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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.
Bai et al (2012) stated that transcatheter LAA closure with the Watchman device has become one of the therapeutic options in AF patients who are at high risk for ischemic stroke. However, the incidence and evolution of incomplete occlusion of the LAA during and after placement of the Watchman device has not been reported. A total of 58 consecutive patients who had undergone Watchman device implant were included in the study. Intra-procedural, 45-day and 12-month TEE images were reviewed and analyzed. Peri-device gap was noted in 16 (27.6 %), 17 (29.3 %), and 20 (34.5 %) patients across the 3 time points. Intra-procedural gaps are more likely to be persistent until 12 months and become larger in size over time. New gap also occurs during follow-up even if the LAA was completely sealed at implantation. One patient had an ischemic stroke 4.7 months after implant; another patient developed a left atrial thrombus over the device 21.6 months after implant. Both patients had intra-procedural gap and discontinued warfarin therapy after the 45-day evaluation. The authors concluded that incomplete LAA occlusion with a gap between the Watchman device surface and the LAA wall is relatively common. Intra-procedural gaps are more likely to become bigger over time and persist, while new gaps also occur during follow-up. They stated that further studies are needed to verify if the presence and persistence of a peri-device gap is associated with increased risk of thrombo-embolic event in AF patients implanted with a Watchman device.
Alli et al (2013) evaluated quality-of-life (QOL) parameters in a subset of patients enrolled in the PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial. Quality-of-life using the Short-Form 12 Health Survey, version 2, measurement tool was obtained at baseline and 12 months in a subset of 547 patients in the PROTECT AF trial (361 device and 186 warfarin patients). The analysis cohort consisted of patients for whom either paired QOL data were available after 12 months of follow-up or for patients who died. With the device (the Watchman), the total physical score improved in 34.9 % and was unchanged in 29.9 % versus warfarin in whom 24.7 % were improved and 31.7 % were unchanged (p = 0.01). Mental health improvement occurred in 33.0 % of the device group versus 22.6 % in the warfarin group (p = 0.06). There was a significant improvement in QOL in patients randomized to device for total physical score, physical function, and in physical role limitation compared to control. There were significant differences in the change in total physical score among warfarin naive and not-warfarin naive subgroups in the device group compared to control, but larger gains were seen with the warfarin naive subgroup with a 12-month change of 1.3 ± 8.8 versus -3.6 ± 6.7 (p = 0.0004) device compared to warfarin. The authors concluded that patients with non-valvular AF at risk for stroke treated with LAA closure have favorable QOL changes at 12 months versus patients treated with warfarin. The major drawbacks of this study were small sample size and short follow-up period.
In an observational study, Reddy et al (2013) assessed the safety and effectiveness of LAA closure in non-valvular AF patients ineligible for warfarin therapy. A multi-center, prospective, non-randomized study was conducted of LAA closure with the Watchman device in 150 patients with non-valvular AF and CHADS₂ (congestive heart failure, hypertension, age greater than or equal to 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score greater than or equal to 1, who were considered ineligible for warfarin. The primary efficacy end-point was the combined events of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular/unexplained death. The mean CHADS₂ score and CHA₂DS₂-VASc (CHADS₂ score plus 2 points for age greater than or equal to 75 years and 1 point for vascular disease, aged 65 to 74 years, or female sex) score were 2.8 ± 1.2 and 4.4 ± 1.7, respectively. History of hemorrhagic/bleeding tendencies (93 %) was the most common reason for warfarin ineligibility. Mean duration of follow-up was 14.4 ± 8.6 months. Serious procedure- or device-related safety events occurred in 8.7 % of patients (13 of 150 patients). All-cause stroke or systemic embolism occurred in 4 patients (2.3 % per year): ischemic stroke in 3 patients (1.7 % per year) and hemorrhagic stroke in 1 patient (0.6 % per year). This ischemic stroke rate was less than that expected (7.3 % per year) based on the CHADS₂ scores of the patient cohort. The authors concluded that LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation. The main drawbacks of this study were its observational nature (prone to selection bias), non-randomization design, as well as the lack of a control or alternative treatment group.
In an observational study, Bartus and colleagues (2013) stated that embolic stroke is the most devastating consequence of AF. Exclusion of the LAA is believed to decrease the risk of embolic stroke. In an observational study, these researchers determined the safety and effectiveness of LAA closure via a percutaneous LAA ligation approach. A total of 89 patients with AF were enrolled to undergo percutaneous ligation of the LAA with the Lariat device. The catheter-based Lariat device consists of a snare with a pre-tied suture that is guided epicardially over the LAA. Closure of the LAA was confirmed with TEE and contrast fluoroscopy immediately, then with TEE at 1 day, 30 days, 90 days, and 1 year post-LAA ligation. Eighty-five (96 %) of 89 patients underwent successful LAA ligation. Eighty-one of 85 patients had complete closure immediately. Three of 85 patients had a less than or equal to 2-mm residual LAA leak by TEE color Doppler evaluation. One of 85 patients had a less than or equal to 3-mm jet by TEE. There were no complications due to the device. There were 3 access-related complications (during peri-cardial access, n = 2; and trans-septal catheterization, n = 1). Adverse events included severe pericarditis post-operatively (n = 2), late peri-cardial effusion (n = 1), unexplained sudden death (n = 2), and late strokes thought to be non-embolic (n = 2). At 1 month (81 of 85) and 3 months (77 of 81) post-ligation, 95 % of the patients had complete LAA closure by TEE. Of the patients undergoing 1-year TEE (n = 65), there was 98 % complete LAA closure, including the patients with previous leaks. The authors concluded that LAA closure with the Lariat device can be performed effectively with acceptably low access complications and peri-procedural adverse events. They noted that this observational study provided evidence of the reliability of LAA exclusion with acceptable low access complications and adverse events; enabling this percutaneous LAA ligation procedure to be used in future randomized clinical trials to determine whether LAA exclusion prevents thrombo-embolic events in patients with AF. They also noted that future prospective studies will require a systematic protocol for discontinuing anti-coagulation by a pre-specified time point to accurately evaluate the long-term risk reduction for thrombo-embolic events following LAA ligation. The major drawbacks of this study included (i) this was a non-randomized, single-center trial. Much of the experience was concentrated with several operators, thus potentially skewing the efficiency of performing the procedures, (ii) the assessment of LAA closure by TEE might be over-estimated due to AF resulting in decreased inflow and outflow velocities in the LAA. This may result in the lack of detection of small communications between the LA and a sutured LAA by color flow or spectral Doppler flow assessment, and (iii) long-term results for thrombo-embolic event reduction were confounded by the high proportion (61 %) of patients on warfarin at the time of last follow-up.
Massumi et al (2013) noted that AF increases by 5-fold a patient's risk for thrombo-embolic stroke. The main source of emboli in AF is the LAA. Thus, LAA closure could reduce the risk for thrombo-embolic events in AF. These investigators reported the first U.S. experience with a novel percutaneous LAA closure device, the Lariat snare device, and its outcomes in 21 patients with AF, CHADS(2) scores greater than or equal to 2, and contraindications to anti-coagulation. The LAA was closed with a snare containing suture from within the peri-cardial space. The intra-operative success of the procedure was confirmed by left atrial angiography and TEE color Doppler flow. The effectiveness of the procedure was evaluated by follow-up TEE. The incidence of peri-procedural and short-term complications was assessed by reviewing medical records. Twenty patients (100 %) had successful LAA exclusion that was preserved at 96 ± 77 days. No patient had a stroke during an average of 352 ± 143 days of follow-up. One patient had right ventricular perforation and tamponade that required surgical exploration and repair. Two patients required prolonged hospitalization: 1 because of peri-cardial effusion that required repeat peri-cardiocentesis and 1 because of non-cardiac co-morbidities. Three patients developed pericarditis less than 1 month after the procedure, of whom 1 had associated peri-cardial effusion that required drainage. The authors concluded that percutaneous LAA exclusion can be achieved successfully and with an acceptable incidence of peri-procedural and short-term complications. Moreover, they stated that further studies are needed to determine whether LAA exclusion lowers the long-term risk for thrombo-embolic events in patients with AF and contraindications to anti-coagulation. The authors also stated that “the present case series has the inherent limitations of all such retrospective series, including potential case selection bias, incomplete data, and the absence of a control group. No conclusions can be made about the clinical or stroke prevention efficacy of this procedure compared to long-term anticoagulation or other LAA exclusion techniques. Experience with many more patients and longer follow-up are necessary to demonstrate the efficacy of this novel technique and to refine its indications and contraindications to maximize patient safety”.
Urena et al (2013) evaluated the results associated with LAA closure (LAAC) with the AMPLATZER Cardiac Plug (ACP) (St. Jude Medical, Minneapolis, MN) in patients with non-valvular AF and absolute contraindications to anti-coagulation therapy. A total of 52 patients with non-valvular AF underwent LAAC with the ACP device in 7 Canadian centers. Most patients received short-term (1 to 3 months) dual-antiplatelet therapy after the procedure and single-antiplatelet therapy thereafter. A TEE was performed in 74 % of patients at the 6-month follow-up. No patient was lost to follow-up (greater than or equal to 12 months in all patients). The mean age and median (interquartile range) CHADS2 score were 74 ± 8 years and 3 (2 to 4), respectively. The procedure was successful in 98.1 % of the patients, and the main complications were device embolization (1.9 %) and peri-cardial effusion (1.9 %), with no cases of peri-procedural stroke. At a mean follow-up of 20 ± 5 months, the rates of death, stroke, systemic embolism, peri-cardial effusion, and major bleeding were 5.8 %, 1.9 %, 0 %, 1.9 %, and 1.9 %, respectively. The presence of mild peri-device leak was observed in 16.2 % of patients at the 6-month follow-up as evaluated by TEE. There were no cases of device thrombosis. The authors concluded that in patients with non-valvular AF at high risk of cardio-embolic events and absolute contraindications to anti-coagulation, LAAC using the ACP device followed by dual-/single-antiplatelet therapy was associated with a low rate of embolic and bleeding events after a mean follow-up of 20 months. No cases of severe residual leak or device thrombosis were observed at the 6-month follow-up. Moreover, the authors stated that “these results do not provide sufficient evidence to state that LAAC without anti-coagulation provides sufficient safety to recommend this approach until adequate data from clinical trials can be obtained. Also, larger studies with a longer follow-up and a more complete echocardiographic follow-up will have to confirm these results”.
Nietlispach et al (2013) reported a 10-year single center experience with Amplatzer devices for LAA occlusion. Short- and intermediate-term outcomes of patients who underwent LAA occlusion were assessed. All procedures were performed under local anesthesia without TEE. Patients were discharged on acetylsalicylic acid and clopidogrel for 1 to 6 months. Occlusion of the LAA was attempted in 152 patients (105 males, age of 72 ± 10 years, CHA2 DS2 -Vasc-score 3.4 ± 1.7, HAS-BLED-score 2.4 ± 1.2). Non-dedicated devices were used in 32 patients (21 %, ND group) and dedicated Amplatzer Cardiac Plugs were used in 120 patients (79 %, ACP group). A patent foramen ovale or atrial septal defect was used for left atrial access and closed at the end of LAA occlusion in 40 patients. The short-term safety end-points (procedural complications, bleeds) occurred in 15 (9.8 %) and the efficacy end-points (death, stroke, systemic embolization) in 0 patients. Device embolization occurred more frequently in the ND as compared to the ACP group (5 patients or 12 % versus 2 patients or 2 %). Mean intermediate-term follow up of the study population was 32 months (range of 1 to 120). Late deaths occurred in 15 patients (5 cardiovascular, 7 non-cardiac, and 3 unexplained). Neurologic events occurred in 2, peripheral embolism in 1, and major bleeding in 4 patients. The composite safety and effectiveness end-point occurred in 7 % and 12 % of patients. The authors concluded that LAA closure may be a good alternative to oral anti-coagulation. They stated that this hypothesis needs to be tested in a randomized clinical trial to ensure that all potential biases of this observational study are accounted for.
Ohtsuka et al (2013) evaluated thoracoscopic stand-alone left atrial appendectomy for thrombo-embolism prevention in non-valvular AF. A total of 30 patients (mean age of 74 ± 5.0 years) who had had thrombo-embolisms were selected. A subgroup of 21 patients (mean age of 75 years; mean CHA2DS2 VASc score of 4.5) urgently needed an alternative treatment to anti-coagulation: warfarin was contraindicated due to hemorrhagic side effects in 13, the international normalized ratio was uncontrollable in 7, and transient ischemic attacks had developed immediately after the warfarin dose was reduced for oncological treatment in 1. The LAA was thoracoscopically excised with an endoscopic cutter. Thoracoscopic appendectomy (mean operating time of 32 mins, switched to mini-thoracotomy in 2 cases) led to no mortality and no major complications. Three-month post-operative 3-dimensional enhanced computed tomography, performed with patients' consent, confirmed the completeness of the appendectomy. Patients have been followed for 1 to 38 months (mean of 16 ± 9.7 months [18 ± 9.4 months for the subgroup]). One patient died of breast cancer 28 months after surgery. Despite discontinued anti-coagulation, no patients had experienced recurrence of thrombo-embolism. The authors concluded that thoracoscopic stand-alone appendectomy is potentially safe and may allow surgeons to achieve relatively simple, complete LAA closure. Moreover, they stated that further experience may demonstrate this technique to be a viable option for thrombo-embolism prevention in non-valvular AF. Drawbacks of this study included small sample size, short follow-up, as well as lack of randomized, controlled comparisons with other therapeutic options.
In an editorial that accompanied the afore-mention study, Turi (2013) stated that “although this approach looks potentially useful, the single site, small number of patients, limited data, and limited follow-up do not allow for any claim of safety and efficacy …. It has the appeal of simplicity and ready availability of a generally inexpensive technology, but the safety in particular needs to be established …. Until then, although long-term anticoagulation is cumbersome and has its own significant 9but well established) toxicities, for those who are appropriate candidates, it remains the best studied approach as well as standard of care”.
Don and colleagues (2013) stated that occlusion of the LAA may reduce the risk of stroke in patients with AF. Trials comparing LAA occlusion to warfarin anti-coagulation in patients with non-valvular AF showed a reduction in hemorrhagic stroke, although an increase in safety events due to procedural complications. While long-term follow-up suggested possible superiority of LAA occlusion due to fewer strokes and bleeding events, the superior dosing and safety profiles of the novel oral anti-coagulants raise the accepted threshold for safety and effectiveness of LAA occlusion procedures, and underscore the need for randomized studies comparing LAA occlusion with these newer anti-coagulants.
Emmert et al (2014) reported on the long-term safety and effectiveness data on LAA closure using a novel epicardial LAA clip device in patients undergoing cardiac surgery. A total of 40 patients with AF were enrolled in this prospective “first-in-man” trial. The inclusion criterion was elective cardiac surgery in adult patients with AF for which a concomitant ablation procedure was planned. Intra-operative TEE was used to exclude LAA thrombus at baseline and evaluated LAA perfusion after the procedure, while CT was used for serial imagery work-up at baseline, 3-, 12-, 24- and 36-month follow-up. Early mortality was 10 % due to non-device-related reasons, and thus 36 patients were included in the follow-up consisting of 1,285 patient-days and mean duration of 3.5 ± 0.5 years. On CT, clips were found to be stable, showing no secondary dislocation 36 months after surgery. No intra-cardial thrombi were seen, none of the LAA was re-perfused and with regard to LAA stump, none of the patients demonstrated a residual neck of greater than 1 cm. Apart from 1 unrelated transient ischemic attack (TIA) that occurred 2 years after surgery in a patient with carotid plaque, no other strokes and/or neurological events demonstrated in any of the studied patients during follow-up. The authors concluded that this was the first prospective trial in which concomitant epicardial LAA occlusion using this novel epicardial LAA clip device is 100 % effective, safe and durable in the long-term. Closure of the LAA by epicardial clipping is applicable to all-comers regardless of LAA morphology. The authors concluded that minimal access epicardial LAA clip closure may become an interesting therapeutic option for patients in AF who are not amenable to anti-coagulation and/or catheter closure. Moreover, they stated that further data are needed to establish LAA occlusion as a true and viable therapy for stroke prevention.
Furthermore, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) practice guideline on “Management of patients with atrial fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations)” (Anderson et al, 2013) does not mention the use of epicardial clipping of the LAA, left atrial appendectomy, and cardiac devices for occlusion of the LAA as therapeutic options.
The European Society of Cardiology’s updated guidelines on “The management of atrial fibrillation” (Camm et al, 2012) and the Agency for Healthcare Research and Quality’s comparative effectiveness review on “Treatment of atrial fibrillation” (Al-Khatib et al, 2013) did not mention LAA occlusion (LAAO) as a therapeutic option.
Freixa et al (2014) noted that the Amplatzer™ Amulet™ (Amulet) is the evolution of the Amplatzer™ Cardiac Plug, a dedicated device for percutaneous LAAO. The new device has been designed to facilitate the implantation process, improve the sealing performance and further reduce the risk of complications. In a prospective, single-center study, these investigators described the initial experience with the Amplatzer Amulet for percutaneous LAAO. The indication for LAA closure was a formal contraindication for oral anti-coagulation or previous history of stroke due to international normalized ratio (INR) lability. All procedures were done under general anesthesia and TEE guidance. Transthoracic echocardiography was performed 24 hours after the procedure in order to rule out procedural complications before discharge. Further follow-up was done with a clinical visit and TEE at 1 to 3 months. Between July 2012 and June 2013, a total of 25 patients with a mean CHA2DS2-VASC of 4.3 ± 1.7 underwent LAAO with the Amplatzer Amulet. The device was successfully implanted in 24 patients (96 %) without any procedural stroke, pericardial effusion or device embolization. None of the patients presented any clinical event at follow-up. Follow-up TEE showed complete LAA sealing in all patients with no residual leaks greater than 3 mm and no device embolization. One patient (4.1 %) presented a device thrombosis at follow-up without clinical expression. The authors concluded that in this initial series of patients, the Amulet showed a remarkable acute and short-term performance in terms of feasibility and safety as depicted by the high successful implantation rate and the low incidence of complications. Moreover, they stated that further investigation is needed to ascertain the effectiveness of the Amulet.
Hussain et al (2014) stated that AF is the most commonly encountered clinical arrhythmia, and stroke prevention remains an integral part of management of AF. Long-term therapy with oral anti-coagulants, though effective, has many limitations, and these limitations have encouraged the search for device-based alternatives. In patients with non-valvular AF, approximately 90 % of thrombi are thought to arise from the LAA. The LAA can be obliterated surgically or percutaneously, and this should reduce the incidence of systemic thrombo-embolic events in AF, ideally without the need for further anti-coagulation. These investigators examined the currently available LA O devices and the evidence behind these devices. They concluded that although additional evidence from randomized controlled trials (RCTS) is needed to fully characterize the safety and effectiveness of all of these devices; LAAO has the potential to offer an attractive alternative for those at high stroke risk but are under-protected because of contraindications to anti-coagulant therapy.
In a meta-analysis, Tsai and colleagues (2014) evaluated current evidence on the safety and effectiveness between LAAO and LAA preservation cohorts for patients undergoing cardiac surgery. Electronic searches were performed using 6 electronic databases from their inception to November 2013, identifying all relevant comparative randomized and observational studies comparing LAAO with non-LAAO in AF patients undergoing cardiac surgery. Data were extracted and analyzed according to pre-defined end-points including mortality, stroke, post-operative AF and re-operation for bleeding. A total of 7 relevant studies identified for qualitative and quantitative analyses, including 3,653 patients undergoing LAAO (n = 1,716) versus non-LAAO (n = 1,937). Stroke incidence was significantly reduced in the LAAO group at the 30-day follow-up [0.95 versus 1.9 %; odds ratio (OR) 0.46; p = 0.005] and the latest follow-up (1.4 versus 4.1 %; OR 0.48; p = 0.01), compared with the non-LAAO group. Incidence of all-cause mortality was significantly decreased with LAAO (1.9 versus 5 %; OR 0.38; p = 0.0003), while post-operative AF and re-operation for bleeding was comparable. The authors concluded that while acknowledging the limitations and inadequate statistical power of the available evidence, the findings of this meta-analysis suggested that LAAO is a promising strategy for stroke reduction peri-operatively and at the short-term follow-up without a significant increase in complications. Moreover, they stated that larger RCTs are needed, with clearer surgical and anti-coagulation protocols and adequate long-term follow-up, to validate the clinical effectiveness of LAAO versus non-LAAO groups.
Lau and Lip (2014) discussed the anti-platelet agents, vitamin K antagonists (VKA) and non-vitamin K antagonist oral anticoagulants (NOACs), and their safety and effectiveness for stroke prevention in AF. Focus was placed on the NOACs, their limitations as well as special considerations. A short assessment of other non-pharmacological anti-thrombotic procedures was also made. An extensive PubMed search was used to identify suitable papers. The authors concluded that despite the advent of NOACs, the VKAs will remain as an important oral anti-coagulant due to its versatility. However, convenience and limited food or drug interactions will make NOACs attractive options. The choice between various NOACs will depend on several important factors. Over time, the role for anti-platelet agents will gradually diminish. Moreover, they stated that LAAO devices have shown promising results and may have the potential to change the way clinicians manage thrombo-embolism risks related to AF.
Horstmann et al (2014) evaluated the safety and feasibility of percutaneous LAAO in patients with AF and previous intra-cranial hemorrhage (ICH). In an explorative, prospective, single-center, observational study, LAAO was performed in patients with previous ICH and AF using the Amplatzer Cardiac Plug device. Risks of ischemic strokes and hemorrhagic complications were estimated using the CHA2DS2Vasc score and the HAS-BLED score. Before and 1, 6, 12, and 24 months after the procedure, clinical status and complications were recorded. Major complications were predefined as peri-procedural stroke, death, peri-cardial effusion, and device embolism. Left atrial appendage occlusion was performed in 20 patients. Based on CHA2DS2Vasc score (mean 4.5 ± 1.4) and HAS-BLED score (mean 4.7 ± 1.0), annual risks of stroke and hemorrhagic complications were 4.0 % to 6.7 % and 8.7 % to 12.5 %, respectively. No patient had a procedure-related complication. Minor post-procedural complications were observed in 4/20 patients (2 inguinal hematoma, 1 self-limiting asystole, and 1 thrombus formation on device). No ischemic or hemorrhagic stroke occurred during a mean follow-up of 13.6 ± 8.2 months. The authors concluded that in this first study of LAAO in patients with previous ICH, LAAO appears feasible and safe. Moreover, they stated that a larger, controlled trial is needed to evaluate the safety and effectiveness of the procedure compared to other preventive measures.
Whitlock et al (2014) stated that occlusion of the LAA is a promising approach to stroke prevention in AF. However, evidence of its safety and effectiveness to-date is lacking. These researchers described the rationale and design of a definitive LAAO trial in cardiac surgical patients with AF. These investigators plan to randomize 4,700 patients with AF in whom on-pump cardiac surgical procedure is planned to undergo LAAO or no LAAO. The primary outcome is the first occurrence of stroke or systemic arterial embolism over a mean follow-up of 4 years. Other outcomes include total mortality, operative safety outcomes (chest tube output in the first post-operative 24 hours, rate of post-operative re-exploration for bleeding in the first 48 hours post-surgery and 30-day mortality), re-hospitalization for heart failure, major bleed, and myocardial infarction. Left Atrial Appendage Occlusion Study (LAAOS) III is funded in a vanguard phase by the Canadian Institutes for Health Research (CIHR), the Canadian Network and Centre for Trials Internationally, and the McMaster University Surgical Associates. As of September 9, 2013, a total of 162 patients have been recruited into the study. The authors concluded that LAAOS III will be the largest trial to explore the effectiveness of LAAO for stroke prevention. Its results will lead to a better understanding of stroke in AF and the safety and effectiveness of surgical LAA occlusion.
An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBCA, 2014) concluded that percutaneous left atrial appendage closure for the prevention of stroke did not meet the TEC criteria. The assessment explained: "RCT data do not provide convincing evidence of a treatment benefit or noninferiority compared with anticoagulation for patients for whom anticoagulation is not contraindicated. Case series data are inadequate to support conclusions about efficacy in patients for whom anticoagulation is contraindicated. A preventive treatment should have definitive efficacy evidence, particularly when the treatment—a complicated procedure—has known acute risks and complications."
In summary, there is currently insufficient evidence to support the use of cardiac devices/procedures for occlusion of the LAA.
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