Targets
in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
AT II
SNS
Activation
AT1 Receptors
Epinephrine
Norepinephrine
Target Cells
ACE Inhibitors in Heart Failure

~7000 patients evaluated in long-term placebocontrolled clinical trials

Improvement in cardiac function, symptoms,
and clinical status; equivocal effects on
exercise tolerance

Decrease in all-cause mortality by 20-25%
(P<.001) and decrease in combined risk of
death and hospitalization by 30-35%
(P<.001)
Garg and Yusuf, 1995.
Mortality in Patients Receiving
ACE Inhibitors
1.0
SOLVD-Prevention
0.8
Survival
SOLVD-Treatment
PROMISE
DIG
0.6
V-HeFT
CONSENSUS
0.5
PRAISE
0
0
1
2
3
Year
ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials.
Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors).
4
5
Neurohormonal Targets
in Heart Failure
Angiotensinogen
ACE Inhibitors
b-Blockers
Angiotensin I
AT II
SNS
Activation
AT1 Receptors
Epinephrine
Norepinephrine
b-Blockers
Target Cells
Effect of b-Blockade on All-Cause Mortality
CIBIS-I: 1.9 years
placebo 67/321 (20%); bisoprolol 53/320 (16%)
P=.22
P=.0001
CIBIS-II: 1.3 years
placebo 228/1320 (17%); bisoprolol 156/1327 (12%)
P=.006
MERIT-HF: 12 months
placebo 217/2001 (11%); metoprolol 145/1990 (7%)
US Carvedilol Trials: 7.6 months
placebo 31/398 (8%); carvedilol 22/696 (3%)
P=.001
0
0.25
0.5
0.75
1
1.25
1.5
Relative risk and 95% confidence intervals
1.75
2
COPERNICUS
All-cause mortality: 35% decreased risk
100
90
Carvedilol
(n=1156)
80
70
Placebo
(n=1133)
60
P=0.00014
50
0
4
8
12
16
Months
20
.
24
28
The CHF Trials in Perspective:
Patients Needed to Treat for One Year to
Save One Life
HF Stage
A
B
C
C
C
D
Trial
# of Patients
HOPE
SOLVD-Prevention
SOLVD-Treatment
CIBIS-II
MERIT-HF
COPERNICUS
333
285
77
23
25
14
Neurohormonal Targets
in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
AT II
ARBs
SNS
Activation
AT1 Receptors
Epinephrine
Norepinephrine
Target Cells
CHARM-Added: Primary Endpoint
50
Placebo
40
CV death or HF
hospitalization (%)
538 (42.3%)
483 (37.9%)
15% risk reduction
30
Candesartan
20
HR 0.85 (95% CI 0.75-0.96), P=0.011
Adjusted HR 0.85, P=0.010
10
0
0
Number at risk:
1276
Candesartan
1272
Placebo
1
1176
1136
2
Time (years)
1063
1013
HF, heart failure; HR, hazard ratio; CI, confidence interval.
McMurray JJV et al. Lancet. 2003;362:767-771.
3
3.5
948
906
457
422
A-HEFT: Role of Hydralazine/Nitrates
Mortality 43%
Hospitalization 33%
Taylor AL, et al. N Engl J Med. 2004;351:2049-57
A-HeFT: Hydralazine/Nitrates






African-Americans (n = 1050)
LVEF < 35% or <45% 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. 2004;351:2049-57
Neurohormonal Targets
in Heart Failure
Angiotensinogen
ACE Inhibitors
Angiotensin I
AT II
SNS
Activation
AT1 Receptors
Epinephrine
Norepinephrine
Aldosterone
Receptor Blockers
Target Cells
RALES: Aldosterone Receptor Blockade
Spironolactone
n = 1663
NYHA III/IV
LVEF < 40%
mortality 27%
hospitalization 36%
(p<0.0002)
Pitt B, et al. N Engl J Med. 1999;341:709-717
Mode of Death in MERIT-HF
NYHA II
Other
15%
Other
24%
HF
12%
NYHA III
Sudden
cardiac
death
64%
HF
26%
Sudden
cardiac
death
59%
MERIT-HF Study Group. Lancet. 1999;353(9169):2001-2007.
Device Therapies in Heart
Failure: Implantable
Cardioverter-Defibrillators
MADIT II: Study Design
Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio
71 US centers and 5 European centers
Implantable defibrillator
Conventional medical therapy
(n=742)
(n=490)
All Cause Mortality - Average follow-up of 20 months
Stopped early by Data Safety Monitoring Board
MADIT II: All-Cause Mortality
Death
25%
20%
Avg. follow-up=20 months
P=0.016
19.8%
15%
Hazard
Ratio =
0.65
14.2%
10%
5%
0%
Conventional
Therapy
ICD
SCD-HeFT: Enrollment Scheme
DCM + CAD and CHF
EF < 35%
NYHA Class II or III
6 minute walk, Holter
R
n=2521, 1:1:1
Placebo Amiodarone
ICD
Bardy G et al. NEJM 2005; 352:3
SCD-HeFT: Death from Any Cause
23% RR Reduction in Death
7.2% Absolute Reduction at 5 yrs
Bardy G et al. NEJM 2005; 352:3
SCD-HeFT: Death from Any Cause
in Ischemic CHF
Bardy G et al. NEJM 2005; 352:3
SCD-HeFT: Death from Any Cause
in Nonischemic CHF
Bardy G et al. NEJM 2005; 352:3
SCD-HeFT: Primary Conclusions

In class II or III CHF patients with EF < 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; 352:3
Mortality Benefits of HF Therapies
Absolute Annual Mortality Reduction During Trial
3.8
% Absolute Reduction
4
3.5
3
2.5
1.9
2
1.5
1.3
1
0.5
0
SOLVD
MERIT -HF
SCD-HeFT
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
Device Therapies in Heart
Failure: Cardiac
Resynchronization
Myocardial Dyssynchrony
Cardiac Resynchronization
in Heart Failure
Indications:

EF <35%

NYHA III-IV

QRS >130-150ms
Change in 6-minute Walking Distance (m)
Cardiac Resynchronization
in Heart Failure
60
P = 0.004
P = 0.003
Control
Resynchronized
P = 0.005
40
20
0
MIRACLE Trial, N Engl J Med 2002;346:1845-53
-20
0
1
3
Months after Randomization
6
Cardiac Resynchronization
in Heart Failure
0
Change in Quality-of-Life Score
P < 0.001
P = 0.001
-5
P < 0.001
Control
Resynchronized
-10
-15
-20
MIRACLE Trial, N Engl J Med 2002;346:1845-53
-25
0
1
3
Months after Randomization
6
The COMPANION Trial






1520 patients (1:2:2)
NYHA Class III-IV
EF </=35%
QRS > 120 ms
11.9-16.5 month f/u
Study withdrawal
26% Placebo
6% Bi-V Pacemaker
7% Bi-V-ICD
The COMPANION Trial
Bristow MR, et al. N Engl J Med. 2004;350:2140-50
The COMPANION Trial
Bristow MR, et al. N Engl J Med. 2004;350:2140-50
Optimal Therapy for
Chronic Heart Failure
In Symptomatic Patients:


Diuretics
Digoxin
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)
Optimal Therapy for
Chronic Heart Failure
In Persistent Class III-IV CHF:


Spironalactone
Bi-ventricular pacer (Prolonged QRS)
MADIT II: CHF
New or Worsening Heart Failure
P=0.09
20%
19.9%
14.9%
15%
10%
5%
0%
Conventional
Therapy
ICD
Heart Failure Hospitalizations
The number of heart failure hospitalizations is increasing in both men and women
600,000
Discharges
500,000
400,000
300,000
200,000
Women
Men
100,000
AHA, 1998
Heart discharges
and Statistical
Updatepatients both living and dead.
CDC/NCHS:
Hospital
include
NCHS,
National
Center
for
Health
Statistics
AHA Heart and Stroke Statistical Update
2001
7
'9
5
'9
3
'9
1
'9
9
'8
7
'8
5
'8
3
'8
1
'8
'7
9
0
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
Emergency Department Visits for
Congestive Heart Failure
Initial Episode *
21%
Repeat Visit 79%
Approximately 80% of
the ED visits for CHF
result in hospitalizations
Rates of Hospital Readmission
2% within 2 days 20% within 1 month
50% within 6 months
Cardiology Roundtable 1998
Patients Treated (%)
Utilization of HF Medications
100
90
80
70
60
50
40
30
20
10
0
80.8
57.4
50.8
41
12.8
ACE-I
ARBII-B
Beta-Blocker
Diuretics
Digoxin
*Excludes patients with documented contraindications
2300/7883 patients hospitalized with HF; prior known LV systolic dysfunction; outpatient medical
regimen
ADHERE™ Registry Report Q1 2002 (4/01–3/02) of 180 US Hospitals. Presented at the HFSA Satellite Symposium, September
23, 2002
Causes of Hospital Readmission
for Heart Failure
Diet Noncompliance
24%
16%
Inappropriate Rx
19%
Failure to Seek Care
Vinson J Am Geriatr Soc 1990;38:1290-5
Rx Noncompliance
24%
17%
Other
Heart Failure Costs
60.6%
Hospitalizations
$23.1 billion
38.6%
Outpatient care
$14.7 billion
(3.4 visits/year/patient)
0.7%
Transplants
$270 million
Total = $38.1 billion
(5.4% of total healthcare costs)
O’Connell and Bristow. J Heart Lung Transplant. 1994;13:S107-S112.
ADHF: Clinical Assessment
Cardiac output/
Perfusion
at Rest
Congestion at Rest
No
Yes
Warm & Dry
Warm & Wet
Normal
(normal)
Low
Cold & Dry
Cold & Wet
Signs/symptoms
of congestion





Orthopnea/PND
JVD
Ascites
Edema
Rales
Possible evidence of low perfusion
 Narrow pulse pressure
 Sleepy/obtunded
 Low serum sodium
 Cool extremities
 Hypotension with ACE inhibitor
 Renal dysfunction (one cause)
Stevenson LW. Eur J Heart Fail. 1999;1:251
Risk Stratification of Patients with ADCHF
<
BUN 43
N=32,324
>
2.68%
n=25,122
8.98%
n=7,202
SYS BP 115
SYS BP 115
n=24,933
n=7,147
<
5.49%
n=4,099
>
>
15.28%
n=2,048
2.14%
n=20,834
%’s = mortality rates
Fonarow et al. 2003
<
<
12.42%
n=1,425
Cr 2.75
n=2,045
6.41%
n=5,102
>
21.94%
n=620
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 catheterguided therapy

No difference in mortality or length of stay

However, patients felt better with the PA catheter
Stevenson, LW. AHA 2004
Therapies for Acute Decompensated
Heart Failure
Congestion at Rest
No
No
Yes
Warm and Dry
PCW and CI
normal
Warm and Wet
PCW elevated
CI normal
CI decreased
Cold and Wet
PCW elevated
CI decreased
Low
Perfusion
Cold and Dry
at Rest Yes PCW
low/normal
Nl SVR
Vasodilators
Diuretics
High SVR
Inotropes
R. Bourge, UAB Cardiology (adapted from L. Stevenson), Stevenson LW. Eur J Heart Failure 1999;1:251-257
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
Intravenous Inotropic Agents for
Decompensated Heart Failure
60 Day Follow-up
Days until Discharge
*
Milrinone
n=477
Control
n=472
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
35.0%
35.3%
Death
3.8%
2.3%
P<0.001
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
NTG
Nesiritide
* P<0.05 pooled nesiritide compared to nitroglycerin
*
Time
Young JB et al. AHA Meeting 2000 Late Breaking Trials Session
48 h
*
36 h
*
24 h
9h
*
12 h
*
*
* *
6h
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
-11
3h
Mean Change (mm Hg)
VMAC: PCWP Through 48 Hours
Precedent: 6 Month Survival
Cumulative Mortality Rate (%)
Log - rank Test:
Dobutamine vs nesiritide 0.015 g/kg/min p=0.041
Dobutamine vs nesiritide 0.030 g/kg/min p=0.445
Nes 0.015 g/kg/min vs nes 0.030 g/kg/min p=0.187
Dobutamine (n=141)
Nes 0.030 g/kg/min (n=179)
Nes 0.015 g/kg/min (n=187)
35
30
25
20
15
10
5
0
0
30
60
90
120
150
Time from start of treatment (days)
180
Elkayam U. et al, J. Cardiac Failure 2000;6 (Suppl 2):169
VMAC: Mortality Rates
100
Stratified Log - rank Test:
Cumulative Mortality Rate %
90
NTG vs Nesiritide 0.01 µg/kg/min
80
p=0.616
NTG vs All Nesiritide doses p=0.319
NTG (n = 216)
70
Nesiritide 0.01 µg/kg/min (n = 211)
60
All Nesiritide (n = 273)
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
Pooled mortality outcomes, extracted
from revised nesiritide labeling*
End point, number of
studies pooled
Nesiritide
(%)
Control
(%)
30-day mortality, 7 studies
(n=1717)
5.3
4.3
180-day mortality, 4 studies
(n=1167)
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/natrecor_pi.pdf.
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
. . .The Forest for the Trees
Digoxin
b-Blocker
AldoRB
Bi-V Pacing
ACE-I
ARB
Diuretics
BNP
ICD
LVAD/Transplant