disclosure left atrial appendage (laa) and stroke · left atrial appendage (laa) and stroke kenneth...

1

Left Atrial Appendage (LAA) and Stroke

Kenneth C. Huber, MD, FACC CEO, Saint Luke’s Cardiovascular Consultants

Co-Executive Medical Director, Saint Luke’s Mid America Heart Institute

Professor of Medicine, UMKC School of Medicine

Kenneth C. Huber, MD, FACC

Disclosure

WATCHMAN Advisory Board – Boston Scientific

WATCHMAN Professional Training Event - Proctor

Learning Objectives

• At the conclusion of this session, the learner should be able to:

– Identify the role the Left Atrial Appendage (LAA) plays in stroke risk for patients with Atrial Fibrillation

– Review data on LAA closure as an alternative to oral anticoagulants for stroke prevention in patients with Atrial Fibrillation

– Develop strategies to incorporate LAA closure into contemporary clinical practice

LAA and Stroke

• Role of LAA in embolic stroke is in setting of patients with ATRIAL FIBRILLATION (AF)

Atrial Fibrillation An Epidemic

Savelieva, et al. Clin Cardiol 2008;31

5 Million

10 Million

Distribution of AF by Age

Over 50% of AF occurs in the 6% of the population ≥ 75 years of age

WM Feinberg, et al. Arch Int Med 1995;155:469-73

2

Atrial Fibrillation Stroke Risk • AF increases the risk of stroke 5-fold (5-6% annual risk)

• AF is responsible for 15-20% of all strokes

D.R. Holmes. Seminars in Neurology. 2010;30:528 Heart Disease and Stroke Statistical Update: 2009 Circulation, 1-27-09

Stroke 1991;22(18)

0%

10%

20%

30%

40%

50–59 60–69 70–79 80–89

% A

F S

tro

ke

s

Age (years)

• 800,000 strokes/yr in U.S. = 100,000 AF strokes/yr

Functional Impact of AF-Related Stroke

CATASTROPHIC

60% 30%

10%

DR Holmes. Seminars in Neurology 2010;30:528 HT Tu et al. Cerebrovascular Disease 2010;30(4):389

Death or Severe

Disability

50% = Hemiparesis 19% = Aphasia 26% = Dependent ADL 26% = Nursing Homes Generally occlude large intracranial arteries

No Disability/ Transient

Mod Dis

Atrial Fibrillation - Stroke

Pathophysiology

Linking-Diastolic Function, Left Atrial Size, and LAA Size and Function

Atrial Fibrillation as a Systemic Vascular Disease

Arterial Stiffness Microvascular Dysfunction Diastolic Dysfunction LA Enlargement

Neurohormonal (Ang II, TGF B) Tissue Factors (CTGF, MMPs) Vascular/Hemostatic (PDGF,

Endothelin-1) Oxidative/Inflammation (CRP)

Genetic/Telomere

Risk Factor Risk Marker

Modifier

Atrial Fibrillation

Hypertension

Obesity

Sleep Apnea

Sedentary Lifestyle

Thrombosis/Embolization

Electrical Fibrillation

Insufficient contraction of LAA

Stagnant blood flow

Thrombosis / clot formation

Thromboembolism

Stroke

Johnson, Eur J Cardiothoracic Surg 2000;17

Left Atrial Appendage Thrombosis

3

LAA – Culprit Location of Thrombi in Left Atrium

0

20

40

60

80

100

Sto

dd

ard

: J

AC

C, '9

5

Ma

nn

ing

: C

irc

, '9

4

Ab

erg

: A

cta

Me

d S

ca

n, '6

9

Ts

ai:

JF

MA

, '9

0

Kle

in:

Int

J C

ard

Im

ag

: '9

3

Ma

nn

ing

: C

irc

, '9

4

Kle

in:

Cir

c,

'94

Le

un

g: J

AC

C, '9

4

Ha

rt:

Str

ok

e, '9

4

To

tal

Left Atrial Appendage Left Atrium

Blackshear et al., Ann Thoracic Surg, 1996;61:755

Location

Fre

quency (

%) 90%

in

LAA

LAA Anatomy: Thrombi Haven

• LA: mostly smooth and “vein like” derived from sinus venosus

• LAA: derived from the embryonic/ primordial muscular atrium

LAA : Highly Variable Structure LAA Anatomy: Imaging Techniques

TEE CT Angio


Risk Assessment

Stroke Risk Stratification

CHADS2 Score Points

C = Congestive Heart Failure 1

H = Hypertension 1

A = Age > 75 1

D = Diabetes 1

S = Stroke 2

Maximum Score 6

CHA2DS2-VASC CHADS2 Score

Risk Factor Score

Congestive Heart Failure/LV dsyfunction 1

Hypertension 1

Age ≥ 75 2

Diabetes mellitus 1

Stroke/TIA/thrombo-embolism 2

Vascular disease 1

Age 65-74 1

Sex category (i.e., female sex) 1

Maximum Score 9

CHA2DS2-VASC Score

Patients (n=7329)

Adjusted Stroke Rate

0 1 0%

1 422 1.3%

2 1230 2.2%

3 1730 3.2%

4 1718 4.0%

5 1159 6.7%

6 679 9.8%

7 294 9.6%

8 82 6.7%

9 14 15.2%

Adjusted Stroke Rate (%/yr) by CHA2DS2-VASC Score

4

Comparing Risk Scores for the Prediction of Stroke in AF

18.9%

29.7%

51.4%

6.6% 10.8%

82.6%

0

20

40

60

80

100

Low Risk Moderate Risk High Risk

Pro

po

rtio

n o

f P

atie

nts

(%

)

CHADS2 CHA2DS2-VASc

H.A. van den Ham, et al. JACC 2015;66(17):1851-9

Why CHA2DS2-VASC?

• Patient:

– Female

– Age 72

– Diabetes,

– Vascular Disease

• CHADS2 = 1

• CHA2DS2-VASC = 4

• Greater discriminatory ability

Significant Limitations

• c-statistic 0.65

• Incomplete clinical variables

• Biomarkers absent

• Anatomic factors not considered

CHA2DS2-VASc Score for Stroke Prediction in AF: Stroke Rates for All Patients

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

1 2 3 4 5 6 7 8 9

CHA2DS2-VASc

36

5-d

ay S

tro

ke R

ate

Black Non-Black

R. Kabra, et al. JACC 2016;68:461-70

CHA2DS2-VASc-R Score

Order of Importance

CHA2DS2-VASc-R Factor

Univariate Models Multivariate Models

with All Patient Factors

Chi Square Relative Hazard Chi-Square Relative Hazard

1 History of Stroke 1,959.99 1.42, p<0.001 1,387.48 1.35, p<0.001

2 Age ≥ 75 yrs 1,296.73 1.95, p<0.001 906.27 1.77, p<0.001

2 Female 579.34 1.50, p<0.001 319.98 1.36, p<0.001

4 African American 323.74 1.60, p<0.001 197.18 1.45, p<0.001

5 Hypertension 243.87 1.44, p<0.001 23.80 1.13, p<0.001

6 Heart Failure 227.37 1.27, p<0.001 40.86 1.11, p<0.001

7 Other vascular

disease 173.28 1.23, p<0.001 1.30 1.02, p<0.001

8 Diabetes 118.63 1.19, p<0.001 40.45 1.11, p<0.001

R. Kabra, et al. JACC 2016;68:461-70

Relative Contribution of Each Risk Factor of CHA2DS2-VASc-R Score in Stroke Prevention

CHA2DS2-VASc-R = CHF, HTN, age≥75 yrs, DM, prior stroke, vascular disease, age 65-74, female sex, and African American ethniticy

CV Biomarker Score and Clinical Outcomes in Patients with Afib: Subanalysis of ENGAGE AF-TIMI 48 Clinical Trial

JAMA Cardiology. Oct 5, 2016

Biomarkers: • Troponin I • NT-proBNP • D-Dimer

Comparing Risk Scores for the Prediction of Stroke in AF

18.9%

29.7%

51.4%

6.6% 10.8%

82.6%

40%

11%

49%

0

20

40

60

80

100

Low Risk Moderate Risk High Risk

Pro

po

rtio

n o

f P

ati

en

ts (

%)

CHADS2 CHA2DS2-VASc ATRIA

H.A. van den Ham, et al. JACC 2015;66(17):1851-9

5

Prognostic Value of Low LAA Wall Velocity in Patients with Ischemic Stroke and AF

1.00

5.04

0

1

2

3

4

5

6

High TTE-LAWV>8.7cm/sec

Low TTE-LAWV<8.7cm/sec

Rel

ativ

e R

isk

H. Tamura et al. JASE 2012;25(5):576–583

Stroke Prevalence Based Upon Left Atrial Appendage Morphology

0

5

10

15

20

ChickenWing

Windsock Cactus Cauliflower

OR 0.2 (.04-0.8)

OR 1.1 (0.4-3.2)

OR 2.5 (1.0-6.1)

OR 2.0 (0.2-7.2)

4%

12%

0

2

4

6

8

10

12

14

Chicken Wing Non-ChickenWing

Stro

ke R

ate

(%

)

Stro

ke R

ate

(%

)

Di Biase, L, et al. JACC 2012


Therapies

Gold Standard Therapy

Johnson, Eur J Cardiothoracic Surg 2000;17

Electrical Fibrillation

Insufficient contraction of LAA

Stagnant blood flow

Thrombosis / clot formation

Thromboembolism

Stroke

2014 AHA/ACC/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with HF

• 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

– Threshold of Benefit > Risk

• 1.7% / yr for warfarin

• 0.9% / yr for NOAC 2014 AHA/ACC/HRS

Guideline for the Management

of Patients with AF

January, CT. et al.. JACC. 2014; doi: 10.1016/j.jacc.2014.03.022

Stroke Prevention: Medical Therapy: Oral Anticoagulants

Cornerstone of Therapy: Warfarin

Hart et al. Ann Int Med 1999;131:492-501

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

Aggregate

100% 50% 0 -50% -100%

Warfarin Better Control Better (placebo)

Reduction of all-cause mortality

RRR 26%

Reduction of stroke

RRR 62%

6

-5

-

-4

-

-3

-

-2

-

-1

INR

Over-a

nti-

coagula

ted

Under-a

nti-

coagula

ted

Therapeutic

Range

INR >3

doubles

incidence of

intracranial

hemorrhage

INR < 2

increases

stroke risk

70%

Oake N, et al. Can Med Assoc J. 2007:176(11);1589−1594 Budnitz, et al. Annals of Internal Medicine. 2007:147(11); 229 Baker WL, J. Manag Care Pharm 2009 Walker et al. Heart Rhythm Society 2008

Warfarin Problematic

33 37 27

48 54

63

19 9 11

0%

20%

40%

60%

80%

100%

GroupHealth

Cooperative

KaiserPermanente

SC

ATRIA

Above Range Within RangeBelow INR Range

(TTR)

Warfarin Problematic Relative/Absolute contraindication

in up to 40% of patients

25% Intolerant

15% Contraindicated

60% Treated

with Warfarin

WHY? Patel et al. Cariol Res Proct 2012;610827 Wysowski, Arch Int Med 2007;167:1414

Reynolds. Am J Cardiol 2006;97:538

Bleeding

• Cooper Metaanalysis Given:

– 51 ischemic strokes / 1000 pt-yr follow up

Warfarin Rx:

– Prevents 28 ischemic strokes (55% RR ↓)

– Expense 11 major/fatal bleeds (21% RR ↑)

Cooper, Arch Int Med 2006

• Cooper Meta-analysis Given:

– 51 ischemic strokes / 1000 pt-yr follow up

Warfarin Rx:

– Prevents 28 ischemic strokes (55% RR ↓)

– Expense 11 major/fatal bleeds (21% RR ↑)

Bleeding Risk Assessment

Lip GY, JACC 2011 Apostolakis et al. JACC 2013;Dec 12

ATRIA / HEMORR2HAGES / HAS-BLED

HAS-BLED

• Similar predictors for stroke and bleed

• Primarily identifies patients at risk for extracranial bleeding

Letter Clinical Characteristic Points Awarded

H Hypertension 1

A Abnormal renal and liver function (1

point each) 1 or 2

S Stroke 1

B Bleeding 1

L Labile INRs 1

E Elderly (e.g., age > 65 years) 1

D Drugs or Alcohol (1 point each) 1 or 2

Maximum 9 points

Bleeding • 10,000 A/C-related

intracerebral hemorrhages annually in US

• 30-day mortality: 44%

• US Death Certificates 2003, 2006

– A/C rated first in total mentions of death from drugs causing adverse effects in therapeutic use

VanWalraven C, JAMA 2002 NHLBI and ARK. Circ 1/08

Hylek EM, NEJM 2003

NVAF: Odds of Intracranial Hemorrhage & Age in 145 Case-patients (INR 2.0-3.0) and 870 Controls

MC Fang et al. Ann Int Med 2004;141:745

0

1

2

3

4

5

< 60 60-64 65-69 70-74 75-79 80-84 ≥85

Intracerebral (> INR)

Subdural (> Trauma)

Age (yrs)

Rel

ativ

e O

dd

s

7

Bleeding Risk Assessment

• SPORTIF Cohort Bleeding Risk

Lip GY, JACC 2011 Gage BF, Am Heart J 2006

Pisters, Chest 2010

HAS-BLED

Low

Moderate

High ≥ 3

Score (9)

0

1

2

3

4

5

Major Bleed

Events

0.9

3.4

4.1

5.8

8.9

9.1

SPORTIF cohort

(n=7,329) %

20.4

35

25.9

13.2

4.9

0.6

3.2

6.7

61%

18.7%

• 20% at high risk of bleed ~ 7%/year

“Real World” Bleeding

• Real-life annual risk: 6-8%

• Age > 80: 13%

• OAC + DAPT: 15.7%

• OAC + Clopidogrel: 13.9%

Hylek et al. Circ 2007;115(21):2689

Outcomes According to Triple Therapy vs. DAPT

CN Hess et al. JACC 2015;66(6):616-27

Net Benefit: Risk / Reward

• Balance difficult → specific patient

CHA2DS2VASC

0

1

2

3

4

5

% Stroke

0

1.3

2.2

3.2

4.0

6.7

% Bleed

0.9

3.4

4.1

5.8

8.9

9.1

HAS-BLED

0

1

2

3

4

5

?

?

?

Mod

High

Low

High

Mod

Low

Fundamental Treatment Dilemma

Significant Undertreatment

44.3%

58.1% 60.7%

57.3%

35.4%

0%

10%

20%

30%

40%

50%

60%

70%

< 55 55-64 65-74 75-84 85+

% U

se o

f W

arf

ari

n

Age (years)

• Especially those at high risk

40 to 50% not treated

• Levy S, Circulation 1999 • Baker WL, J Man Care Pharm 2009 • Samsa, Arch Int Med 2000 • Reynolds MR, Am J Cardiol 2006

Low Warfarin Use in High-risk Patients

• Medicare claims data, 2006-2007

– 27,174 patients

– Warfarin use less than 60%

• Piccini. Heart Rhythm 2012

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6

CHADS2 Score

Warfarin Use by CHADS2 Score

p<0.001

8

Net Clinical Benefit of Warfarin by Age

JS Chinitz et al. Ann NY Acad Sci. 2012;1254:140 DE Singer et al. Ann Intern Med 2009;151:297

Variability in Care by Site “Real World” Cardiology Practices

J. Hsu et al. JACC 2016;67(25):2913-23

Pra

ctice

Proportion of Patients in Practice Prescribed an Oral Anticoagulant

CHA2DS

2-VAScScore 2 Cohort

121

111

101

91

81

71

61

51

41

31

21

11

120100 30 40 50 60 70 80 90 100

PINNACLE Registry • 300,000 patients • 40% ASA only

Relative Prescription Rate of Aspirin (vs OAC) in Patients with CHA2DS2-VASc Score ≥ 2

J. Hsu et al. JACC 2016;67(25):2913-23

Antithrombotic Therapy in AF: ACTIVE-W Trial Aspirin + Clopidogrel vs. Warfarin

Cumulative Risk of Stroke

Connolly et al. Lance 2006;367:1903-12

Apixaban vs. ASA in NVAF: AVERROES Primary Endpoint: Stroke or Systemic Embolism

KH Ng et al. Age Ageing 2016;45:77-83

Aspirin ineffective

New OAC Strategies • Underused

• Suboptimally applied

• Difficult pharmacology

• Inappropriately discontinued

• Bleeding concerns

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Game Changer?

Edoxaban

9

Novel Anticoagulants: Overview

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban (Lixiana)

Mechanism Direct thrombin

inhibition Factor Xa inhibition

Factor Xa inhibition

Factor Xa inhibition

Dosing: Normal, Low

150mg, 75mg BID

20mg, 15mg QDAY

5mg, 2.5mg BID

60mg, 30mg QDAY

Oral Bioavailability 6.5% 80-100% 66% 62%

Half-Life (hours) 12-14 7-13 8-13 24

Renal Clearance 80% 66% ~ 25% ~ 35%

Involvement of CYP No CYP3A4 CYP3A4 CYP3A4

Potential Drug Interactions

p-Glycoprotein inhibitors

CYP3A4 and p-Glycoprotein

inhibitors

CYP3A4 inhibitors

p-Glycoprotein inhibitors

Novel Anticoagulants: Trial Comparison Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban (Lixiana)

Trial RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF TIMI 48

No. of patients 18,113 14,264 18,201 20,500

Design RCT, open label RCT, double blind RCT, double blind RCT, double blind

Inclusion criteria Non-valvular AF,

1 risk factor Non-valvular AF,

CHADS2 ≥ 2 Non-valvular AF,

1 risk factor Non-valvular AF,

CHADS2 ≥ 2

Age, Female % 71, 36.4% 73, 39.7% 70, 35.2%

Previous VKA use 49.6% 62.4% 57.2%

Avg. CHADS2 score 2.2 3.5 2.1

Persistent/ Permanent AF 66.6% 80.9% 84.7%

Follow-up Event driven, >12 months

Event driven, >14 months

Event driven, >12 months

24 months

Primary outcome Stroke/systemic

embolism Stroke/systemic

embolism Stroke/systemic

embolism stroke/systemic

embolism

Secondary outcomes MI, PE, Hosp,

Mort(CV & Tot) MI, Vasc mort, TIA, Total mort

Total mort, major bleeding, MI

Total mortality, major bleeding

High Dose NOACs vs. Warfarin for AF

Outcome Median

F/U Event Rate

NOAC Event Rate Warfarin

RR (95% CI) ARR/ARI NNT/NNH

Stroke/Systemic Embolism 2.2 3.11% 3.79% 0.81 (0.73-0.91) 0.68% 147

Hemorrhagic Stroke 2.2 0.44% 0.90% 0.49 (0.38-0.64) 0.46% 219

Major Bleeding

2.2 5.26% 6.17% 0.86 (0.73-1.00) NS NS

Intracranial Hemorrhage 2.2 0.70% 1.45% 0.48 (0.39-0.59) 0.76% 132

Gastrointestinal Bleeding

2.2 2.56% 2.02% 1.25 (1.01-1.55) -0.54% -185

All-cause Mortality 2.2 6.90% 7.68% 0.90 (0.85-0.95) 0.78% 128

Preventing Stroke in Non-Valvular AF Imputed Benefit of Different Strategies (vs. Control)

Advantages/Disadvantages of Novel Anticoagulants

Advantages Disadvantages No need for monitoring level of

anticoagulation Unable to verify compliance

Fewer drug-drug interactions No specific approved antidote to

reverse anticoagulation

Decreased adverse outcomes compared to warfarin

Cost

No variability in dosing schedule between individuals

Complex dosing schedule

Short onset of action - no need for heparin bridging

Unable to use in valvular AF, prosthetic valves, existing thrombus,

dialysis patients

The Optimal OAC for Stroke Prevention in AF: Suggestions for Treatment Options

Lip, JACC 2015;66

10

NOAC Avaialability Increases Appropriate Use of Anticogulants for Nonvalvular AF in Clinical Practice

0

5

10

15

20

25

30

35

2007-2008 2009-2010 2011-2012 2013-2014

NOAC & Warfarin

NOAC Only

Warfarin Only

Pat

ien

t %

Use of OACs in Patients with NVAF and CHADS2 score ≥1

N=3787 N=4062 N=4031 N=4646 J Am Coll Cardiol. 2016;67(13_S):787. doi:10.1016/S0735-1097(16)30788-4.

27.3%

26.9%

30.3%

31.3%

P<0.0001 Treatment Study Drug

Discontinuation Rate

Major Bleeding (rate/year)

Rivaroxaban 24% 3.6%

Apixaban 25% 2.1%

Dabigatran (150 mg) 21% 3.3%

Edoxaban (60mg/30mg) 33% / 34% 2.8% / 1.6%

Warfarin 17-28% 3.1-3.6%

1 Connelly SJ et al, NEJM 2009;361:1139-51 2 Patel MR et al, NEJM 2011;365:883-91 3 Granger J. et al, NEJM 2011;365:981-92

Stroke Treatment Option: Novel Oral Anticoagulants (NOACs)

There is an unmet need of stroke risk reduction for patients

with AF who are seeking an alternative to long-term OACs

Atrial Fibrillation – Stroke

Non-Pharmacologic Treatment

Non-pharmacologic Treatments

Transcatheter LAA Closure

• Watchman

• Amplatzer Plug

• Coherex WaveCrest

Ligation

Surgical

• Excision/suture

• Suture

• Staples/Clip

Non-surgical

• Lariat

• Surgical approaches to thromboembolic prophylaxis have been explored

since the 1940s

• LAA closure or obliteration has most often been considered as an adjunct

to other cardiac procedures such as mitral valvotomy or CABG

• Studies on patients undergoing LAA closure have shown a trend toward

reduction in embolic events → no definite data as standalone

• A review of the literature on LAA

closure prior to 2010 found closure

rates of 10%-73%

• LAAOS III target enrollment

4,700

1 Dawson AG, et al. Interact Cardiovasc Thorac Surg 2010, 10:306-11 2 Kanderian et al. JACC 2008, 52:924–9

73%

23%

10%

0%

20%

40%

60%

80%

Excision Ligation w/ Sutures

Ligation w/ Staples

Meth

od o

f S

uccessfu

l LA

A C

losure

2

LAA Ligation: Open Surgical Approach

A need exists for a less invasive approach that can consistently close the LAA

LAA Closure Devices

11

Watchman® LAA Closure

Frame: Nitinol structure • Available sizes:

– 21, 24, 27, 30, 33 mm (diam.)

– 10 Fixation anchors around device perimeter engage LAA tissue

– Contour shape accommodates most LAA anatomy

Fabric Cap: PET Fabric

(Polyethyl terephthalate)

• Designed to prevent harmful emboli from exiting during the healing process

• 160 micron filter

Anchors

PET fabric

WATCHMAN® LAA Closure System Implanted Device

CAUTION: The Watchman is an investigational device and is limited by Federal law to investigational use only in the U.S. Not for sale in the U.S.

Double Curve

Single Curve

Transseptal Access System

• Double or Single Curve styles

• 14F O.D. (4.7 mm), 12F I.D.

• 75 cm working length

Preformed curve shapes

guide position in LAA

WATCHMAN® LAA Closure System WATCHMAN Access System

WATCHMAN

Examples WATCHMAN Implant: Healing Process

Canine Model – 45 days Human Pathology – 9 months

12

WATCHMAN® Device LAA Case Presentation

13

WATCHMAN

Clinical Studies and Results

WATCHMAN: Clinical and Regulatory Timeline

PROTECT

AF

2005

Registry

CAP 2 2008

ASAP 2009

PREVAIL 2010

Registry

CAP 2 2012

FDA

Approval 2015

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

FDA PANEL

1 4/09

FDA PANEL

2 12/13

FDA PANEL

3 10/14

2/16

CMS

NCD

Approval

CLINICAL

REGULATORY

WATCHMAN Clinical Studies

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.

Patient Demographics

Characteristic PROTECT AF

(n=707) CAP

(n=566) PREVAIL (n=407)

Age, mean ± SD 72.0 ± 8.9 74.0 ± 8.3 74.3 ± 7.4

Age, range 41-95 44-94 50-94

Sex (Male) 70.3% 65.5% 70.0%

Ethnicity/Race

Asian 0.7% 1.6% 0.5%

Black 1.6% 1.9% 1.7%

Caucasian 91.5% 91.9% 94.4%

Hispanic/Latino 5.7% 3.5% 2.7%

Other 0.6% 1.1% 0.7%

Majority of Patients at High Stroke Risk, All Eligible for Anti-coagulation

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5 6-9

PROTECT AF

CHA2DS2-VASc Score ≥22

93%

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5 6-9

High Risk1

CAP PREVAIL CAP2

Patients (%)

CHA2DS2-VASc Score

96% 100% 100%

Anticoagulation Eligible1

Source: Holmes, DR et al. JACC 2015. In Press. 1. AHA/ACC/HRS Guidelines (2014).

14

Majority of Patients in the Trial were at Moderate to High Bleeding Risk1

1. Estimated HAS BLED score. Labile INR and liver function were not collected and given a score of zero Source: Holmes DR, et al. Holmes, DR et al. JACC 2015;

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1-2 3+

PROTECT AF

CAP

PREVAIL

CAP2

Patients (%)

HAS BLED* Score

Warfarin Time in Therapeutic Range (TTR) for Control Groups

Study Warfarin Control Group Mean TTR

PROTECT AF 70%

PREVAIL 68%

RE-LY1 (Dabigatran) 64%

ARISTOTLE2 (Apixaban) 62%

ROCKET AF3 (Rivaroxaban) 55%

1. Cannoly SJ et al. NEJM 2009 2. Granger CB et al. NEJM 2011

3. Patel MR et al. NEJM 2011

Implant Success & Warfarin Cessation

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.

p = 0.04

Endpoints

“Primary effectiveness endpoint captures the events that would also be considered significant safety events (i.e., stroke, death and systemic embolism)”

FDA Executive Summary

Efficacy

Events

Stroke (ischemic)

Systemic Embolism

CV / Unexplained

Death

Safety

Events

Device Embolization

Major Bleeding

Events

Pericardial Effusions

Stroke

(hemorrhagic)

Stroke

(procedure related)

Both Efficacy

& Safety

WATCHMAN Clinical Trial

Safety

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.

50% New Operators

15

Key Procedural Safety Events PROTECT AF vs. CAP/PREVAIL

*Overall embolization rate across studies is 0.5%

WATCHMAN Clinical Trial

Efficacy

Long-term PROTECT AF Primary Efficacy

CAP PREVAIL

PAF

RRR 39%

Hemorrhagic Stroke RRR 85%

PROTECT AF: Final Primary Efficacy Events Favor WATCHMAN

Event Rate (per 100 pt-yrs)

Rate Ratio

Posterior Probabilities

WATCHMAN Control Non-

inferiority Superiority

Primary Efficacy 2.3 3.7 0.61 >99.9% 95.4%

Stroke (all) 1.5 2.2 0.68 99.9% 83%

Ischemic 1.3 1.1 1.2 78% 15%

Hemorrhagic 0.2 1.1 0.15 >99.9% 99%

Systemic Embolism

0.2 0.0 NA NA NA

Death (CV & Unexplained)

1.0 2.3 0.4 >99.9% 98.9%

PROTECT AF: 5 Year Mortality WATCHMAN vs. Warfarin

V. Reddy, H. Sievert, J. Halperin et al. JAMA 2014;312:1988

RRR 60% RRR 34%

All Cause Mortality Relative Reduction (vs warfarin) In Context

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

% R

R in

All

-Cau

se M

ort

alit

y

Dabigatran 110

Dabigatran 150

Rivaroxaban

Apixaban

WATCHMAN 4 yrs

P=0.051

P=0.13 (NS)

P=0.047

PROTECT AF4 RE-LY1 ROCKET-AF2 ARISTOTLE3

1Connolly, S. NEJM 2009; 361:1139-1151 – 2 yrs f-up 2Patel, M. NEJM 2011; 365:883-891 – 1.9 yrs f-up, ITT 3Granger, C NEJM 2011; 365:981-992 – 1.8 yrs f-up 4Reddy, V. LBCT HRS 2012 – 4 yrs f-up.

P=0.15 (NS)

P=0.0379

ENGAGE-AF

RRR 14%

RRR 34%

16

Meta-Analysis Shows Comparable Primary Efficacy Results to Warfarin

Holmes, DR et al. JACC 2015

HR 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 0.22 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)

Stroke Severity in PROTECT AF/PREVAIL

• Disabling stroke defined as MRS change of 2 or more or death

• Similar results if defined as absolute MRS > 2

V.Reddy et al, FDA Panel Presentation, October 2014

0.0%

0.4%

0.8%

1.2%

1.6%

2.0%

Non-Disabling Stroke Disabling/Fatal Stroke

Warfarin WATCHMAN

RRR 56%

PROTECT AF & PREVAIL Meta-analysis: WATCHMAN Strokes Are Less Disabling

Disabling Strokes p-value

WATCHMAN Warfarin

All Strokes 27% 61% 0.009

Ischemic Only Strokes 19% 33% 0.43

Based on stroke with MRS change of 2 or more or cause of death related to stroke

Stroke Severity in LAAC vs NOAC Trials Non-Disabling vs. Disabling Fatal Strokes

0%

20%

40%

60%

80%

100%

Warfarin WATCHMAN Warfarin NOACs

Non-disablingStroke

Disabling/FatalStroke

V.Reddy et al, manuscript in preparation

PROTECT/PREVAIL RELY/ROCKET/ENGAGE/ARISTOTLE

RRR 56%

50

60

70

80

90

100

0 7

Time (months)

Free of Major

Bleeding Event

(%)

6 6046 1808 45

Time (days)

Warfarin

+Aspirin

Warfarin

+Aspirin

Aspirin+ Clopidogrel

Aspirin

WATCHMAN Warfarin

71% Relative Reduction

In Major Bleeding

after cessation of anti-thrombotics

HR = 0.29

p<0.001

WATCHMAN Device Arm

Drug Protocol

PROTECT AF/PREVAIL Pooled Analysis: Less Bleeding with WATCHMANTM Device 6 Months Post-Implant

bleeding: Serious bleeding event that required intervention or hospitalization according to adjudication committee

Price, MJ. Avoidance of Major Bleeding with WATCHMAN Left Atrial Appendage Closure Compared with Long-Term Oral Anticoagulation : Pooled Analysis of the PROTECT-AF and PREVAIL RCTs. TCT 2014 (abstract)

PROTECT AF: Quality of Life

Alli O, JACC 2008

*p<0.005

17

Economic Analysis: Cost Effectiveness WATCHMAN vs. NOACs vs Warfarin

• Patient level Markov micro-simulation decision analytic model

• Assess Time-to-Cost Effectiveness (not just Lifetime horizon – 20 yrs)

• Economic costs from the US perspective, and costs in 2015, US$

– For LAAC procedure, we used the newest DRG 273/274 (effective Oct 2015)

• Longest WATCHMAN follow up: PROTECT AF data (6 yrs f/u)

• NOAC meta-analysis of all 4 NOACs (Ruff et al. Lancet 2014;383:955)

• Incorporated costs based on the level of disability resulting from strokes

VY.Reddy, RL.Akehurst, SO.Armstrong, SL.Amarosi, SM.Beard, DL.Holmes. JACC 2015

Time to Cost Effectiveness (Cost/QALY)

Time to Dominance (More Effective,

Less Costly)

LAAC vs warfarin Year 7

($42,994/QALY) Year 10

NOACs vs warfarin Year 16

($48,446/QALY) N/A

LAAC vs NOACs Year 5

(Dominant) Year 5

Economic Analysis: Cost Effectiveness WATCHMAN vs. NOACs vs Warfarin

VY.Reddy, RL.Akehurst, SO.Armstrong, SL.Amarosi, SM.Beard, DL.Holmes . JACC 2015

Device-related Thrombus

PROTECT AF (n=408)

CAP (n=534)

PREVAIL (n=252)

Thrombus subjects 16 (3.9%) 13 (2.4%) 12 (4.8%)

Thrombus events 16 18 13

Experienced ischemic stroke 2 1 0

Experienced serious adverse event 3 2 0

Annual Device thrombus related stroke rate (per 100 pt-yrs) 0.11 0.07 0.0

WATCHMAN Thrombus

Real World Safety/Efficacy Data

EWOLUTION WATCHMAN Registry

• 1,025 patients

• CHD2DS2-VASc ≥ 5: 50%

• 72% “Unsuitable” for warfarin

• Procedural success 98.5%

– Stroke: 0.4%

– Embolization: 0.4%

– Tamponade: 0.7%

• Post-implant anticoagulation regimen

– DAPT 607; WAR 159; NOAC 113; Nothing 67

• 0.5% had device related serious adverse events not resolved at 3 months

18

ASAP Registry Contraindicated Pts (n=150): WATCHMAN ASA/Clop x 6 mo

7.3%

1.5%

0

1

2

3

4

5

6

7

8

Expected, based on CHADS2 Score

Observed Rate in ASAP

• CHADS2 = 2.8 ±1.2

• Prior CVA/TIA in 41%

• Follow up: 16.5 months

V. Reddy et al. JACC 2013;61:2551

ASAP Registry Long-term (5 year) Outcomes

D. Sharma et al. JACC 2016

WATCHMANTM Device Reduces Ischemic Stroke 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

PROTECT AF PREVAIL Only CAP

Imputed IschemicStroke Rate*

ObservedWATCHMAN IschemicStroke RateIs

chem

ic S

tro

ke R

isk

(Ev

ents

/100

Pat

ien

t-Ye

ars)




Baseline CHA2DS2-VASc = 3.4



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

Preventing Stroke in Non-Valvular AF Imputed Benefit of Different Strategies (vs. Control)

Strategies to Incorporate LAA Closure into Clinical Practice

19

FDA Approval 3/20/2015 WATCHMAN Device Patient Selection

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:

•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.

NOT a broad replacement for oral anticoagulation

• Effective 2/20/2016: CMS National Coverage Determination (NCD)

• Medicare coverage “when specific conditions are met”

• 124 page document

CMS “Conditions” • Eligible patients must have CHADS2 score ≥2 or

CHA2DS2-VASc score ≥3

• There must be documented evidence of a formal shared decision interaction between patients and an independent, non-interventional physician

• Patients must be suitable for short-term warfarin, but deemed unable to take long-term OAC

CMS “Conditions” • The procedure must be performed in a hospital with an

established structural heart disease or EP program

• The procedure must be performed by an interventional cardiologist or electrophysiologist, meeting following criteria:

– trained by 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

Frequently Asked Questions About CMS “Conditions”

• Who is this “independent, non-interventional physician” involved in this shared decision process?

• What is this “evidence-based decision tool” that is to be used in the formal shared decision making interaction with the patient?

• What is the prospective national registry that we need to enroll our patients into?

Clinical Scenarios: Potential Candidates

• CHA2DS2-VASc ≥ 3 AND Deemed unable to take long term OAC

• History of Major Bleeding: on OAC

– GI/GU

– Intracranial

– ENT

• High risk for major bleeding: Not on OAC

– HAS-BLED ≥ 3 (6% risk/yr)

– Frailty/Fall Risk

– CKD, Liver disease

– Inflammatory Bowel Disease

– Malignancy (Chemotherapy)

– Seizure disorder)

20

Clinical Scenarios: Potential Candidates

• Non-adherence/Non-compliance

– Frailty/Dementia

– Cost

– Choice/Refusal

• Polypharmacy

– Triple therapy – ACS/Vascular disease

• Occupation/Lifestyle

– High risk of trauma

Clinical Scenarios: Not Candidates

• CHA2DS2-VASc 0, 1, or 2 (for Medicare pts)

• No issues with OAC

• Other reason to be on OAC

– Valvular AF/Prosthetic valve

– DVT

– Hypercoagulable state

• LAA anatomy

– Size/shape

– Thrombus/sludge

• Vascular access issues

• Anesthesia risks

Clinical Scenarios: Contraindications

• Absolute contraindication to OAC or DAPT

– Post Implant: 6 weeks OAC 6 months DAPT

– Time for endothelialization

ASAP-TOO Trial • WATCHMAN (DAPT x 3 mo, ASA x 12 mo) • Medical Therapy (no Tx, ASA alone, DAPT

can be considered) • 2:1 randomization

MAHI Shared Clinical Decision Process

• Goal: Educate patient and family on the risks vs benefits of the three different scenarios

Shared Clinical Decision Tool

1 2 3

No Rx • ASA • DAPT

OAC • Vit K antagonist • Direct Thrombin

inhibitor • Factor Xa inhibitor

LAA Closure • WATCHMAN • LARIAT • Surgical Ligation

Shared Clinical Decision Process 1. Discuss personal risk of stroke

– CHA2DS2-VASC score: % risk/year

2. Discuss benefits of 3 treatment options

– RRR minor if any

↓60-70% (Class IA)

Non-inferior/Imputed placebo (↓70%)

3. Discuss Personalized relative risks of OAC; both warfarin & NOACS

– Quantify if possible (HAS-BLED) variable threshold

– Individual assessment of risk/benefit centered around pharmacotherapy issues

4. Discuss the risks of procedure

– Risks (procedural/device embolization/device related thrombosis)

1

2

3

21

Cardiovascular / Unexplained Death (includes CV deaths preceded by stroke)

Non-fatal Hemorrhagic Stroke

Non-fatal Ischemic Stroke /

Systemic Embolism

Event-free

WATCHMAN N=1000

Warfarin N=1000

200

400

600

800

1000

200

400

600

800

1000

N=1000; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years

WATCHMAN Comparable to Warfarin for Primary Efficacy




Systemic Embolism

Event-free

WATCHMAN Warfarin

100

200

300

400

500

100

200

300

400

500

Zoomed in to show N=500 of 1000 patients for each study arm; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years

CV Death Lower with WATCHMAN vs. Warfarin




Systemic Embolism

Event-free

WATCHMAN Warfarin

100

200

300

400

500

100

200

300

400

500


Hemorrhagic Stroke Lower with WATCHMAN vs. Warfarin

Ischemic Stroke/SE Lower with Warfarin vs. WATCHMAN




Systemic Embolism

Event-free


WATCHMAN Performs Better than Warfarin for Major Bleeding

WATCHMAN and Warfarin Reduce Ischemic Stroke vs. No Therapy

22

Conclusions

Conclusions

• The LAA plays a significant role in stroke risk in patients with AF

• CHA2DS2-VASc score is current goal standard but has significant limitations

– Assessment of risk is key to understanding relative benefits of different treatment options

• Oral anticoagulation is the primary therapy of choice and should be prescribed in virtually all patients

– Warfarin is cornerstone but problematic

– Is NOAC better but not perfect with major benefit due to decreased ICH; similar for non-cranial bleeding

Conclusions • Significant Under treatment

– Unprotected 5,000,000 x 0.4 = 2,000,000 patients

• LAA closure with WATCHMAN has been well studied as currently the only device approved by FDA as an alternative to OAC

– Overall efficacy non-inferior to warfarin, ischemic stroke ↑; hemorrhagic stroke ↓, mortality ↓

• Post FDA approval and CMS clarification on payment, appropriate case selection using a robust, shared, clinical decision making process should identify patients that will benefit

OAC Patient…

$$$

Did I take my medicine?

Joints hurt! Need NSAID

Will the cruiseship doctor know what Rivaroxaban is???

Snow and ice … what

if I fall?

if I fall, can the bleeding be stopped?

Out to dinner… what can I

eat?

Bronchitis… need antibiotic.

Do I need to check INR?

FREEDOM!!!!

LAA

Closure

disclosure left atrial appendage (laa) and stroke · left atrial appendage (laa) and stroke kenneth...

Documents