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Review
Left atrial appendage occlusion
  1. Oluseun Alli,
  2. David Holmes Jr
  1. 1The Division of Cardiovascular Diseases and Department of Internal Medicine, University of Alabama, Birmingham, Alabama, USA
  2. 2The Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
  1. Correspondence to Dr Oluseun Alli, Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; oalli{at}uabmc.edu

Abstract

Left atrial appendage (LAA) occlusion for stroke and thromboembolism prevention in patients with atrial fibrillation (AF) represents a significant advancement in the field of cardiovascular disease. Prevention and avoidance of the devastating consequences of thromboembolic complications from AF continues to be central in the management of these patients. The role of LAA as a nidus for thrombus formation is well documented. Multiple approaches to exclude the LAA from the circulation either percutaneously or surgically have been described and are undergoing testing. Although pharmacological therapy for stroke prevention remains the cornerstone of treatment, device and surgical exclusion of the LAA have proven to be viable alternatives in carefully selected patients. Even though current evidence show that LAA occlusion is safe and effective, approval and adoption of this strategy has been quite difficult due to paucity of randomised clinical trial data on the risk and benefit ratio, cost effectiveness and the issues of procedural risk as well as longer-term outcome. This review aims to provide an update on the current status of LAA occlusion, specifically looking at interpretation of current clinical data, available techniques and devices, issues with current devices and future direction.

https://doi.org/10.1136/heartjnl-2014-306255

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    Introduction

    Thromboembolism in patients with atrial fibrillation (AF) most commonly leads to stroke, and by virtue of its endemic nature and devastating consequences, approaches to reduce thrombus formation in patients with AF remain a major cardiovascular issue, a great clinical need and a fertile field of investigation.1 The left atrial appendage (LAA) has been implicated in 90% of thrombus formation in patients with non-valvular AF,2 ,3 and approaches aimed at reducing thrombus formation in LAA continue to be explored.4–7 In recent years, mechanical approaches for the exclusion of LAA from the circulation using surgical or percutaneous means have been developed and have been found to be a viable alternative to antithrombotic therapy using oral anticoagulants for stroke prevention. This review will focus on the latest developments in the field and areas of controversy regarding this technique.

    Rationale

    LAA has long been recognised as the site of clot formation in a majority of patients with non-valvular AF. Weiss and colleagues proposed the theory that clot formation occurs in LAA in patients with rheumatic mitral stenosis.8 Madden then reported the first two cases of surgical LAA removal in patients with rheumatic mitral stenosis and AF.2 Blackshear and Odell, in their review of 23 studies in which LAA was examined, found that 222 (17%) of 1288 non-valvular patients with AF had LAA thrombus and 201 (91%) of these were localised to LAA.9

    Stroke and bleeding risk prediction models

    Given the risk of stroke versus the issue of bleeding, a variety of risk stratification scores have been developed and tested. The CHADS2 score is the most widely used risk stratification scheme that has been validated to provide significant risk discrimination for evaluation of stroke risk in patients with AF.10 It assigns one point for heart failure, hypertension, age ≥75 years, and diabetes mellitus and two points for prior stroke or transient ischaemic attack. A more recent update that is now more widely used is the CHA2DS2-VASc score, which includes three additional risk factors for ischaemic stroke; age 65–74 years, female sex and vascular disease have supplanted the CHADS2 score and have been validated in several cohorts of patients with AF providing significant discrimination of stroke risk.11 ,12

    In terms of bleeding risk prediction, the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score has been validated and shown to offer useful predictive capacity for assessment of bleeding risk compared with other risk tools.13 A recent study compared the HAS-BLED score with two other bleeding risk prediction scores,14 ATRIA (anticoagulation and risk factors in AF) and HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, rebleeding, hypertension, anaemia, genetic factors, excessive fall risk and stroke), with the HAS-BLED score performing best in predicting clinically relevant bleeds.

    Imaging LAA

    In recent years, an important advance has been the use of multimodality imaging techniques (cardiac CT, cardiac MRI and transesophageal echocardiography (TEE)) to accurately characterise the anatomy of LAA. The use of cardiac CT imaging has led to detailed assessment of LAA. Although the orifice of LAA was initially thought to be circular in shape, it has now been defined as being irregular.

    The anatomic variability of LAA has important implications for endovascular device closure; the LAA orifice is oval or irregular and current devices are circular, accordingly placement may leave behind residual leaks. The length and angulation of LAA may also make device closure difficult, as all current endovascular devices require a definite but variable length for safe deployment. The Amplatzer cardiac plug (ACP) device is anchored in the neck of LAA while the WATCHMAN device is anchored in the ostium of LAA.

    The LARIAT device, which is an epicardial suture device, also requires specific LAA anatomy for appropriate device use; the LAA width must be <40 mm and superiorly oriented LAA. With this device, bilobed or a multilobed LAA and a posteriorly rotated heart are unfavourable characteristics for device closure using the LARIAT device.

    Transesophageal echocardiography still plays a central role in device closure of LAA; the addition of 3D imaging also aids measurement of the LAA orifice for device sizing. Preprocedural TEE helps detect the presence of LAA thrombus and would also determine the presence or absence of pericardial effusion. TEE views should demonstrate the orifice, neck and body of the LAA, as well as the left circumflex artery. A sweep of LAA is performed from 0° to 180°; LAA is interrogated in the 0, 45, 90 and 135° views. The orifice, depth and dimensions of the landing zone are assessed and measured with TEE. 2D-TEE may grossly underestimate the size of the LAA orifice and a recent study15 demonstrated that the use of Definity contrast imaging improved LAA visualisation, accuracy of LAA dimensions and aided LAA thrombus detection.

    Current devices

    LAA can be closed with percutaneous or surgical therapies; table 1 gives a brief overview of the current devices used in this arena.

    View this table:
    Table 1

    Summary of devices used for left atrial appendage occlusion

    Postprocedure patients are maintained on aspirin 75–81 mg daily and warfarin to maintain an INR of 2.0–3.0 for a minimum of 45 days after the procedure. A TEE is performed at 45 days postprocedure to evaluate device placement, thereafter cessation of warfarin is at physician's discretion. Patients who had cessation of warfarin should begin clopidogrel 75 mg daily and continue aspirin daily for 6 months, thereafter clopidogrel can be discontinued.

    Surgical LAA closure

    The first LAA excision in humans was performed by Madden in 19492 in two patients with AF and rheumatic mitral disease. The Left Atrial Appendage Occlusion Study (LAAOS) is the first randomised trial examining the feasibility, safety and efficacy of LAA exclusion at the time of elective coronary artery bypass graft procedure using suture or staples.16 Occlusion was successful in 29 patients (66%), and its efficacy increased with the use of staples compared with sutures, 72% vs 45%, p=0.14. The LAAOS III (ClinicalTrials.gov NCT01561651) study is currently enrolling; it will compare surgical LAA occlusion (suture or stapler) with no intervention and looks to enrol 4700 patients with AF and CHADS score ≥2, the primary end point being the occurrence of stroke or systemic arterial embolism.

    One major reason for failure to demonstrate a benefit with surgical LAA exclusion was the high rates of incomplete occlusion of LAA as demonstrated by TEE. Indeed, patients with incomplete exclusion of LAA continue to be exposed to the risk of thromboembolic events and may be at an increased risk for these events.

    The EXCLUDE trial evaluated the use of the Atriclip device at 7 US sites in 70 patients. Intraprocedural success occurred in 67 of 70 patients (95.7%) with significant adverse events occurring in 34 of 70 patients (48.6%), which were not device related. At 3-month follow-up, there had been 1 death, 61 patients underwent imaging and 60 (98.4%) had successful LAA occlusion. The Tiger Paw System (Terumo Cardiovascular Systems, Ann Arbor, Michigan, USA) is another device approved for commercial use in the USA.17

    Current clinical data on percutaneous LAA occlusion

    Currently, there are two randomised clinical trials completed and published that have examined the efficacy of percutaneous LAA occlusion devices versus warfarin in this arena. The paucity of multiple randomised clinical trials on this particular subject has been one of the limitations of the adoption of this technology. Table 2 summarises the clinical trial and registry data in this field. The Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation (PROTECT AF) trial5 was a pivotal trial in this field,18 but some of the limitations/criticisms of this trial were the low mean CHADS2 score at enrolment of 2.2±1.2, the initial use of warfarin in the device group for 45 days that may have contributed to improved early outcome in the device group or alternatively improved safety risks, the boundaries of non-inferiority, the reintroduction of warfarin later during follow-up for other reasons, restricting the trial to patients who were candidates for warfarin, inclusion of both ischaemic and haemorrhagic strokes as an efficacy endpoint and finally device safety. The issue of device safety was subsequently addressed in the second randomised trial Prospective Randomized Evaluation of the WATCHMAN Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation Versus Long-Term Warfarin Therapy (PREVAIL), which showed significant improvements in procedural safety.19 Reddy and colleagues recently published long-term follow-up of the patient population in the PROTECT AF trial who were followed for a mean of 2.3±1.1 years (1588 patient-years); they found that therapy with the WATCHMAN LAA device was non-inferior to systemic therapy with warfarin, and the failure of the LAA closure device to achieve superiority was due to the acute procedure-related stroke events. Patients with a prior embolic event received sustained benefit from LAA closure20  (figure 1). The WATCHMAN device has also been shown to improve quality of life in patients with AF; a quality-of-life analysis of the PROTECT AF trial revealed significant improvements in quality of life in patients randomised to device compared with warfarin.21

    View this table:
    Table 2

    Results of clinical studies percutaneous left atrial occlusion

    Figure 1
    Figure 1

    Follow-up at 2.3 years of the Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation trial. Reproduced with permission from Reddy et al. LAA, left atrial appendage.

    The Percutaneous Left Atrial Appendage Suture Ligation Using the LARIAT Device in Patients with Atrial Fibrillation (PLACE-2) trial22 evaluated the safety and efficacy of the LARIAT device. Eighty-nine patients with AF were enrolled in the trial; there was a 96% success rate and adverse events included pericarditis, pericardial effusion with tamponade, late strokes and unexplained sudden cardiac death. Ninety-five per cent of patients had complete LAA closure by TEE at 3 months. A recently published US registry23 on the use of the LARIAT device looked at 154 patients undergoing LAA closure with the device. A total of 154 patients were enrolled with a median CHADS2 score of 3; device success was 94% with 86% procedural success rate. Also, 9.7% of patients experienced a major complication, 9.1% had major bleeds and 10.4% had significant pericardial effusion. The median follow-up period was 112 days and death, myocardial infarction or stroke occurred in 2.9% of patients, and among 63 patients that had acute LAA closure follow-up TEE revealed that 20% had residual leak and 4.8% had thrombus in LAA.

    Issues

    Patient selection

    Currently, it is unclear which patient groups would benefit the most from LAA occlusion as there are no clinical trials looking at this issue. Current evidence and expert opinion would suggest that LAA occlusion offers the greatest benefit in patients with AF who have a high-stroke risk but who are also at a high risk of bleeding or have suffered a major bleed and are therefore intolerant of oral anticoagulants. Unfortunately, the current clinical trial data do not sufficiently address the use of LAA occlusion in patients not treated with oral anticoagulants. Approximately 50% of patients with AF who are at risk for stroke are not treated with oral anticoagulation;24 device therapy in this patient population would be an important therapeutic alternative. Currently, the only data available in this high-risk population subset come from the European Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) study25 and the Aspirin Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP) registry.7 In the ASAP registry, the predicted stroke rate based on CHADS2 score was 7.3% per year while the actual stroke rate following LAA closure was 2.3% per year. Table 3 shows the conditions in which LAA occlusion may be considered in patients intolerant of oral anticoagulants. A recent European expert consensus statement26 proposed a patient algorithm for stroke prevention in AF; this is summarised in figure 2.

    View this table:
    Table 3

    Conditions in which percutaneous LAA occlusion may be considered

    Figure 2
    Figure 2

    Algorithm for stroke prevention in patients with atrial fibrillation. Recommendations of the European Heart Rhythm Society and the European Association of Percutaneous Cardiovascular Interventions 2014. Reproduced by permission from Meier et al.26 HAS-BLED, Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly; LAA, left atrial appendage; OAC, oral anticoagulants.

    Device/procedural safety

    Device and procedural safety has always been of utmost importance among physicians involved with this technology. The early studies (PLAATO, PROTECT AF) revealed a substantial incidence of periprocedural safety events that included cardiac perforation requiring surgical repair, pericardial effusion with tamponade requiring pericardiocentesis, device embolisation, procedure-related stroke and vascular complications. Fortunately, the incidence of these complications has markedly decreased with increasing experience among operators, device iterations and improved training techniques. In the PROTECT AF trial, the first half of the study revealed a procedure-related safety event of 9.9% that dropped by 50% to 4.8% in the second half of the study. The reduction in these events was also seen in the Continued Access Protect AF (CAP) registry where the rate of procedure-related safety events was 4.1%.6 The recently published PREVAIL trial was designed to assess the safety and efficacy of the WATCHMAN LAA device. There were significant reductions in safety events in this trial compared with the PROTECT AF trial; early safety events were seen in 2.2% of device patients compared with 4.8% in the same group in PROTECT AF, and overall adverse events were lower in PREVAIL compared with PROTECT AF, 4.2% vs 8.7%; p=0.004. Importantly the rates of pericardial effusions needing surgical repair decreased from 1.6% to 0.4%, p=0.027, and those requiring pericardiocentesis decreased from 2.9% to 1.5%. It should be noted that mortality is worse in patients with pericardial effusion/tamponade treated surgically versus those treated with pericardiocentesis. Table 4 details the comparison of outcomes in device patients in PROTECT AF, CAP and PREVAIL trials. Eventually, the early safety hazard of device closure procedures, which is currently in the range of 2.2–4.2%, must be balanced against the long-term bleeding risk associated with oral anticoagulants. For example, the annual bleeding risk for warfarin has been estimated at 0.6% for fatal bleeds, 3% for major bleeds and 9.6% for all bleeds.27–29 There is a 2–5 time increase in the incidence of intracranial haemorrhage with the use of warfarin, which translates to 3500 intracranial bleeds annually.27 ,30

    View this table:
    Table 4

    Comparison of outcomes in device patients in PROTECT AF, CAP and PREVAIL

    Incomplete closure of LAA following epicardial or endocardial device closure has also been investigated. As previously mentioned, surgical data indicate that there is a higher incidence of stroke following incomplete surgical exclusion of LAA.31 A recent analysis of the PROTECT AF trial32 found that incomplete LAA occlusion defined as any flow around the device was found in 40.9% of patients at the 45-day TEE examination and decreased over time to 33.8% at 6 months and 32.1% at 12 months, p=0.001. The clinical impact of peri-device flow was negligible as the authors found no interaction between peri-device flow and outcomes and the use of continued anticoagulation did not decrease the risk of thromboembolic events

    Cost effectiveness

    There are very few studies that have looked at the cost effectiveness of LAA device occlusion versus oral anticoagulants. A recent study33 examined the lifetime costs, quality-adjusted life-years and incremental cost-effectiveness ratio of LAA occlusion with the WATCHMAN device in relation to dabigatran and warfarin in patients with AF. This analysis was performed in the context of the Ontario health services in Canada. Warfarin therapy was found to have the lowest discounted quality-adjusted life-years at 4.55, followed by dabigatran at 4.64 and LAA occlusion at 4.68 (table 5). Compared with warfarin, the incremental cost-effectiveness ratio for LAA occlusion was $41 565 and dabigatran was extendedly dominated given that dabigatran was more expensive per additional unit of cost effectiveness. They concluded that LAA occlusion is cost effective compared with warfarin. A similar analysis by Bryan Yan et al34 looked at LAA occlusion with the WATCHMAN device compared with aspirin, aspirin and clopidogrel, warfarin and dabigatran 150 mg or 110 mg. They concluded that LAA occlusion was cost effective with an incremental cost-effectiveness ratio of $975 per quality-adjusted life-years gained.

    View this table:
    Table 5

    Cost effectiveness of LAA occlusion

    There are issues with the current cost-effectiveness data; estimates of effectiveness are obtained from a single randomised trial with restrictive enrolment and limited follow-up, thus these are not based on actual real-world clinical use data; second, there would be regional and geographical variability in cost effectiveness that would be reflective of insurance and medical costs in these localities; third, multiple assumptions were made in the development of this cost-effectiveness analyses due to limited data on the new strategies; and finally, it is unclear what would happen in the real world once the device is formally approved for clinical use.

    Other benefits of LAA exclusion

    The LARIAT device has been shown to lead to electrical isolation of LAA, leading to acute reduction in the LAA voltage with inhibition of the capture of LA during LAA pacing.35 Similarly, a recent analysis also suggested that there might be a decrease in arrhythmia burden with ligation of LAA.

    Real-world practice

    Insights into the current real-world practice with the use of device occlusion of LAA can be gleaned from the recent results of the European Heart Rhythm Association survey.36 The current European Society of Cardiology guidelines on AF37 recommends that LAA closure may be considered in patients with high-stroke risk contraindications for long-term oral anticoagulation (class IIb recommendation).

    The survey looked at data from 24 European centres that performed LAA occlusion; on average, each centre performed 10.6±11.7 (range 1–50) LAA occlusion procedures per year. The majority were performed by interventional cardiologists, and the most common indication was 'patient has absolute contraindication to long-term anticoagulants'. Complication rates reported varied widely, pericardial tamponade in 1–10%, major bleeding in 0–8%, thromboembolism in 0–10% and device dislodgement in 0–20%, but the majority of the centres (65%) reported a 0% complication rate. Obstacles to widespread use device occlusion of LAA included reimbursement/device pricing, limited efficacy data for stroke prevention, risks of complications and technical difficulties regarding device placement.

    Summary, recommendations and future direction

    Prevention of stroke in patients with AF remains an important goal in the management of these patients. Device closure of LAA has been found to be non-inferior to warfarin in patients with AF, but there are still some unanswered questions.

    There is still paucity of randomised clinical trial in the field with limited data comparing the efficacy of device closure to the newer oral anticoagulants and the use of the device in patients with contraindications to long-term anticoagulation. The issue of health economics and cost effectiveness will also need to be addressed in a prospective fashion.

    Solutions to overcome some of the paucity of clinical data would be the use of well-designed studies and postmarketing registries that include standardised forms, detailed inclusion criteria, procedural outcome and clinical follow-up focusing on stroke events and bleeding. Development of new devices and device iteration of the existing devices with the aim of reducing device complications and improving procedural safety is also an area that needs to be explored. The approach to LAA occlusion will require a heart team approach with electrophysiologists, interventional cardiologists, cardiac surgeons and cardiovascular imaging specialists working together to determine the best approach for each individual patient.

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    Footnotes

    • Competing interests Dr. Holmes (along with the Mayo Clinic) has a financial interest in technology related to this research; that technology has been licensed to Atritech.

    • Provenance and peer review Commissioned; externally peer reviewed.

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