Dileep R. Yavagal

A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke

BACKGROUND Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear. METHODS In this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead). RESULTS Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14). CONCLUSIONS A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care. (Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.).

2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. When there is overlap, the recommendations made here supersede those of previous guidelines. Methods— This focused update analyzes results from 8 randomized, clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. Results— Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, for the endovascular procedure, and for systems of care to facilitate endovascular treatment. Conclusions— Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.Purpose— The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. Where there is overlap, the recommendations made here supersede those of previous guidelines. Methods— This focused update analyzes results from 8 randomized clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee (MOC). Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. Results— Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, the endovascular procedure and for systems of care to facilitate endovascular treatment. Conclusions— Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.

Recommendations on Angiographic Revascularization Grading Standards for Acute Ischemic Stroke A Consensus Statement

See related article, p 2509 Intra-arterial therapy (IAT) for acute ischemic stroke (AIS) has dramatically evolved during the past decade to include aspiration and stent-retriever devices. Recent randomized controlled trials have demonstrated the superior revascularization efficacy of stent-retrievers compared with the first-generation Merci device.1,2 Additionally, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) 2, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and the Interventional Management of Stroke (IMS) III trials have confirmed the importance of early revascularization for achieving better clinical outcome.3–5 Despite these data, the current heterogeneity in cerebral angiographic revascularization grading (CARG) poses a major obstacle to further advances in stroke therapy. To date, several CARG scales have been used to measure the success of IAT.6–14 Even when the same scale is used in different studies, it is applied using varying operational criteria, which further confounds the interpretation of this key metric.10 The lack of a uniform grading approach limits comparison of revascularization rates across clinical trials and hinders the translation of promising, early phase angiographic results into proven, clinically effective treatments.6–14 For these reasons, it is critical that CARG scales be standardized and end points for successful revascularization be refined.6 This will lead to a greater understanding of the aspects of revascularization that are strongly predictive of clinical response. The optimal grading scale must demonstrate (1) a strong correlation with clinical outcome, (2) simplicity and feasibility of scale interpretation while ensuring characterization of relevant angiographic findings, and (3) high inter-rater reproducibility. To address these issues, a multidisciplinary panel of neurointerventionalists, neuroradiologists, and stroke neurologists with extensive experience in neuroimaging and IAT, convened at the “Consensus Meeting on Revascularization Grading Following Endovascular Therapy” with the goal …

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

BACKGROUND The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility‐weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility‐weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90‐day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)

Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: protocol for a randomized, controlled, multicenter study comparing the Solitaire revascularization device with IV tPA with IV tPA alone in acute ischemic stroke.

Rationale Early reperfusion in patients experiencing acute ischemic stroke is critical, especially for patients with large vessel occlusion who have poor prognosis without revascularization. Solitaire™ stent retriever devices have been shown to immediately restore vascular perfusion safely, rapidly, and effectively in acute ischemic stroke patients with large vessel occlusions. Aim The aim of the study was to demonstrate that, among patients with large vessel, anterior circulation occlusion who have received intravenous tissue plasminogen activator, treatment with Solitaire revascularization devices reduces degree of disability 3 months post stroke. Design The study is a global multicenter, two-arm, prospective, randomized, open, blinded end-point trial comparing functional outcomes in acute ischemic stroke patients who are treated with either intravenous tissue plasminogen activator alone or intravenous tissue plasminogen activator in combination with the Solitaire device. Up to 833 patients will be enrolled. Procedures Patients who have received intravenous tissue plasminogen activator are randomized to either continue with intravenous tissue plasminogen activator alone or additionally proceed to neurothrombectomy using the Solitaire device within six-hours of symptom onset. Study Outcomes The primary end-point is 90-day global disability, assessed with the modified Rankin Scale (mRS). Secondary outcomes include mortality at 90 days, functional independence (mRS ≤ 2) at 90 days, change in National Institutes of Health Stroke Scale at 27 h, reperfusion at 27 h, and thrombolysis in cerebral infarction 2b/3 flow at the end of the procedure. Analysis Statistical analysis will be conducted using simultaneous success criteria on the overall distribution of modified Rankin Scale (Rankin shift) and proportions of subjects achieving functional independence (mRS 0–2).

Stem Cells as an Emerging Paradigm in Stroke 3 Enhancing the Development of Clinical Trials

Cell-based therapy continues to grow as a new field to explore investigational treatments for stroke. Leaders from academia and industry convened an inaugural meeting in 2007 with members of the National Institutes of Health and Food and Drug Administration (FDA) to generate consensus-based guidelines on the development of cell therapies for stroke, entitled “Stem Cells as an Emerging Paradigm in Stroke” (STEPS).1 These guidelines focused on preclinical studies that are considered important as part of a development program to support clinical testing of cell therapies. The STEPS meeting also provided recommendations on the conduct of early-stage clinical trials. Given the rapid advances in the field, a second meeting was held in 2009 to update and expand these guidelines, which were published as STEPS 2.2 In December 2011, investigators in academia, industry leaders, and members of the National Institutes of Health and FDA gathered at a third meeting, STEPS 3, to discuss emerging data on the mechanisms of action of cell therapy, the barriers to successful translation from animal models to patients, and the design of current clinical trials for acute and chronic stroke. Since the prior STEPS meeting, there are now several active cell therapy platforms for stroke and other neurological disorders, in stages that range from preclinical to clinical trials, and with sponsors that include industry, the National Institutes of Health, and the California Institute of Regenerative Medicine. As the field continues to progress and as pilot clinical studies are starting to show safety for some cell types, it has become necessary to formulate a new set of guidelines that address topics not covered in prior STEPS publications. Specifically, the current document reflects a compilation of recommendations that focus on more advanced stages of clinical testing, as well as the testing of cell therapies in a broader …

Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME

Within the context of a prospective randomized trial (SWIFT PRIME), we assessed whether early imaging of stroke patients, primarily with computed tomography (CT) perfusion, can estimate the size of the irreversibly injured ischemic core and the volume of critically hypoperfused tissue. We also evaluated the accuracy of ischemic core and hypoperfusion volumes for predicting infarct volume in patients with the target mismatch profile.

Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. METHODS We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. FINDINGS The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83). INTERPRETATION Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. FUNDING Athersys Inc.

Efficacy and Dose-Dependent Safety of Intra-Arterial Delivery of Mesenchymal Stem Cells in a Rodent Stroke Model

Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1×106, 5×105, 2×105, 1×105 and 5×104) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1×105 and below did not compromise MCA flow and hence an IA MSC dose of 1×105 considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1×105 delivered at 24 hours in rodent model of stroke.

Revascularization grading in endovascular acute ischemic stroke therapy

Background: Recanalization and angiographic reperfusion are key elements to successful endovascular and interventional acute ischemic stroke (AIS) therapy. Intravenous recombinant tissue plasminogen activator (rt-PA), the only established revascularization therapy approved by the US Food & Drug Administration for AIS, may be less effective for large artery occlusion. Thus, there is enthusiasm for endovascular revascularization therapies, which likely provide higher recanalization rates, and trials are ongoing to determine clinical efficacy and compare various methods. It is anticipated that clinical efficacy will be well correlated with revascularization of viable tissue in a timely manner. Method: Reporting, interpretation, and comparison of the various revascularization grading methods require agreement on measurement criteria, reproducibility, ease of use, and correlation with clinical outcome. These parameters were reviewed by performing a Medline literature search from 1965 to 2011. This review critically evaluates current revascularization grading systems. Results and Conclusion: The most commonly used revascularization grading methods in AIS interventional therapy trials are the thrombolysis in cerebral ischemia (TICI, pronounced “tissy”) and thrombolysis in myocardial ischemia (TIMI) scores. Until further technical and imaging advances can incorporate real-time reliable perfusion studies in the angio-suite to delineate regional perfusion more accurately, the TICI grading system is the best defined and most widely used scheme. Other grading systems may be used for research and correlation purposes. A new scale that combines primary site occlusion, lesion location, and perfusion should be explored in the future.