MADITII Multicenter Automatic Defibrillator Implantation Trial II1 Primary Prevention of Sudden Card

1
MADIT-IIMulticenter Automatic Defibrillator
Implantation Trial II1Primary Prevention of
Sudden Cardiac Arrest
1 Moss AJ. N Engl J Med. 2002346877-83.
2
Presentation Overview

• Overview of Sudden Cardiac Arrest (SCA)
• Magnitude/Etiology/Risk-Stratification in the
  CAD/post-MI population
• Summary of Post-MI ICD Studies
• MADIT II Study Design and Results
• Key MADIT II Sub-Studies (NASPE 2003)
• Answer the Questions
• Who are the MADIT II patients?
• Where are the MADIT II patients?
• Is there a MADIT II device?
• Proposed Identification/Treatment Algorithm for
  MADIT II Patients
• Economics of ICD Therapy in the High-Risk Post-MI
  Population
• Overall Conclusions on MADIT II and the Primary
  Prevention of Sudden Cardiac Arrest

3
Overview of SCA
4
Sudden Cardiac Arrest (SCA) Statistics

• Accounts for 63 of all cardiac related deaths in
  the US1.
• One of the most common causes of death in
  developed countries

1 MMWR. Vol 51(6) Feb. 15, 2002. 2 Myerberg 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
Circulation. 20011042158-2163. 4
Vreede-Swagemakers JJ et al. J Am Coll Cardiol
1997 30 1500-1505.
5
Magnitude of SCA in the US
SCA claims more lives each year than these other
diseases combined
167,366
Stroke3
450,000
SCA 4
Lung Cancer2
157,400
Breast Cancer2
40,600
The 1 Killer in the U.S.
42,156
AIDS1
1 U.S. Census Bureau, Statistical Abstract of
the United States 2001. 2 American Cancer
Society, Inc., Surveillance Research, Cancer
Facts and Figures 2001. 3 2002 Heart and Stroke
Statistical Update, American Heart Association. 4
Circulation. 20011042158-2163.
6
Leading Causes of Death in the US in 19991
Septicemia
Nephritis
Only after the deaths from ALL cancers are
combined does anything cause more deaths each
year than sudden cardiac arrest .
Alzheimers Disease
Influenza/pneumonia
Diabetes
Accidents/injuries
Chronic lower respiratory diseases
Cerebrovascular disease
Other cardiac causes
Sudden cardiac arrest (SCA)
All cancers
1 National Vital Statistics Report, Vol 49
(11), Oct. 12, 2001 2 MMWR. State-specific
mortality from sudden cardiac death US
1999.Feb 15, 200251123-126.
7
Magnitude of SCA in the US

• - 450,000 per year1
• 1200 per day
• 50 every hour
• 1 every 80 seconds
• - Although SCA is the first presentation of
  cardiac disease in 20-25 of patients, most cases
  occur in patients with clinically recognized
  heart disease.2

1Circulation. 20011042158-2163. 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.
8
Arrhythmic Cause of SCD
12Other CardiacCause
88ArrhythmicCause
Albert CM. Circulation. 20031072096-2101.
9
Underlying Arrhythmias of Sudden Cardiac Arrest
Torsades de Pointes13
Bradycardia17
VT62
Primary VF8
Bayés de Luna A. Am Heart J. 1989117151-159.
10
SCA Resuscitation Success vs. Time
Chance of success reduced 7 - 10 each minute
Success Non-linear
Time (minutes)
Cummins RO. Annals Emerg Med. 1989181269-1275.
11
SCA Chain of Survival Statistics

• 5 estimated SCA out-of-hospital survival in the
  U.S. 2,3,4
• Even in the best EMS/early defibrillation
  programs it is difficult to have high survival
  rates due to many SCA events not being witnessed
  and the difficulty of reaching victims within 6-8
  minutes
• 40 SCAs not witnessed or occur in sleep1
• 80 SCAs occur at home1

1 Swagemakers V. J Am Cardiol. 1997301500-1505 2
Ginsburg W. Am J Emer Med. 199816315-319. 3
Cobb LA. Circ. 199285I98-102. 4 Myerburg RJ, et
al. J Cardiovasc Electrophysiol. Vol. 14, pp.
S108-S116, September 2003, Suppl.
12
Incidence of SCD in Specific Populations and
Annual SCD Numbers
General adult population
Multiple risk subgroups
Patients with any previous coronary event
Patients with ejectionfraction SCD-HeFT
AVID, CASH, CIDS
Cardiac arrest, VT/VF survivors
MADIT, MUSTT, MADIT II
High-risk post-MI subgroups
300,000
200,000
100,000
0
10
5
0
25
20
30
Incidence of Sudden Deaths Per Year (number)
Incidence of Sudden Death( of group)
Adapted from Myerburg RJ. Sudden Cardiac Death
Exploring the Limits of Our Knowledge. J
Cardiovasc Electrophysiol Vol. 12, pp. 369-381,
March 2001.
13
Coronary Artery Diseaseand Sudden Cardiac Death
Risk
14
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
ion-channel abnormalities, valvular or
congenital heart disease, other causes
1 American Heart Association. Heart Disease and
Stroke Statistics2003 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.
15
Previous Myocardial Infarctionand Sudden Cardiac
Death Risk
16
People whove had a heart attack have a sudden
death rate thats 4-6 times that of the
general population.1
1American Heart Association. Heart Disease and
Stroke Statistics2003 Update. Dallas, Tex.
American Heart Association 2002.
17
Survival After Acute MI
1.0
A
0.8
B
C
0.6
Survivorship
D
0.4
N 536 113 80 37
EF ??30 ??30 ??30 ??30
VPD ??10/hr ??10/hr A B C D
0.2
0
3
2
1
Year
Bigger JT. Am J Cardiology. 19865712B.
18
Myocardial Infarction

• The prevalence of MI in the U.S. in 2002 was 7.6
  million.1
• The prevalence, although currently higher in men
  than women, increased 30 in women from 1989 to
  1996.
• Death rates were also higher among young African
  Americans.
• Myocardial infarctions are identified in as many
  as 50-75 of sudden cardiac arrest victims.2,3,4
• Within 6 years of a recognized heart attack, 7
  of men and 6 of women will experience sudden
  death.1

1 American Heart Association. Heart Disease and
Stroke Statistics2003 Update. Dallas, Tex.
American Heart Association 2002. 2 Myerberg RJ.
Heart Disease, A Textbook of Cardiovascular
Medicine. 6th ed. Philadelphia WB Saunders Co
1997chapter 24. 3 Lombardi G. JAMA.
1994271678-683. 4 Bigger JT. Circulation.
198469250-258. 5 1David J. Wilber MD, Wojciech
Zareba, W. Jackson Hall . Time-dependence of
Mortality Risk and Defibrillator Benefit
Following Myocardial Infarction Lessons from the
Multicenter Automatic Defibrillator Implantation
Trial II. NASPE 2003. Abstract ID. 100865
19
Time Dependence of Mortality Risk
Post-MIPrediction of Sudden Cardiac Death After
Myocardial Infarction in the Beta-Blocking Era1

• 700 post-MI patients 95 on beta blockers 2
  years after discharge.
• The epidemiologic pattern of SCD was different
  from that reported in previous studies.
• Arrhythmia events or SCDs did not concentrate
  early after the index event, but most of them
  occurred more than 18 months post-MI.

1Huikuri H, et al. J Am Coll Cardiol 2003 42
652-8.
20
Time Dependence of Mortality Risk Post-MI

• Maastricht Circulatory Arrest Registry1
• In 224 sudden cardiac arrest victims, only 4 (10
  cases) were due to an acute MI.
• The median time from MI to sudden cardiac arrest
  was 9.0 years in 92 patients (41 of total).

1 Gorgels PMA. European Heart Journal.
2003241204-1209.
21
LV Dysfunction and Sudden Cardiac Death Risk
22
Reduced left ventricular ejection fraction
(LVEF) remains the single most important risk
factor for overall mortality and sudden cardiac
death.1
1Prior SG, Aliot E, Blonstrom-Lundqvist C, et al.
Task Force on Sudden Cardiac Death of the
European Society of Cardiology. Eur Heart J,
Vol. 22 16 August 2001.
23
Risk of Sudden Death Data from GISSI-2 Trial
1.00
1.00
0.98
0.98
p log-rank 0.002
0.96
0.96
0.94
0.94
Survival
Survival
0.92
0.92
p log-rank 0.0001
0.90
0.90
0.88
0.88
A
B
0.86
0.86
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Days
Days
Patients withLV Dysfunction (LVEF

Patients withoutLV Dysfunction

(LVEF 35)

No PVBs1-10 PVBs/h 10 PVBs/h
Maggioni AP. Circulation. 199387312-322.
24
LVEF and SCA Incidence
7.5
5.1
SCA Victims
2.8
1.4
LVEF
Vreede-Swagemakers JJ. J Am Coll Cardiol.
1997301500-1505.
25
Post MI Patients with LV Dysfunction Have
Mortality Rates Similar to a CHF Population
26
Mortality Rates in Post-MI Patients with LV
Dysfunction
Total Mortality 20-30 SCD accounts for 50
of the total deaths.

• References in slide notes. MADIT II mortality
  values at 20 months.

27
Overview of Clinical Trials of ICD Therapy in
Post-MI Patients With LV Dysfunction
28
ICD Clinical Trials in Post-MI Patients

• MADIT
• Multicenter Automatic Defibrillator Implantation
  Trial
• Moss AJ. N Engl J Med 19963351933-40.
• MUSTT
• Multicenter Unsustained Tachycardia Trial
• Buxton AE. N Engl J Med. 19993411882-90.
• MADIT-II
• Multicenter Automatic Defibrillator Implantation
  Trial-II
• Moss AJ. N Engl J Med. 2002346877-83.

29
MADIT/MUSTT/MADIT-IIStudy Criteria Comparison
1 Moss AJ. N Engl J Med. 19963351933-40. 2
Buxton AE. N Engl J Med. 19993411882-90. 3 Moss
AJ. N Engl J Med. 2002 346877-83.
30
MADITMulticenter Automatic Defibrillator
Implantation TrialMoss AJ. N Engl J Med
19963351933-40.
31
MADIT Survival Results
1.0
0.8
Defibrillator
0.6
Probability of survival
Conventional therapy
0.4
0.2
P-value 0.009
0.0
0
1
2
3
4
5
Year
No. of patients Defibrillator 95 80 53 31 17 3 Con
ventional 101 67 48 29 17 0therapy
Moss AJ. N Engl J Med. 19963351933-40.
32
MADIT ICDs Significantly Reduced Overall and
Arrhythmic Mortality1
75
54
Reduction in Overall Death
Reduction in Arrhythmic Death
1. Moss AJ. N Engl J Med. 19963351933-1940.
33
MUSTTMulticenter Unsustained Tachycardia
TrialBuxton AE. N Engl J Med. 19993411882-90.
34
MUSTT Randomized Patient Results Total Mortality
0.6
EP-Guided Without Defibrillator
0.5
No Antiarrhythmic Therapy
0.4
Event Rate
0.3
p EP-Guided Therapy with Defibrillator
0.2
0.1
0
0
1
2
3
4
5
Time after Enrollment (Years)
Buxton AE. N Engl J Med. 19993411882-90.
35
MUSTT ICDs Significantly Reduce Overall and
Arrhythmic Mortality
76
73
60
55
Mortality Reduction w/ ICDs
Pfor each end point. Adjusted estimates were
made from all available clinical and prognostic
factors.
Buxton AE. N Engl J Med. 19993411882-90.
36
MUSTT Registry Patients Mortality Results
Buxton AE. et al. N Engl J Med 2000 342
1937-45.
37
even patients without inducible
tachyarrhythmias have a relatively high risk of
death.1
1Buxton AE, Lee KL, DiCarlo L, et al. N Engl J
Med 2000 342 1937-45.
38
MADIT-IIMulticenter Automatic Defibrillator
Implantation Trial-IIMoss AJ. N Engl J Med.
2002346877-83.
39
MADIT II Central Hypothesis
ICD will improve survival compared to
conventional therapy in post-MI patients with a
reduced left ventricular ejection fraction (? 35)
40
MADIT-II Inclusion Criteria

• Q-wave or enzyme-positive MI 4 weeks
• LVEF radionuclide or echocardiographic method
• 21 years of age no upper age limitation
• No requirement for NSVT or EPS

Moss AJ. N Engl J Med. 2002346877-83.
41
MADIT-II Exclusion Criteria

• Existing Indication for ICD (history of SCA,
  sustained VT, MADIT I criteria)
• NYHA Class IV at enrollment
• CABG or PTCA within past 3 months
• Enzyme-positive MI
• Patients with angiographic evidence of coronary
  disease who are candidates for coronary
  revascularization and are likely to undergo CABG
  or coronary angioplasty in the foreseeable future
• Advanced cerebrovascular disease
• High likelihood of death from non-cardiac disease
  during trial

Moss AJ. N Engl J Med. 2002346877-83.
42
MADIT-II Endpoints

• Primary
• All cause mortality (intention-to-treat
  analysis)
• Secondary
• Predictability of ICD discharge based on VT
  inducibility at EPS
• Usefulness of SAECG, HRV, TWA in predicting
  mortality or ICD discharge
• Cost-effectiveness
• Quality of life

Moss AJ. Ann Noninvasive Electrocardiol.
1999483-91.
43
MADIT-II Protocol
Inclusion criteria
ICD implant n742
No-ICD implant n490
(EPS after implant)
(Conventional Post-MI drug Rx)
20 months mean follow- up

• Avoid AAD
• Optimize ?B, ACE-I, Diuretics

Moss AJ. N Engl J Med. 2002346877-83.
44
Sample Size/Power Calculations

• Overall mortality rate in the control arm at 2
  years estimated to be approximately 19
• 50 of deaths in control arm arrhythmic
• Overall mortality rate in the ICD arm of 11.8
• Assumes 80 prevention of arrhythmic deaths
• Assumed Cross-over rates
• 2 from ICD to non-ICD
• 10 from non-ICD to ICD
• 95 Power to detect a 35 reduction in mortality
  at 2 years in the intervention arm assuming above
  assumptions are accurate

45
MADIT-II Statistical AnalysisTriangular
Sequential Design
Moss AJ. N Engl J Med. 2002346877-83.
46
MADIT-II Patient Characteristics
Moss AJ. N Engl J Med. 2002346877-83.
47
MADIT-II Baseline Patient Characteristics
Moss AJ. N Engl J Med. 2002346877-83.
48
MADIT-II Medication Use at Last Contact
Moss AJ. N Engl J Med. 2002346877-83.
49
MADIT-II Survival Results
1.0
0.9
Defibrillator
0.8
Probability of Survival
0.7
Conventional
P 0.007
0.6
0.0
0
1
2
3
4
Year
No. At Risk Defibrillator 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. 2002346877-83.
50
MADIT II All-Cause Mortality
31 Relative Reduction
Hazard Ratio 0.69 (p 0.016)
N 742
N 490
Moss AJ. N Engl J Med. 2002346877-83.
51
MADIT II Mortality Events
31 relative risk reduction
61 relative risk reduction
Moss AJ. Presented at ACC Latebreaking Clinical
Trials, March 2002.
52
MADIT-IISurvival Results Subgroup Analyses
There were no statistically significant
interactions in the various subgroups. Note the
overlapping error bars.
Moss AJ. N Engl J Med. 2002346877-83.
53
MADIT-II Mortality Reductions by QRS Duration
NOTE This information was presented by Dr.
Zareba at NASPE Latebreaking Clinical Trials
2002. This information has not been published,
but appears to have been the basis for the recent
CMS coverage decision.

• Zareba W. NASPE 2002, May 11, 2002, Late Breaking
  Clinical Trials Noninvasive Electrocardiology
  and Outcome in MADIT II Patients.
• Moss A. Proprhylactic implantation of a
  defibrillator in patients with MI and reduced
  ejection fraction. N Engl J Med
  2002346877-83
• Excludes patients with paced rhythm
• Figure 3, page 881, New Engl J Med2002346

54
MADIT-II Mortality Reductions by QRS Duration

• The hazard ratios within all subgroups were
  in the hazard ratios within any subgroup. In
  other words, a subset of patients could not be
  identified who obtained a significantly better or
  a significantly worse result from ICD therapy
  compared to conventional therapy. Although some
  trends in ICD efficacy were observed, the overall
  conclusion is that ICD therapy (benefit) was
  similar across the various subsets.
• Arthur J. Moss, M.D.
• J Cardiovasc Electrophysiol. Vol. 14, pp.
  S96-S98, September 2003, Suppl.

55
MADIT II Mortality Results in Context

• Versus Other ICD studies of Primary Prevention of
  SCA
• Versus Secondary Prevention ICD Studies
• Versus Other Landmark Trials in Cardiology

56
ICD Mortality Benefitsin Post-MI Patients with
LV Dysfunction
75
73
61
55
54
Mortality Reduction w/ ICD Rx
31
1
2
3, 4
27 Months
39 Months
20 Months
1 Moss AJ. N Engl J Med. 19963351933-40. 2
Buxton AE. N Engl J Med. 19993411882-90. 3 Moss
AF. N Engl J Med. 2002346877-83. 4 Moss AJ.
Presented before ACC 51st Annual Scientific
Sessions, Late Breaking Clinical Trials, March
19, 2002.
57
Reductions in Mortality with ICD Therapy
75
76
61
55
54
31
Mortality Reduction w/ ICD Rx
ICD mortality reductions in primary prevention
trialsare equal to or greaterthan those in
secondaryprevention trials.
1
3, 4
2
27 months
39 months
20 months
59
56
33
31
Mortality Reduction w/ ICD Rx
28
20
1 Moss AJ. N Engl J Med. 19963351933-40. 2
Buxton AE. N Engl J Med. 19993411882-90. 3 Moss
AJ. N Engl J Med. 2002346877-83 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.
19973371576-83. 6 Kuck K. Circ.
2000102748-54. 7 Connolly S. Circ.
20001011297-1302.
6
7
5
3 Years
3 Years
3 Years
58
MADIT II In Context with Other Landmark Trials
30
p0.019
24.6
p0.016
20.4
19.8
Mortality ()
15
14.2
p pNS
9.0
9.8
7.2
8.0
0
BHAT
CASS
SAVE
MADIT II
N3800
N780
N1200
N2200
HR0.73 HR0.89 HR0.81
HR0.69
Moss, AJ. MADIT II and its implications.
European Heart Journal (2003) 24, 16-18.
59
MADIT II Study Complications
60
MADIT-II Results
Moss AJ. N Engl J Med. 2002346877-83.
61
MADIT II ComplicationsNew or Worsening HF1

• RV pacing causes ventricular dysynchrony and may
  lead to worsening HF.2,3,4
• Intrinsic ventricular activation is better for
  ICD patients with left ventricular dysfunction
  who do not need pacing.2,3
• 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. 2002346877-83. 2 The
DAVID Trial Investigators. JAMA 2002 288
3115-3123. 3Sweeney MO, Hellkamp AS, Ellenbogen
KA, et al. Circulation. 2003 Jun
17107(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. 199922 (1,
part I)79-85.
62
Key MADIT II Abstracts NASPE 2003

• Inducibility
• Time Dependence of Mortality Risk Post-MI

63
EPS Inducibility in MADIT II Patients1

• Inducibility is predictive of VT, but VF is more
  common in non-inducible patients.
• There were no clinical variables that could
  predict which patients would be inducible at EPS.2

in post-infarct patients with LVEF is not indicated for prophylactic ICD
implantation. 1
1 Daubert JP, Zareba W, Schuger CD, et al. NASPE
2003 Abstract ID 100787. 2 Sesselberg HW, Moss
AJ, Steinberg J, et al. The American Journal of
Cardiology. Vol. 91, April 15, 2003.
64
Time Dependence of Mortality Risk Post-MI MADIT
II
Mortality risk in contemporary post- MI pts with
EF from last MI. Correspondingly, survival benefit
from the ICD increases significantly with time,
up to 15 years following MI.
1David J. Wilber MD, Wojciech Zareba, W.
Jackson Hall . Time-dependence of Mortality Risk
and Defibrillator Benefit Following Myocardial
Infarction Lessons from the Multicenter
Automatic Defibrillator Implantation Trial II.
NASPE 2003. Abstract ID. 100865
65
Time from Revascularization and ICD Survival
Benefit MADIT II1

• Mortality following CR significantly increases as
  a function of time from procedure (p0.036 Conv,
  p 0.0003 ICD).
• ICD survival benefit was similar across all
  quartiles (p 0.098).
• Prophylactic ICD implantation may be beneficial
  in post-MI patients with EF setting of recent CR.

1 Wilber DJ, Klein HU, Zareba W, et al. NASPE
2003. Abstract ID 100957.
66
Time Dependence of Mortality Risk Post-MI MADIT
II

• The mean time post-MI in the MADIT II cohort was
  81 78 months.
• Mortality risk in contemporary post-MI pts with
  EF from last MI.
• Survival benefit from the ICD increases
  significantly with time

1David J. Wilber MD, Wojciech Zareba, W.
Jackson Hall . Time-dependence of Mortality Risk
and Defibrillator Benefit Following Myocardial
Infarction Lessons from the Multicenter
Automatic Defibrillator Implantation Trial II.
NASPE 2003. Abstract ID. 100865 Time from MI
was unavailable in 73 of the 1232 patients.
67
Who are the MADIT II Patients?
68
Post-MI trials are not heart failure trials but
theres a high of symptomatic heart failure
and LV dysfunction in the post-MI trials
1Moss A, et al. N Engl J Med. 1996335193340. 2B
uxton, A, et al N Engl J Med. 1999341188290. 3
AVID Investigators N Engl J Med.
1997337157683. 4Moss, A. et al N Engl J Med.
200234687783.
69
Who are the MADIT II Patients?
MADIT II patients had more severe structural
heart disease than AVID patients.
1AVID investigators. N Engl. J Med. 1997 337
1576-1583. 2. Moss AJ. N Engl J Med. 2002 346
877-83. 3 Domanski MJ. Am J Cardiol. 1997 80
299-301. 4AVID _at_ 3 years from the KM curve
36-25, NNT9 N Engl J Med.
19973371576-1583 5MADIT-II _at_ 3 years from KM
curve 31-22, NNT11 N Engl J Med.
2002346877-883
70
Who are the High-Risk Post-MI Patients?Analysis
of Gross Prevalence Groups
Diagrams not to scale References in Slide Notes
Post- MI1 7,500k
EFEFEF)
EFPortion of MUSTT Not Part of MADIT II 95k
71
Who are the MADIT II Patients?Analysis of
Prevalence Groups

• 15 of the U.S. Population does not have access
  to healthcare. Health Insurance Coverage in the
  United States 2002 U.S. Census Bureau, Current
  Population Survey, 2002 and 2003 Annual Social
  and Economic Supplements.
• Of the remaining 85 who have access to health
  coverage, approximately 20 would not be
  considered for ICD therapy due to clinical
  exclusions (e.g., comorbidities, age, patient
  refusal, etc.) Source physician interviews.
• Not overlapping with MADIT II.

72
Where are the MADIT II Patients?
73
Sources of Potential MADIT II Patients?

• 60 of these patients are NYHA Class II/III 1
  CHF Clinics, Internal Medicine and Family
  Medicine
• 70 of these patients have been seen by a
  Cardiologist within the last 12 months2
• Radionucleide, catheterization, and
  echocardiogram lab should be alerted to tag
  patients with EF
• Screen EPS laboratory Holter logs
• CCU Telemetry units
• Cardiac rehab units

• 1 Baseline characteristics of MADIT/MUSTT/MADIT
  II study patients
• Moss AJ. N Engl J Med. 19963351933-40.
• Buxton AE. N Engl J Med. 19993411882-90.
• Moss AF. N Engl J Med. 2002346877-83.
• 2 Reden and Anders Claims data CY2000 Medtronic
  data on file.

74
Is there a MADIT II Device?
75
A special device for MADIT II patients?(compariso
n to current classic patients)

• Similar Therapy Requirements
• Primary prevention patients will need of
  shocks as a secondary-prevention patient.1
• 40 of MADIT II study patients had a potential
  life-threatening VT/VF event terminated by their
  ICD within the first four years after implant. 2
• Ventricular fibrillation is the cause of SCA in
  only a small percentage of cases (Ventricular tachycardia is the underlying
  etiology in 75 of SCA events. 3
• ATP allows PainFree termination of fast VT in
  80 of episodes.4
• Beta-blockers are becoming standard therapy in
  post-MI and HF patients. Pacing capability for
  bradycardia important.5

• Nisam S. A Prophylactic ICD? Who are the
  patients? What is the device? EUROPACE 2001
  3 269-274
• Moss AJ. J Cardiovasc Electrophysiol, Vol. 14,
  pp. S96-S98, September 2003, Suppl.
• Bayés de Luna A. Am Heart J. 1989117151-159.
• Wathen MS, et al. Circulation. 2001 104
  796-801.
• Packer M, et al. N Engl J Med 1996 334 1349-55.

76
A special device for MADIT II patients?(compariso
n to current classic patients)

• Similar Device Longevity Requirements
• Same age and life expectancy as secondary
  prevention patient.1
• Patient survival is 75 at 5 years. 2,3
• Similar Discrimination Technology Requirements
• AF/SVT even more an issue MADIT II patients (more
  severe heart disease than AVID patients)4,5
• 20-30 of ICD patients have atrial fibrillation
  at implant 45 will have AF within 17 months
  post-implant 6,7

• Nisam S. A Prophylactic ICD? Who are the
  patients? What is the device? EUROPACE 2001
  3 269-274
• Moss A, et al. N Engl J Med. 1996 335 1933-40.
• Buxton A, et al. N Engl J Med. 1996 341
  1882-90.
• Moss AJ. N Engl J Med. 2002 346 877-83.
• AVID investigators. N Engl. J Med. 1997 337
  1576-1583.
• Schmitt C, Montero M, Melicherick J. PACE 1994
  17 295-302.
• Medtronic GEM DR clinical data on file.

77
A special device for MADIT II patients?(compariso
n to current classic patients)

• Conclusions
• The clinical profile and needs of the MADIT II
  patients (primary prevention) are similar to the
  classic or secondary-prevention patients.
• There is no single type of device that will meet
  the needs for the entire MADIT II population.

78
Possible Treatment Algorithmfor MADIT-II Type
Patients
79
Treatment Goals After Myocardial Infarction

• Reducing the risk of another heart attack
• Antithrombotic therapy
• CABG, PTCA/stent
• ACE inhibitors
• Beta-blockers
• Statins
• Prevent the occurrence/progression of heart
  failure
• Aldosterone antagonists
• ACE inhibitors
• Beta-blockers
• Reducing the risk of sudden cardiac death
• Above agents especially beta-blockers, statins
  and revascularization
• ICD therapy
• MADIT II provided 31 reduction in mortality in
  patients who were optimized on drug therapy

80
MADIT II Possible Treatment Algorithm

• Screen for Prior MI
• Determine Ejection Fraction
• If LVEF SCD
• Review Exclusion Criteria
• Refer patient to Electrophysiologist as a
  candidate for ICD therapy

81
ICD Cost-Effectivenessin High-Risk Post-MI
Patients
82
Cost-Effectiveness Analysis

• Compare total cost of therapy with its benefit
  or effectiveness
• Average Cost-Effectiveness
• total cost of therapy divided by years of
  life lived after receiving therapy cost per life
  year (/LY)
• Incremental Cost-Effectiveness
• compare differences in total therapy cost and
  effectiveness between two competing therapies
  cost per life year saved (/LYS)

83
Incremental Cost Effectiveness Analysis

• Therapy A versus Therapy B
• Total Cost A Total Cost B
• Life Expectancy A Life Expectancy B
• Cost Per Life Year Saved (/LYS)

84
Incremental Cost-Effectiveness of ICD Therapy and
Other Cardiovascular Interventions
Economically Unattractive
Incremental Cost per Life-Year Saved
Expensive
Borderline Cost-effective
Cost-Effective
HighlyCost-Effective
PTCA(ChronicCAD, mildangina,1 VD)
CABG(Chronic CAD,mild angina,3 VD)
Primarycoronarystenting (CAD,Angina, 1
VD,Male, age 55)
Lovastatin(chol. 290 mg/dL,50 yrs old, male,
no riskfactors)
CardiacTransplant(CHF,transplantcandidate)
Hypertensiontherapy(Diastolic95-104mmHg)
ICD- MADIT
ICD- MADIT II estimate
ICD- AVID
Moss AJ. Presentation at Satellite Symposium,
Cost-Effectiveness of Device Therapy in the
Heart Failure Population, Heart Failure Society
of America Annual Meeting September 23, 2003.
85
Number Needed to Treat To Save A Life
NNTx years 100 / ( Mortality in Control Group
Mortality in Treatment Group)
Drug Therapy
amiodarone
ICD Therapy
simvastatin
Metoprolol succinate
captopril
(5 Yr) (2.4 Yr) (3 Yr)
(3 Yr) (3.5 Yr) (1 Yr)
(6 Yr) (2 Yr)
86
Cost of ICD Therapy
The cost/day of ICD therapy has dropped
dramatically due to reduced procedure costs,
reduced LOS (less invasive implant procedure due
to pectoral implants/endocardial leads, ) and
increased battery life.
Down by 85 Since 1990 !
Calculations and references in slide notes.
87
Can the US afford Expanding Indications For
ICD therapy?

• PERCEPTION
• Sudden cardiac arrest is not a major problem.
• ICDs are a last resort for patients who survive a
  sudden cardiac arrest.
• Millions of patients meet MADIT II criteria.
• ICDs are being over-utilized.
• The current health care system cannot support
  treating all these patients.

• REALITY
• SCA is the 1 cause of death in the U.S.
• Clinical evidence supports ICD as first-line
  therapy for prevention of SCA.
• Only a small fraction of post-MI survivors
  qualify for an ICD under MADIT II criteria
  (approximately 300,000).
• Very few indicated patients are actually
  receiving therapy today.
• The current health care system can afford to
  treat these patients.

88
ICD Therapy Prevents SCA

• Recognized as First Line Therapy to Prevent SCA
• ACC/AHA/NASPE 2002 Guidelines1
• Proven life-saving benefits for both VT/VF and
  high risk post-MI patients

• Gregoratos, G. et al. Circulation
  20021062145-2161.

89
Mortality Outcomes In ICD Trials
1 Moss AJ. N Engl J Med. 19963351933-40. 2
Buxton AE. N Engl J Med. 19993411882-90. 3 Moss
AJ. N Engl J Med. 2002346877-83
4 The AVID Investigators. N Engl J Med.
19973371576-83. 5 Kuck K. Circ.
2000102748-54. 6 Connolly S. Circ.
20001011297-1302.
90
A Closer Look at the Indicated Populations
91
Who are the High-Risk Post-MI Patients?Analysis
of Gross Prevalence Groups
Diagrams not to scale References in Slide Notes
Post- MI1 7,500k
EFEFEF)
EFPortion of MUSTT Not Part of MADIT II 95k
92
Millions of MADIT II Patients?Analysis of
Prevalence Groups
The incidence (annual new cases) of total
high-risk post-MI patients is estimated to be
70,000.

• 15 of the U.S. Population does not have access
  to healthcare. Health Insurance Coverage in the
  United States 2002 U.S. Census Bureau, Current
  Population Survey, 2002 and 2003 Annual Social
  and Economic Supplements.
• Of the remaining 85 who have access to health
  coverage, approximately 20 would not be
  considered for ICD therapy due to clinical
  exclusions (e.g., comorbidities, age, patient
  refusal, etc.) Source physician interviews.
• Not overlapping with MADIT II.
• Calculations in slide notes.

93
Overall U.S. ICD Utilization
66 ICDs Not Utilized
19 ICD Patients Followed (Past Implants)
34 ICDs Utilized
4ReplacementICDs
11 New ICDs
334,735 Potential ICD Candidates Class I
Indications
JCE 20021338-43.
94
Number of Potential ICD Therapy Candidates in
the US
1 Ruskin, N. J Cardiovascular Electrophysiologic,
20021338-43. 2 Medtronic internal estimate.
Weighted average of Class I and Class IIa
penetration estimates.
95
Putting it in Perspective
96
Magnitude of SCA in the US
SCA claims more lives each year than these other
diseases combined
167,366
Stroke3
450,000
SCA 4
Lung Cancer2
157,400
Breast Cancer2
40,600
1 Killer in the U.S.
42,156
AIDS1
1 U.S. Census Bureau, Statistical Abstract of
the United States 2001. 2 American Cancer
Society, Inc., Surveillance Research, Cancer
Facts and Figures 2001. 3 2002 Heart and Stroke
Statistical Update, American Heart Association. 4
Circulation. 20011042158-2163.
97
Direct Medical Expenditures on Diseases with
High Mortality (2001 US)
Despite the higher number of SCD deaths, spending
is lower than for diseases with fewer annual
deaths.
1 Bozzette et al., 1998 2 http//www.cdc.gov/hiv/
stats.htm Accessed 2/04/2003 3
http//www.cancer.org/docroot/mit/content/mit_3_2x
_costs_of_cancer.asp Accessed 12/07/2002 4
Healthcare Financing Review, Medicare and
Medicaid Statistical Supplement, 2000
98
2001 US Expenditures 1,2 Selected CV Drugs and
ICD Therapy
Billion
Billions/Yearly
Billion
Billion
Billion
1 Medtronic ICD industry sales analysis. 2 IMS
America 2001 Pharmaceutical sales figures.
99
Comparison of Healthcare Costs
10.0
9.04
8.97
8.35
9.0
8.0
7.0
6.0
Annual Cost in Billions
5.0
4.0
2.30
3.0
2.0
1.0
0.0
ICD
PTCA
CABG
Statins
Medtronic estimations (total number of implants
x 30,000) Morgan Stanley Dean Witter Research
Report, 2001 / CMS reimbursement data. AHA 2002
/ Cowper, et al American Heart Journal.
143(1)1309.
100
Comparison of Healthcare Costs
350.0
294
300.0
11.6 Bestimated amount due to miscoding,
insufficient documentation, etc. in
Medicare (HCFA 2000 Financial Report)
250.0
Healthcare Administration1
200.0
Annual Cost in Billions
150.0
100
100.0
30
50.0
9
9
8
2
0.0
ICD
CABG
Statins
PTCA
Economic impact of over- prescribing antibiotics
Lost dollars from health care fraud, abuse and
waste
Medtronic estimations (total number of implants
x 30,000). Morgan Stanley Dean Witter Research
Report, 2001 / CMS reimbursement data. AHA 2002
/ Cowper, et al American Heart Journal.
143(1)1309. Pharmacy Times, Top 200 drugs
of 2000 2001. National Institute of Health,
Antimicrobial Resistance, NIAID Fact Sheet.
U.S. General Accounting Office 2001. 1
Woolhandler S, et al. Costs of Healthcare
Administration in the United States and Canada. N
Engl J Med 344, 2003 349 768-75.
101
2000 US Total Health Expenditures1.3 Trillion1
ICD Therapy 2.2 Billion

• 2.2 Billion spent on ICD Therapy2 - 0.17 of
  total US healthcare expenditures
• If ICD implants double, total ICD costs will
  remain a fraction of US healthcare costs

1 www.cms.hhs.gov/statistics/nhe/historical/t2.asp
2 ICD industry sales, implant, and follow-up
cost analysis. Medtronic data on file.
102
Societal Spending on Other Life-Saving
Interventions 1
1. Tengs TO, et al. Five-Hundred Life-Saving
Interventions and Their Cost-Effectivenss. Risk
Analysis, Vol. 15, No. 3, 1995.
103
Medical Device Cost-EffectivenessConclusions

• Cost-effectiveness studies conducted in the
  nascent period of device evolution are likely to
  present a worst-case scenario and can produce
  misleading conclusions.
• High front end costs of implants require that
  economic analyses consider the life-time benefits
  of the therapy.
• Cost-effectiveness metrics generally indicate
  medical devices compare favorably to other
  accepted treatments.

104
Conclusions The US Can Afford ICD Therapy

• In the US, SCA is the 1 cause of death.
• ICD therapy is an accepted first line therapy to
  prevent SCA.
• Clinical evidence supports the benefit of ICD
  therapy for both primary and secondary prevention
  of SCA.
• ICD therapys cost effectiveness is in line with
  other widely accepted cardiovascular therapies.
• ICD therapy represents only a small fraction of
  US healthcare system expenditures.