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FDA Advisory Panel MeetingMay 29, 2003

• Cardima, Inc.
• Linear Ablation REVELATION Tx Microcatheter RF
  Ablation System

3
Panel Presentation

• Corporate Profile Marianne Baldwin
• Treatment Options for Atrial Fibrillation
  Neal Kay, M.D.
• Pre-clinical Studies Hugh Calkins, M.D.
• Protocol Development Hugh Calkins, M.D.
• Clinical Study Results Abe Kocheril, M.D.
• Conclusions Neal Kay, M.D.

4
Indications for Use

• Cardima, Inc., REVELATION Tx Microcatheter
  Ablation System is indicated for the treatment of
  atrial fibrillation in patients with drug
  refractory paroxysmal atrial fibrillation by
  mapping, pacing, and ablating with a set of
  continuous linear lesions in the right atrium.

5
Cardima Background

• Since 1993 Cardima has been developing,
  manufacturing and marketing catheter-based
  systems for the Electrophysiological field,
  exclusively.
• The catheters include the PATHFINDER family of
  mapping devices, the VENAPORT, VUEPORT and
  NAVIPORT guiding catheters and the REVELATION
  family of mapping and ablation systems.

6

• Currently the company is marketing its diagnostic
  and guiding catheters in the USA, Canada, EU (CE
  Mark) and Japan.
• The REVELATION mapping and ablation family of
  devices is marketed in Canada and EU (CE Mark).

Cardima Background
7
Cardima Commercially Available Products (US)

• Diagnostic Microcatheters
• PATHFINDER (1997)
• PATHFINDER mini (1998)
• REVELATION (1998)
• TRACER (1999)
• Guide Catheters
• VENAPORT (1995)
• NAVIPORT (1998)
• VUEPORT (1998)
• Surgical Ablation System (2002)

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PATHFINDER Mapping Catheter
9
REVELATION Series
10
Guide Catheter
8Fr deflectable lumen catheter
11
Technology Comparison
12
Lesion Shape Comparison
Conventional Endocardial Hot Tip Catheter
Cardima Linear Coil Electrode
13
Linear Lesion Formation
Coil Ablation Electrode
Thermocouple
14
Treatment Options for Atrial Fibrillation

• G. Neal Kay, M.D.
• Professor of Medicine
• Director of Electrophysiology
• University of Alabama at Birmingham
• Birmingham, AL

15
US and AF Age Distribution
U.S. populationx 1000
Population with AFx 1000
Population withatrial fibrillation
30,000 20,000 10,000 0
500 400 300 200 100 0
U.S. population
lt5
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
gt95
Age, yr
Feinberg WM. Arch Intern Med 1995155469-473.
16
Classification of Atrial FibrillationACC/AHA/ESC
Guidelines
J Am Coll Cardiol. 2001381231-1265. Fuster V,
Rydén LE, Asinger RW, et al. ACC/AHA/ESC
guidelines for the management of patients with
atrial fibrillation a report of the American
College of Cardiology/American Heart Association
Task Force on Practice Guidelines and the
European Society of Cardiology Committee for
Practice Guidelines and Policy Conferences
(Committee to Develop Guidelines for the
Management of Patients With Atrial Fibrillation.)
J Am Coll Cardiol. 2001381231-1265.
17
d,l-Sotalol vs Placebo for AF/AFlTime to
Symptomatic Recurrence of AF/AFl
P values are vs placebo.Benditt Am J Cardiol
199984270-277.
18
Canadian Trial of Atrial Fibrillation (CTAF)
Excluded recurrence in first 21 days. Roy,
et al NEJM 2000342913-920.
19
Antiarrhythmic Drugs
CHF
Coronary Artery Disease
HTN
LVFW gt 1.4 cm
Sotalol
Amiodarone Dofetilide
Yes
No
Amiodarone Dofetilide
Amiodarone
Type 1C
Amiodarone Dofetilide Sotalol
Non-Pharmacologic Options
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Right Sided Approach to AF

• These results demonstrate that there is a place
  for right sided treatment of AF
• Cardima has demonstrated this approach in a
  clinical study

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Pre-clinical Studies

• Hugh Calkins, M.D.
• Professor of Medicine
• Director of Electrophysiology
• The Johns Hopkins Medical Center
• Baltimore, MD

22
Pre-Clinical Studies

• Biocompatible
• Compliant with applicable ISO 10993 requirements
• Reliable
• Compliant with mechanical and electrical
  performance requirements of Massi guidelines

23
Animal Studies

• Studies submitted in support of PMA
• David Keane, M.D. / Massachusetts General
  Hospital
• Performance of REVELATION Tx in Right Atrium of
  a Goat (n7)
• Mauricio Arruda, M.D. / University of Oklahoma
• Performance of REVELATION Tx in the right atrium
  of a Canine (n6)
• RF Lesion Formation of REVELATION Tx in Canine
  Thigh Muscle (n2)
• RF Ablation Using the NavAblator in the Right
  Atrium (n6)
• Additional independent studies performed..

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Right Atrial Multipolar Catheter Ablation
of Atrial Fibrillation in a Pace-Induced Goat
Model Keane D, Guerrero L, Ettelson L, McGovern
B, Ruskin JJACC 199732A.

• 8 goats
• AF (gt 5 min) inducible at baseline
• 4 linear lesions with Cardima microcatheters
• AF no longer inducible in 8 of 8 goats
• Transmural linear lesions were achieved

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Can Microcatheters Produce Linear Lesions without
Sacrificing Transmurality in the Canine Atrium?
Asirvatham S, Mayo Foundation Circulation 1999
100(18)1-374

• 14 dogs
• Linear right and left atrial lesions with Cardima
  microcatheters
• 30 linear lesions with 8 pole 3.7 Fr
  microcatheters
• 36 linear lesions with 10 pole 4mm ablation
  catheter

Ablation Strategy Cardima vs Stnd multipolar abl
catheter Width 4.21 vs 5.4
1.6 Depth 1.4 0.6 versus 1.3 0.7 Volume 29
15 versus 42 62 Lesion formation 98 vs
95 Transmural lesion 89 vs 85
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NavAblator Canine Study University of
Oklahoma Mauricio Arruda

• 6 dogs
• NavAblator catheter for isthmus ablation
• Lesion length 20 30 mm
• Lesion depth 1.0 to 3.5 mm
• Complete linear isthmus lesion in 5 of 6 dogs

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Prospective Comparison of Lesions Created Using a
Multipolar Microcatheter Ablation System with
Those Created Using a Pullback Approach with
Standard RF Ablation In the Canine Atrium
Jumrussirikil P, Atiga W, Lardo A, Berger R,
Halperin H, Hutchins G, Calkins HPACE 2000
23203-213.

• 10 dogs
• 4 with standard pullback approach
• 6 with Cardima microcatheters
• 4 linear lesions intercaval, septal, flutter,
  anterior lines
• One month to animal sacrifice
• Compared lesion size and shape and complications

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Linear Atrial Ablation Using the Drag and Burn
Technique
Jumrussirikil et al PACE 2000 23203-213.
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Linear Atrial Ablation Using the Cardima
Multielectrode Ablation Catheter
Jumrussirikil et al PACE 2000 23203-213.
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Comparison of Lesion Width
Width of Lesion(mm)
?
4.9
2.6
? p lt 0.05
Jumrussirikil et al PACE 2000 23203-213.
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Comparison of Lesion Length
p 0.NS
Jumrussirikil et al PACE 2000 23203-213.
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Comparison of Lesion Depth
Depth of Lesion(mm)
2.4
2.1
Jumrussirikil et al PACE 2000 23203-213.
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Comparison of Lesions Linearity
?
25 in 25 lesions (100)
6 in 16 lesions (37)
Multipolar Microcatheter
Pullback Approach
? p lt 0.05
Jumrussirikil et al PACE 2000 23203-213.
34
Comparison of Lesion Continuity
Continuous 18/25 (72)
Continuous 6/16(37)
?
Multipolar Microcatheter
Pullback Approach
? p lt 0.05
Jumrussirikil et al PACE 2000 23203-213.
35
Comparison of Lesion Anchoring to an
Anatomic Structure
Anchor 23/25 (92)
Anchor 10/16 (62)
?
Multipolar Microcatheter
Pullback Approach
? p lt 0.05
Jumrussirikil et al PACE 2000 23203-213.
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Conclusions

• 1) Atrial lesions created using MICRO
• are narrower, more continuous, more
  linear, and more likely to be anchored to an
  anatomic structure than those created with STND.
• 2) These differences in lesions characteristics
  may facilitate cure of atrial fibrillation with a
  catheter based MAZE procedure.

Jumrussirikil et al PACE 2000 23203-213.
37
Rationale for a Right Atrial Procedure

• Very likely lower risk than left atrial ablation
• May be more widely applicable
• With lower risks, physicians are likely to offer
  a right atrial ablation procedure to highly
  symptomatic patients

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Protocol Development and Study Design

• Hugh Calkins, M.D.
• Professor of Medicine
• Director of Electrophysiology
• The Johns Hopkins Medical Center
• Baltimore, MD

39
Indications for Use

• The Cardima Inc., REVELATION Tx Microcatheter
  Ablation System is indicated for the treatment of
  atrial fibrillation in patients with drug
  refractory paroxysmal atrial fibrillation by
  mapping, pacing, and ablating with a set of
  continuous linear lesions in the right atrium.

40
Protocol Development Chronology

• Initial Study Design Collaboration with MGH,
  FDA, CARDIMA
• Phase Ia Mapping Study (PATHFINDER AF)
• Phase IIa Mapping and Ablation (REVELATION Tx)
• Circulatory Systems Recommendations for Clinical
  Trial Design
• Advisory Panel for AF Studies
• Phase IIb Mapping and Ablation (REVELATION Tx)
• Circulatory Systems Recommendations for Clinical
  Trial Design
• Advisory Panel for AF Studies
• 2000 Phase III Mapping and Ablation
• (REVELATION Tx and NAVABLATOR)

41
FDA Advisory Panel Recommendations
3 episodes per month
42
FDA Advisory Panel Recommendations (contd)
43
Study Objectives

• Reduction in symptomatic AF episodes
• Safety
• Improvement in quality of life

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Inclusion Criteria

• Three or more symptomatic AF episodes per 30 days
  (documented by cardiac event monitor)
• Refractory to two or more (AADs) or to
  amiodarone alone
• Absence of significant structural heart disease,
  LA size lt 5 cm
• Absence of echocardiographic evidence of
  intra-atrial thrombus, PFO, and/or ASD on TEE

45
Exclusion Criteria

• Acute ablation failure within 2 months
• MI within 6 weeks
• CVA or TIA within 6 months
• Pregnancy
• Coagulopathy or bleeding diathesis

46
Study Schema
47
Patient Follow-up
48
Study Endpoints

• Primary clinical endpoints
• Frequency of spontaneous symptomatic AF episodes
• Incidence of adverse effects

• Secondary clinical endpoint
• Quality of life based on the SF-36 and the AFSS

49
Success Criteria

• Acute Procedural Success
• Reduction in amplitude, fragmentation or widening
  of local electrograms
• Appearance of split potentials
• Increase in pacing threshold

50
Success Criteria, contd

• Primary Endpoint
• ?50 reduction in AF episodes for patients with
  ? 5 AF episodes per month
• ?75 reduction in AF episodes for patients with
  ? 3-4 AF episodes per month
• Clinical Success
• Reduction in AF episodes as specified above
• While maintained on the same anti-arrhythmic
  drug regimen or a reduced dosage

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Sample Size

• N80 evaluable subjects at 6 months follow up
• Based on estimated patient success rate
• Statistical considerations with a clinically
  acceptable margin of error (SE0.056)
• This sample size was specified in the FDA
  approved protocol

52
Summary

• Multiple animal studies have demonstrated safe
  creation of thin , transmural, linear ablation
  lesions
• Clinical study was designed in collaboration with
  the FDA
• Clinical study incorporates a large number of
  measures of safety and efficacy
• As the first AF clinical trial this study is
  charting new waters

53
Patient Population and Study Results

• Abraham G. Kocheril, M.D.
• Head of Cardiac Electrophysiology,
• Carle Heart Center.
• Associate Professor of Medicine,
• University of Illinois COM at U-C,
• Urbana, IL

54
20 Clinical Sites
55
Patient Accountability
Ablated n120
Withdrew lt6 months, n8
?6 Months Post Ablation n87
lt6 Months Post Ablation n18
Withdrew gt6 months n7
56
Effectiveness Cohorts
57
Patients Withdrawn Prior to Six Months (n8)
one patient included in effectiveness analysis
58
Demographic and Baseline Characteristics
59
Prior Cardiac Interventions
60
Breakdown of Ablations(for 87 subjects with 6 mo
FU)
61
Baseline Arrhythmia Symptoms
62
Baseline Symptomatic AFEpisodes Per Month
Mean, SD 10.1 8.9
63
SF-36 Mean Scores at Baseline Study Group vs. US
Population
Adjusted for the age and gender distribution of
the study group
64
Study Results
65
Lesion Locations
66
Procedure Times
67
Acute Procedural Success

• Surrogate for clinical effectiveness
• Initial plans to record specific measurements of
  acute procedural success became unwieldy
• Investigator assessment of acute procedural
  success at the time of the procedure
• 110/118 (93)

68
Six Month Results

• Primary Endpoint
• ?50 reduction for pts with ? 5 sAF episodes per
  month
• ?75 reduction for pts with 3-4 sAF episodes
  per month
• Results
• 69/81 (85) met this endpoint

69
Per-Subject AF Episode Reduction (n81)
70
No symptomatic AF episodes at 6 months 44/81
(54)
AF Episode Reduction
71
Mean Episode Frequency Reduction (n81)
72
Reduction in Common Arrhythmia Symptoms(Pre- vs.
Six Months Post-RFA)
73
Secondary Endpoint

• Improvement in Quality of Life Scores
• Atrial Fibrillation Severity Score (AFSS)
• SF-36

74
AFSS(Pre- vs. Six Months Post-RFA)
75
SF-36 Mean Scores Baseline vs. 6 Months
76
Major Complications

• An adverse event that occurs within 7 days
  following investigational procedure and
• Is life-threatening
• Results in permanent impairment or damage to a
  body structure
• Requires significant intervention to prevent
  permanent impairment
• Requires hospitalization or an extended hospital
  stay
• Results in moderate transient impairment or
  damage to a body structure
• Requires intervention such as medication or
  cardioversion to prevent permanent impairment or
  damage to a body structure

FDA definition of acute major complications for
catheter ablation studies
77
Major Complications 4 /123 (3.3)

• Pericardial effusion requiring pericardial window
  one week post ablation
• Sinus node injury requiring pacemaker
  implantation
• Stroke 4 days post ablation
• AV Fistula

Not major complication 1 pacemaker within 7d,
but with documented preexisting sinus node
dysfunction. Patients with pacemakers addressed
later.
78
Adverse Events during Follow-up31/120 patients
(27)
79
Other Adverse Events
80
Adverse Events during Follow-upSummary

• No reports of
• Mortality
• Cardiac Perforation
• AV Fistula or arterial injury
• Thromboembolism
• 73 reported no adverse events

81
Summary Results
82
Issues for Clarification

• Catheters/Lesion Sets
• Pacemakers
• Clinical Success Antiarrhythmic Drugs
• TTM Compliance

83
Lesion Sets
84
Catheters/Lesion Sets

• REVELATION Tx used for all non-isthmus linear
  lesions
• REVELATION Tx linear catheter could ablate some
  but not all flutter isthmus.
• Thus, investigators used clinically available 4
  mm tip ablation catheters to create the flutter
  line
• NavAblator catheter developed for Phase III
• Some investigators preferred use of their
  standard 4 mm catheters

85
Catheters/Lesion Sets

• Phase III FDA required that a conventional 4mm
  tip ablation catheter be specified.
• Cardima manufactured the NAVABLATOR to be
  specified as part of the system, solely for the
  creation of the flutter line at the isthmus
  when the anatomy was not compatible with the
  REVELATION Tx linear electrode array.

86
Pacemakers

• Per protocol Subjects electing to receive
  implantable ppms prior to 6 mo f/u will be
  considered failures.
• Intent subjects should not require adjunctive
  pacemaker therapy to address AF
• Not all pts receiving ppms fall into this
  category
• Patients with pacemakers not excluded from study

87
Pacemakers
88
Pacemakers

• 3 Pacemakers shortly after procedure
• All 3 had known preexisting sinus node
  dysfunction
• Pt.1 HR 49 when in SR no AVN ablation
• Pt.2 sinus pauses, 34 episodes to 1 at 6 mo no
  AVN ablation
• Pt.3 sinus brady, 3 sec pauses, 6 to 1 no AVN
  ablation
• Not major complications

89
Percentage Of Patients Who Achieved Six Month
Success Including Failures"
90
Clinical Success Antiarrhythmic Drugs

• Primary endpoint was reduction in AF frequency
  independent of AAD use (69/81, 85)
• Study population was drug refractory (avg. 3) and
  had concomitant medical conditions
• Clinical Success defined per protocol
  Reduction in sAF episodes while maintained on
  the same anti-arrhythmic drug regimen or a
  reduced dosage
• As determined by clinical site, 19 of the 69
  successful patients had an increase in AADs
• Thus, the clinical success rate is 50/81 (62)
• Given current information on the efficacy of
  AADs, it is difficult to determine a true
  increase in an AAD regimen

91
Clinical Success Antiarrhythmic Drugs
92
Changes in AADs from BL to 6 Months (n87)
6 Months
Baseline
19 (17, 1, 1)
12
(10, 1, 1)
21
Amiodarone
5
(7, 0)
4
(3, 2)
Membrane Active Drug
7
47 (37, 10)
39
(31, 8)
52
(3, 0)
6
(4, 0)
Rate Control Drug
3
21 (19, 2)
(6, 0)
14
11
(9, 2)
(Success/Failure) 1 patient with unknown sAF
at 6 months
93
Changes AADs from BL to 6 Months for 23
Increases
6 Months
Baseline
4
4
6
Amiodarone
Membrane Active Drug
2
12
15
15
1
Rate Control Drug
3
2
4
1
2/23 had indeterminate baseline episode
frequencies. 21/23 patients were considered
successes.
94
Clinical Success Antiarrhythmic DrugsPatients
with Increased AADs (n21)

• 19 had reduction in AF episodes (success)
• 10/19 show a 100 reduction in sAF episodes at 6
  months with increases to an AAD regimen to
  which they were previously refractory
• The remaining 9/19 had gt 50 reduction in episodes

95
Clinical Success Antiarrhythmic Drugs Patient
Success by AAD Use at Six Months
96
Treatment Algorithm for AF
Sotalol or beta-blockers are the initial drugs
of choice for adrenergic AFIB. Consider
nonpharmacologic options to maintain sinus rhythm
if drug failure occurs. HF heart failure CAD
coronary artery disease LVH left ventricular
hypertrophy
97
Patients with Decrease/No Change in AADs(n60)

• 36 patients had decrease in AADs at six months
• 6 patients were off AADs at 6 months
• 28 patients had no change in AADs

98
Transtelephonic Event Monitoring

• Three redundant mechanisms for symptomatic
  episode monitoring
• TTM (to capture both spontaneous and scheduled
  transmissions)
• Arrhythmic events reports (CRFs)
• Clinical history at baseline, 1, 3, 6, and 12
  months to document reports of AF frequency and
  severity
• EKG at baseline, 1, 3, and 6 months
• AFSS questionnaire
• Additional documentation of AF frequency and
  severity

99
Transtelephonic Event Monitoring

• Record and transmit each symptomatic episode
• Transmit at least weekly (with or without
  symptoms)
• Perform as above at baseline 1, 3 and 6 months
  post ablation

100
Transtelephonic Event Monitoring

• Patients were blinded to number of AF episodes
  required for study eligibility
• TTMs reviewed by independent cardiologist to
  verify sufficient AF episodes for study
  eligibility

101
Transtelephonic Event Monitoring

• 22 subjects did not transmit recordings at six
  months.
• All had EKG/Office Visit at 6 month FU
• One subject not included

102
Transtelephonic Event Monitoring
103
Transtelephonic Event Monitoring
Patient Compliance with 6-Month Assessments of
Arrhythmic Events
104
AFSS Mean Scores at Six Monthsby Six-Month
Transmission Compliance
105
Issues for Clarification

• Although this study design, while consistent with
  the recommendations of the FDA Advisory Panel,
  has some inherent limitations compared to a
  controlled, randomized study (CRT), Cardima
  believes it is unlikely that the patient
  improvements seen in these study results could be
  attributable individually or collectively to the
  effects of these limitations

106
Study Summary

• Effectiveness
• Reduction in AF episodes at 6 mo 69/81
  (85)
• No AF at 6 months 44/81 (54)
• Clinical success 50/81 (62)
• Off all AADs 6/81 (7 )
• Reduction in AADs 36/81 (44)
• Quality of Life Significant improvements
• Safety
• Mortality 0/120 (0)
• Major Complications 4/120 (3)

107
Closing Remarks

• G. Neal Kay, M.D.
• Professor of Medicine
• Director of Electrophysiology
• University of Alabama at Birmingham
• Birmingham, AL

108
Conclusion

• The REVELATION Tx linear ablation system is safe
  and effective in treatment of patients with
  paroxysmal atrial fibrillation in the absence of
  significant structural heart disease.

109
Study Strengths

• Robust Study Design - Patients acted as their own
  control
• Study consistent with FDA Advisory Panel
  recommendations
• Use of TTM provided an objective measure of
  therapy success
• Use of subjective measures of therapy
  effectiveness (i.e., QOL) captured important
  patient parameters
• Study demonstrated excellent safety profile
• Study demonstrated clinically meaningful
  improvement in patient outcomes

110
Summary of Study Results

• This is the first multicenter clinical trial of
  catheter ablation for atrial fibrillation to be
  completed
• Right atrial linear ablation offers a level of
  success for control of paroxysmal atrial
  fibrillation
• Most patients continued on AADs at the same or
  lower dose
• AF did not appear to worsen in most PAF pts, as
  is the natural history of the disease
• This level of success was accomplished with a
  very low risk of serious complications

111
The Atrial Fibrillation Challenge

• PV isolation is effective in about 2/3 of
  patients with paroxysmal AF
• The risks are significant and include
• PV stenosis - 1-8 and is related to experience
• Stroke 1-4
• Tamponade - 1-4
• Major bleeding - 2-3
• Limited to physicians competent to perform
  transeptal catheterization
• There have been no multicenter prospective trials
  of PVI

112
Risk Benefit

• The lower risks of this relatively simple
  procedure are likely to allow it to be performed
  by a wider range of physicians than a complex
  left atrial ablation procedure
• It is likely that a simple right atrial ablation
  procedure will be offered to patients with highly
  symptomatic paroxysmal atrial fibrillation before
  more risky techniques

113
Conclusions

• REVELATION Tx is a new RF catheter ablation
  technology specifically designed to create linear
  lesions in the right atrium
• Provides an important treatment option for many
  patients with drug refractory paroxysmal AF
• Addresses currently unmet public health need for
  safe and effective treatment of AF, a disease of
  great clinical significance to the medical
  community, both in terms of patient suffering and
  high medical costs of treating AF and its
  clinical sequelae
• This technology has been demonstrated to
  eliminate gt 50 of symptomatic AF episodes in
  treated patients

114
REVELATION Tx