New Focus on Endovascular Therapy for Ischemic Stroke

Background: Over the past 2 decades, a growing number of large-scale clinical trials have helped expand the toolkit for emergency management of acute ischemic stroke. This article is intended to be an up-to-date resource to aid nonstroke specialist neurology providers and ophthalmologists in identifying situations and patient populations in which urgent stroke evaluation should be completed with options for emergent reperfusion therapy considered. Evidence acquisition: The literature forming the foundation of the guidelines for early management of patients with acute ischemic stroke was reviewed, annotated, and summarized. Results: Data from both initial and follow-up trials investigating the benefits and indications for use of intravenous thrombolysis and endovascular intervention for stroke are reviewed systematically, with an emphasis on new updates to qualifying patient populations and time periods for treatment. Conclusions: Recent studies underscore the conclusion that timely reperfusion in acute ischemic stroke is the most effective available treatment and that there are a growing number of new scenarios and patients for which interventions maybe applied.

Disease of the Year 2020 Encore: Cerebrovascular Disorders Section Editors: Valerie Biousse, MD Koto Ishida, MD New Focus on Endovascular Therapy for Ischemic Stroke Sean Kelly, MD, PhD, Eytan Raz, MD, PhD, Maksim Shapiro, MD, Koto Ishida, MD Background: Over the past 2 decades, a growing number of large-scale clinical trials have helped expand the toolkit for emergency management of acute ischemic stroke. This article is intended to be an up-to-date resource to aid nonstroke specialist neurology providers and ophthalmologists in identifying situations and patient populations in which urgent stroke evaluation should be completed with options for emergent reperfusion therapy considered. Evidence Acquisition: The literature forming the foundation of the guidelines for early management of patients with acute ischemic stroke was reviewed, annotated, and summarized. Results: Data from both initial and follow-up trials investigating the benefits and indications for use of intravenous thrombolysis and endovascular intervention for stroke are reviewed systematically, with an emphasis on new updates to qualifying patient populations and time periods for treatment. Conclusions: Recent studies underscore the conclusion that timely reperfusion in acute ischemic stroke is the most effective available treatment and that there are a growing number of new scenarios and patients for which interventions maybe applied. Journal of Neuro-Ophthalmology 2021;41:170–175 doi: 10.1097/WNO.0000000000001279 © 2021 by North American Neuro-Ophthalmology Society I schemic strokes result when a vessel supplying blood to the brain is occluded, in turn leading to a disruption in neurologic function. Annually in the United States, more than 795,000 people experience stroke, and more than 6.6 million Americans are currently living with a history of prior stroke (1). Approximately, 87% of these events are due to artery occlusion as opposed to hemorrhage, with a new event occurring every 40 seconds in the United States alone (1). Stroke is even more prominent globally, accounting for a disproportionate amount of the long-term disability Department of Neurology, NYU School of Medicine, New York, New York. The authors report no conflicts of interest. Address correspondence to Sean M. Kelly, MD, PhD, Department of Neurology, NYU School of Medicine, New York, NY 10016; E-mail: [e-mail] 170 burdening health care systems in addition to being a primary source of mortality. Fortunately, with advances in diagnostic imaging techniques as well as both medical and interventional management approaches, outcomes are steadily improving for patients who are able to receive timely medical attention at primary or comprehensive stroke centers (2). Tools have been developed to aid the neurologist in the initial triage of stroke cases, particularly modalities of diagnostic imaging that may aid the identification of infarct localization and mechanism. Although relatively recently developed, approaches of computed tomography (CT) or magnetic resonance (MR) angiography and perfusion imaging provide an in depth characterization of evolving stroke within minutes, noncontrast head CT remains the first image obtained in most patients with stroke. In many centers, fast acquisition MRI has begun to play a growing role in the acute management of ischemic stroke as well on the basis of recent data using diffusion-weighted imaging to estimate the time a stroke began. Nonetheless, the value of CT has only grown with the introduction of increasingly standardized image analysis. For example, in the case of anterior circulation strokes involving the internal carotid artery (ICA) or middle cerebral artery (MCA), criteria such as the Acute Stroke Prognosis Early CT Score (ASPECTS) can be helpful in uniformly characterizing the volume of tissue that may already be infarcted to determine whether the patient may be a candidate for endovascular therapy (3). Several related scoring systems such as the posterior circulation ASPECTS (pc-ASPECTS) or formal scoring of leptomeningeal collateral circulation have been developed for characterizing early imaging changes in other vascular territories and may aid the neurologist in identifying viable areas of brain tissue during stroke (4). Such criteria provide an initial approximate quantification of the brain areas already affected by an evolving infarct, whereas advanced techniques such as CT angiography and perfusion imaging help identify the corresponding vascular pathology as well as the salvageable at-risk territory. These first pass images can be acquired rapidly during initial stroke assessments in the emergency room setting; however, each of these standardized systems has limitations, Kelly et al: J Neuro-Ophthalmol 2021; 41: 170-175 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020 Encore: Cerebrovascular Disorders particularly related to variations in both technical aspects of imaging and inter-rater reliability. Ultimately, the primary objective of both clinical and radiographic tools is to help rapidly triage acute stroke patients to a stroke center with the resources necessary to provide for the expected plan of care. Here, we review the latest developments in the management of acute ischemic stroke, with an emphasis on thrombolytic therapy and intra-arterial intervention in increasingly broad categories of patients during an extended time window. UPDATE ON INTRAVENOUS THROMBOLYSIS A large number of domestic and international studies have now established the value of timely administration of intravenous t-PA (IV-tPA) for qualifying stroke patients presenting within the first 4.5 hours from symptom onset. The recommendations from these collective studies have been summarized and endorsed within 2 similar sets of guidelines by the Food and Drug Administration (3 hours) and American Heart Association (4.5 hours), respectively (5). Importantly, the benefit conferred by IV-tPA was much more significant when the therapy was given within the first 90 minutes after symptom onset, with a number needed to treat (NNT) of 3.6 compared with 4.3 for presentations between 91 and 180 minutes after symptom onset (6). Although the absolute benefit is smaller, new randomized controlled trials (RCTs) also demonstrate that both older patients and those with extracranial artery dissection or severe symptoms of proximal vessel occlusion can benefit from IV-tPA despite having a generally smaller margin of benefit (7). Although such vulnerable patients have overall worse outcomes both with and without treatment than the overall stroke population, these studies confirm similar or even greater relative benefit from thrombolysis in those who may be at highest risk. Similarly, in another example of expanding indications for IV thrombolysis, the WAKEUP trial showed that patients who presented within 4.5 hours of awakening with stroke symptoms had a small benefit with IV-tPA if MRI showed a diffusion-restricting lesion without matching hyperintense signal on fluidattenuated inversion recovery (FLAIR) sequence (8). This research paved the way in expanding the indications for safe and effective delivery of IV-tPA. At the same time, research has been conducted to explore whether a lower dose of IV-tPA may be equivalently effective with a more benign side effect profile (“ENCHANTED” Phase 3 trial); however, the dose of 0.6 mg/kg was found to be inferior to the standard dose of 0.9 mg/kg for both the endpoints of mortality and disability at 90 days (9). Similarly, adjunctive treatments to IV-tPA, particularly GIIb/IIIa inhibitors such as argatroban, have been investigated as well, with early data suggesting safety with no increase in symptomatic intracranial hemorrhage Kelly et al: J Neuro-Ophthalmol 2021; 41: 170-175 and outcomes favoring the argatroban plus IV-tPA treatment group by a small margin before trial enrollment declined because of most patients being referred instead for mechanical thrombectomy (MT) (10). Although lower doses of IV-tPA were not found to be as effective, there have been multiple studies evaluating the safety and efficacy of alternative thrombolytic agents, namely, tenecteplase, a bioengineered form of recombinant tPA. The EXTEND-IA TNK trial directly compared 0.25 mg/kg of tenecteplase with standard dose IV-tPA in patients with large vessel occlusion (LVO) planned for endovascular therapy. This trial demonstrated that these patients actually achieved higher rates of recanalization and functional recovery with similar adverse events (11). Although promising, it is important to note that EXTEND-IA TNK and most of the other initial randomized controlled trials were phase 2 trials. The only completed Phase 3 trial was the Norwegian Tenecteplase Stroke Trial, which demonstrated the safety and efficacy of using a dose of 0.4 mg/kg of tenecteplase with similar rates of symptomatic intracerebral hemorrhage and functional independence when compared with IV-tPA, but did not show tenecteplase to be superior (12). Thus, tenecteplase use is currently supported by class IIb level evidence in the most recent American Heart Association (AHA) stroke guidelines specifically in the setting of patients eligible for thrombectomy or those with minor neurological impairment without major intracranial occlusion (5). UPDATE ON ENDOVASCULAR THERAPY FOR ACUTE ISCHEMIC STROKE Although mechanical clot retrieval has long been conceptualized as a potential approach for limiting ischemic injury, it was not formally studied until the 1980s and 1990s, which brought about a renaissance of percutaneous cardiac catheterization and stenting for coronary artery disease. Along with this progress came advances in procedural equipment and approaches as well as a vast body of data supporting the safety and efficacy of endovascular therapy in treating ischemic heart disease (13). Investigations began to determine whether similar benefits would be demonstrated in the cerebrovascular realm, but notable distinctions between the anatomy and physiology of the heart and brain posed challenges along the way. Most prominently, the exceptional metabolic demands of neurons and glia make brain tissue exquisitely sensitive to hypoxia when compared, for example, with cardiac tissue (14,15). Moreover, although the presence of even small volume intraparenchymal hemorrhage in the setting of disruption to the blood–brain barrier may have catastrophic consequences for neural function given the risk of seizure and other secondary events, while both the likelihood and impact of similar hemorrhage in the myocardium are much lower (16). Because the brain performs such diverse tasks as integration of sensory perception, direction of movement, 171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020 Encore: Cerebrovascular Disorders control of autonomic activities including respiration, and organization of higher cognition and language, the functional disability and resulting quality of life after stroke have been rated as even worse than after a heart attack (17). Fundamental differences between the heart and brain include smaller and more fragile vasculature, extensive collateral circulation, and a propensity to develop widespread vasogenic or cytotoxic edema that may complicate intracranial endovascular procedures. The resulting risk of local brain tissue damage causing permanent neurologic disability is significant enough that the margin for error in intervening on cerebrovascular occlusions is narrower than for cardiac catheterization (18). Despite these challenges, interventional reperfusion strategies are rapidly improving the acute management of ischemic stroke and complementing the progress made with IV thrombolysis. Although effective in many cases, pharmacologic thrombolysis is not locally targeted to clots, has been shown to have limited efficacy on large occlusive clots, and comes with a host of contraindications that are common in the highest risk stroke patients including systemic anticoagulation or history of recent major surgeries and bleeding diatheses (19). In addition, although IV thrombolysis has only been demonstrated to be beneficial within a narrow time window, endovascular intervention has now been proven to benefit patients for a period of up to 5 times as long (20). Moreover, ongoing advances and widespread availability of pre-procedure diagnostic assessment (i.e. CT angiography and perfusion imaging) and interventional techniques such as retrievable stents have increased the precision and efficacy of thrombectomy, which has in turn led to improved patient outcomes. SUMMARY OF INITIAL RANDOMIZED CONTROLLED TRIALS Endovascular intervention has taken on an increasingly central role in the early management of ischemic stroke. An initial group of trials comparing MT after IV-tPA to IV-tPA alone failed to establish a clear benefit in the primary endpoint of improved functional independence. Nonetheless, these pioneering randomized controlled trials, IMS3, SYNTHESIS, and MR RESCUE, established the safety of endovascular treatment and paved the way for future studies (21–23). Among the factors in these trials that may have influenced the lack of superiority in the intervention subgroups were incidents of equipment breakdown as well as instances in which patients improved before intervention or were ultimately found not to have vessel occlusion (22). Importantly, as advanced neurovascular imaging techniques were more routinely incorporated in triage and with increasing utilization of modern clot retrieval devices, the first suggestion of benefit in functional independence was noted in the data(23). 172 The first large-scale multicenter RCTs that definitively showed a benefit from interventional revascularization for stroke came with the MR CLEAN and SWIFT PRIME trials, both published in 2015 (24,25). These trials evaluated the efficacy of endovascular therapy in patients with anterior circulation large vessel occlusion who were candidates for IV thrombolysis. Unlike previous trials, both demonstrated significant improvement in functional outcome as measured by the Modified Rankin Scale (mRS) Score of 0– 2 at 90 days. MR CLEAN reported an absolute difference of 13.5 percentage points [95% confidence interval (CI), 5.9–21.2] in functional independence favoring the intervention (32.6% vs 19.1%). SWIFT PRIME similarly supported the safety and efficacy of intra-arterial treatment and specifically demonstrated improved outcomes with use of more modern stent-retriever devices (25). The EXTENDIA trial highlighted the value of CT perfusion in characterizing salvageable penumbra to identify patients who would benefit most from MT (25). In this study, mRS of 0–2 at 90 days was achieved in 71% of interventionally treated patients compared with 40% for medical patients, with an absolute risk reduction (ARR) of 31%. In this trial, the NNT for benefit was 3.22 (26). Another related trial suggested that not only was thrombectomy effective in improving functional independence after ischemic stroke, but also led to reduced severity of long-term disability (27). The ESCAPE trial evaluated patients with distal internal carotid or proximal middle cerebral artery occlusions, ASPECTS between 6 and 10, and moderate vascular collateralization on multiphase CT angiography. Patients who were quickly triaged for endovascular therapy within 60 minutes had an increased likelihood of functional recovery and significant reduction in overall mortality with no increase in the rate of symptomatic intracranial hemorrhage (28). Enrollment in many of these trials was halted prematurely once published data from MR CLEAN clearly supported MT. It is important to note that although endovascular intervention did not result in more symptomatic intracranial hemorrhage, there was an increase in asymptomatic hemorrhage in this group and a significant increase in embolic strokes in different territories than those reperfused by thrombectomy. Nonetheless, these studies collectively established the overall safety and efficacy of interventional endovascular treatment for acute ischemic stroke. The sophistication of endovascular procedures has continued to evolve even since this relatively recent phase of investigation, as have imaging techniques such as CT perfusion and CT angiography, which are now more widely available. These data, along with recent confirmatory studies discussed below, have been incorporated into current class IA recommendations from the AHA, stating that patients older than age 18 presenting within 6 hours of symptom onset with baseline mRs of 0 or 1 and imaging demonstrating causative occlusion of ICA or MCA segment 1 with Kelly et al: J Neuro-Ophthalmol 2021; 41: 170-175 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020 Encore: Cerebrovascular Disorders NIH stroke scale (NIHSS) $6 and ASPECT score $6 should unanimously receive MT using a stent retrieval device when qualifying for intervention (5). PIONEERING ADVANCES IN NEUROVASCULAR INTERVENTION Recent studies have shown that certain patients may safely benefit from intervention up to 24 hours after symptom onset, opening up an enormous new opportunity for large vessel occlusions to be definitively addressed. Two trials in particular (DAWN and DEFUSE3) expanded the temporal window for intervention, changing the calculation facing patients and neurologists in both the inpatient and outpatient setting (29,30). As a result, many more people may now benefit from urgent referral to the emergency department even in cases where patients were last known to be well overnight or the previous day. This population includes patients presenting non-urgently to outpatient clinic who may still be viable candidates for endovascular intervention. Designed as prospective, randomized, multicenter controlled trials, DAWN and DEFUSE were instrumental in reinforcing specific imaging parameters to guide “go” vs. “no-go” decision-making for endovascular therapy in emergent situations, using CT perfusion imaging to quantitatively estimate volume of core infarct and differentiate this from surrounding ischemic but not-yet-infarcted brain. Such measures have helped to better identify appropriate patients for intervention and standardize guidelines using objective, data-supported benchmarks (29,30). At the outset of the trial, existing data supported MT for up to 8 hours from when the patient was last known to be well. DAWN analyzed the benefit of intervention at later time points up to 24 hours from last known well by comparing outcomes of mRs, functional independence, and mortality for patients with confirmed LVO after IV-tPA therapy. The trial included those with MCA and/or ICA occlusion presenting within 6–24 hours of last known well with NIHSS scores of 10 or more and a relatively small volume of core infarct based on perfusion imaging (ideally less than 30 cc) (30). Concurrently, the DEFUSE3 trial examined the outcomes for endovascular intervention for a similar population of patients with anterior circulation LVO between 6 and 16 hours of last known well, with slightly distinct qualifying criteria. Importantly, DEFUSE3 included patients with NIHSS between 6 and 9 in addition to those with NIHSS .10, core infarcts of 70 cc or more, patients over 90 years old, and those with baseline mRs of 2 (29). Both trials included patients with wake up stroke and quantitative criteria for estimating the volume of penumbra or tissue at risk. Other exclusion criteria were generally similar; recent bleeding diatheses, hypertension .185/110, hypoglycemia ,50, or evidence of coagulopathy. These similar designs permitted a broad yet overlapping population of patients to be studied after thrombectomy, with Kelly et al: J Neuro-Ophthalmol 2021; 41: 170-175 many retrospective comparative and subgroup analyses completed since. Ultimately, the overall range of NNT was found to be 3–7, highly favorable for an intervention that may be offered to up to 10% of presenting acute ischemic stroke patients (29,30). Together, these 2 large trials were complementary in extending the intervention window and allowing emergent treatment for patients that would previously have been excluded based on time. In particular, this included those who awoke with symptoms already present and those with last known well time between 6 and 24 hours before presentation. Moreover, the studies inveterate the role of CT angiography and perfusion imaging as a standard mechanism to estimate viable brain tissue. This paradigm shift is evidenced by recently updated AHA guidelines for stroke management, with a Class IA recommendation for selected patients with anterior circulation LVO presenting within 6–16 hours meeting either DAWN or DEFUSE3 eligibility criteria to receive MT, and IV-tPA should not be withheld in such patients (5,31). Researchers have since continued to build on this progress, both by extrapolating results and designing related studies to investigate related questions for other patient populations. For example, although randomized data are much more limited, posterior circulation strokes are often treated much the same way, favoring intervention even in patients at higher risk for poor outcome given the sensitive brainstem structures perfused by the vertebral and basilar arteries (32). In particular, acute basilar occlusion has traditionally been challenging to manage, easily missed because of fluctuating or nonspecific deficits with a lasting impact that is often difficult to predict. The Basilar Artery International Cooperation Study (BASICS) was designed to investigate such strokes to determine whether it is reasonable to pursue reperfusion up to and in some cases beyond 24 hours from onset (33). Review of the initial data overall showed that outcomes after endovascular therapy were not superior to those receiving optimal medical management, although the safety of intervention was demonstrated in the trial and subgroup analysis showed that endovascular therapy should possibly be favored in certain patients with severe stroke or in patients over 70 who may be less responsive to medical management alone. In sum, advances in both technique and technology used for MT have led to improved outcomes for patients, literally extending the reach of what interventions are possible for strokes in increasingly distal branches of cerebral arteries in addition to expanding the time periods during which these measures are safe and effective. These practices are now supported by rigorous data for patients who present within 6 hours of symptom onset, with meta-analyses demonstrating a NNT of approximately 3–7 for a patient to achieve full functional independence after intervention and a NNT of 2.6 to achieve a one level improvement in the Modified Rankin Score (13). Accordingly, the most 173 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020 Encore: Cerebrovascular Disorders recent American Heart Association and American Stroke Association guidelines have been updated to reflect this body of literature (5). There has been major progress in advancing technology and therapeutic pathways available to neurologists and emergency medicine responders collaborating with neurointerventionalists for stroke patients who present in the minutes and hours after symptom onset. From a procedural perspective, areas of the ongoing study involve type of anesthesia best suited for intervention (ranging from none to conscious sedation to general anesthesia) and identifying optimal embolus retrieval strategies (stent retriever, contact aspiration, or combined methods). In addition, a key to further progress is gaining an understanding of the reasons behind the minority of thrombectomy failures, with possibilities relating to the original stroke mechanism or poor collateral circulation in many cases. Current consideration includes whether failures may more commonly result from strokes because of nonembolic atheromatous disease, intracranial dissection, or atypical removal–resistant emboli. Beyond the aforementioned Class 1A evidence, thrombectomy is increasingly performed in vascular territories where robust evidence is lacking, such as in the posterior circulation, anterior cerebral artery, and distal MCA occlusions. Although the optimal field triage of suspected large vessel occlusion patients continues to evolve and is subject to debate given significant geographic variations, an ever growing number of patients are eligible for reperfusion therapy, expanding the arsenal of hyperacute treatments for stroke, ultimately resulting in less disability and improved outcomes. 2. 3. 4. 5. 6. 7. 8. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each participated in category 1: conception and design of the article, in addition to writing and editing all parts; b. acquisition of data: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each participated in acquisition of all data presented and reviewed; c. analysis and interpretation of data: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each participated in analysis and interpretation of data. Category 2: a. drafting the article: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each participated in drafting the article; b. revising it for intellectual content: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each participated in revising the article for intellectual content. Category 3: a. final approval of the completed article: S. M. Kelly, E. Raz, M. Shapiro, and K. Ishida each reviewed the article for final approval. 9. 10. REFERENCES 1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. 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