Marc Unterman, M.D. • Interventional Cardiologist at Gwinnet Medical Specialists • American Board of Internal Medicine • American Board of Internal Medicine Cardiovascular • Interventional Cardiology – Subspecialty • Special interests Include: Interventional Cardiology, Coronary Angioplasty, Coronary Atherectomy, Intracoronary Stents, and Peripheral Vascular Angioplasty. Medical School: Emory University School Of Medicine Residency: Grady Health System Fellowship: University of Cincinnati
1. Marc Unterman, M.D. Interventional Cardiologist at Gwinnet
Medical Specialists American Board of Internal Medicine American
Board of Internal Medicine Cardiovascular Interventional Cardiology
Subspecialty Special interests Include: Interventional Cardiology,
Coronary Angioplasty, Coronary Atherectomy, Intracoronary Stents,
and Peripheral Vascular Angioplasty. Medical School: Emory
University School Of Medicine Residency: Grady Health System
Fellowship: University of Cincinnati Hospital
2. WATCHMAN Clinical Summary
3. WATCHMAN LAAC Device Background People with AF have 5 times
the risk of stroke compared to people without AF1 Stroke more
severe with AF 70% chance of death or permanent disability1 The
economic burden of stroke will rise globally as the incidence
increases2 1. Holmes DR. Seminars in Neurology. 2010;30:528536 2.
Klein A et al, Datamonitor. July 2011. 3. Blackshear JL. Odell JA.,
Annals of Thoracic Surgery. 1996;61:755-759 In non-valvular AF,
>90% of stroke-causing clots that come from the left atrium are
formed in the LAA3 The WATCHMAN LAAC device is intended to reduce
the risk of stroke by closing off the left atrial appendage.
4. WATCHMAN Evidence-Based Medicine 2012: ESC Guidelines &
Expanded Indication 2002 Pilot Endpoints: Feasibility and Safety
Comparison: nonrandomzed Incl/Excl: CHADS21, able to tolerate
warfarin 2005 PROTECT AF Endpoints: Safety and Efficacy Comparison:
warfarin Incl/Excl: CHADS2 1, able to tolerate warfarin 2008 CAP
Registry Endpoints: Collect safety & efficacy data to be pooled
with PROTECT AF Incl/Excl: same as PROTECT AF 2009 ASAP Endpoint:
Efficacy Comparison: CHADS2 score expected stroke rate Incl/Excl:
intolerant or contra-indicated for warfarin 2010 PREVAIL Endpoint:
Safety and Efficacy Comparison: warfarin Incl/Excl: CHADS22, some
exceptions for CHADS2=1 no clopidogrel within 7 days of procedure
2013 EU & Asia Registries Endpoint: Additional information in a
real-world setting Incl/Excl: All comers 2014 PREVENT (Post
Approval Study) Endpoint: Additional information in a real-world
setting Incl/Excl: US Indication
5. All Studies: Favorable Procedural Safety Profile for 7-day
Safety Events 9.9% 4.8% 4.1% 4.1% 3.8% 0.0% 2.0% 4.0% 6.0% 8.0%
10.0% 12.0% CAP PREVAIL CAP2 Patients with Safety Event (%) PROTECT
AF 1st Half 2nd Half N=232 N=231 N=566 N=269 N=579 All Device
and/or procedure-related serious adverse events within 7 Days
including composite of vascular complications such as cardiac
perforation, pericardial effusion with tamponade, ischemic stroke,
device embolization, and other vascular complications such as PE
not necessitating intervention, AV fistula, major bleeding
requiring transfusion, pseudoaneurysm, hematoma and groin bleeding
1 FDA Panel October 2014.
6. PROTECT AF 4 Year: Primary Efficacy Endpoint a Events per
100 patient-years (95% credible interval); b Composite of stroke,
systemic embolization, or cardiovascular/unexplained death For
Bayesian analysis, a posterior probability of 97.5% represents
non-inferiority; 95% represents superiority. Reddy, VY et al. JAMA.
2014; 312(19):1988-1998.
7. 2.3 1.5 1.0 0.5 3.8 2.2 2.4 1.2 0 1 2 3 4 5 6 Primary
Efficacy All Stroke CV or Unexplained Death Disabling Stroke
PROTECT AF 4 Year: Results Rateper100patientyears PS = 96% 40%
lower WATCHMAN N=463 Warfarin N=244PN = Posterior Probability for
Non-Inferiority Ps = Posterior Probability for Superiority
Disabling or fatal strokes were those with an MRS of 3-6 post
stroke. Non-disabling were those with an MRS of 0-2 post stroke.
For Bayesian analysis, a posterior probability of 97.5% represents
non-inferiority; 95% represents superiority. PN > 99% 32% lower
PS = 99% 60% lower PS = 98% 63% lower Reddy, VY et al. JAMA. 2014;
312(19):1988-1998.
8. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 ` CAP & PROTECT:
Consistent Efficacy, No Signal of Increased Late Events Primary
Efficacy Event-free Probability Time (years) PROTECT AF PROTECT AF
CAP CAP 463 382 360 337 321 235 566 503 468 435 293 59 3.5 1.6 3.9
1.5 CHA2DS2-VASc Score FDA Panel October 2014. PAF=2717 Pt yrs,
CAP=2022 Pt yrs
9. PREVAIL Trial Primary Endpoints At the protocol
pre-specified endpoint evaluation (all patients completed minimum
of 6 months follow-up)1: Safety: Acute (7-day) occurrence of death,
ischemic stroke, systemic embolism and procedure or device related
complications requiring major cardiovascular or endovascular
intervention Endpoint Success: 6 events in device group = 2.2%
(6/269) 1st Primary Efficacy: Comparison of composite of stroke,
systemic embolism, and cardiovascular/unexplained death Similar
18-month event rates in both device and control groups = 0.064 vs.
0.063 Upper credible interval crossed pre-specified bound for
non-inferiority 2nd Primary Efficacy: Comparison of ischemic stroke
or systemic embolism occurring >7 days post randomization
Endpoint met in the presence of an over performing control group
Upper credible interval crossed pre-specified bound for
non-inferiority with additional follow-up2 1Holmes, DR et al. JACC.
2014; 64(1):1-12 2 FDA Panel October 2014. PREVAIL=860 Pt yrs The
PREVAIL trial results published in JACC are based on the final
pre-specified analysis from January 2013.
10. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 PROTECT AF, CAP, and
PREVAIL Consistent WATCHMAN Efficacy Free from Efficacy Primary
Endpoint (%) Time (years) 463 382 360 337 321 235 566 503 468 435
293 59 269 234 182 37 0PREVAIL PROTECT AF CAP PREVAIL PROTECT AF
CAP EC-15 FDA Panel October 2014. PAF=2717 Pt yrs; CAP=2022 Pt yrs;
PREVAIL=860 Pt yrs
11. PREVAIL: Warfarin Ischemic Stroke Rate Differs from Other
Trials Trial (Warfarin Arm) Ischemic Stroke Rate per 100 pt-yrs
Mean CHADS2 PREVAIL2 2.6 PROTECT AF1 2.2 RE-LY3 2.1 ROCKET AF3 3.5
ARISTOTLE3 2.1 ENGAGE4 2.8 Rate per Patient-years 0.3 1.1 1.2 1.42
1.05 1.25 0.1 1 10 1Reddy, VY et al. JAMA. 2014; 312(19):1988-1998.
2Holmes, DR et al. JACC. 2014; 64(1):1-12 3Miller. AJC (2012).
4Giugliano. NEJM (2013)
12. Rate of Success with implantation in warfarin
contraindicated patients Patients had a history of hemorrhagic
& bleeding tendencies or a hypersensitivity to warfarin 150
patients enrolled at 4 European centers Average CHADS2 = 2.8 Post
procedure anti-platelet regimen Clopidogrel through 6 months
Aspirin indefinitely Patients were followed for up to 1 year
Follow-up @ 3, 6, 12, 18 & 24 months TEE at 3 and 12 months
ASAP 150 AF patients contraindicated for long term warfarin therapy
94.7% successfully implanted Reddy, et al. JACC 2013;
61(25):25516
13. 7.3% 5.0% 1.7% 0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% 7.0% 8.0%
Expected, based on CHADS Score Expected, if Clopidogrel was used
throughout follow-up Observed rate in ASAP ASAP Reduction in
ischemic stroke versus expected rate IschemicStrokeRate(%/pt-yr)
77% Reduction 64% Reduction Reddy, et al. JACC 2013;
61(25):25516
14. WATCHMAN Pilot Study 6-year Follow-up 4.8% 0.5% 0.0% 1.0%
2.0% 3.0% 4.0% 5.0% 6.0% IschemicStrokeRate(%/pt-yr)* Expected,
based on CHADS Score of 1.8 Observed rate in 6 year follow up *One
stroke at 2 months and one at 39 months in the setting of severe
carotid disease 90% Reduction 2 embolic strokes over 6 years of
follow up* 90% reduction when compared to a CHADS expected stroke
rate Sick , et al., WATCHMAN Pilot data; ESC 2012
15. WATCHMAN Robust Clinical Portfolio >2,500 patients with
>6,000 patient years follow-up Significantly improved safety
results2 and efficacy consistent with PROTECT AF1,5 Pilot Early
feasibility with >6 years of follow-up Consistent procedural
safety results5 CAP Registry CAP2 WATCHMAN primary efficacy, CV
death, and less disabling strokes superior to warfarin at 4 years1
Expected rate of stroke reduced by 77% in patients contraindicated
to warfarin3 Improved implant success procedure safety confirmed
with new and experienced operators4 PROTECT-AF ASAP PREVAIL 1
Reddy, VY et al. JAMA. 2014; 312(19):1988-1998. 2 Reddy, VY et al.
Circ. 2011;123:417-424; 3 Reddy, et al. JACC 2013; 61(25):25516. 4
Holmes, DR et al. JACC. 2014; 64(1):1-12. 5 FDA Panel October
2014.
16. ABBREVIATED STATEMENT (US) WATCHMANTM Left Atrial Appendage
Closure Device with Delivery System and WATCHMAN Access System
INDICATIONS FOR USE The WATCHMAN Device is indicated to reduce the
risk of thromboembolism from the left atrial appendage in patients
with non-valvular atrial fibrillation who: Are at increased risk
for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc
scores and are recommended for anticoagulation therapy; Are deemed
by their physicians to be suitable for warfarin; and Have an
appropriate rationale to seek a non-pharmacologic alternative to
warfarin, taking into account the safety and effectiveness of the
device compared to warfarin. The WATCHMAN Access System is intended
to provide vascular and transseptal access for all WATCHMAN Left
Atrial Appendage Closure Devices with Delivery Systems.
CONTRAINDICATIONS Do not use the WATCHMAN Device if: Intracardiac
thrombus is visualized by echocardiographic imaging. An atrial
septal defect repair or closure device or a patent foramen ovale
repair or closure device is present. The LAA anatomy will not
accommodate a device. See Table 46 in the DFU. Any of the customary
contraindications for other percutaneous catheterization procedures
(e.g., patient size too small to accommodate TEE probe or required
catheters) or conditions (e.g., active infection, bleeding
disorder) are present. There are contraindications to the use of
warfarin, aspirin, or clopidogrel. The patient has a known
hypersensitivity to any portion of the device material or the
individual components (see Device Description section) such that
the use of the WATCHMAN Device is contraindicated. WARNINGS Device
selection should be based on accurate LAA measurements obtained
using fluoro and ultrasound guidance (TEE recommended) in multiple
angles (e.g., 0, 45, 90, 135). Do not release the WATCHMAN Device
from the core wire if the device does not meet all release
criteria. If thrombus is observed on the device, warfarin therapy
is recommended until resolution of thrombus is demonstrated by TEE.
The potential for device embolization exists with cardioversion 90%
of stroke-causing clots that come from the left atrium are formed
in the LAA3.
22. SH 286002 AB MAR 2015 2014 AHA/ACC/HRS Treatment Guidelines
to Prevent Thromboembolism in Patients with AF Assess stroke risk
with CHA2DS2-VASc score Score 1: Annual stroke risk 1%, oral
anticoagulants or aspirin may be considered Score 2: Annual stroke
risk 2%-15%, oral anticoagulants are recommended Balance benefit
vs. bleeding risk 2014 AHA/ACC/HRS Guideline for the Management of
Patients with AF January, CT. et al. 2014 AHA/ACC/HRS Guideline for
the Management of Patients With Atrial Fibrillation. JACC. 2014;
doi: 10.1016/j.jacc.2014.03.022
23. SH 286002 AB MAR 2015 Oral Anticoagulation is Standard of
Care, but Not Ideal for All Warfarin Bleeding risk Daily regimen
High non-adherence rates Regular INR monitoring Food and drug
interaction issues Complicates surgical procedures Novel Oral
Anticoagulants Bleeding risk Daily regimen High non-adherence rates
Complicates surgical procedures Lack of reversal agents High cost
1. Piccini, et al.. Pharmacotherapy in Medicare beneficiaries with
atrial fibrillation. Heart Rhythm. 2012;9:1403-1408 0% 10% 20% 30%
40% 50% 60% 70% 80% 90% 100% 1 2 3 4 5 6 CHADS2 Score p < 0.001
(n=27,164) AFPatientsUsing Anticoagulation Anticoagulation Use
Declines with Increased Stroke Risk1
24. SH 286002 AB MAR 2015 Anticoagulant Therapy Carries Risk of
Intracerebral Hemorrhage or Death Spontaneous intra- parenchymal
bleed Hemorrhagic transformation
25. SH 286002 AB MAR 2015 Despite Increasing NOAC Adoption,
Overall Rate of Anticoagulation in High Risk NVAF Patients has Not
Improved 1. Jani, et al. Uptake of Novel Oral Anticoagulants in
Patients with Non-Valvular and Valvular Atrial Fibrillation:
Results from the NCDR-Pinnacle Registry. ACC 2014 Results from the
NCDR PINNACLE Registry1 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
2011 Q1 2011 Q2 2011 Q3 2011 Q4 2012 Q1 2012 Q2 2012 Q3 2012 Q4
Total on Oral Anticoagulation Warfarin NOACs Anticoagulant Use in
Patients with NVAF and CHADS2 2 n=25719 n=29194 n=31582 n=36490
n=67102 n=70667 n=70320 n=71396
26. SH 286002 AB MAR 2015 Discontinuation and Major Bleeding
Rates with NOACs 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% There is an unmet need of
stroke risk reduction for patients with AF who are seeking an
alternative to long-term OACs 1Connolly, S. NEJM 2009;
361:1139-1151 2 yrs follow-up (Corrected) 2Patel, M. NEJM 2011;
365:883-891 1.9 yrs follow-up, ITT 3Granger, C NEJM 2011;
365:981-992 1.8 yrs follow-up, 4Giugliano, R. NEJM 2013; 369(22):
2093-2104 2.8 yrs follow-up.
27. SH 286002 AB MAR 2015 WATCHMANTM Left Atrial Appendage
Closure Device First-of-its-Kind, Proven Alternative to Long-Term
Warfarin Therapy for Stroke Risk Reduction in Patients with
Non-Valvular Atrial Fibrillation The most studied LAAC device, and
the only one proven with long-term data from randomized trials or
multi-center registries Commercially available internationally
since 2009, with over 10,000 implants worldwide Registered in over
70 countries SH 286002 AB MAR 2015
28. SH 286002 AB MAR 2015 Favorable Procedural Safety Profile:
7-Day Safety Events 9.9% 4.8% 4.1% 4.1% 3.8% 0.0% 2.0% 4.0% 6.0%
8.0% 10.0% 12.0% CAP PREVAIL CAP2 Patients with Safety Event (%)
PROTECT AF 1st Half 2nd Half n=232 n=231 n=566 n=269 n=579 All
Device and/or procedure-related serious adverse events within 7
Days Learning Curve ~50% New Operators in PREVAIL Source: FDA Oct
2014 Panel Sponsor Presentation.
29. SH 286002 AB MAR 2015 Implant Success & Warfarin
Cessation p = 0.04 Study 45-day 12-month PROTECT AF 87% >93% CAP
96% >96% PREVAIL 92% >99% Implant success defined as
deployment and release of the device into the left atrial appendage
Warfarin Cessation PREVAIL Implant Success No difference between
new and experienced operators Experienced Operators n=26 96% New
Operators n=24 93% p = 0.28 PROTECT AF and CAP: Reddy, VY et al.
Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC
2014; 64(1):1-12.
30. SH 286002 AB MAR 2015 Most Studied LAAC Device. Only One
with Long-Term Clinical Data PROTECT AF CAP Registry PREVAIL CAP2
Registry Totals Enrollment 2005-2008 2008-2010 2010-2012 2012-2014
Enrolled 800 566 461 579 2406 Randomized 707 --- 407 --- 1114
WATCHMAN: warfarin (2:1) 463 : 244 566 269 :138 579 1877: 382 Mean
Follow-up (years) 4.0 3.7 2.2 0.58 N/A Patient-years 2717 2022 860
332 5931 Source: FDA Oct 2014 Panel Sponsor Presentation.
31. SH 286002 AB MAR 2015 Patient Risk Factors Across Trials
Characteristic PROTECT AF N=707 CAP N=566 PREVAIL N=407 CAP2 N=579
p-value CHADS2 Score 2.2 1.2 2.5 1.2 2.6 1.0 2.7 1.1