Left Atrial Appendage Closure to Prevent Stroke in Patients With Atrial Fibrillation Matthew J. Price and Miguel Valderrábano Circulation. 2014;130:202-212 doi: 10.1161/CIRCULATIONAHA.114.009060 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/130/2/202
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New Drugs and Technologies Left Atrial Appendage Closure to Prevent Stroke in Patients With Atrial Fibrillation Matthew J. Price, MD; Miguel Valderrábano, MD
A
trial fibrillation (AF) is the most common sustained arrhythmia and is associated with substantial morbidity. The prevalence of AF in the United States is expected to rise to between 5.6 and 12 million in 2050.1 AF is associated with a 4to 5-fold increased risk of ischemic stroke after adjustment for other risk factors,2 and paroxysmal, persistent, or permanent AF increases stroke risk to a similar degree. Oral anticoagulants (OACs) reduce the risk of thromboembolism, yet they are underused.3–6 Novel OACs are noninferior or superior to warfarin for the prevention of stroke and systemic embolism and are more convenient because they do not require ongoing monitoring.7–10 However, major challenges to long-term therapy with vitamin K antagonists and novel OACs include a substantial ongoing hazard of major bleeding, noncompliance, side effects, and, in the case of the novel OACs, lack of an available antidote. The left atrial appendage (LAA) is the predominant nidus for thrombus formation in AF, and transcatheter LAA closure has emerged as a potential alternative to oral anticoagulation in at-risk AF patients.
The LAA and Stroke in AF AF is associated with mechanical dysfunction of atrial tissue. Loss of contractile function in the LAA can lead to local stasis and thrombus formation, which may then embolize into the systemic circulation. The observation that >90% of thrombi found in patients with nonvalvular AF and stroke are in the LAA supports this mechanistic sequence.11 In addition, low Doppler inflow velocities, spontaneous echocardiographic contrast, and the presence of thrombus in the LAA have been associated with high stroke rates in AF patients.12 These data lend support to the hypothesis that the elimination of the LAA may serve as a preventive strategy for AF-related stroke. Morphological features of the LAA may influence stroke risk. Larger LAA neck diameter and LAA depth have been associated with a higher prevalence of prior stroke in AF patients.13 A chicken wing shape appears to correlate less with prior embolic events than cauliflower, cactus, or windsock shapes,14 but although this finding was reproduced in 1 small study,15 it was disputed by another, larger study.16 Such categorization of LAA morphology may be a poorly reproducible oversimplification of anatomy. The extent of trabeculations within the LAA may be a better predictor of thromboembolic events.16 Therefore, LAA characteristics appear to influence
stroke risk, but to date, there are no reproducible LAA features sufficiently validated for risk stratification. Stroke risk is influenced by a multitude of factors. Although the LAA is the most common site of thrombus in patients with nonvalvular AF and stroke, thrombi were identified only in the minority of such patients.11 Although the offending thrombi could have embolized before LAA assessment, additional data suggest that not all strokes in AF may be prevented by LAA-targeted therapies. As many as 25% of strokes in AF patients can be linked to intrinsic cerebrovascular disease.17 The CHADS2 and CHA2DS2VASc scores are based on a particular individual’s comorbidities (Tables 1 and 2). They can estimate a yearly risk of thromboembolic events18,19 and identify which patients may derive clinical benefit from anticoagulation,20 yet they do not include parameters of LAA function or anatomy. Although hypertension and aortic atherosclerosis have been associated with an increased prevalence of LAA thrombus, spontaneous contrast, and low LAA inflow velocity,21 the mechanistic connections between the LAA and many risk factors known to be predictive of stroke in AF remain to be fully elucidated. Despite these uncertainties, the LAA is a consistent and predictable site of origin of cerebral and systemic emboli in AF and thus constitutes an opportunity for stroke prophylaxis.
General Concepts for LAA Closure Device Evaluation The appropriate assessment of transcatheter LAA devices requires a critical evaluation of the types of outcomes studied. Efficacy outcomes may include anatomic efficacy, that is, success of LAA closure on imaging studies, and clinical efficacy, that is, stroke prevention in the absence of oral anticoagulation. Although anatomic closure is commonly used as a surrogate for clinical efficacy, LAA closure may not guarantee long-term efficacy, whereas small residual leaks may not necessarily result in clinical failure.22 Because the mechanism, material, and consequences of closure may differ between devices, clinical efficacy of 1 device may not necessarily translate into clinical efficacy of another device that has been shown to provide only anatomic closure. Safety outcomes are particularly important because LAA closure is a prophylactic procedure. The transcatheter devices share certain types of procedural complications (eg, vascular access bleeding,
From the Scripps Clinic, La Jolla, CA (M.J.P.); and Methodist Hospital, Houston, TX (M.V.). Correspondence to Matthew J. Price, MD, Scripps Clinic, 10666 N Torrey Pines Rd, Mail Drop S1056, La Jolla, CA 92037. E-mail [email protected] (Circulation. 2014;130:202-212.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.114.009060
Downloaded from http://circ.ahajournals.org/ at YORK UNIV SCOTT LIB on July 8, 2014 202
Price and Valderrábano LAA Closure for Stroke Prevention 203 Table 1. The CHADS2 Model for Thromboembolic Risk in AF
pericardial effusions, and air embolism), but the rates of complications may differ as a result of differences in implantation technique, device design, and operator experience.
Device in Patients Undergoing Concomitant Cardiac Surgery (EXCLUDE) study was a prospective observational study that examined device safety and anatomic closure in 71 patients undergoing concomitant cardiac surgery via a median sternotomy.32 There were no device-related adverse events, and LAA closure was achieved in 95% of patients who completed 3-month imaging follow-up. However, efficacy data for stroke prevention in the absence of oral anticoagulation are lacking. Successful standalone thoracoscopic implantation of the AtriClip has been reported.33 The safety and anatomic efficacy of such a minimally invasive approach in AF patients with contraindications to anticoagulation are being evaluated in the observational Stroke Feasibility Study (http://www.clinicaltrials.gov; NCT01997905).
Surgical LAA Exclusion and Excision
Transcatheter Closure Strategies
Characteristic
Points
Congestive heart failure
1
Hypertension
1
Age ≥75 y
1
Diabetes mellitus
1
Stroke or transient ischemic attack
2
AF indicates atrial fibrillation.
Madden23 suggested >60 years ago that resection of the LAA could prevent recurrent arterial emboli caused by AF. Surgical exclusion or removal of the LAA during cardiac surgery in AF patients is now commonplace and forms in part the rationale for the development of transcatheter approaches to LAA closure. However, surgical LAA closure frequently appears to be incomplete, and residual flow may be associated with thromboembolic events. In the pilot Left Atrial Appendage Occlusion Study (LAOOS), 34% of patients had residual flow into the LAA after surgical exclusion.24 Imaging studies of patients after surgical exclusion or excision have also documented relatively high rates of incomplete closure, although it is least frequent with LAA excision.25–28 The findings of observational studies that have examined the association between surgical LAA closure and stroke reduction are conflicting.28,29 A large, randomized trial examining the clinical efficacy of surgical LAA closure for stroke prevention is currently ongoing.30 Devices to improve anatomic closure of the LAA during surgery have been developed. The AtriClip (Atricure, West Chester, OH) consists of 2 parallel titanium tubes and 2 nitinol springs with a knit-braided polyester fabric31 delivered with a deployment tool consisting of a distal articulating head connected to a shaft and proximal actuator. The US Food and Drug Administration (FDA) approval states that it is indicated for LAA occlusion under direct visualization in conjunction with other open cardiac surgical procedures. The Exclusion of Left Atrial Appendage With AtriClip Exclusion Table 2. The CHA2DS2VASC Model for Thromboembolic Risk in AF Characteristic
Points
Congestive heart failure
1
Hypertension
1
Age 65–74 y
1
Age ≥75 y
2
Diabetes mellitus
1
Stroke or transient ischemic attack
2
Vascular disease
1
Female sex
1
AF indicates atrial fibrillation.
PLAATO The PLAATO system was the first transcatheter device developed for the purpose of LAA closure.34 The device consisted of a self-expanding nitinol cage covered with an expanded polytetrafluoroethylene membrane. Device feasibility was evaluated in a nonrandomized, multicenter study of 64 patients who were at high thromboembolic risk but were not candidates for warfarin.35 There was a high rate of anatomic closure at the time of the procedure (residual flow ≤3 mm in 98%), and safety was excellent. At the 5-year follow-up, the observed rate of stroke or transient ischemic attack was 3.8%/y compared with an expected rate of 6.6% based on the CHADS2 score of the study population. Although this device was not evaluated further, the PLAATO experience serves as a proof of principle for device occlusion of the LAA for stroke prevention.
WATCHMAN Device Characteristics The WATCHMAN (Boston Scientific, Natwick, MA) consists of a self-expanding nitinol frame and membrane cap (Figure 1). The device is delivered through a 14F sheath placed within the LAA, guided by a combination of fluoroscopy and transesophageal echocardiography (TEE; Figure 2). Clinical Data The safety and clinical efficacy of the WATCHMAN have been examined in 2 randomized, clinical trials; a nonrandomized, continuing-access registry was performed for the purpose of evaluating device and procedural safety (Table 3). The WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT-AF) and Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) studies, which enrolled 707 and 407 patients, respectively, were noninferiority trials that evaluated the WATCHMAN compared with warfarin in AF patients who were candidates for long-term anticoagulation.36,39 PROTECT-AF required enrolled subjects to have a CHADS2 score ≥1, whereas PREVAIL required a CHADS2 score ≥2 or 1 if additional stroke risk factors were present and warfarin therapy was
Downloaded from http://circ.ahajournals.org/ at YORK UNIV SCOTT LIB on July 8, 2014
204 Circulation July 8, 2014 randomly assigned to either device implantation or warfarin therapy in a 2:1 fashion. Patients allocated to device implantation were treated with 6 weeks of warfarin and aspirin, at which time a follow-up TEE was performed. If the TEE findings were adequate (ie, no thrombus and peri-device leak
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/130/2/202
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ at YORK UNIV SCOTT LIB on July 8, 2014
New Drugs and Technologies Left Atrial Appendage Closure to Prevent Stroke in Patients With Atrial Fibrillation Matthew J. Price, MD; Miguel Valderrábano, MD
A
trial fibrillation (AF) is the most common sustained arrhythmia and is associated with substantial morbidity. The prevalence of AF in the United States is expected to rise to between 5.6 and 12 million in 2050.1 AF is associated with a 4to 5-fold increased risk of ischemic stroke after adjustment for other risk factors,2 and paroxysmal, persistent, or permanent AF increases stroke risk to a similar degree. Oral anticoagulants (OACs) reduce the risk of thromboembolism, yet they are underused.3–6 Novel OACs are noninferior or superior to warfarin for the prevention of stroke and systemic embolism and are more convenient because they do not require ongoing monitoring.7–10 However, major challenges to long-term therapy with vitamin K antagonists and novel OACs include a substantial ongoing hazard of major bleeding, noncompliance, side effects, and, in the case of the novel OACs, lack of an available antidote. The left atrial appendage (LAA) is the predominant nidus for thrombus formation in AF, and transcatheter LAA closure has emerged as a potential alternative to oral anticoagulation in at-risk AF patients.
The LAA and Stroke in AF AF is associated with mechanical dysfunction of atrial tissue. Loss of contractile function in the LAA can lead to local stasis and thrombus formation, which may then embolize into the systemic circulation. The observation that >90% of thrombi found in patients with nonvalvular AF and stroke are in the LAA supports this mechanistic sequence.11 In addition, low Doppler inflow velocities, spontaneous echocardiographic contrast, and the presence of thrombus in the LAA have been associated with high stroke rates in AF patients.12 These data lend support to the hypothesis that the elimination of the LAA may serve as a preventive strategy for AF-related stroke. Morphological features of the LAA may influence stroke risk. Larger LAA neck diameter and LAA depth have been associated with a higher prevalence of prior stroke in AF patients.13 A chicken wing shape appears to correlate less with prior embolic events than cauliflower, cactus, or windsock shapes,14 but although this finding was reproduced in 1 small study,15 it was disputed by another, larger study.16 Such categorization of LAA morphology may be a poorly reproducible oversimplification of anatomy. The extent of trabeculations within the LAA may be a better predictor of thromboembolic events.16 Therefore, LAA characteristics appear to influence
stroke risk, but to date, there are no reproducible LAA features sufficiently validated for risk stratification. Stroke risk is influenced by a multitude of factors. Although the LAA is the most common site of thrombus in patients with nonvalvular AF and stroke, thrombi were identified only in the minority of such patients.11 Although the offending thrombi could have embolized before LAA assessment, additional data suggest that not all strokes in AF may be prevented by LAA-targeted therapies. As many as 25% of strokes in AF patients can be linked to intrinsic cerebrovascular disease.17 The CHADS2 and CHA2DS2VASc scores are based on a particular individual’s comorbidities (Tables 1 and 2). They can estimate a yearly risk of thromboembolic events18,19 and identify which patients may derive clinical benefit from anticoagulation,20 yet they do not include parameters of LAA function or anatomy. Although hypertension and aortic atherosclerosis have been associated with an increased prevalence of LAA thrombus, spontaneous contrast, and low LAA inflow velocity,21 the mechanistic connections between the LAA and many risk factors known to be predictive of stroke in AF remain to be fully elucidated. Despite these uncertainties, the LAA is a consistent and predictable site of origin of cerebral and systemic emboli in AF and thus constitutes an opportunity for stroke prophylaxis.
General Concepts for LAA Closure Device Evaluation The appropriate assessment of transcatheter LAA devices requires a critical evaluation of the types of outcomes studied. Efficacy outcomes may include anatomic efficacy, that is, success of LAA closure on imaging studies, and clinical efficacy, that is, stroke prevention in the absence of oral anticoagulation. Although anatomic closure is commonly used as a surrogate for clinical efficacy, LAA closure may not guarantee long-term efficacy, whereas small residual leaks may not necessarily result in clinical failure.22 Because the mechanism, material, and consequences of closure may differ between devices, clinical efficacy of 1 device may not necessarily translate into clinical efficacy of another device that has been shown to provide only anatomic closure. Safety outcomes are particularly important because LAA closure is a prophylactic procedure. The transcatheter devices share certain types of procedural complications (eg, vascular access bleeding,
From the Scripps Clinic, La Jolla, CA (M.J.P.); and Methodist Hospital, Houston, TX (M.V.). Correspondence to Matthew J. Price, MD, Scripps Clinic, 10666 N Torrey Pines Rd, Mail Drop S1056, La Jolla, CA 92037. E-mail [email protected] (Circulation. 2014;130:202-212.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.114.009060
Downloaded from http://circ.ahajournals.org/ at YORK UNIV SCOTT LIB on July 8, 2014 202
Price and Valderrábano LAA Closure for Stroke Prevention 203 Table 1. The CHADS2 Model for Thromboembolic Risk in AF
pericardial effusions, and air embolism), but the rates of complications may differ as a result of differences in implantation technique, device design, and operator experience.
Device in Patients Undergoing Concomitant Cardiac Surgery (EXCLUDE) study was a prospective observational study that examined device safety and anatomic closure in 71 patients undergoing concomitant cardiac surgery via a median sternotomy.32 There were no device-related adverse events, and LAA closure was achieved in 95% of patients who completed 3-month imaging follow-up. However, efficacy data for stroke prevention in the absence of oral anticoagulation are lacking. Successful standalone thoracoscopic implantation of the AtriClip has been reported.33 The safety and anatomic efficacy of such a minimally invasive approach in AF patients with contraindications to anticoagulation are being evaluated in the observational Stroke Feasibility Study (http://www.clinicaltrials.gov; NCT01997905).
Surgical LAA Exclusion and Excision
Transcatheter Closure Strategies
Characteristic
Points
Congestive heart failure
1
Hypertension
1
Age ≥75 y
1
Diabetes mellitus
1
Stroke or transient ischemic attack
2
AF indicates atrial fibrillation.
Madden23 suggested >60 years ago that resection of the LAA could prevent recurrent arterial emboli caused by AF. Surgical exclusion or removal of the LAA during cardiac surgery in AF patients is now commonplace and forms in part the rationale for the development of transcatheter approaches to LAA closure. However, surgical LAA closure frequently appears to be incomplete, and residual flow may be associated with thromboembolic events. In the pilot Left Atrial Appendage Occlusion Study (LAOOS), 34% of patients had residual flow into the LAA after surgical exclusion.24 Imaging studies of patients after surgical exclusion or excision have also documented relatively high rates of incomplete closure, although it is least frequent with LAA excision.25–28 The findings of observational studies that have examined the association between surgical LAA closure and stroke reduction are conflicting.28,29 A large, randomized trial examining the clinical efficacy of surgical LAA closure for stroke prevention is currently ongoing.30 Devices to improve anatomic closure of the LAA during surgery have been developed. The AtriClip (Atricure, West Chester, OH) consists of 2 parallel titanium tubes and 2 nitinol springs with a knit-braided polyester fabric31 delivered with a deployment tool consisting of a distal articulating head connected to a shaft and proximal actuator. The US Food and Drug Administration (FDA) approval states that it is indicated for LAA occlusion under direct visualization in conjunction with other open cardiac surgical procedures. The Exclusion of Left Atrial Appendage With AtriClip Exclusion Table 2. The CHA2DS2VASC Model for Thromboembolic Risk in AF Characteristic
Points
Congestive heart failure
1
Hypertension
1
Age 65–74 y
1
Age ≥75 y
2
Diabetes mellitus
1
Stroke or transient ischemic attack
2
Vascular disease
1
Female sex
1
AF indicates atrial fibrillation.
PLAATO The PLAATO system was the first transcatheter device developed for the purpose of LAA closure.34 The device consisted of a self-expanding nitinol cage covered with an expanded polytetrafluoroethylene membrane. Device feasibility was evaluated in a nonrandomized, multicenter study of 64 patients who were at high thromboembolic risk but were not candidates for warfarin.35 There was a high rate of anatomic closure at the time of the procedure (residual flow ≤3 mm in 98%), and safety was excellent. At the 5-year follow-up, the observed rate of stroke or transient ischemic attack was 3.8%/y compared with an expected rate of 6.6% based on the CHADS2 score of the study population. Although this device was not evaluated further, the PLAATO experience serves as a proof of principle for device occlusion of the LAA for stroke prevention.
WATCHMAN Device Characteristics The WATCHMAN (Boston Scientific, Natwick, MA) consists of a self-expanding nitinol frame and membrane cap (Figure 1). The device is delivered through a 14F sheath placed within the LAA, guided by a combination of fluoroscopy and transesophageal echocardiography (TEE; Figure 2). Clinical Data The safety and clinical efficacy of the WATCHMAN have been examined in 2 randomized, clinical trials; a nonrandomized, continuing-access registry was performed for the purpose of evaluating device and procedural safety (Table 3). The WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT-AF) and Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) studies, which enrolled 707 and 407 patients, respectively, were noninferiority trials that evaluated the WATCHMAN compared with warfarin in AF patients who were candidates for long-term anticoagulation.36,39 PROTECT-AF required enrolled subjects to have a CHADS2 score ≥1, whereas PREVAIL required a CHADS2 score ≥2 or 1 if additional stroke risk factors were present and warfarin therapy was
Downloaded from http://circ.ahajournals.org/ at YORK UNIV SCOTT LIB on July 8, 2014
204 Circulation July 8, 2014 randomly assigned to either device implantation or warfarin therapy in a 2:1 fashion. Patients allocated to device implantation were treated with 6 weeks of warfarin and aspirin, at which time a follow-up TEE was performed. If the TEE findings were adequate (ie, no thrombus and peri-device leak
