4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

The Effectiveness of 

Procedures to Remove or 

Occlude the Left Atrial 

Appendage: A Systematic 

Review of the Evidence

October 2015

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) 

Portland VA Medical Center

Portland, OR

Devan Kansagara, MD, Director

Investigators:

Principal Investigator: 

North Noelck, MD

Co-Investigators: 

Joel Papak, MD

Michele Freeman, MPH

Robin Paynter, MLIS

Allison Low, BA

Makalapua Motu’apuaka, BA

Karli Kondo, PhD

Devan Kansagara, MD
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PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice 

guidelines and performance measures; and 

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations.

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov.

Recommended citation: Noelck N, Papak J, Freeman M, Paynter R, Low A, Motu’apuaka M, Kondo 

K, Kansagara D. The Effectiveness of Procedures to Remove or Occlude the Left Atrial Appendage: A 

Systematic Review of the Evidence. VA ESP Project #05-225; 2015.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans 

Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. The 

findings and conclusions in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the 

United States government. Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or 

royalties) that conflict with material presented in the report.
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TABLE OF CONTENTS 

EXECUTIVE SUMMARY ................................................................................................................... 1

Introduction ................................................................................................................................. 1

Methods....................................................................................................................................... 1

Data Sources and Searches ..................................................................................................... 1

Study Selection ....................................................................................................................... 2

Data Abstraction and Quality Assessment .............................................................................. 2

Data Synthesis and Analysis ................................................................................................... 2

Peer review.............................................................................................................................. 2

Summary of Findings .................................................................................................................. 2

Summary of evidence ............................................................................................................. 2

Research Gaps/Future Research ............................................................................................. 3

Conclusions ............................................................................................................................. 3

Table 1. Summary of evidence on the effectiveness of procedures to remove or occlude the left 

atrial appendage .......................................................................................................................... 4

ABBREVIATIONS ............................................................................................................................. 5

INTRODUCTION ............................................................................................................................... 6

METHODS ........................................................................................................................................ 7

Topic Development ..................................................................................................................... 7

Search Strategy ........................................................................................................................... 7

Study Selection ........................................................................................................................... 8

Data Abstraction ....................................................................................................................... 11

Quality Assessment ................................................................................................................... 11

Data Synthesis ........................................................................................................................... 11

Rating the Body of Evidence .................................................................................................... 11

Peer Review .............................................................................................................................. 11

RESULTS ....................................................................................................................................... 12

Literature Flow.......................................................................................................................... 12

Figure 1. Literature flow diagram ............................................................................................. 13

Percutaneous LAA interventions .............................................................................................. 14

KQ1: What is the effectiveness of LAA exclusion interventions compared with usual care?

............................................................................................................................................... 14

KQ2: What are the harms associated with LAA exclusion?................................................. 15

KQ3a: How do the benefits of LAA exclusion vary in different subgroups? ...................... 15

KQ3b: How do the harms of LAA exclusion vary in different subgroups? ......................... 16
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KQ4: What are the comparative effects of different techniques on health outcomes and rates 

of procedural success? .......................................................................................................... 16

Surgical LAA interventions ...................................................................................................... 22

KQ1: What is the effectiveness of LAA exclusion interventions compared with usual care?

............................................................................................................................................... 22

KQ2: What are the harms associated with LAA exclusion?................................................. 23

KQ3: How do the benefits and harms of LAA exclusion vary in different subgroups? ....... 23

KQ4: What are the comparative effects of different techniques on health outcomes and rates 

of procedural success? .......................................................................................................... 23

SUMMARY AND DISCUSSION ......................................................................................................... 28

Percutaneous LAA exclusion ................................................................................................ 28

Surgical LAA exclusion ........................................................................................................ 30

Limitations ................................................................................................................................ 32

Research Gaps/Future Research ............................................................................................... 32

Conclusions ............................................................................................................................... 33

REFERENCES ................................................................................................................................. 34

TABLES AND FIGURES

Table 1. PICOTS and Key Questions for Percutaneous LAA Interventions .............................. 9

Table 2. PICOTS and Key Questions for Surgical LAA Interventions .................................... 10

Figure 1. Literature flow diagram ............................................................................................. 13 

Table 3. Health outcomes, adverse effects, and procedural success in trials comparing 

percutaneous LAAO to warfarin therapy .................................................................................. 17

Table 4. Procedural success, harms, and long-term stroke risk in registry studies of 

percutaneous LAA exclusion .................................................................................................... 18

Table 5. Characteristics and findings of trials of cardiac surgery with vs without concomitant 

LAA occlusion or removal........................................................................................................ 25

Table 6. Characteristics and findings of cohort studies of cardiac surgery with vs without 

concomitant LAA occlusion or removal ................................................................................... 26

Table 7. Summary of the evidence on percutaneous and surgical interventions to occlude or 

remove the LAA ....................................................................................................................... 31

Table 8. Ongoing studies of percutaneous and surgical LAA interventions ............................ 32

APPENDIX A. SEARCH STRATEGIES ............................................................................................. 38

APPENDIX B. STUDY SELECTION ................................................................................................. 41

APPENDIX C. QUALITY ASSESSMENT .......................................................................................... 42

Table 9. Quality assessment of trials of percutaneous LAA interventions ............................... 42
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Table 10. Quality assessment of trials of surgical LAA interventions ..................................... 43

Table 11. Quality assessment of cohort studies surgical LAA interventions ........................... 45

APPENDIX D. LAA DEVICE MANUFACTURERS ........................................................................... 47

APPENDIX E. PEER REVIEWER COMMENTS AND AUTHOR RESPONSES ..................................... 48
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EXECUTIVE SUMMARY 

INTRODUCTION 

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting between 2.7 and 6.1 

million people in the United States. The prevalence of AF increases with age and is often 

associated with structural heart disease and co-morbidities that are common in the Veteran 

population. AF is the most important cause of cardioembolic stroke, which accounts for 14-36% 

of all ischemic strokes. While patients at highest risk for AF-related stroke also often have other 

independent risk factors for stroke secondary to atherosclerotic aortic or carotid disease, most 

cardiac sources of embolism are thought to be due to thrombus formation from blood stasis in the 

left atrium. Among patients with non-valvular AF more than 90% of thrombi develop in the left 

atrial appendage (LAA). Antithrombotic therapy with aspirin, warfarin, or one of several newer 

oral anticoagulants reduces the risk of stroke due to both atrial fibrillation and atherosclerotic 

disease but is associated with a risk of serious bleeding. As a potential alternative to long-term 

anticoagulant therapy, various LAA exclusion procedures have been developed in an attempt to 

isolate the LAA from circulating blood flow. These procedures, including both surgical 

occlusion and removal of the LAA and percutaneous catheter-based interventions to occlude the 

LAA, may be beneficial in reducing risk of cardioembolic stroke originating from the LAA. 

The purpose of this report is to systematically review the literature to better understand the 

balance of benefits and harms of surgical or percutaneous LAA exclusion procedures. 

METHODS

The research questions for this systematic review were developed in consultation with key 

stakeholders and content experts. The key questions (KQs) that this review sought to address 

were: 

KQ1. What is the effectiveness of surgical or percutaneous LAA exclusion compared with usual 

care?

KQ2. What are the harms associated with surgical or percutaneous LAA exclusion?

KQ3. How do the benefits and harms of LAA exclusion vary in different subgroups? 

KQ4. What are the comparative effects of different techniques (surgical and percutaneous) of 

LAA exclusion on rates of procedural success?

Data Sources and Searches 

We developed search strategies in consultation with a research librarian, who conducted database 

searches in Ovid MEDLINE®, Embase®, the Cochrane databases, the FDA Devices database, 

ClinicalTrials.gov, the Conference Abstracts database, and the World Health Organization 

International Clinical Trials Registry Platform (WHO ICTRP) from database inception through 

January 7, 2015. We reviewed the bibliographies of systematic reviews and other relevant 

articles for additional studies, and contacted device manufacturers to inquire for unpublished trial 

data. 
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Study Selection 

We reviewed titles and abstracts using pre-specified inclusion/exclusion criteria. Potentially 

relevant full-text articles underwent independent review by at least 2 investigators for final 

decisions on inclusion/exclusion. 

We included controlled clinical trials to assess the effectiveness of percutaneous LAA exclusion 

procedures. To assess the harms of percutaneous LAA procedures we also included cohort and 

registry studies with 50 or more patients. 

We included cohort studies and controlled clinical trials to review both benefits and harms of 

surgical LAA procedures. Because LAA exclusion procedures were usually done in the context 

of heart surgery, and harms related to LAA exclusion are difficult to distinguish from those of 

the heart surgery itself, we only included cohort studies with a control group of patients who 

received heart surgery without LAA exclusion. 

Data Abstraction and Quality Assessment 

One author abstracted data from each study and a second author reviewed the entries for 

accuracy.

Two reviewers (among NN, DK, JP, and MF) independently assessed the quality of each study 

using published criteria. We graded the strength of evidence for each outcome using published 

criteria which consider the consistency, coherence, directness, and applicability of a body of 

evidence, as well as the internal validity of individual studies. We resolved disagreements 

through discussion. 

Data Synthesis and Analysis 

We qualitatively synthesized the evidence on the benefits and harms of LAA exclusion. Clinical 

heterogeneity and the small number of trials precluded the possibility of combining the findings 

in meta-analysis. 

Peer Review

A draft version of this report was reviewed by 5 individuals with technical expertise and clinical 

leadership. Their comments and our responses are presented in Appendix E. 

SUMMARY OF FINDINGS

We reviewed 2,566 titles and abstracts from the combined searches. We selected 207 articles for 

full-text review, of which 20 studies contained primary data relevant to the effectiveness and/or 

harms of LAA interventions. We contacted 7 device companies to request information about 

unpublished studies but received no response. 

Summary of Evidence 

There is low-strength evidence that percutaneous LAA exclusion is associated with a similar risk 

of long-term stroke and mortality as continued oral anticoagulation therapy. This finding is based 

on trials of one device studied in patients without contraindications to oral anticoagulant therapy. 

Most patients who received the Watchman device were able to discontinue oral anticoagulant 
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therapy after undergoing follow-up transesophageal echocardiography (TEE) showing persistent 

closure of the LAA at 3-6 months. However, there is moderate strength evidence that a 

substantial proportion of patients undergoing various percutaneous LAA exclusion procedures 

experienced serious periprocedural harms. For example, patients undergoing placement of a 

Watchman device experienced 4.1-10.5% periprocedural adverse events. There is insufficient 

evidence to determine whether factors such as operator experience, patient selection criteria, or 

choice of device can modify these risks. There is insufficient data to assess the balance of 

benefits and harms of percutaneous LAA exclusion procedures in patients who are ineligible for 

long-term oral anticoagulation therapy. 

We found insufficient evidence to determine the efficacy of surgical LAA exclusion in reducing 

stroke. We found low-strength evidence that surgical LAA exclusion in the context of heart 

surgery done for another indication is unlikely to be associated with significant incremental 

harm. In 2 studies, successful closure of the LAA was demonstrated in follow-up in only 40-66% 

of patients. 

Table 1 summarizes the evidence on percutaneous and surgical LAA exclusion interventions. 

Research Gaps/Future Research 

Trials of percutaneous LAA interventions were limited to studies of the Watchman device in 

patients who were eligible for long-term warfarin therapy. Trials of surgical LAA interventions 

were few and limited by sample size. Several studies that should add substantively to this body 

of evidence are underway, including a large RCT of surgical interventions with an estimated 

sample size of 4,700 patients, studies of recently developed percutaneous devices (LAmbre and 

Occlutech), and a trial comparing Watchman with Apixaban in patients ineligible for warfarin 

therapy. 

Conclusions 

Overall, there is limited evidence that percutaneous LAA exclusion using the Watchman device 

may be an effective alternative to long-term oral anticoagulation in selected patients who are 

closely followed and in whom procedural success is sustained. However, in many studies, 

percutaneous LAA exclusion has been associated with high rates of serious procedure-related 

harms. There is insufficient evidence to assess the benefits of surgical LAA exclusion. While 

surgical LAA exclusion does not appear to be associated with a significant increase in harms 

over the heart surgery during which the procedures are typically performed, rates of procedural 

success may be low. Overall, there is insufficient evidence to support the routine use of surgical 

LAA exclusion to reduce stroke risk or future need for anticoagulant therapy. 
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Table 1. Summary of evidence on the effectiveness of procedures to remove or occlude the left atrial 

appendage

Outcome

Device or procedure

N studies 

(N=combined participants)

Findings

Strength of 

Evidence* Comments

Percutaneous interventions

Mortality Watchman

2 RCTs (N=1,114)

No significant difference in 

mortality.

RR (95% CI) in 2 RCTs:

1.20 (0.31 to 4.56) 

0.62 (0.34 to 1.24)

Low Limited applicability: 

only one device has been 

studied in 2 RCTs.

Patients were eligible to 

receive LT-OAC. 

Low precision (wide 

confidence intervals). 

Stroke Watchman

2 RCTs (N=1,114)

No significant difference in risk of 

stroke. 

RR (95% CI): in 2 RCTs: 

0.71 (0.35 to 1.64)

3.28 (0.37 to 25.31)

Harms ACP: 3 registries (N=147)

Coherex: 1 registry (N=4)

Lariat: 2 registries (N=93)

PLAATO: 5 registries 

(n=441)

Watchman: 2 RCTs + 

4 registries (N=742)

Device not specified: 

2 registries (N=211)

Serious procedure- or device-related 

safety events (% of patients): 

1.6 to 13.6.

Overall, rate of serious adverse 

events within 7 days of device 

implantation was 6.5% (98/1506). 

Moderate A range of devices were 

examined among 2 trials 

and 11 observational 

studies. Strength of 

finding limited by wide 

range of event rates 

across studies, relatively 

small number of patients 

treated in each 

observational study. 

Surgical interventions

Mortality Sutures or stapler in 3 RCTs 

(N=171)

Various excision and 

exclusion techniques in 4 

Cohort studies (N=1695)

No significant difference in 

mortality, among studies in which at 

least one event occurred in both 

groups:

In 1 RCT: 7.7 vs 12% (P > .05)

RR (95% CI) 0.64 (0.12, 3.52) 

In 1 cohort: 5.0 vs 8.4% (P > .05) 

RR (95% CI) 0.60 (0.22 to 1.60)

Insufficient Trials too small and 

event rates too low to 

determine effectiveness 

of procedure. 

Stroke 3 RCTs (N=171)

2 cohort studies (N=1500)

No significant difference in risk of 

stroke, among studies in which at 

least one event occurred in both 

groups:

In 1 RCT: 3.8 vs 12% (P > .05); 

RR (95% CI) 0.32 (0.03 to 2.88)

In 2 cohorts: 

1.0 vs 1.4% (P = .44) 

0.84 vs 1.7% (P > .05) 

Insufficient

Harms 3 RCTs (N=171)

1 cohort study (N=238)

Serious safety events: 

6.9-32.0% of patients 

No significant differences in most 

major harms between cardiac 

surgery groups with and without 

LAA exclusion

Low Limited number of 

studies and limited 

number of patients 

included. 

Abbreviations: ACP = Amplatzer cardiac plug; CI = confidence interval; LT-OAC = long term oral anticoagulation; RCT = 

randomized controlled trial; PLAATO = percutaneous left atrial appendage transcatheter occlusion; RR = relative risk
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ABBREVIATIONS 

ACP Amplatzer cardiac plug

AF Atrial fibrillation

CABG Coronary artery bypass grafting

CAD Coronary artery disease

CHADS2 Stroke risk score in AF (congestive heart failure, hypertension, age 75+, 

diabetes mellitus, and stroke/TIA)

CHA2DS2-VASc Stroke risk score in AF that includes CHADS2 with age in 2 categories and 

vascular disease

CHF Congestive heart failure

CI Confidence interval

CT Computerized tomography

DM Diabetes mellitus

HAS-BLED Score that estimates risk of major bleeding for patients on anticoagulation 

for atrial fibrillation

HR Hazard ratio

HTN Hypertension

Hx History (of)

INR International normalized ratio

LAA Left atrial appendage

LT-OAC Long-term oral anticoagulation therapy

LVEF Left ventricular ejection fraction

MI Myocardial infarction

MRI Magnetic resonance imaging

PICOTS Population, Intervention, Comparator, Outcome, Timing, Study Design

PLAATO Percutaneous Left Atrial Appendage Transcatheter Occlusion

PSM Propensity score matching

QoL Quality of life

RCT Randomized controlled trial

RR Relative risk

TEE Transesophageal echocardiography

TIA Transient ischemic attack

VATS Video assisted thoracoscopy

WHO ICTRP World Health Organization International Clinical Trials Registry Platform
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EVIDENCE REPORT

INTRODUCTION

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting between 2.7 and 6.1 

million people in the United States.1 The prevalence of AF increases with age and is often 

associated with structural heart disease and co-morbidities that are common in the Veteran 

population. Complications related to AF can be classified as hemodynamic or thromboembolic. 

Cardioembolic strokes account for 14-36% of all ischemic strokes, and AF is the most important 

cause of cardioembolic stroke. In general, the risk of stroke in patients with non-valvular AF is 2 

to 7 times higher than patients without AF.2 Antithrombotic therapy with aspirin, warfarin, or 

one of several newer oral anticoagulants have been the mainstay of stroke prevention in atrial 

fibrillation, but may be cumbersome and are associated with an increased risk of bleeding.

The mechanism of thrombosis formation is stasis of blood in the left atrium and it is currently 

believed that a high percentage of thromboemboli develop in the left atrial appendage (LAA).3,4

Thus, various procedures have been developed that attempt to isolate the LAA from circulating 

blood flow in an effort to reduce the risk of thromboembolic stroke. These methods include 

surgical occlusion or removal of the LAA, and percutaneous, catheter-based approaches to 

occlude the LAA. The LAA is, however, only one potential source of strokes and patients at the 

highest risk of stroke related to AF frequently have associated risk factors for stroke that are 

independent of AF. These risk factors – including hypertension, diabetes, and advanced age –

increase a patient’s likelihood of an ischemic stroke secondary to atherosclerotic aortic or carotid 

disease which would not be addressed by exclusion or removal of the LAA.

Prior to 2002, surgery was the only option for exclusion of the LAA. This could be done in 

conjunction with surgery being performed for other reasons, such as coronary artery bypass 

grafting (CABG) or valve replacement in patients who also have or are at risk for AF, or as part 

of a mini-thoracotomy typically in association with a maze procedure. Surgical approaches to 

LAA exclusion include simple suture ligation, oversewing the base without excision, excising 

the appendage and oversewing the base, or surgical stapling and excision.

1

More recently, a number of devices designed to occlude the LAA percutaneously have been 

developed. The devices currently in use include the Percutaneous Left Atrial Appendage 

Transcatheter Occlusion (PLAATO) device (Appriva Medical, Plymouth, Minnesota), the 

Amplatzer device (AGA Medical Corporation/St. Jude Medical, Golden Valley, Minnesota), the 

Watchman device (Boston Scientific, Natick, Massachusetts), and the LARIAT suture delivery 

device (SentreHeart, Redwood City, California). Given the high prevalence of atrial fibrillation 

in the general and Veteran population, along with the potential risks and inconvenience of longterm oral anticoagulant therapy, there is a growing interest in LAA occlusion or removal as an 

alternative stroke risk reduction strategy. The purpose of this report is to systematically review 

the literature to better understand the balance of benefits and harms of surgical or percutaneous 

LAA occlusion or removal. We use the general term LAA exclusion throughout the report to 

refer to either removal or isolation of the LAA, except where otherwise specified.
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METHODS

TOPIC DEVELOPMENT

The topic of this review was nominated by Dr. Alaa Shalaby, a member of the VHA Cardiology 

Field Advisory Committee and Director of Cardiac Electrophysiology at the VA Pittsburgh 

Healthcare System. Dr. William Gunnar, National Director of Surgery for the Veterans Health 

Administration, also served as an operational partner.

The research questions for this systematic review were developed after a topic refinement 

process that included a preliminary review of published peer-reviewed literature, consultation 

with internal partners and investigators, and consultation with content experts and key 

stakeholders. The key questions (KQs) that this review sought to address are as follows:

KQ1. What is the effectiveness of surgical or percutaneous LAA exclusion compared with usual 

care?

KQ2. What are the harms associated with surgical or percutaneous LAA exclusion?

KQ3. How do the benefits and harms of LAA exclusion vary in different subgroups? 

KQ4. What are the comparative effects of different techniques (surgical and percutaneous) of 

LAA exclusion on rates of procedural success?

A protocol describing the review plan was posted to a publicly accessible website before the

study was initiated.5

SEARCH STRATEGY

Search strategy was developed in consultation with a research librarian, and was peer reviewed 

by a second research librarian using the instrument for Peer Review of Search Strategies 

(PRESS).6,7 To identify relevant articles, we searched Ovid MEDLINE®, Embase®, the Cochrane 

databases, and the FDA Devices database from database inception through January 7, 2015. We 

further reviewed the bibliographies of systematic reviews and other relevant articles for 

additional studies. To identify in-progress or unpublished studies, we searched ClinicalTrials.gov, 

the Conference Abstracts database, the World Health Organization International Clinical Trials 

Registry Platform (WHO ICTRP), and contacted device manufacturers to inquire for

unpublished trial data.

Using pre-specified inclusion/exclusion criteria, we reviewed titles and abstracts for relevance to 

the key questions. At the full-text screening stage, 2 independent reviewers concurred on final 

inclusion/exclusion decisions, with input from a third investigator when needed to resolve 

questions and reach consensus. Articles meeting eligibility criteria were included for data 

abstraction. 
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STUDY SELECTION

The criteria for patient population, intervention, comparator, outcome, timing parameters, and 

study designs (PICOTS) that apply to each key question are specified in Table 1 (percutaneous 

procedures) and Table 2 (surgical procedures). Given the availability of larger-scale trials of 

percutaneous procedures, along with recent systematic reviews of percutaneous approaches to 

LAA exclusion, we only included controlled clinical trials to assess the effectiveness of 

percutaneous LAA exclusion procedures. On the other hand, we included cohort studies with or 

without a control population to examine harms of percutaneous interventions.8 After an initial 

survey of the literature, we found there were a number of larger cohort studies providing harms 

data and therefore set a sample size cut-off of 50 or more patients for inclusion.

We included cohort studies in addition to controlled clinical trials for all key questions 

examining benefits and harms of surgical procedures.8 However, given that the LAA exclusion 

procedures were usually done in the context of heart surgery and that the harms related to LAA 

exclusion would be difficult to distinguish from those of the heart surgery itself, we only 

included cohort studies with a control population of patients who received heart surgery but no 

LAA exclusion.
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Table 1. PICOTS and Key Questions for Percutaneous LAA Interventions

Key Question KQ1. What is the effectiveness of 

LAA exclusion interventions 

compared with usual care?

KQ2. What are the harms associated 

with LAA exclusion?

KQ3a. How do the benefits LAA 

exclusion vary in different subgroups?

KQ3b. How do the harms of LAA 

exclusion vary in different subgroups?

KQ4. What are the comparative 

effects of different techniques on 

rates of procedural success?

Population Patients with atrial fibrillation who are eligible for percutaneous LAA exclusion

Intervention AMPLATZERTM Cardiac Plug (company: AGA Medical, Corp., North Plymouth, MN, USA)

WATCHMAN® Left Atrial Appendage Closure Technology/Device/System (company: Atritech, Inc., North Plymouth, MN, USA)

PLAATOTM Percutaneous Left Atrial Appendage Transcatheter Occlusion (company: Appriva Medical, Inc., Sunnyvale, CA)

Coherex WaveCrestTM LAA Occluder System (company: Coherex Medical, Inc., Salt Lake City, Utah, USA)

LARIAT suture delivery device (SentreHeart, Redwood City, California)

Lifetech LAmbreTM Left Atrial Appendage Occluder Device (Lifetech Scientific Co., Ltd) Nanshan District, Shenzhen, PEOPLE’S REPUBLIC OF 

CHINA

Comparator Usual care without LAA exclusion Compares percutaneous intervention 

to another LAA closure technique 

(surgical, thoracoscopic, or 

percutaneous)

Outcomes Primary outcomes:

§ Stroke

§ Mortality

§ Cardiovascular morbidity 

§ Other reported health outcomes

§ Harms other than primary outcomes 

for KQ1

§ length of stay (hospital and ICU)

§ bleeding

§ infection 

§ need for surgical intervention

§ Primary outcomes listed in KQ1

§ Other reported benefits and harms 

§ Rates of bleeding.

Procedural outcome:

Successful closure/LAA removal, 

assessed by methods such as 

transesophageal echocardiogram; 

CT; MRI.

Health outcomes: 

Same as those listed for KQ1.

Timing Short- and long-term outcomes

Study design Include: Systematic reviews, meta-analyses, or randomized controlled trials. For KQ2 and KQ3b, we will additionally include cohort and trial extension studies 

that report data on adverse events. 

Exclude: Non-systematic or narrative reviews, non-randomized trials, opinions, case studies, case series, and quasi-experimental studies. 
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Table 2. PICOTS and Key Questions for Surgical LAA Interventions

Key Question KQ1. What is the effectiveness of 

LAA exclusion interventions 

compared with usual care?

KQ2. What are the harms 

associated with LAA exclusion?

KQ3. How do the benefits and harms of 

LAA exclusion vary in different 

subgroups?

KQ4. What are the comparative 

effects of different techniques on 

health outcomes and rates of 

procedural success?

Population Patients undergoing cardiac 

surgery: coronary bypass surgery; 

valvular surgery; or both bypass 

and valve surgery.

Patients undergoing surgical 

LAA occlusion/removal in 

combination with surgery for 

atrial fibrillation (ie, MAZE).

Patients undergoing surgical LAA 

exclusion.

Non-selected population of patients 

with atrial fibrillation

Intervention LAA occlusion/removal techniques that involve major surgery (sternotomy or thoracotomy), eg: 

§ specific devices such as AtriClip, or 

§ techniques such as stapling or suturing

LAA occlusion/removal via thoracoscopic surgery

Minimally invasive Maze procedures if there are data about the incremental effects of concomitant LAA exclusion.

Comparator Cardiac surgery without LAA 

removal or occlusion.

Surgery for atrial fibrillation 

without LAA removal. 

Non-surgical/usual care for 

thromboembolic stroke prevention, such 

as aspirin for patients with CHADS2 of 0 

or 1, and antithrombotic therapy with 

warfarin or a NOAC (apixiban, 

dabigatran, rivaroxaban) for CHADS2 of 

>=1.

Compares surgical intervention to 

another LAA closure technique 

(surgical, thoracoscopic, or 

percutaneous)

Outcomes Primary outcomes:

§ Stroke

§ Mortality

§ Cardiovascular morbidity 

§ Other reported health outcomes

§ Harms other than primary 

outcomes for KQ1

§ length of stay (hospital and 

ICU)

§ time on bypass

§ bleeding

§ ventilator days

§ infection 

§ Primary outcomes listed in KQ1

§ Other reported benefits and harms 

§ Rates of bleeding.

Procedural outcome:

Successful closure/LAA removal, 

assessed by methods such as 

transesophageal echocardiogram; 

CT; MRI.

Health outcomes: 

Same as those listed for KQ1.

Timing Short- and long-term outcomes

Study design Include: Systematic reviews, meta-analyses, controlled clinical trials (randomized or non-randomized), and methodologically rigorous observational studies 

(case control/cohort studies) that adjust for important confounders, eg, propensity score matching

Exclude: Non-systematic or narrative reviews, opinions, case studies, case series, and quasi-experimental studies.
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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DATA ABSTRACTION 

One investigator (among NN, JP, and MF) abstracted data from published reports into a 

customized database, and entries were confirmed by a second reviewer. From each study, we 

abstracted study design, objectives, setting, population characteristics (including sex, age, 

race/ethnicity), subject eligibility and exclusion criteria, number of subjects, years of enrollment, 

duration of follow-up, the study and comparator interventions, important co-interventions, health 

outcomes, and adverse events. A second author reviewed the entries for accuracy.

QUALITY ASSESSMENT 

Two reviewers (among NN, DK, JP, and MF) independently assessed the quality of each trial 

using a tool developed by the Cochrane Collaboration (Appendix C).9 We assigned each trial an 

overall summary assessment of low, high, or unclear risk of bias. 

For evaluating cohort studies of surgical LAA interventions, we used the Newcastle-Ottawa 

criteria to assess methodological rigor and consider potential sources of bias.10 We did not assign 

overall quality ratings, however, as validated criteria for ranking observational studies are not 

currently available. 

DATA SYNTHESIS 

We qualitatively synthesized the evidence on the benefits and harms of LAA exclusion. Clinical 

heterogeneity and the small number of trials precluded the possibility of combining the findings 

in meta-analysis. 

RATING THE BODY OF EVIDENCE 

We assessed the overall quality of evidence for each outcome using a method developed by the 

Agency for Healthcare Research and Quality (AHRQ).11 We considered the consistency, 

coherence, and applicability of the body of evidence, as well as the internal validity of individual 

studies, to classify the strength of evidence for each outcome as follows: 

High = Further research is very unlikely to change our confidence on the estimate of effect.

Moderate = Further research is likely to have an important impact on our confidence in the 

estimate of effect and may change the estimate.

Low = Further research is very likely to have an important impact on our confidence in the 

estimate of effect and is likely to change the estimate.

Insufficient = Any estimate of effect is very uncertain.

PEER REVIEW

A draft version of this report was reviewed by 5 individuals with technical expertise and clinical 

leadership. Their comments and our responses are presented in Appendix E. 
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RESULTS 

We reviewed 2,566 titles and abstracts, including 2,469 from the electronic search and an 

additional 98 from reviewing reference lists and performing manual searches for recently 

published and unpublished or ongoing studies. After applying inclusion/exclusion criteria at the 

abstract level, we reviewed 207 full-text articles from which we found 20 primary studies that 

met our inclusion criteria. We also identified 5 systematic reviews of the effectiveness of 

percutaneous LAA devices. We contacted 7 device companies to request information about 

unpublished studies but received no response (Appendix D). 

LITERATURE FLOW 

The diagram on the following page shows the yield of citations from database searches and other 

sources, the numbers of excluded abstracts and full-text articles, and the final yield of included 

studies (Figure 1). 
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Figure 1. Literature flow diagram

2,469 Citations identified from electronic database searches 

 1,211 from Ovid MEDLINE® on 1/07/2015 

 1,250 from EMBASE on 1/07/2015 

 8 from the EBM Reviews/Cochrane library on 1/07/2015 

98 Citations identified from reference lists of review articles, and 

 searches for recent, unpublished or ongoing studies, including:

 32 from Clinicaltrials.gov on 1/07/2015 

 3 from WHO ICTRP on 1/22/2015 

 57 from the Conference Papers Index on 1/22/2015

2,566 Citations compiled for review of titles and abstracts

2359 Titles and abstracts excluded for lack 

 of relevance, or full text not accessible 

207 Potentially relevant articles retrieved for further review

187 Excluded articles:

Non-English publication = 3 

 Intervention, objectives, or outcomes not in scope = 17 

 No primary data or excluded study design = 24 

 Duplicate publications of other studies = 27 

Systematic reviews = 5 

 Retrieved for background, discussion, or methods = 45

Grey literature reviewed for relevant unpublished studies = 66

20 included

primary studies

Percutaneous interventions:

2 RCTs

 11 registry studies

Surgical interventions:

3 RCTs

 4 Cohort studies 
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PERCUTANEOUS LAA INTERVENTIONS

KQ1: What is the effectiveness of LAA exclusion interventions compared with 

usual care? 

We found 2 randomized controlled trials (RCTs) with low risk of bias, both of which compared 

the Watchman(R) Left Atrial Appendage Closure Device (Atritech, Inc., North Plymouth, MN, 

USA) to medical therapy with warfarin (Table 3). Inclusion into the PROTECT-AF12-14 trial 

required subjects to have non-valvular atrial fibrillation (NVAF) and a CHADS215 score of at 

least 1, while the PREVAIL16 trial enrolled subjects with higher risk of stroke; patients were 

excluded from these trials if they had contraindication to warfarin therapy, recent stroke, or a 

patent foramen ovale/atrial septal defect.

The PROTECT-AF trial included 463 intervention and 244 control patients with non-valvular 

atrial fibrillation, and excluded patients with low stroke risk (CHADS2 of 0). The device was 

successfully deployed in 88% (408/463) of patients, though it was not attempted in 14 patients. 

Successful closure was obtained in 86% (348/401) of patients at 45 days and in 92% (355/385) at 

6 months. Warfarin was typically discontinued with complete closure or if residual peri-device

flow was less than 5 mm width on surveillance transesophageal echocardiogram (TEE). At 6 

months, successful closure was demonstrated in 92% (355/385), although 5.6% (23/408) refused 

follow-up TEE. Most patients were able to stop warfarin therapy (7.5% (30/401), 3.6% (14/385), 

and 2.7% (10/370) of subjects in the LAA exclusion group remained on warfarin therapy at 45 

days, 6 months, and 2 years respectively.13,14 The control arm was within therapeutic 

international normalized ratio (INR) range 66% of the time.

There was no difference in a composite primary efficacy endpoint including 

ischemic/hemorrhagic stroke, cardiovascular/unexplained death, and systemic embolism with 3.0 

(1.9 to 4.5) events per 100 patient-years in the LAA exclusion group versus 4.9 (2.8 to 7.1) 

events per 100 patient-years in the warfarin group (rate ratio 0.62, 0.35 to 1.25). Cumulative 

events at 2.3 years mean follow up (standard deviation 1.1 years, median 2.4, range 0.5 to 9 

years) were also similar with 3.0 (2.15 to 4.3) events per year in the LAA exclusion group versus 

4.3 (2.6 to 5.9) events per year in the warfarin group. Overall, there was >99.9% posterior 

probability for non-inferiority for the LAA exclusion group compared to the warfarin treated 

group.

13,14 Additionally, there was no statistically significant difference in mortality between the

2 groups. 

In a subset of patients in the PROTECT-AF trial, quality of life on some subscales was modestly 

improved in the intervention group. However, the absolute differences were small and the 

findings subject to bias given lack of patient blinding and differential rates of follow-up in each 

group.12

The PREVAIL trial enrolled 407 subjects (269 assigned to LAA exclusion and 138 assigned to 

warfarin therapy) and followed them for an average of 11.8 months (standard deviation 5.8 

months, median 12 months, range 0.03 to 25.9 months).

16 Patients were slightly older and had a 

higher risk of stroke than the population included in the PROTECT-AF trial. Device deployment 

was successful in 95.1% (252/269) patients. At 6 months, device closure was demonstrated in 

98.3% (235/239), though 11.2% (30/269) refused follow-up TEE.
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The PREVAIL trial did not meet its target of non-inferiority for overall efficacy, although event 

rates were low and numerically comparable for both arms. Overall mortality was 2.6% in the 

LAA exclusion group versus 2.2% in the warfarin group. A composite outcome of death, 

ischemic/hemorrhagic stroke, or systemic embolism occurred in 5.2% of the LAA exclusion 

group and 2.9% of the warfarin group. On the other hand, the rate of events adjusted for persontime of observation months was similar: 18 month rate ratio of composite events was 1.07 

(credible interval 0.57 to 1.89).

16 The discrepancy in the reported results may be related to a later 

occurrence of outcomes in the device group.

KQ2: What are the harms associated with LAA exclusion?

We found 2 trials and 11 observational studies reporting harms data (Tables 3 and 4). Serious

periprocedural adverse events were reported in 1.6-13.6% of patients. Overall, the rate of 

periprocedural harms occurring within 7 days of device placement was 6.5% (98/1506). The 

types of periprocedural events most commonly reported included pericardial effusions with and 

without associated tamponade, bleeding, device thrombus, and device embolization.

Two trials examined harms associated with placement of the Watchman device.

13,16 In 

PROTECT-AF 10.6% (49/463) of patients experienced a safety event with 55.1% (27/49) of 

those occurring on the day of the procedure. Significant pericardial effusion followed by major 

bleeding accounted for most of these events. The authors note the rate of pericardial effusion 

declined with operator experience. In contrast, the safety event rate was much lower (2.2%) in 

the more recently conducted PREVAIL trial.16 Adverse event rates were similar in the single 

center17-22 and the multicenter studies.

23-26

We did not find robust comparative effectiveness data to directly assess the relative rates of 

serious safety events according to the device used. However, there were serious periprocedural

events including death or need for emergent surgery reported for all included devices.

Overall, patients had low rates of stroke and bleeding and there were no reported technical

device failures over the long term. Data on longer-term safety from the observational studies is 

limited in part by either high rates of attrition24 or lack of information about the loss to followup.17,21,22,26,27 Additionally, the duration of follow-up ranged from 6 months to 5 years and there 

was no clear standard for which events were reported. 

KQ3a: How do the benefits of LAA exclusion vary in different subgroups?

The evidence for use of LAA exclusion devices in different subgroups is limited to retrospective 

analysis of a single randomized controlled trial of the Watchman device. In PROTECT-AF the 

use of the Watchman appeared equally effective in men and women and was non-inferior to 

warfarin in patients with CHADS2 score greater than 1, patients who are greater than or equal to 

75 years old, patients with normal and reduced left ventricular ejection fraction (LVEF), patients 

with prior stroke, and in those with higher CHADS2.25 Findings were also consistent in patients 

with paroxysmal and permanent atrial fibrillation.25 However, the strength of these findings 

should be considered low because of the post-hoc nature of these analyses and the relatively 

wide confidence intervals associated with the findings.
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KQ3b: How do the harms of LAA exclusion vary in different subgroups?

The PROTECT-AF and PREVAIL trials of the Watchman device did not address harms in 

different subgroups.13,14,16 The observational studies did not directly compare rates of harms 

across patient subgroups. In these studies, there were a substantial proportion of older patients 

with higher stroke risk and the rates and types of periprocedural harms were similar across the 

studies.

While the 2 RCTs excluded patients who were ineligible to receive anticoagulant therapy, 7 of 

11 observational studies included patients who were ineligible for long-term oral anticoagulant 

therapy. In most of these studies, the long-term rates of stroke were low – 2.1% (12/565) over the 

course of 6-24 months of follow-up.

17,19,21,24,25 One study of the PLAATO device found a higher

incidence of stroke (12.5%) during a follow-up period which lasted up to 5 years,

20 though the 

annual rate of stroke is similar to studies with shorter follow-up periods. Long-term 

complications were not reported as part of the CAP Registry.26,27

KQ4: What are the comparative effects of different techniques on health 

outcomes and rates of procedural success?

Given that RCT data is limited to a single device, the Watchman, and a single technique, it is 

impossible to compare the effectiveness of different techniques. The PREVAIL trial included 

analysis of the learning curve for implantation of the Watchman by requiring a minimum of 20% 

of participants from centers that had not previously participated in LAA exclusion trials with this 

device, as well as a requirement that a minimum of 25% of randomized patients be treated by 

new operators. The study found an overall implantation success of 95.1%., with no statistically 

significant difference in successful deployment when comparing experienced operators (96.3%)

to new operators (93.2%; P = .256).16 Similarly, there were no significant differences in 

complication rates between experienced and new operators.

A number of different devices were represented among the observational studies; however, the 

Watchman and PLAATO devices were the most frequently studied. In these studies, the device 

was successfully deployed in most patients selected to undergo the procedure, regardless of the 

device used. In one study, device deployment rates were similar in the Watchman device (98.8%, 

165 of 167) and the Amplatzer Cardiac Plug (ACP) device (90%, 9 of 10).

22 Rates of device 

closure as determined by follow-up TEE were high among studies of different devices reporting 

this outcome, but there was substantial variation in the timing of follow-up, and a substantial 

proportion of patients did not undergo follow-up TEE.
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Table 3. Health outcomes, adverse effects, and procedural success in trials comparing percutaneous LAAO to warfarin therapy 

Study,

Setting, 

Mean followup time

Patient characteristics, 

T vs C

KQ1. Health outcome effects,

T vs C 

KQ2. Harms associated with LAA 

exclusion, T vs C 

KQ4. Rates of procedural 

success, T vs C 

PREVAIL16

50 sites, USA

11.8 months

N patients: 269 vs 138

Mean age: 74.0 vs 74.9

Male %: 67.7 vs 74.6

CHADS2 mean: 2.6 vs 2.6

CHA2DS2-VASc mean: 

3.8 vs 3.9

AF %: 100 vs 100

Stroke %: 27.5 vs 28.3

CHF %: 23.4 vs 23.2

HTN %: 88.5 vs 97.1 

(P = .003)

DM %: 33.8 vs 29.7

Ischemic stroke: 5 of 269 (1.9%) vs 1 of 138 (0.7%)

Hemorrhagic stroke: 1 of 269 (0.4%) vs 0 of 138 

(0.0%)

Death (cardiovascular/unexplained): 7 of 269 (2.6%) vs

3 of 138 (2.2%)

Systemic embolism: 1 of 269 (0.4%) vs 0 of 138 

(0.0%)

Total serious AEs: 11 (4.1%) of 269**

Device embolization: 2 of 269 (0.7%)

Arteriovenous fistula: 1 of 269 (0.4%)

Cardiac perforation: 1 of 269 (0.4%)

Pericardial effusion requiring surgery: 1 

of 269 (0.4%)

Pericardial effusion with 

pericardiocentesis: 4 of 269 (1.5%)

Major bleed requiring transfusion: 1 of 

269 (0.4%)

Procedure-related stroke: 1 of 269 (0.4%)

252 (95.1%) successfully 

implanted of 265 attempted.

Discontinuation of 

warfarin*, among N 

assessed by TEE: 

227 (92.2%) of 246 at 45 

days

235 (98.3%) of 239 at 6 

months

141 (99.3%) of 142 at 12 

months

PROTECT 

AF12-14

59 sites

USA, Europe

12 months

N patients: 463 vs 244

Mean age: 71.7 vs 72.9

Male %: 70.4 vs 70.1

Mean CHADS: 2.2 vs 2.4 

(P = .0517)

AF %: 100 vs 100

Stroke/TIA %: 17.7 vs 20.1

CAD %: 39.6 vs 49.5 

(P = .0275)

CHF %: 26.8 vs 27.0

HTN %: 90.9 vs 90.3

DM %: 24.9 vs 30.6

Ischemic stroke: 15 of 463 (3.0%) vs 6 of 244 (2.5%)

Cardiovascular/unexplained death: 5 of 463 (1.1%) vs

10 of 244 (4.1%), P <.05

Hemorrhagic stroke: 1 of 463 (0.2%) vs 6 of 244 

(2.5%)

Systemic embolism: 2 of 463 (0.4%) vs 0 of 244 (0%)

All strokes: 16 of 463 (3.4%) vs 12 of 244 (4.9%) 

All-cause mortality: 21 of 463 (4.5%) vs 18 of 244 

(7.4%)

Quality of Life (QoL) assessed by Short-Form 12 vs 2, 

Mean change from baseline to 12 months:

Total physical score: +0.4 vs -0.2, P = .0015

Total mental score: 0.0 vs -0.9, P = .6400

Physical functioning: +0.1 vs -3.0, P = .0005 

Physical role limitation: +0.4 vs -2.35, P = .0021

Pain: -0.1 vs -1.0, P = .5668

General health: +0.8 vs -0.2, P = .0606

Vitality: +0.2 vs -1.4, P = .1614

Social functioning: +0.5 vs -1.6, P = .0650

Emotional role limitation: -0.3 vs -1.8, P = .1115

Mental health: 0.0 vs -0.9, P = .6780

Total serious AEs: 49 (10.5%) of 463 vs

20 (8.2%) of 244

Pericardial effusion requiring surgery: 15 

of 463 (3.2%)

Pericardial effusion with 

pericardiocentesis: 7 of 463 (1.5%)

Device embolization: 3 of 463 (0.6%)

Major bleeding: 16 of 463 (3.4%)

Procedure-related stroke: 6 of 463 (1.1%)

Other: 2 of 463 (0.4%)

27 (55%) of 49 primary safety events 

occurred on the day of the procedure.

Timing of specific AEs not otherwise 

stated.

408 (91%) successfully 

implanted of 449 attempted.

Discontinuation of 

warfarin*, among N 

assessed by TEE: 

At 45 days:

348 (86%) of 401. 

30 (7.5%) of 401 continued 

warfarin due to continued 

shunt

At 6 months: 

355 (92%) of 385.

14 (3.6%) of 385 continued 

warfarin due to continued 

shunt

Control arm was within 

therapeutic INR range 66% 

of the time.

*Implies complete closure or residual peri-device flow <5mm in width on TEE.

**Total serious AEs in our report differs from primary source as we included procedure related strokes and pericardial effusions requiring any intervention.
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Table 4. Procedural success, harms, and long-term stroke risk in registry studies of percutaneous LAA exclusion

Study, 

Setting

Device;

Mean follow-up;

N patients;

Eligible/ineligible 

for LT-OAC

Patient characteristics Periprocedural harms 

occurring within 7 days Longer-term harms

Procedural success:

Deployment, N (%) of 

attempted

Closure, N (%) of 

patients assessed by TEE

Bartus, 

201317

Poland

Lariat

1 year

N=89

Ineligible for LTOAC

Mean age: 62

Male %: 57

CHADS2 mean: 1.9

CHA2DS2-VASc mean: 2.8

HAS-BLED mean: 2.4

Stroke/TIA %: 25 

CAD %: 4 

CHF %: 12 

HTN %: 94

DM %: 10

Serious procedure- or device-related safety 

events:

Pericarditis: 2 (2.4%) of 85

Pericardial effusion: 

1 (1.2%) of 85

At 3 months, sudden 

cardiac death: 

1 (1.2%) of 85 

At 6 months, hemorrhagic 

stroke: 1 (1.2%) of 85 

At 1 year, lacunar stroke: 

1 (1.2%) of 85 

Deployment: 

85 (95.5%) of 89 

Closure:: 

1 day: 81 (95%) of 85

30 days: 81 (95%) of 85

90 days: 77 (95%) of 81 

1 year: 64 (98%)of 65 

Price, 201423

8 sites

USA

Lariat

112 days, median

N=154

No criteria for LTOAC; 

60% were using an 

OAC at baseline

Mean age: 72

Male %: 62

CHADS 2 mean: 2.8

Cha2DS2-VASc mean: 4.1

HAS-BLED mean: 3.2

CHF %: 34

Stroke/TIA %: 38

HTN %: 81

DM %: 36

Serious procedure- or device-related safety 

events occurred in 21 (13.6%) of 154 

Major bleed: 

14 (9.1%) of 154 

Cardiac tamponade: 

7 (4.5%) of 154 

Thrombus formation: 

4 (3%) of 134 with 

follow-up available

Deployment: 

145 (94.2%) of 154 

Closure at end of 

procedure: 

133 (92%) of 145

Closure at follow-up: 

50 (79%) of 63

Nietlispach, 

201318

Single center

Switzerland

Nondedicated LAA

occlusion devices 

(off-label use of 

Amplatzer

PFO, ASD and VSD 

occluders), N=32 

Amplatzer ACP,

N=120

32 months 

Eligible for LTOAC

Mean age 72

Male %: 69

Mean CHA2DS2-Vasc: 3.46

Mean HASBLED score: 2.46

Stroke %: 31

HTN %: 75

DM %: 23

Serious procedure- or device-related safety 

events: 19 (12.5%) of 152 

Cardiac tamponade: 4 (2.6%) of 152 

Device embolizations: 6 (4.0%) of 152 

Device dislocations: 3 (1.7%) of 179 

Pericardial effusion: 2 (1.1%) of 179 

Neurologic events (2 TIA and 1 minor 

stroke): 3 (2.0%) of 152 

GI bleeding resulting in death: 

1 (0.7%) of 152 

Embolization: 

1 (0.7%) of 152 

Bleeding: 

13 (8.6%) of 152

4 were major bleeds 

(2.6%): 

2 intracerebral bleeds

2 subdural hematoma 

Ischemic stroke: 1 (0.7%)

Deployment: 

146 (96.0%) of 152

Closure at 3-6 months: 

137 (93.8%) of 146
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Study, 

Setting

Device;

Mean follow-up;

N patients;

Eligible/ineligible 

for LT-OAC

Patient characteristics Periprocedural harms 

occurring within 7 days Longer-term harms

Procedural success:

Deployment, N (%) of 

attempted

Closure, N (%) of 

patients assessed by TEE

Bayard, 

201028

18 centers

Europe

PLAATO

N=180

9.6 months

Ineligible for LTOAC

Mean age: 70

Male %: 66

Mean CHADS2 score: 3.1

CHF %: 42

Stroke/TIA %: 59

HTN %: 83

DM %: 29

Serious procedure- or device-related safety 

events: 8 (4.9%) of 162

Cardiac tamponade: 6 (3.7%) of 162

Cardiac death, procedure related: 

2 (1.2%) of 162

Stroke (at 129 patientyears follow-up): 2.3%

Cardiac death: 5 (3.1%) 

of 162

Deployment: 

162 (90%) of 180

Closure at 2 months: 

126 (90%) of 140

Block, 200920

USA

PLAATO

5 years

N=64

Ineligible for LTOAC

Mean age: 73

Male %: 60.9

CHADS2 score of 1, %: 23.4

CHADS2 score 2+, %: 76.6

CHF %: 44 

Stroke/TIA %: 69 

HTN %: 77 

DM %: 23.4

Serious procedure- or device-related safety 

events: 1 (1.6%) of 64

(cardiac tamponade requiring surgery) 

Stroke: 8 of 64 (12.5%) Deployment: 

61 (95.3%) of 64

Closure immediately after 

procedure: 

55 (98.2%) of 56 

Closure at 1 month: 

22 (100%) of 22

Park, 200919

Single-center 

prospective 

registry,

Germany

PLAATO

2 years

N=73

Ineligible for LTOAC

Age 72.7 

Male %: 50.7

CHADS2 mean score: 2.52

Stroke: 34.2

CAD %: 53.4

HTN%: 94.4

DM %: 36.1

Serious procedure- or device-related safety 

events: 4 (5.5%) of 73 

Pericardial effusion: 1 (1.4%) of 73

Device embolization resulting in sudden 

cardiac death 1 (1.4%) of 73 

Stroke: 1 (1.4%) of 73 

Device instability, explanted by open-heart 

surgery to avoid device embolization: 

1 (1.4%) of 73 

Stroke: 0 (0.0%) Deployment: 

71 (97.2%) of 73

Closure at 3-6 months: 

52 (100%) of 52

18 patients refused followup TEE

Ostermayer, 

200524

Multisite: 

USA,

Europe, 

Canada

PLAATO

9.8 months

N=111

Ineligible for LTOAC

Age >= 65 yrs: 84%

Age >75 yrs: 35%

Male %: NR

Mean CHADS2: 2.5

Stroke/TIA: 38%

CAD: 41%

CHF or LVEF <40%: 39%

HTN: 72%

Serious procedure- or device-related safety 

events occurred in 7 (6.3%) of 111 

Respiratory failure: 1 (0.9%) of 111 

Pericardial effusion: 2 (1.8%) of 111; 

only 1 required pericardiocentesis

Cardiac Tamponade: 2 (1.8%) of 111; 

both had pericardiocentesis

Hemothorax: 1 (0.9%) of 111 

Stroke: 2 of 111 (1.8%) Deployment: 

108 (97.3%) of 111

Closure at end of 

procedure: 

86 (97.7%) of 88

1 month: 60 (100%) of 60

6 months: 49 (98.0%) of 50
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Study, 

Setting

Device;

Mean follow-up;

N patients;

Eligible/ineligible 

for LT-OAC

Patient characteristics Periprocedural harms 

occurring within 7 days Longer-term harms

Procedural success:

Deployment, N (%) of 

attempted

Closure, N (%) of 

patients assessed by TEE

Reddy, 

201325

Multisite

Germany, 

Czech 

Republic, 

New York

Watchman

14.4 months

N=150

Ineligible for LTOAC

Age 72.5

Male %: 64

Mean CHADS2 score: 2.8

Mean CHAD2DS2-VASC 

score: 4.4

Stroke/TIA %: 40.7

CHF/reduced LVEF %: 28.7

Vascular disease %: 18

HTN %: 94.7

DM %: 32

Serious procedure- or device-related safety 

events occurred in 13 (8.7%) of 150 

Pericardial effusion (with/without 

tamponade): 

5 (3.3%) of 150 

Device embolization: 

2 (1.3%) of 150 

Device thrombus: 

6 (1.0%) of 150 

Device thrombus with 

ischemic stroke, 341 days 

post-implant: 

1 (0.7%) of 150 

All-cause stroke or 

systemic embolism: 4 

(2.7%) of 150 

Ischemic stroke: 

3 (2.0%) of 150 

Hemorrhagic stroke: 

1 (0.7%) of 150 

Deployment: 

142 (94.7%) of 150

Closure NR

CAP 

Registry26,27

26 centers

Watchman

16 months

N=566

Eligible for LTOAC

Mean age: 74 

Male %: 65.5

CHADS mean: 2.4

CHADS score 1 = 25%

CHADS score 2+ = 76%

Stroke/TIA; 30.6%

CHF %: 18.9

HTN %: 88.3

DM %: 24.7

Serious procedure/device-related safety AE: 

17 (3.7%) of 460

Serious pericardial effusion: 

10 of 460 (2.2%)

Bleeding: 3 of 460 (0.7%)

Respiratory failure: 2 of 460 (0.4%)

NR Deployment: 

437 (95.0%) of 460

Closure NR

Gafoor, 

201421

Single center

Retrospective case 

review, single 

center

Germany

Watchman, n=26

ACP, n=27

PLAATO, n=13

Lariat, n=4

Coherex, n=4

1 year

Ineligible for LTOAC

Mean age: 83.4

Male %: 53.3

Mean CHADS2 = 3.3

Mean CHA2DS-VASc = 5.2

Stroke %: 21.3

CAD %: 41.3

CHF %: 36

HTN %: 96

DM %: 22.7

Serious procedure- or device-related safety 

events occurred in 3 of 74 (4.1%) 

TIA: 1 of 74 (1.3%) 

Femoral bleeding (access site): 

1 of 74 (1.3%) 

Device thrombus (patient not on 

anticoagulation): 1 of 74 (1.3%) 

Death due to renal failure: 

1 (1.4%) of 74 

Stroke: 1 (1.4%) of 74 

Deployment: 

75 (100%) of 75

Closure at: 

1 day: 68 (90.1% of 75

1 year: 97.4%, N with TEE 

not reported
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Study, 

Setting

Device;

Mean follow-up;

N patients;

Eligible/ineligible 

for LT-OAC

Patient characteristics Periprocedural harms 

occurring within 7 days Longer-term harms

Procedural success:

Deployment, N (%) of 

attempted

Closure, N (%) of 

patients assessed by TEE

Matsuo, 

201422

Single center

Germany

Watchman® or 

Amplatzer Cardiac 

Plug (ACP®) 

device)

6 months

N=179

Ineligible for LTOAC

Mean age 72.7

Male %: 58.7

Mean CHADS2 score = 2.9 

Mean CHA2DS2VASC = 4.3

Mean HASBLED = 3.9

Prior stroke/TIA %: 27.9

CHF %: 39.1

Vascular disease %: 24.0

HTN %: 95.0

DM %: 44.7

Serious procedure- or device-related safety 

events: 13 (7.3%) of 179 

Cardiac tamponade: 2 (1.1%)

Device dislocations: 3 (1.7%)

Pericardial effusion: 2 (1.1%) 

Air embolization: 3 (1.7%)

Device thrombus: 3 (1.7%)

Thrombus: 

7 (4.2%) of 165

Among 145 with followup data at 6-months:

Bleeding complications: 

3 (2.0%)

Upper GI bleeding: 

2 (1.4%)

Subdural hematoma: 

1 (0.7%)

Stroke: 0 (0.0%)

Deployment:

Watchman: 

163 (98.8%) of 165

ACP: 9 (90.0%) of 10

Closure at 45 days: 

164 (99.4%) of 165

Discontinuation of OAC or 

Enoxaparine: 

156 (94.5%) of 165

Abbreviations are found on page 5.
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SURGICAL LAA INTERVENTIONS

KQ1: What is the effectiveness of LAA exclusion interventions compared with 

usual care? 

Three randomized controlled trials and 2 observational studies evaluated the effectiveness of 

surgical LAA exclusion compared with usual care (Table 5).

In one trial of 43 patients undergoing open mitral valve surgery randomized to either LAA 

exclusion or control,29 no postoperative death or stroke occurred in either group. The composite 

outcome of death, stroke or transient ischemic attack (TIA), and myocardial infarction (MI) in 

the postoperative period was also not significantly different (9.1% vs 4.5%, P = 1.00). 

The LAAOS trial randomized 77 patients at risk for stroke undergoing elective coronary artery 

bypass grafting (CABG) without concomitant valve surgery to either LAA exclusion or 

control.30 Two patients in the LAA exclusion group had perioperative stroke or TIA (2.6% vs

0%, P-value not reported). After being followed for an average of 13 +/- 7 months, no additional 

patients had stroke.

The LAAOS II trial randomized 51 patients with AF and increased stroke risk undergoing 

cardiac surgery using cardiopulmonary bypass to LAA exclusion or no occlusion with oral 

anticoagulation.31 At one year of follow-up there was no significant difference in the primary 

composite efficacy outcome of rate of death, MI, stroke, non-CNS embolism, and major bleeding 

(RR 0.7, 95% CI 0.2 to 2.7).

The 3 randomized controlled trials were found to have a low risk of bias. However, all were 

small pilot studies conducted to assess the safety and feasibility of larger trials and therefore 

were not powered and did not have adequate follow-up to detect clinically significant outcomes. 

The 2 observational studies used propensity score matching to create comparator groups. One 

study reviewed 119 pairs of patients who underwent surgical ablation of AF over a mean followup of 3.1 +/- 2.8 years and found no significant differences in stroke-free survival (P = .88) and 

freedom from AF while off antiarrhythmic drugs (P = .46) between the 2 groups.

32

The other study reviewed 631 pairs of patients who had undergone a variety of cardiac surgical 

procedures and found that while the rate of postoperative atrial fibrillation was higher in the 

LAA exclusion group (23% vs 18%, P = .037), fewer of these patients had stroke through 

postoperative day 30 (0.0% vs 6.1%, P = .003).

33 However, there were more strokes in the LAA 

ligation group among patients without postoperative atrial fibrillation, so the overall rate of 

cerebrovascular accident (CVA) was not significantly different between the 2 groups (P = .44).

All patients in this study underwent surgery by the same cardiothoracic surgeon, whose practices 

changed over the course of 10 years from performing no LAA exclusion to routine LAA 

exclusion during cardiac surgery. Other concurrent changes over time, such as changes in 

anticoagulation strategy in patients developing AF, may confound the findings of this study.
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KQ2: What are the harms associated with LAA exclusion?

The same 3 randomized controlled trials and 2 observational studies evaluated the harms of 

surgical LAA exclusion (Tables 5 and 6).

One RCT found a trend towards longer median mechanical ventilation time in the LAA 

exclusion group (11.5 h vs 8 h, P = .078).29 There was no significant difference in the composite 

of 10 major complications (death, cerebrovascular events, MI, respiratory failure, intra-aortic 

balloon pump, renal dysfunction, permanent pacemaker, septicemia, mediastinitis, and reoperation for bleeding) between the exclusion and control groups (32% vs 38%, P = .75).

The LAAOS trial found more intraoperative tears involving the left atrial appendage or the left 

atrium in the LAA exclusion group than the control group (15% vs 4%, P-value not reported).30

However, performance of LAA occlusion did not significantly prolong cardiopulmonary bypass 

time (P = .63) and did not increase perioperative bleeding (P = .53), the occurrence of 

postoperative AF (P = .56), or diuretic use (P = .87).

The LAAOS II trial found no significant difference between the LAA exclusion and control 

groups for rates major bleeding (RR 0.4, 95% CI 0.0 to 4.6) or reoperation for bleeding (RR 1.9, 

95% CI 0.2 to 19.9) and neither of the 2 reoperations in the LAA occlusion group was deemed 

secondary to bleeding at the LAA occlusion site.

31 No significant difference was found for the 

total bypass time or cross-clamp time between the 2 groups.

Only one observational study reported harms associated with LAA exclusion and found no 

significant difference in early operative complications including reoperation due to bleeding 

(10.9% vs 5.0%, P = .17), requirement for dialysis (7.6% vs 8.4%, P > 0.99), permanent 

pacemaker insertion (3.4% vs 1.7%, P = .63), mediastinitis (0% vs 0.8%, P > 0.99), wound 

revision (0.8% vs 1.7%, P > 0.99) or pericardial effusion (6.7% vs 5.0%, P = .77).

32

KQ3: How do the benefits and harms of LAA exclusion vary in different 

subgroups?

We identified no trials evaluating subgroup differences in the benefits and harms of surgical 

LAA exclusion.

KQ4: What are the comparative effects of different techniques on health 

outcomes and rates of procedural success?

Two observational studies reported the comparative effects of different surgical techniques for 

LAA exclusion. 

One study evaluated success of surgical LAA closure as determined by postoperative TEE after a 

mean time of 8.1 +/- 12 months.34 Of 137 patients who underwent surgical excision, only 40% of 

all closures were successful. Successful LAA exclusion was found to be more common with 

excision (73%, P < .001) than suture exclusion (23%, P > .001) or stapler exclusion (0%, P = 

.002).

Another study compared anterior thoracotomy to video-assisted thoracoscopy (VATS) for LAA 

exclusion in 58 patients with chronic nonrheumatic AF. While there was no significant 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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difference between the groups for hospital stay (11.3 vs 9.1 days, P = .61) or duration of chest 

tube (4.3 vs 3.7 days, P = .11), there was a significant increase in operative time (77.3 vs 121.3 

min, P > .001) in the VATS group.

35
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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Table 5. Characteristics and findings of trials of cardiac surgery with vs without concomitant LAA occlusion or removal 

Study, 

Setting, 

Surgery 

performed

Technique; 

length of 

follow-up

Sample size and

patient characteristics, 

T vs C

KQ1. Health outcome 

effects, T vs C 

KQ2. Harms associated with LAA 

exclusion, T vs C 

KQ4. Rates of procedural success, 

T vs C 

Healey, 

200530

Single site, 

Canada

CABG

Sutures or 

stapler

Mean 13 +/- 

7 months 

N: 52 vs 25

Age, mean: 72 vs 71

Male %: 73 vs 72

History of AF %: 17 vs 8 

Stroke %: 17 vs 0 

HTN %: 75 vs 92

DM %: NR

Mortality: 0 vs 0

Postoperative AF: 

12/52 vs 4/25

Intraoperative ischemic 

stroke: 1/52 vs 0/25

TIA: 1/52 vs 0/25

Total serious AEs: 10 (19.2%) of 52 

vs 1 (4%) of 25

Cross-clamp time (min): 72 vs 75 

Intraoperative LAA tears: 

8/52 vs 1/25

LAA tears in Tx group: 

Stapler: 4 

Forceps: 2 

Suture: 1 

Not specified: 1 

Perioperative stroke/TIA: 

2 (2.6%) vs 0

TEE at 8 weeks postop:

29/44 (66%) with occlusion defined as 

no flow beyond the line of occlusion 

and a residual stump of <1 cm.

8 patients refused follow-up TEE. 

% with complete occlusion at 8 

weeks, suture vs stapler (P = .14): 

5/11 (45%) vs 24/33 (72%)

Complete occlusion, stapling device 

vs sutures alone (P = .14.): 

24 (72%) of 33 vs 5 (45%) of 11

Nagpal, 

200929

Single center

Italy

Mitral valve 

surgery

Suture

Postop 

period

N: 22 vs 21

Age, mean: 57.8 vs 59.2

Male %: 50 vs 57.1 

AF %: 18.2 vs 19

TIA/stroke %: 0 vs 4.8

CAD %: 0 vs 0 

DM %: 4.5 vs 0

Mortality: 0/22 vs 0/21 

Stroke: 0/22 vs 0/21

TIA: 1/22 vs 1/21

MI: 1/22 vs 0/21

Total serious AEs: 7 (32%) of 22 vs

8 (38%) of 21 (P = .75)

Mechanical ventilation time: 11.5 h 

vs 8 h (P = .078)

Mean days in ICU: 

2 vs 1 (P = .56)

Composite of AEs (respiratory

failure, IABP, renal dysfunction, 

PPM, sepsis, mediastinitis, re-op for 

bleeding): 5/22 vs 7/21 

NR

Whitlock, 

201331

4 sites, 

Canada

CABG and/or 

valve 

replacement

Sutures or 

stapler

30 days (in 

person);

1 year 

(telephone)

N: 26 vs 25

Age, mean: 77.4 v 74.6

Male %: 76.92 vs 76

AF %: 100 vs 100

CVA %: 23 vs 20

TIA %: 12 vs 24

CAD %: 81 vs 84

CHF %: 27 vs 40

Valvular heart disease %: 81 vs 48*

HTN %: 92 vs 92

DM %: 27 vs 28

Mortality: 2/26 vs 3/25

RR (95% CI): 

0.64 (0.12 to 3.52)

Stroke: 1/26 vs 3/25

RR (95% CI): 

0.32 (0.03 to 2.88)

Total serious AEs: 4 (15.4%) of 26 

vs 5 (20.0%) of 25

Major GI bleeding: 1/26 vs 2/25

Re-op for bleeding: 2/26 vs 1/25

NR

*"Baseline characteristics were well-balanced between the groups, with the exception that there was more valvular disease (P = .01) and a trend toward more valve surgery (P = 

.06) in the occlusion arm"31
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Table 6. Characteristics and findings of cohort studies of cardiac surgery with vs without concomitant LAA occlusion or removal 

Study, 

Setting, Surgery 

performed

Technique; length of 

follow-up

Sample size and

patient characteristics, 

T vs C

KQ1. Health outcome 

effects, T vs C 

KQ2. Harms associated 

with LAA exclusion, 

T vs C

KQ4. Rates of procedural 

success, T vs C 

Kanderian, 200834

U.S.A.

Valve surgery: 

62%

CABG + valve 

surgery: 31%

Maze surgery: 

39%

Excision (via scissors 

or an amputating 

stapling device)

vs

Exclusion (via suture 

or stapler exclusion 

with the LAA 

remaining attached).

Mean time to TEE was 

8.1 +/- 12 months

N: 52 excision vs 73 suture 

exclusion vs 12 stapler exclusion:

Age: 64 vs 67 vs37

Male %: 67 vs 48 vs 75

AF %: 54 vs 30 vs 8 

HTN %: 58 vs 70 vs 50

Stroke %: 17 vs 14 vs 8 

CHF %: 54 vs 73 vs 25

DM %: NR

Warfarin use %: 69 vs 51 vs 33

Valve surgery %: 62 vs 59 vs 75

CABG + Valve surgery %: 

20 vs 41 vs 25

Maze surgery %: 67 vs 22 vs 25 

Stroke/TIA: 

18 (13.1%) of 137: 

6 with LAA excision

11 with suture exclusion, 

and 1 with stapler 

exclusion, (P = NS). 

Stroke/TIA among patients 

with successful vs

unsuccessful LAA closure: 

6 (11%) vs 12 (15%)

(P = .61) 

--- Excision: 

38/52 (73%), P > .001

Suture exclusion: 

17/73 (23%), P > .001

Stapler exclusion:

0/12, P = .002

Total: 55/137 (40%)

Kim, 201333

U.S.A.

CABG %: 82.1

Valve surgery: 

8.8%

Combined CABG 

+ valve surgery % 

= 8.6

LAA techniques 

varied over time: 

ligation; excision and 

oversewn; stapled.

Retrospective chart 

review spanning 10 

years.

N: 631 vs 631

CHADS2 score: 2.25 vs 2.29

Age: 66.2 vs 65.7 

After propensity score matching:

Male %: 68 vs 68

Hx stroke: 5 vs 5 

CHF %: 81 vs 81 

HTN %: 75 vs 75

DM %: 34 vs 34

PSM model included CA BG 

procedure, valve replacement, 

gender, age risk, Hx CHF, Hx HTN, 

Hx DM, and Hx CVA.

After propensity score 

matching: 

Postop AF %: 

22.9 vs 18.2 (P = .037) 

Postop CVA %: 

1.0 vs 1.4 (P = .44)

Postop AF with CVA %: 

0 vs 1.1 (P = .003)

Among subjects with 

postop AF, N=145 vs 115:

Postop CVA %: 0 vs 6% 

(P = .037)

--- ---
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Study, 

Setting, Surgery 

performed

Technique; length of 

follow-up

Sample size and

patient characteristics, 

T vs C

KQ1. Health outcome 

effects, T vs C 

KQ2. Harms associated 

with LAA exclusion, 

T vs C

KQ4. Rates of procedural 

success, T vs C 

Lee, 201432

Korea

Mitral valve 

surgery with cryoMaze procedure

Resection.

Mean follow-up: 62.6 

+/- 44.0 months.

TEE at 1,3,6, and 12 

months;

ECG at 1,3,6,12,24, 

and 36 months. 

N: 119 vs 119

After propensity matching:

Age: 53.4 vs 54.1

Male %: 37.8 vs 41.2

HTN %: 18.5 vs 19.3

CHF %: 55.5 vs 53.8

DM %: 7.6 vs 7.6

Hx stroke: 5.0 vs 5.9

Hx cardiac surgery: 6.7 vs 4.2

Within 6 months:

Mortality: 0/119 vs 1/119

Stroke: 1/119 vs 1/119

After 6 months: 

Mortality: 6/119 (5.0%) vs

10/119 (8.4%),

RR (95% CI) 0.60 (0.22 to 

1.60)

Stroke/TIA 1/119 (0.8%) 

vs 2/119 (1.7%),

RR (95% CI) 0.50 (0.05 to 

5.44)

AF: 11/119 vs 9/119

Total serious AEs: 35 

(29.4%) of 119 vs 29 

(24.4%) of 119

Reoperation due to bleeding: 

13/119 vs 6/119 

Requirement for dialysis: 

9/119 vs 10/119

Permanent pacemaker 

insertion 4/119 vs 2/119

Mediastinitis: 0/119 vs 1/119

Wound revision: 

1/119 vs 2/119

Pericardial effusion 

8/119 vs 6/119

---

Muhammad, 

201435

Saudi Arabia 

Anterior 

thoracotomy 

versus videoassisted 

thoracoscopy 

(VATS)

Anterior thoracotomy 

(open) vs VATS

2 years, by phone 

every 6 months

N: 29 (open) vs 29 (VATS)

Age: 62

Male %: 60.3

HTN %: NR

CHF %: NR

DM %: NR

--- Total serious AEs: 2 (6.9%) 

of 29 vs 0 (0.0%) of 29

Open thoracotomy vs VATS:

Operative time (min): 

77.3 vs 121.3 (P < .001)

Wound infection: 

2/29 vs 0/29

Hospital stay, days: 

11.3 vs 9.1

Duration of chest tube, days: 

4.3 vs 3.7
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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SUMMARY AND DISCUSSION

Interest in mechanical exclusion of the LAA to reduce the risk of stroke in patients with atrial 

fibrillation has grown rapidly in recent years. We systematically reviewed the literature and 

found 12 studies assessing the benefits and harms of percutaneous approaches to LAA exclusion, 

and 7 studies assessing the benefits and harms of surgical LAA exclusion. Overall, there is 

limited evidence that one specific approach to percutaneous LAA exclusion may be an effective 

alternative to long-term oral anticoagulation in selected patients who are closely followed and in 

whom procedural success is sustained, though there are significant procedure-related harms.

There is insufficient evidence to assess the benefits of surgical LAA exclusion, though these 

procedures do not appear to be associated with a significant increase in harms over the heart 

surgery during which the procedures are typically performed (Table 7).

Our findings corroborate and add to several recent systematic reviews,36-39 A recently published 

patient-level meta-analysis40 similarly found no significant difference in risk of stroke between 

percutaneous LAA exclusion using the Watchman device and long-term warfarin therapy (HR 

1.02, 95% CI 0.62 to 1.7).

40 In contrast to prior reviews we examined both percutaneous and 

surgical approaches to LAA exclusion. Also, we systematically examined both trial and 

observational study data.

Percutaneous LAA exclusion

There is low-strength evidence that percutaneous LAA exclusion with the Watchman device is 

associated with a similar risk of long-term stroke and mortality as continued oral anticoagulation 

therapy. Most patients who received the Watchman device were able to discontinue oral 

anticoagulant therapy after undergoing a follow-up TEE showing persistent closure of the LAA 

at 3-6 months. However, there is moderate-strength evidence that a substantial proportion of 

patients experienced serious periprocedural harms. There is insufficient evidence to determine 

whether factors such as operator experience, patient selection criteria, or choice of device can 

modify these risks.

There are several clinical situations in which percutaneous LAA exclusion may be a potentially 

attractive option, though the data directly supporting use in these circumstances is limited. First, 

LAA exclusion might be especially attractive for patients unable to take oral anticoagulants.

However, the trial data most closely apply to patients who do not have contraindications to longterm oral anticoagulant therapy. In these trials, warfarin was used typically for 3-6 months until 

device endothelialization and LAA closure was achieved.

A number of observational studies included patients ineligible for long-term oral anticoagulant 

therapy,

19-22,24,25 and while most found low rates of stroke over 1-2 years of follow-up, at least 

one study found higher incidence of stroke over a longer follow-up period.

20 Of note, even 

though warfarin was not used, patients in most of these studies used dual antiplatelet therapy for 

a duration ranging from 4 weeks to 6 months. Dual antiplatelet therapy (DAPT) in the population 

of patients with atrial fibrillation who have increased risk of stroke and for whom vitamin-K

antagonists are unsuitable is associated with a 2.0% risk of major bleeding annually.41 It is 

notable that in a large study of warfarin versus DAPT for prevention of stroke in AF the risk of 

major bleeding was similar between groups (respectively 2.21% annual risk of stroke vs 2.42%, 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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RR 1.10, 95% CI 0.83-1.45, P = .53). Minor bleeding and overall bleeding was increased in 

patients taking DAPT compared to warfarin (15.4% risk per year vs 13.2%, RR 1.21, 95% CI 

1.08-1.35, P = .001).42 Thus as long as the protocol for the use of LAA closure devices includes 

DAPT for any significant length of time it may not be an attractive option for patients who are 

high risk for bleeding complications and who do not wish to take, or have contraindications to, 

warfarin.

The clinical circumstances which contribute to anticoagulant ineligibility could also contribute to 

one’s risk of suffering a periprocedural harm. While we do not have data to directly compare 

rates of periprocedural harms in patients eligible and ineligible for anticoagulant therapy, up to 

8.7% of patients experienced a serious periprocedural safety event among 8 observational studies 

in patients ineligible for oral anticoagulant therapy.

17,19-22,24,25,28

The second clinical circumstance in which LAA exclusion might provide a useful alternative is 

for patients who might otherwise accrue a more substantial bleeding risk from oral anticoagulant 

therapy over longer time horizons. Take, for example, a 70 year-old woman with a history of 

atrial fibrillation, hypertension, and a prior stroke who is living independently and is a candidate 

for OAC. She has an annual stroke risk of 6.7% (based on CHADS2-VASC = 5)1 and would be 

expected to have a significant benefit from OAC. This same patient would be considered at high 

risk of major bleed (HAS-BLED = 3) with an expected 3.7 bleeds per 100 patient-years of 

follow-up while on OAC.43 She will experience these annual risks of bleeding for the duration of 

her OAC therapy. In the PROTECT-AF trial, most events in the LAA exclusion group accrued 

earlier on in the study, while event rates in the control group increased steadily (though remained 

lower overall) over 3 years of follow-up.

14 Theoretically, then, it is possible that the risks of 

long-term anticoagulation might eventually offset the near-term risks of LAA exclusion device 

placement. However, this has not been tested empirically and, given that not all cardioembolic 

strokes in atrial fibrillation originate in the left atrial appendage, it is certainly possible that longterm stroke risk in patients receiving a device who remain off anticoagulation may increase.

Third, some patients may simply prefer the placement of an LAA exclusion device over the 

inconvenience of long-term OAC. Policy makers will need to consider whether routine 

availability of periprocedural LAA exclusion for preference-sensitive indications is warranted.

There are a variety of devices being used for LAA exclusion, but there is not adequate evidence 

that the efficacy and safety of each of these devices is similar enough to comfortably extrapolate 

data from one device and apply to the use of a different device. While the techniques used for 

many of the devices are similar, there are still important differences, perhaps most notably for 

the Lariat device which takes an epicardial approach to snaring and externally excluding the 

LAA. For the time being, the evidence for device efficacy applies most closely to the Watchman 

device and there is insufficient evidence to determine the efficacy of other devices.

There is enough variation in the reported safety of percutaneous exclusion devices that, if the 

VHA does choose to pursue more widespread use of LAA exclusion procedures, an outcomes 

registry carefully tracking periprocedural and longer term harms should be established first, with 

results reviewed at periodic intervals. The finding that the multicenter observational studies often 

reported fairly high rates of serious periprocedural harms is troubling though the reasons for this 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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finding are not clear. It is possible that patient selection may be less restrictive and operator 

experience more variable with broader adoption of a procedure. 

Finally, it should be noted that the decision to discontinue anticoagulant therapy in the included 

studies was based on demonstrated LAA closure on follow-up TEE. Up to 4-6% of patients had 

continued evidence of LAA blood flow at 6 months, and this may be an underestimate as these 

figures do not account for the proportion of patients in trials and observational studies who 

refused follow-up TEE. The benefits and harms of percutaneous LAA exclusion in patients for 

whom TEE monitoring is infeasible remain essentially unknown. 

Surgical LAA exclusion

We found insufficient evidence to determine the efficacy of surgical LAA exclusion in reducing 

stroke. We found low strength evidence that surgical LAA exclusion in the context of heart 

surgery performed for another indication is unlikely to be associated with significant incremental 

harm. 

While surgical LAA exclusion might seem analogous to performing an appendectomy during an 

exploratory laparotomy, the clinical implications may be quite different. The promise of surgical 

LAA exclusion is to reduce long-term risk of stroke and, possibly, to obviate the need for longterm oral anticoagulant therapy. However, we do not have sufficient evidence to determine 

whether prophylactic surgical LAA exclusion actually does reduce stroke. In the meantime, there 

is at least the theoretic possibility that surgical LAA exclusion may offer false reassurance to 

patients who then decide to discontinue oral anticoagulant therapy. 

Limited data from one trial and one observational study suggest that a relatively high proportion 

of patients have persistent LAA blood flow detected on follow-up TEE.30,34 Given the lack of 

robust efficacy data, and the relatively low rates of long-term procedural success, patients who 

do undergo LAA exclusion during heart surgery should likely not discontinue long-term oral 

anticoagulant therapy. 
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Table 7. Summary of the evidence on percutaneous and surgical interventions to occlude or remove the 

LAA

Outcome

Device or procedure

N studies (N=combined

participants)

Findings Strength of 

Evidence* Comments

Percutaneous interventions

Mortality Watchman

2 RCTs (N=1,114)

No significant difference in mortality.

RR (95% CI) in 2 RCTs: 

1.20 (0.31 to 4.56) 

0.62 (0.34 to 1.24)

Low Limited applicability: only 

one device has been studied 

in 2 RCTs. Patients were 

eligible to receive LT-OAC. 

Low precision (wide 

confidence intervals). 

Stroke Watchman

2 RCTs (N=1,114)

No significant difference in risk of 

stroke. 

RR (95% CI): in 2 RCTs: 

0.71 (0.35 to 1.64)

3.28 (0.37 to 25.31)

Harms ACP: 3 registries (N=147)

Coherex: 1 registry (N=4)

Lariat: 2 registries (N=93)

PLAATO: 5 registries 

(N=441)

Watchman: 2 RCTs + 

4 registries (N=742)

Device not specified: 

2 registries (N=211)

Serious procedure- or device-related 

safety events (% of patients): 

1.6 to 13.6

Overall, rate of serious adverse events 

within 7 days of device implantation 

was 6.5% (98/1506). 

Moderate Various devices were 

examined among 2 trials and 

11 observational studies.

Wide range of event rates 

across studies and relatively 

small number of patients 

treated in each observational 

study limited strength of 

findings.

Surgical interventions

Mortality Sutures or stapler in 3 

RCTs (N=171)

Various excision and 

exclusion techniques in 4 

Cohort studies (N=1695)

No significant difference in mortality, 

among studies in which at least one 

event occurred in both groups:

In 1 RCT: 7.7 vs 12% (P > .05)

RR (95% CI) 0.64 (0.12, 3.52) 

In 1 cohort: 5.0 vs 8.4% (P > .05) 

RR (95% CI) 0.60 (0.22 to 1.60)

Insufficient Trials too small and event 

rates too low to determine 

effectiveness of procedure. 

Stroke 3 RCTs (N=171)

2 cohort studies (N=1500)

No significant difference in risk of 

stroke, among studies where at least 

one event occurred in both groups:

In 1 RCT: 3.8 vs 12% (P > .05); 

RR (95% CI) 0.32 (0.03 to 2.88)

In 2 cohorts: 

1.0 vs 1.4% (P = .44) 

0.84 vs 1.7% (P > .05) 

Insufficient

Harms 3 RCTs (N=171)

1 cohort study (N=238)

Serious safety events: 

6.9-32.0% of patients 

No significant differences in most 

major harms between cardiac surgery 

groups with and without LAA 

exclusion

Low Limited number of studies

and limited number of 

patients included. 

*The overall quality of evidence for each outcome is based on the consistency, coherence, and applicability of the body of 

evidence, as well as the internal validity of individual studies. The strength of evidence is classified as follows:11 

High = Further research is very unlikely to change our confidence on the estimate of effect.

Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and 

may change the estimate.

Low = Further research is very likely to have an important impact on our confidence in the estimate of effect and is 

likely to change the estimate.

Insufficient = Any estimate of effect is very uncertain.
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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32

LIMITATIONS

While we adhered to published standards for systematic review conduct, there are several 

potential methodologic limitations to note. First, we excluded non-English language studies.

There is empiric data, however, suggesting that reviews restricted to English-language studies 

are largely concordant with reviews without language restrictions.44 Second, we excluded 

observational studies enrolling fewer than 50 participants. However, we felt that these typically 

single-center studies with very small denominators were unlikely to yield reliable information 

about rates of harms or procedural success. 

There are significant limitations in this body of evidence as a whole, and these are noted 

throughout our report. Clearly, one of the biggest limitations is simply the relative paucity of 

methodologically rigorous studies examining the efficacy of percutaneous and surgical LAA 

exclusion. 

RESEARCH GAPS/FUTURE RESEARCH 

Trials of percutaneous LAA interventions were limited to studies of the Watchman device in 

patients who were eligible for long-term warfarin therapy. Trials of surgical LAA interventions 

were few and limited by sample size. Several studies that should add substantively to this body 

of evidence are underway (Table 8), including a large RCT of surgical interventions with an 

estimated sample size of 4,700 patients; studies of recently developed percutaneous devices 

(LAmbre and Occlutech); and a trial comparing Watchman with Apixaban in patients ineligible 

for warfarin therapy. 

Table 8. Ongoing studies of percutaneous and surgical LAA interventions

Study title; 

Clinicaltrials.gov ID 

Device or 

technique 

vs control

Study design;

Estimated enrollment;

Status; 

Estimated completion date

Country;

Funding 

source

Comment

Percutaneous interventions

Feasibility and Safety Study of 

LAmbre Left Atrial Appendage 

Occluder; NCT01920412

LAmbre Single-group, open-label

N=20

Recruiting as of Aug 2013; 

Est. completion: Sept 2014

China;

Lifetech 

Scientific 

(Shenzhen) 

Co., Ltd.

First-in-man study

Safety and Efficacy Study of 

LAmbre LAA Closure Device 

for Treating AF Patients Who 

Cannot Take Warfarin; 

NCT02029014

LAmbre Single group, open-label

N=154

Recruiting as of Mar 2014; 

Est. completion: Jul 2016

China;

Lifetech 

Scientific 

(Shenzhen) 

Co., Ltd.

Includes patients 

who cannot be 

treated long-term 

with Warfarin

Prospective, Non-randomized, 

Safety and Efficacy Study of a 

New Occluder Design for 

Minimally Invasive Closure of 

the Left Atrial Appendage 

(LAA) in Patients With Atrial 

Fibrillation (OLAAC); 

NCT02105584

Occlutech Single group, open-label

N=105

Recruiting as of Apr 2014; 

Est. completion: Apr 2016

Germany

Occlutech 

International 

AB

Includes patients 

eligible or noneligible for longterm oral 

anticoagulation 

therapy 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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33

Study title; 

Clinicaltrials.gov ID 

Device or 

technique 

vs control

Study design;

Estimated enrollment;

Status; 

Estimated completion date

Country;

Funding 

source

Comment

Left Atrial Appendage Closure 

vs Novel Anticoagulation Agents 

in Atrial Fibrillation (PRAGUE17); NCT02426944

Watchman vs

Apixaban

RCT, open-label

N=400

Ongoing not recruiting as of 

April 2015; 

Est. completion: May 2020

Czech 

Republic; 

Charles 

University

and Ministry 

of Health

Includes patients 

with significant 

bleeding during 

warfarin treatment

Surgical interventions

Left Atrial Appendage Occlusion 

Study III (LAAOS III); 

NCT01561651

Cardiac surgery 

with vs without

LAA occlusion 

via suture and/

or surgical 

stapler

RCT, double-blinded

N=4700

Recruiting as of May 2014; 

Est. completion: May 2019

Canada;

Population 

Health 

Research 

Institute

Estimated mean 

follow-up of 4 

years

Left Atrial Appendage 

CLOSURE for the Prevention of 

Thromboembolisms in Patients 

Undergoing Aortic Bioprosthesis 

Surgery (LAA-CLOSURE); 

NCT02321137

Valve surgery 

with vs without 

surgical LAA 

closure

RCT, open-label

N=1040

Recruiting as of Dec 2014; 

Est. completion: Dec 2027

Finland and 

Netherlands; 

5 regional/

university 

hospitals

Includes patients 

with no indication 

for long-term 

anticoagulation

CONCLUSIONS 

Overall, there is limited evidence that percutaneous LAA exclusion may be an effective 

alternative to long-term oral anticoagulation in selected patients who are closely followed and in 

whom procedural success is sustained. However, only one percutaneous device has been studied 

rigorously in trials, and percutaneous LAA exclusion has been associated with high rates of 

serious procedure-related harms in many studies. There is insufficient evidence to assess the 

benefits of surgical LAA exclusion. While surgical LAA exclusion does not appear to be 

associated with a significant increase in harms over the heart surgery during which the 

procedures are typically performed, rates of procedural success may be low. Overall, there is 

insufficient evidence to support the routine use of surgical LAA exclusion to reduce stroke risk 

or future need for anticoagulant therapy. There are a number of ongoing studies that should add 

substantively to this body of evidence over the next several years. 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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34

REFERENCES 

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the 

management of patients with atrial fibrillation: executive summary: a report of the 

American College of Cardiology/American Heart Association Task Force on practice 

guidelines and the Heart Rhythm Society. Circulation. Dec 2 2014;130(23):2071-2104. 

2. Arboix A, Alio J. Cardioembolic Stroke: Clinical Features, Specific Cardiac Disorders 

and Prognosis. Curr Cardiol Rev. Aug 2010;6(3):150-161. 

3. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical 

patients with atrial fibrillation. Ann Thorac Surg. Feb 1996;61(2):755-759. 

4. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from 

atrial fibrillation without prolonged anticoagulation with use of transesophageal 

echocardiography to exclude the presence of atrial thrombi. The New England journal of 

medicine. 1993;328(11):750-755. 

5. Kansagara D, Noelck N, Papak J, et al. The effectiveness of procedures to remove or 

occlude the left atrial appendage. PROSPERO 2015:CRD42015016685 Available from 

http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015016685. 

Accessed July 28, 2015. 

6. Sampson M, McGowan J, Lefebvre C, Moher D, Grimshaw J. PRESS: Peer Review of 

Electronic Search Strategies. Ottawa: Canadian Agency for Drugs and Technologies in 

Health; 2008. 

7. Relevo R, Paynter R. Peer review of search strategies. Rockville (MD): Agency for 

Healthcare Research and Quality (AHRQ Publication No. 12-EHC068-EF); 2012.

8. Chou R, Aronson N, Atkins D, et al. Assessing Harms When Comparing Medical 

Interventions. Rockville, MD Agency for Healthcare Research and Quality (AHRQ), 

Methods Reference Guide for Effectiveness and Comparative Effectiveness 

Reviews;2008. 

9. Higgins JPT, Altman DG, editors. Chapter 8: Assessing risk of bias in included studies. 

In: Cochrane Handbook for Systematic Reviews of Interventions. 2008;Version 5.0.1. 

The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org

Accessed Dec 5, 2014. 

10. Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing 

the quality of nonrandomized studies in meta-analyses. 

http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp Accessed July 30, 2015. 

11. Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence 

When Assessing Health Care Interventions for the Effective Health Care Program of the 

Agency for Healthcare Research and Quality: An Update. Methods Guide for 

Comparative Effectiveness Reviews (Prepared by the RTI-UNC Evidence-based Practice 

Center under Contract No. 290-2007-10056-I). AHRQ Publication No. 13(14)-EHC130-

EF. Rockville, MD: Agency for Healthcare Research and Quality. November 2013. 

http://www.effectivehealthcare.ahrq.gov/ehc/products/457/1752/methods-guidancegrading-evidence-131118.pdf Accessed on July 23, 2015 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

Occlude the Left Atrial Appendage 

35

12. Alli O, Doshi S, Kar S, et al. Quality of life assessment in the randomized PROTECT AF 

(Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for 

Prevention of Stroke in Patients With Atrial Fibrillation) trial of patients at risk for stroke 

with nonvalvular atrial fibrillation. J Am Coll Cardiol. Apr 30 2013;61(17):1790-1798. 

13. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage 

versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a 

randomised non-inferiority trial.[Erratum appears in Lancet. 2009 Nov 

7;374(9701):1596]. Lancet. Aug 15 2009;374(9689):534-542. 

14. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for 

stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the 

PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in 

Patients with Atrial Fibrillation) Trial. Circulation. Feb 12 2013;127(6):720-729. 

15. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of 

clinical classification schemes for predicting stroke: results from the National Registry of 

Atrial Fibrillation. Jama. 2001;285(22):2864-2870. 

16. Holmes DR, Jr., Kar S, Price MJ, et al. Prospective randomized evaluation of the 

Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus 

long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. Jul 8 2014;64(1):1-12. 

17. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation 

using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J 

Am Coll Cardiol. Jul 9 2013;62(2):108-118. 

18. Nietlispach F, Gloekler S, Krause R, et al. Amplatzer left atrial appendage occlusion: 

single center 10-year experience. Catheter Cardiovasc Interv. Aug 1 2013;82(2):283-289. 

19. Park J-W, Leithauser B, Gerk U, Vrsansky M, Jung F. Percutaneous left atrial appendage 

transcatheter occlusion (PLAATO) for stroke prevention in atrial fibrillation: 2-year 

outcomes. J Invasive Cardiol. Sep 2009;21(9):446-450. 

20. Block PC, Burstein S, Casale PN, et al. Percutaneous left atrial appendage occlusion for 

patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the 

PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study. JACC 

Cardiovasc Interv. Jul 2009;2(7):594-600. 

21. Gafoor S, Franke J, Bertog S, et al. Left atrial appendage occlusion in octogenarians: 

short-term and 1-year follow-up. Catheter Cardiovasc Interv. Apr 1 2014;83(5):805-810. 

22. Matsuo Y, Sandri M, Mangner N, et al. Interventional closure of the left atrial appendage 

for stroke prevention. Circ J. 2014;78(3):619-624. 

23. Price MJ, Gibson DN, Yakubov SJ, et al. Early safety and efficacy of percutaneous left 

atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation 

consortium. J Am Coll Cardiol. Aug 12 2014;64(6):565-572. 

24. Ostermayer SH, Reisman M, Kramer PH, et al. Percutaneous left atrial appendage 

transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with 

non-rheumatic atrial fibrillation: results from the international multi-center feasibility

trials. J Am Coll Cardiol. Jul 5 2005;46(1):9-14. 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

Occlude the Left Atrial Appendage 

36

25. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the 

Watchman device in patients with a contraindication for oral anticoagulation: the ASAP 

study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure 

Technology). J Am Coll Cardiol. Jun 25 2013;61(25):2551-2556. 

26. Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial 

appendage closure: results from the Watchman Left Atrial Appendage System for 

Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued 

Access Registry. Circulation. Feb 1 2011;123(4):417-424. 

27. Gangireddy SR, Halperin JL, Fuster V, Reddy VY. Percutaneous left atrial appendage 

closure for stroke prevention in patients with atrial fibrillation: an assessment of net 

clinical benefit. Eur Heart J. Nov 2012;33(21):2700-2708. 

28. Bayard Y-L, Omran H, Neuzil P, et al. PLAATO (Percutaneous Left Atrial Appendage 

Transcatheter Occlusion) for prevention of cardioembolic stroke in non-anticoagulation 

eligible atrial fibrillation patients: results from the European PLAATO study. 

EuroIntervention. Jun 2010;6(2):220-226. 

29. Nagpal AD, Torracca L, Fumero A, Denti P, Cioni M, Alfieri O. Concurrent prophylactic 

left atrial appendage exclusion: results from a randomized controlled trial pilot study. Eur 

J Cardiothorac Surg. Sep 2009;36(3):553-557. 

30. Healey JS, Crystal E, Lamy A, et al. Left Atrial Appendage Occlusion Study (LAAOS): 

results of a randomized controlled pilot study of left atrial appendage occlusion during 

coronary bypass surgery in patients at risk for stroke. Am Heart J. Aug 2005;150(2):288-

293. 

31. Whitlock RP, Vincent J, Blackall MH, et al. Left Atrial Appendage Occlusion Study II 

(LAAOS II). Can J Cardiol. Nov 2013;29(11):1443-1447. 

32. Lee C-H, Kim JB, Jung S-H, Choo SJ, Chung CH, Lee JW. Left atrial appendage 

resection versus preservation during the surgical ablation of atrial fibrillation. Ann Thorac 

Surg. Jan 2014;97(1):124-132. 

33. Kim R, Baumgartner N, Clements J. Routine left atrial appendage ligation during cardiac 

surgery may prevent postoperative atrial fibrillation-related cerebrovascular accident. J 

Thorac Cardiovasc Surg. Feb 2013;145(2):582-589; discussion 589. 

34. Kanderian AS, Gillinov AM, Pettersson GB, Blackstone E, Klein AL. Success of surgical 

left atrial appendage closure: assessment by transesophageal echocardiography. J Am 

Coll Cardiol. Sep 9 2008;52(11):924-929. 

35. Muhammad MIA. Role of video-assisted thoracoscopy in the management of stroke. 

Asian Cardiovasc Thorac Ann. Feb 2014;22(2):155-159. 

36. Chatterjee S, Herrmann HC, Wilensky RL, et al. Safety and Procedural Success of Left 

Atrial Appendage Exclusion With the Lariat Device: A Systematic Review of Published

Reports and Analytic Review of the FDA MAUDE Database. JAMA internal medicine. 

Jul 1 2015;175(7):1104-1109. 

37. Bajaj NS, Parashar A, Agarwal S, et al. Percutaneous left atrial appendage occlusion for 

stroke prophylaxis in nonvalvular atrial fibrillation: a systematic review and analysis of 

observational studies. JACC Cardiovasc Interv. Mar 2014;7(3):296-304. 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

Occlude the Left Atrial Appendage 

37

38. Munkholm-Larsen S, Cao C, Yan TD, Pehrson S, Dixen U. Percutaneous atrial 

appendage occlusion for stroke prevention in patients with atrial fibrillation: a systematic 

review. Heart. Jun 2012;98(12):900-907. 

39. Bode WD, Patel N, Gehi AK. Left atrial appendage occlusion for prevention of stroke in 

non-valvular atrial fibrillation: A meta-analysis. Circulation. 2014;130((Bode W.D.; Gehi 

A.K.) Dept of Medicine, Div of Cardiology, Univ of North Carolina at Chapel Hill, 

Chapel Hill, United States).

40. Holmes DR, Jr., Doshi SK, Kar S, et al. Left Atrial Appendage Closure as an Alternative 

to Warfarin for Stroke Prevention in Atrial Fibrillation: A Patient-Level Meta-Analysis. J 

Am Coll Cardiol. Jun 23 2015;65(24):2614-2623. 

41. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients 

with atrial fibrillation. N Engl J Med. May 14 2009;360(20):2066-2078. 

42. Active Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. 

Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial 

fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE 

W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912. 

43. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly 

score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial 

fibrillation: the Euro Heart Survey. Chest. Nov 2010;138(5):1093-1100. 

44. Moher D, Pham B, Lawson ML, Klassen TP. The inclusion of reports of randomised 

trials published in languages other than English in systematic reviews. Health technology 

assessment (Winchester, England). 2003;7(41):1-90. 

45. Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial 

appendage closure with the Watchman Device in patients with atrial fibrillation: a 

PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin 

Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll 

Cardiol. Mar 6 2012;59(10):923-929. 
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APPENDIX A. SEARCH STRATEGIES 

Database Strategy:

Medline (Ovid) 

Embase (Elsevier)

Cochrane Library (EBM Reviews)

Conference Papers Index (ProQuest) 

Grey Literature Sources

Clinicaltrials.gov

WHO ICTRP

ISRCTN Registry

US FDA medical devices website: Advisory Committee/Panel Meetings (CDRH); 

Premarket Approvals (PMA); Premarket Notifications (510(k)s) 

Device manufacturer scientific information request

Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946-November Week 3 2014, 

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations January 06, 2015

Searched: January 7, 2015

1 atrial appendage/ and left.ti,ab. 1060 

2 (left adj1 ((atrial or atrium or auricular) adj1 appendage*)).ti,ab. 2410 

3 1 or 2 2552 

4 Atrial Fibrillation/su or exp cardiovascular surgical procedures/ or ligation/ or 

thoracic surgical procedures/ or sternotomy/ or thoracoscopy/ or thoracic surgery, 

video-assisted/ or thoracotomy/ or (excis* or excision* or occlude* or occlusion* 

or closure* or destruction or obliterat* or ligation* or ligat* or sutur* or 

exclusion* or exclud* or appendectom* or thoracoscop* or minithoracotom* or 

mini-thoracotom* or stapling or stapled or stapler* or sew or sewn or oversew* or 

clamp* or clip* or atriclip or Gillinov-Cosgrove or ligasure or amputat* or resect* 

or removal or remove* or surger* or surgical or CABG or MAZE or AVR or 

sternotom* or percutaneous* or Watchman or Lariat or PLAATO or Amplatzer or 

Coherex or LAmbre).ti,ab.

2716235 

5 3 and 4 1457 

6 remove duplicates from 5 1421 

7 limit 6 to "all child (0 to 18 years)" 145 

8 limit 7 to "all adult (19 plus years)" 48 

9 7 not 8 97 

10 6 not 9 1324 

11 animals/ not humans/ 4025968 

12 10 not 11 1213 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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ELSEVIER EMBASE.COM : 1950-present

Searched: January 7, 2015 

#13 #9 NOT #12 2,164

#12 #10 NOT #11 373

#11 #10 AND ({young adult}/lim OR {adult}/lim OR {middle aged}/lim OR 

{aged}/lim OR {very elderly}/lim) 68

#10 #9 AND ({newborn}/lim OR {infant}/lim OR {child}/lim OR 

{preschool}/lim OR {school}/lim OR {adolescent}/lim OR {animal 

experiment}/lim OR {animal model}/lim)

441

#9 #7 OR #8 2,537

#8 'left atrial appendage closure device'/exp 184

#7 #3 AND #6 2,485

#6 #4 OR #5 4,435,729

#5 'heart atrium fibrillation'/exp AND 'surgery'/lnk OR 'cardiovascular 

surgery'/de OR 'ligation'/de OR 'thorax surgery'/de OR 'sternotomy'/de OR 

'thoracoscopy'/de OR 'thoracotomy'/de

110,162

#4 excis* OR excision* OR occlude* OR occlusion* OR closure* OR 

destruction OR obliterat* OR ligation* OR ligat* OR sutur* OR exclusion* 

OR exclud* OR appendectom* OR thoracoscop* OR minithoracotom* OR 

mini AND thoractom* OR stapling OR stapled OR stapler* OR sew OR sewn 

OR oversew* OR clamp* OR clip* OR atriclip OR 'gillinov cosgrove' OR 

ligasure OR amputat* OR resect* OR removal OR remove* OR surger* OR 

surgical OR cabg OR maze OR avr OR sternotom* OR percutaneous* OR 

watchman OR lariat OR plaato OR amplatzer OR coherex OR lambre.ti,ab.

4,421,880

#3 #1 OR #2 4,759

#2 ((atrial OR atrium OR auricular) NEXT/1 appendage*):ab,ti 4,553

#1 'heart atrium appendage'/exp AND left:ab,ti 2,855

Ovid EBM Reviews: 

Cochrane Central Register of Controlled Trials: 1991-November 2014

Cochrane Database of Systematic Reviews: 2005-November 2014

Database of Abstracts of Reviews of Effects: 1991-4th Quarter 2014 

Health Technology Assessment: 2001-4th Quarter 2014

NHS Economic Evaluation Database: 1995-4th Quarter 2014

Searched: January 7, 2015

1 (left adj1 ((atrial or atrium or auricular) adj1 appendage*)).mp. 79 

2 (excis* or excision* or occlude* or occlusion* or closure* or destruction or 

obliterat* or ligation* or ligat* or sutur* or exclusion* or exclud* or appendectom* 

or thoracoscop* or minithoracotom* or mini-thoracotom* or stapling or stapled or 

stapler* or sew or sewn or oversew* or clamp* or clip* or atriclip or GillinovCosgrove or ligasure or amputat* or resect* or removal or remove* or surger* or 

surgical or CABG or MAZE or AVR or sternotom* or percutaneous* or Watchman 

or Lariat or PLAATO or Amplatzer or Coherex or LAmbre).mp. 

153735 

3 And/1-2 45 
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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ProQuest COS Conference Papers Index

Searched: January 22, 2015 

(left atrial appendage* OR left atrium appendage* OR left auricular appendage*) AND (excis* 

OR excision* OR occlude* OR occlusion* OR closure* OR destruction OR obliterat* OR 

ligation* OR ligat* OR sutur* OR exclusion* OR exclud* OR appendectom* OR thoracoscop* 

OR minithoracotom* OR mini-thoracotom* OR stapling OR stapled OR stapler* OR sew OR 

sewn OR oversew* OR clamp* OR clip* OR atriclip OR Gillinov-Cosgrove OR ligasure OR 

amputat* OR resect* OR removal OR remove* OR surger* OR surgical OR CABG OR MAZE 

OR AVR OR sternotom* OR percutaneous* OR Watchman OR Lariat OR PLAATO OR 

Amplatzer OR Coherex or Lambre) 

[Search field=anywhere; document type=conference, conference papers; dates=all dates] 

Results=57

ClinicalTrials.gov

https://www.clinicaltrials.gov/ct2/search/advanced

Searched: July 28, 2015 

Search terms = "left atrial appendage" OR "left atrium appendage" OR "left auricular 

appendage" 

Study type = Interventional Studies 

Results = 58 

World Health Organization International Clinical Trials Registry Platform (WHO ICTRP)

http://apps.who.int/trialsearch/

Searched: January 22, 2015 

Search terms: Watchman OR Amplatzer OR Coherex OR Wavecrest OR Ligasure OR Lambre 

OR PLAATO OR Atriclip OR Lariat OR left atrial appendage OR left atrium appendage OR left 

auricular appendage

Results = 3

ISRCTN Registry

http://www.isrctn.com/editAdvancedSearch?q=plaato&filters=&searchType=advanced-search 

Searched: January 22, 2015 

Searched each of the following terms/phrases separately in the text search field:

Watchman OR Amplatzer OR Coherex OR WaveCrest OR Ligasure OR Lambre OR 

PLAATO OR Atriclip OR Lariat OR left atrial appendage OR left atrium appendage OR 

left auricular appendage

Results = 0
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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APPENDIX B. STUDY SELECTION 

Code Definition KQ1. What is the 

effectiveness of LAA 

exclusion interventions 

compared with usual 

care?

KQ2. What are the 

harms associated with 

LAA exclusion?

KQ3a. How do the benefits 

LAA exclusion vary in 

different subgroups?

KQ3b. How do the harms of 

LAA exclusion vary in 

different subgroups?

KQ4. What are the 

comparative effects of 

different techniques on 

health outcomes and 

rates of procedural 

success?

I – Surg Addresses KQ1, KQ2, or KQ3:

Primary trial or cohort study that compares 

surgical LAA technique with usual care, and 

reports outcomes of interest. 

Included surgical interventions:

LAA occlusion/removal techniques that involve major surgery (sternotomy or thoracotomy), eg: 

§ specific devices such as AtriClip, or 

§ techniques such as stapling or suturing. 

LAA occlusion/removal via thoracoscopic surgery, eg: 

§ Thoracoscopic Left Appendage Total Obliteration No cardiac Invasion (LAPTONI) procedure 

Minimally invasive Maze procedures if there are data about the incremental effects of concomitant LAA 

exclusion.

I – Perc Addresses KQ1, KQ2, or KQ3:

For all KQs, include RCTs that compare 

percutaneous LAA technique with usual care, 

and reports outcomes of interest. 

For KQ2 and KQ3b, may also include cohort, 

registry, trial extension, or post market 

surveillance studies that report harms data and 

have a sample size >50.

Included percutaneous interventions:

AMPLATZERTM Cardiac Plug (company: AGA Medical, Corp., North Plymouth, MN, USA) a.k.a. 

“Amulet”

WATCHMAN® Left Atrial Appendage Closure Technology/Device/System (company: Atritech, Inc., 

North Plymouth, MN, USA)

PLAATOTM Percutaneous Left Atrial Appendage Transcatheter Occlusion (company: Appriva Medical, 

Inc., Sunnyvale, CA)

Coherex WaveCrestTM LAA Occluder System (company: Coherex Medical, Inc., Salt Lake City, Utah, 

USA) 

LARIAT suture delivery device (SentreHeart, Redwood City, California)

Lifetech LAmbreTM Left Atrial Appendage Occluder Device (Lifetech Scientific Co., Ltd., Shenzhen, 

CHINA)

I4 – Surg Addresses KQ4:

Primary trial or cohort study that compares 

different surgical techniques to close LAA, and 

reports either procedural or health outcomes. 

Included outcomes for KQ4: 

Procedural outcomes: successful closure/LAA removal, assessed by methods such as transesophageal 

echocardiogram; CT; MRI.

I4 – Perc Addresses KQ4: Health outcomes: stroke, mortality, cardiovascular morbidity, or other reported health outcomes

Include RCTs only.

Study compares different percutaneous LAA 

techniques, and reports either procedural or health 

outcomes.

I–SR Systematic review or meta-analysis of surgical / 

percutaneous techniques that addresses any of the 

4 KQs
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APPENDIX C. QUALITY ASSESSMENT

Table 9. Quality assessment of trials of percutaneous LAA interventions 

Study

Was the allocation 

sequence 

adequately 

generated?

Was allocation 

adequately 

concealed?

Was knowledge 

of the allocated 

intervention 

adequately 

prevented 

during the 

study?

Were incomplete outcome 

data adequately 

addressed?

Are reports 

of the study 

free of 

suggestion of 

selective 

outcome 

reporting?

Was the study 

apparently 

free of other 

problems that 

could put it at 

a high risk of 

bias?

Summary 

assessment

High/Low/ 

Unclear

Risk of Bias

Study was 

funded by

PREVAIL

Holmes, 

201416

Yes: "computergenerated 

randomization" for 

most of the 

subjects:

407 were enrolled 

thru randomization; 

the remaining 68 

were enrolled 

through "roll-in 

process" 

Yes

Centralized 

system 

performed 

block 

randomization 

stratified by 

clinical center;

password 

protected; 

accessed by PI 

and study 

coordinator

No: Participants 

and clinicians 

were not masked 

to treatment 

assignment

Yes, presumably:

"All follow-up information 

from the post-182-day period 

was used in the final hazards 

analysis in the model, 

contributing to the 

calculation of the probability 

of 18-month events."

Yes Yes Low Atritech/Boston 

Scientific.

PROTECT 

AF

Alli, 201312

Holmes, 

200913

Reddy, 

201314

VilesGonzales, 

201245

Yes: "randomly 

assigned by a 

computergenerated 

randomization 

sequence" in a 2:1 

intervention:control 

ratio

Yes

Centralized 

system 

performed 

block 

randomization 

stratified by 

clinical center; 

password 

protected; 

accessed by PI 

and study 

coordinator

No: Participants 

and clinicians 

were not masked 

to treatment 

assignment

Yes.

Reports "Analyses were 

performed on randomized 

subjects for those with a 

paired mental and physical 

component score at baseline 

and 12 months, or in subjects 

who died before 1 year of 

follow-up irrespective of 

actual treatment received, 

following the intention-totreat principle." 

Caveat: patients with 

unsuccessful implantation 

were censored at 45 days 

and, therefore, did not have 

12 month reported QoL data 

and were excluded.

Yes Yes Low;

High for 

QOL 

outcomes 

owing to 

lack of 

blinding, 

subjective 

nature of the 

outcome, 

and 

differential 

rates of 

follow-up

for this 

outcome.

Atritech, Inc. 
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Table 10. Quality assessment of trials of surgical LAA interventions

Study; 

Setting

Was the allocation 

sequence adequately 

generated?

Was allocation 

adequately 

concealed?

Was knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Were incomplete 

outcome data adequately 

addressed?

Are reports of 

the study free 

of suggestion 

of selective 

outcome 

reporting?

Was the study 

apparently free 

of other 

problems that 

could put it at a 

high risk of 

bias?

Summary 

assessment

High/Low/ 

Unclear

Risk of 

Bias

Nagpal, 200929

Single center

Italy

Yes: "Simple 

randomization, 

stratified by presence

of preoperative atrial 

fibrillation, was 

carried out using a 

computer program"

Yes: "sealedenvelope 

technique was 

used

to assign each 

patient to a 

treatment group"

Yes: "sealed-envelope" Yes: ITT analysis Yes Yes Low

Whitlock, 

201331

LAAOS II

Yes

"participants were 

randomly assigned to 

either the occlusion 

arm or the noocclusion arm by a 

central 24-hour 

automated interactive 

voice-activated 

randomization system. 

Treatment allocation 

was performed 

according to a 

computer-generated 

randomization list and 

was stratified based 

on preoperative OAC 

use."

Yes Yes

"Treatment was not blinded" 

but unlikely that outcomes 

measured would be 

influenced by lack of 

blinding.

"Although the study will not 

be blinded, the following 

steps will be taken to reduce 

the risk of bias in the 

assessment of outcome 

events. Patients will be 

assessed by standardized 

questionnaire at each visit. 

All reported outcome events 

will be reviewed by an

adjudication committee 

blinded to treatment 

allocation. All hospital 

admissions occurring during 

the study will be reported, 

including all admission and 

discharge diagnoses, to detect 

possible stroke."

Yes

"Assessment of the 

secondary clinical 

outcomes was based on 

the intention-to-treat 

principle, in which all 

participants are included 

in their assigned treatment 

groups regardless of 

actual surgical procedure 

performed."

"One-year data were 

available for 100% of the 

patients

enrolled in the LAAOS II 

trial."

Yes Yes Low
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Study; 

Setting

Was the allocation 

sequence adequately 

generated?

Was allocation 

adequately 

concealed?

Was knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Were incomplete 

outcome data adequately 

addressed?

Are reports of 

the study free 

of suggestion 

of selective 

outcome 

reporting?

Was the study

apparently free 

of other 

problems that 

could put it at a 

high risk of 

bias?

Summary 

assessment

High/Low/ 

Unclear

Risk of 

Bias

Healey, 200530

LAAOS

Yes

"consecutively 

ordered, opaque, 

sealed envelope"

"randomized, using 

sealed envelopes, to 

undergo LAA 

occlusion or serve as a 

control. Patients were 

randomized 2:1, 

favoring occlusion."

Yes Yes

"Treatment was not blinded" 

but unlikely that outcomes 

measured would be 

influenced by lack of 

blinding.

"Although the study will not 

be blinded, the following 

steps will be taken to reduce 

the risk of bias in the 

assessment of outcome 

events. Patients will be 

assessed by standardized 

questionnaire at each visit. 

All reported outcome events 

will be reviewed by an

adjudication committee 

blinded to treatment 

allocation. All hospital 

admissions occurring during 

the study will be reported, 

including all admission and 

discharge diagnoses, to detect 

possible stroke."

Yes

no missing outcome data 

for KQ2

Yes

prespecified 

outcomes 

(Crystal 2003) 

all reported

Yes Low risk of 

bias
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Table 11. Quality assessment of cohort studies surgical LAA interventions

Study

Representativeness 

of the exposed 

cohort 

Selection 

of the 

non 

exposed 

cohort 

Ascertainment 

of exposure 

Demonstration 

that outcome 

of interest was 

not present at 

start of study

Comparability 

of cohorts on 

the basis of 

the design or 

analysis

Assessment 

of outcome

Was follow-up long 

enough for outcomes to 

occur?

Adequacy of follow up of 

cohorts

Kim, 201333 1

all patients who 

underwent surgery 

with a single 

cardiothoracic 

surgeon over the 

course of 10 years

1 1 1 2

study controls 

for 8 variables 

in PSM model

1 1?

only looks at 30 days 

post-op, difficult to say 

how this would change 

the data. Could see more 

of a benefit in decreased 

CVA in the LAA ligation 

group with longer followup, however may have 

also seen more harm from 

the increased incidence of 

post-op AF.

1

A total of 2078 patients 

underwent cardiac surgery 

during the 10-year study 

time period. Eleven 

patients were excluded

from the study (10 

patients died and 1 patient 

had an incomplete 

medical record because of 

transfer to another

facility on postoperative 

day 1), leaving a sample 

size of 2067.

Lee, 201432 1 1 1 1 2

PSM model 

with 20 

variables

1 1 1

Kanderian, 

200834

0

only 173 of 1,546 

who underwent 

surgical LAA 

closure (follow-up 

complete TEE with 

color Doppler 

interrogation of 

LAA)

1 1 1 0 1 1 1

Muhammad, 

201435

0 1 1 1 0 0 1 1
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Newcastle-Ottawa10 criteria and code definitions used in Table 10: 

Representativeness of the exposed cohort 

1 = truly representative of the average pt in the community 

1 = somewhat representative of the average pt in the community 

0 = selected group of users eg nurses, volunteers 

0 = no description of the derivation of the cohort 

Selection of the non exposed cohort 

1 = drawn from the same community as the exposed cohort 

0 = drawn from a different source 

0 = no description of the derivation of the non exposed cohort 

Ascertainment of exposure 

1 = secure record (eg surgical records)

1 = structured interview 

0 = written self-report

0 = no description 

Demonstration that outcome of interest was not present at start of study 

1= yes

0 = no 

Comparability of cohorts on the basis of the design or analysis

Add points: Minimum 0 , Maximum 2

1 = study controls for ___ (select most important factor) 

1 = study controls for any additional factor (a second important factor) 

0 = no adjustment for potential confounders 

Assessment of outcome

1 = independent blind assessment 

1 = record linkage

0 = self-report 

0 = no description 

Was follow-up long enough for outcomes to occur?

1 = yes (need to define adequate follow up period for outcome of interest) 

0 = no 

Adequacy of follow up of cohorts

1 = complete follow up; all subjects accounted for. 

1 = subjects lost to follow up unlikely to introduce bias; small number (define %) lost, or 

description was provided of those lost. 

0 = follow up rate < ____% (define adequate %) and no description of those lost. 

0 = no statement
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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APPENDIX D. LAA DEVICE MANUFACTURERS 

Scientific information requests were sent January 17, 2015, to the companies listed below. 

LAA exclusion device Device manufacturer

AMPLATZERTM Cardiac Plug, 

Cardiac Plug 2, Cardiac Plug 3, 

and AmuletTM

ST. JUDE MEDICAL, INC.

ATTN: Medical Information Officer 

St. Jude Medical, Inc.

One St. Jude Medical Drive 

St. Paul, MN 55117-9983 

Email form: http://sjm.com/corporate/data/forms/email-us

ATRICLIP® PRO LAA 

Occlusion System 

ATRICURE, INC.

ATTN.: Medical Information Officer

6217 Centre Park Drive 

West Chester, OH 45069 

Email form: http://www.atricure.com/contact-atricure-usa

WATCHMAN® Left Atrial 

Appendage Closure Device

BOSTON SCIENTIFIC, CORP.

ATTN: Medical Information Officer 

100 Boston Scientific Way 

Marlborough, MA 01752

Online form (scroll to bottom right): 

https://www.bostonscientific.com/en-US/contact-us.html

COHEREX WAVECRESTTM LAA 

Occluder System

COHEREX MEDICAL, INC. 

ATTN: Medical Information Officer 

3598 West 1820 South 

Salt Lake City, UT 84104 

Online contact form: http://www.coherex.com/contact/

Lifetech LAmbreTM Left Atrial 

Appendage Occluder Device

LIFETECH SCIENTIFIC (SHENZHEN) CO., LTD.

ATTN.: Medical Information Officer

Cybio Electronic Building, 

Langshan 2nd Street, 

Nanshan District, Shenzhen 518057, 

PEOPLE’S REPUBLIC OF CHINA

Email: lifetechmed@lifetechmed.com

LARIAT® Suture Delivery 

Device

SENTREHEART, INC.

ATTN: Medical Information Officer

300 Saginaw Drive

Redwood City, CA 94063 

Email: info@sentreheart.com

LigaSureTM COVIDIEN

ATTN: Michael Tarnoff, MD FACS

Corporate Chief Medical Officer

Medical Devices/Medical Supplies

15 Hampshire Street

Mansfield, MA 02048
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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APPENDIX E. PEER REVIEWER COMMENTS AND AUTHOR RESPONSES

Question Reviewer Comment Response

Are the 

objectives, 

scope, and 

methods for this 

review clearly 

described?

1 Yes Noted.

2 Yes Noted.

3 Yes Noted.

4 Yes Noted.

5 Yes Noted.

Is there any 

indication of 

bias in our 

synthesis of the 

evidence?

1 No Noted.

2 No Noted.

3 Yes - The method section clearly identifies the process for evidence 

collection and synthesis.

Noted.

4 No Noted.

5 No Noted.

Are there any 

published or 

unpublished

studies that we 

may have 

overlooked?

1 Yes - Medtronic sponsored and run The Cardioblate Closure Device Study 

(FDA IDE G080156) “An evaluation of the Cardioblate Closure Device in 

Facilitating Occlusion of the Left Atrial Appendage". Enrollment was 

suspended in 2009. The data was not published but is available by the FDA.

We came across this study in our search for trials in clinicaltrials.gov.

We decided not to include it because the study was terminated due to 

a Medtronic business decision, and no study results were posted. We 

were unable to find the study on the FDA website.

2 No Noted.

3 No Noted.

4 No Noted.

5 No Noted.

Additional 

suggestions or 

comments can 

be provided 

below. If 

applicable, 

1 No comment.

2 This analysis of the safety and efficacy of procedures to occlude or remove 

the left atrial appendage is comprehensive, informative, and well written. The 

conclusions are well supported and though the paper does not provide 

definitive guidance on the role of LAA exclusion in reducing the risk of AF 

associated stroke it will be very useful for clinicians and policy makers.

Noted, thank you.
The Effectiveness of Procedures to Remove or Evidence-based Synthesis Program

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Question Reviewer Comment Response

please indicate 

the page and line 

numbers from 

the draft report.

I have a minor disagreement with the point in the introduction that since 90% 

of thrombi that develop in the atrium are in the appendage it would make 

sense that elimination of the appendage would reduce the risk of stroke. This 

point is certainly true but a more nuanced discussion of the etiology on stroke 

in AF would be helpful in understanding why exclusion of the appendage 

may not eliminate the risk of stroke in AF. It is worth mentioning that the 

appendage is not the only source of strokes in AF patients. The patients at 

highest risk AF associated stroke have risk factors for stoke that are 

independent of AF such as hypertension, diabetes, and advanced age. Each of 

these puts patients at risk for mechanisms of stroke that are not related to AF 

such as aortic and carotid atherosclerosis. I do not know if it is really known 

what percentage of strokes in patients with AF are from appendage thrombus 

versus other mechanisms. Thus the point is that though 90% of clots in the 

heart are in the appendage it is not known what percentage of AF associated 

strokes are due to the embolism of clots from the appendage. This is 

especially true as one does more extensive monitoring for occult AF in stroke 

patients.

Edits made to reflect our uncertainty regarding source of thrombi in 

the introduction of the executive summary and evidence report.

Minor points:

Maze is not consistently capitalized (single or all caps) in the manuscript

Corrected. We will use “all caps” MAZE.

Page 10 Table 2 (and elsewhere): There is some inconsistency in whether the 

CHADS2 score or the CHA2DS2-VASC is used for risk stratification. If 

possible the CHA2DS2-VASC should be used though I understand that not 

all studies will report it.

We will continue to use CHADS2 and CHADS2-VASC as 

appropriate for individual studies, however, when making general 

comments/summary statements we will use low risk (CHADS2 <2 or 

CHADS2-Vasc <2) when patients/providers have been given the 

option of aspirin versus warfarin therapy.

In the PREVAIL trial statistical methods it states, “Data on endpoints from 

PROTECT AF subjects meeting the inclusion/exclusion criteria for 

PREVAIL were used in a historical previous distribution, with 50% 

discounting to reduce the influence of the earlier data. “ To me this sounds 

that some patients acted as controls in both PROTECT and PRVAIL. Was 

this taken into account in your analysis? Should it be?

The PREVAIL study used the data from PROTECT in power 

calculations to determine the study size. Patients from PREVAIL 

were not included in the PREVAIL trial.

Page 15: It does not seem to make sense to me that the composite endpoint 

would be 5.2% in the LAA exclusion group and 2.9% in the warfarin group 

but that the 18 month composite event rate ration was only 1.07.

We agree this is confusing, and have added wording to clarify the % 

vs rate ratio which is based on person-time of observation. It is likely 

because the event rates are reported for the total duration of the study 

(longer than 18 months) and some of the events in the device group 

occurred later in the study.

Table 3: The PROTECT AF quality of life data is suspect in my mind in that 

the study was unblinded and one group had a complex procedure. Such a 

procedure it would seem to me could have a profound placebo effect that 

might influence the patient’s assessment of quality of life.

We agree, and have rated the ROB for QOL outcomes as follows:

High for QOL outcomes owing to lack of blinding, subjective nature 

of the outcome, and differential rates of follow-up for this outcome.
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Question Reviewer Comment Response

Page 29: It might be worth mentioning that in one large study of warfarin 

versus aspirin and clopidogrel for AF associated stroke prevention the risk of 

major bleeding was similar between with warfarin compared to the 

combination of ASA and clopidogrel and that minor bleeding and overall 

bleeding were higher with ASA and clopidogrel compared to warfarin. Thus 

as long as the protocol for the use of the watchman device requires that drug 

combination for up to 6 months it will not be an attractive device for patients 

that are at high risk for bleeding complications and do not want to take 

warfarin.

We appreciate this point and have added it to our discussion.

There is a very wide range of reported % rate of stroke in various studies 

reported in the manuscript. I believe some of this variation is due to variable 

follow-up time and differing risk stroke factor profiles. There probably is no 

easy way to correct for these factors and make the numbers comparable 

across studies but it would be nice if possible. Perhaps as you have done just 

having follow-up time and risk factors in the tables is the best you can do.

Challenging. This represents that variable populations which were 

enrolled and different follow-up time. We hope to provide the data in 

a clear format so that the differences are relatively clear.

3 The report is overall very well-conceived and written. I am not clear why the 

RCTs that are listed in appendix C while satisfying most of the questions are 

still considered low quality evidence. I did not find enough support for that 

determination in the narrative as well.

Low = Low risk of bias.

4 In the summary of evidence (page 2) please expand the statement pertaining 

to LAA percutaneous LAA exclusion (line 51) to include comment for all 

devices not just Watchman.

We agree and have made the suggested change. 

I am unclear as to the statements made regarding surgical ablation of the 

LAA during routine cardiac procedures (page 30, lines 4-27). Specifically, 

why could the clinician not avoid anticoagulation if the patient had a prior 

LAA ablation (whether open surgical or percutaneous)? Please consider 

clarifying that no evidence exists to evaluate whether prophylactic LAA 

oblation prevents or minimizes stroke risk associated with later onset AF.

We have edited this to reflect the uncertainty of the literature 

regarding reduction in stroke risk from surgical LAA exclusion.
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Question Reviewer Comment Response

5 Noelck and colleagues from the ESP Center performed a systematic review 

of the effectiveness and harms of percutaneous catheter-based and surgical 

interventions to occlude, exclude, or remove the left atrial appendage (LAA). 

They were charged with addressing 4 key questions regarding effectiveness 

compared to usual care (ie anticoagulation or antiplatelet agents), harms, 

variance of effects among subgroups, and comparative effects of different 

techniques. They concluded that the Watchman device may be an effective 

alternative to long-term oral anticoagulation in selected patients, though the 

evidence (for efficacy) was deemed low-strength, and high rates of serious 

procedure-related harms were noted in many studies. Specific comparisons 

between devices or patient groups was not possible due to insufficient 

evidence; most notably this included the subgroup of patients who are 

ineligible for long-term oral anticoagulation. Though additional harms 

appeared low with surgical procedures for LAA exclusion/resection, there 

was insufficient evidence to evaluate efficacy, with some studies suggesting 

low procedural success. For this reason the routine use of surgical LAA 

exclusion for the purpose of stroke prevention or cessation of anticoagulation 

could not be recommended. Dr. Noelck and team should be congratulated for 

an exhaustive and fair review. Some specific comments follow.

Thank you.

Major:

1. Perhaps due to the structure of the key questions there is no direct 

comparison of risks of intervention versus standard of care (long-term oral 

anticoagulation). Within key question #1 the harms of stroke or death are 

addressed in a comparative fashion. Key question #2 primarily examines all 

other harms only on the side of intervention. This may bias the reader’s 

resulting assessment of the risks and benefits between intervention and 

anticoagulation. I do agree with the assessment that percutaneous intervention 

on the LAA has had high rates of serious procedure-related harms in many 

studies (perhaps lessening with experience, as the authors mentioned). Given 

the indefinite nature of the risks of anticoagulation though, if a patient has a 

reasonable life expectancy, this risk will likely eventually be equaled and 

surpassed. A bit more detailed statement of risks on the standard of care side 

of the equation, other than the brief mention of its “cumbersome” nature in 

the introduction would seem to be appropriate.

Addressed in discussion (page 36).

Minor:

1. Might be reasonable to add a sentence to the findings in the harms row of 

the table on 3 in the executive summary that pertains to harms found 

specifically with Watchman device (even if only to say percentages fit in 

range above), since that is the only percutaneous intervention in which 

efficacy was addressed, ie, the most relevant.

Added Watchman example of periprocedural event rates (from RCTs 

PROTECT & PREVAIL) to executive summary of findings.
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Question Reviewer Comment Response

2. In Table 1 p9 PICOTS and key questions for percutaneous LAA 

interventions time on bypass is listed as an outcome for KQ2, presumably for 

symmetry with Table 2. Might favor listing need for surgical intervention 

instead. Ventilator days also probably is less relevant for percutaneous 

intervention category, whereas device migration or emboli formation could 

potentially be included.

Agree. Revised as suggested.

3. In Table 2 p10 PICOT and key questions for surgical LAA interventions 

the comparator for KQ2 is listed as surgery for atrial fibrillation without LAA 

removal. To my review, studies included in this comparison were primarily 

CABG and/or valve surgeries with or without LAA intervention. It would be 

surprising to find a study of surgery for AF only/specifically that did not 

include intervention on the LAA.

We agree, we searched more broadly but did not find any studies on 

these.

4. In Table 3 p17, might consider adding DM statistics to patient 

characteristics as all other aspects of CHADS score already included. Is it of 

interest to add race as well?

Agree, and we have added data on DM. Information on race was 

mostly unreported among both RCTs and observational studies. 

5. KQ4 text on p22 addresses comparison of surgical techniques. Ref 28, 

Healey et al, also reported comparison numbers between stapler and suture 

technique, which were different. Is there a reason this data / inconsistency 

was not mentioned?

While this study reported results for both stapler and suture LAA 

occlusion, the surgical technique was not randomized. Over time the 

percentage of surgeries performed using staplers increased, making it 

difficult to determine whether it was increasing surgeon experience or 

change to stapler technique that led to higher rates of successful LAA 

occlusion.