Exploring the Dark Side of Left Atrial Appendage Closure Devices Pasquale Santangeli, MD, PhD; Andrew E. Epstein, MD, FAHA, FACC, FHRS Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, PA Corresponding Author: Andrew E. Epstein, MD, FAHA, FACC, FHRS Electrophysiology Section, Cardiovascular Division Hospital of the University of Pennsylvania 3400 Spruce St. 9 Founders Pavilion Philadelphia, PA 19104 E-mail: [email protected]
Disclosures: None
The most feared complication of atrial fibrillation (AF) is cardio-embolic stroke. Despite the 1
decline in stroke-related mortality over the last decade , AF-related strokes remain the most severe type of ischemic cerebrovascular accidents due to their strong association with severe disability (worse than with non-AF-related strokes), recurrent thromboembolism, and death.
2, 3
Randomized
controlled trials have shown that systemic anticoagulation reduces the risk of stroke in patients with 4
non-valvular AF. Oral anticoagulant therapy, however, carries inherent bleeding risks, significant drug-drug interactions and dietary interactions (for vitamin K antagonists), non-linear
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jce.13358.
This article is protected by copyright. All rights reserved.
pharmacodynamic response in patients with fluctuating renal function (for novel direct oral anticoagulants), and challenges related to long-term patient compliance. Imaging studies have shown that the majority of AF-associated intracardiac thrombi are located within the left atrial appendage (LAA),
5, 6
a finding that has provided the basis and justification for the
development of mechanical catheter-based technologies for left atrial appendage occlusion (LAAO) as an alternative to oral anticoagulant therapy. Currently, 3 LAAO devices are in use in the US: 2 of these devices (WATCHMAN™ [Boston Scientific, Natick, Massachusetts], and AMPLATZER™AMULET™ [St Jude Medical/Abbott, St. Paul, MN) are for endocardial LAAO, ®
whereas the LARIAT (SentreHEART, Redwood city, California) is used for epicardial LAAO. The WATCHMAN™ is the only device that has been approved by the Food and Drug Administration (FDA) as an alternative to warfarin for stroke prevention in non-valvular AF. The clinical evaluation of the WATCHMAN™ device has followed a rigorous process that included two multicenter randomized trials against dose-adjusted warfarin and two prospective registries.
7-11
Overall, the available data
show substantial equivalence of WATCHMAN™ compared with warfarin for all-cause stroke, and a significant reduction of serious intracranial bleeding events, disabling/fatal strokes and cardiovascular death with WATCHMAN™.
7, 8, 10
The safety of the device has also been thoroughly investigated in the
setting of randomized controlled trials and, more recently, within post-approval registries. The most recent assessment of the safety of WATCHMAN™ included 3,822 cases of device implant within a national US registry.
11
Notably, 71% of the operators who performed 50% of the procedures were new
implanters not participating to the prior clinical trials. The procedure was successfully completed in more than 95% of cases, and the overall rate of periprocedural complications was 2.75%, which included pericardial tamponade (1.02%), procedure-related stroke (0.078%), device embolization (0.24%), and periprocedural death (0.078%). These figures were similar to those reported in the randomized PREVAIL study, in which the primary safety endpoint (composite of all-cause death, ischemic stroke, systemic embolism, need for emergent surgery or major endovascular intervention) 7
occurred in 2.2% of the patients randomized to WATCHMAN™. Whether the efficacy and safety of LAAO with WATCHMAN™ can be generalized to other types of LAAO devices needs to be evaluated in similarly designed randomized controlled trials. In this regard, a randomized trial comparing the
2 This article is protected by copyright. All rights reserved.
AMULET™ device with the WATCHMAN™ for endocardial LAAO is underway and will formally 12
evaluate whether the 2 devices perform similarly in terms of efficacy and safety. ®
The bulk of the evidence supporting the clinical use of the LARIAT device for LAAO is substantially different from what is already available for WATCHMAN™ or will soon be available for ®
AMULET™. The LARIAT is a suture delivery device that has received a 510(k) class II device approval by FDA to deliver a pre-tied stich for soft tissue approximation during surgery. The approval ®
process was facilitated by the substantial similarities between the LARIAT system and other FDAapproved suture systems such as the Ethicon Endosuture System (Ethicon US LLC) that are typically ®
used during laparoscopic surgeries. Given the broad indication by the FDA, the LARIAT device has been used by multiple centers for epicardial LAAO. Although mechanistically sound, it is important to ®
emphasize that the role of the LARIAT device to prevent stroke in AF patients has not been formally tested in a randomized trial. However, the possibility of achieving durable exclusion of the LAA without the need for an endocardial device is certainly appealing, as it may obviate the need for shortterm anticoagulation and virtually eliminate the risk of device-related thrombosis.
13
Furthermore, from
a physiological perspective, there is no reason to suspect that, if adequate LAA sealing is obtained, ®
the benefits of the LARIAT device would be any different from what shown with the WATCHMAN™. In this issue of the Journal, Jazayeri et al. present an analysis of complications of the ®
WATCHMAN™ and LARIAT reported to the FDA Manufacturer and User Facility Device Experience 14
®
(MAUDE) database between years 2006 and 2016. During the study period, the LARIAT was implanted in 4,889 patients while the WATCHMAN™ in 5,849 patients. Interestingly, the complication 11
rate observed with WATCHMAN™ appeared higher than what reported in recent registries,
with
higher point estimates for pericardial tamponade (0.5% higher), pericardial effusion (+0.15%), 14
periprocedural stroke (+0.082%), device embolization (+0.28%) and death (+0.21%). In addition, the composite endpoint of stroke/TIA, pericardiocentesis, cardiac surgery, and death appeared higher ®
with WATCHMAN™ compared with LARIAT (1.93% vs. 1.15%, P=0.001 for comparison). The authors concluded that MAUDE-reported data show that post-approval new technology adoption may be associated with increased complications compared with pre-market data.
3 This article is protected by copyright. All rights reserved.
This is an important paper since, while it describes complications specifically related to LAAO, it serves as a warning that “real-world” experience is not necessarily the same as that observed in premarketing approval studies or in fact any clinical trial. The power of this observation in this case is extremely important since it is offered by advocates of LAAO technology. While advocates can easily minimize the significance of reported complications, Jazayeri et al. reported with no holds barred. They bring attention to real problems and warnings from those intimately involved with the premarketing approval trials of these devices will be especially powerful. Furthermore, their call for collaboration between operators, device manufacturers, and regulators is laudable. With enhanced monitoring and reporting of complications, patients can only be helped. The authors’ call for transparent monitoring, reporting and training is critically important and indeed applicable to all interventions we deliver, both new and old. In this context, this report has wider implications than those related to only LAA closure devices. On the other hand, some limitations of their analysis should be acknowledged. First and ®
foremost, the conclusion of a possible increased safety profile with the LARIAT device compared with WATCHMAN™, albeit intriguing, should be interpreted with caution. Indirect comparisons like the one reported in the present study should only be used to generate hypotheses. The comparative ®
analysis of LARIAT versus WATCHMAN™ provided no adjustments for baseline confounders, and it remains difficult to establish whether the reported differences in event rates are indeed due to a real difference in device safety profile or simply related to heterogeneous patient risk profiles. Moving forward, this finding also brings to attention the different ways in which new technology is evaluated ®
for FDA approval. As mentioned, LARIAT received 510(k) approval for soft tissue ligation with offlabel use for LAAO, while WATCHMAN™ was approved through the FDA pre-market approval pathway that required two randomized controlled trials, two prospective registries, and multiple reviews by the FDA Circulatory Systems Advisory Panel prior to approval. In this context, the authors explain the observation of a higher complication rate with WATCHMAN™ compared with LARIAT® opining that, by virtue of different approval pathways, LARIAT® operators may have hurdled a steep learning curve more rapidly than operators who used WATCHMAN™ resulting in different complication rates post-approval.
4 This article is protected by copyright. All rights reserved.
Other limitations are inherent to the MAUDE databank itself. First, reporting is voluntary, very different than that which occurs in clinical trials. Second, reports submitted to the MAUDE system undergo no peer review. Reports may be made both individuals (called “voluntary”) and industry (called “mandated”). Since entries in the MAUDE are made only when there is a problem, there is no “denominator” to allow ascertainment of the magnitude of the problem. The authors have managed this limitation by extrapolating from company data regarding number of procedures performed. The problem of absent peer review is captured by the observation that of 622 medical device reports, only ®
356 were unique, relevant and therefore analyzed. Of the 167 LARIAT reports, 47 (28%) were irrelevant to the suture delivery device, and of the 455 WATCHMAN™ reports, 25 (0.6%) including 12 deaths contained inadequate data to be included for analysis. Thus, 9% (57/622) of the reports had to be excluded from analysis. Data gaps of this magnitude are unacceptable by any standard, especially when some of the gaps were related to death. Finally, the problem of under-reporting is highlighted by the absence of reports for post-procedural LAA leaks and intracardiac thrombi, as correctly 14
®
highlighted by Jazayeri et al. It is even more unlikely that there were no LARIAT -related complications reported to the MAUDE database during the 2016 portion of the study. One wonders if the increased incidence of complications related to the WATCHMAN™ device were also underreported. In conclusion, Jazayeri et al.
14
have taught us several valuable lessons: first, FDA approval does
not insure safety. Second, the approval process itself may influence post-approval safety. Third, better reporting is required to determine accurately safety and efficacy of interventions whether it be pharmacologic or device-related technology. And fourth, findings such as these beg the question if new technology or technology whose use may be associated with significant complications should be restricted to centers of excellence to diminish the rates of complications associated with its usage. References [1] Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, Kissela BM, Kittner SJ, Lichtman JH, Lisabeth LD, Schwamm LH, Smith EE, Towfighi A, American Heart Association Stroke C, Council on C, Stroke N, Council on Quality of C, Outcomes R, Council on
5 This article is protected by copyright. All rights reserved.
Functional G, Translational B: Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 2014; 45:315-353. [2] Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946-952. [3] Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB: Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27:1760-1764. [4] January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice G: 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1-76. [5] Leung DY, Black IW, Cranney GB, Hopkins AP, Walsh WF: Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 1994; 24:755-762. [6] Manning WJ, Silverman DI, Katz SE, Riley MF, Come PC, Doherty RM, Munson JT, Douglas PS: Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol 1994; 23:1535-1540. [7] Holmes DR, Jr., Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY: Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014; 64:1-12. [8] Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P, Investigators PA: Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374:534-542.
6 This article is protected by copyright. All rights reserved.
[9] Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S: Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011; 123:417-424. [10] Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber K, Whisenant B, Kar S, Swarup V, Gordon N, Holmes D, Committee PAS, Investigators: Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014; 312:1988-1998. [11] Reddy VY, Gibson DN, Kar S, O'Neill W, Doshi SK, Horton RP, Buchbinder M, Gordon NT, Holmes DR: Post-Approval U.S. Experience With Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation. J Am Coll Cardiol 2017; 69:253-261. [12] AMPLATZER™ Amulet™ LAA Occluder Trial (Amulet IDE). https://clinicaltrialsgov/ct2/show/NCT02879448. [13] Lempereur M, Aminian A, Freixa X, Gafoor S, Kefer J, Tzikas A, Legrand V, Saw J: Deviceassociated thrombus formation after left atrial appendage occlusion: A systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter Cardiovasc Interv 2017. [14] Jazayeri M, Vuddanda V, Turagam MK, Parikh V, Lavu M, Atkins D, Earnest M, Di Biase L, Natale A, Wilber D, Reddy M, Lakkireddy D: Safety profiles of percutaneous left atrial appendage closure devices: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 - 2016. J Cardiovasc Electrophysiol 2017;28: In Press.
7 This article is protected by copyright. All rights reserved.
Disclosures: None
The most feared complication of atrial fibrillation (AF) is cardio-embolic stroke. Despite the 1
decline in stroke-related mortality over the last decade , AF-related strokes remain the most severe type of ischemic cerebrovascular accidents due to their strong association with severe disability (worse than with non-AF-related strokes), recurrent thromboembolism, and death.
2, 3
Randomized
controlled trials have shown that systemic anticoagulation reduces the risk of stroke in patients with 4
non-valvular AF. Oral anticoagulant therapy, however, carries inherent bleeding risks, significant drug-drug interactions and dietary interactions (for vitamin K antagonists), non-linear
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jce.13358.
This article is protected by copyright. All rights reserved.
pharmacodynamic response in patients with fluctuating renal function (for novel direct oral anticoagulants), and challenges related to long-term patient compliance. Imaging studies have shown that the majority of AF-associated intracardiac thrombi are located within the left atrial appendage (LAA),
5, 6
a finding that has provided the basis and justification for the
development of mechanical catheter-based technologies for left atrial appendage occlusion (LAAO) as an alternative to oral anticoagulant therapy. Currently, 3 LAAO devices are in use in the US: 2 of these devices (WATCHMAN™ [Boston Scientific, Natick, Massachusetts], and AMPLATZER™AMULET™ [St Jude Medical/Abbott, St. Paul, MN) are for endocardial LAAO, ®
whereas the LARIAT (SentreHEART, Redwood city, California) is used for epicardial LAAO. The WATCHMAN™ is the only device that has been approved by the Food and Drug Administration (FDA) as an alternative to warfarin for stroke prevention in non-valvular AF. The clinical evaluation of the WATCHMAN™ device has followed a rigorous process that included two multicenter randomized trials against dose-adjusted warfarin and two prospective registries.
7-11
Overall, the available data
show substantial equivalence of WATCHMAN™ compared with warfarin for all-cause stroke, and a significant reduction of serious intracranial bleeding events, disabling/fatal strokes and cardiovascular death with WATCHMAN™.
7, 8, 10
The safety of the device has also been thoroughly investigated in the
setting of randomized controlled trials and, more recently, within post-approval registries. The most recent assessment of the safety of WATCHMAN™ included 3,822 cases of device implant within a national US registry.
11
Notably, 71% of the operators who performed 50% of the procedures were new
implanters not participating to the prior clinical trials. The procedure was successfully completed in more than 95% of cases, and the overall rate of periprocedural complications was 2.75%, which included pericardial tamponade (1.02%), procedure-related stroke (0.078%), device embolization (0.24%), and periprocedural death (0.078%). These figures were similar to those reported in the randomized PREVAIL study, in which the primary safety endpoint (composite of all-cause death, ischemic stroke, systemic embolism, need for emergent surgery or major endovascular intervention) 7
occurred in 2.2% of the patients randomized to WATCHMAN™. Whether the efficacy and safety of LAAO with WATCHMAN™ can be generalized to other types of LAAO devices needs to be evaluated in similarly designed randomized controlled trials. In this regard, a randomized trial comparing the
2 This article is protected by copyright. All rights reserved.
AMULET™ device with the WATCHMAN™ for endocardial LAAO is underway and will formally 12
evaluate whether the 2 devices perform similarly in terms of efficacy and safety. ®
The bulk of the evidence supporting the clinical use of the LARIAT device for LAAO is substantially different from what is already available for WATCHMAN™ or will soon be available for ®
AMULET™. The LARIAT is a suture delivery device that has received a 510(k) class II device approval by FDA to deliver a pre-tied stich for soft tissue approximation during surgery. The approval ®
process was facilitated by the substantial similarities between the LARIAT system and other FDAapproved suture systems such as the Ethicon Endosuture System (Ethicon US LLC) that are typically ®
used during laparoscopic surgeries. Given the broad indication by the FDA, the LARIAT device has been used by multiple centers for epicardial LAAO. Although mechanistically sound, it is important to ®
emphasize that the role of the LARIAT device to prevent stroke in AF patients has not been formally tested in a randomized trial. However, the possibility of achieving durable exclusion of the LAA without the need for an endocardial device is certainly appealing, as it may obviate the need for shortterm anticoagulation and virtually eliminate the risk of device-related thrombosis.
13
Furthermore, from
a physiological perspective, there is no reason to suspect that, if adequate LAA sealing is obtained, ®
the benefits of the LARIAT device would be any different from what shown with the WATCHMAN™. In this issue of the Journal, Jazayeri et al. present an analysis of complications of the ®
WATCHMAN™ and LARIAT reported to the FDA Manufacturer and User Facility Device Experience 14
®
(MAUDE) database between years 2006 and 2016. During the study period, the LARIAT was implanted in 4,889 patients while the WATCHMAN™ in 5,849 patients. Interestingly, the complication 11
rate observed with WATCHMAN™ appeared higher than what reported in recent registries,
with
higher point estimates for pericardial tamponade (0.5% higher), pericardial effusion (+0.15%), 14
periprocedural stroke (+0.082%), device embolization (+0.28%) and death (+0.21%). In addition, the composite endpoint of stroke/TIA, pericardiocentesis, cardiac surgery, and death appeared higher ®
with WATCHMAN™ compared with LARIAT (1.93% vs. 1.15%, P=0.001 for comparison). The authors concluded that MAUDE-reported data show that post-approval new technology adoption may be associated with increased complications compared with pre-market data.
3 This article is protected by copyright. All rights reserved.
This is an important paper since, while it describes complications specifically related to LAAO, it serves as a warning that “real-world” experience is not necessarily the same as that observed in premarketing approval studies or in fact any clinical trial. The power of this observation in this case is extremely important since it is offered by advocates of LAAO technology. While advocates can easily minimize the significance of reported complications, Jazayeri et al. reported with no holds barred. They bring attention to real problems and warnings from those intimately involved with the premarketing approval trials of these devices will be especially powerful. Furthermore, their call for collaboration between operators, device manufacturers, and regulators is laudable. With enhanced monitoring and reporting of complications, patients can only be helped. The authors’ call for transparent monitoring, reporting and training is critically important and indeed applicable to all interventions we deliver, both new and old. In this context, this report has wider implications than those related to only LAA closure devices. On the other hand, some limitations of their analysis should be acknowledged. First and ®
foremost, the conclusion of a possible increased safety profile with the LARIAT device compared with WATCHMAN™, albeit intriguing, should be interpreted with caution. Indirect comparisons like the one reported in the present study should only be used to generate hypotheses. The comparative ®
analysis of LARIAT versus WATCHMAN™ provided no adjustments for baseline confounders, and it remains difficult to establish whether the reported differences in event rates are indeed due to a real difference in device safety profile or simply related to heterogeneous patient risk profiles. Moving forward, this finding also brings to attention the different ways in which new technology is evaluated ®
for FDA approval. As mentioned, LARIAT received 510(k) approval for soft tissue ligation with offlabel use for LAAO, while WATCHMAN™ was approved through the FDA pre-market approval pathway that required two randomized controlled trials, two prospective registries, and multiple reviews by the FDA Circulatory Systems Advisory Panel prior to approval. In this context, the authors explain the observation of a higher complication rate with WATCHMAN™ compared with LARIAT® opining that, by virtue of different approval pathways, LARIAT® operators may have hurdled a steep learning curve more rapidly than operators who used WATCHMAN™ resulting in different complication rates post-approval.
4 This article is protected by copyright. All rights reserved.
Other limitations are inherent to the MAUDE databank itself. First, reporting is voluntary, very different than that which occurs in clinical trials. Second, reports submitted to the MAUDE system undergo no peer review. Reports may be made both individuals (called “voluntary”) and industry (called “mandated”). Since entries in the MAUDE are made only when there is a problem, there is no “denominator” to allow ascertainment of the magnitude of the problem. The authors have managed this limitation by extrapolating from company data regarding number of procedures performed. The problem of absent peer review is captured by the observation that of 622 medical device reports, only ®
356 were unique, relevant and therefore analyzed. Of the 167 LARIAT reports, 47 (28%) were irrelevant to the suture delivery device, and of the 455 WATCHMAN™ reports, 25 (0.6%) including 12 deaths contained inadequate data to be included for analysis. Thus, 9% (57/622) of the reports had to be excluded from analysis. Data gaps of this magnitude are unacceptable by any standard, especially when some of the gaps were related to death. Finally, the problem of under-reporting is highlighted by the absence of reports for post-procedural LAA leaks and intracardiac thrombi, as correctly 14
®
highlighted by Jazayeri et al. It is even more unlikely that there were no LARIAT -related complications reported to the MAUDE database during the 2016 portion of the study. One wonders if the increased incidence of complications related to the WATCHMAN™ device were also underreported. In conclusion, Jazayeri et al.
14
have taught us several valuable lessons: first, FDA approval does
not insure safety. Second, the approval process itself may influence post-approval safety. Third, better reporting is required to determine accurately safety and efficacy of interventions whether it be pharmacologic or device-related technology. And fourth, findings such as these beg the question if new technology or technology whose use may be associated with significant complications should be restricted to centers of excellence to diminish the rates of complications associated with its usage. References [1] Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, Kissela BM, Kittner SJ, Lichtman JH, Lisabeth LD, Schwamm LH, Smith EE, Towfighi A, American Heart Association Stroke C, Council on C, Stroke N, Council on Quality of C, Outcomes R, Council on
5 This article is protected by copyright. All rights reserved.
Functional G, Translational B: Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 2014; 45:315-353. [2] Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946-952. [3] Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB: Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27:1760-1764. [4] January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice G: 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1-76. [5] Leung DY, Black IW, Cranney GB, Hopkins AP, Walsh WF: Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 1994; 24:755-762. [6] Manning WJ, Silverman DI, Katz SE, Riley MF, Come PC, Doherty RM, Munson JT, Douglas PS: Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol 1994; 23:1535-1540. [7] Holmes DR, Jr., Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY: Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014; 64:1-12. [8] Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P, Investigators PA: Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374:534-542.
6 This article is protected by copyright. All rights reserved.
[9] Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S: Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011; 123:417-424. [10] Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber K, Whisenant B, Kar S, Swarup V, Gordon N, Holmes D, Committee PAS, Investigators: Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014; 312:1988-1998. [11] Reddy VY, Gibson DN, Kar S, O'Neill W, Doshi SK, Horton RP, Buchbinder M, Gordon NT, Holmes DR: Post-Approval U.S. Experience With Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation. J Am Coll Cardiol 2017; 69:253-261. [12] AMPLATZER™ Amulet™ LAA Occluder Trial (Amulet IDE). https://clinicaltrialsgov/ct2/show/NCT02879448. [13] Lempereur M, Aminian A, Freixa X, Gafoor S, Kefer J, Tzikas A, Legrand V, Saw J: Deviceassociated thrombus formation after left atrial appendage occlusion: A systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter Cardiovasc Interv 2017. [14] Jazayeri M, Vuddanda V, Turagam MK, Parikh V, Lavu M, Atkins D, Earnest M, Di Biase L, Natale A, Wilber D, Reddy M, Lakkireddy D: Safety profiles of percutaneous left atrial appendage closure devices: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 - 2016. J Cardiovasc Electrophysiol 2017;28: In Press.
7 This article is protected by copyright. All rights reserved.
