Download Post-MI Patients at High Risk of SCD

Prevention of Sudden Cardiac Death in
Heart Failure Patients with
Left Ventricular Dysfunction:
The Role of Drugs and Devices
William T. Abraham, MD, FACP, FACC
Professor of Medicine
Chief, Division of Cardiovascular Medicine
Associate Director, Davis Heart & Lung Research Institute
The Ohio State University
Columbus, Ohio
Presentation Objectives
Review the scientific evidence to support the contentions that:
– In patients with LV dysfunction, the combined use of ACE inhibition and
beta-blockade is recommended as the cornerstone of therapy.
– Modest incremental benefit may be seen with the addition of other
antagonists of the RAS in post-MI LV dysfunction and in chronic heart
failure.
– While neurohormonal interventions reduce morbidity and mortality across
the cardiovascular disease continuum, post-MI and HF patients with LV
dysfunction still have a high rate of sudden cardiac death.
– Therapy with ICDs significantly reduces mortality in post-MI patients with
LV dysfunction. These mortality benefits are on top of optimal
pharmacologic therapy. ICD therapy should be considered standard of
care in these patients.
– Data from SCD-HeFT will be critical to understand the role of ICD therapy
in ischemic and non-ischemic CHF patients with LV dysfunction.
Presentation Overview
1. Heart Failure and Sudden Cardiac Arrest:
– Epidemiology, etiology, pathophysiology
2. SCD Prevention in Heart Failure:
– Suppression of the Adrenergic Renin-AngiotensionAldosterone Pathway and the Sympathetic Nervous System
– Are we making progress in reducing SCD with neurohormonal
interventions?
3. Overview of ICD therapy to prevent SCD in heart
failure patients
4. Summary and conclusions
The Epidemic of Heart Failure
Key Heart Failure Statistics
• Prevalence
– ~5 million Americans with heart failure
– >10% of adults in their 70s and 80s
• Incidence
– 550,000 new cases HF/year
• Morbidity
– ~1,000,000 HF hospitalizations
• Mortality
– Causes or contributes to >600,000 deaths/yr
– >50% of patients die suddenly (SCD)
American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex: American Heart Association;
2002.
90
80
70
60
50
40
30
80
Millions of persons
60
40
Percent of population
20
10
0
20
0
1960
1980
2000
2020
US Census Bureau
2040
Percent of population > 65 Yr Old
Millions of persons >65 Yr Old
Projected increase in the
US population 65 years of Age or Older
Hospitalizations/100,000 Population
Heart Failure: A Public Health Crisis
250
Hospitalizations Have Tripled in last 25 Years
200
65+ years
150
100
45-64 years
50
0
1970
1975
1980
1985
1990
Year
NHLBI. Morbidity and Mortality: 2000 Chartbook on Cardiovascular, Lung, and Blood
Diseases. Geneva: World Health Organization; 1996.
1995
CHF Patients Survival Results1
Probability of survival, %
100
Men (n = 237)
Women (n = 230)
90
80
80% of men and 70% of
women who have CHF
will die within 8 years.2
70
60
50
40
30
20
10
0
0
2
4
6
8
Time after CHF diagnosis, years
1 Framingham Heart Study (1948 – 1988) in Atlas of Heart Diseases.
2 American Heart Association. Heart Disease and Stroke Statistics—2003 Update.
10
The Epidemic of Sudden Cardiac Arrest
Sudden Cardiac Death: Definition
• Sudden cardiac death is natural death due to
cardiac causes, heralded by abrupt loss of
consciousness within one hour of the onset of
acute symptoms, as in an individual with or
without known pre- existing heart disease, but
in whom the time and mode of death are
unexpected.
Gaziano JM in Braunwald Zipes Libby Heart Disease,6th ed.W.B. Saunders 2001:1
Sudden Cardiac Arrest
• Accounts for 63% of all cardiac related deaths in the US1.
• One of the most common causes of death in developed countries:
Geography
Incidence
Survival
3,000,0002
<1%2
US
450,0003
~5%2
W. Europe
400,0004
<5%4
Worldwide
1
MMWR. Vol 51(6) Feb. 15, 2002.
RJ, Catellanos A. Cardiac Arrest and Sudden Cardiac Death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular
Medicine. 5th Ed. New York: WB Saunders. 1997: 742-779.
3 Zheng Z. Circulation. 2001;104:2158-2163.
4 Vreede-Swagemakers JJ et al. J Am Coll Cardiol 1997; 30: 1500-1505.
2 Myerberg
Magnitude of SCA in the US
Stroke3
167,366
Lung
Cancer2
157,400
Breast
Cancer2
40,600
42,156
AIDS1
1
2
3
4
SCA claims
more lives each
year than these
other diseases
combined
U.S. Census Bureau, Statistical Abstract of the United States: 2001.
American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures 2001.
2002 Heart and Stroke Statistical Update, American Heart Association.
Circulation. 2001;104:2158-2163.
450,000
Sudden
Cardiac
Arrest 4
The #1 Cause
of Death
Magnitude of SCA in the US
- ~450,000 per year1

1200 per day
•
50 every hour
•
1 every 80 seconds
- The majority of SCA occurs in patients with clinically
recognized heart disease, particularly previous
myocardial infarction and congestive heart
failure.2,3
1Circulation.
2001;104:2158-2163.
2
Myerburg RJ, Castellanos A. Cardiac Arrest and Sudden Cardiac Death, in Braunwald E, Zipes DP, Libby P, Heart Disease, A textbook of
Cardiovascular Medicine. 6th ed. 2001. W.B. Saunders, Co.
3
Every N, et al. Risk of Sudden versus Non Sudden Cardiac Death in Patient with Coronary Artery Disease. Am Heart J 2002; 144: 390-6.
Etiology of Sudden Cardiac Death
Coronary Heart Disease
•
•
An estimated 13 million people had CHD in the U.S. in 2002. 1
Sudden death was the first manifestation of coronary heart disease in
50% of men and 63% of women. 1
•
CHD accounts for at least 80% of sudden cardiac deaths in Western
cultures.3
Etiology of Sudden Cardiac Death2,3
5% Other*
15%
Cardiomyopathy
1
American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex.:
American Heart Association; 2002.
2
Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001.
3
Myerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6th ed. P. 895.
80%
Coronary
Heart
Disease
* ion-channel abnormalities, valvular or
congenital heart disease, other causes
Arrhythmic Cause of SCD
12%
Other Cardiac
Cause
88%
Arrhythmic
Cause
.
Albert CM. Circulation. 2003;107:2096-2101
Underlying Arrhythmias of
Sudden Cardiac Arrest
Torsades de Pointes
13%
Bradycardia
17%
VT
62%
Bayés de Luna A. Am Heart J. 1989;117:151-159.
Primary VF
8%
Incidence of SCD in Specific Populations
and Annual SCD Numbers
General adult
population
Multiple risk
subgroups
Patients with any
previous coronary
event
Patients with ejection
fraction <35% or CHF
SCD-HeFT
Cardiac arrest, VT/VF
survivors
AVID, CASH, CIDS
MADIT, MUSTT, MADIT II
High-risk post-MI
subgroups
0
5
10
20
25
30
Incidence of Sudden Death
(% of group)
0
100,000 200,000 300,000
Incidence of Sudden
Deaths Per Year
(number)
Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp. 369381, March 2001.
Heart Failure
and Sudden Cardiac Death
Age-adjusted annual
rate/1000
Heart Failure and Sudden Death
16
14
12
10
8
6
4
2
0
SCD-NoCHF
8
15
SCD-CHF
60-115%
increase in
sudden death if
CHF present.
7
5
Women
Men
During a 39-year follow-up of subjects in the Framingham Heart Study,
the presence of CHF significantly increased sudden death and overall
mortality in both men and women.1
1 Redrawn from Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212
Severity of Heart Failure
Modes of Death
NYHA II
NYHA III
CHF
12%
CHF
Other
24%
64%
26%
Other
59%
Sudden
Death
Sudden
Death
15%
n = 103
n = 103
NYHA IV
33%
11%
CHF
Other
56%
Sudden
Death
The greatest opportunity for
SCD prevention is in patients
that have mild to moderate
CHF.
n = 27
MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized
intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07.
Pathophysiology and Mechanisms in
Heart Failure that Precipitate SCA
Pathological Progression of CV Disease 1
Coronary artery
disease
Underlying etiology
in ~60% of CHF 1
Arrhythmia
Left ventricular
injury
Pathologic
remodeling
Low ejection
fraction
Pump
failure
Hypertension
Cardiomyopathy
Valvular Disease
Underlying etiology in
~40% of CHF 1
Death
• Neurohormonal
stimulation
• Endothelial
dysfunction
• Myocardial toxicity
• Vasoconstriction
• Renal sodium
retention
Symptoms:
Dyspnea
Fatigue
Edema
1 Adapted from Cohn JN. N Engl J Med. 1996;335:490–498.
2 He J, Ogden LG, Bazzano LA, et al. Risk Factors for Congestive Heart Failure in US Men and women: NHANES I
epidemiologic follow-up study. Arch Intern Med 2001, 161: 996-1002.
Chronic
heart
failure
RAS Pathophysiology
Angiotensin I
ACE
inhibitor
Angiotensin II
AT receptor
antagonist
Hypertrophy
Apoptosis
ACE inhibitors also  kinins
( positive effect on
hypertrophy/apoptosis)
Deleterious Effects Of Angiotensin II
In CV Disease
Angiotensin II
CNS
Dypsogenia
 AVP
Vasoconstriction
Efferent
Constriction
Na+
Retention
Mesangial
Contraction
 Aldosterone
Vessel
Hypertrophy
Myocardial
Hypertrophy
Increased
NE Release
Deleterious Effects of Norepinephrine
in CV Disease
Injury to the heart (eg, MI, HTN, DM)
 Levels of norepinephrine
Negative cardiac effects
b1
b2
1
Cardiac injury
Hypertrophy
Arrhythmias
Negative vascular effects
Negative renal effects
1
Vasoconstriction
b1
Activation
of RAS
Disease progression
1
Sodium retention
Conditions Predisposing to Ventricular
Arrhythmia in Heart Failure Patients
• Electrophysiological abnormalities
– Cellular hypertrophy & interstitial fibrosis can result
in prolongation of the action potential
– Increases propensity for early after depolarizations
– Mechanical stretch can produce electrical activity
with slow conduction favoring reentry
Singh S.J Cardiovas Electrophysiol 1997;8:89-97
Conditions Predisposing to Ventricular
Arrhythmia in Heart Failure Patients
• Neurohormonal Activation
– Chronic heart failure triggers maladaptive
neurohormonal responses that may predispose to
arrhythmia
– Persistent adrenergic stimulation of the failing heart
is maladaptive & arrhythmogenic
– Adrenergic stimulation enhances automaticity in the
His-Purkinje system & areas of scar and  the
incidence of VF during ischemia in animal models
Sweeney MO. PACE 2001;24:871-888.
Conditions Predisposing to Ventricular
Arrhythmia in Heart Failure Patients
• Electrolyte abnormalities
– Predisposition to hypokalemia is caused by diuretic
therapy, activation of the renin-angiotensinaldosterone system, and sympathetic activation
– The effects of hypokalemia on ventricular
arrhythmias are amplified in the setting of structural
heart disease
Sweeney MO. PACE 2001;24:871-888.
SCD Prevention:
Suppression of the Adrenergic
Renin-Angiotension-Aldosterone
Pathway and the
Sympathetic Nervous System
Neurohormonal Blockade Across the
CV Disease Continuum
 Angiotensin II
 Norepinephrine
(Renin-Angiotensin System [RAS])
(Sympathetic Nervous System [SNS])
RAS Inhibition
b-Blockade
Disease Progression
Neurohormonal Blockade Across the
CV Disease Continuum
 Angiotensin II
 Norepinephrine
(Renin-Angiotensin System [RAS])
(Sympathetic Nervous System [SNS])
RAS Inhibition
b-Blockade
Disease Progression
Effect of ACE Inhibitors on Mortality Reduction in
Patients With LVD or Heart Failure
Mortality
Trial
ACEI
Controls
RR (95% CI)
CONSENSUS I
39%
54%
0.56 (0.34–0.91)
SOLVD (Treatment)
35%
40%
0.82 (0.70–0.97)
SOLVD (Prevention)
15%
16%
0.92 (0.79–1.08)
SAVE
20%
25%
0.81 (0.68–0.97)
AIRE
17%
23%
0.73 (0.60–0.89)
TRACE
35%
42%
0.78 (0.67–0.91)
SMILE
6.5%
8.3%
0.78 (0.52–1.12)
Average
21%
25%
Chronic CHF
Post MI
Garg R et al. JAMA. 1995;273:1450–1456.
Neurohormonal Interventions
Across the Continuum
Post-MI
LV dysfunction
AIRE/SAVE/TRACE
(ramipril/captopril/
trandolapril)
Mild
CHF
Moderate
CHF
SOLVD Treatment
(enalapril)
Severe
CHF
CONSENSUS
(enalapril)
Angiotensin Receptor Blockade
CHARM and Val-HEFT Trials:
Addition of candesartan or valsartan to ACE
inhibitor and b-blocker in class II-III heart failure
• 0-10% lower risk of death (P > 0.05)
• 13-15% lower risk of death or hospitalization
for heart failure in both trials, both P < 0.01
• Higher risk of hypotension, renal insufficiency
and hyperkalemia with ARB treatment
Neurohormonal Interventions
Across the Continuum
Post-MI
LV dysfunction
Mild
CHF
Moderate
CHF
Severe
CHF
AIRE/SAVE/TRACE
(ramipril/captopril/
trandolapril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
?
CHARM/Val-HeFT
(candesartan/valsartan)
?
Trials with Aldosterone Blockade
Primary Endpoint: All-Cause Mortality
Placebo
Aldosterone
Blockade
Hazard
Ratio
Log-rank
P-Value
EPHESUS
554/3319
478/3313
0.85
0.008
(0.75,0.96)
RALES
386/841
284/822
0.70
< 0.001
(0.60,0.82)
Neurohormonal Blockade Across the
CV Disease Continuum
Post-MI
LV dysfunction
Moderate
CHF
Mild
CHF
Severe
CHF
AIRE/SAVE/TRACE
(ramipril/captopril/
trandolapril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
EPHESUS
(eplerenone)
?
RALES
(spironolactone)
Neurohormonal Blockade Across the
CV Disease Continuum
 Angiotensin II
 Norepinephrine
(Renin-Angiotensin System [RAS])
(Sympathetic Nervous System [SNS])
RAS Inhibition
b-Blockade
Disease Progression
Effect of b-Blockade on Outcome in Patients
With Heart Failure and Post-MI LVD
Study
Drug
HF
Severity
Target
Dosage
(mg/day)
Outcome
US Carvedilol1
carvedilol
mild/
moderate
6.25 to 25
bid
48% disease progression†
(P=.001)
CIBIS-II2
bisoprolol
moderate/
severe
10 qd
34% mortality
(P<.0001)
MERIT-HF3
metoprolol
succinate
mild/
moderate
200 qd
34% mortality
(P=.0062)
COPERNICUS4
carvedilol
severe
25 bid
35% mortality
(P=.0014)
CAPRICORN5
carvedilol
Post-MI LVD
25 bid
23% mortality
(P=.031)
1Colucci
WS et al. Circulation. 1996;94:2800–2806.
II Investigators and Committees. Lancet. 1999;353:9–13.
3MERIT-HF Study Group. Lancet. 1999;353:2001–2007.
4Packer M et al. N Engl J Med. 2001;344:1651–1658.
5The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
2CIBIS
CAPRICORN: Killip Class at
Randomization
Placebo
(n=984)
n
(%)
Killip Class*
Class I
Class II
Class III/IV
Missing
670
279
33
2
(68)
(28)
(3)
(<1)
Carvedilol
(n=975)
n
(%)
672
277
24
2
*Definitions in CAPRICORN protocol:
Class I: No hemodynamic compromise
Class II: Few bibasilar pulmonary crackles
Class III: Frank pulmonary edema (extensive crackles, hypoxia)
Class IV: Cardiogenic shock (hypotension, organ hypoperfusion)
(69)
(28)
(2)
(<1)
CAPRICORN:
All-Cause Mortality
Proportion Event Free
1
0.95
0.9
0.85
Carvedilol
0.8
Placebo
P=.03
0.75
0.7
0
0.5
1
1.5
2
Years
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
2.5
 23%
CAPRICORN: Mortality Reduction in
LVD Patients With No Symptoms of Heart Failure
Proportion Alive
1
0.95
Carvedilol
0.9
 31%
0.85
P=.07
Placebo
0.8
0
0.5
1
1.5
Years
Data on file, GlaxoSmithKline.
2
2.5
CAPRICORN:
Effect on Recurrent Infarction
Placebo
Carvedilol
Hazard ratio
(95% CI)
P
value
Hospitalization for nonfatal
myocardial infarction
57
34
0.59
(0.39–0.90)
.014
Fatal or nonfatal
myocardial infarction
66
40
0.60
(0.40–0.89)
.010
CV death or nonfatal
myocardial infarction
181
128
0.70
(0.56–0.87)
.002
Any death or nonfatal
myocardial infarction
192
139
0.71
(0.57–0.89)
.002
Among first events leading to death or CV hospitalization (co-primary end point), 45 of such
events on placebo and 27 such events on carvedilol were due to a recurrent infarction.
Total number of hospitalizations for myocardial infarction (including first and recurrent) was
60 in the placebo group and 37 in the carvedilol group.
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
Neurohormonal Interventions Across the Continuum
Post-MI
LV dysfunction
Mild
CHF
Moderate
CHF
Severe
CHF
AIRE/SAVE/TRACE
(ramipril/captopril/
trandolapril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
CAPRICORN
(carvedilol)
US Carvedilol Trials
(carvedilol)
MERIT-HF
(metoprolol)
CIBIS II
(bisoprolol)
COPERNICUS
(carvedilol)
Neurohormonal Interventions in Heart Failure
Drug Effects on Total and Sudden Cardiac Death Risks1
Patients
LVEF
Drug Tested
Randomized
ACE-I
(% of Pts)
Total Death
Risk
Reduction
SCD Risk
Reduction
(p-value)
(p-value)
TRACE
2,606
<36%
Trandolapril
100%
-22% (<0.001)
-24% (<0.03)
HOPE
9.297
Nominal
lly >40%
Ramipril
100%
-26% (<0.005)
-38% (<0.02)
RALES
1,663
25%
Spironolactone
95%
-30% (<0.001)
-29% (<0.02)
CIBIS-II
2,647
28%
Bisoprolol
96%
-34% ( <0.0001)
-44% (<0.001)
MERIT-HF
3,991
28%
Metoprolol
96%
-34% (<
0.00009)
-41% (<0.0002)
COPERNICUS
2,289
20%
Carvedilol
97%
-35% (< 0.001)
Not reported
SOLVD-T
2,569
25%
Enalapril
100%
-16% (0.004)
-10% (NS)
SOLVD-P
4,228
28%
Enalapril
100%
-8% (0.3)
-7% (NS)
1
Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp. 764-775, July 2003.
SCD Prevention by
Ion Channel-Active Drugs
CAST-I
Prognosis of Post-MI Patients Treated with
Placebo vs. Encainide/Flecainide
Patients Without Event (%)
100
95
Placebo
(n = 743)
90
Encainide or
Flecainide (n = 755)
85
P = 0.001
80
0
91
182
273
364
Days After Randomization
Echt DS. N. Engl J Med. 1991;324:781-788.
455
CAST-II
Absence of Benefit of Moricizine Over Placebo
100
Placebo
Moricizine
Survival (%)
80
60
40
20
Adjusted P = 0.40
0
0
No. at risk (% surviving)
Placebo
574 (100)
Moricizine 581 (100)
1
Year
351 (95.2)
350 (94.9)
CAST-II Investigators. N Engl J Med. 1992;327:227-233.
2
175 (89.6)
181 (88.8)
3
56 (88.0)
56 (85.0)
EMIAT and CAMIAT Trials
FACTOR
Protocol
Patient characteristics
Recruitment
Risk reduction of arrhythmic
death at 24 months
All-cause mortality at 24
months
EMIAT1
CAMIAT2
Amiodarone vs. placebo
Amiodarone vs.
placebo
Poor LV function
Frequent ventricular
ectopic activity (VEA; >
10 VPDs/hr)
(LVEF < 40%)
5-21 days post-MI
6-45 days post-MI
35%
48.5%
No difference
No difference
While amiodarone was effective in reducing arrhythmic
death, it did not reduce total mortality.
1 Julian
DG. Lancet. 1997;349:667-674.
JA. Lancet. 1997;349:675-682.
2 Cairns
Proportion event-free
SWORD Survival Results
Study stopped prematurely
in Nov. 1994 due to
increased mortality in
patient population treated
with d-sotalol
1.00
.99
.98
.97
.96
.95
.94
.93
.92
.91
.90
.89
.88
.87
Placebo
dsotalol
Z = -2.5, P = 0.006
0
120
180
240
300
Time from randomisation (days)
Patients at risk
Placebo
d-sotalol
60
1572
1549
Waldo AL. Lancet. 1996;348:7-12.
1170
1150
874
844
551
544
330
323
The Impact of Neurohormonal
Interventions on SCD in Heart Failure:
Are We Making Any Progress?
Neurohormonal Interventions:
Impact on Survival and Sudden Death
• Use of ace-inhibitors and beta blockers has
yielded substantial reductions in mortality due to
progressive pump failure and have provided some
protection from sudden cardiac death.
• However, mortality from heart failure remains
high.
• Several recent studies suggest that perhaps more
work is needed to prevent SCD in heart failure.
Survival Trends in Heart Failure
Despite favorable trends in
survival, heart failure remains
highly fatal; among subject who
were given a diagnosis of heart
failure in the 1990s, more than
50% were dead in 5 years.1
Temporal Trends in Age-Adjusted Survival after the Onset of
Heart Failure among Men (Panel A) and Women (Panel B).
Values were adjusted for age (<55, 55 to 64, 65 to 74, 75 to
84, and 85 years). Estimates are shown for subjects who
were 65 to 74 years of age.
1 Levy
D, et al. Long-Term Trends in the Incidence of and Survival
with Heart Failure. N Engl J Med 2002; 347: 1397-402.
Survival Trends: CHD and SCA
Mayo Clinic; Olmsted County, Minnesota1:
•Analyzed secular trends in CHD deaths and unexpected SCD over
a 20-year period (1979-1998)
•In-hospital deaths declined at a greater rate than out-of-hospital:
– RRR of in-hospital death in 1998: 0.36
– RRR of out-of-hospital death in 1998: 0.71
•50% of deaths were unexpected
– Similar to Framingham results from two decades earlier—even with the
intensified secondary and primary prevention efforts
“…these data underscore the increasing importance of primary
prevention in sustaining the decline in CHF mortality.”
1
Goraya TY, et al. Coronary Heart Disease and Sudden Cardiac Death: A 20-Year Population-based Study. Am J
Epidemiol 2003; 157: 763-770.
Risk of Sudden Death in HF Trials
Study
MERIT-HF1
HF
Class
Control
Treatment
(n)
(n)
Total
Mortality
Reduction
w/Treatment
2-4
2001
1990
34%
(Metroprolol)
BEST2
3,4
1354
1354
10%
(Bucindolol)
CIBIS-II3
3,4
1320
1327
34%
(Bisoprolol)
CARVEDILOL
- (U.S.)4
2-4
RALES5
3, 4
398
841
696
882
References in slide notes.
65%
30%
Sudden
Death as a
% of Total
Death in
Control
Arm
Sudden
Death- as a
% of Total
Death in
Treatment
Arm
(60%)
(54%)
132/217
79/145
(45%)
(44%)
203/449
182/411
(36%)
(31%)
83/228
48/156
(48%)
(54%)
15/31
12/22
(28%)
(29%)
110/386
162/478
Residual Risk of SCD in Treatment Arms
of CHF-Beta Blocker Trials
156
160
145
Number of Deaths
140
Sudden Deaths
Total Deaths
120
100
79
80
60
48
40
20
12
22
0
CIBIS II (1999)
MERIT-HF (1999)
U.S. CARVEDILOL
(1996)
Sudden Death % of
Total Death
31%
54%
54%
No. Pts in Treatment Arm:
Average Follow Up:
n= 1327
16 months
n= 1990
12 months
n = 696
6.5 months
1.
CIBIS-II Investigators. Lancet 1999; 353: 9-13.
2.
MERIT-HF Study Group. Lancet. 1999; 353: 2001-07.
3.
Packer, M, et al. N Engl J Med 1996: 334: 1349-55.
SCD in Heart Failure
1, 2
• Despite improvements in medical therapy,
symptomatic HF still confers a 20-25%
risk of pre-mature death in the first 2.5 yrs
after diagnosis.
–  50% of these premature deaths are SCD
(VT/VF)
• The role of device therapy?
1
Bardy G. The Sudden Cardiac Deatth-Heart Failure Trial (SCD-HeFT) in Woosley RL, Singh S, Arrhythmia Treatment and Therapy,
Copyright 2000 by Marcel Dekker, Inc. , pp. 323-342,
2 Sweeney
MO PACE 2001;24:871-888.
SCD Prevention by
Implantable Device Therapy
1. Post-MI and LV Dysfunction:
•
MADIT/MUSTT/MADIT II
2. Heart Failure and LV Dysfunction:
•
SCD-HeFT
MADIT/MUSTT/MADIT-II
Study Criteria Comparison
Inclusion Criteria
CAD/Post-MI
LV Dysfunction
NSVT
Inducible VT on EPS
Inducible, nonsuppressible VT on EPS
1 Moss
AJ. N Engl J Med. 1996;335:1933-40.
AE. N Engl J Med. 1999;341:1882-90.
3 Moss AJ. N Engl J Med. 2002; 346:877-83.
2 Buxton
MADIT1
MUSTT2
MADIT II3
(196 patients)
(704 patients)
(1232 patients)






(<35%)
(<40%)
(<30%)





MADIT
Multicenter Automatic Defibrillator
Implantation Trial
Moss AJ. N Engl J Med 1996:335:1933-40.
MADIT Survival Results
Probability of survival
1.0
0.8
Defibrillator
0.6
Conventional
therapy
0.4
0.2
P-value = 0.009
0.0
0
1
2
3
4
5
95
80
53
31
17
3
101
67
48
29
17
0
No. of patients
Defibrillator
Conventional
therapy
Moss AJ. N Engl J Med. 1996;335:1933-40.
Year
MADIT: ICDs Significantly Reduced
Overall and Arrhythmic Mortality1
75%
% Mortality Reduction
w/ICDs
80%
54%
60%
40%
20%
0%
Reduction in
Overall Death
1. Moss AJ. N Engl J Med. 1996;335:1933-1940.
Reduction in
Arrhythmic Death
MUSTT
Multicenter Unsustained Tachycardia
Trial
Buxton AE. N Engl J Med. 1999;341:1882-90.
MUSTT Randomized Patient Results:
Total Mortality
0.6
EP-Guided Without
Defibrillator
0.5
No Antiarrhythmic
Therapy
Event Rate
0.4
0.3
p < 0.001
EP-Guided Therapy
with Defibrillator
0.2
0.1
0
0
1
Buxton AE. N Engl J Med. 1999;341:1882-90.
2
3
Time after Enrollment (Years)
4
5
% Mortality Reduction w/ ICDs
MUSTT: ICDs Significantly Reduce
Overall and Arrhythmic Mortality
80%
76%
73%
60%
55%
60%
40%
20%
0%
Versus EP-Guided Rx w/No ICD
Versus No EP-Guided Rx
Arrhythmic Death Reduction
Overall Mortality Reduction
* P<0.001 for adjusted estimates of relative risk for each end point.
Adjusted estimates were made from all available clinical and prognostic factors.
Buxton AE. N Engl J Med. 1999;341:1882-90.
MUSTT Registry Patients
Mortality Results
Rate of Cardiac Arrest
or Arrhythmic Death
Overall Mortality Rate
Registry
No AA Rx
Registry
No AA Rx
(non-inducible)
(inducible)
(non-inducible)
(inducible)
N= 1397
N= 353
N= 1397
N=353
2-year rate (%)
12
18
21
28
5-year rate (%)
24
32
44
48
Adjusted PValue
<0.001
Buxton AE. et al. N Engl J Med 2000; 342: 1937-45.
0.005
MADIT-II
Multicenter Automatic Defibrillator
Implantation Trial-II
Moss AJ. N Engl J Med. 2002;346:877-83.
MADIT-II Inclusion Criteria
• Q-wave or enzyme-positive MI > 4 weeks
• LVEF < 30% as measured by angiographic,
radionuclide or echocardiographic method
• > 21 years of age; no upper age limitation
• No requirement for NSVT or EPS
Moss AJ. N Engl J Med. 2002;346:877-83.
MADIT-II Protocol
Inclusion criteria
ICD implant n=742
No-ICD implant n=490
(EPS after implant)
(Conventional Post-MI drug Rx)
20 months mean follow- up
• Avoid AAD
• Optimize: bB, ACE-I, Diuretics
Moss AJ. N Engl J Med. 2002;346:877-83.
MADIT-II Survival Results
Probability of Survival
1.0
0.9
Defibrillator
0.8
0.7
Conventional
P = 0.007
0.6
0.0
0
1
3
4
Year
No. At Risk
Defibrillator
2
742
502 (0.91)
274 (0.94)
110 (0.78)
9
Conventional 490
329 (0.90)
170 (0.78)
65 (0.69)
3
Moss AJ. N Engl J Med. 2002;346:877-83.
MADIT II: All-Cause Mortality
19.8%
20.00%
31% Relative
Reduction
Hazard Ratio=
0.69
(p= 0.016)
14.2%
10.00%
0.00%
Conventional Therapy
N= 490
Moss AJ. N Engl J Med. 2002;346:877-83.
ICD Therapy
N= 742
MADIT II: Mortality Events
20%
15%
20%
31% relative risk
reduction
14%
13.7%
10.0%
10%
5%
0%
5.5%
3.7%
4.1%
3.5%
All Cause
NonCardiac
9.4%
Cardiac
Conv
Moss AJ. Presented at ACC Latebreaking Clinical Trials, March 2002.
ICD
61% relative
risk reduction
3.6%
NonArrhythmic
Arrhythmic
MADIT-II
Survival Results – Subgroup Analyses
There were no
statistically significant
interactions in the
various subgroups.
Note the overlapping
error bars.
Moss AJ. N Engl J Med. 2002;346:877-83.
MADIT II:
In Context with Other Landmark Trials
30
p=0.019
Mortality (%)
24.6
p=0.016
20.4
15
Non-active Rx
19.8
14.2
p<0.01
p=NS
9.8
7.2
9.0
8.0
0
BHAT
CASS
N=3800
N=780
HR=0.73
HR=0.89
SAVE
N=2200
HR=0.81
Moss, AJ. MADIT II and its implications. European Heart Journal (2003); 24, 16-18.
MADIT II
N=1200
HR=0.69
Active Rx
MADIT II: Complications
New or Worsening HF1
19.9%
20.00%
14.9%
10.00%
0.00%
• Intrinsic ventricular activation is
better for ICD patients with left
ventricular dysfunction who do not
“need” pacing.2,3
(p= 0.09)
Conventional Therapy
N= 490
•RV pacing causes ventricular
dysynchrony and may lead to
worsening HF.2,3,4
ICD Therapy
N= 742
•<10% of ICD patients have a Class I
pacing indication at the time of
implant.5,6
•Physicians, when appropriate, should
consider programming of ICDs to
avoid frequent RV pacing.4
1
Moss AJ. N Engl J Med. 2002;346:877-83.
The DAVID Trial Investigators. JAMA 2002; 288: 3115-3123.
3Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Circulation. 2003 Jun 17;107(23):2932-7
4 Steinberg JS. Presented at the 24th Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology, Late
breaking Clinical Trials, Section 2; May 17, 2003.
5 The DAVID Trial Investigators. JAMA 2002; 288: 3115-3123.
6 BEST. PACE. 1999;22 (1, part I):79-85.
2
Mortality Benefits in ICD Trials
% Mortality Reduction w/ ICD
Rx
80
75%
Overall Death
Arrhythmic Death
73%
61%
60
54%
56%
55%
40
31%
31%
20
0
1
MADIT 1
MUSTT
27 Months
39 Months
2
MADIT-II
3, 4
20 Months
AVID
24 Months
Moss AJ. N Engl J Med. 1996;335:1933-40.
Buxton AE. N Engl J Med. 1999;341:1882-90.
3 Moss AF. N Engl J Med. 2002;346:877-83.
4 Moss AJ. Presented before ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, 2002.
5 The AVID Investigators. N Engl J Med. 1997;337:1576-83.
2
5
Post-MI trials are not heart failure
trials but…
… there’s a high % of symptomatic heart failure and LV
dysfunction in the post-MI trials
MADIT1
MADIT II2
MUSTT3
(n=1232)
(n=704)
63
64
68
LVEF
0.26
0.23
0.30
NYHA I
37%
39%
37%
NYHA II or III
63%
57%
63%
NYHA IV
Excluded
4%
Excluded
CAD (%)
100
100
100
73/27
60/45
56/23
(n=196)
Age
Previous CABG/PTCA (%)
1Moss
A, et al. N Engl J Med. 1996;335:1933–40.
A, et al; N Engl J Med. 1999;341:1882–90.
3AVID Investigators; N Engl J Med. 1997;337:1576–83.
4Moss, A. et al; N Engl J Med. 2002;346:877–83.
2Buxton,
SCD Rates in Post-MI Patients with LV Dysfunction
Total Mortality
Arrhythmic Mortality
Control Group Mortality at 2 years
32
30
28
28
21
20
20
18
16
14
16
12
10
10
19.8
9.4
7
0
TRACE
CAPRICORN
EMIAT
MADIT
MUSTT
Inducible
MUSTT
Registry
MADIT II*
Total Mortality ~20-30%; SCD accounts for ~50% of the total deaths.
References in slide notes. * MADIT II mortality values at 20 months.
SCD Rates in CHF Patients with LV Dysfunction
42
41
39.7
Total Mortality
Sudden Death
44
Control Group Mortality
30
20
20
19
17
15
11
9
10
7
8
6
4
0
CHF-STAT
45 months
GESICA
13 months
SOLVD
V-HeFT I
41.4 months
27 months
MERIT-HF
12 months
CIBIS-II
16 months
CARVEDILOL-US
6 months
Total Mortality ~15-40%; SCD accounts for ~50% of the total deaths.
References in slide notes. * MADIT II mortality values at 20 months.
Primary Prevention ICD Trials:
Extent of Beta-Blocker/ACE-I Use in Control Patients
77
80
72
70
55
60
51
40
%
70
54
50
72
30
35
20
24
10
0
8
MADIT
Year of
Publication
1996
CABG- MUSTT MUSTT MADIT II
PATCH
Registry
1997
1999
1999
2002
References for each study in slide notes.
BB
ACE-I
Number Needed to Treat To Save A Life
NNTx years = 100 / (% Mortality in Control Group – % Mortality in Treatment Group)
50
Drug Therapy
45
37
40
35
26
30
amiodarone
25
20
ICD Therapy
20
simvastatin
11
15
10
28
9
metoprolol
3
4
MUSTT
MADIT
MADIT II
AVID
SAVE
Merit-HF
(2.4 Yr)
(3 Yr)
(3 Yr)
(3.5 Yr)
(1 Yr)
captopril
5
0
(5 Yr)
4S
(6 Yr)
Amiodarone
Metaanalysis
(2 Yr)
Sudden Cardiac Death
SCD -HeFT
Heart Failure Trial
Sponsored by
The National Heart, Lung, & Blood Institute,
Medtronic, Inc., & Wyeth-Ayerst
Key Points
• Largest Study – Landmark
– 2,521 patients, 150 centers, min 2.5 yr f/u
• Randomized Placebo Controlled Design
• DCRI – Best in class study management
• Sponsored by NHLBI, additional funding by
Medtronic, Wyeth
Key Trial Question
• Will Amiodarone and/or an ICD improve survival
compared to placebo in patients with NYHA Class
II and III CHF and reduced left ventricular ejection
fraction (< 35%) without a history of sustained VT
or VF?
SCD-HeFT Inclusion Criteria
• Symptomatic CHF (NYHA class II and III) due to
ischemic or nonischemic dilated
cardiomyopathy
• LVEF < 35%
• > 18 years of age; no upper age limitation
• CHF  3 months
• Appropriate dose of ACE I and Beta Blocker
therapy, if tolerated, for at least 1 month prior to
randomization
Bardy G
SCD-HeFT Endpoints
• Primary
– To compare all cause mortality after
2.5 years of follow-up (Power: 90% to detect 25% benefit)
• Secondary
– Mortality – Ischemic, Non-Ischemic, Class II, III
– Cause-Specific Death
– HF Morbidity & Mortality
– Consistency of treatment effects across sub groups defined by other
variables – age, gender, EF, Hx of MI, time of MI, QRS width
– Quality of Life
– Cost of Care & Cost Effectiveness
Recommended ACE I &
BB Dosages
Ace inhibitor:
• E.g., enalapril 10 mg bid
• Administered for at least 1 month prior to randomization
Beta Blocker:
• Carvedilol: 3.125 mg bid for first 2 weeks; 6.25 mg bid for weeks 24; 12.5 mg bid for weeks 4-6; and 25 mg bid for weeks 6-8.
• Metoprolol (Toprol XL): 12.5 mg qd for first 2 weeks; 25 mg qd for
weeks 2-4; 37.5 mg qd for weeks 4-6; and 50 mg qd for weeks 6-8.
• Wait 2 weeks after last anticipated increase in beta-blocker dosage
or wait 2 weeks after maximally tolerated dose prior to
randomization.
Bardy G
SCD-HeFT Protocol
Inclusion criteria
Placebo n=847
Amiodarone n=845
ICD implant n=829
2.5 years minimum follow- up
• Optimize: bB, ACE-I, Diuretics
SCD-HeFT Trial Design
Versus MADIT II
Sponsor
Number of Centers
Region
PI
Study design
Primary Objective
Stratification
Treatment Arms
Cardiac Disease
EF
Hx of VT/VF
NYHA
Pharmacotherapy
SCD-HeFT
NHLBI, Medtronic, Wyeth
150
US, Canada, New Zealand
Drs. Gust Bardy, Kerry Lee & Dan Mark
3 arm RPCT
Total Mortality
NYHA, Ischemic
Amio/ICD/Placebo
Ischemic/non-Ischemic
< 35%
no
II, III
ACEi/BB
MADIT II
Guidant
76
US, Europe
Dr. Arthur Moss
2 arm RCT
Total Mortality
na
ICD/standard care
Ischemic + MI
< 30%
no
no requirement
ACEi/BB
SCD-HeFT Enrolled Patient
Characteristics vs. MADIT II
Enrollment
Sample Size
Placebo
Amiodarone
ICD
Age
% Ischemic
Mean EF
QRS interval > 0.12 sec
NYHA - I
NYHA - II
NYHA - III
NYHA - IV
Beta Blockers
ACE inhibitors
Digitalis
Diuretics
Lipid Lowering Statins
SCD-HeFT
Sept 97 to July 01
2521
847
845
829
60
52%
25%
tbd
NA
70%
30%
NA
tbd
tbd
tbd
tbd
tbd
MADIT II
July 97 to Nov 01
1232
490
NA
742
64-65
100%
23%
50%
35%
35%
24%
5%
70%
68%
57%
72%
67%
Pharmacologic and Device Therapy Across the Continuum
Post-MI
LV dysfunction
Mild
CHF
Moderate
CHF
Severe
CHF
AIRE/SAVE
(ramipril/captopril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
CAPRICORN
(carvedilol)
US Carvedilol/MERIT
(carvedilol/metoprolol)
COPERNICUS
(carvedilol)
EPHESUS
(eplerenone)
CHARM/Val-HeFT
(candesartan/valsartan)
RALES
(spironolactone)
MADIT, MUSTT
MADIT II
(ICD)
SCD-HeFT (?)
(ICD)
Conclusions
– In patients with LV dysfunction, the combined use of ACE
inhibition and beta-blockade is recommended as the cornerstone
of therapy.
– Modest incremental benefit may be seen with the addition of other
antagonists of the RAS in post-MI LV dysfunction and in chronic
heart failure.
– While neurohormonal interventions reduce morbidity and mortality
across the cardiovascular disease continuum, post-MI and HF
patients with LV dysfunction still have a high rate of sudden
cardiac death.
– Therapy with ICDs significantly reduces mortality in post-MI
patients with LV dysfunction. These mortality benefits are on top
of optimal pharmacologic therapy. ICD therapy should be
considered standard of care in these patients.
– Data from SCD-HeFT will be critical to understand the role of ICD
therapy in ischemic and non-ischemic CHF patients with LV
dysfunction.