current therapies for the management of chronic and acute heart failure john l. tan, md, phd heart...
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Current Therapies for the Management of Chronic and
Acute Heart Failure
John L. Tan, MD, PhDHeart Failure Program at the
North Texas Heart Center
Presbyterian Hospital of Dallas
Adapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994AHA. 2001 Heart and Stroke Statistical Update.
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%
$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 MedicareAdapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994AHA. 2001 Heart and Stroke Statistical Update.
Cost of Heart Failure
Etiology of Heart Failure (SOLVD Registry)
Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A.
Ischemic heart disease68.6%
Hypertension7.2%
Other11.3%
Idiopathic cardiomyopathy
12.9% N=6063Valvular heart disease
Congenitalheart disease
ViralToxic
ThyroidPeripartum
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. 2001;38:2101–2113.
Heart failure is more than a symptomatic diseaseProduces symptoms, limits functional capacity, and impairsquality of life
Heart failure is a progressive diseaseWorsening symptoms and clinical deterioration, repeatedhospitalization, and death
Death occurs frequently even in the presence of minimalsymptoms or the absence of progressive symptoms
Symptoms do not always correspond with ejection fraction
Symptom Relief is Not Sufficient
Ventricular RemodelingVentricular Remodeling After Acute Infarction
Ventricular Remodeling in Diastolic and Systolic HF
Initial infarct
Expansion of infarct(hours to days)
Global remodeling(days to months)
Normal heart
Hypertrophied heart(diastolic HF)
Dilated heart(systolic HF)
Jessup M et al. N Engl J Med. 2003;348:2007
Myocardial InjuryMyocardial Injury Fall in LV performanceFall in LV performance
Activation of RAAS, SNS, ET,Activation of RAAS, SNS, ET,and othersand others
Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionHemodynamic alterationsHemodynamic alterations
Remodeling andRemodeling andprogressiveprogressive
worsening ofworsening ofLV functionLV function Heart failureHeart failure
symptomssymptomsMorbidityMorbidity
and mortalityand mortality
ANPANPBNPBNP
-
-
Heart Failure PathophysiologyHeart Failure Pathophysiology
Neurohormonal Targets in Heart Failure
Angiotensinogen
Angiotensin I
AT II
AT1 Receptors
ACE Inhibitors
SNS Activation
EpinephrineNorepinephrine
Target Cells
~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% (P<.001) and decrease in combined risk of death and hospitalization by 30-35% (P<.001)
Garg and Yusuf, 1995.
ACE Inhibitors in Heart Failure
1.0
0.8
0.6
0.5
0
0 21 3 4 5
Survival
Year
CONSENSUS
PROMISE
PRAISE
SOLVD-Prevention
SOLVD-Treatment
DIG
V-HeFT
ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials.Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors).
Mortality in Patients Receiving ACE Inhibitors
Neurohormonal Targets in Heart Failure
Angiotensinogen
Angiotensin I
AT II
AT1 Receptors
ACE Inhibitors
SNS Activation
EpinephrineNorepinephrine
Target Cells
-Blockers
-Blockers
Effect of -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
CIBIS-I: 1.9 yearsplacebo 67/321 (20%); bisoprolol 53/320 (16%)P=.22
CIBIS-II: 1.3 yearsplacebo 228/1320 (17%); bisoprolol 156/1327 (12%)P=.0001
MERIT-HF: 12 monthsplacebo 217/2001 (11%); metoprolol 145/1990 (7%)P=.006
US Carvedilol Trials: 7.6 months placebo 31/398 (8%); carvedilol 22/696 (3%)
P=.001
All-cause mortality: 35% decreased risk
.
100
90
80
60
70
50
240 20161284 28
Placebo(n=1133)
Carvedilol(n=1156)
Months
% S
urv
ival
P=0.00014
COPERNICUS
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
Neurohormonal Targets in Heart Failure
Angiotensinogen
Angiotensin I
AT II
AT1 Receptors
ACE Inhibitors
SNS Activation
EpinephrineNorepinephrine
Target Cells
ARBs
12761272
11761136
10631013
948906
457422
Number at risk:CandesartanPlacebo
Time (years)
CHARM-Added: CHARM-Added: Primary EndpointPrimary Endpoint
HF, heart failure; HR, hazard ratio; CI, confidence interval.McMurray JJV et al. Lancet. 2003;362:767-771.
CV death or HF hospitalization (%)
0 1 2 30
10
20
30
40
50
Placebo
Candesartan
3.5
HR 0.85 (95% CI 0.75-0.96), P=0.011Adjusted HR 0.85, P=0.010
483 (37.9%)
538 (42.3%)
15% risk reduction
A-HEFT: Role of Hydralazine/NitratesA-HEFT: Role of Hydralazine/Nitrates
Taylor AL, et al. N Engl J Med. 2004;351:2049-57
Mortality 43%
Hospitalization 33%
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 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
Angiotensin I
AT II
AT1 Receptors
ACE Inhibitors
SNS Activation
EpinephrineNorepinephrine
Target Cells
Aldosterone Receptor Blockers
RALES: Aldosterone Receptor BlockadeRALES: Aldosterone Receptor Blockade
Pitt B, et al. N Engl J Med. 1999;341:709-717
Spironolactonen = 1663
NYHA III/IVLVEF < 40%
mortality 27%
hospitalization 36%(p<0.0002)
NYHA II NYHA III
HF12%
Other24%
Suddencardiacdeath64%
HF26%
Other15%
Suddencardiacdeath59%
Mode of Death in MERIT-HF
MERIT-HF Study Group. Lancet. 1999;353(9169):2001-2007.
Device Therapies in Heart Failure: Implantable
Cardioverter-Defibrillators
Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers
Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers
Conventional medical therapy
(n=490)
Conventional medical therapy
(n=490)
Implantable defibrillator
(n=742)
Implantable defibrillator
(n=742)
All Cause Mortality - Average follow-up of 20 monthsAll Cause Mortality - Average follow-up of 20 months
Stopped early by Data Safety Monitoring BoardStopped early by Data Safety Monitoring Board
MADIT II: Study Design
19.8%
14.2%
0%
5%
10%
15%
20%
25%
19.8%
14.2%
0%
5%
10%
15%
20%
25%
ConventionalTherapy
ConventionalTherapy
ICDICD
P=0.016P=0.016
DeathAvg. follow-up=20 months
DeathAvg. follow-up=20 months
MADIT II: All-Cause Mortality
Hazard Ratio =
0.65
Hazard Ratio =
0.65
R
SCD-HeFT: Enrollment SchemeDCM + CAD and CHF
EF < 35%
NYHA Class II or III
6 minute walk, Holter
Placebo Amiodarone ICDBardy G et al. NEJM 2005; 352:3
n=2521, 1:1:1
SCD-HeFT: Death from Any Cause
Bardy G et al. NEJM 2005; 352:3
23% RR Reduction in Death7.2% 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
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
1.3
3.8
1.9
0
0.5
1
1.5
2
2.5
3
3.5
4
SOLVD MERIT -HF SCD-HeFT
Absolute Annual Mortality Reduction During Trial
% A
bsol
ute
Red
ucti
on
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 ResynchronizationCardiac Resynchronization in Heart Failure in Heart Failure
Indications: EF <35%
NYHA III-IV
QRS >130-150ms
Cha
nge
in 6
-min
ute
Wal
king
Dis
tanc
e (m
)
Months after Randomization
60
40
20
0
-20 0 1 3 6
P = 0.005
P = 0.003
P = 0.004
MIRACLE Trial, N Engl J Med 2002;346:1845-53
ControlResynchronized
Cardiac Resynchronizationin Heart Failure
Cha
nge
in Q
uali
ty-o
f-L
ife
Sco
re
Months after Randomization
0 1 3 6
0
-5
-10
-15
-20
-25
P < 0.001
P < 0.001P = 0.001
MIRACLE Trial, N Engl J Med 2002;346:1845-53
ControlResynchronized
Cardiac Resynchronizationin Heart Failure
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 TrialThe 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)
14.9%
19.9%
0%
5%
10%
15%
20%
14.9%
19.9%
0%
5%
10%
15%
20%
ConventionalTherapy
ConventionalTherapy
ICDICD
P=0.09P=0.09
New or Worsening Heart FailureNew or Worsening Heart Failure
MADIT II: CHF
Heart Failure Heart Failure Hospitalizations
0
100,000
200,000
300,000
400,000
500,000
600,000
Dis
char
ges
Women
Men
AHA, 1998 Heart and Statistical UpdateNCHS, National Center for Health Statistics
The number of heart failure hospitalizations is increasing in both men and women
CDC/NCHS: Hospital discharges include patients both living and dead.AHA Heart and Stroke Statistical Update 2001
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%
Rates of Hospital Readmission2% within 2 days 20% within 1 month
50% within 6 months
Approximately 80% of the ED visits for CHF
result in hospitalizations
Cardiology Roundtable 1998
Utilization of HF Medications
50.8
12.8
57.4
80.8
41
01020304050
60708090
100
ACE-I ARBII-B Beta-Blocker Diuretics Digoxin
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
*Excludes patients with documented contraindications
Pat
ien
ts T
reat
ed (
%)
Causes of Hospital Readmissionfor Heart Failure
17%Other19%
Failure to Seek Care
16%Inappropriate Rx
Rx Noncompliance 24%
Diet Noncompliance24%
Vinson J Am Geriatr Soc 1990;38:1290-5
Heart Failure Costs
60.6%Hospitalizations$23.1 billion
38.6%Outpatient care$14.7 billion(3.4 visits/year/patient)
O’Connell and Bristow. J Heart Lung Transplant. 1994;13:S107-S112.
0.7%Transplants$270 million
Total = $38.1 billion(5.4% of total healthcare costs)
Congestion at Rest
Car
dia
c ou
tpu
t/P
erfu
sion
at R
est
Normal
No Yes
Low
Warm & Dry
(normal)
Warm & Wet
Cold & WetCold & Dry
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
ADHF: Clinical Assessment
Risk Stratification of Patients with ADCHF
SYS BP 115 n=24,933
SYS BP 115 n=7,147
6.41% n=5,102
15.28% n=2,048
21.94% n=620
12.42% n=1,425
5.49% n=4,099
2.14% n=20,834
BUN 43 N=32,324
2.68% n=25,122
8.98% n=7,202
Cr 2.75 n=2,045
Fonarow et al. 2003Fonarow et al. 2003
%’s = mortality rates%’s = mortality rates
< >
<
< >
>
><
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
Therapies for Acute Decompensated Heart Failure
Yes
R. Bourge, UAB Cardiology (adapted from L. Stevenson), Stevenson LW. Eur J Heart Failure 1999;1:251-257
No
Warm and DryPCW and CI
normal
Warm and WetPCW elevated
CI normal
Cold and WetPCW elevatedCI decreased
Cold and DryPCW low/normal
CI decreased
Vasodilators
Diuretics
Inotropes
Nl SVR High SVR
Congestion at Rest
LowPerfusion
at Rest
No
Yes
Parenteral Therapies for Decompensated Heart Failure
Treatment Limitations
Dobutamine Heart rate, arrhythmias,
Milrinone
Nitroglycerin Tolerance, side effects
Nitroprusside Difficult administration (titration), side effects
Heart rate, arrhythmias, hypotension
MVO2, ischemia, and tolerance
Intravenous Inotropic Agents for Decompensated Heart Failure
OPTIME. Gheorghiade et al. ACC Meeting 2000 Late Breaking Trials Session
Milrinonen=477
Controln=47260 Day Follow-up
Days until Discharge
48-hour infusion of milrinone (0.5mcg/kg/min) within 48 hours for worsening of CHF.
Adverse Events
Sustained Hypotension
Acute MI
Rehospitalized or Death
Death
5.7 + 13 5.9 + 13
12.6% 2.1%
10.7%
1.5%
3.2%
0.4%
35.3%
2.3%
35.0%
3.8%
*
*
* P<0.001
* P<0.05 pooled nesiritide compared to nitroglycerin
VMAC: PCWP Through 48 Hours
Young JB et al. AHA Meeting 2000 Late Breaking Trials Session
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Time
NTG Nesiritide
Mea
n C
han
ge (
mm
Hg)
3 h
6 h
9 h
12 h
24 h
36 h
48 h
Dobutamine (n=141)
Nes 0.015 g/kg/min (n=187)
Cum
ulat
ive
Mor
talit
y R
ate
(%)
Time from start of treatment (days)
Nes 0.030 g/kg/min (n=179)
Precedent: 6 Month Survival
05
10
15
20
25
30
35
0 30 60 90 120 150 180
Log - rank Test:Dobutamine vs nesiritide 0.015 g/kg/min p=0.041Dobutamine vs nesiritide 0.030 g/kg/min p=0.445Nes 0.015 g/kg/min vs nes 0.030 g/kg/min p=0.187
Elkayam U. et al, J. Cardiac Failure 2000;6 (Suppl 2):169
0 30 60 90 120 150 1800
10
20
30
40
50
60
70
80
90
100
Time Observed from the Start of Treatment (days)
NTG (n = 216)
Nesiritide 0.01 µg/kg/min (n = 211)
All Nesiritide (n = 273)
Stratified Log - rank Test:
NTG vs Nesiritide 0.01 µg/kg/min p=0.616
NTG vs All Nesiritide doses p=0.319
VMAC: Mortality RatesC
um
ula
tive
Mo
rtal
ity
Rat
e %
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
Scios. Natrecor label update. Revised April 25, 2005. Available at: http://www.natrecor.com/pdf/natrecor_pi.pdf.
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.
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
Diuretics
Digoxin ACE-I
-Blocker ARB
AldoRB BNP
Bi-V Pacing ICD
LVAD/Transplant
. . .The Forest for the Trees