1. Left Atrial Appendage Closure: Prevention of Thromboembolism in Atrial Fibrillation
Thank you for inviting me here – it’s a real pleasure to be able to be with you this evening. I’ve been the chief medical officer for CRM and EP for over a year now and I thought that this would be a great opportunity to reflect back on what I’ve learned in my time here and to share with you my thoughts on what practicing EPs need from you and from BSC.
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Maurice Buchbinder, MD, FACC, FSCAI
Director, Foundation for Cardiovascular Medicine, San Diego, CA
Director, Advanced Interventional Therapies, Gagnon Cardiovascular Institute, Morristown, NJ

2. Maurice Buchbinder, MD Advisory Committee Abbott Laboratories
Boston Scientific Corporation
Ownership Interest (Stocks, Stock Options, or other Ownership Interest):
Cordis Corporation
EndoCross

3. Intellectual Property
MiCardia
Board Membership

4. Atrial Fibrillation and Stroke
Atrial Fibrillation is one of the MOST common cardiac Dysrrhythmias seen in clinical practice 1,2
Untreated, it is associated with nearly FIVEFOLD increase in stroke rates
Strokes are often more severe in patients with AF
Paroxysmal AF and persistent AF are associated with the same incremental risk of cerebrovascular events
1Go, et al. Prevalence of Diagnosed Atrial Fibrillation in Adults. JAMA. 2001; 285:
2ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. JACC. 2001; 38:1.
3Wolf, Abbott, Kannel. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke, 1991; 5

5. CHADS2 Score and Stroke Rate
Annual Risk of Stroke
Adapted from Gage et al, JAMA 2001;285:2864–2870

6. Camm et al, European Heart Journal doi:10.1093/eurheartj/ehq278
CHA2DS2-VASc
2010 ESC AF Guidelines now call for use of CHA2DS2-VASc score
Recommend oral anticoagulation for score 2 or greater and either anticoagulation or aspirin for score =1
Camm et al, European Heart Journal doi: /eurheartj/ehq278

7. Inadequate VKA Treatment for AF
Adequacy of Anticoagulation in Patients with AF in Primary Care Practice
INR above target 6%
INR in target range 15%
No warfarin 65%
Sub-therapeutic INR 13%
Samsa GP, et al. Arch Intern Med 2000;160:967. 8

8. Anticoagulation and Bleeding
“An assessment of bleeding risk should be part of the patient assessment before starting anticoagulation ... It would seem reasonable to use the HAS-BLED score to assess bleeding risk in AF patients, whereby a score of ≥3 indicates ‘high risk’, and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy,whether with VKA or aspirin.”
According to HAS-BLED, 61% of pts currently on warfarin for AF are at “moderate” risk of bleeding and additional 19% are at “high” risk!
Camm et al, European Heart Journal doi: /eurheartj/ehq278
Pisters R, et al Chest 2010; 138:

9. New Anticoagulants for AF: Potential Changes in Recommendations
Medication
Action
Phase III Trial
Comparator
Design n
Dabigatran
DTI
RE-LY
Warfarin
Non-inferiority
18 113
Apixaban
Anti Xa
AVERROES
Aspirin
Superiority
5 599
ARISTOLE
18 201
Rivaroxaban
ROCKET AF
14 269
Edoxaban
ENGAGE
21 500
Biotinylated Idraparinux
BOREALIS-AF
9 600
Tecarfarin
VKA
EmbraceAC
612
Others include: betrixaban (EXPLORE-Xa), darexaban (OPAL-1), AZD0837 10

10. Stroke Prevention: Anticoagulant Effect
Meta-analysis of ischemic stroke or systemic embolism
Favors warfarin
0.3
0.6
0.9
1.2
1.5
Favors other Rx
W vs Placebo
W vs Wlow dose
W vs Aspirin
W vs Aspirin + Clop
W vs Ximelagatran
W vs Dabigatran 110
W vs Rivaroxaban
W vs Dabigatran 150
Category
1.8
2.0
Modified from Camm AJ. EHJ 2009;30:2554-5 12 8 9 11

11. Bleeding Risks with Old and New Drugs
P=.31
P=.003
Bleeding Risk
% per year
Connolly SJ, et.al., N Engl J Med Sep 17;361(12):

12. Thromboembolism versus Haemorrhage
Bleeding risk
? Left Atrial Occlusion Device
3-4% pa
Thromboembolic risk
1-2% pa 13

13. WATCHMAN® LAA Closure: Rationale and Technique14

14. LAA Thrombus

15. Location of Thombi in Left Atrium
Location Frequency (%)
91% in LAA
Blackshear J.L. Odell J.A., Annals of Thoracic Surgery, 1996;61:

16. WATCHMAN® LAA Closure System Implanted Device
Frame: Nitinol structure
Available sizes: 21, 24, 27, 30 & 33mm (diameter)
10 Fixation anchors around device perimeter engage LAA tissue
Contour shape accommodates most LAA anatomy
Fabric Cap: (PET) Fabric Polyethyl terephthalate prevents harmful emboli from exiting during the healing process
160 micron filter
PET fabric
Anchors

17. WATCHMAN® LAA Closure System WATCHMAN Access System
Transseptal Access System
Double or Single Curve styles
14F O.D. (4.7 mm), 12F I.D cm working length
Double Curve
Single Curve
Preformed curve shapes guide position in LAA

18. OPTIMAL POSITION

19. WATCHMAN® LAA Closure: Clinical Program20

20. Continued Access Registry (CAP)
Clinical Studies
STUDY
PATIENTS
SITES
COMMENTS
Pilot 66 8
318 patient years of follow-up
30 patients with 5+ years of follow-up
PROTECT AF
800 59
1,500 patient years of follow-up
27 months average follow-up per patient
Continued Access Registry (CAP)
566 26
Significantly improved safety results
ASAP
135 4
Treat patients contra-indicated for warfarin
EVOLVE 69 3
Evaluate next generation WATCHMAN®
PREVAIL
253
≤50
Same endpoints as PROTECT AF
Revised inclusion/exclusion criteria
Initiate enrollment October 2010
Total
1,889 21

21. PROTECT AF Clinical Trial
Prospective, randomized study of WATCHMAN® LAA Device vs. Long-term warfarin Therapy
2:1 allocation ratio device to control
800 patients enrolled from February 2005 to June 2008
93 roll-in; 707 randomized
59 enrolling centers (U.S. & Europe)
Follow-up requirements
TEE follow-up at 45 days, 6 months and 1 year
Clinical follow-up biannually up to 5 years
INR monitoring every 2 weeks for 6 months and monthly thereafter
Holmes D R et. Al, Lancet 2009;374:534-42 22 22

22. Holmes D R et. Al, Lancet 2009;374:534-42
Patient Risk Factors
Baseline Risk Factors
WATCHMAN®
N= 463
Control
N= 244
P-value
CHADS2 Score: 1 2 3 4 5 6
157/463
158/463
88/463
37/463
19/463
4/463
33.9%
34.1%
19.0%
8.0%
4.1%
0.9%
66/244
88/244
51/244
24/244
10/244
5/244
27.0%
36.1%
20.9%
9.8%
2.0%
0.39
AF Pattern:
Paroxysmal
Persistent
Permanent
Unknown
200/463
97/463
160/463
6/463
43.2%
21.0%
34.6%
1.3%
99/244
50/244
93/244
2/244
40.6%
20.5%
38.1%
0.8%
0.76
LVEF (%)
57.3 ± 9.7
460
30.0, 82.0
56.7 ± 10.1
239
30.0, 86.0
0.42 23
Holmes D R et. Al, Lancet 2009;374:534-42 23

23. Intent-to-Treat: Primary Efficacy Results
Primary composite efficacy: - stroke (ischaemic or haemorrhagic) death (cardiovascular or unexplained)
- systemic embolism
Cohort
WATCHMAN®
Control
Relative Risk
(95% CI)
Posterior Probabilities
Rate (95% CI)
Non-inferiority
Superiority
600 pt-yrs
4.4
(2.6, 6.7)
5.8
(3.0, 9.1)
0.76
(0.39, 1.67)
0.992
0.734
900 pt-yrs
3.4
(2.1, 5.2)
5.0
(2.8, 7.6)
0.68
(0.37, 1.41)
0.998
0.837
1065 pt-yrs*
3.0
(1.9, 4.5)
4.9
(2.8, 7.1)
0.62
(0.35, 1.25)
>0.999
0.900
1350 pt-yrs
2.9
(2.0, 4.3)
4.2
(2.5, 6.0)
0.69
(0.42, 1.37)
0.830
1500 pt-yrs
(2.1,4.3)
4.3
(2.6, 5.9)
0.71
(0.44, 1.30)
0.846
Results are consistent over time, demonstrating approximately a 30% reduction in primary efficacy, stroke and mortality risk
Presented by Holmes, MD, TCT 2010
*Published Results: Holmes D R et. Al, Lancet 2009;374:534-42 24

24. Intent-to-Treat: All Cause Mortality
Cohort
WATCHMAN®
Control
Relative Risk
(95% CI)
Posterior Probabilities*
Rate (95% CI)
Non-Inferiority
Superiority
600 pt-yrs
3.4
(1.8, 5.4)
4.9
(2.3, 7.8)
0.69
(0.33, 1.66)
0.991
0.779
900 pt-yrs
2.9
(1.7, 4.4)
4.7
(2.5, 7.1)
0.61
(0.32, 1.32)
0.999
0.889
1065 pt-yrs*
3.0
(1.9, 4.5)
4.8
(2.8, 7.1)
0.62
(0.34, 1.24)
>0.999
0.907
1350 pt-yrs
3.1
(2.1, 4.4)
4.4
(2.6, 6.1)
0.70
(0.43, 1.36)
0.823
1500 pt-yrs
3.2
(2.3, 4.5)
4.5
(2.8, 6.2)
0.71
(0.46, 1.28)
0.852
*No adjustment made for multiple comparisons
29% lower relative risk in WATCHMAN® Group
Presented by Holmes, MD, TCT 2010
*Published Results: Holmes D R et. Al, Lancet 2009;374:534-42 25

25. PROTECT AF Primary Safety Endpoint*
Peri-procedural events
On going bleeding events
*Major bleeding and events considered life threatening as defined by CEC
David R Holmes, Lancet Vol 374 August 15, 2009
CRV AA-Oct2011

26. Reddy VY et al, Circulation AHA 2011
CAP Results versus Early and Late PROTECT AF: Progression of Procedural Success and Safety
Procedure Metrics
Pimplant success = 0.001*
Pproc. time<0.001*
n=271
n=460
Procedure Outcomes
P=0.006*
P=0.018*
P=0.039*
*From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP) 27
Reddy VY et al, Circulation AHA 2011 27

27. PREVAIL Study Overview
Scope and Duration:
Currently Enrolling
Up to 50 U.S. Centers
Up to 475 patients (75 roll-in, 400 randomized)
25% randomized patients must be enrolled by new operators
Key entry criteria
Calculated CHADS2 score of 2 or greater. Patients with a CHADS2 score of 1 may be included if any of the following apply:
Female age 75 or older
Baseline LVEF ≥ 30 and < 35%
Aged and has diabetes or coronary artery disease
Aged 65 or greater and has congestive heart failure 28

28. LAA Occlusion – The Future
ASAP Trial – 127 Patients enrolled
Use in patients contraindicated to oral anticoagulation, even for short periods
EVOLVE Trial – Enrollment complete in EU
Next Generation Watchman Device 29

29. Conclusions
Thromboembolism is AF is a major cause of morbidity and mortality although Oral Anticoagulation is Effective, many patients will not tolerate it due to ONGOING risk of major bleeding
WATCHMAN® LAA Closure Device obliterates the Left Atrial Appendage preventing emboli from forming in LAA
In Protect-AF (800 patients, 1500 patient-years of follow-up), the device was non-inferior to oral anticoagulation in patients at high-risk of thrombo embolism with a trend toward improved outcomes
The PREVAIL, ASAP and EVOLVE trials will provide further
information on the safety and effectiveness of the present device
in the indicated population as well as in the next generation technology.