ABSTRACT: Purpose. In more than 90% of patients with atrial fibrillation (AF), stroke is due to thrombotic embolization from the left atrial appendage (LAA). Transcatheter occlusion with percutaneous left atrial appendage transcatheter occlusion (PLAATO), a self-expanding, membrane-covered spherical nitinol cage, is feasible and an alternative to anticoagulation therapy. Methods. This was a single-center prospective registry study for verification of stroke risk reduction in patients with AF 2 years after PLAATO. Results. Seventy-three patients with AF (permanent 65, paroxysmal 8) in whom anticoagulation therapy was contraindicated or rejected underwent transcatheter LAA occlusion with PLAATO. One patient died periprocedurally due to implant embolization, and 1 patient underwent open-heart surgery because of implant instability. The remaining 71 patients were followed for 24 months. In 52 patients a stable anchoring of the PLAATO device without migration or dislocation was documented by transesophageal echocardiography (TEE). No thrombotic deposition was found on the LA luminal surface of the device. Statistically, in our patient cohort, 7 strokes would have been expected without any treatment within 24 months. In fact, no strokes were reported. Ten out of 71 patients died during follow up: 6 in our hospital and 4 at home. None of them died from a stroke. Conclusions. Ninety-seven percent of AF patients were successfully treated with PLAATO. After mechanical LAA occlusion, the 2-year risk of stroke in AF patients is markedly reduced. Therefore, this therapeutic concept is a clear alternative for patients with AF and contraindications for oral anticoagulation.
J INVASIVE CARDIOL 2009;21:446–450
In the U.S. and Europe, 4 million patients suffer from atrial fibrillation (AF), representing, thus, the most common arrhythmia in clinical practice.1–3 It affects 3–5% of the population > 65 years of age and is responsible for 15–20% of ischemic strokes. More than 90% of these embolic strokes are from clots originating in the left atrial appendage (LAA).4–7 Cardioembolic strokes are more frequently associated with persistent and severe disabilities compared to ischemic events attributable to vascular disease.8–10 The associated mortality is 38% within 12 months, and the 12-month recurrence rate is 17%.11 The socioeconomic dimension of this disease is therefore relevant.
The risk of left atrial thrombi to embolize is dependent on left atrial size, sludge formation in the left atrial cavity, blood flow velocity in the left atrial appendage, patients’ age, risk factor profile, and other factors.12–14 However, the main risk of an embolic event in patients with AF is the lack of adequate oral anticoagulation, which is the current therapeutic gold standard. On the one hand, it is very effective and reduces the stroke risk by 60–70%,15,16 but aspirin is also effective.9,16 On the other hand, for sufficient warfarin or dicoumarol therapy, the international normalized ratio (INR) must be continuously monitored due to their narrow therapeutic range. This requires frequent venipuncture and increases costs and patient discomfort. Oral anticoagulants interact with food, drugs and patients’ individual lifestyle, and insufficient anticoagulation management may lead to life-threatening adverse events.17 Therefore, in a substantial number of patients, oral anticoagulation cannot be established or must be interrupted due to contraindications.
The alternative is to exclude the LAA cavity from circulation. A surgical approach was used with favorable results in a patient who underwent mitral valve surgery.1,18 Today, atrial appendectomy is recommended by the current guidelines for management of patients with valvular heart disease.19 Moreover, thoracoscopic exclusion of the LAA is also feasible and effective, but has the risk of incomplete occlusion with persistent in- and outflow of blood.20 The third possibility is to occlude the LAA utilizing a percutaneous catheter-based procedure.21 Up to now, three systems have proven feasibility: the PLAATO device was the first to be successfully deployed in humans,22 but was withdrawn from the market by the manufacturer in 2006. Preliminary data with the Watchman® system (Atritech, Inc., Plymouth, Minnesota) suggest that LAA occlusion is safe and feasible.23 The ongoing randomized study is comparing oral anticoagulation with percutaneous closure.24 The Amplatzer® double-disk system (AGA Medical Corp., Plymouth, Minnesota) was designed for closure of atrial septal defects and patent foramen ovale, but can also be used for LAA closure. It led to device embolization in 1 out of 16 patients during a feasibility study.25
The present work is a single-center prospective registry designed to prove the safety and efficacy of the PLAATO device during a 2-year follow-up period in patients AF who experienced a thromboembolic stroke despite oral anticoagulation or had contraindications to oral anticoagulation, respectively.
Patients and Methods
All consecutive patients who underwent a PLAATO device implantation in the Department for Cardiology/Angiology, Hoyerswerda Hospital, Hoyerswerda, Saxony, Germany, were included in this single-center, prospective registry. The clinical follow-up period was 2 years. The indication was restricted to patients with permanent or paroxysmal AF who either experienced a thromboembolic stroke despite sufficient oral anticoagulation with dicoumarol, or had contraindications to oral anticoagulation. Congenital heart disease or a persistent foramen ovale, particularly if combined with an atrial septal aneurysm, respectively, were contraindications for percutaneous LAA occlusion. All patients signed written informed consent. Patient data concerning medical history with concomitant diseases and current medication, heart failure assessment according to New York Heart Association (NYHA) classification and the CHADS2 stroke risk index,26 as well as findings of physical examination, laboratory testing, transthoracic and transesophageal echocardiography (TEE) and coronary angiography were recorded in a registry case report form. In cases of thrombus detection within the left atrial cavity or LAA by TEE, the procedure was postponed and the patient received weight-adjusted low-molecular-weight heparin subcutaneously for 10 days until TEE was repeated.
Implantation of the PLAATO device. The PLAATO system (ev3, Inc., Roissy, France) consists of an implant and a delivery catheter. The implant is a self-expanding nitinol cage covered with an occlusive expanded polytetrafluoroethylene membrane. The expanded membrane has intimate contact with the inner wall of the appendage to achieve complete closure of the ostium. The diameter of the nitinol cage ranges from 15–32 mm. Small hooklets along the struts and passing through the membrane assist with device anchoring. The device is delivered through a custom 12 Fr transseptal sheath curved to point at the left atrial appendage.
Details of the recommended standard procedure of PLAATO device implantation under fluoroscopic and TEE guidance are described elsewhere.22 At the beginning of the procedure, the left atrium and the LAA were again searched for thrombus formation. Prior to the release of the device, five recommended “CLASS” criteria to determine proper positioning of the implant were strictly checked in all patients. The “CLASS” criteria are: residual compression, implant location, anchor engagement, seal quality and stability. After successful implantation, all patients received 100 mg daily of aspirin sine die, and clopidogrel 75 mg daily for 6 months.
Follow up. A clinical evaluation including TEE was performed 3–6 months after LAA occlusion. Major cerebral or cardiac adverse events (any hospital admission due to cerebrovascular or cardiovascular symptoms like transient or permanent neurological deficits, syncope, thromboembolic events or vascular symptoms of unknown reason) were assessed and documented. The TEE examination looked for device dislocation, thrombus deposition, particularly on the atrial cavity-sided surface of the device, and for remaining shunt flow at the transseptal access site. Twenty-four months after LAA occlusion, the patients were questioned about possible “major adverse cerebro- and cardiovascular events,” most of them via telephone.
The determination of stroke risk was performed according the CHADS2 index.26 CHADS2 is an acronym derived from the individual stroke risk factors including congestive heart failure (ejection fraction 75 years, diabetes mellitus and prior major or minor stroke. Each stroke risk factor is scored 1 point except prior major or minor stroke, which is scored 2 points. The estimated stroke incidence in patients with AF without oral anticoagulation according to the CHADS2 score was compared with the actual number of strokes in the study population during a 24-month follow-up period.
Results
A total of 73 patients underwent the PLAATO device implantation procedure. The implantation was technically feasible in all patients. The mean age of the patients was 72.7 ± 9.7 years, 37 were male and 36 female. Sixty-five patients suffered from permanent AF, and 8 from paroxysmal AF. The indications for LAA occlusion are provided in Table 1. The baseline patient characteristics are shown in Table 2. The baseline TEE revealed LAA thrombus in 6 patients. The procedure was postponed for 10 days and the patients received weight-adjusted low-molecular-weight heparin therapy until a second-look TEE excluded persistent thrombus formation.
PLAATO implantation procedure. The mean echocardiographic and angiographic LAA sizes as measured by TEE or angiography were: diameter of LAA orifice 20.1 ± 5.4 mm and 19.9 ± 5.4 mm, LAA length 33.0 ± 9.5 mm and 31.4 ± 9.6 mm, respectively. In 9 patients the implant was removed after a first attempt and exchanged for a different size. The finally implanted device sizes are given in Table 3. The mean procedure time was 57.7 ± 18.4 minutes, and the mean fluoroscopic time was 10.9 ± 5.2 minutes. One patient died from sudden cardiac death 30 minutes after the end of the procedure due to PLAATO device (size: 32 mm) embolism, resulting in an acute occlusion of the left ventricular outflow tract; resuscitation measures were unsuccessful (Figure 1). In 1 patient the implant was washed around with contrast medium in angiography indicating device instability. To avoid a device embolization it was explanted by open-heart surgery on the catheterization table. One patient experienced a procedure-related small pericardial effusion due to LAA tip perforation, however pericardial puncture was not necessary afterward. One patient experienced a minor stroke, which completely resolved within 24 hours with heparin therapy.
Follow-up. Because 1 patient died shortly after the implantation procedure and 1 patient underwent surgical removal of the PLAATO implant, the long-term follow-up data included 71 patients. All 71 patients underwent 3–6 months of post-procedural clinical control. Twenty-four month follow-up information was available for all 71 patients.
A control investigation with TEE was performed in 52 patients, but was not technically possible for 1 patient, and the remaining 18 patients refused to undergo TEE. In all 52 patients for whom a TEE study was available, a stable anchoring of the implant in LAA was observed. The comparison with prior individual TEE findings directly after LAA occlusion of every patient revealed no dislocation or migration of the device. Furthermore, none of the patients were found to have thrombotic depositions on the left atrial-sided surface of the occluding device. Localized minor gaps with color-Doppler signals indicating blood flow between the membrane of the nitinol cage and LAA wall were demonstrated in 12 patients. The size of the gaps was smaller than 10% of the LAA orifice. No atrial septal shunt flow could be demonstrated at the transseptal access site by TEE color-Doppler examination.
Incidence of stroke and death. The mean stroke risk prior to LAA occlusion on the basis of individual risk factors profile was 2.52 ± 1.4 (CHADS2 score), which would have resulted in a calculated annual stroke rate of 5%. Considering a constant lack of anticoagulation, a stroke could have been expected in 7 patients during the 24 months of follow-up. Indeed, after LAA occlusion, none of our patient showed evidence of a stroke.
During the 24-month follow-up period, 10 out of 71 patients died (annual mortality rate of 7.0%). Six patients died in our hospital due to: lung cancer (1); colon cancer (1); stomach perforation (1); acute right-heart failure due to pulmonary embolism (1); and cardiac arrest (2) (known dilated cardiomyopathy or nonobstructive hypertrophic cardiomyopathy, respectively, both with implanted internal defibrillators). Four patients died a natural death at home (according to the family practitioners’ death certificate). Three patients suffered from angiographically proven coronary artery disease, 2 of whom had a history of coronary artery bypass graft surgery.
Discussion
AF has numerous potential complications, of which stroke is the most serious and life-threatening. The risk for cardioembolic events leading to stroke is 4.5% annually.4,8 The Stroke Prevention in Atrial Fibrillation Studies have documented the benefits of continuous anticoagulation therapy in reducing the risk of stroke by about 70%; however, problems associated with the long-term use of warfarin are well established.27 Restrictions in everyday life, pharmacological interactions and the potential risk of major hemorrhage are considerable limitations of this treatment method.27 These concerns lead to an extensive anticoagulation underuse in general clinical practice.28
Because more than 90% of embolizing thrombi come from the LAA,4–7 occlusion of the appendage was introduced as a surgical approach1,5 to exclude it from the circulation, thus preventing thrombus formation and subsequent embolism. The PLAATO system allows percutaneous transcatheter occlusion of the LAA via a transseptal approach. This method of mechanical occlusion of the LAA may be an attractive alternative to long-term treatment with a vitamin K antagonist, especially in patients with contraindications to anticoagulation or a history of poor compliance. In a multicenter feasibility study a relative stroke risk reduction of 65% was achieved.29
We were able to successfully occlude the LAA using the PLAATO system in 98% of our patients suffering from permanent and paroxysmal AF. During the 24-month follow-up period, our patients showed no clinical or echocardiographic signs of migration or dislocation, nor of thrombotic deposition on the left atrial-sided surface of the device. Furthermore, no strokes occurred among our study population, unlike the expected incidence of 7 strokes in a 24-month period. This result confirms the marked reduction of thromboembolic stroke risk in the aforementioned study.29 A recently published study reported the absence of stroke in 54 patients after 9 months of LAA closure24 and may further underscore the proof of concept.
Although the PLAATO device was safely implanted in the majority of our patients, we experienced 3 major clinical events (4.1%): 1 death due to implant embolism, 1 open-heart surgery due to implant instability and 1 minor stroke, which completely resolved with heparin therapy. Unfortunately, the fatality was due to an acute left ventricular outflow tract occlusion caused by a 32 mm-sized implant.
Embolization or instability of the implant is the most severe periprocedural complication leading to emergency cardiac surgery or death. Although this occurred with the PLAATO system,30 there have been no other published reports of such an incident with the PLAATO system. Like others, we experienced 1 case of pericardial effusion, but without cardiac tamponade.29 Both the Amplatzer and the Watchman devices have been reported to cause embolic complications.24,25,31
Moreover, serious concerns about LAA closure have been raised in the past. Available data, mainly from animal studies, indicate that the elimination of the LAA may impede thirst in the case of hypovolemia, impair the hemodynamic response to volume or pressure overload, decrease cardiac output, and may promote heart failure.32,33 We neither observed cases of beginning heart failure, nor worsening of preexisting heart failure after LAA closure. Nevertheless, long-term adverse developments after surgical or percutaneous closure of the LAA remain to be seen.
Very recently, the results of the Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) study were presented,23 showing that in AF patients who were candidates for warfarin therapy, device closure of a LAA using the Watchman device was associated with a reduction in hemorrhagic stroke risk compared to warfarin therapy. All-cause stroke and all-cause mortality outcomes were noninferior to warfarin. In the study, 800 patients from 59 enrolling centers in the U.S. and Europe were randomized in a device-to-control ratio of 2:1. Notably, the risk of ischemic stroke was significantly higher in the device arm than in the control arm, but there was a higher rate of hemorrhagic stroke in the warfarin control arm. One of the major drawbacks of this study is that patients were included who were at low risk for stroke. Roughly one-third of patients had a CHADS2 score of 1, while 67% had a score of 1 or 2. The American College of Cardiology/American Heart Association recommendations state that patients with a CHADS2 score of 1 can be treated with aspirin rather than warfarin.19
More recently, and on the basis of the PROTECT-AF results, a U.S. Food and Drug Administration Circulatory System Devices Advisory Panel voted to recommend premarket approval of the PLAATO system.34 The recommendation came with requirements that implantation be performed at centers with surgical backup and that a physician certification program be created. This must be underscored with respect to our complication experience with the PLAATO system. The panel also recommended the creation of a registry and extended follow up of current clinical trials. Furthermore, the labeling should describe that there are alternatives to device or warfarin treatment in patients with a CHADS2 score of 1.
Study limitations. Although this is a prospective registry study, it is likely to suffer from the inherent limitations of observational studies on nonrandomized patient groups. Furthermore, the study population consisted of strictly selected patients who experienced a thromboembolic stroke despite anticoagulation or who had a contraindication to anticoagulation. Currently, the PLAATO device is not available because the project was stopped by the manufacturer for economic reasons.
Conclusions
In the vast majority of AF patients (97%), the LAA was stably occluded using the PLAATO implant. After successful mechanical LAA occlusion, the 2-years risk of stroke in AF patients is markedly reduced. However, it must be clearly stated that LAA occlusion is not a preventive strategy for all cardioembolic events and that LAA occlusion at present cannot be recommended as an alternative to anticoagulation. Pending the results of further prospective studies, it may become an alternative for AF patients who are at increased risk for stroke and who have a contraindication for long-term anticoagulation treatment.
_________________________
From Hoyerswerda Hospital, 1st Medical Department, Cardiology, Angiology, Nephrology, Academic Teaching Hospital of the Technical University of Dresden, Hoyerswerda, Germany, and the *Berlin-Brandenburg Center for Regenerative Therapy, Charité, Campus Virchow-Klinikum, Berlin, Germany.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 9, 2009, provisional acceptance given May 4, 2009, final version accepted May 18, 2009.
Address for correspondence: Jai-Wun Park, MD, PhD, Department of Cardiology/Angiology, Asklepios Clinic Harburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany. E-mail: jai-wunpark@t-online.de
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34. Available at http://www.fda.gov/cdrh/panel/summary/circ-042309.html
