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Left Atrial Appendage OcclusionAn Alternative to Anticoagulation
Jonathon Adams, MD, FACC, FHRS
DISCLOSURE
Relevant Financial Relationship(s)None
Off Label UsageNone
AcknowledgementKen Huber, MD, FACC
OBJECTIVES• Background• What is left atrial appendage occlusion?• How do the efficacy and safety of LAAC compare to OAC?• Who to refer for evaluation?
Atrial Fibrillation → An Epidemic
Savelieva, et al. Clin Cardiol 2008;31
5Million
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
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;30:528Heart 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 St
roke
s
Age (years)
• 800,000 strokes/yr in U.S. = 100,000 AF strokes/yr
Thrombosis/Embolization
Electrical Fibrillation
Insufficient contraction of LAA
Stagnant blood flow
Thrombosis / clot formation
Thromboembolism
Stroke
Johnson, Eur J Cardiothoracic Surg 2000;17
LAA – CulpritLocation of Thrombi in Left Atrium
0
20
40
60
80
100St
odda
rd: J
ACC
, '95
Man
ning
: Circ
, '94
Aber
g: A
cta
Med
Sca
n, '6
9
Tsai
: JFM
A, '9
0
Kle
in: I
nt J
Car
d Im
ag: '
93
Man
ning
: Circ
, '94
Kle
in: C
irc, '
94
Leun
g: J
ACC
, '94
Har
t: St
roke
, '94
Tota
l
Left Atrial Appendage Left Atrium
Blackshear et al., Ann Thoracic Surg, 1996;61:755
Loca
tion
Freq
uenc
y (%
) 90%in
LAA
Chart1
Stoddard: JACC, '95Stoddard: JACC, '95
Manning: Circ, '94Manning: Circ, '94
Aberg: Acta Med Scan, '69Aberg: Acta Med Scan, '69
Tsai: JFMA, '90Tsai: JFMA, '90
Klein: Int J Card Imag: '93Klein: Int J Card Imag: '93
Manning: Circ, '94Manning: Circ, '94
Klein: Circ, '94Klein: Circ, '94
Leung: JACC, '94Leung: JACC, '94
Hart: Stroke, '94Hart: Stroke, '94
TotalTotal
Left Atrial Appendage
Left Atrium
99
1.5
97
2.9
74
25.5
50
50
92
7.7
73
27.3
95
5
100
0
100
0
91
9.5
Sheet1
Stoddard: JACC, '95Manning: Circ, '94Aberg: Acta Med Scan, '69Tsai: JFMA, '90Klein: Int J Card Imag: '93Manning: Circ, '94Klein: Circ, '94Leung: JACC, '94Hart: Stroke, '94Total
Left Atrial Appendage9997745092739510010091
Left Atrium1.52.925.5507.727.35009.5
LAA : Variable Structure
Stroke Prevalence Based UponLeft 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
ANTICOAGULATION
Eur Heart J 2012;33:2719-2747
HypertrophicCardiomyopathy
WHAT ABOUT ASPIRIN?AVERROES Study
Outcome Apixaban(N=2808)Aspirin
(N=2791)
Hazard Ratio
(95% CI)P Value
Stroke or systemic embolism
51(1.6% per yr)
113(3.7% per yr)
0.45(0.32-0.62)
Preventing Stroke in Non-Valvular AFImputed Benefit of Different Strategies (vs. Control)
Limitations of Anticoagulation
Warfarin• Bleeding risk• Daily regimen• Noncompliance• INR monitoring• Drug interactions
DOAC• Bleeding risk• Daily or BID regimen• Noncompliance• High cost• Lack of reversal agents
• Except Dabigatran
Major Bleeding
Treatment Drug D/C Rate Major Bleeding
Warfarin 17-28% 3.1-3.6%
Dabigatran (150 mg) 21% 3.3%
Rivaroxaban (20 mg) 24% 3.6%
Apixaban (5 mg) 25% 2.1%
Edoxaban (60 mg) 33% 2.8%
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.
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)
Rela
tive
Odd
s
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 War
farin
Age (years)
• Especially those at high risk40 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 Usein 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 6CHADS2 Score
Warfarin Useby CHADS2 Score
p
Bleeding Risk Assessment
Lip GY, JACC 2011Apostolakis 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 AwardedH Hypertension 1
A Abnormal renal and liver function (1 point each) 1 or 2
S Stroke 1B Bleeding 1L Labile INRs 1E Elderly (e.g., age > 65 years) 1D Drugs or Alcohol (1 point each) 1 or 2
Maximum 9 points
Net Benefit: Risk / Reward
• Balance difficult → specific patientCHA2DS2VASC
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
Atrial Fibrillation – Stroke Non-pharmacologic Treatment
Non-Pharmacologic Options
WATCHMAN LAAC Device• FDA approved alternative to anticoagulation for stroke risk
reduction in non-valvular AF • Only device with long-term data from RCTs and multicenter
registries• Noninferior to warfarin for stroke risk reduction in nonvalvular
AF• Statistically superior to warfarin for hemorrhagic stroke,
disabling stroke, and cardiovascular death over long-term follow-up
1. Reddy, V et al. JAMA 2014; Vol. 312, No. 19.2. Reddy, V et al. Watchman I: First Report of the 5-Year PROTECT-AF and Extended
PREVAIL Results. TCT 2014.
WATCHMANTM DeviceMinimally Invasive, Local Solution• Available sizes: 21, 24, 27, 30, 33 mm diameter
Intra-LAA design• Avoids contact with left atrial wall to help prevent
complications
Nitinol Frame• Conforms to unique anatomy of the LAA to reduce
embolization risk• 10 active fixation anchors - designed to engage
tissue for stability
Proximal Face• Minimizes surface area facing the left atrium to
reduce post-implant thrombus formation• 160 micron membrane PET cap designed to block
emboli and promote healing
Warfarin Cessation• 92% after 45 days, >99% after 12 months1• 95% implant success rate1
Anchors
160 Micron Membrane
Who is Eligible?The WATCHMAN™ Device is indicated to reduce the risk of thromboembolism from the LAA in patients with non-valvular atrial fibrillation who:
• Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy
• Are deemed by their physicians to be suitable for short-term 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.
Who is Eligible?• Non-valvular atrial fibrillation
• i.e. NOT due to mitral stenosis or prior mitral valve surgery• Stroke risk
• CHADS2 ≥ 2• CHADS2VASc ≥ 3
• Reason to seek non-pharmacologic alternative• Bleeding • Falls• Intolerant of anticoagulation• Compliance issues
• Ability to tolerate short-term warfarin (~6 weeks)
Implantation Procedure• One-time implant that does not need to be replaced• Performed in a cardiac cath lab/EP suite, or hybrid OR• Performed by a Watchman Team (EP, IC, Imaging, Anesthesia) • Catheter advanced to the LAA via the femoral vein
(Does not require open heart surgery)
• General anesthesia*• 1 hour procedure*• 1-2 day hospital stay*
* Typical to patient treatment in U.S. clinical trials
WATCHMANTM Device
Device Endothelialization
Canine Model – 30 Day
Canine Model – 45 Day Human Pathology - 9 Months Post-implant (Non-device related death)
Post-Implant Management
Implant TEE
45 Days 6 Months (from implant Indefinite
Warfarin + ASA 81
ASA 325 +Clopidogrel ASA 325
Warfarin Cessation
p = 0.04
Study 45-day 12-month
PROTECT AF 87% >93%
CAP 96% >96%
PREVAIL 92% >99%
Implant success defined as deployment and release of the device into the left atrial appendage
Warfarin Cessation PREVAIL Implant Success
No difference between new and experienced operators
Experienced Operators• n=26• 96%
New Operators• n=24• 93%
p = 0.28
PROTECT AF5-Year Results
Event Rate (per 100 Pt-Yrs) Rate Ratio
(95% CrI)Posterior Probability
WATCHMAN Warfarin Non-inferiority Superiority
Primary efficacy 2.2 3.7 0.61(0.42, 1.07) >99.9% 95.4%
Stroke (all) 1.5 2.2 0.68 (0.42, 1.37) 99.9% 83%
Systemic embolism 0.2 0.0 N/A -- --
Death (CV/unexplained) 1.0 2.3
0.44(0.26, 0.90) >99.9% 98.9%
Source: FDA Oct 2014 Panel Sponsor Presentation.
Meta-AnalysisHR 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
Series1, 0.785, 8.8
Series1, 1.02, 7.8
Series1, 1.951, 6.8Series1, 0.216,
6.1Series1, 1.556,
5.2Series1, 0.478,
4.3
Series1, 0.734, 3
Series1, 0.995, 2.2
Series1, 0.508, 1.2
Favors WATCHMAN Favors warfarin
Hazard Ratio (95% CI)
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
10.10.01 10
Chart1
0.7850.3710.252
1.020.6690.404
1.9511.8520.95
0.2160.3960.14
1.5561.5310.772
0.4780.330.195
0.7340.2960.21
0.9950.4480.309
0.5080.2650.175
8.8
7.8
6.8
6.1
5.2
4.3
3
2.2
1.2
Sheet1
X-ValuesY-ValuesLBUBNEPE
0.7858.80.5331.1560.2520.371Efficacy
1.027.80.6161.6890.4040.669All stroke or SE
1.9516.81.0013.8030.951.852Ischemic stroke or SE
0.2166.10.0760.6120.140.396Hemorrhagic stroke
1.5565.20.783.090.7721.531Ischemic stroke or SE post 7 days
0.4784.30.2830.8080.1950.33CV/unexplained death
0.73430.5241.030.210.296All-cause death
0.9952.20.6861.4430.3090.448Major bleed, all
0.5081.20.3330.7730.1750.265Major bleeding, non procedure-related
PROTECT AF: 5 Year MortalityWATCHMAN vs. Warfarin
V. Reddy, H. Sievert, J. Halperin et al. JAMA 2014;312:1988
RRR 60% RRR 34%
Preventing Stroke in Non-Valvular AFImputed Benefit of Different Strategies (vs. Control)
Complications – All Studies
Reddy VR, J. Am. Coll Cardiol. 2017;69(3)
SUMMARY• AF is common & associated with increased risk of stroke• Anticoagulation is the standard first line therapy for stroke risk
reduction in patients with risk factors• Not all patients tolerate systemic anticoagulation• Left atrial appendage occlusion offers a safe and effective
therapy for stroke risk reduction in these patients
Who to Refer?• Patients with non-valvular AF who have:
• Risk factors for stroke• Concerns about safety of long-term anticoagulation
Left Atrial Appendage Occlusion�An Alternative to Anticoagulation DISCLOSUREOBJECTIVESAtrial Fibrillation An EpidemicDistribution of AF by AgeAtrial Fibrillation Stroke RiskThrombosis/EmbolizationLAA – Culprit�Location of Thrombi in Left AtriumLAA : Variable StructureStroke Prevalence Based Upon�Left Atrial Appendage MorphologyANTICOAGULATIONWHAT ABOUT ASPIRIN?�AVERROES StudyPreventing Stroke in Non-Valvular AF�Imputed Benefit of Different Strategies (vs. Control)Limitations of AnticoagulationMajor BleedingNVAF: Odds of Intracranial Hemorrhage & Age in 145 Case-patients (INR 2.0-3.0) and 870 ControlsSignificant UndertreatmentLow Warfarin Use�in High-risk PatientsBleeding Risk AssessmentNet Benefit: Risk / RewardSlide Number 23Non-Pharmacologic OptionsWATCHMAN LAAC DeviceWATCHMANTM DeviceWho is Eligible?Who is Eligible?Implantation ProcedureWATCHMANTM DeviceDevice EndothelializationPost-Implant ManagementWarfarin CessationPROTECT AF�5-Year ResultsMeta-AnalysisPROTECT AF: 5 Year Mortality�WATCHMAN vs. WarfarinPreventing Stroke in Non-Valvular AF�Imputed Benefit of Different Strategies (vs. Control)Slide Number 42Complications – All StudiesSUMMARYWho to Refer?