FDA Advisory Panel

1
Medtronic InSync ICD Cardiac Resynchronization
System

• FDA Advisory Panel
• March 5, 2002

2
Agenda
3
Introduction and Background

• William T. Abraham, MD

4
Introduction

• Over a third of moderate to severe heart failure
  patients (in NYHA Functional Class III or IV)
  have ventricular dysynchrony, evidenced by a QRS
  duration ? 130 ms1
• Associated with
• Limited exercise tolerance
• Impaired quality of life and functional capacity
• Poor left ventricular systolic function2

1 Aaronson KD, et al. Circulation 1997
952660-2667. 2 Zardini M, et al. Eur Heart J
2000 2(Suppl J) J16-J22
5
InSync Study Design
Implant Attempt
Successful Implant
Pre-discharge Randomization
Baseline
? 1 week
Stable Medical Therapy
Double Blinded
Control
CRT
1, 3, 6 Month Follow-up
1, 3, 6 Month Follow-up

• Control VDI mode
• Treatment (CRT) VDD mode

CRT
CRT
Long term follow up every 6 months
6
InSync Study Primary Endpoints
PMA P010015, approved 8/28/01
7
InSync Study Secondary Clinical Endpoints
8
InSync Primary Safety Results Summary

• Achieved all primary 6-month safety objectives
  including
• Implant success
• 6-month device related complications attributed
  to
• InSync Model 8040
• Attain Models 2187 and Model 2188 LV leads
• InSync system
• Attain Models 2187 and 2188 LV lead 6-month
  pacing threshold

9
InSyncDeath or Worsening Heart Failure
RequiringHospitalization or IV Medications
P 0.02
CRT
Control
Patients At Risk
10
Combining Resynchronization and ICD Function in
a Single Device

• Model 7272 InSync ICD
• Dual-chamber VT and VF detection
• Antitachycardia (ATP) pacing, cardioversion and
  defibrillation VT and VF therapies
• Simultaneous biventricular pacing
• RV sensing only

11
Study Design, Methodology andPatient Population

• James B. Young, MD

12
Entry Criteria

• Chronic heart failure
• ? 18 years of age
• NYHA Functional Class II, III or IV
• QRS duration ? 130 ms
• LVEF ? 35
• LVEDD ? 55 millimeters (echo measure)
• Stable HF medical regimen for ? 1 month
• ACE-I or substitute, if tolerated
• ß-blocker - stable regimen for ? 3 months
• Indication for an ICD

13
InSync ICD Study Design
Implant Attempt
Successful Implant
Pre-discharge Randomization
Baseline
? 1 week
Stable Medical Therapy
Double Blinded
Control
CRT
1, 3, 6 Month Follow-up
1, 3, 6 Month Follow-up

• Control DDI mode
• Treatment (CRT) DDD mode
• ICD active in all patients
• Heart failure medication stability maintained

CRT
CRT
Long term follow up every 6 months
14
Timing of Baseline Tests
15
Study Features to Maintain the Blind

• Blinded
• Patients (study ID card)
• Heart failure staff
• Listed on study blinding log
• Blinded to ECGs
• Conducted QOL, 6 minute hall walk, patients
  global assessment, NYHA classification and HF
  exam
• Events Classification Committee
• Unblinded
• EP staff
• Listed on study blinding log
• Viewed ECGs, device printouts, etc
• Data placed into secure study envelopes

16
Primary Safety Objectives

• InSync ICD-related complication-free survival at
  3 months
• Attain Model 4189 LV lead-related
  complication-free survival at 6 months
• Attain Model 2187/2188 LV lead- related
  complication-free survival at 6 months
• InSync ICD system-related complication-free
  survival at 6 months

17
Secondary Safety Objectives

• Characterize patient survival
• Characterize complication events
• Characterize observation events

18
Lead Effectiveness Objectives

• Implant success
• Evaluate the electrical performance of the Model
  4189 LV lead
• Evaluate the electrical performance of the Model
  2187 and Model 2188 LV leads

19
Evaluation of Integrity of ICD Function

• Spontaneous VT/VF therapy effectiveness
• Comparison of VT/VF event rates in the control
  and treatment arms
• ATP therapy efficacy with biventricular pacing
• Implant ventricular defibrillation criterion

20
Primary Effectiveness Endpoints

• As pre-specified in the investigational plan for
  NYHA Class III and IV patients, the following
  change from baseline to 6-month visit between
  control and treatment groups in
• Quality of life (MLWHF Questionnaire)
• NYHA class
• 6-minute hall walk distance
• As pre-specified in the investigational plan, all
  3 endpoints must be met at P lt 0.05, or 2 met at
  P lt 0.025, or 1 met at P lt 0.0167

21
Secondary Effectiveness Endpoints

• Clinical endpoints
• Exercise performance
• Clinical composite response
• Health care utilization
• Physiological variables
• Echocardiographic variables
• QRS duration
• Neurohormonal variables

22
Study Milestones
PMA Update submitted November 9, 2001
PMA submitted May 3, 2001
1st implant October 4, 1999
100 NYHA Class III IV 6-month visitsMarch, 2001
224 NYHA Class III IV 6-month visitsOctober,
2001
23
Patient Disposition
As pre-specified in the I.P., data from NYHA
Class III/IV patients are discussed in this
presentation
Implant Attempts n636
NYHA Class III/IV n421
NYHA Class II n215
Randomized n362
Randomized n192
Control n176
CRT n186
Control n106
CRT n86
24
Patient Disposition
Implant Attempts n421
Unsuccessful Implants n50
Implant Success n371
Not Randomized n9
Randomized n362
Control n176
CRT n186
25
Patient Disposition
Control n 176
CRT n 186
26
Methodology Overview

• Safety Data
• As pre-specified in the investigational plan,
  data from NYHA Class II, III and IV patients were
  submitted to FDA for the primary safety
  objectives
• At FDAs request, safety data from NYHA Class III
  and IV patients only are included in the Panel
  Pack and in this presentation

27
Methodology Overview

• Efficacy Data
• The investigational plan pre-specified that the
  primary efficacy analysis was to be based on
  patients with paired data at 6 months, excluding
  crossovers
• Results presented are based on an intent-to-treat
  analysis for patients with paired data at 6
  months, including crossovers
• Results of the pre-specified crossover excluded
  and last-observation-carried forward analyses
  will also be summarized

28
Patient Demographics
29
Patient Demographics
30
Safety Results

• Angel R. Leon, MD

31
Primary Safety Objectives

• InSync ICD-related complication-free survival at
  3 months
• Attain Model 4189 LV lead-related
  complication-free survival at 6 months
• Attain Model 2187/2188 LV lead- related
  complication-free survival at 6 months
• InSync ICD system-related complication-free
  survival at 6 months

32
Secondary Safety Objectives

• Characterize patient survival
• Characterize complication events
• Characterize observation events

33
Lead Effectiveness Objectives

• Implant success
• Evaluate the electrical performance of the Model
  4189 LV lead
• Evaluate the electrical performance of the Model
  2187 and Model 2188 LV leads

34
Evaluation of Integrity of ICD Function

• Spontaneous VT/VF therapy effectiveness
• Comparison of VT/VF event rates in the control
  and treatment arms
• ATP therapy efficacy with biventricular pacing
• Implant ventricular defibrillation criterion

35
Lead Placement and LV Venous Anatomy
A. Lateral (marginal) cardiac vein B.
Postero-lateral cardiac vein C. Posterior
cardiac vein D. Middle cardiac vein E. Great
cardiac vein
A

• Attain LV Model 4189
• Transvenous, 4 French
• Stylet/catheter Delivered
• Unipolar

B
C
E
D
36
Adverse Event Definitions

• Complication An adverse event requiring invasive
  intervention or that results in the death of or
  serious injury to the patient or in the
  termination of a significant device function
• Observation An adverse event not requiring
  invasive intervention or resolves spontaneously
• System-related complication A device-related
  complication that occurs after the initially
  implanted functioning system, comprised of
  Model 7272 InSync ICD, a Model 4189, 2187 or 2188
  LV lead, and RA and RV leads

37
Implant Success
Patient Implant Attempts n421
Unsuccessful Implants n50
Implant Success n371
Implant success defined per the protocol as a
successfully placed LV lead.
38
Unsuccessful Implants (n50)
Not mutually exclusive
39
Adverse Events During the Implant Procedure
40
Resolution of Adverse Events During the Implant
Procedure
Categories not mutually exclusive.
41
Resolution of Implant Dissection/Perforation
Events

• 432 implant attempts
• 22 events (22 patients)

No patient deaths related to these events.
42
Primary Safety Objective 1 Freedom From InSync
ICD Related Complications at 3 Months

• 371 patients implanted
• 7 complications in 7 patients
• Observed 3-month rate 98.6
• Lower 95 confidence bound 97.6
• Performance objective 95 LCB ? 89

Performance Objective
43
Freedom From InSync ICD Related Complications at
3 Months

• 371 patients implanted
• 7 events (7 patients)

44
Primary Safety Objective 2 Freedom From Attain
Model 4189 LV Lead-Related Complications at 6
Months

• 315 patients implanted
• 49 events (in 44 patients)
• Observed 6-month rate 85.1
• Lower 95 confidence bound 81.7
• Performance objective 95 LCB ? 75

Performance Objective
45
Freedom From Attain Model 4189 LV Lead-Related
Complications at 6 Months

• 315 patients implanted
• 49 events (44 patients)

Not mutually exclusive
46
Attain Model 4189 LV Lead Related Complication
Event Resolution
Not mutually exclusive
47
Primary Safety Objective 3Freedom From Attain
Model 2187/2188 LV Lead-Related Complications at
6 Months

• 56 patients implanted
• 5 events in 5 patients
• Observed 6-month rate 89.9
• Lower 95 confidence bound 82.9
• Performance objective 95 LCB ? 75

Performance Objective
48
Freedom From Attain Model 2187/2188 LV
Lead-Related Complications at 6 Months

• 56 patients implanted
• 5 events (5 patients)

49
Primary Safety Objective 4InSync ICD
System-Related Complications at 6 Months

• 371 patients implanted
• 79 events in 65 patients
• Observed 6 month rate 81.1
• Lower 95 confidence bound 77.6
• Performance objective 95 LCB ? 67

Performance Objective
50
Primary Safety Results Summary

• All primary safety objectives satisfied
• Device-related complications attributed to
• InSync ICD Model 7272
• Attain Models 4189, 2187 and 2188 leads
• InSync ICD system

51
Secondary Safety Results
52
Spontaneous VT/VF Therapy Effectiveness

• VT terminated after all therapies were delivered
  (5 episodes)
• FVT/VT terminated after redetection but before
  additional therapies could be delivered (4
  episodes)
• VF terminated after all therapies were delivered
  (1 episode)

53
VT/VF Episodes Control vs. CRTPatients
Completing 6 Months of Follow-up
54
ATP Efficacy During Spontaneous VT
55
Ventricular Defibrillation Testing
56
Lead Effectiveness Results
57
Lead Effectiveness Objective 1Implant Success
Results

• Performance Objective
• Lower 95 Confidence Limit gt 83
• Results
• Observed rate 371 successes / 421 attempts
  88.1
• Lower Limit of 2-Sided 95 C.I. 84.6

Implant success defined per the protocol as a
successfully placed LV lead.
58
Lead Effectiveness Objective 2 Attain Model
4189 LV Lead Pacing Threshold Performance

• Performance Objective
• The upper 95 confidence bound for the mean
  pacing voltage threshold is lt 3.0 Volts
• Results
• Mean 6-month pacing threshold 1.5 Volts ? 0.9
  Volts
• Upper limit of 2-sided 95 confidence interval
  1.7 Volts

59
Voltage Pacing Threshold for Attain Model 4189 LV
Leads
n424
n416
n381
n306
n125
n35
n441
1.5
1.7
1.6
1.5
1.5
1.7
1.5
60
Lead Effectiveness Objective 3 Attain Model
2187/2188 LV Lead Pacing Threshold Performance

• Performance Objective
• The upper 95 confidence bound for the mean
  pacing voltage threshold is lt 3.0 Volts
• Results
• Mean 6-month pacing threshold 1.9 Volts ? 1.0
  Volts
• Upper limit of 2-sided 95 confidence interval
  2.2 Volts

61
Voltage Pacing Threshold for Attain Model
2187/2188 LV Leads
n82
n79
n74
n62
n29
n18
n79
1.6
1.7
2.3
1.9
1.7
1.7
1.9
62
Effectiveness Results

• James B. Young, MD

63
Primary Efficacy Endpoints
Change from baseline to 6-month follow up between
control and treatment groups in

• QOL score
• NYHA class
• 6 minute hall walk distance

64
Change in Quality of Life Score
P0.0098
Score (Median)
? -19
? -10
Control n 119
CRT n 128
65
Change in NYHA Functional Class
P0.028
66
Change in NYHA Functional Class
Control (n 123)
CRT (n 131)
67
Change in 6-Minute Hall Walk Distance
P0.408
Distance Walked (Median)
? 56
? 53
Control n 118
CRT n 122
68
Summary of Effect on Primary Endpoints
69
Secondary Effectiveness Results
70
Secondary Effectiveness Endpoints

• Clinical endpoints
• Exercise performance
• Clinical composite response
• Healthcare utilization
• Physiological variables
• Echocardiographic variables
• QRS duration
• Plasma neurohormones

71
Secondary Effectiveness ResultsClinical
Endpoints
72
Exercise PerformancePeak VO2 and Exercise
Duration
P0.05
Plt0.001
? 0.0
? -26
? 58
? 1.1
Control n 93
CRT n 96
Control n 96
CRT n 97
73
Clinical Composite Response - Definition

• Improved
• Improved NYHA class or global assessment
• Worsened
• Death worsening heart failure leading to
  hospitalization or permanent withdrawal of
  therapy or worsening of NYHA class or global
  assessment
• No Change

Packer et al. J Cardiac Failure 20017176-182.
74
Clinical Composite Response Results
P 0.038
75
Hospitalization ResultsTotal Days Hospitalized
Through 6 Months
All-Cause Hospitalization
Heart Failure Hospitalization
P 0.18
P 0.11
Control Group  134 hospitalizations
(79 pts) CRT Group  127
hospitalizations (75 pts)
Control Group  70 hospitalizations (47
pts) CRT Group  54
hospitalizations (39 pts)
76
InSync ICDDeath or Worsening Heart Failure
RequiringHospitalization or IV Medications
P 0.07
CRT
Control
Patients At Risk
77
Secondary Effectiveness ResultsPhysiological
Variables
78
Change in Echo Parameters
79
Change in Echo/ECG Parameters
80
Change in Neurohormone Levels
81
Comparison of InSync and InSync ICD

• William T. Abraham, MD

82
InSync ICD Study Design
Implant Attempt
Successful Implant
Pre-discharge Randomization
Baseline
? 1 week
Stable Medical Therapy
Double Blinded
Control
CRT
1, 3, 6 Month Follow-up
1, 3, 6 Month Follow-up

• Control DDI mode
• Treatment (CRT) DDD mode
• ICD active in all patients
• Heart failure medication stability maintained

CRT
CRT
Long term follow up every 6 months
83
Timing of Baseline Tests
84
Comparison of Patient Demographics InSync and
InSync ICD
85
Comparison of Patient Demographics InSync and
InSync ICD
86
Change in Quality of Life Score(InSync ICD vs.
InSync)
InSync
InSync ICD
P0.010
P0.003
87
Change in NYHA Class(InSync ICD vs. InSync)
InSync
InSync ICD
Plt0.001
P0.02
88
Change in 6-Minute Hall Walk Distance (InSync
ICD vs. InSync)
InSync
InSync ICD
P0.003
P0.408
89
InSync and InSync ICD StudiesPrimary Endpoints
White InSync Study Yellow InSync ICD Study
90
InSync and InSync ICD StudiesSecondary Clinical
Endpoints
White InSync Study Yellow InSync ICD Study
91
InSync ICDDeath or Worsening Heart Failure
RequiringHospitalization or IV Medications
P 0.07
CRT
Control
Patients At Risk
92
InSyncDeath or Worsening Heart Failure
RequiringHospitalization or IV Medications
P 0.02
CRT
Control
Patients At Risk
93
Hospitalization Results InSync ICDTotal Days
Hospitalized Through 6 Months
All-Cause Hospitalization
Heart Failure Hospitalization
P 0.18
P 0.11
Control Group  134 hospitalizations
(79 pts) CRT Group  127
hospitalizations (75 pts)
Control Group  70 hospitalizations (47
pts) CRT Group  54
hospitalizations (39 pts)
94
Hospitalization Results InSyncTotal Days
Hospitalized Through 6 Months
All-Cause Hospitalization
Heart Failure Hospitalization
P0.002
P0.083
Control Group  99 hospitalizations (60 pts)
CRT Group  80 hospitalizations (57 pts)
Control Group 39 hospitalizations (27 pts)
CRT Group  20 hospitalizations (14 pts)
95
The End