Expert Review of Medical Devices
ISSN: 1743-4440 (Print) 1745-2422 (Online) Journal homepage: http://www.tandfonline.com/loi/ierd20
Evaluation of the WATCHMAN left atrial appendage closure device Oluseun Alli & David Holmes Jr To cite this article: Oluseun Alli & David Holmes Jr (2014) Evaluation of the WATCHMAN left atrial appendage closure device, Expert Review of Medical Devices, 11:6, 541-551 To link to this article: http://dx.doi.org/10.1586/17434440.2014.940315
Published online: 25 Jul 2014.
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Date: 20 October 2015, At: 17:59
Device Profile
Evaluation of the WATCHMAN left atrial appendage closure device Expert Rev. Med. Devices 11(6), 541–551 (2014)
Downloaded by [New York University] at 17:59 20 October 2015
Oluseun Alli1 and David Holmes Jr*2 1 The Division of Cardiovascular Diseases and Department of Internal Medicine, University of Alabama, Birmingham, AL, USA 2 The Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 255 5846 Fax: +1 507 255 2550 [email protected]
Left atrial appendage device occlusion for the preventions of systemic thromboembolism and stroke represents a major breakthrough in the field of cardiovascular disease. The wide prevalence of atrial fibrillation with devastating consequences of thromboembolic stroke as a result of thrombus arising from the left atrial appendage has led to the development of transcatheter and surgical based occlusion devices. Though this device is yet to be formally approved for a clinical indication in the USA, the WATCHMAN appendage occlusion device remains the most rigorously examined and studied of all transcatheter-based devices in this space. This review will focus on the needs assessment in this space, the technology of the current WATCHMAN device, trials and studies looking at safety and efficacy, specific patient populations who might benefit as well as future perspectives. KEYWORDS: atrial fibrillation • left atrial appendage • left atrial appendage occlusion • oral anticoagulant • PROTECT AF • WATCHMAN
Atrial fibrillation (AF) remains the most common arrhythmia encountered in clinical practice, and current estimates suggest that over 2 million individuals suffer from AF in the USA with the number expected to increase to over 6 million by 2050 [1]. AF has several deleterious effects, of which thromboembolism leading to stroke is the most devastating. Approximately 20% of all ischemic strokes are secondary to AF and the overall risk of stroke in nonrheumatic AF is on average 5% per year, though the risk varies from individual to individual based on risk factors and comorbidities [2]. AF leads to loss of organized contraction, leading to stasis in the left atrial appendage (LAA), which subsequently leads to thrombus formation with the potential for embolization [3]. LAA anatomy & role in thromboembolism
Embryologically, the LAA is the remnant of the original embryonic left atrium (LA), which is formed from the outgrowth of the pulmonary veins. It overlies the circumflex artery and the great cardiac vein as it lies in the atrioventricular groove. The orifice of the LAA itself is oval in shape, has a diameter of 10–40 mm
informahealthcare.com
10.1586/17434440.2014.940315
and is located between the left upper pulmonary vein and the left ventricle. The LAA anatomically is quite variable, often multilobed made of muscular tissue with trabeculate muscle bars (pectinate muscles FIGURE 1). It ranges in size from 0.77 to 19.27 cm3 and in length from 16 to 51 mm [4]. The specific anatomy of the LAA has been evaluated using transesophageal, computed tomographic and MRI techniques. The use of computed tomography imaging has led to detailed assessment of the LAA, in a study by Wang and colleagues [5]. LAA morphology was characterized using computed tomography imaging. The LAA was classified as follows (FIGURE 2): • LAA with obvious bend (the Chicken Wing); • LAA without an obvious bend – subdivided into three categories; The windsock LAA – one dominant lobe is the primary structure;The cauliflower LAA – LAA with limited length but more complex characteristics;The cactus LAA – has dominant central lobe with secondary lobe extending superiorly and inferiorly. Characterization of the LAA orifice was also performed: the LAA orifice is typically
2014 Informa UK Ltd
ISSN 1743-4440
541
Downloaded by [New York University] at 17:59 20 October 2015
Device Profile
Alli & Holmes Jr
Figure 1. Left atrial appendage anatomy. Measurements of the LAA in an anatomic specimen, the LAA is outlined in black. LA: Left atrium; LAA: Left atrial appendage. Reproduced with permission from [44].
irregular and can be classified into five types; oval (68.9%), foot like (10%), triangular (7.7%), water drop (7.7%) and round (5.6%) (FIGURE 2). The varying shapes of the LAA orifice have important implications for device closure; although the orifice is typically oval or irregular, the current devices are round and accordingly placement may leave behind residual leaks. In addition, by virtue of the length and angulation of the LAA itself, device placement may be difficult because all current devices require a definite but variable length for safe deployment. An additional issue relates to the presence and location of lobes of the LAA: in order to fully protect the patient from the potential for thromboembolism, all of the lobes should be covered. This may be problematic with a short neck of the LAA and prominent proximal lobes. Inability to cover the lobes fully exposes the patient to thrombus formation in the residual uncovered lobes and the potential for thromboembolism. Another issue to be considered relates to the fact that thrombus may form not only in the LAA but also in the body of the LA itself. This is more commonly the case in the setting of valvular AF related to mitral valve disease, but may also be a factor in some albeit uncommon patients with nonvalvular AF [6]. Thromboembolic & bleeding risk in AF
One of the major consequences of AF is thromboembolism leading to stroke; medical therapy has long been the main stay of thrombophylaxis. In patients with nonvalvular AF, there is approximately fivefold increase in the incidence of stroke. The relationship with increasing age, an increasing incidence of AF and increasing rates of stroke has been well documented. Appropriate risk stratification and the need to balance the benefit of stroke prevention with the risk of bleeding from oral anticoagulants are essential. The CHADS2 (Congestive heart 542
failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke/transient ischemic attack) score is the most widely used score in clinical practice [7]; this integer-based scoring system allots one point for congestive heart failure, diabetes, hypertension or patients aged 75 years or older and two points for previous stroke, transient ischemic attack or systemic embolic event. The sum of the points determines the CHADS2 score; the adjusted annual stroke rate increases from 1.9% for patients with a CHADS2 score of 0–18% in a patient with a score of 6 [7]. Current guidelines indicate that patients with CHADS2 score of 2 or more should be treated with warfarin [7–9]. A newer risk score called the CHADS2-VASc score is now being used more commonly and forms the basis for professional societal guidelines for patient assessment [10,11]. This scoring system attempts to overcome the limitations of the CHADS2 score. It has the major advantage of discriminating risk probability in lower risk patients. In the initial CHADS2 score, some patients with a score of 1 were at increased risk of stroke, while others with the same score were at quite low risk. The CHADS2-VASc score is better able to differentiate risk in this group and for that reason is now preferred [10,11]. This specific score assigns points as follows: congestive heart failure/LV dysfunction 1; hypertension 1; age 2; diabetes 1; previous stroke or transient ischemic attack 2; vascular disease–myocardial infarction, peripheral vascular disease, aortic atheroma 1; age 65–74 years 1 and female gender 1 [12]. Low-risk score is defined as a CHADS2-VASc score of 0, intermediate risk is defined as a score of 1 while a high-risk CHADS2-VASc score is defined by a score of 2 or greater. In a study by Lip et al., low-risk patients were found to have 0 events per patient-year, intermediate-risk patients had 0.46 events per patient-year while high-risk patients had greater than 1.71 events per patient-year (p < 0.0001) [13]. As a part of consideration of risk/benefit, the issue of bleeding must be considered. There are several risk prediction models available to assess the risk of bleeding; the HAS-BLED (hypertension, abnormal renal/ liver function, stroke, bleeding history or pre-disposition, labile international normalized ratio (INR), age >65 years, drugs or alcohol use) [14] has become the most widely used. As can be seen, several patient characteristics are common to both stroke and bleeding risk scores, for example, hypertension and age. Pharmacological prevention of stroke
Warfarin and aspirin have been evaluated in several randomized trials for their ability to reduce the risk of stroke associated with nonvalvular AF [15–20]. Hart and colleagues compared the effectiveness of aspirin to warfarin; they found that adjusteddose warfarin reduces the relative risk of stroke by 60–70% compared to placebo [21]. The absolute risk reduction of stroke risk by adjusted-dose warfarin compared to placebo was 2.7% annually for primary prevention and 8.7% annually for secondary prevention. Aspirin has been shown to be less effective than warfarin for stroke prevention in patients with AF. In the same Expert Rev. Med. Devices 11(6), (2014)
Downloaded by [New York University] at 17:59 20 October 2015
Evaluation of the WATCHMAN LAA closure device
Device Profile
meta-analysis, aspirin was shown to A B C reduce the relative risk of stroke by 22%, with an absolute risk reduction of 1.5% annually for primary prevention compared with placebo [21]. Dual antiplatelet therapy (DAPT) with a combination of aspirin and clopidogrel has also been studied for stroke prevention. The ACTIVE W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for the D E F Prevention of Vascular Events) trial compared DAPT to warfarin while the ACTIVE A trial compared DAPT to aspirin alone in patients with AF who were not candidates for warfarin [22,23]. The efficacy of aspirin alone or DAPT with aspirin and a thienopyridine for stroke prevention is low (20–30% relative risk reduction) with an increased risk of significant bleeding [24,25]. G H I There are major limitations to the use of warfarin; these range from the multiple food and drug interactions, its narrow therapeutic window, frequent monitoring and dose adjustments and fatal bleeding consequences. The annual bleeding risk for warfarin has been estimated at 0.6% for fatal bleeds, 3% for major bleeds and 9.6% for all bleeds [25–27]. There is a twoJ K L to fivefold increase in the incidence of intracranial hemorrhage with the use of warfarin that translates to 3500 intracranial bleeds annually [25,28]. The addition of aspirin to warfarin also increases the rate of bleeding with a threefold increase in the rates of intracranial hemorrhage [25,28]. There are multiple issues concerning maintenance of target INR [24,25,29]; several series have highlighted the Figure 2. General morphology classification of LAA and the shape of LAA orifice difficulties of maintaining the INR in the were shown. LAA could be classified into four types including ChickenWing type therapeutic range, 29% of patients are (A, B), WindSock type (C, D), cauliflower type (E) and cactus type (F). The shape of the said to be subtherapeutic on warfarin, LAA orifice could be classified into five types including oval (G), triangular (H), foot-like while 15% are supratherapeutic [30]. New (I, J), water drop-like (K) and round type (L). oral anticoagulants have been developed Reproduced with permission from [5]. and introduced to address the issues of what had been the standard-of-care warfarin. TABLE 1 compares the safety and efficacy of the newer In patients with a CHADS2-VASc score ‡2, the guidelines recommend dabigatran, rivaroxaban, apixaban or adjusted-dose oral anticoagulants to warfarin. Currently, the American College of Cardiology and the warfarin with target INR range of 2.0–3.0 for stroke American Heart Association guidelines recommend the use of prevention [10]. CHADS2-VASc score for risk stratification in patients with AF. In patients with CHADS2-VASc score of 0, it is reason- Non-pharmacological treatment for stroke prevention able to omit antithrombotic therapy and in patients with a Based on the aforementioned issues with oral anticoagulant and CHADS2-VASc score of 1, no antithrombotic therapy or treat- antiplatelet therapies, the increasing knowledge that most clots ment with an oral anticoagulant or aspirin may be considered. originate in the LAA and the location and discrete nature of informahealthcare.com
543
Device Profile
Alli & Holmes Jr
Table 1. Results of large randomized clinical trials of new oral anticoagulants versus warfarin. Clinical events and RCTs
Novel drug and dose
Novel agent (%/yr)
Warfarin (%/yr)
HR (95% CI)
p-value
Dabigatran 110 mg twice daily
1.53
1.69
0.91 (0.74–1.11)
0.34
Dabigatran 150 mg twice daily
1.11
1.69
0.66 (0.53–0.82)
ISSN: 1743-4440 (Print) 1745-2422 (Online) Journal homepage: http://www.tandfonline.com/loi/ierd20
Evaluation of the WATCHMAN left atrial appendage closure device Oluseun Alli & David Holmes Jr To cite this article: Oluseun Alli & David Holmes Jr (2014) Evaluation of the WATCHMAN left atrial appendage closure device, Expert Review of Medical Devices, 11:6, 541-551 To link to this article: http://dx.doi.org/10.1586/17434440.2014.940315
Published online: 25 Jul 2014.
Submit your article to this journal
Article views: 89
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierd20 Download by: [New York University]
Date: 20 October 2015, At: 17:59
Device Profile
Evaluation of the WATCHMAN left atrial appendage closure device Expert Rev. Med. Devices 11(6), 541–551 (2014)
Downloaded by [New York University] at 17:59 20 October 2015
Oluseun Alli1 and David Holmes Jr*2 1 The Division of Cardiovascular Diseases and Department of Internal Medicine, University of Alabama, Birmingham, AL, USA 2 The Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 255 5846 Fax: +1 507 255 2550 [email protected]
Left atrial appendage device occlusion for the preventions of systemic thromboembolism and stroke represents a major breakthrough in the field of cardiovascular disease. The wide prevalence of atrial fibrillation with devastating consequences of thromboembolic stroke as a result of thrombus arising from the left atrial appendage has led to the development of transcatheter and surgical based occlusion devices. Though this device is yet to be formally approved for a clinical indication in the USA, the WATCHMAN appendage occlusion device remains the most rigorously examined and studied of all transcatheter-based devices in this space. This review will focus on the needs assessment in this space, the technology of the current WATCHMAN device, trials and studies looking at safety and efficacy, specific patient populations who might benefit as well as future perspectives. KEYWORDS: atrial fibrillation • left atrial appendage • left atrial appendage occlusion • oral anticoagulant • PROTECT AF • WATCHMAN
Atrial fibrillation (AF) remains the most common arrhythmia encountered in clinical practice, and current estimates suggest that over 2 million individuals suffer from AF in the USA with the number expected to increase to over 6 million by 2050 [1]. AF has several deleterious effects, of which thromboembolism leading to stroke is the most devastating. Approximately 20% of all ischemic strokes are secondary to AF and the overall risk of stroke in nonrheumatic AF is on average 5% per year, though the risk varies from individual to individual based on risk factors and comorbidities [2]. AF leads to loss of organized contraction, leading to stasis in the left atrial appendage (LAA), which subsequently leads to thrombus formation with the potential for embolization [3]. LAA anatomy & role in thromboembolism
Embryologically, the LAA is the remnant of the original embryonic left atrium (LA), which is formed from the outgrowth of the pulmonary veins. It overlies the circumflex artery and the great cardiac vein as it lies in the atrioventricular groove. The orifice of the LAA itself is oval in shape, has a diameter of 10–40 mm
informahealthcare.com
10.1586/17434440.2014.940315
and is located between the left upper pulmonary vein and the left ventricle. The LAA anatomically is quite variable, often multilobed made of muscular tissue with trabeculate muscle bars (pectinate muscles FIGURE 1). It ranges in size from 0.77 to 19.27 cm3 and in length from 16 to 51 mm [4]. The specific anatomy of the LAA has been evaluated using transesophageal, computed tomographic and MRI techniques. The use of computed tomography imaging has led to detailed assessment of the LAA, in a study by Wang and colleagues [5]. LAA morphology was characterized using computed tomography imaging. The LAA was classified as follows (FIGURE 2): • LAA with obvious bend (the Chicken Wing); • LAA without an obvious bend – subdivided into three categories; The windsock LAA – one dominant lobe is the primary structure;The cauliflower LAA – LAA with limited length but more complex characteristics;The cactus LAA – has dominant central lobe with secondary lobe extending superiorly and inferiorly. Characterization of the LAA orifice was also performed: the LAA orifice is typically
2014 Informa UK Ltd
ISSN 1743-4440
541
Downloaded by [New York University] at 17:59 20 October 2015
Device Profile
Alli & Holmes Jr
Figure 1. Left atrial appendage anatomy. Measurements of the LAA in an anatomic specimen, the LAA is outlined in black. LA: Left atrium; LAA: Left atrial appendage. Reproduced with permission from [44].
irregular and can be classified into five types; oval (68.9%), foot like (10%), triangular (7.7%), water drop (7.7%) and round (5.6%) (FIGURE 2). The varying shapes of the LAA orifice have important implications for device closure; although the orifice is typically oval or irregular, the current devices are round and accordingly placement may leave behind residual leaks. In addition, by virtue of the length and angulation of the LAA itself, device placement may be difficult because all current devices require a definite but variable length for safe deployment. An additional issue relates to the presence and location of lobes of the LAA: in order to fully protect the patient from the potential for thromboembolism, all of the lobes should be covered. This may be problematic with a short neck of the LAA and prominent proximal lobes. Inability to cover the lobes fully exposes the patient to thrombus formation in the residual uncovered lobes and the potential for thromboembolism. Another issue to be considered relates to the fact that thrombus may form not only in the LAA but also in the body of the LA itself. This is more commonly the case in the setting of valvular AF related to mitral valve disease, but may also be a factor in some albeit uncommon patients with nonvalvular AF [6]. Thromboembolic & bleeding risk in AF
One of the major consequences of AF is thromboembolism leading to stroke; medical therapy has long been the main stay of thrombophylaxis. In patients with nonvalvular AF, there is approximately fivefold increase in the incidence of stroke. The relationship with increasing age, an increasing incidence of AF and increasing rates of stroke has been well documented. Appropriate risk stratification and the need to balance the benefit of stroke prevention with the risk of bleeding from oral anticoagulants are essential. The CHADS2 (Congestive heart 542
failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke/transient ischemic attack) score is the most widely used score in clinical practice [7]; this integer-based scoring system allots one point for congestive heart failure, diabetes, hypertension or patients aged 75 years or older and two points for previous stroke, transient ischemic attack or systemic embolic event. The sum of the points determines the CHADS2 score; the adjusted annual stroke rate increases from 1.9% for patients with a CHADS2 score of 0–18% in a patient with a score of 6 [7]. Current guidelines indicate that patients with CHADS2 score of 2 or more should be treated with warfarin [7–9]. A newer risk score called the CHADS2-VASc score is now being used more commonly and forms the basis for professional societal guidelines for patient assessment [10,11]. This scoring system attempts to overcome the limitations of the CHADS2 score. It has the major advantage of discriminating risk probability in lower risk patients. In the initial CHADS2 score, some patients with a score of 1 were at increased risk of stroke, while others with the same score were at quite low risk. The CHADS2-VASc score is better able to differentiate risk in this group and for that reason is now preferred [10,11]. This specific score assigns points as follows: congestive heart failure/LV dysfunction 1; hypertension 1; age 2; diabetes 1; previous stroke or transient ischemic attack 2; vascular disease–myocardial infarction, peripheral vascular disease, aortic atheroma 1; age 65–74 years 1 and female gender 1 [12]. Low-risk score is defined as a CHADS2-VASc score of 0, intermediate risk is defined as a score of 1 while a high-risk CHADS2-VASc score is defined by a score of 2 or greater. In a study by Lip et al., low-risk patients were found to have 0 events per patient-year, intermediate-risk patients had 0.46 events per patient-year while high-risk patients had greater than 1.71 events per patient-year (p < 0.0001) [13]. As a part of consideration of risk/benefit, the issue of bleeding must be considered. There are several risk prediction models available to assess the risk of bleeding; the HAS-BLED (hypertension, abnormal renal/ liver function, stroke, bleeding history or pre-disposition, labile international normalized ratio (INR), age >65 years, drugs or alcohol use) [14] has become the most widely used. As can be seen, several patient characteristics are common to both stroke and bleeding risk scores, for example, hypertension and age. Pharmacological prevention of stroke
Warfarin and aspirin have been evaluated in several randomized trials for their ability to reduce the risk of stroke associated with nonvalvular AF [15–20]. Hart and colleagues compared the effectiveness of aspirin to warfarin; they found that adjusteddose warfarin reduces the relative risk of stroke by 60–70% compared to placebo [21]. The absolute risk reduction of stroke risk by adjusted-dose warfarin compared to placebo was 2.7% annually for primary prevention and 8.7% annually for secondary prevention. Aspirin has been shown to be less effective than warfarin for stroke prevention in patients with AF. In the same Expert Rev. Med. Devices 11(6), (2014)
Downloaded by [New York University] at 17:59 20 October 2015
Evaluation of the WATCHMAN LAA closure device
Device Profile
meta-analysis, aspirin was shown to A B C reduce the relative risk of stroke by 22%, with an absolute risk reduction of 1.5% annually for primary prevention compared with placebo [21]. Dual antiplatelet therapy (DAPT) with a combination of aspirin and clopidogrel has also been studied for stroke prevention. The ACTIVE W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for the D E F Prevention of Vascular Events) trial compared DAPT to warfarin while the ACTIVE A trial compared DAPT to aspirin alone in patients with AF who were not candidates for warfarin [22,23]. The efficacy of aspirin alone or DAPT with aspirin and a thienopyridine for stroke prevention is low (20–30% relative risk reduction) with an increased risk of significant bleeding [24,25]. G H I There are major limitations to the use of warfarin; these range from the multiple food and drug interactions, its narrow therapeutic window, frequent monitoring and dose adjustments and fatal bleeding consequences. The annual bleeding risk for warfarin has been estimated at 0.6% for fatal bleeds, 3% for major bleeds and 9.6% for all bleeds [25–27]. There is a twoJ K L to fivefold increase in the incidence of intracranial hemorrhage with the use of warfarin that translates to 3500 intracranial bleeds annually [25,28]. The addition of aspirin to warfarin also increases the rate of bleeding with a threefold increase in the rates of intracranial hemorrhage [25,28]. There are multiple issues concerning maintenance of target INR [24,25,29]; several series have highlighted the Figure 2. General morphology classification of LAA and the shape of LAA orifice difficulties of maintaining the INR in the were shown. LAA could be classified into four types including ChickenWing type therapeutic range, 29% of patients are (A, B), WindSock type (C, D), cauliflower type (E) and cactus type (F). The shape of the said to be subtherapeutic on warfarin, LAA orifice could be classified into five types including oval (G), triangular (H), foot-like while 15% are supratherapeutic [30]. New (I, J), water drop-like (K) and round type (L). oral anticoagulants have been developed Reproduced with permission from [5]. and introduced to address the issues of what had been the standard-of-care warfarin. TABLE 1 compares the safety and efficacy of the newer In patients with a CHADS2-VASc score ‡2, the guidelines recommend dabigatran, rivaroxaban, apixaban or adjusted-dose oral anticoagulants to warfarin. Currently, the American College of Cardiology and the warfarin with target INR range of 2.0–3.0 for stroke American Heart Association guidelines recommend the use of prevention [10]. CHADS2-VASc score for risk stratification in patients with AF. In patients with CHADS2-VASc score of 0, it is reason- Non-pharmacological treatment for stroke prevention able to omit antithrombotic therapy and in patients with a Based on the aforementioned issues with oral anticoagulant and CHADS2-VASc score of 1, no antithrombotic therapy or treat- antiplatelet therapies, the increasing knowledge that most clots ment with an oral anticoagulant or aspirin may be considered. originate in the LAA and the location and discrete nature of informahealthcare.com
543
Device Profile
Alli & Holmes Jr
Table 1. Results of large randomized clinical trials of new oral anticoagulants versus warfarin. Clinical events and RCTs
Novel drug and dose
Novel agent (%/yr)
Warfarin (%/yr)
HR (95% CI)
p-value
Dabigatran 110 mg twice daily
1.53
1.69
0.91 (0.74–1.11)
0.34
Dabigatran 150 mg twice daily
1.11
1.69
0.66 (0.53–0.82)
