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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