Elsevier

Heart, Lung and Circulation

Volume 26, Issue 9, September 2017, Pages 918-925
Heart, Lung and Circulation

Review
Dealing With the Left Atrial Appendage for Stroke Prevention: Devices and Decision-Making

https://doi.org/10.1016/j.hlc.2017.05.113Get rights and content

Left atrial appendage (LAA) device occlusion represents a major evolution in stroke prevention for atrial fibrillation (AF). Left atrial appendage device occlusion is now a proven strategy which provides long-term thromboembolic stroke prevention for patients with non-rheumatic AF. Evidence supports its benefit as an alternative to long-term anticoagulation while mitigating long-term bleeding risks and improving cardiovascular mortality. The therapy offers expanded options to physicians and patients negotiating stroke prevention (both primary and secondary prevention), but a good understanding of the risks and benefits is required for decision-making. This review aims to summarise the evolution of LAA device occlusion therapy, current knowledge in the field and a snapshot of current status of the therapy in clinical practice in Australia and around the world.

Introduction

Embolic stroke is potentially the most serious complication from atrial fibrillation (AF) with an approximate five-fold increase in lifetime risk [1]. Atrial fibrillation-related stroke is generally associated with increased stroke severity, poorer survival and greater disability among survivors along with higher recurrence rates of stroke than other stroke aetiologies [2].

The recognition of the mechanism of stroke as thromboembolism led to the use of oral anticoagulation with Vitamin K antagonists for thromboprophylaxis. A meta-analysis of randomised controlled trials (RCTs) comparing Vitamin K antagonists with control or placebo suggested a risk reduction in stroke incidence of 64% in favour of warfarin [3]. Indeed, the widespread practice and use of warfarin anticoagulation has led to a decrease in the incidence of AF-related stroke over the past two decades according to observational studies [4], [5].

However, warfarin has many well-known limitations including variable pharmacokinetics, narrow therapeutic window, risk of bleeding complications, requirement for monitoring and long-term patient compliance issues. A range of new oral anticoagulants with more predictable pharmacokinetics has recently penetrated global clinical practice with similar demonstrated stroke prophylaxis efficacy [6], [7], [8]. These agents have overcome many of the limitations of warfarin therapy and, importantly, have been shown to significantly decrease the risk of haemorrhagic stroke when compared with warfarin. However, they are still associated with a significant risk of bleeding complications and show surprisingly high non-compliance rates over time.

There are now multiple lines of evidence to support the left atrial appendage (LAA) as being the predominant source of thrombi leading to thromboembolism in atrial fibrillation in patients with non-rheumatic aetiologies with over 90% of thrombi located in the LAA [9], [10], [11]. The incidence of cerebral emboli also appears to correlate with the structural complexity of the appendage [12]. These findings contributed to a hypothesis that a local solution of excluding the LAA from the systemic circulation might prove to be an effective strategy for stroke prophylaxis.

Interestingly, LAA exclusion or obliteration has existed as an open surgical procedure for almost seven decades with the first recorded resection of the LAA in a human in 1949 [13]. However, data from surgical LAA exclusion have shown mixed results with regards to efficacy of stroke prevention likely impacted by marked variation in exclusion techniques which have included attempts at suture ligation, clip fasteners and surgical amputation with oversew or stapling. The different techniques appear to have significant variation in achieved occlusion rates [14] as well as the documented potential for incomplete closure to actually increase the subsequent risk of thromboembolic stroke [15].

Catheter-based delivery of a device to occlude the LAA was first conceived in 1998 with the development of the Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) device. It consisted of a self-expanding nitinol cage with external facing anchor struts and covered with an occlusive membrane of thromboresistant polytetrafluoroethylene (PTFE). Animal studies initially confirmed the feasibility of successful percutaneous implant, successful occlusion of the LAA and subsequent endothelialisation of the device surface [16]. The first LAA device occlusion procedure in a human was performed in 2001 with the PLAATO device [17]. Although the technology was subsequently withdrawn for commercial reasons, observational data from several hundred patients with (non-rheumatic) AF and contra-indications to oral anticoagulation implanted with the PLAATO device pointed to a significant reduction in observed stroke rates when compared to the expected stroke rate as predicted by the CHADS2 score [18].

The WATCHMAN device (Boston Scientific Corp, Marlborough, MA, USA) developed by Atritech Inc will remain the pivotal advance which demonstrated with RCT data that LAA device occlusion could provide effective stroke protection when compared with warfarin [19]. Also a self-expanding nitinol structure with external fixation barbs, the WATCHMAN device was initially patented as a filter with a permeable polyethyleneterephthalate (PET) membrane cover designed to sit in the ostium of the LAA (Figure 2, Panel A). Subsequent studies have pointed to the device atrial surface generally undergoing full endothelialisation over several months [20].

Two RCTs have compared WATCHMAN LAA implant with warfarin in patients with non-valvular (non-rheumatic) AF. Protection in Patients With AF (PROTECT-AF) enrolled 707 patients with a mean CHADS2 score of 2.2 and a total follow-up time of five years [19]. Warfarin was continued up to 45 days in the WATCHMAN arm until satisfactory LAA occlusion was demonstrated on follow-up transoesophageal echo study, with 92% of WATCHMAN patients subsequently discontinuing warfarin. The primary efficacy endpoint of all cause stroke, systemic embolism and cardiovascular death met criteria for non-inferiority of WATCHMAN vs. warfarin at 18 months follow-up with event rates of 3.0% and 4.9% respectively. With longer follow-up at 3.8 years WATCHMAN demonstrated statistical superiority with event rates (per 100 patient years) of 2.3% and 3.8% respectively [21]. However, adverse event rates (procedure–related events and major bleeding) for the WATCHMAN arm were significant at 7.4% vs 4.4% in the warfarin group [19]. A learning curve for the pioneering procedure was acknowledged with already a significant reduction in peri-procedural complications (mainly peri-procedural stroke and pericardial effusion) noted for patients enrolled and implanted in the latter half of the trial as compared with initial subjects [22].

The WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) study was a further RCT mandated by the FDA in the USA to re-examine the safety issues [23]. This study enrolled 407 patients with a higher mean CHADS2 score of 2.6. The required safety endpoint was met with a seven-day safety event rate of 2.2% in the WATCHMAN arm. The primary efficacy composite endpoint (all cause stroke, systemic embolism and cardiovascular death) did not meet non-inferiority at 18 months in PREVAIL with annual event rates of 1.07% for WATCHMAN and 0.7% for warfarin. Discussion has centred around the unusually low event rate in the warfarin controls as compared with annual event rates for warfarin subjects in PROTECT AF or anticoagulation trials; PROTECT AF 1.6% [19], Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY) 1.7% [6], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) 2.2% [7], Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) 1.6% [8]. Subsequently a meta-analysis of the two RCTs has been published which showed comparable efficacy for WATCHMAN and warfarin with no statistically significant difference in the rates of all cause stroke or systemic embolism [24] (Figure 1). A significant reduction in haemorrhagic stroke was seen in favour of WATCHMAN (HR 0.22) as well as a reduction in major bleeding beyond seven days (HR 0.51) and a reduction in cardiovascular mortality (HR 0.48).

A number of other registries and case-control studies using the WATCHMAN device have further contributed to knowledge in the field. The ASA Plavix Feasibility Study With WATCHMAN Left Atrial Appendage Closure Technology (ASAP) study enrolled 150 subjects with a mean CHADS2 score of 2.8 who were contraindicated for anticoagulation and employed dual antiplatelet therapy for six months following implant [25]. At 14 months follow-up the observed ischaemic stroke rate was 1.7% per year which represented a 77% reduction when compared with the expected stroke rate based on CHADS2 score. The (Registry on WATCHMAN Outcomes in Real-Life Utilization) EWOLUTION registry was a real-world prospective registry conducted in Europe, Russia and the Middle East between 2013 and 2015 which collected data on procedural success, safety and long-term patient outcomes [26]. Initial 30-day outcomes were reported for 1021 patients with a mean CHADS2 score 2.8, CHA2DS2-VASc score 4.5 and HAS-BLED score of 2.3. Implant success was 98.5% with a seven-day procedure/device-related adverse event rate of 2.8%. Long-term follow-up outcomes are still pending. The WATCHMAN Asia Pacific (WASP) registry was the equivalent design prospective registry conducted in Asia Pacific (including Australia) between 2014 and 2015 [27]. A total of 201 patients were enrolled with a mean CHA2DS2-VASc score of 3.9 and HAS-BLED score of 2.1. Implant success was 98.5% with a seven-day procedure/device-related adverse event rate of 2.0%.

The Amplatzer Cardiac Plug (Abbott, Abbott Park, IL, USA) was a first generation LAA closure device adapted from other Amplatzer devices traditionally used for atrial septal defect closure [28], [29]. It is a self-expanding two-part nitinol disc and lobe connected by a central waist [29]. An occlusive polyester mesh is contained within the disc and lobe, and anchoring wires are present externally on the lobe for fixation within the body of the LAA. The disc is designed to sit over the true junction of the LAA and left atrium achieving occlusion by traction from the inner lobe (Figure 2). The second generation Amplatzer Amulet was redesigned with a wider lobe, more stabilising wires and recessed proximal end screw to address issues of device embolisation and device-associated thrombus seen with the Cardiac Plug [30]. Following demonstration of feasibility of implant of the Amplatzer Cardiac Plug in 2008, the device was widely commercialised in Europe in the absence of clinical trial data. Multiple small observational studies have been published on the Cardiac Plug and Amulet. The largest Amplatzer Cardiac Plug registry to date has included 1047 patients in Europe with a mean CHADS2 score of 2.8, CHA2DS2-VASc score of 4.5 and HAS-BLED score of 3.1. The implant success was 97.1%, the seven-day procedure/device-related adverse event rate 4.97% and the observed stroke rate at follow-up 2.3% [31]. In the recently presented Amplatzer Amulet Observational Post-Market registry, a prospective international study of 1073 patients, the implant success was 98.8% and the seven-day procedure/device-related adverse event rate was 2.7% suggesting further improvements in procedural technical success [32]. A RCT comparing Amplatzer Amulet with WATCHMAN to more rigorously assess stroke prevention efficacy is currently enrolling in USA, European and Australian sites.

The Coherex Wavecrest device (Biosense Webster Inc. Diamond Bar, CA, USA) is a two-part design with a self-expanding umbrella covered by occlusive PTFE membrane attached to an independently operated anchoring system of microtines. The network of microtines is rolled out into the body of the LAA to achieve fixation of the umbrella at the LAA ostium (Figure 2, Panel C). The device achieved CE mark following a feasibility study which demonstrated successful deployment in 96% with a major adverse event rate of 2.7% in a study size of 63 patients [33]. A RCT of Wavecrest device vs. WATCHMAN is planned to commence enrolment in 2017.

The Lariat device (Sentreheart, Redwood City, CA, USA) is an endo-epicardial percutaneous procedure to deliver a teflon-coated braided polyester suture over the epicardial surface of the LAA to achieve permanent suture ligation [34]. Endocardial and epicardial magnets must be linked up at the tip of the LAA to allow railroading of the suture delivery system over the epicardial surface of the LAA. The procedure was initially commercialised without a clinical trial in the USA in 2010 following use of a FDA approval ‘loophole’. A safety alert was issued by the FDA in 2015 with regards reports of patient deaths and serious adverse events warning that the safety and effectiveness of the LARIAT Suture Delivery Device to close the LAA and prevent stroke in patients with atrial fibrillation had not been established [35]. Several single and multicentre observational studies have been published indicating a high degree of technical success but with significant variability in long-term LAA closure rates and major complications (including complete avulsion of the LAA) [36], [37], [38].

The LAmbre device (Lifetech Scientific, Shenzhen, PR China) is a two-part design with a self-expanding nitinol disc containing an occlusive polyester membrane (similar to Amulet) attached by a waist to a self-expanding umbrella of atrial facing hooks which provides fixation within the LAA [39]. The device obtained CE mark in 2016 following a feasibility study in China.

The varying percutaneous LAA device occlusion procedures share common elements which contribute to procedural risk. Transoesophageal (TOE) imaging is generally used to guide implants and assess acute LAA occlusion [19], [29]. Documented procedural risks include vascular access complications from large French (10–14Fr) femoral venous puncture and oesophageal injury due to TOE imaging [22], [29]. Cardiac perforation and tamponade can be life-threatening and is caused by atrial transseptal puncture, manipulation of catheter equipment in the left atrium or, more particularly, from instrumentation of the thin-walled LAA [22]. Pericardial effusion rates have decreased significantly across all device studies as implant techniques have matured [26], [27], [31] (Table 1). Peri-procedural stroke due to thromboembolism or air embolism is a small but significant risk [19], [29]. Device dislodgement, device embolisation rates and retrieval options (percutaneous retrieval vs. open cardiac surgery vs. peripheral arterial surgical retrieval) vary across the devices [19], [22], [29]. Major seven-day peri-procedural adverse event rates in more recent multicentre registry experiences are reported as 2.8% for WATCHMAN [26] and 2.7% for Amplatzer Amulet [32].

Device-associated thrombus is a relatively frequently observed ‘phenomenon’ detected early during routine TOE imaging follow-up protocols [40]. The vast majority of reported cases are asymptomatic and appear to resolve without sequelae over weeks or months with anticoagulation (or occasionally no treatment) [40].

There are few reports of any long-term complications emerging from the presence of a LAA closure device, however reported experience beyond five years currently remains limited. In spite of the commonality of LAA device occlusion procedures an in-depth understanding of each device design, delivery technique and long-term follow-up data will be required to inform clinical practice in future.

Section snippets

Clinical Guidelines

Catheter-based LAA device occlusion first appeared in the ESC Clinical Guidelines for the Management of Atrial Fibrillation in 2012 with a Class IIb recommendation for use in patients with a high stroke risk and contraindications for long-term oral anticoagulation [41]. The guideline recommendation would seem to reflect clinical opinion and evolving clinical practice in Europe (following the early commercialisation of WATCHMAN and Amplatzer Cardiac Plug devices in Europe from 2009) rather than

Conclusion

Left atrial appendage device occlusion is now a proven strategy which provides long-term thromboembolic stroke prevention for patients with non-rheumatic AF [24]. Left atrial appendage device occlusion represents a major evolution in stroke prevention for AF. Evidence supports its benefit as an alternative to long-term anticoagulation while mitigating long-term bleeding risks and improving cardiovascular mortality [24]. The therapy offers expanded options to physicians and patients negotiating

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

K Phillips has received honoraria and consulting fees from St Jude Medical and Boston Scientific Corp. V Paul has received honoraria and consulting fees from St Jude Medical and Boston Scientific Corp.

References (51)

  • V.Y. Reddy 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

    (2013)
  • K. Bartus et al.

    Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience

    J Am Coll Cardiol

    (2013)
  • M.J. Price 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

    (2014)
  • M.A. Miller et al.

    Multicenter study on acute and long-term safety and efficacy of percutaneous left atrial appendage closure using an epicardial suture snaring device

    Heart Rhythm

    (2014)
  • Y.Y. Lam et al.

    Preclinical evaluation of a new left atrial appendage occluder (Lifetech LAmbre™ device) in a canine model

    Int J Cardiol

    (2013)
  • J.L. Anderson et al.

    Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

    J Am Coll Cardiol

    (2013)
  • K.P. Phillips et al.

    Combined catheter ablation for atrial fibrillation and Watchman® left atrial appendage occlusion procedures: Five-year experience

    J Arrhythm

    (2016)
  • A. Alipour et al.

    Ablation for Atrial Fibrillation Combined With Left Atrial Appendage Closure

    JACC: Clinical Electrophysiol

    (2015)
  • P.A. Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

    Stroke

    (1991)
  • H.J. Lin et al.

    Stroke severity in atrial fibrillation. The Framingham Study

    Stroke

    (1996)
  • R.G. Hart et al.

    Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation

    Ann Intern Med

    (2007)
  • S. DeWilde et al.

    Trends in the prevalence of diagnosed atrial fibrillation, its treatment with anticoagulation and predictors of such treatment in UK primary care

    Heart

    (2006)
  • D.T. Lackland et al.

    Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association

    Stroke

    (2014)
  • S.J. Connolly et al.

    Dabigatran versus warfarin in patients with atrial fibrillation

    N Engl J Med

    (2009)
  • M.R. Patel et al.

    Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

    N Engl J Med

    (2011)
  • View full text