1. Left Atrial Appendage Closure Device
David R. Holmes, Jr., M.D.
Mayo Clinic, Rochester
CRT 2017
Washington, DC
February 2017
test

2. Presenter Disclosure Information
David R. Holmes, Jr., M.D.
“Left Atrial Appendage Closure Device”
The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

3. Left Atrial Appendage Occlusion What Do We Know?
Stroke and AF
NOACs
IFU
Post FDA approval
What about adjunctive therapy

4. AFib, Stroke and TIA Systematic Review & Meta-Analysis Background
Meta-analysis to estimate the proportion of patients after a stroke or TIA who have newly diagnosed AFib after sequential phases of cardiac monitoring
50 studies and 11,658 patients
Sposato et al: Lancet Neurol 14: 377, 2015

5. AFib, Stroke and TIA Systematic Review & Meta-Analysis Findings
Prevalence of AFib either known or newly diagnosed is ~40%
Newly detected AFib might be diagnosed in nearly 25% of patients with stroke/TIA
Sequential cardiac monitoring increases the yield of detection
Sposato et al: Lancet Neurol 14: 377, 2015

6. Adherence to OAC
U.S. commercial insurance data base (administrative claims) 66,661 patients with atrial fibrillation treated between November 2010 and December 2014
CHA2DS2VASc score ≥2
~90%
HAS-BLED ≥3
~50%
Median F/U
1.1 yrs
6.0
15.8
59.1
19.1

7. Adherence to OAC Proportion of Days Covered
Median: 1.1 yrs
% Adherence
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

8. Adherence to OAC ≥6 Months Findings
No significant effect between non-adherence and risk of stroke with CHA2DS2VASc score 0/1
In non-adherent patients risk of stroke with CHA2DS2VASc score 2/3; HR 2.73 (95% CI )
In non-adherent patients risk of stroke with CHA2DS2VASc score ≥4 markedly elevated
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

9. US Reimbursement Status CMS National Coverage Decision (2/8/16)
Criteria for coverage
CHADS2 score 2 or CHA2DS2-VASc score 3
A formal shared decision making interaction with an independent noninterventional physician using an evidence-based decision tool on oral anticoagulation in patients with NVAF
Suitable for short-term warfarin but deemed unable to take long term oral anticoagulation

10. Left Atrial Appendage Closure vs Warfarin in AF A Patient-Level Meta-Analysis
HR P
Efficacy
All Stroke or SE
Ischemic Stroke or SE
Hemorrhagic Stroke
CV/Unexplained Death
All-Cause Death
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Left Atrial Appendage Closure
VOL. 65, NO. 24, 2015 ISSN /$
as an Alternative to Warfarin for
Stroke Prevention in Atrial Fibrillation
A Patient-Level Meta-Analysis
David R. Holmes, JR, MD,* Shephal K. Doshi, MD,y Saibal Kar, MD,z Matthew J. Price, MD,x Jose M. Sanchez, MD,k Horst Sievert, MD,{ Miguel Valderrabano, MD,# Vivek Y. Reddy, MD**
This study sought to assess composite data regarding left atrial appendage closure (LAAC) in 2 ran- domized trials compared to warfarin for prevention of stroke, systemic embolism, and cardiovascular death in patients with nonvalvular AF.
METHODS Our meta-analysis included 2,406 patients with 5,931 patient-years (PY) of follow-up from the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trials, and their respective registries (Continued Access to PROTECT AF registry and Continued Access to PREVAIL registry).
RESULTS With mean follow-up of 2.69 years, patients receiving LAAC with the Watchman device had significantly fewer hemorrhagic strokes (0.15 vs events/100 patient-years [PY]; hazard ratio [HR]: 0.22; p 1⁄ ), cardiovascular/ unexplained death (1.1 vs. 2.3 events/100 PY; HR: 0.48; p 1⁄ ), and nonprocedural bleeding (6.0% vs. 11.3%; HR: 0.51; p 1⁄ ) compared with warfarin. All-cause stroke or systemic embolism was similar between both strategies (1.75 vs events/100 PY; HR: 1.02; 95% CI: 0.62 to 1.7; p 1⁄4 0.94). There were more ischemic strokes in the device group (1.6 vs. 0.9 and 0.2 vs. 1.0 events/100 PY; HR: 1.95 and 0.22, respectively; p 1⁄ and 0.004, respectively). Both trials and registries identified similar event rates and consistent device effect in multiple subsets.
CONCLUSIONS In patients with NVAF at increased risk for stroke or bleeding who are candidates for chronic antico- agulation, LAAC resulted in improved rates of hemorrhagic stroke, cardiovascular/unexplained death, and nonprocedural bleeding compared to warfarin.
Favors Watchman 
 Favors warfarin
0.01
0.1 1 10
Hazard ratio (95% CI)
Combination of PROTECT AF and PREVAIL patients receiving the Watchman device, vs warfarin for overall stroke, ischemic stroke, and all-cause death.
J Am Coll Cardiol; 65:2614, 2015

11. Mortality Reduction (vs warfarin)
P=0.0379
Reduction in all-cause
mortality (%)
P=0.051
P=0.047
P=0.13 (NS)
P=0.15 (NS)
RE-LY
ROCKET-AF
ARISTOTLE
PROTECT AF
Results from different clinical trials:
1Connolly, S. NEJM 2009; 361: – 2 yrs f-up
2Patel, M. NEJM 2011; 365: – 1.9 yrs f-up, ITT
3Granger, C NEJM 2011; 365: – 1.8 yrs f-up
4Reddy, V. LBCT HRS 2013 – 4 yrs f-up

12. EWOLUTION Serious Procedure-/Device-Related Events through 7 days%
Boersma et al: Euro Heart J, doi: /eurheartj/ehv730

13. Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals
Bleeding Outcomes after Left Atrial Appendage Closure Compared with Long-term Warfarin
Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals
72%
>6 months post-procedure
p < 0.001
Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15):

14. Procedural Success ~50% new operators ~50% new operators N=449 N=566
Implant success defined as deployment and release of the device into the LAA; no leak ≥ 5 mm

15. Outcomes in the Post-FDA Approval Watchman Experience N=3822
Post-FDA Approval Experience
Complications
Pericardial Tamponade
39 (1.02%)
Treated with Pericardiocentesis
24 (0.63%)
Treated Surgically
12 (0.31%)
Resulted in Death
3 (0.078%)
Pericardial Effusion – No Intervention
11 (0.29%)
Procedure-Related Stroke
Device Embolization
9 (0.24%)
Removed Percutaneously 3
Removed Surgically 6
Death
Procedure-Related Mortality
Additional Mortality within 7 days
1 (0.026%)

16. Summary
Following United States FDA approval, this dataset represents the first patients implanted with this novel therapy
Device usage, procedure time, and implant success rates are consistent with clinical trial results
Safety complications rates in the initial experience are consistent with clinical trial results 
Cardiac tamponade and procedure-related mortality occurred in ~1% and <0.1% of patients, respectively

17. Watchman Implantation NOACs vs Warfarin
Multicenter Registry
214 patients undergoing clinically indicated Watchman implantation treated with NOAC
212 patients undergoing clinically indicated Watchman implantation treated with Warfarin as per IFU
Enomoto et al: Heart Rhythm 14:19-24, 2017

18. Watchman Implantation NOACs vs Warfarin
Adverse events
NOACs
(n=214)
Warfarin
(n=212) P
Stroke, TIA, or systemic embolism
Periprocedure
0 (0%)
1.0
Postprocedure
1 (0.5%)
Other complications
2 (0.9%)
0.3
LAA thrombosis
LAA thrombosis or embolic event (including stroke, TIA, or systemic embolism)
3 (1.4%)
Enomoto et al: Heart Rhythm 14:19-24, 2017

19. Conclusion: NOACs proved to be a feasible peri- and postprocedural alternative regimen to warfarin for preventing device-related thrombosis and thromboembolic complications expected early after appendage closure with the Watchman device, without increasing the risk of bleeding.

20. ASAP-TOO Up to 888 randomized patients Primary effectiveness endpoint
Time to first occurrence of ischemic stroke or systemic embolism
Primary safety endpoint
MACE during index hospitalization
All-cause death
Ischemic stroke
Systemic embolism
Device/procedural events requiring significant intervention

21. Left Atrial Appendage Occlusion What Do We Know?
Stroke and AF
NOACs
IFU
Post FDA approval
What about adjunctive therapy

24. EWOLUTION: 3-months outcome of Left Atrial Appendage Closure with the WATCHMAN device in Europe
Thrombus at the device, leakage at follow-up, device embolisation, post-procedural drug regimen and impact of center experience data from the prospective 1,025 patients EWOLUTION Registry
M. W. Bergmann1, B. Schmidt2, T. Betts3, E. Teiger4, C. Tamburino5, E. Pokushalov6, S. Kische7, T. Schmitz8, H. Ince9, H. Sievert10, L.V.A. Boersma11 – (1) Cardiologicum Hamburg, Germany (2) Cardiology Centre Bethanien (CCB), Frankfurt, Germany (3) John Radcliffe Hospital, Oxford, United Kingdom (4) University Hospital Henri Mondor, Creteil, France (5) Ferrarotto Hospital, Catania, Italy (6) State Research Institute of Circulation Pathology, Novosibirsk, Russian Federation (7) Vivantes Klinikum Friedrichshain, Berlin, Germany (8) Elisabeth Krankenhaus Essen, Germany (9) Vivantes Klinikum Urban, Berlin, Germany (10) CardioVascular Center Frankfurt, Germany (11) St Antonius Hospital, Nieuwegein, Netherlands.
test

25. Potential Conflicts of Interest
Speaker's name: Martin W. Bergmann
I have the following potential conflicts of interest to report:
Consultant: Biosense Webster, BOSTON SCIENTIFIC
Honorarium: BAYER PHARMA AG, BIOTRONIK, Boehringer Ingelheim, DAIICHI SANKYO and ELI-LILLY, Novartis, ST. JUDE MEDICAL

26. Topics EWOLUTION study design & population
EWOLUTION 3 months
Open question: impact of center experience?
Open question: impact of post-implant drug regimen?
Conclusions
Prof. M.W. Bergmann 2016

27. EWOLUTION Study Design & Population
Study objective
Collect real-world WATCHMAN LAAO experience outside of selected populations in prior RCT
Study design
Prospective, single-arm, multi-center registry of the Watchman LAA Closure Technology
Primary endpoint
Primary analysis includes procedural success and safety, incidence of stroke, bleeding, and death after 2 yr of FU Investigator and Medical Safety Group for adjudication
Patient population
>1,000 patients
Number of sites
47 throughout Europe, Russia and Middle East
Enrollment
Started October 2013 – completed May 2015
Follow-up
Standard practice at participating centers
Normally 1-3 months post-procedure
Annually thereafter for a total of 2 years
Prof. M.W. Bergmann 2016

28. EWOLUTION Study Design & Population
Top 10 enrolling centers
Pt Enrolled (no.)
Berlin, Germany (Atmowihardjo/Ince) 86
Berlin, Germany (Kische) 68
Hamburg, Germany (Meincke/Bergmann) 55
Novosibirsk, Russia (Pokushalov) 51
Essen, Germany (Schmitz) 48
Frankfurt, Germany (Schmidt) 40
Dublin, Ireland (Foley) 37
Mainz, Germany (Gori) 33
Krasnoyarsk, Russia (Protopopov) 29
n=1,025
Prof. M.W. Bergmann 2016

29. EWOLUTION Study Design & Population
Informed consent obtained
Reassess per
physician’s discretion
LAA criteria met? NO
Withdrawal
(Intent)
YES
n=5
reimplant
Implant of WATCHMAN
***subject is enrolled***
Device not
implanted
Device implanted
n=1,005
Follow-up according to
center’s practice
Withdrawal (attempt)
n=15
Boersma LVA et al. Catheter Cardiovasc Interv 2015
EWOLUTION: design of a registry to evaluate real-world clinical outcomes in patients with AF and high stroke risk-treated with the WATCHMAN left atrial appendage closure technology
Prof. M.W. Bergmann 2016

30. EWOLUTION: Patient Flow Up to 3 Months
Informed consent obtained: n=1,025
Anatomy considered not suitable at prescreening:
n=5
study population
Implant of WATCHMAN:
n=1,020
Unsuccessful Implant:
n=15
Patients with Watchman implant:
n=1,005
Death: n=21
Withdrawals: n=5
Patients with Watchman 3 months:
n=979
Prof. M.W. Bergmann 2016

31. EWOLUTION: Device Sizing
Mean
Compression (%)
15%
16%
17%
21%
18%
(n=124)
(n=285)
(n=307)
(n=154)
(n=98)
Prof. M.W. Bergmann 2016

32. EWOLUTION: Procedural Results @ 3 Months%
Implant
success
First device
release
successful
First device
size correct
Complete
Seal or jet
size 5 mm
at implant
Complete seal
or jet size
5 mm
at first FU
Prof. M.W. Bergmann 2016

33. Effect of Center Experience – Procedural
Enrolment Quartile
Subjects (Mean ± SD
Min – Max)
First Device Release Successful (%)
First Device Size correct (%)
Complete Seal or Jet Size 5 mm at implant (%)
Complete Seal or Jet Size 5 mm at First FU (%) 1
11 ± 5
1 – 18
65.2
88.6
100.0
99.1 2
23 ± 2
20 – 27
70.4
92.5
99.0 3
33 ± 5
28 – 40
65.0
92.3
99.6 4
63 ± 18
48 – 86
84.4
98.8
99.2
98.2
P-value
<0.0001
0.3545
0.8332
Prof. M.W. Bergmann 2016

34. EWOLUTION: Safety @ 3 mo. Other SAEs
# pts
(n=1,020)
Pts (%)
Heart Failure 19
9.5 18
1.8
Pulmonary 13
6.5 12
1.2
Arrhythmias 10
5.0 9
0.9
Systemic Infection 7
3.5
0.7
Peripheral Vascular Disease 6
3.0 5
0.5
Vascular puncture site
2.5 4
0.4
Genito-urinary 3
0.3
Cancer
2.0
Prof. M.W. Bergmann 2016

35. EWOLUTION: SAE Distribution @ 3 Months

36. Effect of Center Experience – SAEs @ 3 Mo
Quartile 1 (1-18 pts enrolled)
Quartile 2 (20-27 pts enrolled)
Quartile 3 (28-40 pts enrolled)
Quartile 4 (48-86 pts enrolled)
Prof. M.W. Bergmann 2016

37. Post-Implant Drug Regimen Patient Baseline Characteristics
Nothing (n=67)
Single APT (n=72)
Dual APT (n=607)
Warfarin (n=159)
NOAC (n=113)
P<0.0001
P<0.0001
Prof. M.W. Bergmann 2016

38. SAE Stratified for Post-Implant Drug Regimen
Nothing (n=67)
Single APT (n=72)
Dual APT (n=607)
Warfarin (n=159)
NOAC (n=113)
P=0.275 %
P=0.792
P=0.768
P=0.498
Prof. M.W. Bergmann 2016

39. EWOLUTION: Summary
LAAC with WATCHMAN has a high success rate and low periprocedural events even in a high risk, mostly oral anticoagulation contraindicated patient population
With current training standards, centers with less experience have the same high success rates with low complication rate
Within the first three months after LAA closure, bleeding itself is the issue with the highest event rate
All drug regimen appear safe, with NOAC presenting with the  lowest bleeding rate without an increase in thrombus at the device or stroke SAE rates
Prof. M.W. Bergmann 2016

40. Proportion with thromboembolic event
Effectiveness of LAAO for the Reduction of Thromboembolism in Patients With AFib
HR 0.61, CI , P=0.009
HR 0.85, CI , P=0.015
Proportion with thromboembolic event
Proportion dead
LAAO
No LAAO
LAAO
No LAAO
Days
Days

41. Left Atrial Appendage Obliteration LAA and Obliteration
Schwartz et al: JACC Intv 3:870, 2010

42. Left Atrial Appendage Obliteration Dog Heart 72 Hours After Device Implantation
Schwartz et al: JACC Intv 3:870, 2010

43. Expected Annual Rate of Stroke Based on CHADS2 Score
Gage 2004
Gage 2001
Event rate – pt/yr (%)
CHADS2 score of the
ASAP population
CHADS2 score
Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

44. ASAP Registry All cause stroke/SE 2.3% / year Ischemic stroke
Hemorrhagic stroke
0.6% / year
Expected by CHADS2
7.3% / year
Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

45. ASAP Study Clinical Outcomes
Entire Cohort
Events/Pt-Yrs*
Primary efficacy
8/175.0 (4.6%)
Death, all cause
9/180.0 (5.0%)
All stroke
4/176.0 (2.3%)
Ischemic stroke
3/176.9 (1.7%)
Hemorrhagic stroke
1/179.1 (0.6%)
Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

46. ASAP Study Procedure & Device-Related Serious Adverse Events
Device embolization
2 (1.3%)
Pericardial effusion with tamponade (percutaneous drainage)
Pericardial effusion, no tamponade
(no intervention required)
3 (2.0%)
Device thrombus with ischemic stroke
1 (0.7%)
Femoral pseudoaneurysm ( surgically repaired)
1. (0.7%)
Femoral hematoma/bleeding
Other
Total patients with procedure- and device-related SAEs
13 (8.7%)
Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

47. EWOLUTION
Multicenter registry of 1,021 patients treated with Watchman LAAC –
47 centers
13 countries
Objective: obtain clinical data on
Procedural success and 30-day outcomes
Long-term outcomes
Bleeding
Stroke/TIA
Boersma et al: Euro Heart J, doi: /eurheartj/ehv730

48. EWOLUTION Age (yrs) 73 ± 9 History TIA 10.7% History Stroke 19.7%
History hemorrhagic stroke
15.0%
Not eligible for OAT
61.8%
CHA2DS2-VASc
4.5 ± 1.6
HAS-BLED Score
2.3 ± 1.2
Boersma et al: Euro Heart J, doi: /eurheartj/ehv730

49. EWOLUTION 30-Day Outcome
34 SAEs in 32 patients – 3.6%
Major bleeding requiring transfusion – 17
Pericardial effusion – 7
Ischemic stroke – 3
Overall mortality – 0.7%
Boersma et al: Euro Heart J, doi: /eurheartj/ehv730

50. EWOLUTION Implant Success Comparison%
Boersma et al: Euro Heart J, doi: /eurheartj/ehv730

51. Conclusion: Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure.

52. Watchman Implantation Patients not taking Warfarin
Single center study
59 consecutive patients with relative/absolute contraindications to warfarin treated with Watchman
Approach
Device size chosen to be 15-30% larger than the LAA diameter in contrast to usual practice (8-20%)
Meincke et al: EuroIntervention 9: , 2013

53. Procedural and Clinical Outcome
Pericardial effusion
2 (3.3%)
Ischemic stroke
1 (1.7%)
Follow-up (6.3 mo)
TIA
Device thrombus (no events)
3 (5.0%)
Meincke et al: EuroIntervention 9: , 2013

54. Conclusions: Our data suggest that DAPT can be used safely during the first 45 days in patients with contraindications to warfarin. An algorithm employing larger devices in relation to the LAA ostium with consecutively larger compression improved procedural safety compared to the current standard regarding leakage and device repositioning.

55. ASAP Study Watchman Device
Multicenter Registry
150 patients with nonvalvular AF who were ineligible for warfarin
Clinical (N=150) %
Age, yrs
72.5 ± 7.4
Male
96 (64.0)
Stroke risk factors
Heart failure or reduced LVEF
43 (28.7)
Hypertension
142 (94.7)
Age ≥ 75 yrs
64 (42.7)
Diabetes mellitus
48 (32.0)
Prior stroke or TIA
61 (40.7)
Vascular disease
27 (18.0)
Age 65 to 74 years
Female
54 (36.0)
Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

56. ASAP (Aspirin Plavix) Study
Patients history of hemorrhagic & bleeding tendencies or a warfarin hypersensitivity
150 patients, 4 European centers
Average CHADS2 = 2.8
Post procedure anti-platelet regimen
Clopidogrel through 6 months
Aspirin indefinitely
Patients followed to 2 years
3, 6, 12, 18 & 24 months
TEE at 3 and 12 months
Average follow-up was 14.4 months
Rate of success with implantation in warfarin contraindicated patients1
94.7% successfully implanted
Avg. Procedure Time = 51.5 mins
1 Braut A et al, LAA closure with the WATCHMAN Device in patients with contraindications to warfarin: preliminary results from the ASA Plavix registry (ASAP), ESC Congress 2011, Paris August 2011
The WATCHMAN Device is not approved for patients contraindicated to OACs

57. Results
Expected and Observed Stroke Rates (per 100 patient-years)
7.3%
77% Reduction
Expected, based on CHADS2 score Expected, if Clopidogrel was used throughout follow-up Observed rate in ASAP
5.0%
1.7%
Observed rate of ischemic stroke represents a 77% reduction from the expected event rate

58. Conclusions: LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation.

59. EWOLUTION: Patient Baseline Characteristics%
Male Gender 60
History of Ischemic Stroke 20
Previous Hemorrhagic Stroke 15
Prior Major or predisposition to bleeding 39
CHA2DS2-VASc score 5 49
HAS-BLED 3 40
Contra-indication for oral anticoagulation 72
Age 80 years 26
Hypertension (uncontrolled or history of hypertension) 86
Congestive heart failure 34
Type II diabetes 29
Vascular disease 42
Abnormal renal function 16
Abnormal liver function 4
Prof. M.W. Bergmann 2016

60. EWOLUTION: Safety Results @ 3 Months%
All SAEs
(n pt=146)
Device/
procedure
related
SAEs
(n pts=42)
Bleeding
SAEs
(n pts=38)
Thrombus
on the
device
(n pts=20)
All
deaths
(n pts=21)
PE/
cardiac
tamponade
(n pts=7)
Strokes
(n pts=4)
Device
embolization
(n pts=4)
Prof. M.W. Bergmann 2016

61. EWOLUTION: Safety Results @ 3 Months N=1025, AC contraindicated 72%
All SAEs
(n pt=146)
Device/
procedure
related
SAEs
(n pts=42)
Bleeding
SAEs
(n pts=38)
Thrombus
on the
device
(n pts=20)
All
deaths
(n pts=21)
PE/
cardiac
tamponade
(n pts=7)
Strokes
(n pts=4)
Device
embolization
(n pts=4)
Prof. M.W. Bergmann 2016

63. Oral Anticoagulation in NVAF
Medical and pharmacy claims data base
45,092 newly diagnosed NVAF patients
Nov – Nov. 2013
41% treated with an OAC, warfarin and NOAC
Average F/U – 2.25 years
72.7% discontinued OAC
17.7% within 3 months
55% within 12 months
<2
39.8%
2/3
42.4%
>3
40.3%
Jain, Circulation 134:A15102, 2016

64. Adherence to OAC Proportion of Days Covered
Median: 1.1 yrs
% Adherence
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

65. Adherence to OAC Incidence of Stroke/100 person years
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

66. OAC Survival Analysis using Bleeding as Outcome
Time not taking OAC
All major bleeding
Gastrointestinal bleeding
Intracranial hemorrhage
CHA2DS2VASc score 0 or 1
<1 wk
Ref
1 wk to 1 mo
0.93 ( )
1.13 ( )
0.33 ( )
1-3 mo
0.59 ( )
0.48 ( )
0.25 ( )
3-6 mo
0.29 ( )
0.36 ( )
0.23 ( )
≥6 mo
0.46 ( )
0.46 ( ) NA
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

67. OAC Survival Analysis using Bleeding as Outcome
Time not taking OAC
All major bleeding
Gastrointestinal bleeding
Intracranial hemorrhage
CHA2DS2VASc score 2 or 3
<1 wk
Ref
1 wk to 1 mo
1.04 ( )
1.03 ( )
0.99 ( )
1-3 mo
1.07 ( )
1.14 ( )
1.05 ( )
3-6 mo
0.87 ( )
0.79 ( )
1.17 ( )
≥6 mo
0.68 ( )
0.64 ( )
0.90 ( )
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

68. OAC Survival Analysis using Bleeding as Outcome
Time not taking OAC
All major bleeding
Gastrointestinal bleeding
Intracranial hemorrhage
CHA2DS2VASc score ≥4
<1 wk
Ref
1 wk to 1 mo
1.11 ( )
1.04 ( )
0.31 ( )
1-3 mo
0.90 ( )
0.84 ( )
1.23 ( )
3-6 mo
0.94 ( )
0.91 ( )
1.20 ( )
≥6 mo
0.79 ( )
0.75 ( )
1.06 ( )
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

69. Adherence to OACs
Apixaban
(n=3,900)
Dabigatran
(n=10,235)
Rivaroxaban (n=12,336)
All NOACs
(n=26,471)
Warfarin
(n=38,190)
P ( NOACs vs Warfarin)
Adjusted adherence, 955 CI
All (%)
52.1 ( )
45.9 ( )
47.6 ( )
47.5 ( )
38.7% ( )
<0.001
CHA2DS2VASc score 0 or 1 (%)
40.6 ( )
28.6 ( )
30.8 ( )
30.8 ( )
25.2 ( )
CHA2DS2VASc score 2 or 3 (%)
51.9 ( )
46.9 ( )
48.8 ( )
48.3 ( )
37.3 ( )
CHA2DS2VASc score ≥4 (%)
54.1 ( )
48.7 ( )
50.1 ( )
50.1 ( )
42.0 ( )
Yao et al: J Am Heart Assoc doi: /JAHA , 2006

70. Conclusions: Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA2DS2VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA2DS2VASc score 0 or 1.

71. FRACTAL Registry Warfarin Use
1005 patients, first documented episode of atrial fibrillation %
Study population
Ideal candidates
Women
Age >85
Follow-up (months)
Initially, 65% of subjects were prescribed warfarin at baseline, but only 44% were taking it at 30 months.
Reynolds et al: Am J Cardiol 97:538, 2006

72. Atrial Fibrillation in Cryptogenic Stroke
Multicenter RCI
572 patients with cryptogenic ischemic stroke/TIA within past 6 months
Randomization to
Additional non-invasive ambulatory ECG with 30-day event triggered records, or
Conventional 24-hr Holter
Gladstone et al: N Engl J Med; 370:2467, 2014

73. AFib in Patients with Cryptogenic Stroke
Intervention Group (n=286)
Control Group
(n=285)
Absolute Difference
(95% CI) P
No. of patients
needed to screen
Outcome
no./total no. (%)
Points (%)
Primary outcome: detection of AFib with duration 30 sec within 90 days†
45/280 (16.1)
9/277 (3.2)
12.9 ( )
<0.001
8 ( )
Secondary outcomes
Detection of Afib with duration 30 sec
44/284 (15.5)
7/277 (2.5)
13.0 ( )
8 ( )
Detection of AFib
with duration 2.5 min
28/284 (9.9)
7.4 ( )
14 ( )
of any duration
56/284 (19.7)
13/277 (4.7)
15.0 ( )
7 ( )
Gladstone et al: N Engl J Med; 370:2467, 2014

74. AFib in Patients with Cryptogenic Stroke
Therapy
Intervention Group
(n=286)
Control Group
(n=285)
Absolute Difference
(95% CI) P
After study monitoring
no./total no. (%)
Points (%)
Therapy at 90 days after randomization
Anticoagulant therapy
52/280 (18.6)
31/279
(11.1)
7.5 (1.6 to 13.3)
0.01
Antiplatelet therapy only
223/280 (79.6)
246/279 (88.2)
-8.6 (-14.6 to -2.5)
0.006
Therapy at randomization changed by 90 days
From antiplatelet therapy to anticoagulant therapy
38/280 (13.6)
13/279 (4.7)
8.9 (4.2 to 13.6)
<0.001
From anticoagulant therapy to
antiplatelet therapy
3/280 (1.1)
2/279 (0.7)
0.4 (-1.2 to 1.9)
0.66
Gladstone et al: N Engl J Med; 370:2467, 2014

75. AFib in Patients with Cryptogenic Stroke
Patients with AFib
detected (%)
Duration of ECG Monitoring
Gladstone et al: N Engl J Med; 370:2467, 2014

76. Conclusions: Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal AFib was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of AFib by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT )
Gladstone et al: N Engl J Med; 370:2467, 2014

77. AFib After Stroke and TIA
Hazard ratio
5.8 (95% CI )
Log-rank P<0.0001
Mobile cardiac outpatient telemetry
Cumulative probability of diagnosis of PSAF (%)
Implantable loop recording
Days between start of cardiac monitoring and first diagnosis of PSAF
Sposato et al: Lancet Neurol 14: 377, 2015

78. AFib, Stroke and TIA Systematic Review & Meta-Analysis Background
Atrial fibrillation associated with 5x increase in stroke
In patients with AFib, those with stroke have a 15% incidence of recurrence within 1 year
20% of patients with stroke have prior diagnosis of AFib
Concern
A substantial proportion of patients with stroke may have clinically undetected PAF
Sposato et al: Lancet Neurol 14: 377, 2015

79. AFib, Stroke and TIA Systematic Review & Meta-Analysis
Diagnostic modalities
Admission ECG
Serial ECGs
Continuous in-patient ECG
Holter monitoring
Mobile out-patient telemetry
External loop recording
Implantable loop recording
Post-stroke atrial fibrillation
AFib or flutter – chronic or paroxysmal irrespective of duration
Sposato et al: Lancet Neurol 14: 377, 2015

80. Interpretation By sequentially combining cardiac monitoring methods, atrial fibrillation might be newly detected in nearly a quarter of patients with stroke or transient ischaemic attack. The overall proportion of patients with stroke who are known to have atrial fibrillation seems to be higher than previously estimated. Accordingly, more patients could be treated with oral anticoagulants and more stroke recurrences prevented.
Sposato et al: Lancet Neurol 14: 377, 2015

81. Post-FDA Approval, Initial US Clinical Experience with Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation
Vivek Y. Reddy MD1*, Douglas N. Gibson MD2, Saibal Kar3, William O’Neill MD4, Shephal K. Doshi MD5, Rodney P. Horton MD6, Maurice Buchbinder MD7, Nicole T. Gordon BSEE8, David R. Holmes MD9*
*Both authors contributed equally to the development of this manuscript
1Icahn School of Medicine at Mount Sinai, New York, NY; 2Scripps Clinic, La Jolla, CA; 3Cedars Sinai Medical Center, Los Angeles, CA; 4Center for Structural Heart Disease, Henry Ford Hospital, Detroit, MI; 5St. John’s Health Center, Santa Monica, CA; 6Texas Cardiac Arrhythmia Institute, Austin, TX; 7Foundation for Cardiovascular Medicine, La Jolla, CA; 8Boston Scientific Corporation, St. Paul, MN; 9Department of Cardiology, Mayo Clinic, Rochester, MN
test

82. Presenter Disclosure Information
David R. Holmes, Jr., M.D.
“Post-FDA Approval, Initial US Clinical Experience with Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation”
The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

83. Background
March 2015
FDA approval of left atrial appendage occlusion (LAAC) with Watchman™ device to reduce risk of stroke in NVAF
Clinical procedures initiated using following criteria
Patients met FDA clinical criteria
Local site patient consent and IRB
Physicians experienced with or trained in patient selection, as well as in procedural performance
Procedures performed with trained Watchman clinical specialist in attendance

84. Background Issue Outcome of patients implanted between
March 2015 (FDA approval), and
August 2016 (LAAC Registry certified)
Remains unknown without formalized data on safety or usage.

85. Purpose
In the absence of a prospective registry from the time of FDA approval of the WATCHMAN LAAC device, we sought to analyze procedural safety data in the initial post-approval launch as reported to the manufacturer

86. Methods
March 2015 – May 2016
3,822 consecutive patients underwent LAAC with Watchman™ implantation by 382 physicians at 169 U.S. centers
50% of procedures performed by newly trained operators
Each implant was required to be performed with Watchman clinical specialist in attendance
Details of each procedure recorded on standardized forms, and events reported to manufacturer per de- identified patient data

87. Methods (cont) Major complications
Pericardial effusion, need for urgent cardiac surgery, stroke, device embolization, and death
Reviewed independently by
Sponsors – Medical Safety Group
Authors
VR – electrophysiologist
DRH – interventional cardiologist

88. Outcomes in the Post-FDA Approval Watchman Experience
Post-FDA Approval Experience
Procedural Parameters
No. of Procedures
3822
Implantation Success, %
3653 (95.6%)
Procedure Duration, min
Median
50 min
IQR (1st)
36 min
IQR (3rd)
66 min
Devices Used per Procedure
1.38

89. Procedural Success ~50% new operators ~70% new operators N=449 N=566
Implant success defined as deployment and release of the device into the LAA; no leak ≥ 5 mm

90. Average # of Devices/Implant Attempt
Devices per Case1-2
Average # of Devices/Implant Attempt
1 WATCHMAN FDA Panel Sponsor Presentation. Oct 2014; 2 Boersma, L.et al. EHJ; published online Jan 2016 in press

91. Procedure Duration
WATCHMAN FDA Panel Sponsor Presentation. Oct 2014

92. Outcomes in the Post-FDA Approval Watchman Experience N=3822
Post-FDA Approval Experience
Complications
Pericardial Tamponade
39 (1.02%)
Treated with Pericardiocentesis
24 (0.63%)
Treated Surgically
12 (0.31%)
Resulted in Death
3 (0.078%)
Pericardial Effusion – No Intervention
11 (0.29%)
Procedure-Related Stroke
Device Embolization
9 (0.24%)
Removed Percutaneously 3
Removed Surgically 6
Death
Procedure-Related Mortality
Additional Mortality within 7 days
1 (0.026%)

93. Comparison of Procedural Complications Across Watchman Studies

94. Comparison of Procedural Complications Across Watchman Studies
PROTECT-AF
PREVAIL
CAP
CAP2
EWOLUTION
Post-FDA Approval
Aggregate Data
Pericardial Tamponade
20 (4.3%)
5 (1.9%)
8 (1.4%)
11 (1.9%)
3 (0.29%)
39 (1.02%)
86 (1.28%)
Treated with pericardiocentesis
13 (2.8%)
4 (1.5%)
7 (1.2%)
n/a
2 (0.20%)
24 (0.63%)
Treated surgically
7 (1.5%)
1 (0.4%)
1 (0.2%)
1 (0.10%)
12 (0.31%)
Resulted in death
3 (0.78%)
Pericardial effusion – no intervention
4 (0.9%)
5 (0.9%)
3 (0.5%)
4 (0.39%)
11 (0.29%)
27 (0.40%)
Procedure-related stroke
5 (1.15%)
1 (0.37%)
2 (0.35%)
3 (0.078%)
12 (0.18%)
Device embolization
3 (0.6%)
2 (0.7%)
9 (0.24%)
17 (0.25%)
Removed percutaneously 1 3
Removed surgically 2 6
Death
Procedure-related mortality
1 (0.1%)
4 (0.06%)
Additional mortality within 7 days
1 (0.17%)
1 (0.026%)
5 (0.07%)

95. Device Embolization Details
Device Size
Method of Removal
21 mm
Percutaneous Snare
33 mm
Surgical
30 mm
24 mm
27 mm

96. Summary
Following United States FDA approval, this dataset represents the first patients implanted with this novel therapy
Device usage, procedure time, and implant success rates are consistent with clinical trial results
Safety complications rates in the initial experience are consistent with clinical trial results 
Cardiac tamponade and procedure-related mortality occurred in ~1% and <0.1% of patients, respectively

97. Conclusion
In the real-world post-FDA approval experience of Watchman LAAC, procedural success was high and complication rates low.
Complications were low even with ~50% of the operators being new to the procedure. This demonstrates that early procedure learnings can be transferred through rigorous training.