1. Reducing Stroke in Patients with AF: Paradigm Shift with LAA Closure – What does the future hold?
Sameer Gafoor, MD
Swedish Medical Center, Seattle WA
Cardio Vascular Center, Frankfurt Germany

2. Unmet Need – the Paradigm Shift

3. OAT Discontinuation and Risk of Major Bleeds
Treatment
Study Drug Discontinuation Rate
Major Bleeding
(rate/year)
Rivaroxaban1
24%
3.6%
Apixaban2
25%
2.1%
Dabigatran3
(150 mg)
21%
3.3%
Edoxaban4
(60 mg / 30 mg)
33 % / 34%
2.8% / 1.6%
Warfarin1-4
17 – 28%
3.1 – 3.6%
1 Connolly, S. NEJM 2009; 361: – 2 years follow-up (Corrected); 2 Patel, M. NEJM 2011; 365: – 1.9 years follow-up, ITT. 3 Granger, C NEJM 2011; 365: – 1.8 years follow-up. 4 Giugliano, R. NEJM 2013; 369(22): – 2.8 years follow-up.

4. Estimate of persistence to OAC therapy following AF diagnosis is <80% at 1 year
Real world discontinuation rates consistent with trials, even after accounting for switching between OACs
Martinez, et al. Thromb Haemost 2015; 114: In press. 4 N

5. Trials and Patient Population: the Paradigm Shift

6. WATCHMAN is the most studied LAAC Device- Most Patients and Only One with Long-term Clinical Data
Key Trials N
Highlights
PROTECT AF1
( )
707
Prospective, randomized 2:1, non-inferiority trial of LAA closure vs. warfarin.
CAP2
( )
566
Prospective registry allowing continued access to the WATCHMAN Device and gain further information prior to PMA approval.
PREVAIL3
( )
407
Prospective, randomized 2:1, non-inferiority trial to collect additional information on the WATCHMAN Device.
( )
579
Prospective registry allowing continued access to the WATCHMAN Device prior to PMA approval.
Total patients
>2,000
~6,000 Patient-Years of Follow-up
1 Reddy, et al. JAMA ;312(19): Reddy VY et al. Circulation. 2011; 123: Holmes et al., JACC 2014,;4(1): 1-11.

7. Patient Risk Factors Across Trials
Characteristic
PROTECT AF N=707
PREVAIL N=407
CAP
N=566
CAP2
N=579
p-value
CHADS2 Score
2.2 ± 1.2
2.6 ± 1.0
2.4 ± 1.2
2.7 ± 1.1
<.0001
CHADS2 Risk Factors (% of Patients)
CHF
26.9
19.1
23.3
27.1
0.004
Hypertension
89.8
88.8
91.4
92.5
0.15
Age ≥ 75
43.1
51.8
53.6
59.7
<0.001
Diabetes
26.2
24.9
32.4
33.7
0.001
Stroke/TIA
18.5
30.4
27.8
29.0
<0.0001
CHA2DS2-VASc
3.5 ± 1.6
4.0 ± 1.2
3.9 ± 1.5
4.5 ± 1.3
Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

8. Majority of patients were at a high stroke risk, and all were eligible for anti-coagulation
Anticoagulation Eligible1
High Risk1
CHA2DS2-VASc Score ≥22
93%
PROTECT AF
CAP
PREVAIL
CAP2
96%
100%
Patients
(%)
CHA2DS2-VASc Score
AHA/ACC/HRS Guidelines (2014); Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

9. Paradigm Shift: Increase in Safety and Efficacy Evidence

10. Procedure Safety: 7-Day Event Rates
Patients with Safety Event
(%)
PROTECT AF
N=232
N=231
N=566
N=269
N=579
N=1021
1st Half
2nd Half
All Device and/or procedure-related serious adverse events within 7 Days.
WATCHMAN FDA Panel Sponsor Presentation. Oct Boersma LVA et al., EurHeartJ 2016; In Press.

11. PROTECT AF/PREVAIL Meta-Analysis: WATCHMAN Comparable to WarfarinHR
p-value
Efficacy
0.79
0.22
All stroke or SE
1.02
0.94
Ischemic stroke or SE
1.95
0.05
Hemorrhagic stroke
0.004
Ischemic stroke or SE >7 days
1.56
0.21
CV/unexplained death
0.48
0.006
All-cause death
0.73
0.07
Major bleed, all
1.00
0.98
Major bleeding, non procedure-related
0.51
0.002
Favors WATCHMAN 
 Favors warfarin
Hazard Ratio (95% CI)
Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

12. Warfarin Ischemic Stroke Rate in PREVAIL Differs from Other Trials
Trial (Warfarin Arm)
Ischemic Stroke
Rate per 100 pt-yrs
Mean CHADS2
PREVAIL1
2.6
PROTECT AF1
2.2
RE-LY2
2.1
ROCKET AF2
3.5
ARISTOTLE2
ENGAGE3
2.8
Rate per Patient-years
1 WATCHMAN FDA Panel Sponsor Presentation. Oct Miller. AJC (2012) 3 Giugliano. NEJM (2013).

13. Ischemic Stroke Rate Aligns with Expected Rate Based on Risk Score
Untreated AF
Treated with Anticoagulants
WATCHMAN Arm
Ischemic Stroke Risk (events per 100 pt-yrs)
PREVAIL
PROTECT AF
CAP2
CAP
Baseline CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014). WATCHMAN FDA Panel Sponsor Presentation. Oct 2014

14. Warfarin Cessation: Majority of patients are able to stop long-term warfarin therapy
Study
45-day
12-month
PROTECT AF
87%
>93%
CAP
96%
>96%
PREVAIL
92%
>99%
Reddy, VY et al. Cardiostim 2014 (Abstract). CAP2 Follow-up too limited to report

15. 72% reduction in bleeding events > 6 months post procedure
Landmark Analysis: Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals
72% reduction in bleeding events
> 6 months post procedure
Price MJ et al., J Am Coll Cardiol Interv 2015, In Press

16. What did we learn?
Device procedure is safe across the spectrum of implant experience
In clinical trials, WATCHMAN provided comparable results to warfarin for the prevention of all-stroke events
Superiority for hemorrhagic stroke and CV mortality
Consistent efficacy over entire device experience
Additional reductions in bleeding events after warfarin and clopidogrel therapy

17. Paradigm Shift: Reimbursement and Coverage

18. CMS NCD: Highlights
Eligible patients must have a CHADS2 score ≥2 or a CHA2DS2-VASc score ≥3
Documented evidence of a formal shared decision interaction between the patient and an independent, non-interventional physician
Patients must be suitable for short-term warfarin, but deemed unable to take long-term oral anticoagulation  
Procedure must be performed:
in a hospital with an established structural heart disease or electrophysiology program.
by an IC or EP meeting the following criteria:
Trained by the manufacturer
≥25 interventional cardiac procedures involving transseptal punctures through an intact septum
Continues to perform  ≥25 interventional cardiac procedures involving transseptal punctures through an intact septum, with at least 12 being LAAC over a two year period
Patients must be enrolled in a prospective national registry

19. Cost Effectiveness of LAAC versus warfarin and NOACs
Reddy, V.Y. et al. J Am Coll Cardiol. 2015; 66(24):2728–39.

20. Paradigm Shift: Future Device and Clinical Trials

21. WATCHMAN FLX™ LAA Closure Device Next Gen Design Goals

22. WATCHMAN FLX™ LAA Closure Device Next Gen Design Goals

23. ASAP-TOO Study Design Prospective, randomized, multi-center, global
Patients with non-valvular atrial fibrillation deemed not suitable for oral anti-coagulation therapy to reduce the risk of stroke.
Randomized 2:1 (WATCHMAN vs Control)
Considering Group Sequential Design
Allows early looks; potential to stop early for benefit
900 subjects at up to 100 global sites
Follow-Up*
45 Day with TEE
6,18 month phone visit
12 month with TEE
Years 2-5 annually
* Brain imaging required at baseline if prior stroke or TIA
* Brain imaging required at baseline if prior stroke or TIA

24. ASAP-TOO Reasons for OAC Unsuitability
History of overt bleeding related or unrelated to oral anticoagulants:
Prior history of intracranial or subdural hemorrhage. Other major organ bleeding including: gastrointestinal, genitourinary, ocular, spinal, pulmonary retroperitoneal, pericardial, or ENT
Epistaxis requiring ER visit, hospitalization or physician intervention
Increased risk of bleeding or bleeding tendencies:
Gastrointestinal lesions
Inflammatory bowel disease, peptic ulcer disease
History of falls/seizures and with a likelihood of recurrent falls
Cerebral amyloid angiopathy
Significant thrombocytopenia (level TBD, consider < 50 x 109/L)
Need for long term dual antiplatelet therapy
HAS-BLED ≥3
Contraindications to warfarin and/or DOAC
Severe renal failure (GFR <30)
Allergy to the above agents
Other reasons:
Lifestyle or occupational bleeding risk, or
Poor control on warfarin (time in therapeutic range <50%) and intolerance to the NOACs, or
Patient refusal or inability to take oral anticoagulants, or
Other medical or social reasons that make OATs unsuitable

25. ASAP -TOO Endpoints Primary Effectiveness Endpoint
The occurrence of ischemic stroke and systemic embolism at 24-months.
Primary Safety Endpoint
Same as historical WATCHMAN studies

26. ASAP -TOO Inclusion Criteria
The patient has documented paroxysmal, persistent, permanent or long-term/longstanding persistent non-valvular atrial fibrillation (i.e., the patient has not been diagnosed with rheumatic mitral valvular heart disease)
The patient has a calculated CHA2DS2-VASc score of 2 or greater
The patient is deemed by their physician to be unsuitable for oral anticoagulation 
The patient is deemed by their physician to be suitable for the defined protocol pharmacologic regimen of aspirin and clopidogrel* therapy following WATCHMAN FLX Closure Device implant.
*Ticagrelor may be used in place of clopidogrel if patient has other indication  Initial

27. Thank You