®. cardima ® 1 fda advisory panel meeting may 29, 2003 cardima ®, inc. linear ablation revelation...

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)



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


HTN

LVFW > 1.4 cm

Yes No

Amiodarone Type 1C


Sotalol


I

AVFV1

HBE p

HBE dCS p

CS m

CS d

1-10

9-107-8

5-6

3-4

1-2

PV


Circular Catheter in RSPVCircular Catheter in RSPV

Left Anterior Oblique Right Anterior Oblique


Isolation of RSPVIsolation of RSPV

CARDIMACARDIMA®®

PV StenosisPV Stenosis


Results of PV IsolationResults of PV Isolation

Oral, et al. Circulation 2002;105:1077.


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


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


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


Cardima ProfileCardima Profile


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


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


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


PATHFINDER™PATHFINDER™

PATHFINDER™ mini

PATHFINDER™


Guide CathetersGuide Catheters

NAVIPORT® VUEPORT®


REVELATIONREVELATION®® Series Series

REVELATIONREVELATION®® Tx Tx REVELATIONREVELATION®® Helix Helix


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


Lesion Shape ComparisonLesion Shape Comparison

Conventional Endocardial“Hot Tip” Catheter

Cardima LinearCoil Electrode

Tip AblationElectrode Coil Ablation

Electrode


Linear Lesion FormationLinear Lesion Formation

Coil AblationElectrode Thermocouple


Pre-clinical StudiesPre-clinical Studies

Hugh Calkins, M.D.Professor of Medicine

Director of ElectrophysiologyThe Johns Hopkins Medical Center

Baltimore, MD


Pre-Clinical StudiesPre-Clinical Studies

Biocompatibility

Compliant with applicable ISO 10993 requirements

Reliability

Compliant with Performance Testing requirements of Massi guidelines


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)


Lesion ComparisonLesion Comparison

“Point-to-Point” Technology Cardima Linear Technology


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


“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


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


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.


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™)


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


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…)


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


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


Acute ablation failure within 2 months

MI within 6 weeks

CVA or TIA within 6 months

Pregnancy

Coagulopathy or bleeding diathesis

Exclusion CriteriaExclusion Criteria


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


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


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


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


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


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


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


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


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


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


Patient AccountabilityPatient Accountability

Ablatedn=120

Withdrew n=8

6 Months Post Ablation

n=87

<6 Months Post Ablation

n=18

Withdrewn=7


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


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)


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)


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


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)


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


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


Study ResultsStudy Results


Lesion LocationsLesion Locations

Post-LateralA

IsthmusC

SeptalB

AnteriorD

A – 90.3%B – 93.0%C – 90.3%D – 8.7%ABC – 82.6%


Procedure TimesProcedure Times

Total TimeMean ± SD (minutes)

Procedural Time 250 ± 123

Fluoroscopy Time 47 ± 46


Acute Procedural SuccessAcute Procedural Success

Investigator assessment of acute procedural success at the time of the procedure:

110/118 (93%) success


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


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


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


No symptomatic AF episodes at 6 months: n = 44/81 (54%)

AF episode ReductionAF episode Reduction


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-


Secondary EndpointSecondary Endpoint

Improvement in Quality of Life Scores

Atrial Fibrillation Severity Score (AFSS) SF-36


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


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


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


Effectiveness EvaluationEffectiveness Evaluation


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


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


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


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


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)


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


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


Late Adverse Events SummaryLate Adverse Events Summary

No reports of:

Mortality

Bleeding

Cardiac Perforation

AV Fistula or arterial injury

Thromboembolism

73% reported no complications


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


Study LimitationsStudy Limitations

Catheters/Lesion Sets

Pacemakers

Clinical Success

Antiarrhythmic drugs

TTM Compliance



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


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.



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


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


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


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


Baseline data 6 months follow-upn= 87


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


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


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.


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


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


* 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


Sotalol


DisopyramideProcainamide

Quinidine

CADHypertention

LVH greater thanor equal to 1.4 cm

Yes No

Amiodarone FlecainidePropafenone


Sotalol

Disopyramide, Procainamide, Quinidine


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


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


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


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


Transtelephonic Event MonitoringTranstelephonic Event Monitoring

Three redundant mechanisms for symptomatic episode monitoring

Transtelephonic event monitoring

Investigator interrogation at scheduled assessment intervals

AFSS questionnaire


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


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


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


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


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%



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


Patient Compliance with 6-Month Assessments Patient Compliance with 6-Month Assessments of Arrhythmic Eventsof Arrhythmic Events


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


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


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


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


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%)


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


Closing RemarksClosing Remarks

G. Neal Kay, M.D.Professor of Medicine

Director of ElectrophysiologyUniversity of Alabama at Birmingham

Birmingham, AL


SummationSummation

AF a significant clinical challenge

Maze lesions

Protocol development

Clinical Results

Future technology requirements


Current Clinical NeedCurrent Clinical Need

Catheter with Approved indication for AF

Safe


REVELATIONREVELATION®® Tx Tx

®. cardima ® 1 fda advisory panel meeting may 29, 2003 cardima ®, inc. linear ablation revelation...

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