Original paper
Left atrial appendage occlusion using the PLAATO system in high-risk patients with atrial fibrillation – long-term follow-up

Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia and affects 3% to 5% of the population older than 65 years [1]. Its incidence increases with age. Patients with AF have a five-fold increased risk of stroke, which remains the first leading cause of long-term disability and one of the major causes of death in this group [2]. The annual risk of stroke in patients with non-valvular AF is approximately 5% [3]. It is estimated that 15% of all strokes may be a consequence of atrial fibrillation [4]. Importantly, it is believed that in AF patients more than 90% of thrombi originate in the left atrial appendage (LAA) [3, 5]. Thromboembolic strokes in AF tend to be more serious than other ischaemic cerebral infarcts, possibly due to the larger dimensions of left atrial appendage thrombi [6, 7]. Currently the first line therapy to prevent cardioembolic complications in AF patients is chronic oral anticoagulation (COA) [2]. A number of prospective randomized trials (e.g. AFFIRM, RACE) have clearly confirmed the efficacy of vitamin K antagonists (VKA) in reducing the risk of death and stroke in patients with AF [8, 9]. VKA are superior to both aspirin and combined antiplatelet therapy [10, 11]. Indications for anticoagulation depend on calculated stroke risk. There are several methods adopted from previous clinical trials used to assess this risk, such as the Atrial Fibrillation Investigators, Stroke Prevention in Atrial Fibrillation, CHADS2 (congestive heart failure, hypertension, age ł 75 years, diabetes mellitus, and prior stroke or transient ischaemic attack) index, Framingham score and others [12]. Out of these, the CHADS2 index is most often used to delineate high-risk patients. Based on the CHADS2 score, high-risk patients (previous stroke or transient ischaemic attack or the presence of more than one risk factor: congestive heart failure, hypertension, age ł 75 years, diabetes mellitus) should be treated with VKA, whereas aspirin can be offered for low-risk cases (0 or 1 risk factor) [13]. However, around 54% of all high-risk patients do not receive COA for a variety of reasons, including: poor and difficult INR control, concern about bleeding, allergy, poor tolerance or just patient’s preference [14-16]. In addition, only 60% of VKA treated patients are within the therapeutic INR range [17]. New oral anticoagulants, such as direct thrombin inhibitors and factor Xa inhibitors, do not require regular INR controls and are being studied in randomized clinical trials in AF patients, but they are not available on the market for this indication [18]. In some cases combined antiplatelet therapy may be used as an alternative treatment for high-risk patients unsuitable for VKA, but one must take into account their lower efficacy than COA and similar risk of severe bleeding [10, 11]. Assuming that the left atrial appendage is the major source of emboli, a way to prevent ischaemic stroke among AF patients is to exclude the LAA from circulation [3]. This may be done surgically by LAA ligation if the patient is undergoing cardiac surgery for other reasons [5, 19]. However, surgical LAA exclusion is grossly impractical and sometimes incomplete, increasing in this last instance the risk of thromboembolic complications [20]. In the last decade a method of percutaneous transcatheter occlusion of the LAA was introduced into clinical practice in an attempt to replace COA, at least in selected patients, and avoid bleeding complications [3]. Initial studies have demonstrated the feasibility and short-term benefit of this strategy [21, 22]. However, long-term data are still very limited [23-26]. Several devices have been used for this purpose, such as the PLAATO system (percutaneous left atrial appendage transcatheter occlusion, ev3, Plymouth, Minnesota, USA), WATCHMAN filter system (Atritech, Plymouth, Minnesota, USA) and several types of Amplatzer septal occluders (AGA Medical Corporation, Golden Valley, Minnesota, USA) [3]. The present study was performed as part of the original European PLAATO Study to give some insight into the long-term safety and efficacy of LAA occlusion with the PLAATO device in several AF patients unsuitable for COA, recruited in our centre.

Methods
From May 2004 until April 2005 six patients were included in whom an attempt was made to close the left atrial appendage using the Ev3 PLAATO device (X-Sept transseptal sheath and X-Caliber System). This is a self-expandable nitinol implant covered with polytetrafluoroethylene membrane (ePTFE) on the orifice side. Patients read and signed the informed consent to participate in the trial. The study has been approved by the appropriate Ethics Committee. All patients received a loading dose of 300 mg of aspirin and 300 mg of clopidogrel at least 4 h before the procedure. Clopidogrel was continued for 6 months after the procedure at the maintenance dose (75 mg daily), while aspirin was given indefinitely at a dose of 75-100 mg daily. The procedures were performed under general anaesthesia and were guided by fluoroscopy and transoesophageal echocardiography (TEE). After transseptal puncture unfractionated heparin was given in a dose sufficient to increase the activated clotting time to over 250 s (usually the starting bolus dose was about 100 units per kg). Contrast medium was then injected into the LAA to assess its size and location with respect to the delivery system (fig. 1). LAA orifice diameter was also assessed by TEE and the reference size was calculated as a mean of both measurements. The chosen PLAATO device size was around 20% larger than the calculated reference LAA diameter. After positioning in the LAA the implant was expanded by retracting the delivery sheath. Its position and sealing were then checked by contrast injection and TEE (fig. 2 and 3). Afterwards, the delivery catheter was gently moved back and forth to ensure adequate anchorage and positioning. This was monitored with fluoroscopy and TEE. If repositioning was required, the occluder was retracted into the delivery sheath and reimplanted or a larger device was used. Positioning satisfactory, the implant was released and one more contrast injection into the left atrium to demonstrate sealing and device position was performed (fig. 4). Patients were discharged within 48 h of the procedure. The first follow-up visit was performed after one month. A follow-up visit with TEE assessment was performed after 2 months post-procedure and after that visits with clinical assessment were scheduled at 6 months, 1 year, 2 years and 4 years. Additionally, in April 2009 each patient completed a telephone interview.

Results
Baseline clinical and echocardiographic characteristics of all included patients are presented in tables 1 and 2.

Of the 6 patients in whom device implantation was attempted, percutaneous LAA occlusion was successful in 5 cases (83.3%). In one female patient with unusual LAA anatomy the procedure was unsuccessful due to inability to position the implant securely within the LAA after crossing the septum. The delivery sheath was too stiff and the operator was not able to bend it appropriately. There were no periprocedural deaths or severe complications related to the procedure. In one patient the device implantation evoked an atrial flutter episode that was subsequently treated with DC cardioversion. The average LAA diameter was 22.8 mm in echocardiography and 22.6 mm in fluoroscopy.
The median implant size was 25 mm. Angiography and transoesophageal echocardiographic examination immediately after the procedure confirmed LAA occlusion in all 5 patients, with a mild residual leak in two patients. There were no pericardial effusions noted after the procedures.
Median follow-up was 54 months and ranged 48-59 months. All patients discontinued COA. No patients died. There were no cases of ischaemic or haemorrhagic stroke. Systemic embolization or long-term complications associated with the device were not observed. TEE performed after 2 months confirmed correct and stable positioning of the PLAATO device in all patients, with mild leak persisting in one case. During follow-up there were no cases of intracranial or gastrointestinal bleeding. Of the seven hospitalizations that took place during follow-up one was for unstable coronary artery disease, two were for heart failure exacerbations and four were due to atrial fibrillation episodes.
The average CHADS2 score of the five treated patients was 3.0 (range 2 to 5). One patient had a history of stroke and one of transient ischaemic attack (TIA). On this basis the calculated annual risk for stroke in the treated group would be around 6.5% with no anticoagulation, around 5% assuming they were taking aspirin (22% risk reduction) and 2.1% on COA (67% risk reduction). In our group the event-free survival during median 54-month follow-up was 100%, but one must consider the very small sample size, making most statistical comparisons inappropriate.

Discussion
This is yet another study stemming from the original PLAATO evaluation trial, demonstrating in a small group of patients, during long-term follow-up, the safety and apparent efficacy of LAA occlusion using the PLAATO transcatheter occlusion device [22-26]. There have been other small reports published, all demonstrating the efficacy of the PLAATO occluder, all of which were non-randomized [24, 25]. Shorter term data based on a large patient group are available from the North American and European PLAATO feasibility studies that included 210 patients overall with a mean follow-up of 14.7 months [3, 23]. In those studies procedural success was achieved in 97.6%, while 5 patients experienced stroke, amounting to a 61% reduction from the expected stroke risk in this group. These results are attractive, but it must be taken into account that this is only an indirect comparison in a group of patients with contraindications to COA. A planned randomized PLAATO/COA study was abandoned, reportedly for financial reasons [3].
One of the most important issues associated with atrial fibrillation is the need for anticoagulation to reduce the risk of stroke weighed against the risk of bleeding when anticoagulation is given [2]. VKA remain the treatment of choice, but despite their efficacy, are a solution far from perfect in the prevention of stroke in AF patients. COA is difficult to maintain, has potential significant serious adverse effects, of which the risk of bleeding is the most important, and is inconvenient due to the need of repeated international normalized ratio (INR) assessments. Because of this, nearly half of eligible patients are not treated with VKA [13-15]. Out of the remaining 50% many have unstable or often sub-therapeutic INR values [16]. A solution to this vital clinical problem may lie in oral factor Xa antagonists or direct thrombin inhibitors, currently undergoing evaluation in advanced phase clinical trials. However, it is likely that these new drugs will not eliminate the danger of bleeding, especially in the high bleeding risk patient group. Bleeding is often a serious adverse event, increasing patient morbidity and mortality. It has repeatedly been shown that the patients with high risk of bleeding are also those with a high risk of thromboembolic complications.
If we accept the somewhat uncertain data that in non-valvular AF more than 90% of strokes are caused by thrombi originating from the LAA [5], the potential benefit of LAA occlusion stands out as a nearly ideal treatment for high stroke and bleeding risk patients. Two possibilities of occluding the LAA exist – the surgical and the percutaneous method [3]. The surgical method has been used for many years with mixed results, as a high percentage of residual leaks was reported (13–57%), which could actually increase stroke risk [27]. Currently this method is being evaluated in the LAAOS randomized trial, which is planned to include 2500 patients [28]. Until the results are published there is really no evidence base supporting this approach. An alternative is to exclude the LAA from the circulation using a percutaneously implanted occluding device. Three types of these devices have been used so far. They are the PLAATO system, the Watchman device and several types of Amplatzer septal occluders. All have been shown to be feasible and seemingly efficacious, with the PLAATO occluder probably the most difficult to use of the three because of the rather stiff delivery system [29]. However, only one of these has undergone evaluation in a randomized study [30].
The results of the PROTECT AF study have been made public recently [31]. This randomized study compares the Watchman device to COA in 800 non-valvular AF patients. COA was discontinued in 87% of the LAA occlusion group. The risk of stroke was similar in both groups (risk ratio 0.96; 95% CI 0.43-2.57), but one must take into account that this was a low or moderate stroke risk population (approximately 65% of patients were CHADS2 1 or 2). Unfortunately, there was a 7.2% incidence of periprocedural complications in the Watchman device group (usually pericardial effusions), of which 5% were serious. PROTECT AF is the first study clearly demonstrating the potential of LAA occlusion in stroke prevention, in non-valvular AF patients. Because of some safety issues (risk of serious pericardial effusion and small added risk of periprocedural stroke) it has not been accepted so far by the FDA (American Food and Drug Administration), although the advisory panel voted 7 to 5 in favour of approving the device [32]. As other percutaneous devices lack randomized studies, none of them have received FDA clearance for this indication.
As it is, for the time being there is no valid alternative to COA and until further data are available from randomized trials or the Watchman device is approved, neither percutaneous devices nor surgical closure may be recommended for stroke prevention in high-risk AF patients.

Conclusions
Stroke complicating chronic or paroxysmal AF constitutes a clinical challenge for which currently only COA is a valid treatment. Other methods are under evaluation, which may soon completely change the way we treat AF patients. An attractive therapeutic option is LAA occlusion. However, none of the currently available devices have been approved by the FDA for this indication. Until more data become available and some improvements to the technology are introduced, LAA occlusion should not be viewed as an alternative to COA.
However, our and previous data support the idea of percutaneous LAA closure for selected AF patients with contraindications to VKA, especially those with high risk of serious bleeding.

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