managing the left atrial appendage: concepts & controversies · steering committees: medtronic,...

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Managing the Left Atrial Appendage:Concepts & Controversies

Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC

Professor Department of Cardiac Sciences

Section Chief Cardiology Division, Libin Cardiovascular

Institute, University of Calgary

Zone Head Cardiology, South Eastern Alberta

Alberta Health Services

Adjunct Professor of Medicine/Cardiology

McMaster University

Associate Scientist Arrhythmia & Global Health

Population Health Research Institute

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Conflicts of Interest

I implant LAAC Devices….

Research Grants: Bayer, Biosense Webster, Biotronik, Boston

Scientific, Medtronic, Pfizer, St. Jude Medical, Transoma, CIHR,

WHO-TDR, COLCIENCIAS, Juan Valdez Café de Colombia, Other

Undisclosed Colombian Pharmaceutical Companies!

Honorarium: Biosense Webster, Boston Scientific, BMS,

Biotronik, Daiichi-Sankyo, Medtronic, Pfizer, St. Jude Medical,

Sorin, Transoma, Astra Zeneca, Boeringher Ingelheim, Procaps,

Sanofi-Aventis, Merck, Servier.

Advisory Boards: Medtronic, Biosense Webster, Boston

Scientific, Biotronik, Transoma, Schering Plough, Boeringher

Ingelheim, Sanofi Aventis, Procaps, Biocaps, Servier

Steering Committees: Medtronic, BSCI, Daiichi Sankyo,

Biosense Webster, STOP-HARM, ASAP-TOO

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Overview

LAA & Stroke

NOAC Evidence

LAAC Evidence

Future Trials

Current Guidelines

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Left atrial appendage: cul-de-sac

predisposed to stasis-precipitated thrombi

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“The immobility of the auricular

walls makes them

defenceless against

thrombotic deposits, as a

horse should be against flies without his cutaneous muscles.”

Acta Medica Scanda 1948

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“Serial sections of the left atrial appendage were prepared [in AF-patients with

embolic stroke]…in every case mural thrombus, not obvious to the naked eye,

was found in the interstices of the trabeculae carneae.”C.M. Fisher. Can Med Assoc J 1953; 69: 257.

1913-2012 (b. Waterloo, Ontario)

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Atrial Fibrillation16% of brain infarcts

Left Atrial Thrombi12% of brain infarcts

(3/4ths of AF-associated stroke)

Cerebral Small Artery

Disease

Carotid Atherosclerosis

Other Heart Disease

Aortic Arch Plaque

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91% of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1

1 Blackshear JL. Odell JA., Annals of Thoracic Surgery. 1996;61:755-759

Fibrillation causes blood to stagnate in the LAA

The stagnant blood becomes an ideal environment for a

thrombus or blood clot to form

The blood clot, or portion of it, dislodges from the LAA and

travels through arterial system

The embolism lodges itself in the blood vessels of the brain,

restricting blood flow and causing a stroke

Images on file at Boston Scientific Corporation

Thrombus in the LAA

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Cactus

Chicken wing

Di Biasi L et al JACC2012;60;531-38.

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LAA Anatomy


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Windsock

Cauliflower


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Stroke or systemic emboli (primary outcome events) in 4

large randomized trials comparing DOACs with high-

quality warfarin anticoagulation

Data shown are for higher dosages of dabigatran (150mg twice daily) and edoxaban (60mg daily).

Ruff CT et al. Lancet 2013 (on-line Dec 4th)

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DOACs vs. warfarin phase III RCTs in atrial fib:

Intracerebral hemorrhage

P Value

Dabigatran 110 mg BID P < .001

Dabigatran 150 mg BID P < .001

Rivaroxaban 20 mg QD P = .024

Apixaban 5 mg BID P < .001

Edoxaban 60 mg QD P < 0.001

Edoxaban 30 mg QD P < 0.001

Warfarin betterDOAC betterConnolly SJ, et al. N Engl J Med. 2009;361:1139–1151.Patel MR, et al. N Engl J Med. 2011;365:883–891.Granger C, et al. N Eng J Med. 2011;365:981–992.Giugliano RP, et al. N Engl J Med 2013; online Nov 19

0.25 0.50 0.75 1.00 1.25

HR (95% CI)0.00

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Stroke Treatment Option: Direct Oral

Anticoagulants (DOACs)

This chart is not based on a head-to-head trial and is not intended to suggest

head-to-head comparisons of the separate trials or the therapies under study.

TreatmentStudy Drug Discontinuation

RateMajor 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%

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.

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Stroke Treatment Option: Direct Oral

Anticoagulants (DOACs)

This chart is not based on a head-to-head trial and is not intended to suggest

head-to-head comparisons of the separate trials or the therapies under study.

TreatmentStudy Drug Discontinuation

RateMajor 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%

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.

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SH-23

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V2016

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te NOA

C Ado

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bility t

o

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erence

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agulati

on Re

mains

a Chal

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Sourc

e: Marti

nez C,

et al.

Therap

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istence

in Ne

wly Di

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at 2 y

ears

There is an unmet need of stroke risk

reduction for patients with AF who are

seeking an alternative to long-term OACs

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AF Treatment Options

*BSC currently has no ablation catheters FDA-approved for the treatment of AF

AF

Ablation* PacingDrugs for

Rhythm/Rate Control

Embolic Management

Drugs (warfarin)

Interventions

Surgical Ligation

LAA ClipsEndovascular

LAA

AND/OR

Drugs (dabigatran, rivaroxaban,

apixaban)

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Left Atrial Occluding Devices

LAALA

• PLAATO

(terminated)

• Watchman

• Amplatzer

• LARIAT

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Left atrial appendage clot on echo:91% of stroke in AF is caused by blood clots formed in the LAA1

Clot


1 Blackshear JL, Odell JA, Annals of Thoracic Surgery, 1996;61:755-759

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Invasive procedures can successfully close the LAA

• 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 cardiac bypass surgery

• Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events

73%

23%

0%0%

20%

40%

60%

80%

• Surgical LAA closure prior to the closure rates of 10%-73%1

Excision Ligation w/ Sutures

Ligation w/ Staples

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

Meth

od

of

Successfu

lLA

A C

losure

2

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Currently Reported RCTs

Study Trial Size (N) Trial Type and Comparator Length of Follow up

LAAOS I

Healey, 2005

77 Pilot RCT; Surgical LAA

occlusion vs. No LAA

occlusion (control group).

13 months

Nagpal, 2009 43 Pilot RCT; Surgical LAA



9 days

PROTECT-AF

Reddy, 2013

707 Percutaneous LAA



2.3 years

LAAOS II

Whitlock, 2013

51 Pilot RCT; Surgical LAA



1 year

PREVAIL trial

Holmes, 2014

407 RCT; 2:1 fashion;

Percutaneous LAA



18 months

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WATCHMAN LAA Closure Device in situ

Holmes et al, 2009

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WATCHMAN®: Device Implant Procedure

• Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance

• Access to the left atrium is gained via the femoral vein and transseptal puncture

• The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure

Transseptal puncture

Placement of WATCHMAN ® in LAA


Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

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WATCHMAN®: Device endothelialization

Canine Model – 30 Day

Canine Model – 45 Day

Human Pathology - 9 Months Post-implant (Non-device related death)

Images on file at Boston Scientific Corporation. Results in animal models may not necessarily be indicative of clinical outcomes.


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WATCHMAN™ Device Clinical Program

Significantly improved safety results2

Pilot Early feasibility with >6 years of follow-up

Enrolled up to 1500 patients at ~ 60 sites

CAP

Registry

CAP2

WATCHMAN primary efficacy, CV death, and all-

cause mortality 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. HRS 2013.. 2 Reddy, VY et al. Circulation. 2011;123:417-424; 3 Reddy, et al. JACC. 2013; In Press. 4 Holmes, DR Jr et al., CIT 2013SH-230506-AD June15

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DemographicsDevice Patients

CharacteristicPROTECT AF

N=463

CAP

N=566

PREVAIL

N=269P value

Age, years71.7 ± 8.8 (463)

(46.0, 95.0)

74.0 ± 8.3 (566)

(44.0, 94.0)

74.0 ± 7.4 (269)

(50.0, 94.0)<0.001

Gender (Male) 326/463 (70.4%) 371/566 (65.5%) 182/269 (67.7%) 0.252

CHADS2 Score

(Continuous)

2.2 ± 1.2

(1.0, 6.0)

2.5 ± 1.2

(1.0, 6.0)

2.6 ± 1.0

(1.0, 6.0)<0.001

CHADS2 Risk Factors

CHF 124/463 (26.8%) 108/566 (19.1%) 63/269 (23.4%)

Hypertension 415/463 (89.6%) 503/566 (88.9%) 238/269 (88.5%)

Age ≥ 75 190/463 (41.0%) 293/566 (51.8%) 140/269 (52.0%)

Diabetes 113/463 (24.4%) 141/566 (24.9%) 91/269 (33.8%)

Stroke/TIA 82/463 (17.7%) 172/566 (30.4%) 74/269 (27.5%)

Most notable differences:Age, Diabetes, and Prior Stroke/TIA

PREVAIL results from Holmes, DR Jr et al., CIT 2013PROTECT AF and CAP data from Reddy, VY et al. Circulation. 2011;123:417-424.


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Meta-Analysis Shows Comparable Primary Efficacy Results to Warfarin

Source: Holmes DR, et al. Holmes, DR et al. JACC 2015; In Press. Combined data set of all PROTECT AF and PREVAIL WATCHMAN patients versus chronic warfarin patients

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)

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Meta-

Analy

sis Sh

ows C

ompa

rable

Prima

ry Eff

icacy

Resu

lts to

Warf

arin

PROT

ECT A

F 4 Yr

s/PRE

VAIL

2 Yrs

Sourc

e: Ho

lmes, J

. D. R

., S. K

. Dosh

i, et a

l. JAC

C 201

5; 65

(24): 2

614-2

623.

Comb

ined d

ata se

t of a

ll PRO

TECT

AF an

d PRE

VAIL

WATC

HMAN

patien

ts vers

us chr

onic w

arfari

n patie

nts

HR

p-valu

e

Effica

cy

0.79

0.22

All str

oke or

SE

1.02

0.94

Ische

mic str

oke or

SE

1.95

0.05

Hemo

rrhag

ic stro

ke

0.22

0.004

Ische

mic str

oke or

SE >7

days

1.56

0.21

CV/un

explain

ed de

ath

0.48

0.006

All-ca

use d

eath

0.73

0.07

Major

blee

d, all

1.0

0 0.9

8

Major

blee

ding,

non p

roced

ure-re

lated

0.5

1 0.0

02

0.01

0.11

10

Favo

rs WA

TCHM

AN

Fa

vors

warfa

rin

Hazar

d Rati

o (95

% CI)

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Device Reduced 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

Ischemic Stroke

Rate*

Isc

he

mic

Str

ok

e R

isk

(Eve

nts

/10

0 P

ati

en

t-Y

ears

)

79%Relative

Reduction

67%Relative

Reduction

83%Relative

Reduction

Baseline

CHA2DS2-VASc = 3.4

Baseline

CHA2DS2-VASc = 3.8

Baseline

CHA2DS2-VASc = 3.9

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

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Long-term PROTECT AF Primary Efficacy(2621 Patient-years)

100

90

80

00 1 2 3 4 5

463 382 360 337 317 196

244 218 200 173 147 87

WATCHMAN

Control

Freedom

from

Primary

Efficacy

Event

(%)

Time (Years)

WATCHMAN

Control

HR: 0.61, 95% CI: 0.38 to 0.97;

p=0.0348

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16

Obse

rved R

ates o

f Majo

r Blee

ding O

ver

Time A

ccord

ing to

Trea

tmen

t Grou

p

LAAC

(n=73

2)

Long

-term

warf

arin

(n=38

2) Ra

te

Ratio

P value

Ble

eding

Rate

(n ev

ents

/ N at

risk)

Even

t Rate

per

100 p

t-yrs

(n ev

ents

/ N at

risk)

Bleed

ing Ra

te (n

even

ts/N a

t risk

)

Even

t Rate

per

100 p

t-yrs

(n

even

ts / N

at ris

k)

Overa

ll 10

.8

(79/73

2)

3.5

(79/22

68)

11.3

(43/38

2)

3.6

(43/11

87)

0.96

0.84

Post

Proc

edure

5.9

(40/68

2)

1.8

(40/22

55)

11.3

(43/38

1)

3.6

(43/11

80)

0.49

0.001

Desti

natio

n 3.2

(19/60

1)

1.0

(19/19

58

9.7

(35/36

0)

3.5

(35/10

04)

0.28

<0.00

1

Warfa

rin +

ASA

(81mg

)

daily

Clopid

ogrel

(75m

g) +

ASA (

325 m

g) da

ily

ASA (

325m

g) da

ily

Impla

nt 45

days

* 6 m

onths

Post

Proc

edure

Thera

py

Desti

natio

n The

rapy

*if lea

k >5m

m, pa

tients

rema

ined o

n warf

arin +

ASA u

ntil se

al do

cume

nted,

skipp

ing th

e clop

idogre

l + AS

A pha

rmac

othera

py

Price

, M. J

., V. Y

. Red

dy, e

t al. J

ACC:

CV In

terv 2

015;

8(15):

1925

-1932

Overa

ll peri

od de

fined

as af

ter ra

ndom

izatio

n to t

he en

d of fo

llow-up

; pos

t-proc

edura

l peri

od as

>7 da

ys aft

er ran

domi

zatio

n to t

he en

d of fo

llow-up

;

destin

ation

thera

py pe

riod a

s bey

ond 1

80 da

ys po

st-ran

domi

zatio

n, wh

en pa

tients

assig

ned t

o LAA

closu

re we

re elig

ible to

rece

ive as

pirin

alone

.

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Briceno D, et al. Circ EP 2015

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Network meta-analysis for stroke

• According to the random effects model, LAAC device was found to reduce the risk of stroke by 15% when compared with NOACS

www.HQOntario.ca

0.1 1 10

NOACS versus WARFARIN 0.88 (0.81 – 0.95)0.88 (0.44 – 1.87)

LAAC device versus NOACS 0.81 (0.48 – 1.41)0.85 (0.63 – 1.05)

LAAC device versus WARFARIN 0.71 (0.42 – 1.23)0.75 (0.38 – 1.44)

Treatment 1 vs. Treatment 2 O.R. (95% Cr.I.)

Favours Treatment 1 Favours Treatment 2

Fixed Effects Random Effects (Vague Prior)

Heterogeneity (Vague) = 0.1456 95% CrI (0.02675 – 0.6404)

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League table for the outcome of Stroke

LAAC device

0.85(0.63– 1.05)

NOACS

0.75(0.38 – 1.44)

0.88 (0.44 – 1.87)

WARFARIN

OR <1 Means the Treatment in Top Left is Better

www.HQOntario.ca

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Rankogram for the outcome of Stroke

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3

Pro

babilit

y o

f Bein

g R

anked

Rank

Random Effects (Vague) Rankogram

LAAC device

NOACS

WARFARIN

Best Worse

www.HQOntario.ca

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All cause mortality

0.1 1 10


LAAC device versus NOACS 0.77 (0.52 – 1.17)

0.71 (0.49 – 1.22)

LAAC device versus WARFARIN 0.68 (0.46 – 1.02)

0.63 (0.44 – 1.08)





www.HQOntario.ca

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Hemorrhagic stroke

0.01 0.1 1 10


LAAC device versus NOACS 0.42 (0.11 – 1.35)0.45 (0.29 – 0.79)

LAAC device versus WARFARIN 0.19 (0.05 – 0.60)0.22 (0.05 – 0.94)





www.HQOntario.ca

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Ischemic stroke

www.HQOntario.ca

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GRADE Evidence Profile

www.HQOntario.ca

‡Downgraded for indirectness, precision

Comparison Direct evidence Indirect evidence

Network meta-analysis

LAAO closure device vs NOACS

OR[95% Cr.I]

Quality of evidence

OR[95% Cr.I]

Quality of evidence

OR[95% Cr.I]

Quality of evidence

Not available

Not applicable

0.83[0.43, 1.84]

ǂ

Low

Same as indirect evidence

Same as indirect evidence

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Case Presentation

• 76 yr old male Chronic AF since 2000

• Hypertension, Type II DM, Dyslipidemia, Stroke/TIA

• 2006 Left hemisphere (CT documented)

• July 2013 Right Hemispheric TIA (MRI)

• CKD Creatinine 520 eGRF =14.6, Dialysis 3/week

• Gastric Antral Vascular Ectasia Recurrent severe

bleeding with transfusions every 2 weeks.

• Chronic rheumatoid arthritis, Gout

• Polyclonal gamopathy M Spikes

• Factor XII Deficiency

• Referred to determine best Stroke Prevention Therapy!

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Stroke rate No OAC CKD

• eGRF 30-59 mL/min/1.73m2 =7.5%/yr

• eGRF < 30 mL/min/1.73m2 = 8.1%

• ESRD hemodialysis 2 – 10 greater incidence of stroke RR 6.1, 95% CI 5.1-7.1

• 10 – 33/1000 patient-yrs

• Hemorraghic stroke HR 6.83, 95% CI 5.87-7.92

Banerjee A, et al. Chest 2014;145:1370-82.

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Saw J, et al. J Cardiovasc Electrophysiol. 2017 Jan

27. doi: 10.1111/jce.13168. [Epub ahead of print]

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SS:888

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ESS: 400

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LAAOS III Project Office

Project Office: [email protected]

Co-Principal Investigators: Richard Whitlock and

Stuart Connolly

Research Coordinator: Kate Brady

[email protected]

2947 recruited to date

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J Am Coll Cardiol 2016;68:1929–40.

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APR

2013

managing the left atrial appendage: concepts & controversies · steering committees: medtronic,...

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