Percutaneous closure of left atrial appendage in patients with atrial fibrillation : An overview

I - Anatomy, embryology and function

The left atrial appendage (LAA) is a tubular muscular structure in continuity with the left atrium (LA). LAA resembles a crescent and is located anteriorly to the left superior pulmonary vein ,in the proximity of the free wall of the left ventricle. LAA communicates with the LA through the orifice located between the left superior pulmonary vein and left ventricular wall. During embryogenesis LAA develops from primordial left atrium during the third week of gestation. There is a considerable inter-individual variability in the shape and size of LAA. In approximately 55% of cases LAA has two lobes. Pathology series showed that mean volume of LAA is approximately 5.2 ml and the mean orifice diameters 15-27 mm. Functions of the LAA include modulation of the sympathetic and parasympathetic tone, decompression of the left atrium in the setting of elevated atrial pressure, production of natriuretic peptides (ANP, BNP) and contributes to the diastolic filling of the left ventricle. Interestingly LAA displays a unique quadriphasic pattern of contraction [1-3].

II - Role in the pathology of thromboembolic stroke

Microscopic and macroscopic anatomy of the LAA changes significantly in chronic atrial fibrillation (AF) with smoothening of the internal surface as well as fibrosis and thickening of the endocardium. In addition, the volume of the LAA increases in AF.  LAA plays a major role in the pathology associated with AF, because it is a most common place of thrombus formation. Formation of thrombus and its release from LAA leads to embolic stroke. High risk of thrombus formation is a result of the low-flow hemodynamics in the LAA. It is estimated that as much as 90% of strokes in patients with AF not associated with valvular heart disease, can be attributed to formation of thrombi in the LAA. Thrombi are also located in LAA in 50% of cases of AP coexisting with valvular heart disease. Reduced contractility of the LAA may occasionally lead to thrombus formation even in patients with sinus rhythm [3-6].

III - Rationale for LAA closure

The benefits of oral anticoagulation in chronic AF are proven with regards to prevention of embolic stroke in a multitude of studies (AFASAK, BAATAF, CAFA, SPAF, SPINAF). The clinical efficiency of oral anticoagulants is however limited due to substantial rate of side effects, including a high risk of bleeding and important interactions with food and other medications. Moreover the need for frequent laboratory testing to check the efficiency of anticoagulation by measuring international normalized ratio (INR) and the need to dose titration lead to poor compliance. Several studies have shown that only 40-55% of patients with AF receive warfarin. The use of oral anticoagulants was particularly low in the elderly despite a high risk of stroke. In addition, many patients with AF present with contraindications for life-long use of oral anticoagulants. Given the important role played by LAA in the pathogenesis of embolic stroke, early attempts to reduce the risk by surgical removal or more recently ligation during the cardiac surgery were made. This approach is limited however by the need for major surgical procedure and a high rate of incomplete occlusion of the LAA orifice which might contribute to a high residual risk of stroke. Data on surgical LAA closure showed that such procedure is feasible and safe [3, 7-9]. 
Because of thisa less invasive approach of percutaneous LAA closure was translated from animal models into the clinical setting and a growing body of evidence has shown its safety and feasibility.

IV - Imaging modalities for evaluation of the LAA

Echocardiography. Transthoracic echocardiography (TTE) is not sensitive enough to detect the presence of thrombi and to assess the anatomy and dimensions of the LAA. Recently, the 3-dimensional TTE is recognised as a promising tool for the detection of LAA thrombi. Current gold-standard for the assessment of the LAA is transesophageal echocardiography which plays a crucial role during the procedure of percutaneous closure. Evaluation of the LAA by multiplane TEE is imperative due to the its anatomical complexity. The exact size of the LAA orifice has to be measured in several planes because of its often irregular shape. Computed tomography.  Multi-slice CT (MSCT) is more sensitive for the detection of LA thrombi than TTE and CT angiography yield high quality 3-D images of the LAA anatomy. Probably the sensitivity of MSCT for detection of LAA thrombi is comparable with TEE.  Cardiac magnetic resonance imaging (cMRI) can be used for the imaging of LAA anatomy and when the contrast is used it can detect the thrombi, however the role of cMRI in percutaneous closure of the LAA needs to be established [10-12]. 

V - LAA closure devices

Three dedicated devices for LAA closure were tested in clinics: PLAATO, WATCHMAN and Amplatzer cardiac plug.

1. The first implantation of PLAATO device (ev3 Inc.) was carried out by H. Sievert in 2001. PLAATO consists of a self-expanding nitinol cage with three anchors on each strut and covered with non-thrombogenic PTFE membrane. The anchoring barbs provide the stability and the PTFE membrane prevents the mobilisation of the thrombi from the LAA and promote healing. After withdrawal from the market by the manufacturer the PLAATO device is no longer available for clinical use [3, 13].
2. Design of WATCHMAN device (Atritech Inc.) is based on the self-expanding nitinol frame covered with porous filtering PET membrane. The stability of the device is secured by fixation barbs located circumferentially. The PET membrane located on the surface facing the LA acts as a filter preventing the outflow of the thrombi and promotes endothelialisation. WATCHMAN device is available in following sizes 21, 24, 27, 30 and 33 mm. WATCHMAN can be recaptured and withdrawn in case of suboptimal fixation. This device is CE-marked, FDA-approved and currently used in clinical practice. A new generation (Gen4) filter with sizes of 22, 26, 31 and mm is currently under investigation. The new features include additional bumper stabiliser and prolapse fixation barbs which allow full recapture and multiple redeployments. The delivery system is 12F [3,10,12].
3. Amplatzer Cardiac Plug (Aga Medical Corp.) used for LAA closure is a combination of nitinol frame with polyester patch to seal the orifice. ACP is not designed to fill the LAA as former devices were, but to seal its ostium and therefore is not dependent on the anatomy of the LAA. The retrieval is possible before the release of the device.  It is CE-marked and available for use in clinics. The plug size ranges from 16 to 30 mm and disk from 20 to 36 mm. The fixation is both the active (barbs) and passive. Delivery system is 9-13F depending on the size of the device [3, 10].

From the practical point of view, the most important difference between the last two devices is the regimen of antiplatelet and anticoagulant therapy used after the implantation.

1. Amplatzer Cardiac Plug: no oral anticoagulants routinely used and the long term dual antiplatelet therapy (DAT) is not required. Only initial DAT regimen (6 months of aspirin and 1 month of clopidogrel) is routinely prescribed.   
2. WATCHMAN filter: oral anticoagulants administered for at least 45 days with target INR of 2.0-3.0 and after its withdrawal long-term aspirin is recommended [3].

VI - Overview of the implantation technique

Implantation is carried out without general anesthesia in the majority of cases under conscious sedation. Antibiotic is administered prior to the procedure as prophylaxis. Vascular access through femoral vein is obtained and the delivery system is introduced by superior transseptal puncture using standard transseptal needle and sheath. After the puncture, the bolus of unfractionated heparin is given to achieve clotting time ACT > 200 seconds. TEE or rarely ICE is used to guide the transseptal puncture. TEE or ICE is used to measure the dimensions of the LAA and the size of its ostium. Less often the contrast angiography of the LAA in at least two projections are used for this purpose. Based on these measurements the size of the device is estimated. The positioning of the device in the LAA cavity is ensured by TEE and fluoroscopy. After withdrawal of the sheaths the device is deployed and its proper fixation tested by TEE and manual test and finally the device is released. For the WATCHMAN device the TEE is performed after 45 days to assess proper closure [3,10,12]. 

Complications of percutaneous LAA closure

• Access site complications (hematoma, bleeding)
• Cardiac perforation
• Device migration and embolisation
• Incomplete closure with thrombus formation

Contraindications for percutaneous LAA closure

• Atrial fibrillation in patients with valvular heart disease (mitral stenosis)

• Other than FA indications for long-term or lifetime anticoagulation (mechanical prosthetic valve, pulmonary embolism and deep vein thrombosis, thrombi in the left atrium or ventricle, incomplete surgical LAA closure)

• Low risk: CHADS2 – Vasc Score = 0 (based on PROTECT-AF study)

• Contraindications for transseptal catheterisation (left atrial thrombus or tumor, presence of ASD or PFO closure device, active infection, uncooperative patient) [3,10,12]

VII - Clinical trials for assessment of percutaneous LAA closure

Use of PLAATO device was assessed in several trials which demonstrated the feasibility and safety of the procedure in long term follow-up. Five year follow-up of 64 patients with permanent or paroxysmal AF revealed reduction of the annualised rate of stroke or TIA in comparison to the one predicted by CHADS2 scoring [14,15].

WATCHMAN is currently the most widely used device for transcatheter LAA closure. After initial reports showing the feasibility, effective sealing of the LAA and its relative safety this technology was evaluated in recently published large randomised, multicentre, prospective trial. The study enrolled 800 patients with non-valvular AF of whom approximately 60% had CHADS2 1 or 2 score and excluded patients with contraindications for oral anticoagulants. PROTECT-AF (WATCHMAN®Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) confirmed non-inferiority to warfarin therapy for prevention of stroke. The procedural success rate was high with effective sealing of the LAA. Only 15% of patients approximately had incomplete sealing of the LAA and required anticoagulation after the procedure. Therefore the use of oral anticoagulants is warranted until the follow-up with TEE after 45 days confirms complete closure.
In addition, initially there was an excess (12%) of procedure-related complications including pericardial tamponade and ischemic stroke [16]. Over time the risk of the procedure-related adverse events including device embolisation was reduced as demonstrated by Continued Access Registry which suggest they were related to the learning curve. Recently, improvements in the device design were made and a new generation of WATCHMAN is evaluated in a currently ongoing clinical trial (EVOLVE). So far more than 1,500 patients were treated with WATCHMAN within controlled clinical trials. Amplatzer Cardiac Plug is currently evaluated in multicentre trials and a European registry. Initial experience revealed the 96% procedural success rate and 7% rate of adverse events, including device embolisation (3.5%), tamponade (3.5%) and stroke (2.1%) [3]. Guidelines of the European Society of Cardiology on treatment of AF mention the use of the WATCHMAN device showing non-inferiority to oral anticoagulants in a selected group of patients.