græmmede

®

2CARDIMACARDIMA®®

FDA Advisory Panel MeetingFDA Advisory Panel Meeting

May 29, 2003May 29, 2003

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

3CARDIMACARDIMA®®

Panel PresentationPanel 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.

4CARDIMACARDIMA®®

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.

5CARDIMACARDIMA®®

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.

Cardima BackgroundCardima Background

6CARDIMACARDIMA®®

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

7CARDIMACARDIMA®®

Diagnostic Microcatheters PATHFINDER™ (1997) PATHFINDER™ mini (1998) REVELATION® (1998) TRACER™ (1999)

Guide Catheters VENAPORT® (1995) NAVIPORT® (1998) VUEPORT® (1998)

Surgical Ablation System (2002)

Cardima Commercially Available Products (US)Cardima Commercially Available Products (US)

8CARDIMACARDIMA®®

PATHFINDER™ Mapping CatheterPATHFINDER™ Mapping Catheter

PATHFINDER™ mini

PATHFINDER™

9CARDIMACARDIMA®®

REVELATIONREVELATION®® Series Series

REVELATIONREVELATION®® Tx Tx

10CARDIMACARDIMA®®

Guide CatheterGuide Catheter

NAVIPORT®

8Fr deflectable lumen catheter


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


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


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


J Am Coll Cardiol. 2001;38:1231-1265. 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. 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


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


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


Antiarrhythmic DrugsAntiarrhythmic Drugs

CHF

AmiodaroneDofetilide

Non-Pharmacologic Options

Coronary Artery Disease

Sotalol


HTN

LVFW > 1.4 cm

Yes No

Amiodarone Type 1C


Sotalol


Right Sided Approach to AFRight Sided Approach to AF

These results demonstrate that there is a place for These results demonstrate that there is a place for right sided treatment of AFright sided treatment of AF

Cardima has demonstrated this approach in a Cardima has demonstrated this approach in a clinical studyclinical study


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

Biocompatible

Compliant with applicable ISO 10993 requirements

Reliable

Compliant with mechanical and electrical performance requirements of Massi guidelines


Animal StudiesAnimal Studies

Studies submitted in support of PMA

David Keane, M.D. / Massachusetts General Hospital

Performance of REVELATION® Tx in Right Atrium of a Goat (n=7)

Mauricio Arruda, M.D. / University of Oklahoma

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)

Additional independent studies performed………..


Right Atrial Multipolar Catheter Ablation ofAtrial Fibrillation in a Pace-Induced Goat Model

Keane D, Guerrero L, Ettelson L, McGovern B, Ruskin JJACC 1997;32A.

• 8 goats• AF (> 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


Can Microcatheters Produce Linear Lesions without Can Microcatheters Produce Linear Lesions without Sacrificing Transmurality in the Canine Atrium?Sacrificing Transmurality in the Canine Atrium?

Asirvatham S, Mayo FoundationCirculation 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 catheterWidth 4.2+1 vs 5.4 + 1.6Depth 1.4 + 0.6 versus 1.3 + 0.7Volume 29 +15 versus 42 + 62Lesion formation 98% vs 95%Transmural lesion 89% vs 85%


NavAblator Canine StudyNavAblator Canine StudyUniversity of OklahomaUniversity of Oklahoma

Mauricio ArrudaMauricio Arruda

• 6 dogs• NavAblator catheter for isthmus ablation

Lesion length: 20 – 30 mmLesion depth: 1.0 to 3.5 mmComplete linear isthmus lesion in 5 of 6 dogs


Prospective Comparison of Lesions Created Using a Multipolar Prospective Comparison of Lesions Created Using a Multipolar Microcatheter Ablation System with Those Created Using Microcatheter Ablation System with Those Created Using

a Pullback Approach with Standard RF Ablation a Pullback Approach with Standard RF Ablation In the Canine AtriumIn the Canine Atrium

Jumrussirikil P, Atiga W, Lardo A, Berger R, Halperin H, Hutchins G, Calkins HJumrussirikil P, Atiga W, Lardo A, Berger R, Halperin H, Hutchins G, Calkins HPACE 2000; 23:203-213.PACE 2000; 23:203-213.

• 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


Linear Atrial Ablation Using the Drag and Burn TechniqueLinear Atrial Ablation Using the Drag and Burn Technique

Jumrussirikil et al; PACE 2000; 23:203-213.


Linear Atrial Ablation Using the Cardima MultielectrodeAblation Catheter



0

1

2

3

4

5

6

MICRO STND

Wid

th o

f L

esio

n(m

m)

2.62.6

4.94.9

Comparison of Lesion Width

p < 0.05


CARDIMACARDIMA®®

29.4

21

0

10

20

30

40

50

60

70

80

Length (mm)

CardimaStnd RF

Comparison of Lesion Length

p = 0.NS



0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

MICRO STND

Dep

th o

f L

esio

n(m

m)

2.42.4

Comparison of Lesion Depth

2.12.1



Multipolar Microcatheter Pullback Approach

25 in 25 lesions (100%) 6 in 16 lesions (37%)

Comparison of Lesions Linearity

p < 0.05



Continuous 18/25 (72%)

Continuous 6/16(37%)

Comparison of Lesion Continuity


p < 0.05Jumrussirikil et al; PACE 2000; 23:203-213.


Anchor10/16 (62%)


Comparison of Lesion Anchoring to an Anatomic Structure

Anchor 23/25 (92%)

p < 0.05



ConclusionsConclusions

1) Atrial lesions created using MICRO1) Atrial lesions created using MICRO

are narrower, more continuous, more are narrower, more continuous, more

linear, and more likely to be anchored to an linear, and more likely to be anchored to an

anatomic structure than those created with anatomic structure than those created with

STND. STND.

2) These differences in lesions characteristics may 2) These differences in lesions characteristics may

facilitate cure of atrial fibrillation with a catheter facilitate cure of atrial fibrillation with a catheter

based MAZE procedure.based MAZE procedure.



Rationale for a Right Atrial ProcedureRationale 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


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


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

19981998 Phase IIbPhase IIb Mapping and Ablation Mapping and Ablation (REVELATION(REVELATION®® Tx) Tx)

2000 Circulatory Systems Recommendations for Clinical Trial DesignAdvisory Panel for AF Studies

2000 Phase IIIPhase III Mapping and AblationMapping and Ablation(REVELATION(REVELATION®® Tx and Tx and

NAVABLATORNAVABLATOR™™))


STUDY PARAMETER PANEL GUIDANCE CARDIMA STUDY

Trial Design Single Arm Non-Randomized

Control group Patient as own control

Patient Population Failed 2 AADs or amiodarone

Baseline AF Two episodes over three months *

FDA Advisory Panel Recommendations

* 3 episodes per month


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…)


• Reduction in symptomatic AF episodes

• Safety

• Improvement in quality of life

Study ObjectivesStudy Objectives


Inclusion CriteriaInclusion 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 < 5 cm

Absence of echocardiographic evidence of intra-atrial thrombus, PFO, and/or ASD on TEE


Acute ablation failure within 2 monthsAcute ablation failure within 2 months

MI within 6 weeksMI within 6 weeks

CVA or TIA within 6 monthsCVA or TIA within 6 months

PregnancyPregnancy

Coagulopathy or bleeding diathesisCoagulopathy or bleeding diathesis

Exclusion CriteriaExclusion Criteria


Study SchemaStudy Schema

YesYes Screen FailureScreen Failure Excluded From StudyExcluded From Study

Informed ConsentInformed Consent

30-Day Baseline Monitoring30-Day Baseline Monitoring

3 or more Symptomatic episodes?3 or more Symptomatic episodes?

YesYes

TEETEEThrombus?Thrombus?

NoNo

RF AblationRF Ablation

Pre-DischargePre-DischargeEvaluationsEvaluations

Follow-Up Evaluations at 1, 3, 6, 12, and 24 monthsFollow-Up Evaluations at 1, 3, 6, 12, and 24 months


AssessmentAssessment Study IntervalStudy Interval

History, Physical Exam, 12-Lead EKG

Baseline, and office visits at 1, 3, 6 and 12 months post ablation

TEE Baseline

Echocardiogram and stress test Baseline and 3 months

Cardiac Event Monitor Weekly and symptomatic transmissions @ baseline, months 1, 3, and month 6

Quality of Life Questionnaires Baseline, Months 3 and 6

Telephone interview 24 months

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


Success Criteria, cont’dSuccess Criteria, cont’d

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”


N=80 evaluable subjects at 6 months follow up

Based on estimated patient success rate

Statistical considerations with a clinically acceptable margin of error (SE=0.056)

This sample size was specified in the FDA approved protocol

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


INVESTIGATOR CLINICAL INVESTIGATIONAL SITE

Ruey Sung, M.D. Stanford University Medical Center, Stanford, CAJeremy Ruskin, 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./ 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 <6 months, n=8

6 Months Post Ablation

n=87

<6 Months Post Ablation

n=18

Withdrew >6 monthsn=7


Effectiveness CohortsEffectiveness Cohorts

Baseline data 6 months follow-Baseline data 6 months follow-upup

n= 87n= 87

Evaluable for Evaluable for 11oo effectiveness endpoint effectiveness endpoint

n=81n=81

Indeterminate 6-month Indeterminate 6-month episode dataepisode data

n=1n=1

Indeterminate Indeterminate baseline episode baseline episode

datadatan=5n=5


Reason for Withdrawal (n=8) # pts

Unable/Unwilling to do follow-up 4

AVN ablation and/or PPM implantation 4*

Patients Withdrawn Prior to Six Months (n=8)Patients Withdrawn Prior to Six Months (n=8)

* one patient included in effectiveness analysis


Demographic and Baseline CharacteristicsDemographic and Baseline Characteristics

CharacteristicCharacteristic Freq. (%)Freq. (%)

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 InterventionType of Intervention Freq. (%)Freq. (%)

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 ProceduresPrior RF Ablation Procedures Freq. (%)Freq. (%)

Subjects with Prior RFCA 22/87 (25)

Types:

Atrial Flutter 22

SVT/ Atrial Tachycardia 19


Baseline Arrhythmia SymptomsBaseline Arrhythmia Symptoms

Symptoms 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

# Pa

tient

s

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

82.976.2

72.769.6

37.5

66.3

60.4

44.9

71.374.4

0

10

20

30

40

50

60

70

80

90

100P

hysi

cal

Fu

nct

ion

ing

Role

Ph

ysi

cal

Bo

dil

y P

ain

Role

Em

oti

on

al

Gen

era

l H

ea

lth

Vit

ali

ty

So

cia

l

Fu

nct

ion

ing

Men

tal

Hea

lth

Mean

Sco

re

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 TimeTotal TimeMean ±Mean ± SD SD (minutes)(minutes)

Procedural Time 250 ± 123

Fluoroscopy Time 47 ± 46


Acute Procedural SuccessAcute 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%)


Six Month ResultsSix 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


Per-Subject AF Episode Reduction (n=81)Per-Subject AF 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


No symptomatic AF episodes at 6 months:

44/81 (54%)

AF Episode ReductionAF Episode Reduction


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

Me

an

Nu

mb

er

of

Ep

iso

de

s


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 S

core

(±S

E)

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

76.982.8a

56.3a

75.8c

0

10

20

30

40

50

60

70

80

90

100

PhysicalFunctioning

Role Physical Bodily Pain RoleEmotional

GeneralHealth

Vitality SocialFunctioning

Mental Health

Mea

n Sc

ore

( ± S

E)

Baseline 6 Months

a p<0.0001, b p<0.01, c p<0.05, paired t-test


Major Complications*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


Major Complications

4 /123 (3.3%)

Not major complication:1 pacemaker within 7d, but with documented preexisting sinus node dysfunction. Patients with pacemakers addressed later.

Pericardial effusion requiring pericardial window one week post ablation

Sinus node injury requiring pacemaker implantation

Stroke 4 days post ablation

AV Fistula


Adverse Events during Follow-upAdverse Events during Follow-up

31/120 patients (27%)31/120 patients (27%)

Adverse Event n

AVN Ablation/Permanent Pacemaker 6

Cardioversion 2

Infection (URI, UTI) 2

Sinus Node Dysfunction 1

Stroke (>1yr FU) 1

Other 41

Total 53


Other Adverse EventsOther Adverse Events

Symptom Total Symptom Total

Skin Burns/Irritation 6Back 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

2 Swelling (right hand)

1

Supraventricular Tachycardia

2Asthma 1

Thigh Numbness2 Upper Respiratory

Infection1

Atrial Flutter1 Urinary Tract

Infection1


Adverse Events during Follow-upAdverse Events during Follow-up

SummarySummary

No reports of:

Mortality

Cardiac Perforation

AV Fistula or arterial injury

Thromboembolism

73% reported no adverse events


STUDY ENDPOINT DEFINITION # PTs (%)

Effectiveness

Primary Endpoint ≥ 50/75% 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


Issues for ClarificationIssues for Clarification

Catheters/Lesion Sets

Pacemakers

Clinical Success & Antiarrhythmic Drugs

TTM Compliance


Lesion SetsLesion Sets

Post-LateralA

IsthmusC

SeptalB

AnteriorD

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



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


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.



PacemakersPacemakers

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


PacemakersPacemakers

Post Procedure Device ImplantsPost Procedure Device Implants nn

PPMs >6 monthsPPMs >6 months 77

PPMs < 6 monthsPPMs < 6 months 1313

PPM for pre-existing SSS or bradyPPM for pre-existing SSS or brady 66

ICD for Sinus Node injury at Tx (not WD)ICD for Sinus Node injury at Tx (not WD) 11

DDDR for AV block & NSVTDDDR for AV block & NSVT 11

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

1 1

Insurance coverage changed, new Dr. Insurance coverage changed, new Dr. recommended AVN/PPMrecommended AVN/PPM

11

Treatment failures (n=3)Treatment failures (n=3) 33

Total Post Procedure Device ImplantsTotal Post Procedure Device Implants 2020


Pacemakers 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


Percentage Of Patients Who Achieved Six Month Percentage Of Patients Who Achieved Six Month

Success Including “Failures" Success Including “Failures"

Subject GroupsSuccess (sAF )

n % - 3 failures, - 5 patients with

indeterminate baseline episodes69/81 85.2

+ 3 failures, + 5 with indeterminate baseline episodes

73/89 82.0



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



Evaluable for 1o effectiveness endpoint

n=81

< Req’d reduction in AF episodes

n=12 (14.8%)

≥ 50/75% 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


Changes in AADs from BL to 6 Months (n=87)Changes in AADs from BL to 6 Months (n=87)

Amiodarone

Membrane Active Drug

Rate Control Drug

12 (10, 1, 1*)

Baseline 6 Months

21 19(17, 1, 1*)

52 47(37, 10)

21(19, 2)

14

5

*(Success/Failure)1 patient with unknown # sAF at 6 months

4

739

3

11 (9, 2*)

(31, 8)(3, 2)

(7, 0)

(3, 0)

(4, 0)

(6, 0)

6


Changes AADs from BL to 6 Months for 23 “Increases* Changes AADs from BL to 6 Months for 23 “Increases*

Amiodarone

Membrane Active Drug

Rate Control Drug

4

Baseline 6 Months

4 6

15 15

24

212

3

1

1

* 2/23 had indeterminate baseline episode frequencies.** 21/23 patients were considered successes.



Patients with Increased AADs (n=21)Patients with Increased AADs (n=21)

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 > 50% reduction in episodes



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


* 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 AFHeart disease?

No (or minimal*)

FlecainidePropafenone

Sotalol

Amiodarone, Dofetilide

DisopyramideProcainamide

Quinidine

Considernonpharmacologic

options

Yes+

HF


Sotalol


DisopyramideProcainamide

Quinidine

CAD Hypertention

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 six months

6 patients were off AADs at 6 months

28 patients had no change in AADs


Transtelephonic Event MonitoringTranstelephonic Event Monitoring

Three Three redundantredundant mechanisms for symptomatic episode mechanisms for symptomatic episode monitoringmonitoring::

TTM (to capture both spontaneous and scheduled transmissions)TTM (to capture both spontaneous and scheduled transmissions)

Arrhythmic events reports (CRFs)Arrhythmic events reports (CRFs)

CClinical history at baseline, 1, 3, 6, and 12 months to to document reports of AF frequency and severitydocument reports of AF frequency and severity

EKG at baseline, 1, 3, and 6 monthsEKG at baseline, 1, 3, and 6 months

AFSS questionnaireAFSS questionnaire

Additional documentation of AF frequency and severityAdditional documentation of AF frequency and severity


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




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



DescriptionBaseline (n=86) 6 Months (n=65*)

Mean, SDRang

eMean, 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 # Pts

Completed Completed (n=81)(n=81)

Arrhythmia SymptomsArrhythmia Symptoms 80 (99%)80 (99%)

EKGEKG 80 (99%)80 (99%)

AFSS QuestionnaireAFSS Questionnaire 74 (91%) 74 (91%)


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


AFSS Mean Scores at Six MonthsAFSS Mean Scores at Six Monthsby Six-Month Transmission Complianceby Six-Month Transmission Compliance

51.2 50.7

69.8

57.4

52.6

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


Issues for ClarificationIssues 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


Study Summary 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%)


Closing RemarksClosing Remarks

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

Director of ElectrophysiologyUniversity of Alabama at Birmingham

Birmingham, AL


ConclusionConclusion

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.


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


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

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


The Atrial Fibrillation ChallengeThe 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


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

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


REVELATIONREVELATION®® Tx Tx

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