System Chief of Cardiovascular President, Lankenau Heart ......2012 – CAP2 Registry. Non-Randomzied. Add’l patients and follow -up. 2017 ASAP TOO. Randomized. US Indication Expansion

William A. Gray MDSystem Chief of Cardiovascular

Services, Main Line HealthPresident, Lankenau Heart Institute

Wynnewood, PennsylvaniaUSA

Main Line HealthLankenau Heart Institute

What does “Guilty until Effective” mean?


“A fact is a simple statement that everyone believes. It is innocent unless found guilty.

A hypothesis is a novel suggestion that no one wants to believe. It is guilty, until found effective.”

Edward Teller

SH 286002 AD MAY2017

Despite NOAC Adoption and Ability to Switch NOACs, Adherence to Anticoagulation Remains a Challenge

Source: Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb Haemost. 2015 Dec 22;115(1):31-9. doi: 10.1160/TH15-04-0350.

~30% of NOAC patients stop taking any drug at 2 years

Connection Between Non-Valvular AF-Related Stroke and the Left Atrial Appendage

AF Creates Environment for Thrombus Formation in Left Atrium

1. Stoddard et al. Am Heart J. (2003)2. Goldman et al. J Am Soc Echocardiogr (1999)3 Blackshear JL. Odell JA., Annals of Thoracic Surg (1996)

• Stasis-related LA thrombus is a predictor of TIA1 and ischemic stroke2.

• In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA3.

IC-302501-AD APR 2017

Transcatheter LAA OcclusionSelf-expanding nitinol cage, circa 2002

PLAATO Device

Lankenau Heart InstituteMain Line Health

IC-302501-AD APR 2017

WATCHMAN™Left Atrial Appendage Closure Device

Manufacturer: Boston Scientific

Intra-LAA design

160 µm Polyethylene terephthalate (PET) cap

PET cap designed to block emboli from exiting the LAA

PET cap intended to promote endothelialisation during healing process1,2,3

10 active fixation anchors around device perimeter engage LAA tissue for stabilityand retention

Nitinol frame radially expands to maintain position in LAA

Engineered to conform to the individualanatomy of the LAA

Size metrics: 21, 24, 27, 30, 33 mm (diameter)

1. Data on file Boston Scientific2. Schwartz et al., Healing Stages of Intracardiac Devices. JACC vol. 3. 870-7. 20103. Kar et al. Anatomical Impact of LAA Closure Devices. JACC: Cardiovascular Interventions. Vol. 7: 801-9, 2014

Anchors

160 µm PET fabric cap

Nitinol frame

IC-302501-AD APR 2017

Watchman Implant

Final 3D Echo shows flat

device surface

IC-302501-AD APR 2017

Watchman Implant

45 day TEE Canine at 45 days


Mar 2015FDA Approval2002 – Pilot

nonrandomizedFeasibility and Safety

2005 – PROTECT AFRandomizedComparison: warfarin

2008 – CAP Registrynon-randomizedAdd’l patients and follow-up

2009 – ASAPnon-randomizedPatients Contra-indicated to warfarin*

2010 – PREVAILRandomziedComparison: warfarin

2013 EWOLUTION, WASP Registriesnon-randomizedReal-world, All comers

2016 NCDR LAAO RegistryPost-approval statistical analysis

2012 – CAP2 RegistryNon-RandomziedAdd’l patients and follow-up

2017 ASAP TOORandomizedUS Indication Expansion Worldwide study

Apr 2009FDA Panel #1

Dec 2013FDA Panel #2

Oct 2014FDA Panel #3

WATCHMAN Clinical ProgramMore than 2,400 patients and nearly 6,000 patient-years of follow-up


PROTECT AFCAP

RegistryPREVAIL CAP2

Registry

Enrollment 2005-2008 2008-2010 2010-2012 2012-2014

Purpose

Demonstrate safety and effectiveness of the

WATCHMAN implant compared to long-term

warfarin

Continued Access Registry

Demonstrate safety and effectiveness of

the WATCHMAN implant compared to long-term warfarin

Continued Access Registry

Study Design 2:1 Randomized, non-inferiority Non-randomized2:1 Randomized,

non-inferiority Non-randomized

Primary Endpoints

1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death

2. Safety: Life-threatening events, which include device embolization requiring retrieval and

bleeding events

1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death

2. Effectiveness: Ischemic stroke or systemic embolism, occurring after 7 days post-randomization or WATCHMAN implant

procedure3. Safety: Death, ischemic stroke, systemic

embolism and procedure/device-related complications within 7 days of implantation

procedure


PROTECT AF

CHA2DS2-VASc Score ≥2

93%

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5 6-90%

10%

20%

30%

40%

50%

0 1 2 3 4 5 6-9

CAPPREVAILCAP2

Pat

ient

s (%

)

CHA2DS2-VASc Score

96%100%100%

AHA/ACC/HRS Guidelines (2014); Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):2614-2623. N

Most patient studied were had significant stroke risk and were good candidates for warfarin


Most patients had at least moderate bleeding risk

0%

10%

20%

30%

40%

50%

60%

70%

80%

0 2 3+

Patients (%)

HAS BLED* Score

PROTECT AFCAPPREVAILCAP2


WATCHMAN Clinical DataStroke reduction efficacy


HR p-valueEfficacy 0.79 0.22

All stroke or SE 1.02 0.94

Ischemic stroke or SE 1.95 0.05

Hemorrhagic stroke 0.22 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

0.01 0.1 1 10

Favors WATCHMAN Favors warfarin

Hazard Ratio (95% CI)Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):2614-2623.

PROTECT AF and PREVAIL:Watchman comparable to warfarin


N.B.-PREVAIL had an atypically low stroke rate on warfarin

Trial (Warfarin Arm)Ischemic Stroke

Rate per 100 pt-yrs Mean CHADS2

PREVAIL 2.6

PROTECT AF 2.2

RE-LY1 2.1

ROCKET AF1 3.5

ARISTOTLE1 2.1

ENGAGE2 2.8

1 Miller. AJC (2012) 2 Giugliano. NEJM (2013) Rate per patient-years

0.3

1.1

1.2

1.42

1.05

1.25

0.1 1 10

N


PROTECT AF: Once procedure related embolism is removed embolic stroke

prevention efficacy equivalent

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

WATCHMAN Control

Patie

nts

with

Isch

emic

Str

oke(

%)

Non-Procedure

related

6 Procedure related Strokes (primarily air emboli)


Watchman may reduce ischemic stroke by 67-83% over no therapy

* Imputation based on published rate with adjustment for CHA2DS2-VASc score (3.0); Olesen JB. Thromb Haemost (2011)

0

1

2

3

4

5

6

7

8

PROTECTAF

PREVAILOnly

CAP

Imputed IschemicStroke Rate*

ObservedWATCHMANIschemic StrokeRate

Isch

emic

Str

oke

(Eve

nts/

100

Patie

nt-Y

ears

)

79%Relative

Reduction

67%Relative

Reduction

83%Relative

Reduction

Baseline CHA2DS2-VASc = 3.5



FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract)


Watchman disabling stroke reduction superior to warfarin in PROTECT AF

PROTECT AF

Event Rate (per 100 pt-yrs)

Rate Ratio(95% CrI)

Posterior Probabilities, %

WATCHMANN=463

WarfarinN=244

Non-Inferiority Superiority

Stroke (all) 1.5 2.2 0.68 (0.42, 1.37) >99 83

Disabling 0.5 1.2 0.37 (0.15, 1.00) >99 98

Non-disabling 1.0 1.0 1.05 (0.54, 2.80) 89 34

Bayesian – Posterior prob for NI must be ≥97.5%; Posterior Prob for Superiority must be >95%Reddy, et al. JAMA. 2014

Disabling stroke defined as Modified Rankin Score 3-6

N

63% reduction in disabling/fatal strokes with WATCHMAN


Watchman Efficacy: Bleeding Reduction


Bleeding risks compound over patient lifetime

CHA2DS2-VASc*Score

Annual % Stroke Risk HAS-BLED** Score

Annual % Bleed Risk

10-Year Bleeding

Risk (%)***

0 0 0 0.9 8.6

1 1.3 1 3.4 29.2

2 2.2 2 4.1 34.2

3 3.2 3 5.8 45.0

4 4.0 4 8.9 60.6

5 6.7 5 9.1 61.5

* 2014 AHA / ACC / HRS Guidelines** Lip. JACC (2011)

*** Assumes constant risk despite increasing age and bleeding risk is independent from bleeding risk in previous years

N


72% major bleeding reduction long-term post-implant

LAAC(n=732)

Long-term warfarin(n=382) Rate

RatioP

valueBleeding Rate(n events / N at risk)

Event Rate per100 pt-yrs

(n events / N at risk)

Bleeding Rate(n events/N at risk)

Event Rate per100 pt-yrs

(n events / N at risk)

Overall 10.8 (79/732)3.5

(79/2268)11.3

(43/382)3.6

(43/1187) 0.96 0.84

Post Procedure

5.9(40/682)

1.8 (40/2255)

11.3(43/381)

3.6(43/1180) 0.49 0.001

Destination 3.2 (19/601)1.0

(19/19589.7

(35/360)3.5

(35/1004) 0.28 5mm, patients remained on warfarin + ASA until seal documented, skipping the clopidogrel + ASA pharmacotherapy

Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932

Overall period defined as after randomization to the end of follow-up; post-procedural period as >7 days after randomization to the end of follow-up; destination therapy period as beyond 180 days post-randomization, when patients assigned to LAA closure were eligible to receive aspirin alone.


Landmark analysis of bleeding outcomes

p < 0.001

Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932

72% reduction in major bleed>6 months post-procedure

Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals


Procedural Success and Safety


Procedural success

Implant success defined as deployment and release of the device into the LAA; no leak ≥ 5 mm

~50% new operators

~70% new operators performed 50% of

procedures


Improving and favorable procedural safety profile

9.9%

4.8%4.1% 4.1% 3.8%

2.8%

0%

2%

4%

6%

8%

10%

12%

PROTECT AF1st Half

PROTECT AF2nd Half

CAP PREVAIL CAP2 EWOLUTION*

Patients With

Safety Event w/i

7 days(%)

N=232 N=231 N=566 N=269 N=579 N=10191


Individual components of MAE

0%

1%

2%

3%

4%

5%

PROTECT AF (n=463)CAP (n=566)PREVAIL (n=269)CAP2 (n=579) EWOLUTION (n=1021)US Cohort (n=3822)

Com

plic

atio

n R

ates

Pericardial TamponadeProcedure-Related StrokeDevice EmbolizationProcedure-Related Death

Clinical Trial Experience Post Approval Experience


Net clinical benefit assessment


Watchman-enabled warfarin discontinuation

Warfarin Cessation with WATCHMAN

92% 99%45 Days

92% of patients were able to discontinue warfarin after 45 days, with 99% able to discontinue after 1 year3

92%92%

99%

1 Year


Future Patient Populations


ASAP registry O:E

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 CHADS₂ Score

Expected, ifClopidogrel was usedthroughout follow-up

Observed rate inASAP

Isch

emic

Stro

ke R

ate

(%/p

t-yr)

Ischemic Stroke

77% Reduction

64% Reduction

Reddy et al. JACC 2013; 61(25): 551–6.


Registry on WATCHMAN Outcomes in Real-Life Utilization: EWOLUTION

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 FUInvestigator and Medical Safety Group for adjudication

Patient Population: >1000 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

Boersma LVA, et al. HRS2017; Late Breaking Clinical Trials: Chicago IL, USA.


EWOLUTION: patient flow up to 1-year

Implant of WATCHMAN:N = 1020

Informed consent obtained: N = 1025

Patients with successful Watchman implant:

N = 1005

Anatomy considered not suitable at prescreening: N = 5

Active Pts @ 1 year: N = 893/1005 (89%)

Pts with TEE: N = 875/1005 (87%)

Active Pts with > 11m of data: 804/893 (91%)

End of study < 1 year (N = 112)Deceased: N = 91Withdrawn: N = 8Lost To FU: N = 13


EWOLUTION:Single antiplatelet/no therapy subgroup

baseline characteristics:Characteristic Single AP/no therapy cohort(n=766)

Age (median[IQR]) 74 (67, 79)

Congestive heart failure 34%Hypertension (uncontrolled or history) 87%

Age ≥ 80 years 24%Diabetes (Type I or Type II) 28%Prior Stroke Ischemic / Hemorrhagic 20% / 16%Vascular disease 39%Female gender 40%Abnormal renal / liver function 14% / 4%Prior Major Bleed or predisposition to bleeding 37%

CHADS2 score 2.8 ± 1.3CHA2DS2-VASc score 4.4 ± 1.6HAS-BLED ≥ 3 38%Contra-indication OAC 72%

M.W. Bergmann et al, TCT 2018


EWOLUTION – antiplatelet/OAC treatment at follow-up

766 patients were identified who were on single AP/no therapy for ≥ 12 months (or until study completion) or with events while on single AP/no

therapy. Median (IQR) time on single/none: 559 (464, 663) days

IMPLANT

FIRST CHANGE

2-YR FU

NoneSAPT

DAPT(N)OAC

6% 7%

60%

27%8%

58%

26%

8%

14%

71%

7%

8%

• subgroup representative of whole study population

• postprocedural drug therapy at the discretion of the individual operator

• peri-device leakage or device-thrombus not a reason for continued DAPT or OAC (imaging available)

• several characteristics identified in patients not included in this subgroup (comorbitities like ACS, lost for FU, non-CV mortality) -unrelated to device, procedure or clinical endpoint

study population



EWOLUTION: low annual stroke rate in full cohort

7.2%

10.1%

1.1%1.5%

0%

2%

4%

6%

8%

10%

12%

Ischemic Stroke Ischemic Stroke/TIA/SE

Expected, based onCHA2DS2-VASc*Observed inEWOLUTION

RR 84%

RR 85%

*Effectiveness in stroke reduction vs. estimated in the absence of therapy for comparable CHA2DS2-VASc scores based on Friberg et al. EHJ 2012


EWOLUTION:low annual bleeding rate in full cohort

5.0% 5.0%

2.6%2.3%

0%

1%

2%

3%

4%

5%

6%

Major Bleeding Major Bleeding Excl. Procedural

Expected, based on HAS-BLED* Observed in EWOLUTION

RR 48%

RR 54%

*Effectiveness in bleeding reduction vs. estimated under VKA therapy for comparable HAS-BLED scores based on Lip et al. JACC 2011

These data are for the full cohort of patients, 73% of whom may be contraindicated in the US per current labelingBoersma LVA, et al. HRS2017; Late Breaking Clinical Trials: Chicago IL, USA.


EWOLUTION:low event rates in warfarin-eligible patients

6.4%

1.1%

0%

2%

4%

6%

8%

10%

Ischemic Stroke

Expected, based onCHA2DS2-VASc*

Observed in EWOLUTION

RR 83%

4.7%

1.7%

0%

2%

4%

6%

8%

10%

Major Bleeding

Expected, based onHAS-BLED**Observed in EWOLUTION

RR 65%

*Estimated rates in absence of therapy based on Friberg et al. EHJ 2012

**Estimated rates under VKA therapy based on Lip et al. JACC 2011


single AP/no therapy : ischemic stroke eventsischemic stroke after switch to single AP/no therapy

Days

14 ischemic strokesRate 1.3 / 100 pt-yrs

Disabling strokes: 2/14Fatal Strokes: None



ASAP-TOO (NCT02928497):Overview

Study Objective Evaluate LAA Closure with WATCHMAN in NVAF patients deemed not suitable for oral anti-coagulation therapy

Study DesignProspective, multi-centerRandomized 2:1 (Watchman vs Control)Considering Group Sequential Design

Primary Endpoint

Effectiveness EndpointTime to first occurrence of ischemic stroke or systemic embolism

Safety Endpoint7-day rate of all-cause death, ischemic stroke, systemic embolism, or device- or procedure- related events requiring open cardiac surgery or major endovascular intervention

Patient Population 888

Number of Sites 100 global sites

Follow-up*

• 45 Day with TEE• 6,18 month phone visit• 12 month with TEE• Bi-annually for years 2-5

• Brain imaging required at baseline if prior stroke or TIAHolmes et al. AHJ 2017; in press


LAAO: Endocardial vs. PericardialNo LA foreign bodyEase of delivery

Closure EfficacyComplications

Mark Reisman MD

IC-302501-AD APR 2017

Next generation devices: Watchman FLEX, AMULET, WAVECREST and UltraSeal

WaveCrestAMULETWatchman FLEX

Cardia UltraSeal


Thank you

William A. Gray MD�System Chief of Cardiovascular Services, Main Line Health�President, Lankenau Heart Institute�Wynnewood, Pennsylvania�USA�What does “Guilty until Effective” mean?Slide Number 3Despite NOAC Adoption and Ability to Switch NOACs, Adherence to Anticoagulation Remains a ChallengeConnection Between Non-Valvular AF-Related Stroke and the Left Atrial AppendageTranscatheter LAA Occlusion�Self-expanding nitinol cage, circa 2002WATCHMAN™�Left Atrial Appendage Closure DeviceWatchman ImplantWatchman ImplantWATCHMAN Clinical Program �More than 2,400 patients and nearly 6,000 patient-years of follow-up Slide Number 11Most patient studied were had significant stroke risk and were good candidates for warfarinMost patients had at least moderate bleeding riskWATCHMAN Clinical Data�Stroke reduction efficacyPROTECT AF and PREVAIL:�Watchman comparable to warfarinN.B.-PREVAIL had an atypically low stroke rate on warfarinPROTECT AF: Once procedure related embolism is removed embolic stroke prevention efficacy equivalentWatchman may reduce ischemic stroke by 67-83% over no therapy Watchman disabling stroke reduction superior to warfarin in PROTECT AFWatchman Efficacy: Bleeding Reduction�Bleeding risks compound over patient lifetime72% major bleeding reduction long-term post-implantLandmark analysis of bleeding outcomesProcedural Success and Safety�Procedural successImproving and favorable procedural safety profile �Individual components of MAENet clinical benefit assessmentSlide Number 29Watchman-enabled warfarin discontinuation Future Patient Populations�ASAP registry O:E Registry on WATCHMAN Outcomes in Real-Life Utilization: EWOLUTIONEWOLUTION: �patient flow up to 1-yearEWOLUTION:�Single antiplatelet/no therapy subgroup�baseline characteristics:EWOLUTION – antiplatelet/OAC treatment at follow-upEWOLUTION: �low annual stroke rate in full cohortEWOLUTION:�low annual bleeding rate in full cohortEWOLUTION:�low event rates in warfarin-eligible patientssingle AP/no therapy : ischemic stroke eventsASAP-TOO (NCT02928497):�OverviewLAAO: Endocardial vs. PericardialSlide Number 43Next generation devices: �Watchman FLEX, AMULET, WAVECREST and UltraSealThank you

Documents

System Chief of Cardiovascular President, Lankenau Heart ......2012 – CAP2 Registry. Non-Randomzied. Add’l patients and follow -up. 2017 ASAP TOO. Randomized. US Indication Expansion