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Percutaneous Left Atrial Appendage Exclusion Therapy: Who, Why and How?


Percutaneous Left Atrial Appendage Occlusion Therapy: Who, Why and How?
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Credits:Sven Mobius-Winkler, M.D1, Ingo Dähnert3 , Gerhard C. Schuler M.D1 and Peter B. Sick M.D2
1Universität Leipzig, Herzzentrum GmbH, Department of Internal Medicine/Cardiology, Leipzig, Germany
2Krankenhaus Barmherzige Brüder Regensburg, Department of Internal Medicine III/Cardiology, Regensburg, Germany
3Universität Leipzig, Herzzentrum GmbH, Department of Pediatric Cardiology, Leipzig, Germany

Address for correspondence: Sven Moebius-Winkler M.D., Klinik für Innere Medizin/Kardiologie, Universität Leipzig – Herzzentrum GmbH, Strümpellstr.39, 04289 Leipzig, Germany.

Abstract

The diagnosis of atrial fibrillation (AF) significantly increases the risk of having cardio embolic events. Cerebrovascular events are still a leading cause of death and disability worldwide. Current guidelines recommend an antithrombotic regimen to prevent thromboembolism in medium and high risk patients with AF. However, a substantial number of patients are not eligible for this therapy. Therefore, an exclusion of the left atrial appendage (LAA) from circulation seems to be an alternative strategy for stroke prevention in AF. This review focuses on the different strategies for LAA exclusion with a special focus on the WATCHMAN®-device.


Two devices are currently in use for percutaneous transcatheter occlusion of the LAA: the WATCHMAN®-device and the AMPLATZER®–Cardiac plug. Only for the WATCHMAN®-device safety, feasibility and non inferiority data compared to standard therapy data are currently available.


Additionally, about 200 patients at high risk for thromboembolic stroke and contraindications for oral anticoagulation therapy received the PLAATO® –device which is currently off the market.


The WATCHMAN®-device was implanted in 800 patients that were eligible for long-term anticoagulation therapy with a moderate risk for thromboembolic stroke due to non-valvular AF.


Current evidence indicates an equivalent risk of stroke compared to oral anticoagulation with a reduced rate of bleeding complications at least for the WATCHMAN®-device. Hence, another therapeutic option now is available to prevent thrombembolic events in patients with atrial fibrillation not suitable for medical anticoagulation therapy.

Key Words : atrial fibrillation, stroke, left atrial appendage, WATCHMAN® - device, Amplatzer® septal occluder, Amplatzer® cardiac plug

Incidence and Prevalence

Stroke is a major cause of death and low quality of life worldwide. About 15-20% of ischemic strokes have a cardio embolic origin [1]. Atrial fibrillation (AF) affects 3-5% of the population older than 65 years and is the most common arrhythmia of clinical relevance. The incidence of atrial fibrillation increases with age from about 2% in patients aged 60-69 years to approximately 8% in patients older than 79 years [2]. With an aging population, the prevalence of AF is likely to increase 2.5 fold over the next 50 years [1].


Additionally, several factors have been identified as indicators for an increased risk for thromboembolic events. The CHADS2 stroke risk index was developed to estimate the stroke rate in AF patients and has become a standard tool for estimating the risk of cardioembolic events [Table 1+ 2] [3].

Table 1: CHADS2 * Risk Score
* CHADS2 is an acronym derived from the initial letter from the risk factors and the scoring 2 for prior strok or TIA.
The Score is calculated by the scores of the present risk factors.

Table 2: Classification of risk groups through the CHADS2 Score

Current international guidelines for therapy of AF recommend an antithrombotic regimen with warfarin as a class 1A indication to prevent thromboembolism in all patients with AF and a CHADS2 score of >1, except for those with contraindications [4].


Without anticoagulant therapy the risk of stroke is about 5 % per year in patients < 65 years and increases to over 8% per year in patients over 75 [5].


According to the CHADS2 Score the rates of stroke in patients without anticoagulation therapy were 1.9 per 100 patient-years for those with CHADS2 Score 0; 2.8 per 100 patient-years for those with CHADS2 Score 1; 4.0 per 100 patient-years for CHADS2 Score 2; 5.9 per 100 patient-years for CHADS2 Score 3; 8.5 per 100 patient-years for CHADS2 Score 4; 12.5 per 100 patient-years for CHADS2 Score 5 and 18.2 per 100 patient-years for those patients with CHADS2 Score 6 [6].


Data from Metaanalysis indicate that therapy with Aspirin alone reduces stroke rates by about 20% in AF patients [10].The effectiveness of an anticoagulation therapy to prevent ischemic strokes related to atrial fibrillation was demonstrated in numerous studies. One of the largest, the SPAF – I trial-demonstrated a risk reduction of about 67% with warfarin as compared to placebo [7].


Several studies addressed the effects of warfarin as compared to aspirin, clopidogrel or a combination of both. Currently, none of them were able to show a superiority of one of these alternative therapies over warfarin [7-9].


Unfortunately less than half of all patients with an indication for anticoagulation therapy receive warfarin therapy for various reasons [11, 12].


Additionally, the therapy with oral anticoagulation has a close therapeutic window with the need for a close monitoring and a potential risk of severe bleeding complications when exceeding the therapeutic range. Several pharmacological interactions as well as the influence by diet, herbal supplements or concomitant diseases have been described. The discontinuation rate for those under therapy is estimated to be 38 % per year approximately [13].


Therefore several investigations that are focused on the development of novel therapeutic tools to prevent AF related strokes were conducted. Besides new medical therapy, one development that might be promising is the percutaneous exclusion of the left atrial appendage (LAA) from circulation.

The Left Atrial Appendage as the target

In patients with atrial fibrillation lasting longer than 48h the incidence of thrombus formation is 8-15% [13]. These thrombi were predominantly revealed in the LAA (91% to 98 %) [14].


Although Virchow postulated stasis, hypercoagulation and vascular trauma as the mechanisms leading to thrombus formation, the pathophysiology of thromboembolism in atrial fibrillation remains uncertain [4].


The impaired mechanical contraction of the left atrium and especially the LAA in patients with AF leads to a reduced blood flow velocity and is supposed to result in spontaneous echo contrast, thrombus formation, and consecutive embolic events [15-20].


In addition, the morphology of the LAA might have an impact on the risk of thrombus formation. The LAA is usually a long, tubular, hooked structure with a large variability in morphology. Its size ranges from 20 to 45 mm in length and 15 to 35 mm in orifice diameter [21]  Post mortem analysis indicate a higher volume, larger orifices, and fewer branches of LAA in patients with AF as compared to those of patients with sinus rhythm [22].


Mechanical analyses suggest that the myocardium of the LAA is more distensible then the myocardium of remaining the left atrium which underlines the LAA´s a role as a “decompression“-chamber. Molecular analysis indicates the LAA as a source of production of atrial natriuretic peptide.

Excluding the LAA from circulation as an alternative therapy to warfarin for thrombus prevention

For more than 50 years physicians try to exclude the LAA from circulation in patients with AF for thromboembolie prophylaxis. Even in the pre-warfarin era (1946) the surgical amputation of the LAA was described in two patients for prevention of thromboembolic events [26].


This procedure of LAA obliteration/ amputation has initially been performed in patients undergoing mitral valve surgery or maze procedure. In this setting, the results of LAA exclusion were inconclusive. In 2003 Garcia – Fernandez and coworkers reported a series of 58 patients, in whom ligation of the LAA was performed during mitral valve surgery. In about 10% of patients an incomplete sealing of the LAA was seen in follow up-transesophageal echo studies. In these patients the risk of late embolism was significantly increased with an odds ratio of 6.7 [24].


On the other hand, a recently published prospective study by Almahameed et al. could show that also in patients after LAA exclusion during mitral valve surgery the rate of thromboembolism was 15 % in those without and 10% in patients with postoperative warfarin therapy after 3.6 years of follow up. In 61 % of these patients persistent AF or a history of AF was reported at baseline. The authors concluded that LAA exclusion does not provide optimal protection against thrombembolic events in this small patient cohort [25].


In patients undergoing other cardiac surgery than mitral valve surgery, the amount of available data is limited. The first published data are out of the Left Atrial Appendage Occlusion Study-[LAAOS] pilot trial in 77 patients undergoing coronary artery bypass surgery. In this setting occlusion of the LAA seemed not prolong overall length of procedure. Since data are limited so far, major conclusions cannot be drawn out of the results of this trial and the benefit of surgical LAA occlusion/ amputation, with respect to mortality and morbidity, remains unknown at least until this ongoing study  has enrolled the scheduled 2500 patients [26].


Considering the fact, that several studies reported an incomplete occlusion of the LAA after surgical ligation in a high percentage of patients, the need for an ongoing development of the surgical technique is given [27, 28].


Recently Salzberg and colleagues reported on a new LAA Clip [AtriCure Inc. West Chester, Ohio] that was successfully tested in animals. So far, the clip provided a total exclusion of the LAA from circulation [28]. However, also nonsurgical, interventional devices that exclude the LAA from circulation have been developed.


Three different interventional devices have been described for transcatheter LAA occlusion so far:

A)    PLAATO® System- currently no longer commercially available

B)     Amplatzer septal occluder – commercially available but not approved for this indication

C)    WATCHMAN® Device –FDA-approved

D)    Further Devices- under investigation


A) PLAATO® System

The PLAATO® System (originally produced by ev3 Inc., Plymouth, Minnesota, USA) consists of a self-expandable nitinol cage covered with a non-thrombogenic ePTFE membrane to exclude blood flow from the LAA. Different sizes (15-32mm) of the device were available and a 14 French introducer sheath was required for implantation. (Figure 4)

Figure 4: Plaato Device

Nakai et al. were the first to report on the Percutaneous LAA Transcatheter Occlusion (PLAATO®) – System. Feasibility and safety of this transseptal system was evaluated in 25 dogs [29]. The LAA could be occluded successfully in all 25 dogs safely and quickly. The sealing of the LAA seemed to be complete in all cases.


Sievert et al. published the first in man experience with the PLAATO® System. Fifteen patients with chronic atrial fibrillation and contraindication for warfarin therapy were enrolled into the study. In all patients the LAA could be occluded successfully. At 1 month follow up there were no complications or embolic events [30].


At present, more than 200 patients were treated with the PLAATO® device. 98% of patients could be successfully treated with minor complications. There was one device embolisation but 3% of patients developed pericardial effusions during/after the implantation procedure. One of these patients died due to cerebral hemorrhage after surgical pericardiocentesis [31]. After the implantation procedure all patients received 300 mg Aspirin/day and 75mg Clopidogrel up to 6 months after the implantation.


The study group analyzed a follow up of 250 patient years and documented an annual stroke rate of 3.2 % in patients having the PLAATO® device. The expected annual stroke risk according to the CHADS2 Score was 6.5% under aspirin therapy in these individuals. One percent of the PLAATO® patients developed a flat thrombus attached to the surface of the device, which resolved under therapy with aspirin, clopidogrel and low molecular weight heparin. No mobile clots, mitral valve damage or pulmonary vein obstructions were observed. Therefore, the investigators concluded that LAA occlusion with the PLAATO® device reduces the relative risk of stroke by 51% [31, 32].


Currently the device is no longer available, solely due to commercial and not to medical reasons.


B) Amplatzer® septal occluder

The first and only study of left atrial appendage occlusion with the Amplatzer® septal occluder (AGA Medical Corp. Golden Valley, MN; USA) devices was published in 2003. The ease use of percutaneous devices to occlude patent foramen ovale or atrial septal defects lead to first experimental occlusion of LAA with derived devices by Meier et al [33].


This first report included 16 patients that were treated in four centers with successful implantation in 15 patients. One acute device embolisation occurred which required surgical removement. After 4 months of follow up, there were no further complications, the devices were stable in position and the LAA was completely occluded in all cases. Furthermore, no thromboembolic complications were reported within this follow up period.


Nevertheless, there are no further data available in LAA occlusion with this particular device and large scale studies are lacking. After this first evaluation of the Amplatzer® septal occluder, the company made further development on the device and offers now the Amplatzer® cardiac plug, a system that is CE marked (Figure 5). Currently no data are available for this device.

Figure 5: Amplatzer®cardiac plug


C)WATCHMAN® Device

The Watchman ®- Left Atrial Appendage Occlusion Device (Atritech Inc., Plymouth, Minnesota, USA) is comprised of a self-expanding nitinol frame structure with fixation barbs and a permeable polyester fabric [Figure 1 and 2] that covers the left atrial facing surface of the device. Currently, the device is available in a size ranging from 21 to 33 mm. For WATCHMAN® device implantation, a transseptal access sheath (14 Fr) and a delivery catheter is necessary.

Figure 1: Watchman – Device © by Atritech

Figure 2: Schematic view of an implanted WATCHMAN Device

In a pilot trial 75 patients were included to asses safety and feasibility of the device. Patients had an average CHADS² Score of 1.8 points corresponding to a moderate risk for stroke [31]. Patients with impaired left ventricular function (< 35%), congenital heart disease, symptomatic carotid disease, prosthetic heart valves and significant neurological defects after prior stroke were excluded. The implantation procedure was performed under general anesthesia and TEE guidance.


In 66 of the 75 patients (88 %) the device could be implanted successfully [Figure 3]. Implantation failure occurred in 9 patients due to unsuitable LAA anatomy (7 patients), core wire malfunction (1 patient) and impossible transseptal crossing (1 patient).

Figure 3: : Implanted WATCHMAN Device
a) CT Scan: the device is in situ in the LAA
b) Fluoroscopy: The device was released in the LAA (arrow), the sheath is positioned in LA for fluoroscopic control (asterisk)

Complications occurred in 5 of the first 16 patients treated with the first generation of the device. There were two embolisations of the device, one delivery system failure, one surgical device explantation after incorrect positioning. One patient suffered transient air embolism.


Therefore, the device and the delivery system were modified after these first 16 patients. Fifty-three additional patients were implanted with the second-generation device and no further device embolization occurred. There was one significant pericardial effusion due to an overly vigorous tug test but no other relevant complications [34].


After a mean follow up of 24 months there were no major strokes at all. Two deaths occurred during follow up period, which were not device related. In one patient, who died 9 months after device implantation due to a Type A aortic dissection, a complete endothelialization of the device and the LAA was observed at autopsy.


These data provided considerable evidence that implantation of the re-designed device was safe and feasible.


Another randomized, prospective, multicenter study (The WATCHMAN® Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation (PROTECT AF- study), which is the first controlled trial in this field, compares Watchman device implantation with standard anticoagulation therapy. The recruitment period for this study was finished in summer 2008 [12]. The study included 800 patients at 59 centers in Europe and the United States. Patients were randomized in a 2:1 fashion for device implantation vs. medical therapy only. All patients randomized in this study were eligible for standard warfarin therapy. To demonstrate of non-inferiority of the device compared to warfarin therapy to reduce the incidence of stroke, 900 patient years of follow up were analyzed [35].


The implantation was successful in 88 % of patients. The mean follow up was 16 months. Most patients of the Watchman group were on CHADS2 Score 1, 2 or 3 (34.1%/ 33.9%/ 19%).  After 45 days of follow up 87 % of implanted patients discontinued warfarin and switched over to Clopidogrel 75 mg+ Aspirin 100-300 mg/day until 6 month of follow up, continued by Aspirin 100-300 mg alone.


Recently, the results of this trial were reported by Holmes et al. [35] After a total of 1065 patient years the non inferiority of the WATCHMAN® device compared to medical therapy with warfarin could be demonstrated in this population. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of peri-procedural complications. The primary efficacy event rate, that was defined as a composite of the occurrence of stroke (including ischemic or haemorrhagic stroke), cardiovascular or unexplained death, or systemic embolism, was 3·0 per 100 patient-years in the intervention group and 4·9 per 100 patient-years in the control group.


The safety analysis of the PROTECT-AF data showed that patients in the interventional arm had a higher risk for safety end points like device embolisation, major bleedings or pericardial effusions. Further analysis revealed that most events occurred on the day of device implantation. The most frequent safety event was pericardial effusion which occurred in 4.8% of patients. The rates of occurrence of periprocedural events declined with increasing investigator experience.


The data of these trial lead to approval of the device by FDA


D)Further devices – under investigation

An ecg guided, epicardial approach (engineered by Acess-PointTechnologies, Rogers, MN, USA) was described by Freidman and colleagues in an animal model. The authors used a percutaneous transpericardial access. After implantation of a sheath an appendage grasper was introduced under electrocardiographic control, contrast medium was injected into the pericardial space and the LAA was captured. In a second step a hollow suture was advanced over the LAA, pushed over the base of the LAA and chinched under echocardiographic control. The suture then was cutted by a specific suture cutter and all materials were withdrawn. First data of 4 animals showed a complete closure of LAA in all cases without significant trauma [36].


Another device under investigation is the Anchorage Closure Device™ (Epitek; Bloomington, MN, USA) that was developed to occlude, ligate or appose soft tissue. It is designed to enable physicians to ligate soft tissue in a minimally invasive manner, thus avoiding open surgical procedures. Until now no further data for closure of the LAA are available.

Summary and Conclusion

Patients with atrial fibrillation, especially in the older population, have an increased risk of stroke/TIA or PRIND, presumably due to stagnant blood flow within the left atrial appendage- a highly complex structure of the left atrium-, leading to subsequent thrombus formation. Till date, three therapeutic options exist to reduce thrombembolic events in those patients: The first and most popular is chronic anticoagulation therapy with warfarin, which is highly effective in preventing cardioembolic events and superior to other pharmacological approaches so far [37]. However, oral anticoagulation is associated with several problems and significant risks: In about one third of patients there is a contraindication for anticoagulation [34], the rate of discontinuation of therapy is up to 38%/year [14] and there is a narrow therapeutic window with a potential risk for severe bleeding events of about 2 % per year [39] Furthermore, less than half of all patients who are receiving anticoagulant treatment are within the therapeutic range with regard to INR [12]. Therefore, new oral medication for anticoagulation without the risks and problems of vitamin K antagonists are under way and are tested at present in phase III- studies.


The second way to prevent thromboembolism from the LAA is it´s exclusion from circulation by surgical techniques. Regardless of the technique, first established in 1946, there are rare data available with concerning the rate of successful LAA occlusion and complications. In addition, it has never been addressed that such an approach really reduces the incidence of stroke. Further large scale studies with clinical endpoints are required to underline the effectiveness of these surgical interventions. Studies, investigating new surgical occlusion devices are currently running. However, one has to keep in mind that all these approaches are only suitable for patients undergoing heart surgery for other reasons.


During the last ten years, percutaneous occlusion systems were developed in order to seal the LAA in a less traumatic way as a third way to prevent thrombembolic events in AF patients. The reported periinterventional success rates are high for all the devices. However, the number of patients treated with such devices so far is small in relation to the population receiving warfarin and long term follow up data are still lacking.


The first system developed for interventional LAA occlusion was the PLAATO®- System. The safety and feasibility of the system in humans was shown in patients with contraindication for chronic oral anticoagulation therapy. A risk reduction of about 50% for the incidence of ischemic strokes in this patient population was demonstrated after implantation of the device and chronic aspirin administration as compared with their statistically calculated risk. However, procedural complications like pericardial effusions/tamponade, device embolisation and device failure have been described in about 5% of patients.


The second system developed to occlude the LAA, is the WATCHMAN®- device. Implantation of the device was shown to be safe and feasible in a pilot trial in humans with atrial fibrillation. The patient population in this study had a lower risk for ischemic stroke with a CHADS² Score of 1.8 points as compared to 2.5 points in patients treated with the PLAATO®- device. To avoid thrombus formation on the surface of the device an oral anticoagulation for 45 days after implantation procedure and a double therapy with aspirin and clopidogrel thereafter for up to 6 months is required.


The first generation of the device had a higher complication rate (device embolisation, device failure) which was reduced after re-designing the device. Data from the Protect AF Trial-(a FDA approval trial) clearly show the non inferiority of the device implantation compared to standard warfarin therapy. After more than 1000 patient-years of follow up a strong trend in reduction of the combined primary endpoint was shown in the device group. Given the fact that most complications in this group occurred during the implantation procedure it is expected that the event free survival curves will further diverse with advantage to the device group. Complications of the warfarin group, however occured continuously during follow up. Furthermore this results show that there is a remarkable learning curve for intervenionalists indicating a reduction of complications during device implantation with more experience.


The third interventional method, implantation of an Amplatzer® septal occluder into the orifice of the LAA was shown only in a single center series with few patients. With only short term results. Furthermore the device is not approved for this indication and randomized data are lacking. Therefore the manufacturer now offers a special designed device, the Amplatzer® cardiac plug. Since this device is new, no data are available with regards to safety and feasibility (table 3).

Table 3: Comparison of the three interventional devices for LAA occlusion
* data are only available for the Amplatzer® septal occluder, not approved for LAA occlusion
** Amplatzer® cardiac plaque occluder available

Taken together, only mid term data but no long term data for percutaneous LAA occlusion devices are available so far and the question which therapeutic options do we provide patients with contraindication for warfarin therapy is still not fully addressed. Another point of discussion is the medical treatment after device implantation. Patients with contraindication to warfarin therapy often have contraindication to a combination therapy with aspirin and clopidogrel as well. The issue if it’s really necessary to enact them a combination therapy up to 6 months is not supported by data so far. The development of new oral anti-Xa –inhibitors that are under investigation and probably will be approved within a few months raises even more questions. Will an interventional device still be non inferior as compared to this class of drugs?


Today and with the current knowledge the authors would recommend the implantation of the Watchman® device only in experienced centers with strong surgical back up in patients with middle to high risk of stroke according CHADS2 Score > 1 who have an increased risk for bleeding complications under warfarin therapy. In patients with AF who refuse warfarin therapy for personal reasons, the implantation of the Watchman® device might be eligible.

Conclusion

Percutaneous LAA occlusion with the available devices is safe and feasible. At present only the Amplatzer® cardiac plug and the WATCHMAN® occluder are commercially available, both devices are CE marked but only the Watchman Device is approved by the FDA for the occlusion of the LAA in patients with AF.


The growing prevalence of AF especially in the elderly, where anticoagulation therapy carries a high risk or is contraindicated substantiates these devices as an attractive solution to prevent atrial fibrillation-related thromboembolic events.


Nevertheless, the measurable risk in implanting such new devices with an investigators learning curve at the beginning and newly developed drugs like oral Factor Xa Inhibitors like rivaroxaban (Bayer Health Care; Leverkusen Germany); DU-176 b (Daichi-Sankyo Ltd. Tokyo Japan) or Dabigatran (Boehringer Ingelheim, Ingelheim, Germany) which are currently investigated, have to be considered.


From the authors point of view it is crucial that potential patients derive their decision for either warfarin therapy of LAA occlusion from a balanced and fully informed basis.


When the decision is made, the interventional occlusion of LAA in patients with AF has to be done with strict caution and only in centers with high experience in this technique.

References

  1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370 –5. CrossRef  PubMed
  2. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM.Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).Am J Cardiol 1994;74:236–41. CrossRef  PubMed
  3. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001 Jun 13;285(22):2864-70. CrossRef  PubMed
  4. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: Circulation. 2006 Aug 15;114(7):e257-354.
  5. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–57. CrossRef  PubMed
  6. Gage BF, Waterman A, Shannon W et al. Validation of clinical classification schemes for predicting stroke. JAMA 2001; 285: 2864-2870. CrossRef  PubMed
  7. Aguilar M, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006186.
  8. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study Final Results. Circulation 1991;84:527-539.
  9. Petersen P, Boysen G, Godtfredsen J et al. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989 Jan 28;1(8631):175-9. CrossRef
  10. Aguilar M, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2006, Issue 1.
  11. Ferro D, Loffredo L. Polimeri L.Violi F.; Underuse of oral anticoagulants in patients with nonvalvular atrial fibrillation in Italy. Intern Emerg Med 2007; 2: 24-28. CrossRef  PubMed
  12. Stafford R, Singer D. Recent natonal patterns of warfarin use in atrial fibrillation; Circulation 1998; (97) 1231-1233.
  13. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart. 1999 Nov;82(5):547-54.
  14. Fountain RB, Holmes DR, Chandrasekaran K, Packer D, Asirvatham S, Van Tassel R, Turi Z.: The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation) trial. Am Heart J. 2006 May;151(5):956-61. CrossRef  PubMed
  15. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961–9.
  16. Hwang JJ, Ko FN, Li YH, Ma HM, Wu GJ, Chang H, Wang SM, Schie JT, Tseng YZ, Kuan P, et al.; Clinical implications and factors related to left atrial spontaneous echo contrast in chronic nonvalvular atrial fibrillation. Cardiology. 1994;85(2):69-75. CrossRef  PubMed
  17. 17. Pop GA, Meeder HJ, Roelandt JR, van Oudenaarden W, Bulens C, Verweij W, Gijsbers C, van Domburg R, Koudstaal PJ.Transthoracic echo/Doppler in the identification of patients with chronic non-valvular atrial fibrillation at risk for thromboembolic events. Eur Heart J 1994;15:1545–51.
  18. 18. Li YH, Lai LP, Shyu KG, Hwang JJ, Kuan P, Lien WP.:Clinical implications of left atrial appendage flow patterns in nonrheumatic atrial fibrillation. Chest. 1994 Mar;105(3):748-52. CrossRef  PubMed
  19. Mitusch R, Lange V, Stierle U, Maurer B, Sheikhzadeh A. Transesophageal echocardiographic determinants of embolism in nonrheumatic atrial fibrillation. Int J Card Imaging 1995;11:27–34. CrossRef
  20. Black IW, Chesterman CN, Hopkins AP, Lee LC, Chong BH, Walsh WF.; Hematologic correlates of left atrial spontaneous echo contrast and thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol 1993;21:451–7.
  21. Veinot JP, Harrity PJ, Gentile F, Khandheria BK, Bailey KR, Eickholt JT, Seward JB, Tajik AJ, Edwards WD. Anatomy of the Normal Left Atrial Appendage : A Quantitative Study of Age-Related Changes in 500 Autopsy Hearts: Implications for Echocardiographic Examination. Circulation. 1997 Nov 4;96(9):3112-5.
  22. Ernst G, Stöllberger C, Abzieher F, Veit-Dirscherl W, Bonner E, Bibus B, Schneider B, Slany J. Morphology of the left atrial appendage. Anat Rec 1995; 242:553-61. CrossRef  PubMed
  23. Bayard, YL Ostermayer SH, Sievert H.; Transcatheter occlusion of the left atrial appendage for stroke prevention Expert Rev.Cardiovasc.Ther 2005; 3(6): 1003-1008. CrossRef  PubMed
  24. García-Fernández MA, Pérez-David E, Quiles J, Peralta J, García-Rojas I, Bermejo J, Moreno M, Silva J.; Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Coll Cardiol. 2003 Oct 1;42(7):1253-8. CrossRef  PubMed
  25. Almahameed ST, Khan M, Zuzek RW, Juratli N, Belden WA, Asher CR, etal.Left atrial appendage exclusion and the risk of thromboembolic events following mitral valve surgery. J Cardiovasc Electrophysiol. 2007 Apr;18(4):364-6. CrossRef  PubMed
  26. Healey JS, Crystal E, Lamy A, Teoh K, Semelhago L, Hohnloser SH, Cybulsky I, Abouzahr L, Sawchuck C, Carroll S, Morillo C, Kleine P, Chu V, Lonn E, Connolly SJ. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J. 2005 Aug;150(2):288-93. CrossRef  PubMed
  27. Katz ES, Tsiamtsiouris T, Applebaum RM, Schwartzbard A, Tunick PA, Kronzon I, Applebaum RM et al. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiograhic study J Am Coll Cardiol. 2000 Aug;36(2):468-71. CrossRef  PubMed
  28. Salzberg SP, Gillinov AM, Anyanwu A, Castillo J, Filsoufi F, Adams DH.; Surgical left atrial appendage occlusion: evaluation of a novel device with magnetic resonance imaging.; Eur J Cardiothorac Surg. 2008 Oct;34(4):766-70. CrossRef  PubMed
  29. Nakai T, Lesh MD, Gerstenfeld EP, Virmani R, Jones R, Lee RJ. Percutaneous left atrial appendage occlusion (PLAATO) for preventing cardioembolism: first experience in canine model. Circulation. 2002 May 7;105(18):2217-22. CrossRef  PubMed
  30. Sievert H, Lesh MD, Trepels T, Omran H, Bartorelli A, Della Bella P, Nakai T, Reisman M, DiMario C, Block P, Kramer P, Fleschenberg D, Krumsdorf U, Scherer D. Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience. Circulation. 2002 Apr 23;105(16):1887-9. CrossRef  PubMed
  31. Ostermayer SH, Reisman M, Kramer PH, Matthews RV, Gray WA, Block PC, Omran H, Bartorelli AL, Della Bella P, Di Mario C, Pappone C, Casale PN, Moses JW, Poppas A, Williams DO, Meier B, Skanes A, Teirstein PS, Lesh MD, Nakai T, Bayard Y, Billinger K, Trepels T, Krumsdorf U, Sievert H. Percutaneous left atrial appendage transcatheter occlusion (PLAATO System) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation. J Am Coll Cardiol 2005; 46:9-14. CrossRef  PubMed
  32. El-Chami MF, Grow P, Eilen D, Lerakis S, Block PC. Clinical outcomes three years after PLAATO Implantation. Catheterization and Cardiovascular Interventions 2007; 69: 704-707. CrossRef  PubMed
  33. 33. Meier B, Palacios I, Windecker S, Rotter M, Cao QL, Keane D, Ruiz CE, Hijazi ZM.; Transcatheter left atrial appendage occlusion with Amplatzer devices to obviate anticoagulation in patients with atrial fibrillation. Catheter Cardiovasc Interv 2003; 60(3): 417-422. CrossRef  PubMed
  34. Sick PB, Schuler G, Hauptmann KE, Grube E, Yakubov S, Turi ZG, Mishkel G, Almany S, Holmes DR. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2007 Apr 3;49(13):1490-5. Epub 2007 Mar 21. CrossRef  PubMed
  35. Holmes D Reddy VY, Turi ZG et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fi brillation: a randomised non-inferiority trial. Lancet 2009; 374: 534-42. PubMed
  36. Friedman PA et al. Percutaneous epicardial left atrial appendage closure: Preliminary results of an electrogram guided approach. J Cardiovasc Electrphysiol. 20; 2009 (Aug.); 908-915. CrossRef  PubMed
  37. Stroke Prevention in Atrial Fibrillation Investigators; Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991 Aug;84(2):527-39.
  38. Onalan O, Lashevsky I, Hamad A, Crystal E Nonpharmacologic stroke prevention in atrial fibrillation. Expert Rev Cardiovasc Ther. 2005 Jul;3(4):619-33. CrossRef  PubMed
  39. Levine MN, Raskob G, Landefeld S et al Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: S 108- S 121.
  40. Onalan O, Crystal E. Left atrial appendage exclusion for stroke prevention in patients with nonrheumatic atrial fibrillation. Stroke. 2007 Feb;38(2 Suppl):624-30. CrossRef  PubMed


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