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2CARDIMACARDIMA®®
FDA Advisory Panel MeetingFDA Advisory Panel Meeting
May 29, 2003May 29, 2003
Cardima®, Inc.Linear Ablation REVELATION® Tx Microcatheter RF Ablation System
3CARDIMACARDIMA®®
Indications for UseIndications 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.
4CARDIMACARDIMA®®
AgendaAgenda
Treatment Options for Atrial Fibrillation Corporate Profile Pre-clinical Studies Protocol Development/Validation Clinical Data Presentation Conclusions
5CARDIMACARDIMA®®
Treatment Options for Atrial FibrillationTreatment Options for Atrial Fibrillation
G. Neal Kay, M.D.Professor of Medicine
Director of ElectrophysiologyUniversity of Alabama at Birmingham
Birmingham, AL
6CARDIMACARDIMA®®
US and AF Age DistributionUS and AF Age Distribution
Feinberg WM. Arch Intern Med 1995;155:469-473.
U.S. population
Population withatrial fibrillation
Age, yr
<5 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
>95
U.S. populationx 1000
Population with AFx 1000
30,000
20,000
10,000
0
500
400
300
200
100
0
7CARDIMACARDIMA®®
AHA/ACC Guidelines J Am Coll Cardiol. 2001;38:1231-1265.
Classification of Atrial FibrillationClassification of Atrial Fibrillation
ACC/AHA/ESC GuidelinesACC/AHA/ESC Guidelines
Persistent(Not self-terminating)
Paroxysmal(Self-terminating)
Permanent
First Detected
8CARDIMACARDIMA®®
d,l-Sotalol vs Placebo for AF/AFl:d,l-Sotalol vs Placebo for AF/AFl:Time to Symptomatic Recurrence of AF/AFlTime to Symptomatic Recurrence of AF/AFl
P values are vs placebo.Benditt Am J Cardiol 1999;84:270-277.
Placebo (n=69)
Sotalol 160 mg bid (n=62)
Sotalol 120 mg bid (n=63)
Sotalol 80 mg bid (n=59)
Time (days)
Rec
urre
nce-
Fre
e S
urvi
val
0.5
0.7
0.8
0.9
1.0
0.6
0.1
0.2
0.3
0.4
0.0
0 30 60 90 120 150 180 210 240 270 300 330 360 390
P=.029
P=.325
P=.018
9CARDIMACARDIMA®®
Canadian Trial of Atrial Fibrillation (CTAF)Canadian Trial of Atrial Fibrillation (CTAF)
* Excluded recurrence in first 21 days. Roy, et al NEJM 2000;342:913-920.
Pat
ient
s W
itho
utR
ecur
renc
e, %
100
80
60
40
20
0 1000
200 300 400 500 600
Amiodarone 10 mg/kg x 2 wk, 300 mg x 4 wk, 200 mg/d (n=201)
Propafenone 300-450 mg/d (n=101)
Sotalol 160 mg bid or 80 mg tid (n=101)
Days of Follow-up
10CARDIMACARDIMA®®
Antiarrhythmic DrugsAntiarrhythmic Drugs
CHF
AmiodaroneDofetilide
Non-Pharmacologic Options
Coronary Artery Disease
Sotalol
AmiodaroneDofetilide
HTN
LVFW > 1.4 cm
Yes No
Amiodarone Type 1C
AmiodaroneDofetilide
Sotalol
11CARDIMACARDIMA®®
I
AVFV1
HBE p
HBE dCS p
CS m
CS d
1-10
9-107-8
5-6
3-4
1-2
PV
12CARDIMACARDIMA®®
Circular Catheter in RSPVCircular Catheter in RSPV
Left Anterior Oblique Right Anterior Oblique
13CARDIMACARDIMA®®
Isolation of RSPVIsolation of RSPV
CARDIMACARDIMA®®
PV StenosisPV Stenosis
15CARDIMACARDIMA®®
Results of PV IsolationResults of PV Isolation
Oral, et al. Circulation 2002;105:1077.
16CARDIMACARDIMA®®
Bi-atrial Surgery Bi-atrial Surgery Better Outcome Than LA Alone Better Outcome Than LA Alone
Nogami – Page – Gaïta
30 - 60 %
Sueda
74 %
Melo
60 %
RA LA
80 - 95 %
Cox – Kosakai – Sueda RA LA
RA LA
RA LA
17CARDIMACARDIMA®®
How does surgery work?How does surgery work?
Cox JL, et al. Annals of Surg 1996;224:267
Prevention of PV triggers
Interruption of macroreentry
18CARDIMACARDIMA®®
Comparative ResultsComparative ResultsJapan 2000
0
10
20
30
40
50
60
70
80
Cox Maze 3 Kosakai-maze RA maze Compartment
AF +
AF -
87%
91%
49%55%
P<0.005
P<0.005
Pat
ient
s
19CARDIMACARDIMA®®
Cardima ProfileCardima Profile
20CARDIMACARDIMA®®
Since 1993 Cardima has been developing, manufacturing and marketing catheter based systems for the Electrophysiological field, exclusively.
The devices include the PATHFINDER™ family of mapping devices, the VENAPORT®, VUEPORT®, NAVIPORT® guiding catheters and the REVELATION® family of mapping and ablation systems.
Cardima BackgroundCardima Background
21CARDIMACARDIMA®®
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 BackgroundCardima Background
22CARDIMACARDIMA®®
Diagnostic Microcatheters PATHFINDER™ (1997) REVELATION® (1998) PATHFINDER™ mini (1998) TRACER™ (1999)
Guide Catheters VENAPORT® (1995) NAVIPORT® (1998) VUEPORT® (1998)
Surgical Ablation System (2002)
Cardima FDA Product Approval HistoryCardima FDA Product Approval History
23CARDIMACARDIMA®®
PATHFINDER™PATHFINDER™
PATHFINDER™ mini
PATHFINDER™
24CARDIMACARDIMA®®
Guide CathetersGuide Catheters
NAVIPORT® VUEPORT®
25CARDIMACARDIMA®®
REVELATIONREVELATION®® Series Series
REVELATIONREVELATION®® Tx Tx REVELATIONREVELATION®® Helix Helix
26CARDIMACARDIMA®®
Technology ComparisonTechnology Comparison
FEATURES REVELATION® TX CONVENTIONAL RF
Core Construction Angioplasty guidewire technology
Plastic tube
Manufacturing From the “outside-in” From the “inside-out”
Flexibility Very flexible and torqueable
Stiff, deflectable
Electrode Type Fine-wire coiled Sleeve
Ablation Electrode Number
Eight One
Lesion Type Linear Focal
Power Req’d 7-35 W 50-70 W
27CARDIMACARDIMA®®
Lesion Shape ComparisonLesion Shape Comparison
Conventional Endocardial“Hot Tip” Catheter
Cardima LinearCoil Electrode
Tip AblationElectrode Coil Ablation
Electrode
28CARDIMACARDIMA®®
Linear Lesion FormationLinear Lesion Formation
Coil AblationElectrode Thermocouple
29CARDIMACARDIMA®®
Pre-clinical StudiesPre-clinical Studies
Hugh Calkins, M.D.Professor of Medicine
Director of ElectrophysiologyThe Johns Hopkins Medical Center
Baltimore, MD
30CARDIMACARDIMA®®
Pre-Clinical StudiesPre-Clinical Studies
Biocompatibility
Compliant with applicable ISO 10993 requirements
Reliability
Compliant with Performance Testing requirements of Massi guidelines
31CARDIMACARDIMA®®
Animal StudiesAnimal Studies
David Keane, M.D. / Massachusetts General Hospital
Performance of REVELATION® Tx in Right Atrium of a Goat (n=7)
Mauricio Arruda, M.D.
Performance of REVELATION® Tx in the right atrium of a Canine (n=6)
RF Lesion Formation of REVELATION® Tx in Canine Thigh Muscle (n=2)
RF Ablation Using the NavAblator™ in the Right Atrium (n=6)
Sam Asirvatham, M.D.
Microcatheters Linear Lesion Transmurality (n = 14)
Hugh Calkins, M.D.
Prospective Comparison of Lesions… (n=10)
32CARDIMACARDIMA®®
Lesion ComparisonLesion Comparison
“Point-to-Point” Technology Cardima Linear Technology
33CARDIMACARDIMA®®
Linear Lesions vs. Tip Ablator LesionsLinear Lesions vs. Tip Ablator Lesions
MICROSystem
Standard RF Ablation P Value
Length (mm) 29.6 14.9 25 11.2 NS
Width (mm) 2.6 0.9 4.9 0.9 0.0001
Depth (mm) 2.4 0.8 2.1 0.5 NS
This slide will be revised to summarize my data Hugh Calkins, M.D., The Johns Hopkins
34CARDIMACARDIMA®®
“Can Microcatheters Produce Linear Lesions without Sacrificing Transmurality in the Canine Atrium?” Circulation 1999; 100(18):1-374Sam Asirvatham, M.D., Mayo Foundation
Need data slide of results of this study
35CARDIMACARDIMA®®
Protocol Development and Study DesignProtocol Development and Study Design
Hugh Calkins, M.D.Professor of Medicine
Director of ElectrophysiologyThe Johns Hopkins Medical Center
Baltimore, MD
36CARDIMACARDIMA®®
Indications for UseIndications 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.
37CARDIMACARDIMA®®
Protocol Development ChronologyProtocol Development Chronology1996 Initial Study Design Collaboration with MGH, FDA, CARDIMA®
1997 Phase Ia Mapping Study (PATHFINDER™ AF)
1998 Phase IIa Mapping and Ablation (REVELATION® Tx)
1998 Circulatory Systems Recommendations for Clinical Trial DesignAdvisory Panel for AF Studies
1998 Phase IIb Mapping and Ablation (REVELATION® Tx)
2000 Circulatory Systems Recommendations for Clinical Trial DesignAdvisory Panel for AF Studies
2002 Phase III Mapping and Ablation(REVELATION® Tx and
NAVABLATOR™)
38CARDIMACARDIMA®®
STUDY PARAMETER PANEL GUIDANCE CARDIMA STUDY
Trial Design Single Arm Non-Randomized
Control group Patient as control
Patient Population Failed 2 AADs or amiodarone
Baseline AF Two episodes over three months
FDA Advisory Panel Recommendations
39CARDIMACARDIMA®®
PARAMETER PANEL GUIDANCE CARDIMA STUDY
Long-Term Success
50-75% reduction in frequency of symptomatic AF episodes
Six months evaluation of therapy effectiveness
Safety Incidence of Major Complications
Quality of Life “Improved quality of life may be a very important outcome.”
FDA Advisory Panel Recommendations (cont’d…)
40CARDIMACARDIMA®®
Right atrial ablation using the Cardima linear ablation system to achieve:
Reduction of symptomatic AF episodes
Relief of symptoms
Improvement in quality of life
Study ObjectiveStudy Objective
41CARDIMACARDIMA®®
Inclusion CriteriaInclusion Criteria
Three or more symptomatic AF episodes per month (documented by cardiac event monitor)
Refractory to two or more (AADs) or to amiodarone alone
Absence of significant structural heart disease, LA size < 5 cm
Absence of echocardiographic evidence (TEE) of intra-atrial thrombus, PFO, and/or ASD
42CARDIMACARDIMA®®
Acute ablation failure within 2 months
MI within 6 weeks
CVA or TIA within 6 months
Pregnancy
Coagulopathy or bleeding diathesis
Exclusion CriteriaExclusion Criteria
43CARDIMACARDIMA®®
Study SchemaStudy Schema
No Screen Failure Excluded From Study
Informed Consent
30-Day Baseline Monitoring
3 or more Symptomatic episodes?
Yes
TEEno thrombus?
Yes
RF Ablation
Pre-DischargeEvaluations
Follow-Up Evaluations
1 MonthVisit
3 MonthVisit
6 MonthVisit
12 MonthVisit
24 MonthPhone Contact
StudyComplete
44CARDIMACARDIMA®®
Assessment Study Interval
History, Physical Exam, 12-Lead EKG,
Telephone interview
Baseline, and office visits at 1, 3, 6 and 12 months post ablation
24 months
TEE Baseline
Echocardiogram and stress test
Cardiac Event Monitor
Baseline and 3 months
Weekly and symptomatic transmissions @ baseline, months 1 to 3 and month 6
Quality of Life Questionnaires Baseline, Months 3 and 6
Patient Follow-upPatient Follow-up
45CARDIMACARDIMA®®
Study EndpointsStudy 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
46CARDIMACARDIMA®®
Success CriteriaSuccess Criteria
Acute Procedural Success:
Reduction in amplitude, fragmentation or widening of local electrograms
Appearance of split potentials
Increase in pacing threshold
Primary Success:
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
47CARDIMACARDIMA®®
Success Criteria, cont’dSuccess Criteria, cont’d
Clinical Success
50% or more frequency reduction for subjects with 5 or more episodes in 30-day baseline period
75% or more frequency reduction for subjects with 3-4 episodes in 30-day baseline period.
While maintained on the same anti-arrhythmic drug regimen or a reduced dosage
48CARDIMACARDIMA®®
N=80 evaluable subjects at 6 months follow up
Based on estimated patient success rate
Statistical considerations with a clinical acceptable margin of error (SE=0.056)
This sample size was agreed to by the FDA
Sample SizeSample Size
49CARDIMACARDIMA®®
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.
SummarySummary
50CARDIMACARDIMA®®
Patient Population and Study ResultsPatient 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
51CARDIMACARDIMA®®
Rationale for a Right Atrial ProcedureRationale for a Right Atrial Procedure
Very likely lower risk than left atrial ablation
May be more widely applicable
If the risks are lower, physicians are likely to offer a right atrial ablation procedure to highly symptomatic patients even though the chances of success are lower
May have application in combination with left atrial ablation
52CARDIMACARDIMA®®
PRINCIPAL INVESTIGATOR CLINICAL INVESTIGATIONAL SITE
Ruey Sung, M.D. / Sung Chan, M.D. Stanford University Medical Center, Stanford, CAJeremy Ruskin, M.D. / David Keane, M.D. Massachusetts General Hospital, Boston, MAHugh Calkins, M.D. The Johns Hopkins Medical Center, Baltimore, MDDouglas Packer, M.D. Mayo Clinic, Rochester, MNTed Friehling, M.D. Inova Inst. of Research & Education, Falls Church, VARoger Marinchak, M.D./Douglas Esberg, M.D. Main Line Health Heart Center, Wynnewood, PADavid Wilber, M.D. University of Chicago, Chicago, ILBruce Hook, M.D. Catholic Medical Center, Manchester, NHSeth Worley, M.D. Lancaster Heart Foundation, Lancaster, PATimothy Talbert, M.D. Diagnostic Center, Chattanooga, TNSanjeev Saksena, M.D. Cardiac Medicine & Electrophysiology, Warren, NJAbraham Kocheril, M.D. Carle Heart Center, Urbana, ILLarry Chinitz, M.D. NYU Medical Center, New York, NYImran Niazi, M.D. Wisconsin Center for Clinical Research, Milwaukee, WIJose Nazari, M.D. Cardiac Arrhythmia Consultants, Ltd., Chicago, ILRandy Lieberman, M.D. Harper University Hospital, Detroit, MIRoger Winkle, MD Sequoia Hospital, Redwood City, CAEli Gang, M.D. Access Clinical Trials, Beverly Hills, CABruce Lerman, M.D. Cornell University Medical Center, New York, NYArjun Sharma, M.D. Regional Cardiology Associates, Sacramento, CA
20 Clinical Sites20 Clinical Sites
53CARDIMACARDIMA®®
Patient AccountabilityPatient Accountability
Ablatedn=120
Withdrew n=8
6 Months Post Ablation
n=87
<6 Months Post Ablation
n=18
Withdrewn=7
54CARDIMACARDIMA®®
Reason for Withdrawal # pts
Unable/Unwilling to do follow-up 4
Not included in effectiveness analysis (4)
AVN ablation and/or PPM implantation 4
Included in effectiveness analysis as failure (3)
Included in effectiveness analysis (1)
Patients Withdrawn Prior to Six MonthsPatients Withdrawn Prior to Six Months
55CARDIMACARDIMA®®
Demographic and Baseline CharacteristicsDemographic and Baseline Characteristics
Age, mean ± SD, years 56.9 ± 10.9
Male Gender 89 (77)
Cardiovascular Disease 84 (72)
Other Medical Conditions
Respiratory 30 (26)
Endocrine 30 (26)
Neurologic 22 (19)
Renal 21 (18)
56CARDIMACARDIMA®®
Prior Cardiac InterventionsPrior Cardiac Interventions
Type of Intervention Frequency (%)
RF Ablation 33 (28)CABG 9 (8)DC Cardioversion 8 (7)
Pacemaker 7 (6)
PTCA/Stent 5 (4)Angioplasty 2 (2)
57CARDIMACARDIMA®®
Breakdown of AblationsBreakdown of Ablations
(for 87 subjects with 6 mo FU)(for 87 subjects with 6 mo FU)
Prior RF Ablation Procedures Frequency (%)
Subjects with Prior RFCA 22/87 (25)
Types:
Atrial Flutter 22
Atrial Fibrillation 15
SVT/ Atrial Tachycardia 4
58CARDIMACARDIMA®®
Baseline Arrhythmia SymptomsBaseline Arrhythmia Symptoms
Symptoms Presence, n (%)
Palpitations 101 (87)
Fatigue 68 (59)
Shortness of Breath 58 (50)
Lightheadedness 43 (37)
Chest Pain 22 (19)
Other 34 (31)
59CARDIMACARDIMA®®
Baseline Symptomatic AFBaseline Symptomatic AFEpisodes Per MonthEpisodes Per Month
Mean, SD = 10.1 ± 8.9
32
45
17
9 85
0
10
20
30
40
50
3-4 5-9 10-14 15-19 20-29 30+
# Symptomatic AF Episodes Per Month
# P
atie
nts
Panel Recommended
2 Episodesper 3 Months
0.67
60CARDIMACARDIMA®®
SF-36 Mean Scores at BaselineSF-36 Mean Scores at BaselineStudy Group vs. US Population*Study Group vs. US Population*
78.475.1
70.6
81.1
67.5
61.2
82.9
76.272.7
69.6
37.5
66.3
60.4
44.9
71.374.4
0
10
20
30
40
50
60
70
80
90
100
PhysicalFunctioning
Role Physical Bodily Pain RoleEmotional
GeneralHealth
Vitality SocialFunctioning
MentalHealth
Mea
n S
core
(±
SE
)
US Study Group
* Adjusted for the age and gender distribution of the study group
61CARDIMACARDIMA®®
Study ResultsStudy Results
62CARDIMACARDIMA®®
Lesion LocationsLesion Locations
Post-LateralA
IsthmusC
SeptalB
AnteriorD
A – 90.3%B – 93.0%C – 90.3%D – 8.7%ABC – 82.6%
63CARDIMACARDIMA®®
Procedure TimesProcedure Times
Total TimeMean ± SD (minutes)
Procedural Time 250 ± 123
Fluoroscopy Time 47 ± 46
64CARDIMACARDIMA®®
Acute Procedural SuccessAcute Procedural Success
Investigator assessment of acute procedural success at the time of the procedure:
110/118 (93%) success
65CARDIMACARDIMA®®
Long Term ResultsLong Term 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%) successful
66CARDIMACARDIMA®®
Per-Subject Episode Reduction (n=81)Per-Subject Episode Reduction (n=81)
0
10
20
30
40
50
Baseline 6 Months
Num
ber
of E
piso
des
0
10
20
30
40
50
67CARDIMACARDIMA®®
Mean Episode Frequency Reduction (n=81)Mean Episode Frequency Reduction (n=81)
9.2
3.5
1.2
0
5
10
15
Baseline 3 Months 6 Months
Mea
n N
um
ber
of E
pis
od
es
68CARDIMACARDIMA®®
No symptomatic AF episodes at 6 months: n = 44/81 (54%)
AF episode ReductionAF episode Reduction
69CARDIMACARDIMA®®
Reduction in Common Arrhythmia SymptomsReduction in Common Arrhythmia Symptoms(Pre- vs. Six Months Post-RFA)(Pre- vs. Six Months Post-RFA)
34.5
20.7
30.5
87.4
49.4
57.5
11.5
16.1
41.4
21.819.5
25.3
0
10
20
30
40
50
60
70
80
90
100
Palpitations Fatigue Shortness ofBreath
Lightheadness Chest Pain Other
Sym
ptom
(%
)
Pre-
Post-
70CARDIMACARDIMA®®
Secondary EndpointSecondary Endpoint
Improvement in Quality of Life Scores
Atrial Fibrillation Severity Score (AFSS) SF-36
71CARDIMACARDIMA®®
AFSSAFSS(Pre- vs. Six Months Post-RFA)(Pre- vs. Six Months Post-RFA)
39.6
49.5
40.1
30.2
68.6**
56.4**52.4*
50.4**
0
10
20
30
40
50
60
70
80
Episode Frequency Episode Duration Episode Severity Total AFSS Score
Mea
n Sc
ore
(±SE
)
Pre- Post-
* p<0.0, ** p<0.0001, paired t-test
72CARDIMACARDIMA®®
SF-36 Mean ScoresSF-36 Mean ScoresBaseline vs. 6 MonthsBaseline vs. 6 Months
72.769.6 66.3
60.4
71.374.4
44.937.5
80.1b
59.6a
76.6c
61.8
76.9
82.8a
56.3a
75.8c
0
10
20
30
40
50
60
70
80
90
100
PhysicalFunctioning
Role Physical Bodily Pain RoleEmotional
GeneralHealth
Vitality SocialFunctioning
MentalHealth
Mea
n Sc
ore
(±
SE)
Baseline 6 Months
a p<0.0001, b p<0.01, c p<0.05, paired t-te st
73CARDIMACARDIMA®®
Effectiveness CohortsEffectiveness Cohorts
Baseline data 6 months follow-upn= 87
Evaluable for 1o effectiveness endpoint
n=81
Incomplete 6-month episode data
n=1
Ambiguous baseline episode data
n=5
74CARDIMACARDIMA®®
Effectiveness EvaluationEffectiveness Evaluation
Evaluable for 1o effectiveness endpoint
n=81
< 50% reduction in AF episodes
n=12 (14.8%)
≥ 50% reduction in AF episodes
n=69 (85.2%)
Decrease or No Change in AAD
n= 50
Increase in AADn=19
AVN ablationn= 2
AVN ablationn= 2
75CARDIMACARDIMA®®
Primary Endpoint - SafetyPrimary Endpoint - Safety
#2: Safety
FDA guidelines and OPCs for VT studies state 4% major complications
• FDA Definitions of Complications in VT studies used as this protocol’s definition.
Literature references of complications for other RFCA procedures cited for comparison range from 8.3% to 22.2%
Cardima’s complication rate in 120 treated patients = 3.3% for Major Complications
76CARDIMACARDIMA®®
Safety ResultsSafety Results
Device or Procedure Related* Major Complications
Frequency (%)
Upper 95% CI
Per Patient 4/120 (3%) 8%
Per Procedure (3 patients had a 2nd procedure)
4/123 (3%) 8%
* includes “uncertain” relatedness
77CARDIMACARDIMA®®
Major Complication Definition*Major Complication Definition*
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
78CARDIMACARDIMA®®
Major Complications (Acute)
Not major complications:1 pacemaker within 7d, but with documented preexisting sinus node dysfunction. Patients with pacemakers addressed later.
Pericardial Effusion with Arrhythmia (n=1)
Sinus Node Injury Requiring Pacemaker Implantation (n=1)
Stroke (n=1)
AV Fistula (n=1)
79CARDIMACARDIMA®®
Late Adverse EventsLate Adverse Events
Adverse Event Total
AVN Ablation/Permanent Pacemaker 6
Cardioversion 2
Infection (URI, UTI) 2
Sinus Node Dysfunction 1
Stroke (>1yr FU) 1
Other 41
Total 53
AEs Reported by 31/120 (27%) study subjects
80CARDIMACARDIMA®®
Details of “Other” Adverse EventsDetails of “Other” Adverse Events
Symptom Total Symptom Total
Skin Burns/Irritation 6 Back Pain & Nausea 1
Sore Throat 4 Dehydration 1
Back Pain 2 Discomfort 1
Bleeding (at incision)2
Groin Pain 1
Hematoma2 Increased
Palpitations1
Hospitalization (INR & ataxia)
2Pauses Asystolic 1
Increased Weakness2
Phlebitis 1
Pericarditis2
Pulmonary Hypertension (post PPM)
1
Shortness Of Breath & Chronic Fatigue
2Swelling (right hand) 1
Supraventricular Tachycardia
2Asthma 1
Thigh Numbness2 Upper Respiratory
Infection1
Atrial Flutter1 Urinary Tract
Infection1
81CARDIMACARDIMA®®
Late Adverse Events SummaryLate Adverse Events Summary
No reports of:
Mortality
Bleeding
Cardiac Perforation
AV Fistula or arterial injury
Thromboembolism
73% reported no complications
82CARDIMACARDIMA®®
STUDY ENDPOINT DEFINITION # PTs (%)
Effectiveness
Primary Endpoint ≥ 50% Reduction in Frequency of sAF episodes at 6 Months
69/81 (85)
Clinical Success Reduction in sAF episodes While Maintained on Same AAD Regimen or Reduced Dosage
50/81 (62)
Quality of Life
Secondary Endpoint
1) SF-36 2) AFSS Statistically Significant QOL Improvements
Safety
Major Complications
Serious Adverse Events ≤7 Days Post Procedure
4/120 (3.3)
Summary ResultsSummary Results
83CARDIMACARDIMA®®
Study LimitationsStudy Limitations
Catheters/Lesion Sets
Pacemakers
Clinical Success
Antiarrhythmic drugs
TTM Compliance
84CARDIMACARDIMA®®
Catheters/Lesion Sets
REVELATION® Tx used for all lateral and septal lines to create linear barriers to arrhythmias
4 mm Conventional RFA catheters used for Flutter Lines
Cardima NAVABLATOR™ introduced in Phase III
No significant difference in outcome
Historical data do not support flutter line alone curing AF
85CARDIMACARDIMA®®
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.
Catheters/Lesion Sets
86CARDIMACARDIMA®®
A, B & D LinesA, B & D Lines REVELATION® Tx (n=73)n=73)
Isthmus lineIsthmus line NAVABLATOR™*(n=28)
REVELATION® Tx (n=17)
Other** (n=28)
TotalTotal(n=73)(n=73)
Primary Success1 21/28 (75) 16/17 (94) 26/28 (93) 63/73 (86)
Episode Reduction2 6.0 ± 10.8 8.6 ± 6.1 10.0 ± 10.6 8.2 ± 9.8
Percent Episode Reduction2
76.6 ± 33.5 91.4 ± 16.6 89.1 ± 18.5 84.5 ± 26.1
1 Primary success, 50+% reduction in episodes as per protocol, freq/n, %2 mean ± SD
* Includes 2 subjects treated with the REVELATION® Tx and the NAVABLATOR™
** Includes 20 subjects treated with REVELATION® Tx or the NAVABLATOR™ and “Other”
Primary Endpoint SuccessPrimary Endpoint Success(Episode Reduction) by Flutter Line Device(Episode Reduction) by Flutter Line Device
87CARDIMACARDIMA®®
Pacemakers – Safety RelationshipPacemakers – Safety Relationship
3 Pacemakers Shortly After Procedure
All 3 had known preexisting sinus node dysfunction
II b 802: HR 49 when in SR
II b 607: sinus pauses, 34 episodes to 1 at 6 mo
III 1411: sinus brady, 3 sec pauses, 6 to 1
Not major complications – sinus node dysfunction unmasked by AF ablation
Not likely to have damaged SA node by ablation
88CARDIMACARDIMA®®
Pacemakers – Effectiveness RelationshipPacemakers – Effectiveness Relationship
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 ppm’s fall into this category
Patients with pacemakers not excluded from study
89CARDIMACARDIMA®®
Pacemaker OutcomesPacemaker Outcomes
Total Post Procedure Device ImplantsTotal Post Procedure Device Implants 2020
Post Procedure Device Implants <6monthsPost Procedure Device Implants <6months 1313
PPM for pre-existing SSS or bradyPPM for pre-existing SSS or brady 66 2 WD2 WD
ICD for Sinus Node injury at Tx (not WD)ICD for Sinus Node injury at Tx (not WD) 11 Reported as AEReported as AE
DDDR for AV block & NSVTDDDR for AV block & NSVT 11Due to dofetilide Due to dofetilide from pre-studyfrom pre-study
AVN/PPM <6 moAVN/PPM <6 mo 55
Flutter ablation + AVN/PPM (no sAF Flutter ablation + AVN/PPM (no sAF reported prior to Txreported prior to Tx
11WD (moved to WD (moved to another city)another city)
Insurance coverage changed, new Dr. Insurance coverage changed, new Dr. recommended AVN/PPMrecommended AVN/PPM
11 WD <6 moWD <6 mo
Treatment failuresTreatment failures 33
90CARDIMACARDIMA®®
Baseline data 6 months follow-upn= 87
Evaluable for 1o effectiveness endpoint
n=81
Incomplete 6-month episode data
n=1
< 50% reduction in AF episodes
n=12 (14.8%)
Ambiguous baseline episode data
n=5
≥ 50% reduction in AF episodes
n=69 (85.2%)
Decrease or No Change in AAD
n= 50
AVN ablationn= 2
Increase in AADn=19
AVN ablationn= 2
Effectiveness ResultsEffectiveness Results
91CARDIMACARDIMA®®
Percentage Of Patients Who Achieved Long Term Percentage Of Patients Who Achieved Long Term
Success Including “Failures" Success Including “Failures"
Subject GroupsSuccess (sAF )
n % - 3 failures, - 5 patients with
indeterminate baseline episodes69/81 85
+ 3 failures, + 5 with indeterminate baseline episodes
73/89 82
92CARDIMACARDIMA®®
Clinical Success at Six MonthsClinical Success at Six Months
Reduction in sAF episodes while maintained on the same anti-arrhythmic drug regimen or a reduced dosage
Result: 50/81 study subjects (62%) had a reduction in AF episodes with either no change or a decrease in AAD regimen.
93CARDIMACARDIMA®®
Late Follow Up StatusLate Follow Up Status
DescriptionDescription 12 months n=6112 months n=61 24 months n=3024 months n=30
NSRNSR
AEsAEs
MortalityMortality
AADsAADs
94CARDIMACARDIMA®®
AADsAADs
Primary endpoint was reduction in AF frequency independent of AAD use (69/81)
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, 19/69 had “increase” in AADs
Given current information on the efficacy of AADs, it is difficult to determine a true increase in an AAD regimen
95CARDIMACARDIMA®®
* 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 failureCAD= coronary artery diseaseLVH= left ventricular hypertrophy
Treatment Algorithm for AFTreatment Algorithm for AF
Heart disease?
No (or minimal*)
FlecainidePropafenone
Sotalol
Amiodarone, Dofetilide
DisopyramideProcainamide
Quinidine
Considernonpharmacologic
options
Yes+
HF
AmiodaroneDofetilide
Sotalol
AmiodaroneDofetilide
DisopyramideProcainamide
Quinidine
CADHypertention
LVH greater thanor equal to 1.4 cm
Yes No
Amiodarone FlecainidePropafenone
AmiodaroneDofetilide
Sotalol
Disopyramide, Procainamide, Quinidine
96CARDIMACARDIMA®®
Patients with Decrease/No Change in AADsPatients with Decrease/No Change in AADs
(n=60)(n=60)
36 patients had decrease in AADs at 6 months
6 patients were off AADs at 6 months
18 patients had no change in AADs at 6 months
97CARDIMACARDIMA®®
Patients with Increased AADs (n=21)Patients with Increased AADs (n=21)
19 had reduction in sAF 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 > 50% reduction in episodes
98CARDIMACARDIMA®®
Changes in AADsChanges in AADs
AmiodaroneAmiodarone
Membrane Active Drug
Membrane Active
Drug
Rate Control Drug
Rate Control
Drug
12 (10, 1, 1*)
Baseline 6 Months
21 19(17, 1, 1*)
52 47(37, 10)
21(19, 2)
14
54
739
3
11 (9, 2*)
(31, 8)
(3, 2)
(7, 0)
(3, 0)
(4, 0)
(6, 0)
6
* (Success, Failure) One patient with unknown # sAF at 6 months
99CARDIMACARDIMA®®
Patient Success by AAD Use at Six MonthsPatient Success by AAD Use at Six Months
0
10
20
30
40
50
60
70
80
90
100
Decrease (n = 36) No Change (n = 24) Increase (n = 21)
Baseline to Six Month AAD Use
Per
cent
Suc
cess
100CARDIMACARDIMA®®
Transtelephonic Event MonitoringTranstelephonic Event Monitoring
Three redundant mechanisms for symptomatic episode monitoring
Transtelephonic event monitoring
Investigator interrogation at scheduled assessment intervals
AFSS questionnaire
101CARDIMACARDIMA®®
Record and transmit each symptomatic episode
Transmit at least weekly (with or without symptoms)
Perform as above at 1, 3 and 6 months post ablation
Transtelephonic Event Monitoring ProtocolTranstelephonic Event Monitoring Protocol
102CARDIMACARDIMA®®
Baseline TTMBaseline TTM
Patients were blinded to required number of sAF episodes for study eligibility
TTMs reviewed by independent cardiologist to verify sufficient sAF episodes for study eligibility
103CARDIMACARDIMA®®
sAF Assessment at 6 MonthssAF Assessment at 6 Months
TTMTTM
Capture both spontaneous and scheduled Capture both spontaneous and scheduled transmissionstransmissions
Arrhythmic events/CRFArrhythmic events/CRF
Documentation of AF frequency and severityDocumentation of AF frequency and severity
EKGEKG
AFSS questionnaireAFSS questionnaire
Documentation of AF frequency and severityDocumentation of AF frequency and severity
104CARDIMACARDIMA®®
TTM ComplianceTTM Compliance
DescriptionBaseline (n=86) 6 Months (n=65*)
Mean, SD Range Mean, SD Range
# Transmissions per Month 15.5 ± 11.4 5-53 3.9 ± 2.4 1-11
% Symptomatic AF Episodes per Transmission
57.4 ± 24.4 0-100 29.5 ± 35.6 0-100
# Symptomatic AF Episodes per Month
9.0 ± 8.9 0-50 1.3 ± 2.1 0-11
* 22 subjects did not transmit recordings at six months. All had EKG/Office Visit at 6 month FU
* One subject not included
105CARDIMACARDIMA®®
3.9
15.5
0
2
4
6
8
10
12
14
16
18
Baseline 6 Months
Tra
nsm
issi
ons/
Mon
th
All Transmissions
% Symptomatic AF Episodes /Transmission
57.4%
29.5%
TTM ComplianceTTM Compliance
106CARDIMACARDIMA®®
AssessmentAssessment # Pts Completed # Pts Completed
(n=81)(n=81)
TTM *TTM * 60 (74%)60 (74%)
Arrhythmia SymptomsArrhythmia Symptoms 80 (99%)80 (99%)
EKGEKG 80 (99%)80 (99%)
AFSS QuestionnaireAFSS Questionnaire 74 (91%) 74 (91%)
* 21/81 pts did not transmit at all during 6-month post ablation
TTM ComplianceTTM Compliance
Patient Compliance with 6-Month Assessments Patient Compliance with 6-Month Assessments of Arrhythmic Eventsof Arrhythmic Events
107CARDIMACARDIMA®®
51.2 50.7
69.8
57.452.6
64.6
55.6
47.9
0
10
20
30
40
50
60
70
80
Episode Frequency Episode Duration Episode Severity AFSS Total
AF
SS
Me
an
Sco
re
Did Transmit
Did Not Transmit
AFSS Mean Scores at Six MonthsAFSS Mean Scores at Six Monthsby Six-Month Transmission Complianceby Six-Month Transmission Compliance
108CARDIMACARDIMA®®
Summary of Study ResultsSummary 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
This moderate level of success was accomplished with a very low risk of serious complications
109CARDIMACARDIMA®®
Study StrengthsStudy 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
110CARDIMACARDIMA®®
Risk : BenefitRisk : 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
111CARDIMACARDIMA®®
Conclusions Conclusions
Effectiveness
Reduction in sAF episodes at 6 mo 69/81 (85%)
No sAF at 6 months 44/81 (54%)
Off all AADs 6/81 (7 %)
Reduction in AADs 36/81 (86%)
Off amiodarone 9/81 (11% )
Quality of Life
Significant improvements
Safety
No Mortality 0/120
Major Complications 4/120 (3%)
112CARDIMACARDIMA®®
Conclusions 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 > 50% of symptomatic AF episodes in treated patients
113CARDIMACARDIMA®®
Closing RemarksClosing Remarks
G. Neal Kay, M.D.Professor of Medicine
Director of ElectrophysiologyUniversity of Alabama at Birmingham
Birmingham, AL
114CARDIMACARDIMA®®
SummationSummation
AF a significant clinical challenge
Maze lesions
Protocol development
Clinical Results
Future technology requirements
115CARDIMACARDIMA®®
Current Clinical NeedCurrent Clinical Need
Catheter with Approved indication for AF
Safe
116CARDIMACARDIMA®®
REVELATIONREVELATION®® Tx Tx