IMPLANTABLE DEFIBRILLATOR THERAPY

1
IMPLANTABLE DEFIBRILLATOR THERAPY

• Arthur J. Moss, MD
• University of Rochester Medical Cntr.
• Rochester, NY
• Advances in Heart Failure Management Drugs
  Devices
• November 16, 2002

2
DISCLOSURE INFORMATIONArthur J. Moss, MD

• Company Relationship
• Guidant Corporation Research Grant
• Medtronic, Inc. Research Grant
• Hold no stock or stock options in any device
  company. Not a member of any corporate advisory
  group or speakers bureau.

3
THE PROBLEM
NSCD 37

SCD 63



CDC Cardiac Deaths in the US (1999)
TOTAL 730,000 SCD 460,000
MMWR Feb. 15, 2002
4
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION
TRIAL-II (MADIT-II) 1997-2001 A randomized
trial to determine if prophylactic ICD therapy
saves lives in patients with prior MI and LVD
Supported by a research grant from Guidant Corp.
5
MADIT-II

• Trial started July 8, 1997
• Trial stopped November 20, 2001 by DSMB because
  ICD saved lives
• 1,232 patients enrolled from 76 centers in U.S.
  and Europe

6
MADIT-II Eligibility

• Chronic CAD with prior MI
• EFlt0.30
• No requirement for NSVT or EPS
• No upper age limitation

7
MADIT-II Exclusions

• MADIT-I indication
• NYHA Class IV at enrollment
• MI lt 1 month
• CABG lt 3 months
• Advanced organ system disease

8
MADIT-II Baseline Characteristics

• CONV DEFIB
• (n490) (n742)
• per cent
• Age gt 65 yrs 53 54
• Male 85 84
• Interval gt 5 yrs p MI 48 52
• Anterior MI 52 52
• Hx CABG 56 58
• Ejection Fraction 236 235
• NYHA CHF Class gt II 61 65
• No significant differences between CONV and
  DEFIB groups.

9
MADIT-II MEDS at Last Follow-Up

• CONV DEFIB
• (n490) (n742)
• percent
• ACE inhibitors 72 68
• Amiodarone 10 13
• Antiarrhythmics 2 3
• Beta-blockers 70 70
• Digitalis 57 57
• No significant differences in Rx of CONV and
  DEFIB groups

10
Kaplan-Meier Survival by Treatment Group
0.78
0.69
0.69
P0.007
(probability of survival)
(probability of survival)
11
Probability of Mortality
Probability of 1st VF Shock
CONV
ICD
12
Moss Daubert. NEJM 2000
13
MADIT-II Mortality by Rx Group

• CONV DEFIB
• (n490) (n742)
• no. of patients
• Deaths 97 19.8 105
  14.2
• ---------------------------------
• Hazard Ratio (ICDCONV) 0.69 (31 ? mortality)
• (95 CI) (0.51, 0.93)
• P-value 0.016

14
MADIT-II Mortality Events

• CONV ICD
• Pending 1 1
• Non-cardiac 22 25
• Cardiac 74 79
• Arrhythmia 48 28
• Non-arrhyth 22 45
• Unclassified 4 6
• TOTAL ( mortality) 97 (19.8) 105 (14.2)
• Arrhythmic death 48/4909.8
  28/7423.8

15
CARDIAC DEATHS MADIT-II
SCD 35
NSCD 30
SCD 65
NSCD 57
CONVENTIONAL GROUP
ICD GROUP
Mortality 19.8
14.2
16
Variable
No. of patients
Hazard Ratio
SUBGROUP ANALYSES
Age
lt65 yr
573

gt65 yr
659
Sex
Male
1040

Female
192
LVEF
lt0.25
831
gt0.25
401
NYHA Class
ltII
861
gtII
351
QRS
lt0.12s
597
0.12-0.15s
352
gt0.15s
262
Beta-blockers
Yes
844
No
388
All patients
1232
0.2 0.4 0.6 0.8 1.0 1.2 1.4
1.6
Defibrillator Better
Conventional Better
17
MADIT-II QRS DURATION(substudy)

• HR
• N ICDCT P-value
• Total Pop. 1232 0.69 0.016
• Subgroup Analysis
• RV pacer 98 0.99 0.98
• QRSlt0.12s 587 0.76
• QRS 0.12-0.15s 338 0.65
• QRS gt0.15s 188 0.37

Not significantly different from each other.
18
MADIT-II Subgroup QRSgt0.15sec
Hazard Ratio 0.37 P lt0.01
19
MADIT-II EPS INDUCIBILITY(substudy)

• What is the frequency of EP inducibility in the
  MADIT-II ICD pts.?
• What is the association between EP inducibility
  and ICD utilization for VT and VF?

20
MADIT-II EPS INDUCIBILITY

• Criteria for EP sustained MVT or PVT with lt3
  extrastimuli, or VF with lt2
• EPS in ICD group n583
• Inducible n210 (36)
• Non-inducible n373 (64)

21
EP Inducibility and ICD Therapy for VT
P0.01
22
EP Inducibility and ICD Therapy for VF
P0.02
23
MADIT-II EP INDUCIBILITY

• EP Paradox In high-risk coronary pts., EP
  inducibility is associated with increased risk
  for VT, but decreased risk for VF.
• Implications These findings raise serious
  question about the clinical usefulness of EP
  inducibility for selecting patients for ICD
  therapy. to identify pts. at risk for SCD.

24
MADIT-II in the Context of Other Clinical Trials
25
MADIT-II In Context with Drug Trials
Non-active Rx
Active Rx
330
P0.019
P0.016
22.6
19.8
18.2
Mortality ()
15
Plt0.01
14.2
PNS
9.8
9.0
8.0
7.2
0
BHAT
CASS
SAVE
MADIT-II
N3800
N780
N2231
N1232
HR0.73 HR0.89 HR0.81
HR0.69
26
SAVE
MADIT-II
SAVE
MADIT-II
N1232
N2231
CONV
Mortality Rate
DEFIB
Risk reduction 31 P 0.016
27
MADIT-II In Context with ICD Trials
Hazard Ratio
N196
MADIT-I
EFlt0.35, NSVT, EP
0.46
1996

N1016
AVID
Aborted Cardiac Arrest
0.62
1997
EFlt0.40, NSVT, EP
N704
MUSTT
0.45

1999
N1232
MADIT-II
Prior MI EFlt0.30
0.69
2002

0.6
0.8
1.0
1.2
1.4
1.6 1.8
0.4
ICD Better
28
MADIT-II CONCLUSIONS

• ICD saves lives in high-risk coronary patients
  with LVD
• ICD consistently effective in all MADIT-II
  subgroups, with greatest efficacy in pts. with
  QRS gt0.15s
• EP testing does not identify a high-risk subset
  who will benefit from ICD therapy
• FDA approved MADIT-II indication July 17, 2002