CABANA: Update and Integration

Douglas L. Packer MD Boston, MA

January 13, 2010

Presenter Disclosure Information Catheter Ablation for Atrial Fibrillation:

AF Think Tank April 27, 2009 The following relationships exist related to this presentation:

Siemens / Acuson: Research Funding***/ Scientific Advisory Board*/Consulting** Cryocath: Multi-center Clinical Trial (PI)* / Research Funding** /Consulting** Boston Scientific / EPT: Research Funding*** ESI-St. Jude: Research Funding*** / Patent Royalties* Biosense-Webster: Research Funding*** / Scientific Advisory Board*/Consulting** Cardiofocus: Research Funding*** / Past Scientific Advisory Board** Prorhythm: Research Funding*** Symphony Medical: Research Funding*** / Scientific Advisory Board* Interventional Research Management: Scientific Advisory Board* Medtronic: Symposium Speaker / Consulting** NIH: Research Funding for CABANA*** * None / ** Modest / *** Significant

Catheter Ablation vs Antiarrhythmic Drug Therapy

for Atrial Fibrillation (CABANA) Trial

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Design of the CABANA Study Atrial fibrillation

Eligible for ablation and/or drug therapy

65 yr of age <65 yr w/ ≥1 CVA risk factor

R

Drug Rx & AC • Rate control • Rhythm Rx

1° ablation & AC • PV isolation • Adjunctive

Descriptive analysis • NSR vs AF impact • w/ w/o heart disease • AF type (parox pers

perm) • CT/MR image analysis • ECG/EGM analysis

Follow-up Median of 36 months

CABANA Trial Primary Objective and Hypothesis

The treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art medical therapy with either rate control or rhythm control drugs for reducing total mortality (primary endpoint) and decreasing the composite endpoint of total mortality plus CV hospitalization; and total mortality, disabling stroke, serious bleeding, or cardiac arrest; (key secondary endpoints) in patients with untreated or incompletely treated AF warranting therapy

CABANA Trial Secondary Endpoint/Objectives

• Total mortality, disabling stroke, serious bleeding, or cardiac arrest

• Cardiovascular hospitalization or total mortality • Cardiovascular death • Cardiovascular death or disabling stroke • Arrhythmic death or cardiac arrest • Heart failure death • Freedom from recurrent AF • Cardiovascular hospitalization • Medical costs, resource utilization, and cost effectiveness • Quality of life • Composite adverse events • LA size, morphology and function

Drugs Approved for Rate Control Minimum recommended Drug Administration daily dosage

Digoxin (Lanoxin) Oral 0.125-0.25 mg Beta blockers

Metoprolol (Toprol) Oral 50-100 mg Atenolol (Tenormin) Oral 50-100 mg Propranolol (Inderal) Oral 40-80 mg Acebutolol (Sectral) Oral 200-300 mg Carvedilol (Coreg) Oral 6.25-25 mg Nebivolol (Bystolic) Oral 5-40 mg Bisoprolol (Monocor) Oral 2.5-20 mg

Ca channel blockers Diltiazem (Cardizem) Oral 180-240 mg Verapamil (Calan) Oral 180-240 mg

Ablative Treatment in CABANA Primary

PV isolation

Ancillary

CFAE

Follow-up

Hx / PE

Monitoring

CT / MR

1st Year:

3,6,12 mo

2nd-5th Year:

6,12 mo

GP

Linear

WACA / Antral isolation

1 2 3 4 5 6 7 8 9 10 11 12

CABANA Rhythm Monitoring Plan M

onito

ring

mod

e

Months

TTM

96o

Holter

24o

AC/AFB

TTM symptom 24o auto-capture with AF burden 96o Holter

Blanking

24o

AC/AFB

CABANA Pivotal Trial Results:

• US Sites approached 102 • International Sites 61 • ECG Core running • CT / MR analysis lab running • Econ / QOL running • Executive Committee Really running • Steering Committee running • Patients enrolled 4

CABANA Sties International Approach

Canada 10

U.S. 90

South Am 5

Asia 5

Australia NZ 5

Europe 30

UK 10

Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation: Results of the

CABANA Pilot Study Douglas L. Packer, Kerry Lee, Daniel B. Mark, Kristi H. Monahan, Kathleen

L. Hoffmann, Gail E. Hafley, Jeanne E. Poole, Tristram D. Bahnson, David J. Bradley, Richard Robb, Maryam Rettmann,David R. Holmes III, David J.

Wilber, John D. Hummel, Steven J. Bailin, John D. Day, Anil K. Bhandari, Francis Marchlinski, Neil Kay,Hugh Calkins, William Stevenson

Investigators Meeting November 15, 2009

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Purpose of CABANA Pilot Study

• Determine the freedom from AF with ablation vs drug therapy in patients with more problematic AF and accompanying co-morbidities

• Test the feasibility of a long-term pivotal trial for assessing mortality, stroke, hospitalization and cost outcomes

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CABANA Pilot Study Baseline Characteristics

Drug therapy Ablation therapy All patients n=31 n=29 n=60 Age ≥65 years old 11 (35.5%) 11 (37.9%) 22 (36.7%) Gender Male 26 (83.9%) 20 (69.0%) 46 (76.7%) Female 5 (16.1%) 9 (31.0%) 14 (23.3%) BMI (kg/m2) Mean (SD) 32.2 (9.00) 32.1 (5.83) 32.1 (7.60) Hypertension 24 (77.4%) 24 (82.8%) 48 (80.0%) Diabetes 6 (19.4%) 5 (17.2%) 11 (18.3%) CAD 12 (38.7%) 9 (31.0%) 21 (35.0%) Prior MI 3 (10.0%) 3 (10.7%) 6 (10.3%) Prior CABG/PTCA 7 (22.8%) 5 (21.2%) 13 (22.0%) Cardiomyopathy (dilated) 3 (9.7%) 7 (24.1%) 10 (16.7%) Congestive heart failure 5 (16.1%) 8 (27.6%) 13 (21.7%) NYHA II-III* 9 (29.1%) 12 (42.9%) 21 (35.6%) Ejection Fraction Mean (SD) 55.8 (8.90) 55.5 (10.86) 55.7 (9.75) LA size 4.24 (0.901) 4.61 (0.830) 4.41 (0.877) Left atrial enlargement None 6 (24.0%) 2 (8.0%) 8 (16.0%) Mild 7 (28.0%) 8 (32.0%) 15 (30.0%) Moderate 7 (28.0%) 5 (20.0%) 12 (24.0%) Severe 5 (20.0%) 10 (40.0%) 15 (30.0%) CHADS score* ≤1 18 (39.0%) 18 (64.2%) 36 (61.1%) ≥2 13 (41.9%) 10 (35.7%) 23 (39.0%) Sleep apnea 10 (32.3%) 7 (24.1%) 17 (28.3%)

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CABANA Pilot Study Arrhythmia History

Drug therapy Ablation therapy All patients n=31 n=29 n=60 Type of atrial fibrillation* Paroxysmal 11 (35.5%) 8 (27.6%) 19 (31.7%) Persistent 9 (29.0%) 13 (44.8%) 22 (36.7%) Long standing persistent 11 (35.5%) 8 (27.6%) 19 (31.7%) Years since onset AF Mean (SD) 3.62 (5.76) 3.041 (2.97) 3.34 (4.60) Hospitalized for AF* No 19 (61.3%) 13 (44.8%) 32 (53.3%) Yes 12 (38.8%) 16 (55.1%) 28 (46.7%) Prior antiarrhythmic drugs (no.) 0 23 (74.2%) 19 (65.5%) 42 (70.0%) 1 7 (22.6%) 8 (27.6%) 15 (25.0%) 2 1 (3.2%) 2 (6.9%) 3 (5.0%) CCS AF severity* Class 0 3 (10.0%) 1 (3.7%) 4 (7.0%) Class 1-2 11 (36.7%) 7 (25.9%) 18 (31.6%) Class 3-4 16 (53.3%) 19 (70.4%) 35 (61.4%) Direct current cardio-version No 16 (51.6%) 16 (55.2%) 32 (53.3%) Yes 15 (48.4%) 13 (44.7%) 28 (46.6%) History of atrial flutter 6 (19.4%) 8 (27.6%) 14 (23.3%) Catheter ablation for prior atrial flutter 1 (3.2%) 2 (6.9%) 3 (5.0%) Warfarin 48 (88.9%)

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Meta-Analysis of Catheter Ablation vs Drug Therapy

Nair/Morillo et al: JCE 20:138, 2009

C T C T C T Type of AF Krittayaphong et al C = 15 T = 15 49±15 55±11 8 M/7 F 11 M/4 F 48±64 mo 63±58 mo Paroxysmal and persistent Oral et al C = 69 T = 77 58±8 55±9 62 M/7 F 67 M/10 F 4±4 yr 5±4 yr Chronic Wazni et al C = 37 T = 33 54±8 53±8 NA NA 5±3 mo 5±2 mo Paroxysmal and persistent Stabile et al C = 69 T = 68 62±10 62±9 44 M/25 F 42 M/26 F 7±6 yr 5±7 yr Paroxysmal and persistent Jais et al C = 59 T = 53 51 85% male 6 Paroxysmal Pappone et al C = 99 T = 99 57±10 55±10 64 M/35 F 69 M/30 F 6±6 yr 6±4 yr Paroxysmal CABANA Pilot 62±10 60±11 26 M/9 F 20 M/9 F 3.6±5.8 3±3 1/3 PAF; 1/3 persists; 1/3 LS Persist

Mean age (years) Male/female (no.) Mean duration of AF

CABANA Pilot Study Treatment

13 16

71

%

Drug Therapy

Rate

100

80

60

40

20

0 Rhythm Rate &

Rhythm

Ablation

n=4 n=5 n=22

PVI WACA/ antral

isolation

Linear Abl

CFAE GP

%

PV balloon

100

80

60

40

20

0

44 n=14

94 n=30 86

n=12

19 n=6

3.1 n=1

3.1 n=1

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To Be Presented

Primary Outcomes

CABANA vs SAFARI?

Comparison of RCT vs Registry RCT (CABANA) Registry (SAFARI)

Treatment By randomization Individual Choice Preference

Treatment Design-specified Pre / Post Hoc Comparisons questions

Data generation 3000 patients >50,000 patients

Hypothesis Confirming Generating

Challenge Enrollment Consistency /All patients

Trial funding NIH / Ind funded Pending

Applicability Ideal guideline world Real world Specific

Value of Clinical Trials R

elat

ive

valu

e

Ideal (Guideline) Real

0

20

40

60

80

100

Registries

Large RCTs

Observational studies

Risks of AF Ablation: The Second International AF Ablation Registry

Type of Complication No of Pts Rate,%

Death 25 0.15 Tamponade 213 1.31 Pneumo/ Hemo thorax 19 0.11 Sepsis, abscesses or endocarditis 2 0.01

Permanent diaphragmatic paralysis 28 0.17

Femoral pseudoaneurysm / A-V Fisula 152/88 .93/0.54

Valve damage/requiring surgery 11/7 0.07

Atrium-esophageal fistulae 3 0.02 Stroke / TIA 37 /115 0.23 / 0.71

Pulmonary veins stenoses requiring intervention

48 0.29

TOTAL 741 4.54

Success in AF Ablation: 2nd International Ablation Registry

Success without

AADs

Success with AADs Overall Success Type of AF No. of

Centers

No.

of

Pts No.

of

Pts

No.

of

Pts

No.

of

Pts

Rate

Median

[Interquartile

range]

Paroxysmal 85 9,590 6,580 1,290 7,870 83.2

[79.7-88.6]

Persistent 73 4,712 2,800 595 3,395 75.0

[66.1-80.0]

Permanent 40 1,853 1,108

Rate

Median

[Interquartile

range]

74.9

[64.9-82.6]

64.8

[52.4-72.0]

63.1

[53.3-71.4]

162

Rate

Median

[Interquartile

range]

9.1

[0.2-14.7]

10.0

[0.8-15.2]

7.9

[0.9-15.9]

1,270 72.3

[67.4-72.3]

Capatto et al 2009

Evidence Trajectory in Clinical AF Ablation Trials

Scientific merit

reliability value

quality

Early single center

Single center observ

Multi- center

registries

Single center RCT

Multi- center RCT

Multiple mortality

RCTs

Pt (no.) 20 100 100 1,000 10,000 1,000 3,000

Meta- analysis

CABANA Integration • Similar data elements • Identical data definitions SAFARI STS database CMS database • Comparable Information (apples to apples)

CABANA vs SAFARI? •Synergistic •Cross checking •Interim (SAFARI) and long-term information (CABANA)

•Efficacy and safety / safety