Guest Editorial Guest Editorial: An Update on Stroke Intervention
Stephan A. Munich, MD*‡ Maxim Mokin, MD, PhD§ Kenneth V. Snyder, MD, PhD*‡¶k# Adnan H. Siddiqui, MD, PhD*‡¶#** L. Nelson Hopkins, MD*‡¶#** Elad I. Levy, MD, MBA*‡¶# *Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; ‡Department of Neurosurgery, Gates Vascular Institute at Kaleida Health, Buffalo, New York; §Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa, Florida; ¶Department of Radiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; kDepartment of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; #Toshiba Stroke and Vascular Research Center, University at Buffalo, State University of New York; **Jacobs Institute, Buffalo, New York
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troke affects approximately 795 000 people each year, resulting in 1 of every 20 deaths in the United States.1 It remains the leading cause of long-term disability with more than 50% of stroke patients requiring discharge to a rehabilitation or skilled nursing facility.1 Stroke resulted in an estimated direct medical cost of $17.5 billion in 2011. Intravenous tissue plasminogen activator (IV tPA) remains the only US Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke. However, given the strict eligibility criteria and apprehension surrounding the risk of intracerebral hemorrhage (ICH), which was reported to be 6.4% in the National Institute of Neurological Disorders and Stroke [NINDS] trial,2 less than 10% of stroke patients receive IV tPA.3 At the time of publication of the NINDS trial results (1995), endovascular intervention for acute ischemic stroke was in its infancy, isolated to research laboratories and a few select clinical centers. Yet, over only the past decade, we have witnessed an exponential increase in its implementation, fueled primarily by a transformation in the tools, as well as the clinical approaches to endovascular therapies. Initial questions regarding its benefits have been answered by the recent publication of 4 studies clearly demonstrating its benefits. Here, we discuss the evolution of endovascular therapy for acute ischemic stroke with particular attention to what is becoming a newly established standard of care—IV tPA in combination with endovascular thrombectomy.
INITIAL ATTEMPTS AT ENDOVASCULAR STROKE TREATMENT In the early 1990s, descriptions of local intra-arterial (IA) administration of thrombolytics for treatment of acute ischemic stroke were reported, first in animal models followed by clinical cases.4-6 Additional study of IA thrombolysis found statistically significant improvement in neurological outcome and, although the cost was greater for the acute treatment than for IV therapy, it was offset by the expense saved at long-term care facilities.7 The Prolyse in Acute Cerebral Thromboembolism (PROACT) trial was the first randomized, controlled study designed to test IA local delivery of a thrombolytic agent (prourokinase) vs placebo.8 Administration of pro-urokinase was associated with successful recanalization. The PROACT II study confirmed these findings, with recanalization occurring in 66% of those receiving IA thrombolysis.9 However, complete recanalization (Thrombolysis in Myocardial Infarction [TIMI] grade 310) occurred in only 19%. These findings supported the notion that recanalization was associated with improved outcome, with 40% of patients receiving IA thrombolysis having good neurological outcome (modified Rankin Scale [mRS] score #2) compared with 25% of patients in the control group. Although recanalization rates were higher than those seen with IV thrombolytic administration, they remained relatively unpredictable.11 In 1994, Barnwell et al12 described combined IA thrombolysis and mechanical clot disruption with microcatheter and wire manipulation for the treatment of thromboembolic stroke. In their series of 13 patients, 10 achieved successful recanalization and 9 experienced improvement of more than 4 points on the National Institutes of Health Stroke Scale (NIHSS) score. This early experience, in combination with unpredictable recanalization rates after IA-thrombolytic administration, underscored the need for devices for safe and reliable clot retrieval. The Merci device (Concentric Medical/Stryker Neurovascular, Fremont, California) revolutionized the endovascular treatment of acute stroke, solidifying the concept of mechanical thrombectomy as a cornerstone of endovascular revascularization therapy. The device is designed as a corkscrew, intended to penetrate the thrombus, allowing it to be removed along with the device. The first case in humans was performed at the University of
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Guest Editorial California, Los Angeles, in 2001. The device received FDA approval in 2004, and the subsequent Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial reported a recanalization rate of 46%.13 Good neurological outcome (mRS score of 0-2) was observed in 46% of patients with successful (TIMI 2 or 3) recanalization compared with 10% without recanalization (TIMI 0). These findings were confirmed in the multi-MERCI trial.14 The next major therapeutic system to be developed for stroke treatment was the Penumbra aspiration system (Penumbra, Inc.). Its aim was to prevent distal emboli through aspiration, while effectively removing the thrombus both by aspiration and mechanical disruption using separator wires. The single-arm, prospective Penumbra Pivotal Stroke Trial reported an 81.6% recanalization rate (TIMI 2-3, in treated vessels).15 Symptomatic ICH occurred in 11.2% of patients. Experience with this system, as reported in the postmarket experience of the Penumbra system trial (POST), demonstrated similar results, with successful recanalization achieved in 87% of patients. With the development of self-expanding intracranial stents and building on the interventional experience in the treatment of acute myocardial infarction, stenting as a treatment for acute stroke first was reported in the late 2000s.16-18 The StentAssisted Recanalization in Acute Ischemic Stroke (SARIS) single-arm prospective study was designed to assess the safety and efficacy of the Wingspan self-expanding intracranial stent (Stryker) as a means of revascularization in the setting of thromboembolic stroke in patients who were ineligible for or with occlusions refractory to IV tPA.19 Recanalization (TIMI 2 or 3) was achieved in all patients, with complete recanalization (TIMI grade 3) occurring in 60%. In the context of rapid development of endovascular strategies for stroke treatment and with necessity as the mother of invention, Pérez et al20 first reported successful recanalization using the Solitaire retrievable stent, albeit serendipitously. Although initially intended for use in the treatment of wide-necked intracranial aneurysms, the Solitaire and other retrievable stents (Trevo [Stryker]) have become the first-line devices for mechanical thrombectomy at many institutions. Deployment of the stent within the thrombus results in immediate partial flow restoration as the stent expands. With sufficient stent integration into the clot, removal of the device also extracts the clot, resulting in recanalization. Initial studies evaluating the safety and efficacy of retrievable stents yielded favorable results. The Solitaire With the Intention for Thrombectomy (SWIFT) trial reported greater rates of recanalization (61% with the Solitaire Flow Restoration device vs 37% with the Merci device), as well as improved neurological outcome (mRS score 0-2—58% with Solitaire vs 33% with the Merci device).21 Similar results were reported for the Trevo device (Stryker) in the Trevo vs Merci Retrievers for Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO 2) trial.22 Again, recanalization (Thrombolysis in Cerebral Infarction [TICI] 2a to 323) occurred more frequently in patients treated with the Trevo device than the Merci device (86% vs 60%, respectively); and good neurological outcome (mRS scores 0-2) occurred in 40% of patient treated with the Trevo compared with 22% of those treated with the Merci. A recent meta-analysis of retrievable stent thrombectomy found impressive rates of recanalization across studies (mean of 83% for Trevo and 82% for Solitaire).24 Rates of symptomatic ICH remained low (8% for Trevo and 6% for Solitaire). These findings solidified retrievable stents as the foundation of endovascular treatment of acute stroke and set the stage for large, multicenter trials evaluating their efficacy compared to traditional medical therapy (IV tPA).
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Guest Editorial RECENT HISTORY OF ENDOVASCULAR STROKE TREATMENT Despite favorable early reports of endovascular therapy for acute ischemic stroke, many viewed the publication of the results of the multicenter Interventional Management of Stroke (IMS) III,25 Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE),26 and Synthesis Expansion: A Randomized Controlled Trial on Intra-arterial vs Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)27 trials in the New England Journal of Medicine in 2013 as the final nail in the coffin for such therapy. The IMS III trial demonstrated no benefit of IV tPA 1 endovascular therapy compared with IV tPA alone.25 Similarly, MR RESCUE concluded that embolectomy was not superior to standard care (ie, IV-tPA alone) despite the presence of favorable penumbral imaging patterns.26 The SYNTHESIS Expansion investigators observed similar results comparing IV tPA with endovascular therapy alone.27 (We previously published a detailed review of these studies.28). Although these were randomized controlled trials, their designs produced significant limitations. Recruitment occurred over many years and often failed to incorporate the development of new technology. Since the introduction of the Merci device in 2004, endovascular treatments for acute ischemic stroke have evolved at a rapid pace—from the Merci device, to aspiration, to the use of implantable stents, and, most recently, to retrievable stents. With the development of new devices, not only improved rates of recanalization, but also improved clinical outcomes have been observed. Moreover, the implementation of these new devices in clinical practice and parallel improvements in neuroimaging have improved the neurointerventionist’s ability to select patients suitable for revascularization (namely, those with large-vessel occlusion). In the original IMS III protocol,25 documentation of largevessel occlusion was not required for randomization, resulting in 20% of the patients enrolled in the endovascular arm having no large-vessel occlusion on angiography. Therefore, these patients did not undergo endovascular therapy despite being considered (and statistically analyzed) in the endovascular arm. Additionally, the study design failed to account for the rapidly evolving (and improving) endovascular technology—most patients in the endovascular arm were treated using the Merci device or IA thrombolysis, generally considered outdated approaches. Similarly, the SYNTHESIS Expansion trial did not require confirmation of large-vessel occlusion, again resulting in patients without large-vessel occlusion being randomly assigned to the endovascular group. Again, retrievable stents were used in a minority of patients (13%), with most patients being treated by IA thrombolysis and/or wire disruption of the clot. In the MR RESCUE study, retrievable stents were not used at all for patients randomly assigned to endovascular therapy.
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Additionally, study participants included patients with infarct volumes of up to 90 mL, which are considered by most practitioners very large and refractory to any revascularization. Furthermore, successful recanalization was defined as TICI grade 2a-3, despite TICI 2a being defined as only partial reperfusion. This undoubtedly resulted in skewed outcome measures, as better reperfusion rates are known to be associated with smaller infarct volumes and improved clinical outcomes.29 At the time of their publication, these studies were felt to signal an end to the endovascular treatment of acute ischemic stroke. However, critical review of these studies demonstrated that improper patient selection and outdated endovascular therapy resulted in inadequate recanalization and reperfusion. Thus, the endovascular therapy being studied was not representative of contemporary practice. Although these studies represent the first generation of randomized controlled studies of endovascular stroke therapy, their conclusions should be viewed with caution and judicious consideration of the aforementioned limitations.
IV tPA 1 ENDOVASCULAR THERAPY—THE NEW STANDARD OF CARE (?) Given the significant limitations of IMS-III, SYNTHESIS Expansion, and MR RESCUE, the role of endovascular therapy in acute stroke treatment paradigms remained in question. However, with the recent publication of 5 randomized, controlled studies, endovascular intervention is being established as clearly beneficial and becoming a new standard of care. These studies addressed many of the limitations of IMS-III, SYNTHESIS, and MR RESCUE—recruitment occurred over a shorter period of time, demonstration of large-vessel occlusion with noninvasive imaging was obligatory, comparison was between the addition of endovascular therapy to IV tPA and IV tPA alone, and contemporary devices (including retrievable stents) were utilized to achieve revascularization. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) was the first to be published.30 Eligible patients (n ¼ 500) were those who had proximal arterial occlusion (established by computed tomographic angiography [CTA] or magnetic resonance angiography [MRA] and confirmed with digital subtraction angiography) of the anterior circulation and could be treated within 6 hours after symptom onset. The method of endovascular therapy was left to the discretion of the treating physician, which allowed for the use of contemporary strategies, including IA tPA, aspiration, mechanical thrombectomy, and retrievable stents. The study found a significant benefit to the use of endovascular therapy, with functional independence (mRS score 0-2) occurring in 32.6% of patients who underwent endovascular intervention, compared with 19.1% of those treated with IV tPA alone.
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Guest Editorial The presentation of 3 additional studies at the 2015 International Stroke Conference confirmed the findings reported in MR CLEAN (Table 1). The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial31 included a similar patient population as MR CLEAN—patients with proximal arterial occlusion of the anterior circulation. However, patients were eligible if they could be treated within 12 hours after symptom onset. This study also aimed to include assessment of collateral circulation, excluding those patients deemed to have poor collateral circulation on CTA. The study enrolled 316 patients and found a significantly greater rate of functional independence (mRS score 0-2) among patients treated with endovascular therapy (53.0% vs 29.3% of patients receiving standard medical care [as defined by Bayley et al32]; P , .001). Although critics of preprocedural identification of proximal, large-vessel occlusion cite delay in treatment initiation as a hindrance, the median time from computed tomography (CT) evaluation to reperfusion was only 84 minutes. The Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) trial included the addition of physiological brain imaging (CT perfusion) to the selection criteria.33 Patients who were eligible for this trial received IV tPA within 4.5 hours of symptom onset, and those randomly assigned to endovascular therapy underwent intervention within 6 hours after symptom onset. Randomly assigned patients also demonstrated evidence of salvageable brain tissue and an ischemic core of less than 70 mL on CT perfusion imaging. Ischemic penumbra was identified by a time to maximum delay of more than 6 seconds. Conversely, ischemic core was defined as regions in which the relative cerebral blood flow was less than 30% of that in normal tissue. The study device for the endovascular therapy group was the Solitaire FR. Again, the rate of functional independence (mRS 0-2) was significantly better in patients undergoing
endovascular treatment than in those receiving medical therapy alone (71% vs 40%, respectively P ¼ .01). The final and most recent confirmations of the benefits of endovascular treatment are the Solitaire With the Intention For Thrombectomy as PRIMary Endovascular treatment (SWIFT PRIME) and the Randomized Trial of Revascularization with Solitaire FR Device vs Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) trials.34,35 Similar to the other recent studies, eligible patients in SWIFT PRIME received IV tPA and had confirmed large-vessel occlusion of the anterior circulation.35 Patients with large ischemic core lesions were excluded. Patients were randomly assigned to IV tPA alone or IV tPA 1 endovascular thrombectomy with the Solitaire retrievable stent. The study was stopped early after an interim analysis demonstrated the efficacy of endovascular intervention. The rate of functional independence (mRS score 0-2) was significantly higher in patients treated with endovascular therapy (60.2% vs 35.5%, P , .001, in those treated with IV tPA alone). REVASCAT was similar to previous studies in that it included patients with confirmed large-vessel occlusion (M1 segment of the middle cerebral artery or internal carotid artery) and excluded patients with large core infarcts, and endovascular treatment consisted of the use of a retrievable stent for mechanical thrombectomy.34 Contrary to previous studies, the time window was extended, including patients who presented within 8 hours of symptom onset. Additionally, all patients were either ineligible to receive IV tPA or had lesions that were refractory to the IV tPA they received within 4.5 hours of symptom onset. This served to isolate the endovascular component of treatment, controlling for any beneficial effects of the IV thrombolysis. Recruitment was stopped early after interim analysis demonstrated the efficacy of endovascular intervention. REVASCAT demonstrated the rate of functional independence (mRS score
TABLE 1. Summary of Recent Studies Evaluating the Benefit of IV tPA 1 Endovascular Therapy vs IV tPA Alonea Study MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
Patients Enrolled in Study (Total n) 500 70 315 196 206
IV tPA 1 Endovascular, n (%) 233 35 165 98 70
(46.6) (50) (47.8) (50) (67.9)c
Stentriever, n (% of Intervention Group)b 190 29 130 87 96
(81.5) (82.9) (86.1) (88.8) (98)
IV tPA Alone, n (%) 267 35 150 98 80
(53.4) (50) (37.3) (50) (77.6)c
a
IV tPA, intravenous tissue plasminogen activator. n represents the number of patients who received endovascular treatment with retrievable stents. The percentage is calculated using the number of patients who actually underwent endovascular therapy as the dominator. c REVASCAT included patients with lesions refractory OR who were ineligible for IV tPA. Therefore, all patients did not receive IV thrombolysis. To ease direct comparison, the data indicated by c include only those patients who received IV tPA. There were 33 patients in the endovascular arm and 23 in the control arm who did not receive IV tPA. b
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Guest Editorial 0-2) to be significantly higher in patients treated with endovascular therapy (43.7% vs 28.2% in those in the control group [confidence interval 1.1-4.0]).
RECANALIZATION AND REPERFUSION The rate of rapid and effective recanalization has been demonstrated to be associated with improved patient outcomes. In their meta-analysis of trials of thrombolytic (IA and IV) and mechanical recanalization therapies comprising 2066 patients, Rha et al11 demonstrated good outcome in 58.1% of patients in whom recanalization was achieved compared with 24.8% of those in whom it was not. In all of these recent studies,30,31,33-35 successful recanalization (TICI score 2b or 3) was observed in the majority of patients who underwent endovascular therapy (Table 2). Recanalization was assessed by CTA at 24 hours after treatment in the MR CLEAN study.30 The absence of residual occlusion was significantly more common in the intervention group than the medical group (75.4% vs 32.9%, respectively; confidence interval 4.34-10.94). Similarly, in the ESCAPE trial, successful recanalization was achieved in more patients undergoing endovascular therapy compared with medical therapy alone (72.4% achieved TICI 2b or 3 vs 37.3% achieving a modified arterial occlusive lesion score of 2 or 3 on posttreatment CTA, respectively).31 The EXTEND-IA trial assessed posttreatment reperfusion via CT perfusion analysis.33 Successful reperfusion was defined as the percentage of reduction in the perfusion-lesion volume between initial imaging and that performed 24 hours after treatment. Endovascular therapy was associated with increased reperfusion, with a .90% probability of reperfusion in that treatment group. SWIFT PRIME compared posttreatment reperfusion by means of CT or MR perfusion imaging.35 Similar to EXTEND-IA, successful reperfusion ($90%) occurred statistically more frequently following endovascular thrombectomy (82.8% vs 40.4% at 27 hours of the patients treated with IV tPA alone; P # .001). Although REVASCAT did not directly compare rates of revascularization between groups, TICI 2b or 3 recanalization occurred in 65.7% of those patients undergoing mechanical thrombectomy.34 This rate is slightly lower than those reported
in the other studies. The obligatory inclusion of patients with occlusive lesions refractory to IV tPA may have selected patients with “more stubborn” thrombi, making even mechanical thrombectomy more difficult. Even though the rate of successful recanalization was slightly lower, clinical outcome did not appear to be adversely affected.
TIME As previously mentioned, preprocedural identification of the occlusion site was not a requirement of the IMS-III, SYNTHESIS Expansion, and MR RESCUE trials,25-27 resulting in the enrollment of many patients who lacked large-vessel occlusions. One reason for this study design undoubtedly was the thought that obtaining the necessary imaging studies (eg, CTA, MRA) would delay the initiation of treatment, thereby adversely affecting patient outcome. With minor variations, patients enrolled in MR CLEAN, EXTEND-IA, ESCAPE, and SWIFT PRIME arrived at a study center and underwent radiographic evaluation and assessment for eligibility for IV tPA therapy, endovascular therapy, and the study in parallel, rather than sequentially; they were randomly assigned and, if assigned to endovascular therapy, taken to the interventional suite. With the use of the treatment paradigms outlined in these studies, no difference in the initiation of treatment was observed (Table 3). In all studies, IV tPA was administered within the FDA-required guidelines and without notable delay in the endovascular group. Median times from symptom onset to groin puncture were 260, 210, 185, 224, and 269 minutes in the MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, and REVASCAT trials, respectively. Taken together, these studies demonstrate that obtaining diagnostic imaging does not delay the initiation of IV tPA therapy. Additionally, endovascular intervention can be performed within reasonable timeframes when using the therapeutic framework outlined above.
SAFETY Patients with acute ischemic stroke may be at risk for ICH following endovascular recanalization therapy. We previously reported that decreased cerebral blood volume in the basal ganglia
TABLE 2. Successful Recanalization, Defined as Thrombolysis in Cerebral Infarction (TICI) 2b or 3, Following Endovascular Procedures Study MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
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TICI 2b or 3 (%) 115/196 25/29 113/156 73/83 63/102
(58.7) (86) (72.4) (88) (65.7)
TICI 2b (%)
TICI 3 (%)
68/196 (34.7) 11/29 (38) Data not available 16/83 (19.3) 48/102 (47.1)
47/196 (24) 14/29 (48) Data not available 57/83 (68.7) 19/102 (18.6)
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Guest Editorial TABLE 3. Median Time in Minutes to Treatment in Recently Published Studies Evaluating the Role of Endovascular Treatment in Acute Ischemic Strokea From Symptom Onset to IV tPAb
a b
Study
Endovascular
IV tPA Alone
MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
85 127 110 110.5 117.5
87 145 125 117 105
(67-110) (93-162) (80-142) (85-156) (90-150)
From Symptom Onset to Groin Puncture
From Groin Puncture to Recanalization
260 210 185 224 269
30 43 56 24 59
(65-116) (105-180) (89-183) (80-155) (86-137.5)
IV tPA, intravenous tissue plasminogen activator. Ranges are also provided.
may be associated with risk of hemorrhagic conversion following recanalization and reperfusion.36 Although one may deduce that higher rates of recanalization following endovascular therapy may come at the expense of a higher rate of hemorrhage, this was not observed in MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, or REVASCAT (Table 4). In these studies, the rate of symptomatic ICH in the endovascular groups ranged from 0% to 7.7% and was not different from that observed in patients treated with IV tPA alone. The mortality encountered during follow-up was also similar in both groups across studies (Table 4). In all these studies, practitioners were able to achieve significantly increased rates of recanalization, which resulted in improved functional outcomes, without increasing the risk of symptomatic ICH or death.
controlled studies (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, and REVASCAT), mechanical thrombectomy, when used in combination with IV tPA, has demonstrated a significant radiographic and clinical benefit over traditional strategies with IV tPA alone. These results have placed endovascular therapy at the forefront of stroke treatment, redefining the standard of care. Disclosures Dr Hopkins receives grant/research support from Toshiba; serves as a consultant to Abbott, Boston Scientific, Cordis, and Covidien; holds financial interests in AccessClosure, Apama, Augmenix, Axtria, Boston Scientific, Claret Medical Inc., Ellipse, Endomation, Medina Medical, NextPlain, Ostial Corporation, Photolitec, Silk Road, StimSox, ValenTx, and Valor Medical; holds a board/trustee/officer position with Claret Medical, Inc.; serves on the Abbott Vascular and Toshiba speakers’ bureaus; and has received honoraria from Complete Conference Management, Cordis, Covidien, Memorial Healthcare System. Dr Levy has shareholder/ownership interests in Intratech Medical Ltd., Blockade Medical LLC. and Medina Medical. He serves as a principal investigator for the Covidien US SWIFT PRIME Trials and receives honoraria for training and lecturing from that company. He receives compensation from Abbott for carotid training for physicians. He serves as a consultant to Pulsar, Medina Medical, and Blockade Medical. Dr Siddiqui has received research grants from the National Institutes of Health (co-investigator: NINDS
SUMMARY Endovascular treatment for acute ischemic stroke has changed remarkably over the past decade. Beginning with IA thrombolytic administration, endovascular strategies have evolved to include aspiration, self-expanding intracranial stents, and now retrievable stents. With the recent publication of 5 randomized,
TABLE 4. Rates of Symptomatic Intracerebral Hemorrhage (ICH) and Death in Recently Published Studies Evaluating the Role of Endovascular Treatment in Acute Ischemic Strokea Symptomatic ICH IV tPA 1 Endovascular (%)
Study 30
MR CLEAN EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34 a
18 0 6 0 5
(7.7) (0) (3.6) (0) (4.9)
Death IV tPA Alone (%) 17 2 4 3 2
(6.4) (6) (2.7) (3.1) (1.9)
IV tPA 1 Endovascular (%) 44 3 17 9 19
(18.9) (9) (10.4) (9.2) (18.4)
IV tPA Alone (%) 49 7 28 12 16
(18.4) (20) (19) (12.2) (15.5)
IV tPA, intravenous tissue plasminogen activator.
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Guest Editorial 1R01NS064592-01A1, Hemodynamic induction of pathological remodeling leading to intracranial aneurysms and co-investigator NIBIB 5RO1EB00287307, Micro-Radiographic Image for Neurovascular Interventions), and the University at Buffalo (Research Development Award) (not related to this submission); holds financial interests in Hotspur, Intratech Medical, StimSox, Valor Medical, Blockade Medical, and Lazarus Effect; serves as a consultant to Blockade Medical, Codman & Shurtleff, Inc., Concentric Medical, ev3/ Covidien Vascular Therapies, GuidePoint Global Consulting, Lazarus Effect, MicroVention, Penumbra, Inc., Stryker Neurovascular and Pulsar Vascular; belongs to the speakers’ bureaus of Codman & Shurtleff, Inc. and Genentech; serves on National Steering Committees for the following company-sponsored trials: 3D Separator (Penumbra, Inc.), FRED (MicroVention), and SWIFT PRIME (Covidien); serves on advisory boards for Codman & Shurtleff and Covidien Neurovascular; and has received honoraria from Abbott Vascular and Codman & Shurtleff, Inc. for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. Dr Snyder: Boston Scientific: Research and stockholder; Cordis: Research and financial interest; EndoTex: Research and financial interest; Medtronic: Research and consultant support; Abbott Vascular: Research and consultant support; ev3: Research and consultant support; Toshiba: Research and consultant support; Micrus: research and consultant support and financial interest; Zimmer: Research and consultant support; Access Closure Inc.: Financial interest and stockholder; Niagara Gore Medical: Stockholder; EPI: Research and financial interest; Primus: Financial interest; Guidant: Research; Kerberos: Research. Drs Munich and Mokin have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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REFERENCES 1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics— 2015 update: a report from the American Heart Association. Circulation. 2015; 131(4):e29-e322. 2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. 3. Madsen TE, Khoury JC, Alwell KA, et al. Analysis of tissue plasminogen activator eligibility by sex in the greater Cincinnati/Northern Kentucky stroke study. Stroke. 2015;46(3):717-721. 4. Overgaard K, Sereghy T, Boysen G, Pedersen H, Diemer NH. Reduction of infarct volume and mortality by thrombolysis in a rat embolic stroke model. Stroke. 1992;23(8):1167-1173;; discussion 1174. 5. Casto L, Moschini L, Camerlingo M, et al. Local intraarterial thrombolysis for acute stroke in the carotid artery territories. Acta Neurol Scand. 1992;86(3):308-311. 6. Jahan R, Duckwiler GR, Kidwell CS, et al. Intraarterial thrombolysis for treatment of acute stroke: experience in 26 patients with long-term follow-up. AJNR Am J Neuroradiol. 1999;20(7):1291-1299. 7. Lanzieri CF, Tarr RW, Landis D, et al. Cost-effectiveness of emergency intraarterial intracerebral thrombolysis: a pilot study. AJNR Am J Neuroradiol. 1995;16 (10):1987-1993. 8. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29 (1):4-11. 9. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282(21): 2003-2011. 10. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985;312(14):932-936. 11. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967-973. 12. Barnwell SL, Clark WM, Nguyen TT, O’Neill OR, Wynn ML, Coull BM. Safety and efficacy of delayed intraarterial urokinase therapy with mechanical clot dis-
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22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
ruption for thromboembolic stroke. AJNR Am J Neuroradiol. 1994;15(10):18171822. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36(7): 1432-1438. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39(4): 1205-1212. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8): 2761-2768. Brekenfeld C, Schroth G, Mattle HP, et al. Stent placement in acute cerebral artery occlusion: use of a self-expandable intracranial stent for acute stroke treatment. Stroke. 2009;40(3):847-852. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. AJNR Am J Neuroradiol. 2007;28(5): 816-822. Zaidat OO, Wolfe T, Hussain SI, et al. Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke. 2008;39(8): 2392-2395. Levy EI, Siddiqui AH, Crumlish A, et al. First Food and Drug Administrationapproved prospective trial of primary intracranial stenting for acute stroke: SARIS (stent-assisted recanalization in acute ischemic stroke). Stroke. 2009;40 (11):3552-3556. Pérez MA, Miloslavski E, Fischer S, Bäzner H, Henkes H. Intracranial thrombectomy using the Solitaire stent: a historical vignette. J Neurointerv Surg. 2012;4 (6):e32. Saver JL, Jahan R, Levy EI, et al; for the SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380(9849):1241-1249. Nogueira RG, Lutsep HL, Gupta R, et al; for the Trevo Trialists. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380(9849): 1231-1240. Higashida RT, Furlan AJ, Roberts H, et al; for the Technology Assessment Committees of the American Society of Interventional Therapeutic Neuroradiology and the Society of Interventional Radiology. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109-e137. Walcott BP, Boehm KM, Stapleton CJ, Mehta BP, Nahed BV, Ogilvy CS. Retrievable stent thrombectomy in the treatment of acute ischemic stroke: analysis of a revolutionizing treatment technique. J Clin Neurosci. 2013;20(10): 1346-1349. Broderick JP, Palesch YY, Demchuk AM, et al; for the Interventional Management of Stroke Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903. Kidwell CS, Jahan R, Gornbein J, et al; for the MR Rescue Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. Ciccone A, Valvassori L, Nichelatti M, et al; for the Synthesis Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013; 368(10):904-913. Mokin M, Khalessi AA, Mocco J, et al. Endovascular treatment of acute ischemic stroke: the end or just the beginning? Neurosurg Focus. 2014;36(1):E5. Jayaraman MV, Grossberg JA, Meisel KM, Shaikhouni A, Silver B. The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy. AJNR Am J Neuroradiol. 2013;34(1):135-139. Berkhemer OA, Fransen PS, Beumer D, et al; for the MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20. Goyal M, Demchuk AM, Menon BK, et al; for the ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030. Bayley M, Lindsay P, Hellings C, Woodbury E, Phillips S; Canadian Stroke Strategy. Balancing evidence and opinion in stroke care: the 2008 best practice recommendations. CMAJ. 2008;179(12):1247-1249.
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Guest Editorial 33. Campbell BC, Mitchell PJ, Kleinig TJ, et al; for the Extend-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. 34. Jovin TG, Chamorro A, Cobo E, et al; for the REVASCAT Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296-2306. 35. Saver JL, Goyal M, Bonafe A, et al; for the SWIFT PRIME Investigators. Stentretriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2286-2295.
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36. Mokin M, Morr S, Fanous AA, et al. Correlation between cerebral blood volume values and outcomes in endovascular therapy for acute ischemic stroke. J Neurointerv Surg. [Epub ahead of print]. doi: 10.1136/neurintsurg2014-011279.
Acknowledgment The authors thank Debra J. Zimmer for editorial assistance.
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Stephan A. Munich, MD*‡ Maxim Mokin, MD, PhD§ Kenneth V. Snyder, MD, PhD*‡¶k# Adnan H. Siddiqui, MD, PhD*‡¶#** L. Nelson Hopkins, MD*‡¶#** Elad I. Levy, MD, MBA*‡¶# *Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; ‡Department of Neurosurgery, Gates Vascular Institute at Kaleida Health, Buffalo, New York; §Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa, Florida; ¶Department of Radiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; kDepartment of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; #Toshiba Stroke and Vascular Research Center, University at Buffalo, State University of New York; **Jacobs Institute, Buffalo, New York
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S
troke affects approximately 795 000 people each year, resulting in 1 of every 20 deaths in the United States.1 It remains the leading cause of long-term disability with more than 50% of stroke patients requiring discharge to a rehabilitation or skilled nursing facility.1 Stroke resulted in an estimated direct medical cost of $17.5 billion in 2011. Intravenous tissue plasminogen activator (IV tPA) remains the only US Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke. However, given the strict eligibility criteria and apprehension surrounding the risk of intracerebral hemorrhage (ICH), which was reported to be 6.4% in the National Institute of Neurological Disorders and Stroke [NINDS] trial,2 less than 10% of stroke patients receive IV tPA.3 At the time of publication of the NINDS trial results (1995), endovascular intervention for acute ischemic stroke was in its infancy, isolated to research laboratories and a few select clinical centers. Yet, over only the past decade, we have witnessed an exponential increase in its implementation, fueled primarily by a transformation in the tools, as well as the clinical approaches to endovascular therapies. Initial questions regarding its benefits have been answered by the recent publication of 4 studies clearly demonstrating its benefits. Here, we discuss the evolution of endovascular therapy for acute ischemic stroke with particular attention to what is becoming a newly established standard of care—IV tPA in combination with endovascular thrombectomy.
INITIAL ATTEMPTS AT ENDOVASCULAR STROKE TREATMENT In the early 1990s, descriptions of local intra-arterial (IA) administration of thrombolytics for treatment of acute ischemic stroke were reported, first in animal models followed by clinical cases.4-6 Additional study of IA thrombolysis found statistically significant improvement in neurological outcome and, although the cost was greater for the acute treatment than for IV therapy, it was offset by the expense saved at long-term care facilities.7 The Prolyse in Acute Cerebral Thromboembolism (PROACT) trial was the first randomized, controlled study designed to test IA local delivery of a thrombolytic agent (prourokinase) vs placebo.8 Administration of pro-urokinase was associated with successful recanalization. The PROACT II study confirmed these findings, with recanalization occurring in 66% of those receiving IA thrombolysis.9 However, complete recanalization (Thrombolysis in Myocardial Infarction [TIMI] grade 310) occurred in only 19%. These findings supported the notion that recanalization was associated with improved outcome, with 40% of patients receiving IA thrombolysis having good neurological outcome (modified Rankin Scale [mRS] score #2) compared with 25% of patients in the control group. Although recanalization rates were higher than those seen with IV thrombolytic administration, they remained relatively unpredictable.11 In 1994, Barnwell et al12 described combined IA thrombolysis and mechanical clot disruption with microcatheter and wire manipulation for the treatment of thromboembolic stroke. In their series of 13 patients, 10 achieved successful recanalization and 9 experienced improvement of more than 4 points on the National Institutes of Health Stroke Scale (NIHSS) score. This early experience, in combination with unpredictable recanalization rates after IA-thrombolytic administration, underscored the need for devices for safe and reliable clot retrieval. The Merci device (Concentric Medical/Stryker Neurovascular, Fremont, California) revolutionized the endovascular treatment of acute stroke, solidifying the concept of mechanical thrombectomy as a cornerstone of endovascular revascularization therapy. The device is designed as a corkscrew, intended to penetrate the thrombus, allowing it to be removed along with the device. The first case in humans was performed at the University of
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Guest Editorial California, Los Angeles, in 2001. The device received FDA approval in 2004, and the subsequent Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial reported a recanalization rate of 46%.13 Good neurological outcome (mRS score of 0-2) was observed in 46% of patients with successful (TIMI 2 or 3) recanalization compared with 10% without recanalization (TIMI 0). These findings were confirmed in the multi-MERCI trial.14 The next major therapeutic system to be developed for stroke treatment was the Penumbra aspiration system (Penumbra, Inc.). Its aim was to prevent distal emboli through aspiration, while effectively removing the thrombus both by aspiration and mechanical disruption using separator wires. The single-arm, prospective Penumbra Pivotal Stroke Trial reported an 81.6% recanalization rate (TIMI 2-3, in treated vessels).15 Symptomatic ICH occurred in 11.2% of patients. Experience with this system, as reported in the postmarket experience of the Penumbra system trial (POST), demonstrated similar results, with successful recanalization achieved in 87% of patients. With the development of self-expanding intracranial stents and building on the interventional experience in the treatment of acute myocardial infarction, stenting as a treatment for acute stroke first was reported in the late 2000s.16-18 The StentAssisted Recanalization in Acute Ischemic Stroke (SARIS) single-arm prospective study was designed to assess the safety and efficacy of the Wingspan self-expanding intracranial stent (Stryker) as a means of revascularization in the setting of thromboembolic stroke in patients who were ineligible for or with occlusions refractory to IV tPA.19 Recanalization (TIMI 2 or 3) was achieved in all patients, with complete recanalization (TIMI grade 3) occurring in 60%. In the context of rapid development of endovascular strategies for stroke treatment and with necessity as the mother of invention, Pérez et al20 first reported successful recanalization using the Solitaire retrievable stent, albeit serendipitously. Although initially intended for use in the treatment of wide-necked intracranial aneurysms, the Solitaire and other retrievable stents (Trevo [Stryker]) have become the first-line devices for mechanical thrombectomy at many institutions. Deployment of the stent within the thrombus results in immediate partial flow restoration as the stent expands. With sufficient stent integration into the clot, removal of the device also extracts the clot, resulting in recanalization. Initial studies evaluating the safety and efficacy of retrievable stents yielded favorable results. The Solitaire With the Intention for Thrombectomy (SWIFT) trial reported greater rates of recanalization (61% with the Solitaire Flow Restoration device vs 37% with the Merci device), as well as improved neurological outcome (mRS score 0-2—58% with Solitaire vs 33% with the Merci device).21 Similar results were reported for the Trevo device (Stryker) in the Trevo vs Merci Retrievers for Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO 2) trial.22 Again, recanalization (Thrombolysis in Cerebral Infarction [TICI] 2a to 323) occurred more frequently in patients treated with the Trevo device than the Merci device (86% vs 60%, respectively); and good neurological outcome (mRS scores 0-2) occurred in 40% of patient treated with the Trevo compared with 22% of those treated with the Merci. A recent meta-analysis of retrievable stent thrombectomy found impressive rates of recanalization across studies (mean of 83% for Trevo and 82% for Solitaire).24 Rates of symptomatic ICH remained low (8% for Trevo and 6% for Solitaire). These findings solidified retrievable stents as the foundation of endovascular treatment of acute stroke and set the stage for large, multicenter trials evaluating their efficacy compared to traditional medical therapy (IV tPA).
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Guest Editorial RECENT HISTORY OF ENDOVASCULAR STROKE TREATMENT Despite favorable early reports of endovascular therapy for acute ischemic stroke, many viewed the publication of the results of the multicenter Interventional Management of Stroke (IMS) III,25 Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE),26 and Synthesis Expansion: A Randomized Controlled Trial on Intra-arterial vs Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)27 trials in the New England Journal of Medicine in 2013 as the final nail in the coffin for such therapy. The IMS III trial demonstrated no benefit of IV tPA 1 endovascular therapy compared with IV tPA alone.25 Similarly, MR RESCUE concluded that embolectomy was not superior to standard care (ie, IV-tPA alone) despite the presence of favorable penumbral imaging patterns.26 The SYNTHESIS Expansion investigators observed similar results comparing IV tPA with endovascular therapy alone.27 (We previously published a detailed review of these studies.28). Although these were randomized controlled trials, their designs produced significant limitations. Recruitment occurred over many years and often failed to incorporate the development of new technology. Since the introduction of the Merci device in 2004, endovascular treatments for acute ischemic stroke have evolved at a rapid pace—from the Merci device, to aspiration, to the use of implantable stents, and, most recently, to retrievable stents. With the development of new devices, not only improved rates of recanalization, but also improved clinical outcomes have been observed. Moreover, the implementation of these new devices in clinical practice and parallel improvements in neuroimaging have improved the neurointerventionist’s ability to select patients suitable for revascularization (namely, those with large-vessel occlusion). In the original IMS III protocol,25 documentation of largevessel occlusion was not required for randomization, resulting in 20% of the patients enrolled in the endovascular arm having no large-vessel occlusion on angiography. Therefore, these patients did not undergo endovascular therapy despite being considered (and statistically analyzed) in the endovascular arm. Additionally, the study design failed to account for the rapidly evolving (and improving) endovascular technology—most patients in the endovascular arm were treated using the Merci device or IA thrombolysis, generally considered outdated approaches. Similarly, the SYNTHESIS Expansion trial did not require confirmation of large-vessel occlusion, again resulting in patients without large-vessel occlusion being randomly assigned to the endovascular group. Again, retrievable stents were used in a minority of patients (13%), with most patients being treated by IA thrombolysis and/or wire disruption of the clot. In the MR RESCUE study, retrievable stents were not used at all for patients randomly assigned to endovascular therapy.
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Additionally, study participants included patients with infarct volumes of up to 90 mL, which are considered by most practitioners very large and refractory to any revascularization. Furthermore, successful recanalization was defined as TICI grade 2a-3, despite TICI 2a being defined as only partial reperfusion. This undoubtedly resulted in skewed outcome measures, as better reperfusion rates are known to be associated with smaller infarct volumes and improved clinical outcomes.29 At the time of their publication, these studies were felt to signal an end to the endovascular treatment of acute ischemic stroke. However, critical review of these studies demonstrated that improper patient selection and outdated endovascular therapy resulted in inadequate recanalization and reperfusion. Thus, the endovascular therapy being studied was not representative of contemporary practice. Although these studies represent the first generation of randomized controlled studies of endovascular stroke therapy, their conclusions should be viewed with caution and judicious consideration of the aforementioned limitations.
IV tPA 1 ENDOVASCULAR THERAPY—THE NEW STANDARD OF CARE (?) Given the significant limitations of IMS-III, SYNTHESIS Expansion, and MR RESCUE, the role of endovascular therapy in acute stroke treatment paradigms remained in question. However, with the recent publication of 5 randomized, controlled studies, endovascular intervention is being established as clearly beneficial and becoming a new standard of care. These studies addressed many of the limitations of IMS-III, SYNTHESIS, and MR RESCUE—recruitment occurred over a shorter period of time, demonstration of large-vessel occlusion with noninvasive imaging was obligatory, comparison was between the addition of endovascular therapy to IV tPA and IV tPA alone, and contemporary devices (including retrievable stents) were utilized to achieve revascularization. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) was the first to be published.30 Eligible patients (n ¼ 500) were those who had proximal arterial occlusion (established by computed tomographic angiography [CTA] or magnetic resonance angiography [MRA] and confirmed with digital subtraction angiography) of the anterior circulation and could be treated within 6 hours after symptom onset. The method of endovascular therapy was left to the discretion of the treating physician, which allowed for the use of contemporary strategies, including IA tPA, aspiration, mechanical thrombectomy, and retrievable stents. The study found a significant benefit to the use of endovascular therapy, with functional independence (mRS score 0-2) occurring in 32.6% of patients who underwent endovascular intervention, compared with 19.1% of those treated with IV tPA alone.
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Guest Editorial The presentation of 3 additional studies at the 2015 International Stroke Conference confirmed the findings reported in MR CLEAN (Table 1). The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial31 included a similar patient population as MR CLEAN—patients with proximal arterial occlusion of the anterior circulation. However, patients were eligible if they could be treated within 12 hours after symptom onset. This study also aimed to include assessment of collateral circulation, excluding those patients deemed to have poor collateral circulation on CTA. The study enrolled 316 patients and found a significantly greater rate of functional independence (mRS score 0-2) among patients treated with endovascular therapy (53.0% vs 29.3% of patients receiving standard medical care [as defined by Bayley et al32]; P , .001). Although critics of preprocedural identification of proximal, large-vessel occlusion cite delay in treatment initiation as a hindrance, the median time from computed tomography (CT) evaluation to reperfusion was only 84 minutes. The Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) trial included the addition of physiological brain imaging (CT perfusion) to the selection criteria.33 Patients who were eligible for this trial received IV tPA within 4.5 hours of symptom onset, and those randomly assigned to endovascular therapy underwent intervention within 6 hours after symptom onset. Randomly assigned patients also demonstrated evidence of salvageable brain tissue and an ischemic core of less than 70 mL on CT perfusion imaging. Ischemic penumbra was identified by a time to maximum delay of more than 6 seconds. Conversely, ischemic core was defined as regions in which the relative cerebral blood flow was less than 30% of that in normal tissue. The study device for the endovascular therapy group was the Solitaire FR. Again, the rate of functional independence (mRS 0-2) was significantly better in patients undergoing
endovascular treatment than in those receiving medical therapy alone (71% vs 40%, respectively P ¼ .01). The final and most recent confirmations of the benefits of endovascular treatment are the Solitaire With the Intention For Thrombectomy as PRIMary Endovascular treatment (SWIFT PRIME) and the Randomized Trial of Revascularization with Solitaire FR Device vs Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) trials.34,35 Similar to the other recent studies, eligible patients in SWIFT PRIME received IV tPA and had confirmed large-vessel occlusion of the anterior circulation.35 Patients with large ischemic core lesions were excluded. Patients were randomly assigned to IV tPA alone or IV tPA 1 endovascular thrombectomy with the Solitaire retrievable stent. The study was stopped early after an interim analysis demonstrated the efficacy of endovascular intervention. The rate of functional independence (mRS score 0-2) was significantly higher in patients treated with endovascular therapy (60.2% vs 35.5%, P , .001, in those treated with IV tPA alone). REVASCAT was similar to previous studies in that it included patients with confirmed large-vessel occlusion (M1 segment of the middle cerebral artery or internal carotid artery) and excluded patients with large core infarcts, and endovascular treatment consisted of the use of a retrievable stent for mechanical thrombectomy.34 Contrary to previous studies, the time window was extended, including patients who presented within 8 hours of symptom onset. Additionally, all patients were either ineligible to receive IV tPA or had lesions that were refractory to the IV tPA they received within 4.5 hours of symptom onset. This served to isolate the endovascular component of treatment, controlling for any beneficial effects of the IV thrombolysis. Recruitment was stopped early after interim analysis demonstrated the efficacy of endovascular intervention. REVASCAT demonstrated the rate of functional independence (mRS score
TABLE 1. Summary of Recent Studies Evaluating the Benefit of IV tPA 1 Endovascular Therapy vs IV tPA Alonea Study MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
Patients Enrolled in Study (Total n) 500 70 315 196 206
IV tPA 1 Endovascular, n (%) 233 35 165 98 70
(46.6) (50) (47.8) (50) (67.9)c
Stentriever, n (% of Intervention Group)b 190 29 130 87 96
(81.5) (82.9) (86.1) (88.8) (98)
IV tPA Alone, n (%) 267 35 150 98 80
(53.4) (50) (37.3) (50) (77.6)c
a
IV tPA, intravenous tissue plasminogen activator. n represents the number of patients who received endovascular treatment with retrievable stents. The percentage is calculated using the number of patients who actually underwent endovascular therapy as the dominator. c REVASCAT included patients with lesions refractory OR who were ineligible for IV tPA. Therefore, all patients did not receive IV thrombolysis. To ease direct comparison, the data indicated by c include only those patients who received IV tPA. There were 33 patients in the endovascular arm and 23 in the control arm who did not receive IV tPA. b
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Guest Editorial 0-2) to be significantly higher in patients treated with endovascular therapy (43.7% vs 28.2% in those in the control group [confidence interval 1.1-4.0]).
RECANALIZATION AND REPERFUSION The rate of rapid and effective recanalization has been demonstrated to be associated with improved patient outcomes. In their meta-analysis of trials of thrombolytic (IA and IV) and mechanical recanalization therapies comprising 2066 patients, Rha et al11 demonstrated good outcome in 58.1% of patients in whom recanalization was achieved compared with 24.8% of those in whom it was not. In all of these recent studies,30,31,33-35 successful recanalization (TICI score 2b or 3) was observed in the majority of patients who underwent endovascular therapy (Table 2). Recanalization was assessed by CTA at 24 hours after treatment in the MR CLEAN study.30 The absence of residual occlusion was significantly more common in the intervention group than the medical group (75.4% vs 32.9%, respectively; confidence interval 4.34-10.94). Similarly, in the ESCAPE trial, successful recanalization was achieved in more patients undergoing endovascular therapy compared with medical therapy alone (72.4% achieved TICI 2b or 3 vs 37.3% achieving a modified arterial occlusive lesion score of 2 or 3 on posttreatment CTA, respectively).31 The EXTEND-IA trial assessed posttreatment reperfusion via CT perfusion analysis.33 Successful reperfusion was defined as the percentage of reduction in the perfusion-lesion volume between initial imaging and that performed 24 hours after treatment. Endovascular therapy was associated with increased reperfusion, with a .90% probability of reperfusion in that treatment group. SWIFT PRIME compared posttreatment reperfusion by means of CT or MR perfusion imaging.35 Similar to EXTEND-IA, successful reperfusion ($90%) occurred statistically more frequently following endovascular thrombectomy (82.8% vs 40.4% at 27 hours of the patients treated with IV tPA alone; P # .001). Although REVASCAT did not directly compare rates of revascularization between groups, TICI 2b or 3 recanalization occurred in 65.7% of those patients undergoing mechanical thrombectomy.34 This rate is slightly lower than those reported
in the other studies. The obligatory inclusion of patients with occlusive lesions refractory to IV tPA may have selected patients with “more stubborn” thrombi, making even mechanical thrombectomy more difficult. Even though the rate of successful recanalization was slightly lower, clinical outcome did not appear to be adversely affected.
TIME As previously mentioned, preprocedural identification of the occlusion site was not a requirement of the IMS-III, SYNTHESIS Expansion, and MR RESCUE trials,25-27 resulting in the enrollment of many patients who lacked large-vessel occlusions. One reason for this study design undoubtedly was the thought that obtaining the necessary imaging studies (eg, CTA, MRA) would delay the initiation of treatment, thereby adversely affecting patient outcome. With minor variations, patients enrolled in MR CLEAN, EXTEND-IA, ESCAPE, and SWIFT PRIME arrived at a study center and underwent radiographic evaluation and assessment for eligibility for IV tPA therapy, endovascular therapy, and the study in parallel, rather than sequentially; they were randomly assigned and, if assigned to endovascular therapy, taken to the interventional suite. With the use of the treatment paradigms outlined in these studies, no difference in the initiation of treatment was observed (Table 3). In all studies, IV tPA was administered within the FDA-required guidelines and without notable delay in the endovascular group. Median times from symptom onset to groin puncture were 260, 210, 185, 224, and 269 minutes in the MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, and REVASCAT trials, respectively. Taken together, these studies demonstrate that obtaining diagnostic imaging does not delay the initiation of IV tPA therapy. Additionally, endovascular intervention can be performed within reasonable timeframes when using the therapeutic framework outlined above.
SAFETY Patients with acute ischemic stroke may be at risk for ICH following endovascular recanalization therapy. We previously reported that decreased cerebral blood volume in the basal ganglia
TABLE 2. Successful Recanalization, Defined as Thrombolysis in Cerebral Infarction (TICI) 2b or 3, Following Endovascular Procedures Study MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
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TICI 2b or 3 (%) 115/196 25/29 113/156 73/83 63/102
(58.7) (86) (72.4) (88) (65.7)
TICI 2b (%)
TICI 3 (%)
68/196 (34.7) 11/29 (38) Data not available 16/83 (19.3) 48/102 (47.1)
47/196 (24) 14/29 (48) Data not available 57/83 (68.7) 19/102 (18.6)
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Guest Editorial TABLE 3. Median Time in Minutes to Treatment in Recently Published Studies Evaluating the Role of Endovascular Treatment in Acute Ischemic Strokea From Symptom Onset to IV tPAb
a b
Study
Endovascular
IV tPA Alone
MR CLEAN30 EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34
85 127 110 110.5 117.5
87 145 125 117 105
(67-110) (93-162) (80-142) (85-156) (90-150)
From Symptom Onset to Groin Puncture
From Groin Puncture to Recanalization
260 210 185 224 269
30 43 56 24 59
(65-116) (105-180) (89-183) (80-155) (86-137.5)
IV tPA, intravenous tissue plasminogen activator. Ranges are also provided.
may be associated with risk of hemorrhagic conversion following recanalization and reperfusion.36 Although one may deduce that higher rates of recanalization following endovascular therapy may come at the expense of a higher rate of hemorrhage, this was not observed in MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, or REVASCAT (Table 4). In these studies, the rate of symptomatic ICH in the endovascular groups ranged from 0% to 7.7% and was not different from that observed in patients treated with IV tPA alone. The mortality encountered during follow-up was also similar in both groups across studies (Table 4). In all these studies, practitioners were able to achieve significantly increased rates of recanalization, which resulted in improved functional outcomes, without increasing the risk of symptomatic ICH or death.
controlled studies (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, and REVASCAT), mechanical thrombectomy, when used in combination with IV tPA, has demonstrated a significant radiographic and clinical benefit over traditional strategies with IV tPA alone. These results have placed endovascular therapy at the forefront of stroke treatment, redefining the standard of care. Disclosures Dr Hopkins receives grant/research support from Toshiba; serves as a consultant to Abbott, Boston Scientific, Cordis, and Covidien; holds financial interests in AccessClosure, Apama, Augmenix, Axtria, Boston Scientific, Claret Medical Inc., Ellipse, Endomation, Medina Medical, NextPlain, Ostial Corporation, Photolitec, Silk Road, StimSox, ValenTx, and Valor Medical; holds a board/trustee/officer position with Claret Medical, Inc.; serves on the Abbott Vascular and Toshiba speakers’ bureaus; and has received honoraria from Complete Conference Management, Cordis, Covidien, Memorial Healthcare System. Dr Levy has shareholder/ownership interests in Intratech Medical Ltd., Blockade Medical LLC. and Medina Medical. He serves as a principal investigator for the Covidien US SWIFT PRIME Trials and receives honoraria for training and lecturing from that company. He receives compensation from Abbott for carotid training for physicians. He serves as a consultant to Pulsar, Medina Medical, and Blockade Medical. Dr Siddiqui has received research grants from the National Institutes of Health (co-investigator: NINDS
SUMMARY Endovascular treatment for acute ischemic stroke has changed remarkably over the past decade. Beginning with IA thrombolytic administration, endovascular strategies have evolved to include aspiration, self-expanding intracranial stents, and now retrievable stents. With the recent publication of 5 randomized,
TABLE 4. Rates of Symptomatic Intracerebral Hemorrhage (ICH) and Death in Recently Published Studies Evaluating the Role of Endovascular Treatment in Acute Ischemic Strokea Symptomatic ICH IV tPA 1 Endovascular (%)
Study 30
MR CLEAN EXTEND-IA33 ESCAPE31 SWIFT PRIME35 REVASCAT34 a
18 0 6 0 5
(7.7) (0) (3.6) (0) (4.9)
Death IV tPA Alone (%) 17 2 4 3 2
(6.4) (6) (2.7) (3.1) (1.9)
IV tPA 1 Endovascular (%) 44 3 17 9 19
(18.9) (9) (10.4) (9.2) (18.4)
IV tPA Alone (%) 49 7 28 12 16
(18.4) (20) (19) (12.2) (15.5)
IV tPA, intravenous tissue plasminogen activator.
318 | VOLUME 77 | NUMBER 3 | SEPTEMBER 2015
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Guest Editorial 1R01NS064592-01A1, Hemodynamic induction of pathological remodeling leading to intracranial aneurysms and co-investigator NIBIB 5RO1EB00287307, Micro-Radiographic Image for Neurovascular Interventions), and the University at Buffalo (Research Development Award) (not related to this submission); holds financial interests in Hotspur, Intratech Medical, StimSox, Valor Medical, Blockade Medical, and Lazarus Effect; serves as a consultant to Blockade Medical, Codman & Shurtleff, Inc., Concentric Medical, ev3/ Covidien Vascular Therapies, GuidePoint Global Consulting, Lazarus Effect, MicroVention, Penumbra, Inc., Stryker Neurovascular and Pulsar Vascular; belongs to the speakers’ bureaus of Codman & Shurtleff, Inc. and Genentech; serves on National Steering Committees for the following company-sponsored trials: 3D Separator (Penumbra, Inc.), FRED (MicroVention), and SWIFT PRIME (Covidien); serves on advisory boards for Codman & Shurtleff and Covidien Neurovascular; and has received honoraria from Abbott Vascular and Codman & Shurtleff, Inc. for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. Dr Snyder: Boston Scientific: Research and stockholder; Cordis: Research and financial interest; EndoTex: Research and financial interest; Medtronic: Research and consultant support; Abbott Vascular: Research and consultant support; ev3: Research and consultant support; Toshiba: Research and consultant support; Micrus: research and consultant support and financial interest; Zimmer: Research and consultant support; Access Closure Inc.: Financial interest and stockholder; Niagara Gore Medical: Stockholder; EPI: Research and financial interest; Primus: Financial interest; Guidant: Research; Kerberos: Research. Drs Munich and Mokin have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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REFERENCES 1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics— 2015 update: a report from the American Heart Association. Circulation. 2015; 131(4):e29-e322. 2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. 3. Madsen TE, Khoury JC, Alwell KA, et al. Analysis of tissue plasminogen activator eligibility by sex in the greater Cincinnati/Northern Kentucky stroke study. Stroke. 2015;46(3):717-721. 4. Overgaard K, Sereghy T, Boysen G, Pedersen H, Diemer NH. Reduction of infarct volume and mortality by thrombolysis in a rat embolic stroke model. Stroke. 1992;23(8):1167-1173;; discussion 1174. 5. Casto L, Moschini L, Camerlingo M, et al. Local intraarterial thrombolysis for acute stroke in the carotid artery territories. Acta Neurol Scand. 1992;86(3):308-311. 6. Jahan R, Duckwiler GR, Kidwell CS, et al. Intraarterial thrombolysis for treatment of acute stroke: experience in 26 patients with long-term follow-up. AJNR Am J Neuroradiol. 1999;20(7):1291-1299. 7. Lanzieri CF, Tarr RW, Landis D, et al. Cost-effectiveness of emergency intraarterial intracerebral thrombolysis: a pilot study. AJNR Am J Neuroradiol. 1995;16 (10):1987-1993. 8. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29 (1):4-11. 9. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282(21): 2003-2011. 10. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985;312(14):932-936. 11. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967-973. 12. Barnwell SL, Clark WM, Nguyen TT, O’Neill OR, Wynn ML, Coull BM. Safety and efficacy of delayed intraarterial urokinase therapy with mechanical clot dis-
NEUROSURGERY
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
ruption for thromboembolic stroke. AJNR Am J Neuroradiol. 1994;15(10):18171822. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36(7): 1432-1438. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39(4): 1205-1212. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8): 2761-2768. Brekenfeld C, Schroth G, Mattle HP, et al. Stent placement in acute cerebral artery occlusion: use of a self-expandable intracranial stent for acute stroke treatment. Stroke. 2009;40(3):847-852. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. AJNR Am J Neuroradiol. 2007;28(5): 816-822. Zaidat OO, Wolfe T, Hussain SI, et al. Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke. 2008;39(8): 2392-2395. Levy EI, Siddiqui AH, Crumlish A, et al. First Food and Drug Administrationapproved prospective trial of primary intracranial stenting for acute stroke: SARIS (stent-assisted recanalization in acute ischemic stroke). Stroke. 2009;40 (11):3552-3556. Pérez MA, Miloslavski E, Fischer S, Bäzner H, Henkes H. Intracranial thrombectomy using the Solitaire stent: a historical vignette. J Neurointerv Surg. 2012;4 (6):e32. Saver JL, Jahan R, Levy EI, et al; for the SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380(9849):1241-1249. Nogueira RG, Lutsep HL, Gupta R, et al; for the Trevo Trialists. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380(9849): 1231-1240. Higashida RT, Furlan AJ, Roberts H, et al; for the Technology Assessment Committees of the American Society of Interventional Therapeutic Neuroradiology and the Society of Interventional Radiology. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109-e137. Walcott BP, Boehm KM, Stapleton CJ, Mehta BP, Nahed BV, Ogilvy CS. Retrievable stent thrombectomy in the treatment of acute ischemic stroke: analysis of a revolutionizing treatment technique. J Clin Neurosci. 2013;20(10): 1346-1349. Broderick JP, Palesch YY, Demchuk AM, et al; for the Interventional Management of Stroke Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903. Kidwell CS, Jahan R, Gornbein J, et al; for the MR Rescue Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. Ciccone A, Valvassori L, Nichelatti M, et al; for the Synthesis Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013; 368(10):904-913. Mokin M, Khalessi AA, Mocco J, et al. Endovascular treatment of acute ischemic stroke: the end or just the beginning? Neurosurg Focus. 2014;36(1):E5. Jayaraman MV, Grossberg JA, Meisel KM, Shaikhouni A, Silver B. The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy. AJNR Am J Neuroradiol. 2013;34(1):135-139. Berkhemer OA, Fransen PS, Beumer D, et al; for the MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20. Goyal M, Demchuk AM, Menon BK, et al; for the ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030. Bayley M, Lindsay P, Hellings C, Woodbury E, Phillips S; Canadian Stroke Strategy. Balancing evidence and opinion in stroke care: the 2008 best practice recommendations. CMAJ. 2008;179(12):1247-1249.
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Guest Editorial 33. Campbell BC, Mitchell PJ, Kleinig TJ, et al; for the Extend-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. 34. Jovin TG, Chamorro A, Cobo E, et al; for the REVASCAT Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296-2306. 35. Saver JL, Goyal M, Bonafe A, et al; for the SWIFT PRIME Investigators. Stentretriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2286-2295.
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36. Mokin M, Morr S, Fanous AA, et al. Correlation between cerebral blood volume values and outcomes in endovascular therapy for acute ischemic stroke. J Neurointerv Surg. [Epub ahead of print]. doi: 10.1136/neurintsurg2014-011279.
Acknowledgment The authors thank Debra J. Zimmer for editorial assistance.
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