Exploring the Dark Side of Left Atrial Appendage Closure Devices

Pasquale Santangeli MD, PhD; Andrew E. Epstein MD, FAHA, FACC, FHRS

Disclosures

J Cardiovasc Electrophysiol. 2018;29(1):14-16. 

The most feared complication of atrial fibrillation (AF) is cardio-embolic stroke. Despite the decline in stroke-related mortality over the last decade,[1] AF-related strokes remain the most severe type of ischemic cerebrovascular accidents due to their strong association with severe disability (worse than with non-AF-related strokes), recurrent thromboembolism, and death.[2,3] Randomized controlled trials have shown that systemic anticoagulation reduces the risk of stroke in patients with nonvalvular AF.[4] Oral anticoagulant therapy, however, carries inherent bleeding risks, significant drug–drug interactions and dietary interactions (for vitamin K antagonists), nonlinear pharmacodynamic response in patients with fluctuating renal function (for novel direct oral anticoagulants), and challenges related to long-term patient compliance.

Imaging studies have shown that the majority of AF-associated intracardiac thrombi are located within the left atrial appendage (LAA),[5,6] a finding that has provided the basis and justification for the development of mechanical catheter-based technologies for left atrial appendage occlusion (LAAO) as an alternative to oral anticoagulant therapy. Currently, three LAAO devices are in use in the United States: two of these devices (WATCHMAN™ [Boston Scientific, Natick, MA, USA], and AMPLATZER™ AMULET™ [St Jude Medical/Abbott, St. Paul, MN, USA) are for endocardial LAAO, whereas the LARIAT® (SentreHEART, Redwood City, CA, USA) is used for epicardial LAAO. The WATCHMAN™ is the only device that has been approved by the Food and Drug Administration (FDA) as an alternative to warfarin for stroke prevention in nonvalvular AF. The clinical evaluation of the WATCHMAN™ device has followed a rigorous process that included two multicenter randomized trials against dose-adjusted warfarin and two prospective registries.[7–11] Overall, the available data show substantial equivalence of WATCHMAN™ compared with warfarin for all-cause stroke, and a significant reduction of serious intracranial bleeding events, disabling/fatal strokes and cardiovascular death with WATCHMAN™.[7,8,10] The safety of the device has also been thoroughly investigated in the setting of randomized controlled trials and, more recently, within post-approval registries. The most recent assessment of the safety of WATCHMAN™ included 3,822 cases of device implant within a national U.S. registry.[11] Notably, 71% of the operators who performed 50% of the procedures were new implanters not participating to the prior clinical trials. The procedure was successfully completed in more than 95% of cases, and the overall rate of periprocedural complications was 2.75%, which included pericardial tamponade (1.02%), procedure-related stroke (0.078%), device embolization (0.24%), and periprocedural death (0.078%). These figures were similar to those reported in the randomized PREVAIL study, in which the primary safety endpoint (composite of all-cause death, ischemic stroke, systemic embolism, need for emergent surgery or major endovascular intervention) occurred in 2.2% of the patients randomized to WATCHMAN™.[7] Whether the efficacy and safety of LAAO with WATCHMAN™ can be generalized to other types of LAAO devices needs to be evaluated in similarly designed randomized controlled trials. In this regard, a randomized trial comparing the AMULET™ device with the WATCHMAN™ for endocardial LAAO is underway and will formally evaluate whether the two devices perform similarly in terms of efficacy and safety.[12]

The bulk of the evidence supporting the clinical use of the LARIAT® device for LAAO is substantially different from what is already available for WATCHMAN™ or will soon be available for AMULET™. The LARIAT® is a suture delivery device that has received a 510(k) class II device approval by FDA to deliver a pretied stich for soft tissue approximation during surgery. The approval process was facilitated by the substantial similarities between the LARIAT® system and other FDA-approved suture systems such as the Ethicon Endosuture System (Ethicon US LLC, Somerville, NJ, USA) that are typically used during laparoscopic surgeries. Given the broad indication by the FDA, the LARIAT® device has been used by multiple centers for epicardial LAAO. Although mechanistically sound, it is important to emphasize that the role of the LARIAT® device to prevent stroke in AF patients has not been formally tested in a randomized trial. However, the possibility of achieving durable exclusion of the LAA without the need for an endocardial device is certainly appealing, as it may obviate the need for short-term anticoagulation and virtually eliminate the risk of device-related thrombosis.[13] Furthermore, from a physiological perspective, there is no reason to suspect that, if adequate LAA sealing is obtained, the benefits of the LARIAT® device would be any different from what shown with the WATCHMAN™.

In this issue of the Journal, Jazayeri et al. present an analysis of complications of the WATCHMAN™ and LARIAT® reported to the FDA Manufacturer and User Facility Device Experience (MAUDE) database between years 2006 and 2016.[14] During the study period, the LARIAT® was implanted in 4,889 patients while the WATCHMAN™ in 5,849 patients. Interestingly, the complication rate observed with WATCHMAN™ appeared higher than what has been reported in recent registries,[11] with higher point estimates for pericardial tamponade (0.5% higher), pericardial effusion (+0.15%), periprocedural stroke (+0.082%), device embolization (+0.28%), and death (+0.21%).[14] In addition, the composite endpoint of stroke/TIA, pericardiocentesis, cardiac surgery, and death appeared higher with WATCHMAN™ compared with LARIAT® (1.93% vs. 1.15%, P = 0.001 for comparison). The authors concluded that MAUDE-reported data show that postapproval new technology adoption may be associated with increased complications compared with premarket data.

This is an important paper since, while it describes complications specifically related to LAAO, it serves as a warning that "real-world" experience is not necessarily the same as that observed in premarketing approval studies or in fact any clinical trial. The power of this observation in this case is extremely important since it is offered by advocates of LAAO technology. While advocates can easily minimize the significance of reported complications, Jazayeri et al. reported with no holds barred. They bring attention to real problems, and warnings from those intimately involved with the premarketing approval trials of these devices will be especially powerful. Furthermore, their call for collaboration between operators, device manufacturers, and regulators is laudable. With enhanced monitoring and reporting of complications, patients can only be helped. The authors' call for transparent monitoring, reporting, and training is critically important and indeed applicable to all interventions we deliver, both new and old. In this context, this report has wider implications than those related to only LAA closure devices.

On the other hand, some limitations of their analysis should be acknowledged. First and foremost, the conclusion of a possible increased safety profile with the LARIAT® device compared with WATCHMAN™, albeit intriguing, should be interpreted with caution. Indirect comparisons like the one reported in the present study should only be used to generate hypotheses. The comparative analysis of LARIAT® versus WATCHMAN™ provided no adjustments for baseline confounders, and it remains difficult to establish whether the reported differences in event rates are indeed due to a real difference in device safety profile or simply related to heterogeneous patient risk profiles. Moving forward, this finding also brings to attention the different ways in which new technology is evaluated for FDA approval. As mentioned, LARIAT® received 510(k) approval for soft tissue ligation with off-label use for LAAO, while WATCHMAN™ was approved through the FDA pre-market approval pathway that required two randomized controlled trials, two prospective registries, and multiple reviews by the FDA Circulatory Systems Advisory Panel prior to approval. In this context, the authors explain the observation of a higher complication rate with WATCHMAN™ compared with LARIAT® opining that, by virtue of different approval pathways, LARIAT® operators may have hurdled a steep learning curve more rapidly than operators who used WATCHMAN™ resulting in different complication rates post-approval.

Other limitations are inherent to the MAUDE databank itself. First, reporting is voluntary, very different than that which occurs in clinical trials. Second, reports submitted to the MAUDE system undergo no peer review. Reports may be made by both individuals (called "voluntary") and industry (called "mandated"). Since entries in the MAUDE are made only when there is a problem, there is no "denominator" to allow ascertainment of the magnitude of the problem. The authors have managed this limitation by extrapolating from company data regarding number of procedures performed. The problem of absent peer review is captured by the observation that of 622 medical device reports, only 356 were unique, relevant, and therefore analyzed. Of the 167 LARIAT® reports, 47 (28%) were irrelevant to the suture delivery device, and of the 455 WATCHMAN™ reports, 25 (0.6%), including 12 deaths, contained inadequate data to be included for analysis. Thus, 9% (57 of 622) of the reports had to be excluded from analysis. Data gaps of this magnitude are unacceptable by any standard, especially when some of the gaps were related to death. Finally, the problem of under-reporting is highlighted by the absence of reports for postprocedural LAA leaks and intracardiac thrombi, as correctly highlighted by Jazayeri et al.[14] It is even more unlikely that there were no LARIAT®-related complications reported to the MAUDE database during the 2016 portion of the study. One wonders if the increased incidence of complications related to the WATCHMAN™ device were also underreported.

In conclusion, Jazayeri et al.[14] have taught us several valuable lessons: first, FDA approval does not ensure safety. Second, the approval process itself may influence postapproval safety. Third, better reporting is required to determine accurately safety and efficacy of interventions whether it be pharmacologic or device-related technology. And fourth, findings such as these beg the question if new technology or technology whose use may be associated with significant complications should be restricted to centers of excellence to diminish the rates of complications associated with its usage.

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