22 Lee Left Atrial App Closure - UCSF CME · This device is indicated to reduce the risk of thromboembolism from the left atrial appendage (LAA) in patients with non-valvular atrial

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Left Atrial Appendage Closure –Identifying the Patients Who Will

Benefit the Most

Disclosure

SentreHeart,Inc• Consultant• Equityholder

AcardiacdiseasethatkillsbyproducingemboliThemostsevere

consequenceofAFispotentiallylifethreatening

embolicevents

It’sNottheAnswerToo little = Stroke

Too much = Hemorrhage

INR12345

TARGET

WARFARIN

Risksincreasewithage

Lowcompliance

Contraindications

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Endocardial vs PericardialNo LA foreign bodyEase of Use

Closure EfficacyComplications

LAA Closure Devices Available in the US

Watchman is FDA approved for stroke preventionAtriclip and LARIAT are FDA approved, but not for stroke

prevention

Watchman Atriclip LARIAT

WATCHMAN Clinical History

IntheUS,WATCHMANisaninvestigationaldevice,limitedbyapplicablelawtoinvestigationaluseonlyandnotavailablefor sale.CEMark2005

CAPRegistry566pts,26sites

PREVAIL400pts,<50

sites

Significantlyimprovedsafetyresults

Improvedsuccessandproceduralsafetyconfirmedwithnewandexperiencedoperators

PROTECT-AF800pts,59sites

Watchmandevicewas non-inferiortowarfarininpreventingstrokes;FDAconcernedwithacutesafety

events

PROTECT-AFLong-termF/U

Superiortowarfarinforprimaryefficacy,CVdeath,andall-causemortalityat4years

PROTECT AF 4 Year:CV and All-Cause Mortality

Reddy, VY et al. JAMA. 2014; 312(19):1988-1998.

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Watchman FDA Approval

• 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• 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.

This device is indicated to reduce the risk of thromboembolism from the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation who:

INDICATIONS FOR USE • Intracardiac thrombus is visualized by echocardiographic

imaging. • An ASD repair or closure device or a PFO repair or closure

device is present. • The LAA anatomy will not accommodate a device 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

Watchman FDA ApprovalCONTRAINDICATIONS

Dabigatran Rivaroxaban Apixaban

Mechanism Direct Thrombin Inhibitor

Factor Xa Inhibitor Factor Xa Inhibitor

Dose 110 mg or 150 mg 2x/ day

20 mg/day 5 mg 2x/ day*2.5 mg 2x/day

Efficacy in preventing embolic events

Superior (150 mg) Noninferior (110 mg)

noninferior superior

Hemorrhagicstroke

Significantly less (110 mfg)More (150 mg)at

less less

GI bleeding Not specified (110mg)

Major GI bleedingEpitaxis and hematuria

less

All bleeding events

Less (at 110 mg)Similar (at 150mg)

less

*2.5mgtwicedailyiftwoormore:age>80,weight<60kgorCr>1.5(25%renalexcretion).ExcludedifCr>2.5

OralAnticoagulantsDISCONTINUATIONRATES

0

5

10

15

20

25

RE-LY ARISTOTLE ROCKET-AF

NOACWarfarin

RivaroxabanNEJM2011;365:883-91

ApixabanNEJM2011;365:981-92

DabigatranNEJM2009;361:1139-51

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Potential Incidence of Major BleedingAnticoagulatant AnnualRatefor

MajorBleed*Potentialnumber ofpatients>65yo withmajorbleeding/year(x1000)

Dabigatran150mg 2x/day

3.32% 60.4

Rivaroxaban15– 20mg/day

3.6% 65.6

Apixaban5mg2x/day

2.13% 38.8

Warfarin 3.09%- 3.57% 56.2- 65.0

Wallentin,L.,etal.,.Efficacyandsafetyofdabigatran comparedw ithwarfarinatdifferentlevelsofinternationalnormalised ratiocontrolfor

strokepreventioninatrialfibrillation:ananalysisoftheRE-LYtrial.Lancet,2010,376(9745),975-983.

Patel,M .R.,etal..R ivaroxaban versuswarfarininnonvalvular atrialfibrillation.NEngl JMed,2011,365 (10),883-891.

Granger,C.B.,etal.,Apixaban versuswarfarininpatientsw ithatrialfibrillation. NEngl JMed,2011.365 (11):p.981-92.

*Assumes50%ofAFpatientstreatedwithAFonOAC

• 82 year old woman with paroxsysmol AF

• History of both ICH and cardioembolic stroke, hypertension

• TEE reveals LAA thrombus

Patients with Limited to NO optionsPatients with contraindications to OAC therapy

StrokeandBleedingRiskinPatientswithAFandOACContraindications

BjornRedfors,MD,PhD,WilliamA.Gray,MD,RandallJ.LeeMD,KennethA.EllenbogenMD,

MachaonBonafete PhD,PhD,OriBen-Yehuda,MD

PresentedbyBen-Ydhuda atTCT2015

0

2

4

6

8

10

12

14

16

18

20

%

StudypopulationAdjustedstrokerateinthegeneralAFpopulation(adaptedfromLipetal. ‡)

IschemicStroke:AFandpreviousIntracranialbleedingascontraindicationforOAC(n=5,441)byCHADS2-VASC

0n=141

1n=330

2n=642

3n=1,202

4n=1,330

5n=883

6n=593

7n=272

8n=47

9n=1

‡Stroke2010;41(12):2731-8

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BleedingRates- byCHADS2

0.0%2.0%4.0%6.0%8.0%10.0%12.0%14.0%16.0%

0 1 2 3 4 5 6

Bleeding

CHADS2 Score

n=5,693 n=12,017 n=15,071 n=6,191 n=3,033 n=1,162 n=81

Gastrointestinal,genitourinary,orrespiratorytractbleedingthatrequiredtransfusionorsurgicalintervention.

IncidenceandOutcomesofPatientswithAtrialFibrillationandMajorBleedingComplications:Findingsfromthe

TREAT-AFStudy

• In the mean follow-up of 4.2 years, 11.5% of patients had a major bleed

• Patients with prior bleeding complications had greater risk of subsequent events including TIA, ischemic stroke, repeat bleeding events, and death.

• OAC started in 25% within 90 days of major bleeding event and was associated with a reduced stroke risk (HR 0.85), reduced risk of death (HR 0.88), and increased risk of major bleed (HR 1.49).

Daniel W. Kaiser MD1, Randall J. Lee MD PhD2, Jun Fan MS3, Susan S. Schmitt PhD3, Mintu P. Turakhia MD MAS FACC1,3

1Department of Medicine, Stanford University School of Medicine (Stanford, CA); 2University of California San Francisco 3Veterans Affairs Palo Alto Health Care System (Palo Alto, CA)

PresentedbyKaiseratACC2015

WatchmanReddy et al JACC 2013

ACPTzikas et al EuroIntervention 2015

LARIATSievert et al JACC EP

2015

Number of patients 150 1,047 139

Age 72.5 7.4 75±8 67±11

Mean CHADs2 score

2.8 1.2 4.43 2.4 +1.2

Mean follow-up 14.4 + 8.6 months,

13 months 35 + 12 months

Patient-years 176.9 1,349 401

Absolute # strokes/systemic embolism

4 (stroke) 9 (strokes), 9 (TIA)31 (systemic embolism)

4 (strokes)

Event rate (patient-years)

2.3% 0.7% stroke0.7% TIA2.3% systemicembolism

1%

LAA Exclusion in OAC Contraindicated Patients Watchman Safety Profile

Boersma et al. Eur Heart J. 2016

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Acute&Longterm OutcomesofPercutaneousLeftAtrialAppendageSutureLigation:ResultsFromAUnitedStatesMulticenterEvaluation

Lakkireddy et al. Heart Rhythm 2016

0.2% 0.2%

0.7%0.5%

0.0%

0.5%

2.0%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

ProceduralRelatedMortality

Ptsrequiringsurgery

CardiacPerfs(nosurgery)

Ptsneedingtransfusion

Peri-proceduralstroke

StructuralInjury AllComplications

• Multicenter registry. 18 US centers.

• Safety results of 424 consecutive LARIAT procedures.

• Micropuncture access technique utilizedRestore Maintain Protect

Electrical Isolation LAA Exclusion

Merits of an Epicardial LAA Closure Approach

Thoracoscopic Appendage Exclusion With an AtriclipDevice As a Solo Treatment for Focal Atrial Tachycardia

Stefano Benussi, Patrizio Mazzone, Giuseppe Maccabelli, Pasquale Vergara, Antonio Grimaldi, Alberto Pozzoli, Pietro Spagnolo, Ottavio Alfieri, and Paolo Della Bella

Circulation 123(14):1575-1578, 2011

Clinical success of various ablation techniques for persistent/long-standing persistent atrial fibrillation

Brooks AG, et al. Outcomes of long standing persistent AF: A systematic review. Heart Rhythm . 2010; 7:835-46

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Catheter Ablation ofLong-Standing Persistent Atrial Fibrillation

5-Year Outcomes of the Hamburg Sequential Ablation Strategy

Roland Richard Tilz, MD, Andreas Rillig, MD, Anna-Maria Thum, Anita Arya, MD, Peter Wohlmuth,Andreas Metzner, MD, Shibu Mathew, MD, Yasuhiro Yoshiga, MD, Erik

Wissner, MD, Karl-Heinz Kuck, MD, Feifan Ouyang, MD

JACC 2012;60:1921–9.

After the first ablation procedure, sinus rhythm was documented in 41 of 202 (20.3%) patients.

After multiple procedures, sinus rhythm was maintained in 91 of 202 (45.0%) patients

Fibrillating Areas Isolated within he the Left Atrium after Radiofrequency Linear Catheter AblationRostock et al. Isolated Areas of Atrial Fibrillation 811

Figure 4. A: Schema of the left atrium (LA).Previous ablation lesions are marked by redlines. After ablation at the base of the leftatrial appendage (LAA), sinus rhythm (SR)was restored while the LAA remained in on-going atrial fibrillation (indicated by greenasterisks). MA = mitral annulus. B: SurfaceECG leads I, II, and V1 demonstrating ven-tricular pacing. RF catheter is placed withinthe left atrial appendage (LAA) demonstrat-ing atrial fibrillation with a mean atrial fib-rillation cycle length of 245 ms. A referencecatheter (REF) is placed within the coronarysinus demonstrating SR. C: PostproceduralCARTO-map of the LA revealed a wide areaof spontaneous scar in the anterior LA. TheLAA is in atrial fibrillation (purple) while allthe rest of the heart is in SR.

Implications for AF Mechanisms

It has been postulated that a critical mass of myocardialtissue is required to maintain fibrillatory activity based on themultiple wavelet hypothesis.17 In accordance with this theory,several experimental and clinical studies support the notionthat a minimal tissue mass is mandatory for the myocardiumto sustain fibrillation.18-20 There is a significant associationbetween LA size and chronic AF,21,22 and the reduction ofthe right and left atrial size by the MAZE procedure predictsthe successful maintenance of SR after surgery.23

However, the multiple wavelet theory is conceptually atodds with the role of single or multiple driving sources as amechanism for AF. In the former, a critical mass of atriummust exist to perpetuate AF, while in the latter, a discrete siteof activity can initiate and maintain AF.

The role of apparent dominant generator zones responsi-ble for rapid atrial activity is supported by ablation studies inisolated sheep hearts.24 Morillo et al.25 have shown in a map-ping study of induced AF in dogs that ablation at the sites ofthe shortest AFCL lead to termination and noninducibility ofAF. Recently, it has been reported in human paroxysmal AFthat identification of dominant frequencies by spectral anal-ysis and ablation at these sites resulted in significant slowingof the fibrillatory process and termination of sustained AF.26

Naqvi and Zaky27 reported a patient who presented with atransient ischemic event in whom transesophageal echocar-diography revealed the presence of an accessory lobe withinthe LAA that demonstrated fibrillatory activity, whereas theglobal LAA as well as the left and right atrial chambers werein SR. In chronic AF, the dominant anatomical sites perpet-uating AF outside the PV were the CS region and the LAA,while the septum and the posterior LA were important in asmaller group of patients.28,29 Thus, the capability of sus-tained fibrillatory activity within localized and isolated areasof the atrium as it has been reported after cardiac surgery30

and presented in this study suggest that single driving sourcesmight be also responsible for sustained AF.

The present study emphasizes the need for more focusedmapping of these driver regions to elucidate their contributionto the fibrillatory process and to avoid potentially harmfulisolation of LA regions.

Limitations

Recurrences after ablation of long-lasting AF consist ofAF, macro-reentry, and tachycardias demonstrating focal ac-tivity. The mechanism of AF in the isolated areas could notbe defined because they were not mapped using high-densitymapping catheters. However, a long tachycardia cycle lengthwith minor cycle length variations, as it has been observed inPatients 2 and 4, exhibit electrophysiological characteristicsthat may be compatible with those of focal atrial tachycardias.

Inadvertent isolation of the LAA as a result of extensiveablation will require long-term follow-up and probably life-long anticoagulation.

Conclusions

Catheter ablation within the LA may result in electricalisolation of significant areas with local persistence of AF.Abrupt restoration of SR at the time of complete isolation ofthese areas and maintenance of preisolation AFCL within theisolated areas supports a driving role for these regions in theAF process.

References1. Frustraci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri

A: Histological substrate of atrial biopsies in patients with lone atrialfibrillation. Circulation 1997;96:1180-1184.

2. Li D, Fareh S, Leung TK, Nattel S: Promotion of atrial fibrillation byheart failure in dogs. Atrial remodeling of a different sort. Circulation1999;100:87-95.

3. Garrey WE: The nature of fibrillatory contraction of the heart. Its rela-tion to tissue mass and form. Am J Physiol 1914;33:397-414.

4. Wijffels MC, Kirchhof CJ, Dorland CJ, Allessie MA: Atrial fibrillationbegets atrial fibrillation. A study in awake chronically instrumentedgoats. Circulation 1995;92:1954-1968.

5. Haissaguerre M, Sanders P, Hocini M, Hsu LF, Shah DC, ScaveeC, Takahashi Y, Rotter M, Pasquie JL, Garrigue S, Clementy J,Jais P: Changes in atrial fibrillation cycle length and inducibilityduring catheter ablation and their relation to outcome. Circulation2004;109:3007-3013.

6. Jais P, Hocini H, Hsu LF, Sanders P, Scavee C, Weerasooriya R, MacleL, Raybaud F, Garrigue S, Shah DC, Le Metayer P, Clementy J, Hais-saguerre M: Technique and results of linear ablation at the linear mitralisthmus. Circulation 2004;110:2996-3002.

Rostock…..Haissaguerre JCE 17:807-812, 2006

Conversion of Persistent Atrial Fibrillation to Sinus Rhythm After LAA Ligation

Badhwar et al., HRS abstract 2015

Courtesy of David Wilbur

• Multi-center, prospective randomized superiority trial

• Comparing LAA ligation and PVI versus PVI in patients with persistent and longstanding persistent AF

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Participating Study Sites

BrynMawrMassGeneralNYUSouthsideValleyYale

LoyolaNorthwestern

Vanderbilt

AustinHeartBaylor-St.Luke’sUTSanAntonio

MUSC

USCF

SantaBarbaraCottage

Scripps

KUMC

UCSDSt.Vincent’s

AlbanyMed

UofUtah

Oshner

RogueValley

Emory

FairviewSouthdale/UofM

UPMCOhioSt

JohnHopkins

CaseDiscussions

Case 1• 72 yo woman with persistent AF.• Intolerant to OAC due to fall risk and

hx of traumatic injury• Hx of prior cardioembolic stroke, DM,

HTN and CABG

Case 1• Recommend LAA occlusion device• CABG is a contraindication to the

LARIAT procedure

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Case 2• 68 yo man with PAF• Hx of ICH, HTN,DM

Case 2• Consider LARIAT or Atriclip• Watchman requires at least 45 days

of warfarin therapy post-implantation

Triple Therapy: Benefit vs Risks• Stentthrombosis:highestintheearlyphaseafterPCI

• Bleeding:risk of bleeding with triple therapy increases with duration of therapy

Should We Recommend Oral Anticoagulation Therapy in Patients With Atrial Fibrillation

Undergoing Coronary Artery StentingCase 3

• 65 yo man with persistent AF• Hx of recent stent on ASA and plavix• Hx of DM, HTN

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Case 4 • 87 yo woman with PAF• Hx of both ICH and cardioembolic

stroke, HTN• TEE reveals LAA thrombus

Case 5 • 63 yo man with PAF• Hx HTN

Major Registry Studies Comparing Bleeding on Combinations of Antiplatelet and OAC Therapy

Study No.ofPatients

Follow-up,y

ASA Clopidogrel DAPT OAC OAC + ASA

OAC + Clopidogrel

TOAT

Bureslyetal

21 443 1.8 3.2 NA 6.8 5.9 8.3 NA 8.5

Sørensenetal

40 812 1.3 2.6 4.6 3.7 4.3 5.1 12.3 12.0

Lambertsetal

11 480 1.0 7.0 6.6 7.0 7.0 9.5 10.6 14.2

Hansenetal

118 606

3.3 3.7 5.6 7.4 3.9 6.9 13.9 15.7

ClinicalCardiology36:585-594,2013

Unexpectedly High Incidence of Stroke and Left Atrial Appendage Thrombus Formation after

Electrical Isolation of the Left Atrial Appendage for Treatment of Atrial Tachyarrhythmias:

An undescribed and under recognized complication of left atrial catheter ablation

Andreas Rillig , MD, Roland R. Tilz, MD, Tina Lin, MD, Christian Heeger, MD, Anita Arya, PHD, Andreas Metzner, MD, Shibu Mathew, MD, Erik Wissner, MD, HisakiMakimoto, MD, PHD, Peter Wohlmuth, Karl-Heinz Kuck, MD, Feifan Ouyang, MD

LAAthrombus

Mechanical standstillThrombus formation

LAA thrombus in 21%, and three patients had a stroke while on OAC

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AFStrokePreventionandCoronaryEvents

Adapted from ACCP guidelines (You at al, Chest 2012

Long term follow-up from the Prevail Trial

• The results of PROTECT AF and PREVAIL appear to be diverging, which introduces challenges in the interpretation of results of the pre-specified Bayesian analysis.

• PROTECT AF demonstrated a benefit of the WATCHMAN device driven by a reduction in hemorrhagic stroke rate; however, the Control group hemorrhagic stroke rate was substantially higher than observed in contemporary anticoagulation trials, and there are questions regarding the robustness of this potential benefit.

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

0 1 2 3 4 5 6

CHADS2score

Even

tRa

te(%patient-years)

CHADS2scoreoftheLARIATPopulation

NationalRegistryofAFStrokerateNationalRegistryofAFStrokeratewithASA

6.2%ExpectedERObservedER:1%Reductionof80%

N=139 patientsMean F/U 2.9 +/- 1.1 years405 patient-years

LAA ligation in patients with contraindications to OAC therapy

Sievert et al., JACC EP 2015

Figure 2: Kaplan-Meier Curves

A B

Kaplan-Meier Curves

Survival Stroke

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Tzikas et al EuroIntervention 2015

5.62%

2.30%

-58%

6.0

5.0

4.0

3.0

2.0

1.0

%

Effectiveness in Stroke Reduction vs. EstimatedEstimated based onCHA2DS2-VASc score

Observed ratein study

LARIAT device in AF patients with contraindications to OAC

Reddy and Sievert et al., JACC 61: 2551–6, 2013

Watchman device in AF patients with contraindications to OAC

Expected rate: 7.3%Observed ischemic stroke rate 1.7%77% reduction in stroke rate

PreadmissionmedicationswithknownAF&wereadmittedwithacuteischemicstroke

(high-riskcohort,n=597)PreadmissionmedicationsinpatientsAFandapreviousischemicstroke/TIAwhowereadmittedwithacuteischemicstroke

(veryhigh-riskcohort,n=323).

Stroke.2009;40:235-240

Warfarin use decreases with increasing age & stroke risk

JournalofThrombosisandHaemostasis,6:1500–1506

UK General Practice database n= 41,910

Proportionofpatientspersistingwithwarfarin

Journal of Thrombosis and Haemostasis, 6: 1500–1506

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Should we use LAA closure as an option to prevent stroke

• Medical rationale• Efficacy• Safety• Reimbursement

Long term follow-up from the Prevail Trial

• Greater event rate of embolic stroke and systemic embolism in the Watchman arm compared to the control

• The new ischemic strokes in the updated PREVAIL dataset occurred more than 1 year post-WATCHMAN implantation, raising questions about long-term device effectiveness.