Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche George Couch & Ian Sabir To cite this article: George Couch & Ian Sabir (2015) The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche, Hospital Practice, 43:1, 13-21 To link to this article: http://dx.doi.org/10.1080/21548331.2015.1000795
Published online: 06 Jan 2015.
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Date: 21 December 2015, At: 10:23
http://informahealthcare.com/hop ISSN: 2154-8331 (print) Hosp Pract, 2015; 43(1): 13–21 DOI: 10.1080/21548331.2015.1000795
REVIEW
The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche George Couch1 & Ian Sabir2,3 1
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Bye-Fellow in Pathology, Downing College, Cambridge, UK, 2Academic Clinical Fellow in Cardiology, Downing College, Cambridge, UK, and Rayne Institute, St. Thomas’ Hospital, London, UK
Abstract
Keywords:
Atrial fibrillation is associated with a markedly increased risk of thromboembolic stroke. At present, lifelong antithrombotic therapy with warfarin or a novel oral anticoagulant is indicated for prophylaxis in the majority of patients. Left atrial appendage occlusion devices have been developed as an alternative to these agents, aiming to avoid issues around consistency of anticoagulation, bleeding risk, and drug-related side effects. The best evidence is available for Boston Scientific’s WATCHMAN device. The safety and efficacy of WATCHMAN and other similar devices have been questioned, although the increasing body of evidence supports a role in selected settings. A recently updated randomized controlled trial of WATCHMAN (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation [PROTECT-AF]) demonstrates its noninferiority to warfarin and suggests an advantage in terms of functional outcome for patients, with superior net clinical benefit 6 to 9 months after starting treatment. The procedural risk associated with device implantation remains substantial, although improving device design and increasing operator experience means that this should decrease in the future. As the body of data and overall experience around WATCHMAN grow, it may come to be recognized as the best option in selected patients.
Left atrial appendage occlusion, WATCHMAN, antithrombotic therapy, warfarin, novel oral anticoagulant, atrial fibrillation
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting > 1 in 20 Europeans aged > 55 years [1]. Its prevalence in the United States is predicted to increase as much as 2.5-fold over the next 50 years as the population ages [2]. Atrial fibrillation increases the risk of stroke by ‡ 5 times [3]; in elderly patients up to one quarter of strokes may be directly attributable to AF [4]. What is more, strokes in the context of AF appear to result in worse outcomes than do adverse events among those in sinus rhythm [5]. Antiarrhythmic drugs and ablation procedures have been used to attempt to restore sinus rhythm, thereby eliminating risks associated with AF. However, data from the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study (RACE) and the Atrial Fibrillation Followup Investigation of Rhythm Management (AFFIRM) trial suggest the risks remain even in patients who apparently revert to sinus rhythm, possibly because paroxysms of AF still occur [6]. Therefore, targeting stroke risk directly is of paramount importance for this patient group. Anticoagulant therapy comes with a risk of bleeding; clinically significant bleeding occurs in approximately 2% of
History Received 20 August 2014 Accepted 13 October 2014 Published online 6 January 2015
patients each year [7]. Well-managed warfarin therapy, that is, to an international normalized ratio (INR) of 2.5 with a minimum time in the therapeutic range of 60% [8,9], reduces stroke risk by around 64% and is about 39% more effective than therapy with aspirin [10,11]. However, only 15% to 79% of eligible patients are prescribed warfarin [12], primarily because of issues with side effects, drug–drug and drug–food interactions, and compliance with monitoring requirements [13]. One solution lies in development of novel oral anticoagulant (NOAC) agents [14], though these come with their own side effects, interactions, and costs [15]. Over 90% of nonvalvular AF-related left atrial thrombi originate in the left atrial appendage (LAA) [16], a vestigial remnant of the embryonic primary atrium that is not considered to have clear physiological importance, although it may have a role in left atrial decompression and atrial natriuretic factor secretion [17]. This is likely because hemodynamic changes in the LAA in AF result in hypercoagulability and predispose to thrombus formation [18]. It follows, therefore, that occluding the LAA may directly prevent thrombus formation and subsequent embolization, reducing stroke risk and circumventing the downsides of anticoagulant therapy. Long-term follow-up data from patients treated with WATCHMAN are
Correspondence: Ian Sabir, PhD, MRCP, Rayne Institute, St. Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. Tel: +442071880968. E-mail: [email protected] 2015 Informa UK Ltd.
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beginning to provide a clear picture of its clinical potential [19-23]. This article summarizes the current evidence regarding the safety and efficacy of LAA occlusion devices, focusing in particular on WATCHMAN.
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Methods We searched the PubMed database for full-text articles and abstracts published in the English language from 2006 to 2014, and reviewed related heartwire articles and comments. The search terms were atrial fibrillation, nonvalvular, nonrheumatic, thromboembolism, stroke, prophylaxis, WATCHMAN, PLAATO, AMPLATZER cardiac plug, LARIAT, anticoagulant, warfarin, dabigatran, apixaban, rivaroxaban, PROTECT-AF, PREVAIL, LAAOS, RELY, ARISTOTLE, AVERROES, ROCKETAF, and cost.
Left atrial appendage occlusion devices Early approaches to occlusion of the LAA involved surgical excision or exclusion as part of open chest cardiac surgery [24,25]. The relatively low success rates of these procedures, along with their high overall risk to benefit ratios, greatly limit their usefulness [26]. Ongoing interest in the potential value of LAA occlusion, therefore, led to the development of percutaneous devices [27]. The first such device, the Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) system, was withdrawn from the market in December 2006, with Appriva Medical Inc. citing financial reasons due to projected expenditure for clinical approval [28]. There are currently 3 devices available for clinical use: the LARIAT suture delivery system (SentreHEART, Redwood City, CA), the AMPLATZER Cardiac Plug (ACP; St. Jude Medical, Minneapolis, MN), and WATCHMAN (Boston Scientific, Marlborough, MA) [29]. All devices are produced in a variety of sizes to accommodate anatomical variation in the LAA. These devices are constantly being developed: the ACP2 (the AMPLATZER Amulet) [30] and WATCHMAN
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Generation 4 device [31] are the most recent additions to the family. An overview of these devices is provided in Table 1 [20,21,32-43]. WATCHMAN has lower reported rates of stroke, device embolization, and major bleeding, and a similar rate of severe pericardial effusion to that seen with other devices. WATCHMAN also has a consistently shorter procedure time than most other devices [13,26,29]. Due to the quantity and quality of available data, the remainder of this review focuses on WATCHMAN.
Overview of the WATCHMAN device WATCHMAN can be implanted under local or general anesthesia under continuous transesophageal echocardiographic monitoring and fluoroscopic imaging. The procedure is straightforward. In brief: (1) The left atrium is entered through a standard transseptal puncture, and heparin is administered. (2) An access sheath is placed at the origin of the LAA. (3) The ostium is measured using transesophageal echocardiography and angiography. The length, neck, lobe(s), and relationship to the pulmonary veins of the LAA are appraised. (4) A 21-, 24-, 27-, 30-, or 33-mm device is selected and deployed at the ostium via the sheath. (5) Transesophageal echocardiography and LAA angiography (with contrast injected through the sheath) are performed to confirm the positioning of the device and to assess peri-device flow. The dimensions of the device are measured to ensure appropriate compression (with it measuring 80% to 90% of its free size). (6) Manual traction is applied to ensure stability, and then the device is released and the sheath is withdrawn [44,45]. WATCHMAN is the only device that has been directly compared with warfarin in a randomized controlled trial: Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT-AF) [34,44]. In this trial, 707 patients with nonvalvular AF and 1 other CHADS2 risk factor (Congestive heart failure, Hypertension [>140/90 or treated], Age ‡ 75, Diabetes mellitus, and prior Stroke, transient ischemic attack, or thromboembolism) were randomized 2:1 to WATCHMAN (n = 463) or continued warfarin (n = 244). Warfarin was
Table 1. Summary of left atrial appendage occlusion devices. PLAATO ACP Key publications
Regulatory approval Description Delivery
Of note
Park et al., 2011 [36], Guerios et al., 2012 [35], Lam et al., 2014 [41], Freixa et al., 2014 [40] CE, TGA Occlusive disk to sit over Self-expanding nitinol cage the appendage orifice and a covered with expanded lobe to sit within the LAA polytetrafluoroethylene Endocardial: transseptally following femoral venous access
Ostermayer et al., 2005 [38], Bayard et al., 2005 [39]
WATCHMAN
LARIAT
Holmes et al., 2009 [34], Reddy et al., 2011 [33], Reddy et al., 2013 [20,21], Holmes et al., 2014 [22] CE, TGA Self-expanding nitinol frame covered with permeable polyester fabric
Bartus et al., 2012 [32], Stone et al., 2013 [42] FDA, CE Pre-tied suture loop tightened around the LAA
Endocardial and epicardial access: transseptally following femoral venous access and percutaneously into the pericardium Compared to the percutaneous occlusion devices, the LARIAT procedure has the disadvantages of being more invasive and unsuitable for patients with possible pericardial adhesions [29]
Abbreviations: ACP = AMPLATZER Cardiac Plug; PLAATO = Percutaneous Left Atrial Appendage Transcatheter Occlusion; LAA = Left atrial appendage, FDA = United States Food and Drug Administration; CE = European Conformite Europeenne; TGA = Australian Therapeutic Goods Administration.
The WATCHMAN device for stroke prophylaxis in AF
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Event-free probability
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220 389
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Figure 1. Kaplan-Meier curves of the primary efficacy end point, stroke alone, and all-cause mortality from the PROTECT-AF trial. The number at risk is shown above the x-axis.
continued for 45 days after implantation, followed by 4.5 months of clopidogrel and lifelong aspirin. Discontinuation rates were 15.3% in the WATCHMAN group and 22.5% in the warfarin group. Patient follow-up had a median of 2.4 years and a mean of 2.3 ± 1.1 years (range 0–5.9 years), with an aggregate of 1588.4 patient-years. An intention-totreat analysis was performed [20]. The rate ratio (device compared to warfarin therapy to a target INR of 2.0–3.09) for the primary efficacy end point of stroke, systemic embolism, and cardiovascular or unexplained death was a favorable 0.71 (95% CI, 0.44–1.30), giving a posterior probability for noninferiority (PPN) of > 0.99 and for superiority (PPS) of 0.88 (Figure 1). What is more, there was little difference in the rate of ischemic stroke (rate ratio, 1.30; 95% CI, 0.66–3.60; PPN, 0.76; PPS, 0.18) [20]. Focusing on the more worrisome potential adverse events of therapy, WATCHMAN appears to be superior: rates of significant disability (modified Rankin Scale score of ‡ 2 or death) were significantly lower with WATCHMAN than with warfarin (rate ratio, 0.41; 95% CI, 0.22–0.82) [20]. For the primary safety end point of major bleeding, serious pericardial effusion, device embolization, and procedurerelated stroke, the rate ratio compared with warfarin was 1.53 (95% CI, 0.95–2.70) (Figure 2). If adverse events that occurred on the day of device implantation are excluded, the primary efficacy end point for WATCHMAN had an rate
ratio of 0.58 (95% CI, 0.35–1.09; PPN, > 0.99; PPS, 0.95) and the primary safety end point had an rate ratio of 0.77 (95% CI, 0.45–1.45) compared with warfarin. Of note, the ischemic stroke rate of 1.9 per 100 patient-years seen with WATCHMAN decreased to 1.4 when adverse events occurring on the day of implantation were excluded, making it indistinguishable from the warfarin group [20]. Minor adverse events, such as persistent atrial septal defects created during device implantation or low levels of peri-device blood flow, were also noted. These defects closed spontaneously in 93% of cases within a year, and were not associated with an increased rate of stroke or systemic embolism [46]. Such low levels of peri-device flow do not appear to be associated with increased risk of thromboembolism [47]. Event-free probability
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1.0 0.9 0.8 0.7
244 463
0
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155 303
53 116
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Figure 2. Kaplan-Meier curves of the primary safety end point from the PROTECT-AF trial. The number at risk is shown above the x-axis.
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In all, the greatest net clinical benefit appears to come with warfarin in the short term (< 6–9 months after commencement of therapy), but with WATCHMAN in the longer term. This is because the majority of adverse events in the device groups were associated with the implantation procedure, whereas adverse events in the control group accumulated steadily over time, as indicated by the PROTECT-AF cohort (707 patients) as well as the Continued Access Protocol (CAP) registry (566 patients) [31]. Indeed, in the PROTECTAF study the primary safety end-point adverse event rate for the WATCHMAN group fell from 5.5 to 2.8 adverse events per 100 patient-years when excluding adverse events occurring on the day of implantation, where the adverse event rate of the warfarin group remained at 3.6 [20]. One must be mindful that net clinical benefit is a product of the weighting attributed to adverse events; however, it was only found to favor anticoagulation when the weighting for pericardial effusion was increased to > 1.1 in the PROTECTAF cohort and to > 4.7 in the CAP cohort; death carries an impact weight of 1. Net clinical benefit for LAA occlusion was greatest for patients with the highest risk of stroke, most notably those with higher CHADS2 scores and those in whom LAA occlusion was employed as secondary prevention [31].
Criticisms of WATCHMAN Approval by governmental agencies WATCHMAN has been approved in Europe and Australia, but has not yet been approved by the United States Food and Drug Administration (FDA). In 2009, there was a 7 to 5 vote in favor of approval, leading to the Prospective Randomized EVAluation of the WATCHMAN LAA Closure Device In Patients with AF Versus Long Term Warfarin Therapy (PREVAIL) trial (407 patients with nonvalvular atrial fibrillation with a CHADS2 of ‡ 2, or 1 with an additional risk factor, randomized 2:1 WATCHMAN [n = 269] to warfarin [n = 138]) [22] to confirm safety and efficacy. In late 2013 the FDA voted 13 to 1 in favor, deciding that WATCHMAN was a safe and effective treatment against embolism of thrombi from the LAA; however, the FDA did not approve it, instead putting it forward for a third advisory panel meeting that is as yet unscheduled [48]. Statistical issues with key trials The results of the PROTECT-AF trial have been criticized regarding the wide confidence intervals reported. This is due to the number of patients enrolled, which while large for an interventional study, was smaller than that used in comparable drug trials [49-51]. However, the statistical methodology was sufficiently rigorous to account for this, with the exception of a lack of adjustment for multiple comparisons for the post-hoc analyses [20]. In addition, in the PREVAIL trial, the 95% credibility interval (CrI) upper limit for noninferiority was 1.75 for the primary efficacy end-point rate ratio, and was 0.0275 for the lateischemic primary efficacy end-point risk difference (equivalent
Hosp Pract, 2015; 43(1):13–21
to an rate ratio of > 4.2). As an additional minor point, again no adjustments were made for multiple comparisons [22]. Controversy surrounding the PREVAIL trial was sparked in early 2013 when clinicaltrials.org was updated to change the study description to include a safety review, convert the main goal to 3 separate objectives and to alter the 6-month time period to 18-month rates [52]. The PREVAIL trial recently yielded its first publication, though with a median follow-up of only 12 months (range 0.03–25.9 months). The late-ischemic efficacy end point (ischemic stroke or systemic embolism excluding the first 7 days after randomization) achieved noninferiority with an 18-month risk difference of 0.0053 (95% CrI, 0.0190 to 0.0273), providing some support for the hypothesis that LAA occlusion in the absence of long-term anticoagulation can prevent ischemic adverse events [22]. However, the primary efficacy end point (all stroke, systemic embolism, and cardiovascular/unexplained death) yielded an 18-month rate ratio of 1.07 (95% CrI, 0.57–1.89), exceeding the margin of 1.75, so noninferiority was not achieved. This result could be due to the limited follow-up period, as WATCHMAN has already been demonstrated to show the most benefit in the long term. It is also noteworthy that there was an unexpectedly low adverse event rate in the warfarin control group as compared with recent pharmaceutical randomly controlled trials, with a rate of 0.71 per 100 patient-years in PREVAIL [22], compared to 1.7, 1.6, and 2.2 in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) [49], Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) [53], and Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [50] trials, respectively. This in turn could be due to a higher time in the therapeutic range of 68% compared with 64%, 62%, and 55%, respectively [22,49,50,53,54]. Requirement for concomitant antithrombotic therapy Patients receiving WATCHMAN as part of the PROTECTAF or PREVAIL trials received warfarin therapy for at least the 45 days following device implantation while endothelialization occurred; this was thought to be important because of the device’s permeability to blood [44]. Treatment was continued past this stage in 13.2% of patients in PROTECT-AF and 7.8% of patients in PREVAIL, due to blood flow being detected across more than a 5-mm area of the LAA opening [20,22]. Patients with a contraindication for oral anticoagulants (due to poor INR compliance, risk of bleeding or falls, or intolerable side effects) would not be able to undergo WATCHMAN implantation under this protocol. Given that the only long-term therapeutic intervention available to these patients is antiplatelet agents, WATCHMAN could offer real benefit were the requirement for a period of bridging therapy to be removed [36]. Such bridging therapy was not used in the ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP) study, an initial feasibility
The WATCHMAN device for stroke prophylaxis in AF
assessment undertaken in 150 patients and designed to assess implantation of WATCHMAN in warfarin-ineligible patients (as defined by hemorrhagic or bleeding tendencies [93%], blood dyscrasias, unsupervised patients with senility or high fall risk, or another documented reason such as hypersensitivity to warfarin). Despite the absence of warfarin cover, there was little difference in the incidence of serious procedure or device-related adverse events. After 176.9 patient-years of follow-up, an annual ischemic stroke rate of 1.7% was observed. By comparison, the mean patient CHADS2 score of 2.8 predicted an annual rate of ischemic stroke of 7.4% if untreated, 7.3% if treated with aspirin, and 5.0% if treated with clopidogrel [21]. However, one should keep in mind that this study was uncontrolled and potentially subject to bias. Concern about the possibility that WATCHMAN itself might be prothrombotic has also led to a requirement that patients with a device in situ be treated with 6 months of clopidogrel and lifelong aspirin [20]. In the community, patientinitiated discontinuation of aspirin for secondary prevention of cardiovascular adverse events can be as high as 30% [55]. It will therefore be necessary in clinical practice to appropriately educate patients and to assess their risk of nonadherence to antiplatelet regimes. Procedural risk The clear downside of WATCHMAN implantation is the high rate of procedure-associated adverse events. This can be reduced both by improvements in device design [56] (now approaching the fourth generation [31]) and by increasing operator experience. There is a clear precedent for a volume– outcome relationship in improving safety of percutaneous cardiac device implantation, as seen with Transcatheter Aortic Valve Implantation (TAVI) [57] and Left Atrial Appendage Occlusion Study (LAAOS) [58] trials. The PROTECT-AF operators were interventional cardiologists or electrophysiologists who all routinely performed procedures requiring transseptal punctures clinically and underwent training using a simulation model. Even so, at sites across the entire PROTECT-AF trial, the first 3 patients were at greater risk than the later patients at any single site (P = 0.012) [33]. Based on this finding, operators for the CAP registry had all participated in PROTECT-AF and so were continuing Event-free probability
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Safety event incidence
1.0 0.9 0.8 0.7 0.6
CAP PROTECT-AF later PROTECT-AF earlier 460 250 212 271 240 235 271 226 221
0
133 231 219
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Figure 3. Kaplan-Meier curves of the incidence of procedure- or devicerelated safety adverse events for patients enrolled in the first (earlier) half and the second (later) half of the PROTECT-AF trial and in the CAP Registry. The number at risk is shown above the x-axis.
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to build on prior experience. Comparing the PROTECT-AF patients with the CAP registry patients, the CAP registry had a significantly shorter procedure time (P < 0.001), adverse event rate (P = 0.007), serious pericardial effusion rate (P = 0.019), and stroke rate (P = 0.039), with a higher implant success rate (P = 0.001) (Figure 3) [33]. This was all despite the CAP registry including a patient cohort with a significantly higher CHADS2 score (2.5 compared to 2.2, P < 0.001) [22]. The trends were also consistent when only assessing sites that participated in both trials, though due to the smaller patient numbers involved, only the procedure time and implant success rate were significantly improved [33]. Continuing this trend, the PREVAIL trial met its early safety end point (all-cause death, ischemic stroke, systemic embolism, or device/procedure-related adverse events requiring surgical intervention within 7 days of the procedure or during the index of hospitalization) with a result of 2.2%, statistically less than the performance goal of 2.67%. Compared with the PROTECT-AF trial, the PREVAIL trial showed an increased implant success rate (P = 0.04) and lower rates of all 7-day procedural complications (P = 0.004), pericardial effusion requiring surgery (P = 0.03), and procedure-related strokes (P = 0.02), despite a higher CHADS2 score of 2.6 (P < 0.001). Importantly, in the PREVAIL trial 38.8% of patients were enrolled at new sites that had not implanted WATCHMAN before, and 39.1% of procedures were performed by new operators. This implies that the knowledge gained during PROTECT-AF and CAP can be effectively transferred to new sites and operators [22]. With the increasing body of experience surrounding the insertion procedure, we might expect that adverse event rates will continue to approach a minimum level. As the number of procedural adverse events decreases, the point at which WATCHMAN cohorts will have fewer adverse events than warfarin cohorts will become chronologically sooner after device insertion, potentially making the device the better clinical choice. However, transcutaneous procedures will always carry risk, and it is difficult to predict where the minimum level for this risk will lie.
Aims for future research Relevant comparisons A number of pharmaceutical alternatives to warfarin have recently become available. Three drugs (dabigatran, rivaroxaban, and apixaban), collectively termed the novel oral anticoagulants (NOACs), are now accessible, with further drugs (edoxaban and betrixaban [59]) in late-stage clinical trials. A recent meta-analysis of the main trials for dabigatran (the RE-LY trial) [49], rivaroxaban (the ROCKET AF trial) [50], apixaban (the ARISTOTLE trial) [51], and edoxaban (the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48] trial) [60] reaffirmed their marked benefits (at their higher doses, where applicable) over warfarin, indicating that as a group they offer a significant reduction in all-cause mortality, no significant difference from
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Subanalysis of the PROTECT-AF and CAP Registry cohorts indicated that WATCHMAN provides the greatest net clinical benefit over warfarin for patients with higher CHADS2 scores, with the most benefit for patients with a score of 5 or 6, with a progressive decline for patients with progressively lower scores [31]. The same was seen when ranking patients by AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) [67] bleeding risk score (looking at hypertension or prior hemorrhage, age ‡ 75 years, and severe renal disease or anemia), with the greatest benefit seen in patients with a score ‡ 4 [31]. It has been suggested that LAA occlusion should be considered for all patients with a CHADS2 or CHA2DS2-VASc (which adds Vascular disease, Age 65 to 74 years, and Sex category of female as stroke risk factors to CHADS2) score ‡ 2 and a high risk of bleeding (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [> 65], Drugs/alcohol/medications predisposing to bleeding concomitantly [HAS-BLED] ‡ 3). This is especially true for patients with recurrent ischemic stroke despite good warfarin compliance, previous intracranial haemorrhage, recurrent gastrointestinal bleeding, coagulopathies, intolerance to NOACs, or other relevant comorbidities [68]. Physicians should choose to treat patients with LAA occlusion based on a clinical decision referring to the patient’s overall health, procedural risks, and operator experience, as well as tolerance and compliance with oral anticoagulant drugs, taking into account patient preference.
P = 0.001). The mean and maximum widths of the leak were 2.8 and 6.2 mm, and 7.7%, 59.9%, and 32.4% of leaks were minor (< 1 mm), moderate (1–3 mm), or severe (> 3 mm), respectively, at 45 days. There was no difference found for primary efficacy adverse event rates, ischemic stroke alone, and composite ischemic stroke and systemic embolism between patients with and those without a leak. There was also no association between leak severity and adverse events [47]. In the PROTECT-AF trial, 13.2% of patients who had received the device continued taking warfarin bridging therapy at 45 days postprocedure, decreasing to 6.8% at 12 months. This was due to a leak > 5 mm wide, or on the advice of the treating physician [20]. The subanalysis found that there was no difference between adverse event rates and patients with no leak with discontinued warfarin, no leak with continued warfarin, leak with discontinued warfarin, and leak with continued warfarin [47]. However, as a consequence of the original study design, this subanalysis has limited statistical power. This lack of association between residual peri-device flow and ischemic adverse events was corroborated by a long-term (average 58 ± 9 month) follow-up of a PLAATO device trial (n = 22 patients) [69]. In addition to peri-device flow, thrombi can form on the devices themselves. One analysis noted 4.2% (20/478) of patients with successfully inserted devices in the PROTECTAF trial developed device-associated thrombus, of whom 3 experienced ischemic stroke [33]. It is unclear what the optimal protocol for follow-up imaging and treatment is, but the endothelialization that occurs on the device should minimize this risk [70]. It is also possible for implanted devices to migrate. There is a case report of interest that successfully demonstrates transcatheter closure of an incomplete LAA occlusion using a second device. In this case, a 30-mm WATHCMAN was inserted and was discovered to have a 4 mm leak. The patient was resistant to continuing oral anticoagulation. Three years later, the device was discovered to have migrated distally into a lobe of a multilobar LAA, and a 7-mm leak and thrombus in the residual pouch were noted. The appendage was then successfully closed (leaving the original device remaining in situ) using an ACP2 AMPLATZER amulet device after 3 months of warfarin treatment [71]. The ACP2 device was chosen due to a delivery cable with an inner wire allowing tension-free assessment of the device before delivery, which can be helpful in challenging situations [30,71]. As with any surgical procedure, there are many other potential complications that are much rarer, such as cardiac perforation [43]. Further investigation of difficulties arising after device implantation would benefit decisions regarding clinical relevance and in drafting appropriate criteria for further treatment.
Procedural difficulties
Cost-effectiveness
A subanalysis of the PROTECT-AF trial at 1500 patientyears of follow-up found that 40.9% of patients had peridevice flow on transesophageal echocardiography at 45 days postprocedure (decreasing to 32.1% at 12 months,
Although NOACs are expensive, they are considered potentially fundable by the National Institute of Clinical Excellence, with the most plausible incremental cost-effectiveness ratio being < £20 000 (< $32 000) per quality adjusted life
warfarin in myocardial infarction or ischemic stroke alone, and a 19% reduction in composite stroke or systemic embolism, 51% reduction in hemorrhagic stroke, and 52% reduction in intracranial hemorrhage [54]. The NOACs are not perfect, however. Though apixaban shows reduced rates of major bleeding compared with warfarin, dabigatran and rivaroxaban show significantly increased rates of gastrointestinal bleeding [14,23,54]. There are also questions regarding a potentially increased rate of myocardial infarction with the lower dose regime of dabigatran [15]. Another benefit of the NOACs over warfarin is that they have a short half-life, meaning that they rapidly self-reverse [61]. Although there are no antidotes to them currently available, antidotes will most likely be in clinical use within the year [62]. The NOACs also have far fewer drug and food interactions than warfarin, though care should still be taken by the prescribing physician [63-66]. Thus, the most relevant comparison going forward will be between WATCHMAN and these new agents. No such data are available at present. Patient selection
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The WATCHMAN device for stroke prophylaxis in AF
year gained for apixaban and dabigatran, and £28 700 to 29 500 ($45 900 to 47 200) for rivaroxaban, although these figures vary substantially depending on patient group and prescription protocol [15]. There are currently few data available regarding the cost-effectiveness of therapy with WATCHMAN. Clearly calculations are complex, needing to account for the cost of the procedure, the device itself, the associated training, and the expertise and facilities required.
the community: the Framingham Heart Study. JAMA 2003;290: 1049–56. Tu HT, Campbell BC, Christensen S, et al. Pathophysiological determinants of worse stroke outcome in atrial fibrillation. Cerebrovasc Dis 2010;30:389–95. Blackshear JL, Safford RE; AFFIRM trial; RACE trial. AFFIRM and RACE trials: implications for the management of atrial fibrillation. Cardiac Electrophysiol Rev 2003;7:366–9. DiMarco JP, Flaker G, Waldo AL, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005; 149:650–6. Sabir IN, Matthews GD, Huang CL. Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice. Postgrad Med J 2013;89:346–51. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360–420. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012;172:623–31; discussion 631–623. Ferro D, Loffredo L, Polimeni L, Violi F. Underuse of oral anticoagulants in patients with nonvalvular atrial fibrillation in Italy. Intern Emerg Med 2007;2:24–8. Lam YY, Ma TK, Yan BP. Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation. Int J Cardiol 2011;150:4–11. Potpara TS, Lip GY, Apostolakis S. New anticoagulant treatments to protect against stroke in atrial fibrillation. Heart 2012;98:1341–7. Harris K, Mant J. Potential impact of new oral anticoagulants on the management of atrial fibrillation-related stroke in primary care. Int J Clin Pract 2013;67:647–55. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999;82: 547–54. Pollick C, Taylor D. Assessment of left atrial appendage function by transesophageal echocardiography. Implications for the development of thrombus. Circulation 1991;84:223–31. Alli O, Doshi S, Kar S, et al. Quality of life assessment in the randomized PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial of patients at risk for stroke with nonvalvular atrial fibrillation. J Am Coll Cardiol 2013;61:1790–8. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) trial. Circulation 2013;127:720–9. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the watchman device in patients with a contraindication for oral anticoagulation: ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP study). J Am Coll Cardiol 2013;61:2551–6. Holmes DR Jr, Kar S, Price MJ, et al. 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. Holmes DR Jr, Lakkireddy DR, Whitlock RP, Waksman R, Mack MJ. Left atrial appendage occlusion: opportunities and challenges. J Am Coll Cardiol 2014;63:291–8.
[5] [6] [7]
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Conclusion There is an established demand for thromboembolic prophylaxis in patients with nonvalvular atrial fibrillation. The mainstay of current treatment is warfarin therapy, although advances in pharmacotherapy are producing potentially clinically superior alternatives. The LAA occlusion devices such as WATCHMAN offer another option. Recent updates to the available evidence have added to the data for the device’s noninferior efficacy as compared with warfarin, noting a narrowing in the difference between safety end points. In addition, there is accumulating evidence that improving device design and increasing operator experience reduce the risk of adverse events associated with device implantation. Analyses of patients’ functional outcomes and of net clinical benefit have started to suggest potential benefits of occlusion over lifelong warfarin therapy. WATCHMAN appears to be superior to antiplatelet therapy alone; at the very least, LAA occlusion devices could become a commonplace alternative treatment for patients unable or unwilling to take novel oral anticoagulants.
[8] [9]
[10] [11]
[12] [13] [14] [15] [16]
Acknowledgments The authors gratefully acknowledge support from the Wellcome Trust, the British Heart Foundation, and the National Institute for Healthcare Research. All authors contributed to identification of appropriate papers, manuscript presentation or editing and review prior to submission.
[17] [18] [19]
Declaration of interest G. Couch, BA, has no conflict of interest to declare. I. Sabir, PhD, MRCP, acknowledges the receipt of consulting fees from Daiichi Sankyo Europe GmbH.
[20]
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[24] Dawson AG, Asopa S, Dunning J. Should patients undergoing cardiac surgery with atrial fibrillation have left atrial appendage exclusion? Interact Cardiovasc Thorac Surg 2010;10:306–11. [25] Madden JL. Resection of the left auricular appendix; a prophylaxis for recurrent arterial emboli. JAMA 1949;140:769–72. [26] Apostolakis E, Papakonstantinou NA, Baikoussis NG, Koniari I, Papadopoulos G. Surgical strategies and devices for surgical exclusion of the left atrial appendage: a word of caution. J Cardiac Surg 2013;28:199–206. [27] Landmesser U, Holmes DR Jr. Left atrial appendage closure: a percutaneous transcatheter approach for stroke prevention in atrial fibrillation. Eur Heart J 2012;33:698–704. [28] Khattab AA, Meier B. Transcatheter left atrial appendage closure for stroke prevention among atrial fibrillation patients. Expert Review Cardiovasc Ther 2012;10:819–21. [29] Luis SA, Roper D, Incani A, Poon K, Haqqani H, Walters DL. Non-pharmacological therapy for atrial fibrillation: managing the left atrial appendage. Cardiol Res Pract 2012;2012:304626. [30] Freixa X, Chan JL, Tzikas A, Garceau P, Basmadjian A, Ibrahim R. The Amplatzer Cardiac Plug 2 for left atrial appendage occlusion: novel features and first-in-man experience. EuroIntervention 2013;8:1094–8. [31] Gangireddy SR, Halperin JL, Fuster V, Reddy VY. Percutaneous left atrial appendage closure for stroke prevention in patients with atrial fibrillation: an assessment of net clinical benefit. Eur Heart J 2012;33:2700–8. [32] Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J Am Coll Cardiol 2013;62:108–18. [33] 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;123:417–24. [34] Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised noninferiority trial. Lancet 2009;374:534–42. [35] Guerios EE, Schmid M, Gloekler S, et al. Left atrial appendage closure with the Amplatzer cardiac plug in patients with atrial fibrillation. Arq Bras Cardiol 2012;98:528–36. [36] Park JW, Bethencourt A, Sievert H, et al. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77:700–6. [37] Bayard YL, Omran H, Neuzil P, et al. PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible atrial fibrillation patients: results from the European PLAATO study. EuroIntervention 2010;6:220–6. [38] Ostermayer SH, Reisman M, Kramer PH, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14. [39] Bayard YL, Ostermayer SH, Sievert H. Transcatheter occlusion of the left atrial appendage for stroke prevention. Expert Rev Cardiovasc Ther 2005;3:1003–8. [40] Freixa X, Abualsaud A, Chan J, et al. Left atrial appendage occlusion: initial experience with the Amplatzer Amulet. Int J Cardiol 2014;174:492–6. [41] Lam SC, Bertog S, Gafoor S, et al. Left atrial appendage closure using the amulet device: An initial experience with the second generation amplatzer cardiac plug. Catheter Cardiovasc Interv 2014; doi:10.1002/ccd.25644. [42] Stone D, Byrne T, Pershad A. Early results with the LARIAT device for left atrial appendage exclusion in patients with atrial fibrillation at high risk for stroke and anticoagulation. 2013;Catheter Cardiovasc Interv doi:10.1002/ccd.25065. [43] Sakellaridis T, Argiriou M, Charitos C, et al. Left atrial appendage exclusion—where do we stand? J Thorac Dis 2014;6:S70–7. [44] Fountain RB, Holmes DR, Chandrasekaran K, et al. The PROTECT AF (WATCHMAN Left Atrial Appendage System for
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Embolic PROTECTion in Patients with Atrial Fibrillation) trial. Am Heart J 2006;151:956–61. Bergmann MW, Landmesser U. Left atrial appendage closure for stroke prevention in non-valvular atrial fibrillation: rationale, devices in clinical development and insights into implantation techniques. EuroIntervention 2014;10:497–504. Singh SM, Douglas PS, Reddy VY. The incidence and long-term clinical outcome of iatrogenic atrial septal defects secondary to transseptal catheterization with a 12F transseptal sheath. Circ Arrhythm Electrophysiol 2011;4:166–71. Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9. PREVAIL published: Watchman safe, meets one of two efficacy end points. http://www.medscape.com/viewarticle/827567. Accessed August 8, 2014. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–51. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL). http://clinicaltrials.gov/show/NCT01182441. Accessed October 6, 2013. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. Herlitz J, Toth PP, Naesdal J. Low-dose aspirin therapy for cardiovascular prevention: quantification and consequences of poor compliance or discontinuation. Am J Cardiovasc Drugs 2010;10: 125–41. Sick PB, Schuler G, Hauptmann KE, et al. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2007;49:1490–5. Fairbairn TA, Meads DM, Mather AN, et al. Serial change in health-related quality of life over 1 year after transcatheter aortic valve implantation: predictors of health outcomes. J Am Coll Cardiol 2012;59:1672–80. Healey JS, Crystal E, Lamy A, et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005;150: 288–93. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013;34:1498–505. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. Lai A, Davidson N, Galloway SW, Thachil J. Perioperative management of patients on new oral anticoagulants. Br J Surg 2014;101:742–9. Lauw MN, Coppens M, Eikelboom JW. Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent. Can J Cardiol 2014;30:381–4. Lippi G, Favaloro EJ, Mattiuzzi C. Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring? Semin Thromb Hemost 2014;40:756–65. Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 2014;35:1844–55.
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[69] Viles-Gonzalez JF, Reddy VY, Petru J, et al. Incomplete occlusion of the left atrial appendage with the percutaneous left atrial appendage transcatheter occlusion device is not associated with increased risk of stroke. J Interv Cardiac Electrophysiol 2012;33: 69–75. [70] Schwartz RS, Holmes DR, Van Tassel RA, et al. Left atrial appendage obliteration: mechanisms of healing and intracardiac integration. JACC Cardiovasc Interv 2010;3:870–7. [71] Lam SC, Bertog S, Sievert H. Incomplete left atrial appendage occlusion and thrombus formation after Watchman implantation treated with anticoagulation followed by further transcatheter closure with a second-generation Amplatzer Cardiac Plug (Amulet device). Catheter Cardiovasc Interv 2014;doi:10.1002/ ccd.25456.
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The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche George Couch & Ian Sabir To cite this article: George Couch & Ian Sabir (2015) The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche, Hospital Practice, 43:1, 13-21 To link to this article: http://dx.doi.org/10.1080/21548331.2015.1000795
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Date: 21 December 2015, At: 10:23
http://informahealthcare.com/hop ISSN: 2154-8331 (print) Hosp Pract, 2015; 43(1): 13–21 DOI: 10.1080/21548331.2015.1000795
REVIEW
The WATCHMAN device for stroke prophylaxis in atrial fibrillation: an evolving niche George Couch1 & Ian Sabir2,3 1
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3
Bye-Fellow in Pathology, Downing College, Cambridge, UK, 2Academic Clinical Fellow in Cardiology, Downing College, Cambridge, UK, and Rayne Institute, St. Thomas’ Hospital, London, UK
Abstract
Keywords:
Atrial fibrillation is associated with a markedly increased risk of thromboembolic stroke. At present, lifelong antithrombotic therapy with warfarin or a novel oral anticoagulant is indicated for prophylaxis in the majority of patients. Left atrial appendage occlusion devices have been developed as an alternative to these agents, aiming to avoid issues around consistency of anticoagulation, bleeding risk, and drug-related side effects. The best evidence is available for Boston Scientific’s WATCHMAN device. The safety and efficacy of WATCHMAN and other similar devices have been questioned, although the increasing body of evidence supports a role in selected settings. A recently updated randomized controlled trial of WATCHMAN (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation [PROTECT-AF]) demonstrates its noninferiority to warfarin and suggests an advantage in terms of functional outcome for patients, with superior net clinical benefit 6 to 9 months after starting treatment. The procedural risk associated with device implantation remains substantial, although improving device design and increasing operator experience means that this should decrease in the future. As the body of data and overall experience around WATCHMAN grow, it may come to be recognized as the best option in selected patients.
Left atrial appendage occlusion, WATCHMAN, antithrombotic therapy, warfarin, novel oral anticoagulant, atrial fibrillation
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting > 1 in 20 Europeans aged > 55 years [1]. Its prevalence in the United States is predicted to increase as much as 2.5-fold over the next 50 years as the population ages [2]. Atrial fibrillation increases the risk of stroke by ‡ 5 times [3]; in elderly patients up to one quarter of strokes may be directly attributable to AF [4]. What is more, strokes in the context of AF appear to result in worse outcomes than do adverse events among those in sinus rhythm [5]. Antiarrhythmic drugs and ablation procedures have been used to attempt to restore sinus rhythm, thereby eliminating risks associated with AF. However, data from the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study (RACE) and the Atrial Fibrillation Followup Investigation of Rhythm Management (AFFIRM) trial suggest the risks remain even in patients who apparently revert to sinus rhythm, possibly because paroxysms of AF still occur [6]. Therefore, targeting stroke risk directly is of paramount importance for this patient group. Anticoagulant therapy comes with a risk of bleeding; clinically significant bleeding occurs in approximately 2% of
History Received 20 August 2014 Accepted 13 October 2014 Published online 6 January 2015
patients each year [7]. Well-managed warfarin therapy, that is, to an international normalized ratio (INR) of 2.5 with a minimum time in the therapeutic range of 60% [8,9], reduces stroke risk by around 64% and is about 39% more effective than therapy with aspirin [10,11]. However, only 15% to 79% of eligible patients are prescribed warfarin [12], primarily because of issues with side effects, drug–drug and drug–food interactions, and compliance with monitoring requirements [13]. One solution lies in development of novel oral anticoagulant (NOAC) agents [14], though these come with their own side effects, interactions, and costs [15]. Over 90% of nonvalvular AF-related left atrial thrombi originate in the left atrial appendage (LAA) [16], a vestigial remnant of the embryonic primary atrium that is not considered to have clear physiological importance, although it may have a role in left atrial decompression and atrial natriuretic factor secretion [17]. This is likely because hemodynamic changes in the LAA in AF result in hypercoagulability and predispose to thrombus formation [18]. It follows, therefore, that occluding the LAA may directly prevent thrombus formation and subsequent embolization, reducing stroke risk and circumventing the downsides of anticoagulant therapy. Long-term follow-up data from patients treated with WATCHMAN are
Correspondence: Ian Sabir, PhD, MRCP, Rayne Institute, St. Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. Tel: +442071880968. E-mail: [email protected] 2015 Informa UK Ltd.
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beginning to provide a clear picture of its clinical potential [19-23]. This article summarizes the current evidence regarding the safety and efficacy of LAA occlusion devices, focusing in particular on WATCHMAN.
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Methods We searched the PubMed database for full-text articles and abstracts published in the English language from 2006 to 2014, and reviewed related heartwire articles and comments. The search terms were atrial fibrillation, nonvalvular, nonrheumatic, thromboembolism, stroke, prophylaxis, WATCHMAN, PLAATO, AMPLATZER cardiac plug, LARIAT, anticoagulant, warfarin, dabigatran, apixaban, rivaroxaban, PROTECT-AF, PREVAIL, LAAOS, RELY, ARISTOTLE, AVERROES, ROCKETAF, and cost.
Left atrial appendage occlusion devices Early approaches to occlusion of the LAA involved surgical excision or exclusion as part of open chest cardiac surgery [24,25]. The relatively low success rates of these procedures, along with their high overall risk to benefit ratios, greatly limit their usefulness [26]. Ongoing interest in the potential value of LAA occlusion, therefore, led to the development of percutaneous devices [27]. The first such device, the Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) system, was withdrawn from the market in December 2006, with Appriva Medical Inc. citing financial reasons due to projected expenditure for clinical approval [28]. There are currently 3 devices available for clinical use: the LARIAT suture delivery system (SentreHEART, Redwood City, CA), the AMPLATZER Cardiac Plug (ACP; St. Jude Medical, Minneapolis, MN), and WATCHMAN (Boston Scientific, Marlborough, MA) [29]. All devices are produced in a variety of sizes to accommodate anatomical variation in the LAA. These devices are constantly being developed: the ACP2 (the AMPLATZER Amulet) [30] and WATCHMAN
Hosp Pract, 2015; 43(1):13–21
Generation 4 device [31] are the most recent additions to the family. An overview of these devices is provided in Table 1 [20,21,32-43]. WATCHMAN has lower reported rates of stroke, device embolization, and major bleeding, and a similar rate of severe pericardial effusion to that seen with other devices. WATCHMAN also has a consistently shorter procedure time than most other devices [13,26,29]. Due to the quantity and quality of available data, the remainder of this review focuses on WATCHMAN.
Overview of the WATCHMAN device WATCHMAN can be implanted under local or general anesthesia under continuous transesophageal echocardiographic monitoring and fluoroscopic imaging. The procedure is straightforward. In brief: (1) The left atrium is entered through a standard transseptal puncture, and heparin is administered. (2) An access sheath is placed at the origin of the LAA. (3) The ostium is measured using transesophageal echocardiography and angiography. The length, neck, lobe(s), and relationship to the pulmonary veins of the LAA are appraised. (4) A 21-, 24-, 27-, 30-, or 33-mm device is selected and deployed at the ostium via the sheath. (5) Transesophageal echocardiography and LAA angiography (with contrast injected through the sheath) are performed to confirm the positioning of the device and to assess peri-device flow. The dimensions of the device are measured to ensure appropriate compression (with it measuring 80% to 90% of its free size). (6) Manual traction is applied to ensure stability, and then the device is released and the sheath is withdrawn [44,45]. WATCHMAN is the only device that has been directly compared with warfarin in a randomized controlled trial: Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT-AF) [34,44]. In this trial, 707 patients with nonvalvular AF and 1 other CHADS2 risk factor (Congestive heart failure, Hypertension [>140/90 or treated], Age ‡ 75, Diabetes mellitus, and prior Stroke, transient ischemic attack, or thromboembolism) were randomized 2:1 to WATCHMAN (n = 463) or continued warfarin (n = 244). Warfarin was
Table 1. Summary of left atrial appendage occlusion devices. PLAATO ACP Key publications
Regulatory approval Description Delivery
Of note
Park et al., 2011 [36], Guerios et al., 2012 [35], Lam et al., 2014 [41], Freixa et al., 2014 [40] CE, TGA Occlusive disk to sit over Self-expanding nitinol cage the appendage orifice and a covered with expanded lobe to sit within the LAA polytetrafluoroethylene Endocardial: transseptally following femoral venous access
Ostermayer et al., 2005 [38], Bayard et al., 2005 [39]
WATCHMAN
LARIAT
Holmes et al., 2009 [34], Reddy et al., 2011 [33], Reddy et al., 2013 [20,21], Holmes et al., 2014 [22] CE, TGA Self-expanding nitinol frame covered with permeable polyester fabric
Bartus et al., 2012 [32], Stone et al., 2013 [42] FDA, CE Pre-tied suture loop tightened around the LAA
Endocardial and epicardial access: transseptally following femoral venous access and percutaneously into the pericardium Compared to the percutaneous occlusion devices, the LARIAT procedure has the disadvantages of being more invasive and unsuitable for patients with possible pericardial adhesions [29]
Abbreviations: ACP = AMPLATZER Cardiac Plug; PLAATO = Percutaneous Left Atrial Appendage Transcatheter Occlusion; LAA = Left atrial appendage, FDA = United States Food and Drug Administration; CE = European Conformite Europeenne; TGA = Australian Therapeutic Goods Administration.
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Event-free probability
Primary efficacy end point 1.0 0.9 Control Device
0.8 0.7
244 463
216 382
Event-free probability
54 123
22 Control 31 Device
365 730 1095 Time (days since randomization)
1460
Stroke
1.0 0.9 Control Device
0.8 0.7
244 463
216 382
0
158 313
54 123
22 Control 31 Device
365 730 1095 Time (days since randomization)
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All-cause mortality Event-free probability
1.0 0.9 Control Device
0.8 0.7
244 463 0
220 389
161 321
56 127
22 Control 32 Device
365 730 1095 Time (days since randomization)
1460
Figure 1. Kaplan-Meier curves of the primary efficacy end point, stroke alone, and all-cause mortality from the PROTECT-AF trial. The number at risk is shown above the x-axis.
continued for 45 days after implantation, followed by 4.5 months of clopidogrel and lifelong aspirin. Discontinuation rates were 15.3% in the WATCHMAN group and 22.5% in the warfarin group. Patient follow-up had a median of 2.4 years and a mean of 2.3 ± 1.1 years (range 0–5.9 years), with an aggregate of 1588.4 patient-years. An intention-totreat analysis was performed [20]. The rate ratio (device compared to warfarin therapy to a target INR of 2.0–3.09) for the primary efficacy end point of stroke, systemic embolism, and cardiovascular or unexplained death was a favorable 0.71 (95% CI, 0.44–1.30), giving a posterior probability for noninferiority (PPN) of > 0.99 and for superiority (PPS) of 0.88 (Figure 1). What is more, there was little difference in the rate of ischemic stroke (rate ratio, 1.30; 95% CI, 0.66–3.60; PPN, 0.76; PPS, 0.18) [20]. Focusing on the more worrisome potential adverse events of therapy, WATCHMAN appears to be superior: rates of significant disability (modified Rankin Scale score of ‡ 2 or death) were significantly lower with WATCHMAN than with warfarin (rate ratio, 0.41; 95% CI, 0.22–0.82) [20]. For the primary safety end point of major bleeding, serious pericardial effusion, device embolization, and procedurerelated stroke, the rate ratio compared with warfarin was 1.53 (95% CI, 0.95–2.70) (Figure 2). If adverse events that occurred on the day of device implantation are excluded, the primary efficacy end point for WATCHMAN had an rate
ratio of 0.58 (95% CI, 0.35–1.09; PPN, > 0.99; PPS, 0.95) and the primary safety end point had an rate ratio of 0.77 (95% CI, 0.45–1.45) compared with warfarin. Of note, the ischemic stroke rate of 1.9 per 100 patient-years seen with WATCHMAN decreased to 1.4 when adverse events occurring on the day of implantation were excluded, making it indistinguishable from the warfarin group [20]. Minor adverse events, such as persistent atrial septal defects created during device implantation or low levels of peri-device blood flow, were also noted. These defects closed spontaneously in 93% of cases within a year, and were not associated with an increased rate of stroke or systemic embolism [46]. Such low levels of peri-device flow do not appear to be associated with increased risk of thromboembolism [47]. Event-free probability
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0
158 313
Primary safety end point
1.0 0.9 0.8 0.7
244 463
0
Control Device 212 364
155 303
53 116
365 730 1095 Time (days since randomization)
21 Control 28 Device
1460
Figure 2. Kaplan-Meier curves of the primary safety end point from the PROTECT-AF trial. The number at risk is shown above the x-axis.
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In all, the greatest net clinical benefit appears to come with warfarin in the short term (< 6–9 months after commencement of therapy), but with WATCHMAN in the longer term. This is because the majority of adverse events in the device groups were associated with the implantation procedure, whereas adverse events in the control group accumulated steadily over time, as indicated by the PROTECT-AF cohort (707 patients) as well as the Continued Access Protocol (CAP) registry (566 patients) [31]. Indeed, in the PROTECTAF study the primary safety end-point adverse event rate for the WATCHMAN group fell from 5.5 to 2.8 adverse events per 100 patient-years when excluding adverse events occurring on the day of implantation, where the adverse event rate of the warfarin group remained at 3.6 [20]. One must be mindful that net clinical benefit is a product of the weighting attributed to adverse events; however, it was only found to favor anticoagulation when the weighting for pericardial effusion was increased to > 1.1 in the PROTECTAF cohort and to > 4.7 in the CAP cohort; death carries an impact weight of 1. Net clinical benefit for LAA occlusion was greatest for patients with the highest risk of stroke, most notably those with higher CHADS2 scores and those in whom LAA occlusion was employed as secondary prevention [31].
Criticisms of WATCHMAN Approval by governmental agencies WATCHMAN has been approved in Europe and Australia, but has not yet been approved by the United States Food and Drug Administration (FDA). In 2009, there was a 7 to 5 vote in favor of approval, leading to the Prospective Randomized EVAluation of the WATCHMAN LAA Closure Device In Patients with AF Versus Long Term Warfarin Therapy (PREVAIL) trial (407 patients with nonvalvular atrial fibrillation with a CHADS2 of ‡ 2, or 1 with an additional risk factor, randomized 2:1 WATCHMAN [n = 269] to warfarin [n = 138]) [22] to confirm safety and efficacy. In late 2013 the FDA voted 13 to 1 in favor, deciding that WATCHMAN was a safe and effective treatment against embolism of thrombi from the LAA; however, the FDA did not approve it, instead putting it forward for a third advisory panel meeting that is as yet unscheduled [48]. Statistical issues with key trials The results of the PROTECT-AF trial have been criticized regarding the wide confidence intervals reported. This is due to the number of patients enrolled, which while large for an interventional study, was smaller than that used in comparable drug trials [49-51]. However, the statistical methodology was sufficiently rigorous to account for this, with the exception of a lack of adjustment for multiple comparisons for the post-hoc analyses [20]. In addition, in the PREVAIL trial, the 95% credibility interval (CrI) upper limit for noninferiority was 1.75 for the primary efficacy end-point rate ratio, and was 0.0275 for the lateischemic primary efficacy end-point risk difference (equivalent
Hosp Pract, 2015; 43(1):13–21
to an rate ratio of > 4.2). As an additional minor point, again no adjustments were made for multiple comparisons [22]. Controversy surrounding the PREVAIL trial was sparked in early 2013 when clinicaltrials.org was updated to change the study description to include a safety review, convert the main goal to 3 separate objectives and to alter the 6-month time period to 18-month rates [52]. The PREVAIL trial recently yielded its first publication, though with a median follow-up of only 12 months (range 0.03–25.9 months). The late-ischemic efficacy end point (ischemic stroke or systemic embolism excluding the first 7 days after randomization) achieved noninferiority with an 18-month risk difference of 0.0053 (95% CrI, 0.0190 to 0.0273), providing some support for the hypothesis that LAA occlusion in the absence of long-term anticoagulation can prevent ischemic adverse events [22]. However, the primary efficacy end point (all stroke, systemic embolism, and cardiovascular/unexplained death) yielded an 18-month rate ratio of 1.07 (95% CrI, 0.57–1.89), exceeding the margin of 1.75, so noninferiority was not achieved. This result could be due to the limited follow-up period, as WATCHMAN has already been demonstrated to show the most benefit in the long term. It is also noteworthy that there was an unexpectedly low adverse event rate in the warfarin control group as compared with recent pharmaceutical randomly controlled trials, with a rate of 0.71 per 100 patient-years in PREVAIL [22], compared to 1.7, 1.6, and 2.2 in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) [49], Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) [53], and Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [50] trials, respectively. This in turn could be due to a higher time in the therapeutic range of 68% compared with 64%, 62%, and 55%, respectively [22,49,50,53,54]. Requirement for concomitant antithrombotic therapy Patients receiving WATCHMAN as part of the PROTECTAF or PREVAIL trials received warfarin therapy for at least the 45 days following device implantation while endothelialization occurred; this was thought to be important because of the device’s permeability to blood [44]. Treatment was continued past this stage in 13.2% of patients in PROTECT-AF and 7.8% of patients in PREVAIL, due to blood flow being detected across more than a 5-mm area of the LAA opening [20,22]. Patients with a contraindication for oral anticoagulants (due to poor INR compliance, risk of bleeding or falls, or intolerable side effects) would not be able to undergo WATCHMAN implantation under this protocol. Given that the only long-term therapeutic intervention available to these patients is antiplatelet agents, WATCHMAN could offer real benefit were the requirement for a period of bridging therapy to be removed [36]. Such bridging therapy was not used in the ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP) study, an initial feasibility
The WATCHMAN device for stroke prophylaxis in AF
assessment undertaken in 150 patients and designed to assess implantation of WATCHMAN in warfarin-ineligible patients (as defined by hemorrhagic or bleeding tendencies [93%], blood dyscrasias, unsupervised patients with senility or high fall risk, or another documented reason such as hypersensitivity to warfarin). Despite the absence of warfarin cover, there was little difference in the incidence of serious procedure or device-related adverse events. After 176.9 patient-years of follow-up, an annual ischemic stroke rate of 1.7% was observed. By comparison, the mean patient CHADS2 score of 2.8 predicted an annual rate of ischemic stroke of 7.4% if untreated, 7.3% if treated with aspirin, and 5.0% if treated with clopidogrel [21]. However, one should keep in mind that this study was uncontrolled and potentially subject to bias. Concern about the possibility that WATCHMAN itself might be prothrombotic has also led to a requirement that patients with a device in situ be treated with 6 months of clopidogrel and lifelong aspirin [20]. In the community, patientinitiated discontinuation of aspirin for secondary prevention of cardiovascular adverse events can be as high as 30% [55]. It will therefore be necessary in clinical practice to appropriately educate patients and to assess their risk of nonadherence to antiplatelet regimes. Procedural risk The clear downside of WATCHMAN implantation is the high rate of procedure-associated adverse events. This can be reduced both by improvements in device design [56] (now approaching the fourth generation [31]) and by increasing operator experience. There is a clear precedent for a volume– outcome relationship in improving safety of percutaneous cardiac device implantation, as seen with Transcatheter Aortic Valve Implantation (TAVI) [57] and Left Atrial Appendage Occlusion Study (LAAOS) [58] trials. The PROTECT-AF operators were interventional cardiologists or electrophysiologists who all routinely performed procedures requiring transseptal punctures clinically and underwent training using a simulation model. Even so, at sites across the entire PROTECT-AF trial, the first 3 patients were at greater risk than the later patients at any single site (P = 0.012) [33]. Based on this finding, operators for the CAP registry had all participated in PROTECT-AF and so were continuing Event-free probability
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Safety event incidence
1.0 0.9 0.8 0.7 0.6
CAP PROTECT-AF later PROTECT-AF earlier 460 250 212 271 240 235 271 226 221
0
133 231 219
77 CAP 226 PROTECT-AF later 218 PROTECT-AF earlier
365 730 1095 1460 Time (days since the procedure)
Figure 3. Kaplan-Meier curves of the incidence of procedure- or devicerelated safety adverse events for patients enrolled in the first (earlier) half and the second (later) half of the PROTECT-AF trial and in the CAP Registry. The number at risk is shown above the x-axis.
17
to build on prior experience. Comparing the PROTECT-AF patients with the CAP registry patients, the CAP registry had a significantly shorter procedure time (P < 0.001), adverse event rate (P = 0.007), serious pericardial effusion rate (P = 0.019), and stroke rate (P = 0.039), with a higher implant success rate (P = 0.001) (Figure 3) [33]. This was all despite the CAP registry including a patient cohort with a significantly higher CHADS2 score (2.5 compared to 2.2, P < 0.001) [22]. The trends were also consistent when only assessing sites that participated in both trials, though due to the smaller patient numbers involved, only the procedure time and implant success rate were significantly improved [33]. Continuing this trend, the PREVAIL trial met its early safety end point (all-cause death, ischemic stroke, systemic embolism, or device/procedure-related adverse events requiring surgical intervention within 7 days of the procedure or during the index of hospitalization) with a result of 2.2%, statistically less than the performance goal of 2.67%. Compared with the PROTECT-AF trial, the PREVAIL trial showed an increased implant success rate (P = 0.04) and lower rates of all 7-day procedural complications (P = 0.004), pericardial effusion requiring surgery (P = 0.03), and procedure-related strokes (P = 0.02), despite a higher CHADS2 score of 2.6 (P < 0.001). Importantly, in the PREVAIL trial 38.8% of patients were enrolled at new sites that had not implanted WATCHMAN before, and 39.1% of procedures were performed by new operators. This implies that the knowledge gained during PROTECT-AF and CAP can be effectively transferred to new sites and operators [22]. With the increasing body of experience surrounding the insertion procedure, we might expect that adverse event rates will continue to approach a minimum level. As the number of procedural adverse events decreases, the point at which WATCHMAN cohorts will have fewer adverse events than warfarin cohorts will become chronologically sooner after device insertion, potentially making the device the better clinical choice. However, transcutaneous procedures will always carry risk, and it is difficult to predict where the minimum level for this risk will lie.
Aims for future research Relevant comparisons A number of pharmaceutical alternatives to warfarin have recently become available. Three drugs (dabigatran, rivaroxaban, and apixaban), collectively termed the novel oral anticoagulants (NOACs), are now accessible, with further drugs (edoxaban and betrixaban [59]) in late-stage clinical trials. A recent meta-analysis of the main trials for dabigatran (the RE-LY trial) [49], rivaroxaban (the ROCKET AF trial) [50], apixaban (the ARISTOTLE trial) [51], and edoxaban (the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48] trial) [60] reaffirmed their marked benefits (at their higher doses, where applicable) over warfarin, indicating that as a group they offer a significant reduction in all-cause mortality, no significant difference from
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Subanalysis of the PROTECT-AF and CAP Registry cohorts indicated that WATCHMAN provides the greatest net clinical benefit over warfarin for patients with higher CHADS2 scores, with the most benefit for patients with a score of 5 or 6, with a progressive decline for patients with progressively lower scores [31]. The same was seen when ranking patients by AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) [67] bleeding risk score (looking at hypertension or prior hemorrhage, age ‡ 75 years, and severe renal disease or anemia), with the greatest benefit seen in patients with a score ‡ 4 [31]. It has been suggested that LAA occlusion should be considered for all patients with a CHADS2 or CHA2DS2-VASc (which adds Vascular disease, Age 65 to 74 years, and Sex category of female as stroke risk factors to CHADS2) score ‡ 2 and a high risk of bleeding (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [> 65], Drugs/alcohol/medications predisposing to bleeding concomitantly [HAS-BLED] ‡ 3). This is especially true for patients with recurrent ischemic stroke despite good warfarin compliance, previous intracranial haemorrhage, recurrent gastrointestinal bleeding, coagulopathies, intolerance to NOACs, or other relevant comorbidities [68]. Physicians should choose to treat patients with LAA occlusion based on a clinical decision referring to the patient’s overall health, procedural risks, and operator experience, as well as tolerance and compliance with oral anticoagulant drugs, taking into account patient preference.
P = 0.001). The mean and maximum widths of the leak were 2.8 and 6.2 mm, and 7.7%, 59.9%, and 32.4% of leaks were minor (< 1 mm), moderate (1–3 mm), or severe (> 3 mm), respectively, at 45 days. There was no difference found for primary efficacy adverse event rates, ischemic stroke alone, and composite ischemic stroke and systemic embolism between patients with and those without a leak. There was also no association between leak severity and adverse events [47]. In the PROTECT-AF trial, 13.2% of patients who had received the device continued taking warfarin bridging therapy at 45 days postprocedure, decreasing to 6.8% at 12 months. This was due to a leak > 5 mm wide, or on the advice of the treating physician [20]. The subanalysis found that there was no difference between adverse event rates and patients with no leak with discontinued warfarin, no leak with continued warfarin, leak with discontinued warfarin, and leak with continued warfarin [47]. However, as a consequence of the original study design, this subanalysis has limited statistical power. This lack of association between residual peri-device flow and ischemic adverse events was corroborated by a long-term (average 58 ± 9 month) follow-up of a PLAATO device trial (n = 22 patients) [69]. In addition to peri-device flow, thrombi can form on the devices themselves. One analysis noted 4.2% (20/478) of patients with successfully inserted devices in the PROTECTAF trial developed device-associated thrombus, of whom 3 experienced ischemic stroke [33]. It is unclear what the optimal protocol for follow-up imaging and treatment is, but the endothelialization that occurs on the device should minimize this risk [70]. It is also possible for implanted devices to migrate. There is a case report of interest that successfully demonstrates transcatheter closure of an incomplete LAA occlusion using a second device. In this case, a 30-mm WATHCMAN was inserted and was discovered to have a 4 mm leak. The patient was resistant to continuing oral anticoagulation. Three years later, the device was discovered to have migrated distally into a lobe of a multilobar LAA, and a 7-mm leak and thrombus in the residual pouch were noted. The appendage was then successfully closed (leaving the original device remaining in situ) using an ACP2 AMPLATZER amulet device after 3 months of warfarin treatment [71]. The ACP2 device was chosen due to a delivery cable with an inner wire allowing tension-free assessment of the device before delivery, which can be helpful in challenging situations [30,71]. As with any surgical procedure, there are many other potential complications that are much rarer, such as cardiac perforation [43]. Further investigation of difficulties arising after device implantation would benefit decisions regarding clinical relevance and in drafting appropriate criteria for further treatment.
Procedural difficulties
Cost-effectiveness
A subanalysis of the PROTECT-AF trial at 1500 patientyears of follow-up found that 40.9% of patients had peridevice flow on transesophageal echocardiography at 45 days postprocedure (decreasing to 32.1% at 12 months,
Although NOACs are expensive, they are considered potentially fundable by the National Institute of Clinical Excellence, with the most plausible incremental cost-effectiveness ratio being < £20 000 (< $32 000) per quality adjusted life
warfarin in myocardial infarction or ischemic stroke alone, and a 19% reduction in composite stroke or systemic embolism, 51% reduction in hemorrhagic stroke, and 52% reduction in intracranial hemorrhage [54]. The NOACs are not perfect, however. Though apixaban shows reduced rates of major bleeding compared with warfarin, dabigatran and rivaroxaban show significantly increased rates of gastrointestinal bleeding [14,23,54]. There are also questions regarding a potentially increased rate of myocardial infarction with the lower dose regime of dabigatran [15]. Another benefit of the NOACs over warfarin is that they have a short half-life, meaning that they rapidly self-reverse [61]. Although there are no antidotes to them currently available, antidotes will most likely be in clinical use within the year [62]. The NOACs also have far fewer drug and food interactions than warfarin, though care should still be taken by the prescribing physician [63-66]. Thus, the most relevant comparison going forward will be between WATCHMAN and these new agents. No such data are available at present. Patient selection
DOI: 10.1080/21548331.2015.1000795
The WATCHMAN device for stroke prophylaxis in AF
year gained for apixaban and dabigatran, and £28 700 to 29 500 ($45 900 to 47 200) for rivaroxaban, although these figures vary substantially depending on patient group and prescription protocol [15]. There are currently few data available regarding the cost-effectiveness of therapy with WATCHMAN. Clearly calculations are complex, needing to account for the cost of the procedure, the device itself, the associated training, and the expertise and facilities required.
the community: the Framingham Heart Study. JAMA 2003;290: 1049–56. Tu HT, Campbell BC, Christensen S, et al. Pathophysiological determinants of worse stroke outcome in atrial fibrillation. Cerebrovasc Dis 2010;30:389–95. Blackshear JL, Safford RE; AFFIRM trial; RACE trial. AFFIRM and RACE trials: implications for the management of atrial fibrillation. Cardiac Electrophysiol Rev 2003;7:366–9. DiMarco JP, Flaker G, Waldo AL, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005; 149:650–6. Sabir IN, Matthews GD, Huang CL. Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice. Postgrad Med J 2013;89:346–51. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360–420. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012;172:623–31; discussion 631–623. Ferro D, Loffredo L, Polimeni L, Violi F. Underuse of oral anticoagulants in patients with nonvalvular atrial fibrillation in Italy. Intern Emerg Med 2007;2:24–8. Lam YY, Ma TK, Yan BP. Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation. Int J Cardiol 2011;150:4–11. Potpara TS, Lip GY, Apostolakis S. New anticoagulant treatments to protect against stroke in atrial fibrillation. Heart 2012;98:1341–7. Harris K, Mant J. Potential impact of new oral anticoagulants on the management of atrial fibrillation-related stroke in primary care. Int J Clin Pract 2013;67:647–55. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999;82: 547–54. Pollick C, Taylor D. Assessment of left atrial appendage function by transesophageal echocardiography. Implications for the development of thrombus. Circulation 1991;84:223–31. Alli O, Doshi S, Kar S, et al. Quality of life assessment in the randomized PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial of patients at risk for stroke with nonvalvular atrial fibrillation. J Am Coll Cardiol 2013;61:1790–8. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) trial. Circulation 2013;127:720–9. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the watchman device in patients with a contraindication for oral anticoagulation: ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP study). J Am Coll Cardiol 2013;61:2551–6. Holmes DR Jr, Kar S, Price MJ, et al. 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. Holmes DR Jr, Lakkireddy DR, Whitlock RP, Waksman R, Mack MJ. Left atrial appendage occlusion: opportunities and challenges. J Am Coll Cardiol 2014;63:291–8.
[5] [6] [7]
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Conclusion There is an established demand for thromboembolic prophylaxis in patients with nonvalvular atrial fibrillation. The mainstay of current treatment is warfarin therapy, although advances in pharmacotherapy are producing potentially clinically superior alternatives. The LAA occlusion devices such as WATCHMAN offer another option. Recent updates to the available evidence have added to the data for the device’s noninferior efficacy as compared with warfarin, noting a narrowing in the difference between safety end points. In addition, there is accumulating evidence that improving device design and increasing operator experience reduce the risk of adverse events associated with device implantation. Analyses of patients’ functional outcomes and of net clinical benefit have started to suggest potential benefits of occlusion over lifelong warfarin therapy. WATCHMAN appears to be superior to antiplatelet therapy alone; at the very least, LAA occlusion devices could become a commonplace alternative treatment for patients unable or unwilling to take novel oral anticoagulants.
[8] [9]
[10] [11]
[12] [13] [14] [15] [16]
Acknowledgments The authors gratefully acknowledge support from the Wellcome Trust, the British Heart Foundation, and the National Institute for Healthcare Research. All authors contributed to identification of appropriate papers, manuscript presentation or editing and review prior to submission.
[17] [18] [19]
Declaration of interest G. Couch, BA, has no conflict of interest to declare. I. Sabir, PhD, MRCP, acknowledges the receipt of consulting fees from Daiichi Sankyo Europe GmbH.
[20]
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