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Background
Stroke is one of the leading causes of death and disability in developed countries. Atrial fibrillation (AF), one of the most common cardiac arrhythmias, is a well-known predisposing factor for stroke, raising the risk significantly. Patients with AF have a 5-fold increased risk for stroke. Oral anti-coagulation (OAC) with warfarin is currently the most effective therapy for stroke risk reduction; however, this therapy increases the risk of bleeding and is often underutilized, contraindicated, or when administered, often subtherapeutic. It has been documented that the left atrial appendage (LAA) is the main source of left atrial thrombus, especially in nonrheumatic AF. Meta-analyses have shown that more than 90 % of atrial thrombi in patients with non-rheumatic AF originate in the LAA. Thus, LAA exclusion may reduce the risk of stroke in AF, and retrospective surgical data have demonstrated a reduced risk of embolic events if surgical LAA exclusion was also performed during mitral valve replacement. Recently, several less invasive percutaneous transcatheter techniques of LAA exclusion -- the PLAATO device, the Watchman device, and the Amplatzer Septal Occluder -- have been employed with initially encouraging results. These cardiac devices are designed to seal LAA and avoid risk of clot migration in the blood stream. There is currently an ongoing randomized trial comparing percutaneous LAA exclusion to long-term OAC. Until such data are available, however, OAC should remain the standard of care for stroke prevention in patients with AF (Onalan and Crystal, 2007; Chiam and Ruiz, 2008).
Sievert et al (2002) evaluated the feasibility and safety of implanting a novel device for percutaneous LAA transcatheter occlusion (PLAATO). Occlusion of the LAA using the PLAATO system was attempted in 15 patients with chronic AF at high-risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane. The LAA was successfully occluded in 15/15 patients (100 %). Angiography as well as trans-esophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus. The authors concluded that transcatheter closure of the LAA is feasible in humans. The PLAATO system may be appropriate for patients with AF who are not suitable candidates for anti-coagulation therapy. Moreover, they noted that further trials are needed to show the long-term safety and its effectiveness in reducing stroke.
Ostermayer et al (2005) evaluated the feasibility of percutaneous LAA occlusion using the PLAATO system. Within 2 prospective, multi-center trials, LAA occlusion was attempted in 111 patients (age of 71 +/- 9 years). All patients had a contraindication for anti-coagulation therapy and at least 1 additional risk factor for stroke. The primary end point was incidence of major adverse events (MAEs), a composite of stroke, cardiac or neurological death, myocardial infarction, and requirement for procedure-related cardiovascular surgery within the 1st month. Implantation was successful in 108 of 111 patients (97.3 %, 95 % confidence interval [CI]: 92.3 % to 99.4 %) who underwent 113 procedures. One patient (0.9 %, 95 % CI: 0.02 % to 4.9 %) experienced 2 MAEs within the first 30 days: need for cardiovascular surgery and in-hospital neurological death; 3 other patients underwent in-hospital pericardiocentesis due to a hemopericardium. Average follow-up was 9.8 months; 2 patients experienced stroke. No migration or mobile thrombus was noted on TEE at 1 and 6 months after device implantation. The authors concluded that closing the LAA using the PLAATO system is feasible and can be performed at acceptable risk. It may become an alternative in patients with AF and a contraindication for lifelong anti-coagulation treatment.
Himbert and colleagues (2006) reported the results of a series of 11 consecutive AF patients (7 men and 4 women, mean age of 72 +/- 9 years) in whom percutaneous exclusion of the LAA by the PLAATO System was employed to prevent stroke. Subjects had AF for over 3 months, were at high-risk and had contraindications to OAC. The implantation of the prosthesis was performed after treatment with aspirin and clopidogrel, under general anesthesia radioscopy and TEE guidance with success in 9 cases (1 implantation refused in the catheter laboratory and 1 failure). The only complication observed was transient ST elevation treated by emergency angioplasty. The echographical and angiographical criteria of success of LAA exclusion were fulfilled in all implanted patients. The hospital course was uncomplicated. One recurrence of stroke was observed at the 2nd month: TEE confirmed the absence of thrombosis, of migration of the prosthesis and its impermeability in all patients. After 7 +/- 5 months' follow-up, no other adverse event was observed. The authors concluded that the PLAATO system is technically feasible. Moreover, they noted that despite encouraging results, its long-term effectiveness in the prevention of thrombo-embolic complications of AF remains to be demonstrated.
The Watchman LAA occluder is a parachute-shaped device designed to mechanically block the opening between the atrial appendage and the left atrium, preventing clots formed in the LAA from entering the main atrial cavity. It is composed of a nitinol (a self-expanding metal) frame covered with a polyester mesh and comes in several sizes (i.e., 21 mm, 24 mm, 27 mm, 30 mm, and 33 mm) to accommodate differences in anatomy. The Watchman occluder is implanted within or just behind the opening of the LAA during a percutaneous transcather procedure. Once deployed, it is anchored in place by means of fixation barbs on the nitinol frame, with its convex top bowing out toward the atrial chamber. The device becomes fully endothelialized within 9 months of implantation. The Watchman LAA ocluder is implanted percutaneously using standard cardiac catheterization techniques. The device is contained within the catheter and expands when implanted in the LAA. If repositioning is necessary, the device can be pulled back into the catheter and maneuvered to the correct position. This procedure requires a minimum 24-hour hospital stay, and regular follow-up for up to 1 year after implantation (Ingenix, 2009).
Fountain et al (2006) stated that the Watchman LAA occluder device is currently being tested in a Food and Drug Administration(FDA)-approved clinical trial, the PROTECT AF trial, for patients who are diagnosed with paroxysmal, persistent, or permanent non-valvular AF (NVAF). However, rigorous screening and the study design have resulted in the exclusion of a large number of patients. These researchers assessed the potential utility of this device among those who were eligible but excluded for trial criteria and the reasons for exclusion. Screening logs from the respective sites participating in the PROTECT AF trial were collected and analyzed for potential utilization outside of a research trial. Only 31 patients were enrolled into the research trial from the screening of 1,798 patients. Information from excluded patients was examined and it was determined that 79 % of these patients would be eligible for the device outside the research trial. Twenty-one percent of patients were not able to receive the device because of long-term warfarin need, contraindications to warfarin, unsuitable anatomy as determined by echocardiography, or the inability to take short-term aspirin and clopidogrel for protocol requirements. The authors concluded that should a device like the Watchman LAA occluder be approved, approximately 79 % of all patients with AF would be eligible for device placement.
Sick et al (2007) evaluated the feasibility of implanting a device in the LAA in patients with AF to prevent thrombo-embolic stroke. The investigators explained that the Watchman LAA System is a nitinol device implanted percutaneously to seal the LAA. Patients were followed by clinical and TEE at 45 days and 6 months with annual clinical follow-up thereafter. A total of 66 patients underwent device implantation. Mean follow-up was 740 +/- 341 days. At 45 days, 93 % (54 of 58) devices showed successful sealing of LAA according to protocol. Two patients experienced device embolization, both successfully retrieved percutaneously. No embolizations occurred in 53 patients enrolled after modification of fixation barbs. There were 2 cardiac tamponades, 1 air embolism, and 1 delivery wire fracture (1st generation) with surgical explantation but no long-term sequelae for the patient. Four patients developed a flat thrombus layer on the device at 6 months that resolved with additional anti-coagulation. Two patients experienced transient ischemic attack, 1 without visible thrombus. There were 2 deaths, neither device-related. Autopsy documented a stable, fully endothelialized device 9 months after implantation. No strokes occurred during follow-up despite greater than 90 % of patients with discontinuation of anti-coagulation. The authors concluded that preliminary data suggest LAA occlusion with the Watchman System to be safe and feasible. They stated that a randomized study is ongoing comparing OAC with percutaneous closure.
In April 2009, the FDA's advisory panel on circulatory systems devices voted 7 to 5 to recommend that the FDA approve the pre-market application for the Watchman LAA embolic protection device, subject to certain conditions. It is currently awaiting final approval (Ingenix, 2009).
Maisel (2009) noted that implantation of the Watchman LAA occluder is associated with significant procedural risk. After 449 attempted implantations, the Watchman device was successfully inserted in 408 patients (90.9 %). Overall, 12.3 % of patients had serious procedural complications, including peri-cardial effusion requiring drainage or surgery in about 5 % as well as acute ischemic stroke due to air or thrombo-emboli in 1.1 %. Four patients had to have the device removed because of device embolization or post-implantation sepsis. In total, 2.2 % of attempted implantations resulted in cardiovascular surgical intervention because of device-related complications. In addition, the substantial learning curve associated with device implantation (the rate of serious peri-cardial effusion was 50 % higher at less-experienced centers) has important implications for provider training. Also, although discontinuing warfarin therapy is appealing to many patients with AF, anyone who has a Watchman occluder must receive ongoing anti-coagulation therapy, anti-platelet therapy, or both. Studies in animals in which anti-platelet therapy was withheld showed acute thrombus formation on the device surface; the use of aspirin and clopidogrel in subsequent studies reduced the quantity of thrombus.
Maisel (2009) stated that routine implantation does not appear to be warranted, though the device is promising and may be a reasonable option for selected patients with a particularly high-risk of bleeding complications. Nevertheless, the lessons learned from the well-publicized recent problems with other cardiovascular devices (e.g., drug-eluting stents and implantable defibrillator leads) should be heeded. In those cases, large numbers of patients were rapidly exposed to a new device on which there were limited performance data. The concerns about procedural safety and the need for long-term follow-up should be addressed before the Watchman device is deployed widely.
It is interesting to note that Dr. Maisel was acting chair of the FDA's circulatory system medical device advisory panel, which reviewed data related to the Watchman LAA device and voted 7 to 5 in favor of approval with conditions. As acting panel chair, Dr. Maisel did not vote at the meeting.
The Amplatzer PFO (patent foramen ovale) Occluder is a mesh-covered, nitinol pair of disks containing a radiopaque marker implanted percutaneously. It is FDA-approved for repairing defects in the atrial septum. In limited cases, the Amplatzer has also been used to occlude the LAA, however it is not approved by the FDA for this purpose (Ingenix, 2009).
Cruz-Gonzalez et al (2009) stated that although the Amplatzer septal occluder device was not originally intended to occlude the LAA, it has been used with success in the authors' institution for this purpose. They presented an illustrative case of a patient with AF no longer suitable for chronic OCA referred for percutaneous exclusion of the LAA. She was treated successfully with an Amplatzer septal occluder. Although the authors' experience with this device holds promise, future trials are needed to explore this strategy.
Syed and Halperin (2007) stated that percutaneous LAA occlusion devices have shown some initial successes, but additional safety and effectivenesd data are required before this approach can be routinely considered. Lerakis and Synetos (2008) stated that the PLAATO System and the Watchman LAA system are currently the 2 devices specifically designed for LAA occlusion. Although available data are still limited, LAA occlusion is technically feasible, with good intermediate results, but its long-term safety and ability to reduce stroke incidence remains unproven. They stated that randomized studies will clarify the usefulness of LAA occlusion devices as an alternative treatment strategy to long-term anti-coagulation.
Mobius-Winkler et al (2008) reviewed the different devices for stroke prevention in patients with AF. Recently, 2 devices developed for percutaneous transcatheter occlusion of the LAA have been studied: (i) the PLAATO device, and (ii) the Watchman device. Safety and feasibility data are available for both devices. About 200 patients have received a PLAATO device. These patients were at high-risk for thrombo-embolic stroke and were not candidates for OAC therapy. The Watchman device was implanted in 75 patients who were eligible for long-term anti-coagulation therapy with a moderate-risk for thrombo-embolic stroke due to NVAF. The authors concluded that for both devices, a reduction in the risk of stroke was documented, and device implantation was shown to be safe and feasible. Provided the ongoing trials show non-inferiority to OAC, another therapeutic option will become available to prevent ischemic strokes. In addition, Franke and colleagues (2009) stated that techniques to prevent cardio-embolic stroke by percutaneous occlusion of the LAA in patients with AF are emerging.
The American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines' report on the management of patients with AF (2006), as well as the Institute for Clinical Systems Improvement's guideline on AF (2007) did not mention the use of occluder devices to prevent thrombo-embolic stroke in the LAA of patients with AF.
Guidance from the National Institute for Health and Clinical Excellence (NICE, 2006) concluded: "Current evidence on the safety and efficacy of percutaneous occlusion of the left atrial appendage (LAA) for atrial fibrillation does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research."
Furthermore, the Australian Safety and Efficacy Registrar of New Interventional Procedures - Surgical assessment on percutaneous LAA transcatheter occlusion (PLAATO) system (Lee, 2007) noted that despite promising results, no randomized controlled trials have been conducted at the time of writing and the long-term effectiveness of the PLAATO system remains unknown. Due to the limited evidence available, the Australian agency recommended the monitoring of this technoloby.
Holmes et al (2009) evaluated the safety and effectiveness of percutaneous closure of the LAA for prevention of stroke compared with warfarin treatment in patients with AF. Adult patients with NVAF were eligible for inclusion in this multi-center, randomized non-inferiority trial if they had at least 1 of the following: previous stroke or transient ischemic attack, congestive heart failure, diabetes, hypertension, or were 75 years or older. A total of 707 eligible patients were randomly assigned in a 2:1 ratio by computer-generated randomization sequence to percutaneous closure of the LAA and subsequent discontinuation of warfarin (intervention; n = 463) or to warfarin treatment with a target international normalized ratio between 2.0 and 3.0 (control; n = 244). Effectiveness was assessed by a primary composite endpoint of stroke, cardiovascular death, and systemic embolism. These investigators selected a 1-sided probability criterion of non-inferiority for the intervention of at least 97.5 %, by use of a 2-fold non-inferiority margin. Serious adverse events that constituted the primary endpoint for safety included major bleeding, peri-cardial effusion, and device embolization. Analysis was by intention-to-treat. At 1,065 patient-years of follow-up, the primary efficacy event rate was 3.0 per 100 patient-years (95 % credible interval [CrI]: 1.9 to 4.5) in the intervention group and 4.9 per 100 patient-years (2.8 to 7.1) in the control group (rate ratio [RR] 0.62, 95 % CrI: 0.35 to 1.25). The probability of non-inferiority of the intervention was more than 99.9 %. Primary safety events were more frequent in the intervention group than in the control group (7.4 per 100 patient-years, 95 % CrI: 5.5 to 9.7, versus 4.4 per 100 patient-years, 95 % CrI: 2.5 to 6.7; RR 1.69, 1.01 to 3.19). The authors concluded that the effectiveness of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. 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. They noted that closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with NVAF.
In a commentary on the afore-mentioned study by Holmes et al, Sobieraj-Teague and Eikelboom (2009) stated that major safety concerns need to be overcome and efficacy needs to be better established before the device can be considered as an alternative to warfarin anti-coagulation in patients with AF. Furthermore, Whitlock et al (2009) noted that although recent results with the percutaneous closure device are promising, the evidence of efficacy and safety is insufficient to recommend this approach for any patients other than those in whom long-term warfarin is absolutely contraindicated. They stated that more large randomized controlled trials of the device and surgical approaches should be done. At present, anti-thrombotic medications will remain the standard treatments to prevent stroke in patients with AF.
Dawson et al (2010) examined if patients undergoing cardiac surgery with AF should have LAA exclusion? Altogether 310 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. These investigators concluded that despite finding 5 clinical trials including 1 randomized controlled trial, that studied around 1,400 patients who underwent LAA occlusion, the results of these studies do not clearly show a benefit for appendage occlusion. Indeed of the 5 studies, only 1 showed a statistical benefit for LAA occlusion, with 3 giving neutral results, and in fact 1 study demonstrating a significantly increased risk. One reason for this may be the inability to achieve acceptably high rates of successful occlusion on echocardiography when attempting to perform this procedure. The highest success rate was only 93 % but most studies reported only a 55 to 66 % successful occlusion rate when attempting closure in a variety of methods including stapling, ligation and amputation. Currently, the evidence is insufficient to support LAA occlusion and may indeed cause harm especially if incomplete exclusion occurs.
The American College of Cardiology Foundation Task Force on expert consensus document on cardiovascular magnetic resonance (Hundley et al, 2010) stated that standardization of protocols and further studies are needed to determine if cardiovascular magnetic resonance provides a reliable effective method for detecting thrombi in LAA in patients with AF.
Bartus et al (2011) examined the feasibility of a closed-chest surgical suture ligation of the LAA in man. A total of 13 patients undergoing either mitral valve surgery (n = 2) or electrophysiological study and radiofrequency catheter ablation for AF (n = 11) underwent ligation of the LAA with the Lariat snare device. In patients having an ablation procedure, peri-cardial access was obtained prior to the patients undergoing radiofrequency catheter ablation. After trans-septal catheterization, endocardial and epicaridal magnet-tipped guide wires were positioned under fluoroscopic guidance to stabilize the LAA. Trans-esophageal echocardiography was used as guidance for positioning a marker balloon at the ostium of the LAA. An over-the-wire approach was used to guide the Lariat snare device over the LAA to allow closure and suture ligation of the LAA. Contrast fluoroscopy and TEE were used to confirm acute closure of the LAA. Both mitral valve replacement (MVR) patients had complete closure of the LAA determined by visual inspection; 10 of 11 patients having ablation underwent a successful closed-chest LAA ligation procedure with TEE and contrast fluoroscopy verification of closure of the LAA. Only 1 of 11 procedures was terminated owing to the lack of echocardiography guidance of the snare over the marker balloon. One patient with pectus excavatum did have ligation of his LAA; however, a thorascopic procedure was required to remove the snare from the LAA owing to compression of the Lariat by the concave sternum. There were no other significant complications. The authors concluded that catheter-based surgical suture ligation of the LAA is feasible in humans. They noted that this novel catheter approach may be appropriate for patients with AF who are ineligible for anti-coagulation therapy. Moreover, they stated that further investigation is needed to demonstrate the long-term safety and effectiveness of LAA closure.
Ailawadi et al (2011) reported the initial results of a multi-center FDA trial to assess the safety and effectiveness of a novel LAA exclusion clip (the AtriClip, Atricure Inc, Westchester, OH). Patients undergoing elective cardiac surgery via median sternotomy with AF or a congestive heart failure, hypertension, age greater than 75 Years, diabetes mellitus, stroke score greater than 2 were eligible for concomitant AtriClip device insertion. Device insertion (35, 40, 45, and 50 mm) was performed at any point after sternotomy on or off cardio-pulmonary bypass. Safety was assessed at 30 days, and effectiveness of LAA exclusion was assessed at operation (by TEE) and 3-month follow-up (by computed tomography angiography or TEE). A total of 71 patients (mean age of 73 years) undergoing open cardiac surgery at 7 U.S. centers were enrolled in the study. The LAA in 1 patient was too small and did not meet eligibility criteria; the remaining 70 patients had successful placement of an AtriClip device. Intra-procedural successful LAA exclusion was confirmed in 67 of 70 patients (95.7 %). Although significant adverse events occurred in 34 of 70 patients (48.6 %), there were no adverse events related to the device and no peri-operative mortality. At 3-month follow-up, 1 patient died and 65 of 70 patients (92.9 %) were available for assessment. Of the patients who underwent imaging, 60 of 61 patients (98.4 %) had successful LAA exclusion by computed tomography angiography or TEE imaging. The authors concluded that in this small study, safe and atraumatic exclusion of the LAA can be performed during open cardiac surgery with the AtriClip device with greater than 95 % success and appears to be durable in the short-term by imaging. Moreover, they stated that long-term studies are needed to evaluate the effectiveness of the AtriClip in the prevention of stroke.
Montenegro et al (2012) determined the feasibility of percutaneous occlusion of the LAA in patients at high-risk of embolic events and limitations to the use of anti-coagulation. These investigators reported their initial experience with the Amplatzer Cardiac Plug (St. Jude Medical Inc., Saint Paul, Estados Unidos) in patients with NVAF. They selected patients at high-risk of thrombo-embolism, major bleeding, contraindications to the use or major instability in response to the anti-coagulant. The procedures were performed percutaneously under general anesthesia and TEE. The primary outcome was the presence of peri-procedural complications and follow-up program included clinical and echocardiographic review within 30 days and by telephone contact after 9 months. In 5 selected patients it was possible to occlude the LAA without peri-procedural complications. There were no clinical events in follow-up. The authors concluded that controlled clinical trials are needed before percutaneous closure of the LAA should be considered an alternative to anti-coagulation in NVAF. But the device has shown to be promising in patients at high-risk of embolism and restrictions on the use of anti-coagulants. This is in agreement with the observations of Weglarz et al (2012) who stated that percutaneous closure of the LAA seems to be a promising tool to prevent AF-related strokes in a selected group of patients.
Lam and colleagues (2012) reported the initial safety, feasibility, and 1-year clinical outcomes following AMPLATZER cardiac plug (ACP) implantation. A total of 20 NVAF patients (16 males, age 68 +/- 9 years) with high-risk for developing cardio-embolic stroke (CHADS(2) score: 2.3 +/- 1.3) and contraindications to warfarin received ACP implants from June 2009 to May 2010. Patients received general anesthesia (n = 9) or controlled propofol sedation (n = 11) and the procedures were guided by fluoroscopy and TEE. Clinical follow-up was arranged at 1 month and then every 3 months after implantation, whereas, a TEE was scheduled at 1 month upon completion of dual anti-platelet therapy. The LAA was successfully occluded in 19/20 patients (95 %). One procedure was abandoned because of catheter-related thrombus formation. Other complications included coronary artery air embolism (n = 1) and TEE-attributed esophageal injury (n = 1). The median procedural and fluoroscopic times were 79 (IQR: 59 to 100) and 18 (IQR 12 to 27) minutes, respectively. The mean size of implant was 23.6 +/- 3.1 mm. The average hospital stay was 1.8 +/- 1.1 days. Follow-up TEE showed all the LAA orifices were sealed without device-related thrombus formation. No stroke or death occurred at a mean follow-up of 12.7 +/- 3.1 months. The authors concluded that these preliminary findings suggested LAA closure with ACP is safe, feasible with encouraging 1-year clinical outcomes. They stated that further large-scaled trials are needed to confirm the effectiveness of this device.
Aryana et al (2012) stated that evidence suggests that at least 90 % of left atrial thrombi discovered in patients with AF are localized to the LAA. Surgical ligation or excision of the LAA is considered the standard of care in patients who undergo mitral valve surgery or as an adjunct to a surgical Maze procedure for treatment of AF. In addition, in selected patients with AF and an elevated risk of thrombo-embolic events, particularly in those with contraindication to OAC therapy, it is reasonable to consider LAA exclusion to offer protection against ischemic stroke and other embolic complications. This can be achieved through a number of different strategies, including surgical amputation or ligation of the LAA, percutaneous endocardial occlusion of the LAA by deployment of occlusive devices, and also ligation of the LAA via a closed-chest, percutaneous, epicardial catheter-based approach in select patients. Although results from several recent percutaneous LAA closure and ligation studies are highly promising, the evidence for long-term safety and effectiveness is insufficient to presently recommend this approach to all patients other than those in whom long-term OAC is contraindicated. The authors concluded that future randomized studies are needed to further address the long-term safety and effectiveness of these therapeutic options.
In summary, there is currently insufficient evidence to support the use of cardiac devices for occlusion of the LAA.
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