GENERAL SCIENTIFIC SESSION II: OUR FUTURE IS NOW!: Chapter 2
Stroke Intervention: Evolution of Implementation of Cutting-Edge Technologies
Dumont, Travis M. MD; Hopkins, L. Nelson MD
Dramatic improvements in available technology designed specifically for thrombectomy have allowed neurointerventionists to forget the days of thrombolysis performed with wire manipulation, snare devices, and angioplasty balloons.1-6 The availability of thrombectomy devices designed for the cerebrovasculature, coupled with an improved understanding of the importance of vessel recanalization in acute ischemic stroke, has fueled an increase in stroke intervention procedures performed in the United States.7
Currently, there are 4 devices approved by the Food and Drug Administration (FDA) that are available for use in endovascular mechanical thrombectomy: the Merci retriever (Stryker, Kalamazoo, Michigan), the Penumbra system (Penumbra Inc, Alameda, California), the Solitaire stent-retriever (ev3-Covidien, Irvine, California), and Trevo (Stryker) stent-retriever. This review discusses the development of these devices for use in the United States and other devices currently in development and trial. These devices have in common implementation that was associated with well-designed trials8 with surrogate end points. Phase I trials of 20 to 30 patients have been able to establish the safety of these devices, whereas recent phase II trials of 100 to 200 patients have established their efficacy compared with that of established devices. Establishment of vessel recanalization as a surrogate end point via medical trials9,10 has been important because measuring clinical outcomes would result in larger, less manageable trials that would be unable to keep up with the pace of developing technology.
The first device approved for stroke intervention (“for removal of blood clots from the brain in patients experiencing an ischemic stroke”) was the Merci retriever in August 2004.11 Such a device was initially conceptualized nearly 10 years before FDA approval. Animal studies began in 1996, culminating in the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial (2001-2003).12 This phase I trial13 was designed to test the safety and efficacy of the Merci retriever in mechanical thrombectomy in acute ischemic stroke. Thirty patients were enrolled at 7 US centers between May 2001 and October 2002. Although the rate of revascularization was a modest 43% (achieved in 12 of 28 patients treated), no complications related to the study device were reported. Subsequently, in a somewhat controversial fashion,14 the Merci retriever was granted FDA approval via the 510(k) pathway, with the predicate devices to which the retriever was considered “substantially equivalent” being the Attractor Endovascular Snare (Boston Scientific, Natick, Massachusetts) and the Amplatz GooseNeck Microsnare (ev3-Covidien). The second-generation Merci device was shown to yield an improved revascularization rate (57%, 75 of 131 patients); vessel recanalization was associated with favorable clinical outcomes.15 The 3 other FDA-approved devices have since been approved via the 510(k) pathway, with the Merci retriever considered the predicate device. To obtain clearance to market a device using the 510(k) pathway, the submitter of the 510(k) must show that the medical device is substantially equivalent to a device that is already legally marketed for the same use.
The Penumbra system is a series of aspiration catheters designed for piecemeal removal of intraluminal thrombus. The device was initially designed in the United States, although the phase I trial was ultimately carried out at 6 European centers. In this study, 21 vessels in 20 subjects with acute ischemic stroke were successfully recanalized (100% revascularization) with 4 perioperative complications, including 2 symptomatic intracranial hemorrhages, 1 access-site hematoma requiring transfusion, and 1 subarachnoid hemorrhage from vessel perforation.16 This trial led to a Conformité Européenne (CE) mark for the Penumbra system and a larger trial (The Penumbra Pivotal Stroke Trial) at 24 centers, most in the United States.17 This trial was a single-arm prospective study that enrolled 125 patients with acute ischemic stroke to undergo mechanical thrombectomy with the Penumbra system between June 2006 and June 2007. This study displayed efficacy of the Penumbra system for thrombectomy in acute ischemic stroke, displaying a revascularization rate of 82% (102 of 125 patients) with 3 serious complications (2%).17 Subsequent FDA approval via a 510(k) for the Penumbra system followed in December 2007,18 with the Merci retriever considered the predicate device.
The 2 stent-retriever devices received nearly concurrent FDA approval for use in thrombectomy with unique development but similar pathways to approval. The Solitaire device was designed and used for temporary or permanent aneurysm neck reconstruction and received a CE mark for this use in 2004.19 Its use as a thrombectomy device is serendipitous; it was first used for thrombectomy when no Merci device was available.19 In contrast, the Trevo device was designed specifically for thrombectomy in the setting of acute ischemic stroke.20 Both devices were tested for safety and efficacy in European phase I trials, and both displayed efficacy and safety for thrombectomy in acute ischemic stroke.21,22 Both devices received the CE mark for European use in 2009. Independent trials were conducted subsequently at primarily US centers to compare the efficacy of each stent-retriever device with the Merci retriever for revascularization in the setting of acute ischemic stroke.23,24 The SOLITAIRE™ FR With the Intention for Thrombectomy (SWIFT) trial randomized 113 patients to revascularization with the Merci retriever or Solitaire device between February 2010 and February 2011.24 The Solitaire was superior in revascularization to the Merci retriever, with a recanalization rate of 61% (compared with 24% with Merci). The Thrombectomy Revascularization of Large Vessel Occlusions (TREVO 2) trial randomized 178 patients to revascularization with the Merci retriever or Trevo device between February and December 2011.23 The Trevo was superior in revascularization to the Merci retriever, with a recanalization rate of 86% (compared with 60% with Merci). Subsequent to the SWIFT and TREVO 2 trials, the Solitaire and Trevo devices were approved for use in acute ischemic stroke by the FDA in March and August 2012, respectively, by 510(k) with the Merci retriever as the predicate device.25,26 Use of the Merci devices has waned with the introduction of these thrombectomy devices.
The present pipeline for stroke intervention device implementation has thus been established with the introduction of the Penumbra system and stent-retriever devices. In this model, a device receives a CE mark after a successful European phase I trial, followed by a phase II trial conducted in primarily US centers, leading to FDA approval via 510(k) with predicate thrombectomy devices (Table 113-15171922-2427). Phase III trials are underway for the Penumbra system28 and Solitaire device.29 The next device seemingly in this pipeline is the Penumbra 3D Separator.30 This intraluminal device is deployed at the site of thrombus in fashion similar to a stent but, rather than exert radial force to incorporate the thrombus, has a series of radial spokelike baskets designed to secure the thrombus and to improve the efficiency of thrombectomy. A phase I European study has shown 92% recanalization in 14 patients, with fewer passes required to achieve recanalization.31 A CE mark has been granted, and the 510(k) study is underway at primarily US centers.30 Not all devices are destined for FDA approval, and several devices are marketed for use in acute ischemic stroke outside the United States, mostly by companies from the United States (Table 238).
Technology evolution is a slow process, developing over many years before FDA approval. Even promising prototypes39,40 may stall in any stage of the regulatory or financial hurdles required to implement new stroke technologies. Although many concepts for new stroke intervention devices originate in the United States, difficulty in overcoming FDA regulation has resulted in the testing and use of more products in European countries. As a result, the United States is losing its leadership position in the development of devices for stroke intervention treatment. Furthermore, European companies have little incentive to market successful devices in the United States, presumably because of regulatory hurdles. Mutually beneficial partnerships among basic science, engineering, medicine, and industry, combined with cooperation from the FDA, will enable trials of American devices to take place on American soil.
The Gates Vascular Institute was designed to provide excellent patient care and to foster development of new endovascular devices. This innovative design enables clinical and preclinical research to be conducted in the same building, as well as housing the Jacobs Institute, an independent partner focused on assisting in innovation and collaboration in an effort to treat vascular diseases (Figure). This design will enable research, prototyping, testing, and funding of new stroke technologies.
FIGURE. The innovati...Image Tools
For related video content, please access the Supplemental Digital Content: http://www.youtube.com/watch?v=VfcZrHXs-gw
Dr Dumont reports no financial relationships. Dr Hopkins receives grant/research support from Toshiba; serves as a consultant to Abbott, Boston Scientific, Cordis, Micrus, and Silk Road; holds financial interests in AccessClosure, Augmenix, Boston Scientific, Claret Medical, Endomation, Micrus, and Valor Medical; holds a board/trustee/officer position with Access Closure and Claret Medical; serves on Abbott Vascular's speakers' bureau; and has received honoraria from Bard, Boston Scientific, Cleveland Clinic, Complete Conference Management, Cordis, Memorial Health Care System, and the Society for Cardiovascular Angiography and Interventions (SCAI).
We thank Paul H. Dressel, BFA, for assistance with preparation of the figure and Debra J. Zimmer for editorial assistance.
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