Osama O. Zaidat

Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke

BACKGROUND Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial

BACKGROUND The Solitaire Flow Restoration Device is a novel, self-expanding stent retriever designed to yield rapid flow restoration in acute cerebral ischaemia. We compared the efficacy and safety of Solitaire with the standard, predicate mechanical thrombectomy device, the Merci Retrieval System. METHODS In this randomised, parallel-group, non-inferiority trial, we enrolled patients from 18 sites (17 in the USA and one in France). Patients were eligible for inclusion if they had acute ischaemic stroke with moderate to severe neurological deficits and were treatable by thrombectomy within 8 h of stroke symptom onset. We used a computer-generated randomisation sequence to randomly allocate patients to receive thrombectomy treatment with either Solitaire or Merci (1:1; block sizes of four and stratified by centre and stroke severity). The primary endpoint was Thrombolysis In Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels without symptomatic intracranial haemorrhage, after up to three passes of the assigned device, as assessed by an independent core laboratory, which was masked to study assignment. Primary analysis was done by intention to treat. A prespecified efficacy stopping rule triggered an early halt to the trial. The study is registered with ClinicalTrials.gov, number NCT 01054560. RESULTS Between February, 2010, and February, 2011, we randomly allocated 58 patients to the Solitaire group and 55 patients to the Merci group. The primary efficacy outcome was achieved more often in the Solitaire group than it was in the Merci group (61%vs 24%; difference 37% [95% CI 19-53], odds ratio [OR] 4·87 [95% CI 2·14-11·10]; p(non-inferiority)<0·0001, p(superiority)=0·0001). More patients had good 3-month neurological outcome with Solitaire than with Merci (58%vs 33%; difference 25% [6-43], OR 2·78 [1·25-6·22]; p(non-inferiority)=0·0001, p(superiority)=0·02). 90-day mortality was lower in the Solitaire group than it was in the Merci group (17 vs 38; difference -21% [-39 to -3], OR 0·34 [0·14-0·81]; p(non-inferiority)=0·0001, p(superiority)=0·02). INTERPRETATION The Solitaire Flow Restoration Device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The Solitaire device might be a future treatment of choice for endovascular recanalisation in acute ischaemic stroke. FUNDING Covidien/ev3.

Stenting versus aggressive medical therapy for intracranial arterial stenosis

BACKGROUND Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. METHODS We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. RESULTS Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. CONCLUSIONS In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

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 …

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomised trial

BACKGROUND Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). INTERPRETATION The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. FUNDING National Institute of Neurological Disorders and Stroke (NINDS) and others.

THE NIH REGISTRY ON USE OF THE WINGSPAN STENT FOR SYMPTOMATIC 70–99% INTRACRANIAL ARTERIAL STENOSIS

Background: The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that patients with symptomatic 70% to 99% intracranial arterial stenosis are at particularly high risk of ipsilateral stroke on medical therapy: 18% at 1 year (95% CI = 3% to 24%). The Wingspan intracranial stent is another therapeutic option but there are limited data on the technical success of stenting and outcome of patients with 70% to 99% stenosis treated with a Wingspan stent. Methods: Sixteen medical centers enrolled consecutive patients treated with a Wingspan stent in this registry between November 2005 and October 2006. Data on stenting indication, severity of stenosis, technical success (stent placement across the target lesion with <50% residual stenosis), follow-up angiography, and outcome were collected. Results: A total of 129 patients with symptomatic 70% to 99% intracranial stenosis were enrolled. The technical success rate was 96.7%. The mean pre and post-stent stenoses were 82% and 20%. The frequency of any stroke, intracerebral hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 14.0% at 6 months (95% CI = 8.7% to 22.1%). The frequency of ≥50% restenosis on follow-up angiography was 13/52 (25%). Conclusion: The use of a Wingspan stent in patients with severe intracranial stenosis is relatively safe with high rate of technical success with moderately high rate of restenosis. Comparison of the event rates in high-risk patients in Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) vs this registry do not rule out either that stenting could be associated with a substantial relative risk reduction (e.g., 50%) or has no advantage compared with medical therapy. A randomized trial comparing stenting with medical therapy is needed. GLOSSARY: FDA = Food and Drug Administration; HDE = Humanitarian Device Exemption; ICH = intracerebral hemorrhage; WASID = Warfarin-Aspirin Symptomatic Intracranial Disease.

Length of stay and mortality in neurocritically ill patients: impact of a specialized neurocritical care team.

Objective:To determine predictors of in-hospital and long-term mortality and length of stay in patients admitted to the neurosciences critical care unit. Design:Retrospective analysis of a prospectively collected database. Setting:Neurosciences critical care unit of a large academic tertiary care hospital. Patients:Adult patients (n = 2381) admitted to our neurosciences critical care unit from January 1997 to April 2000. Interventions:Introduction of a specialized neurocritical care team. Measurements and Main Results:Data obtained from the database included demographics, admission source, length of stay, neurosciences critical care unit and hospital disposition, admission Acute Physiology and Chronic Health Evaluation (APACHE) III score, and principal and secondary diagnoses. The introduction of a neurocritical care team in September 1998 was also collected, as was death at 1 yr after admission. Univariate analysis was carried out using Student’s t-test, Mann-Whitney U test, or chi-square test (significance, p < .05). A logistic regression model was used to create a prediction model for in-hospital and long-term mortality. A general linear model was used to determine predictors of length of stay (after log transformation). Independent predictors of in-hospital mortality included APACHE III (odds ratio, 1.07 [1.06–1.08]) and admission from another intensive care unit (odds ratio, 2.9 [1.4–6.2]). The presence of a neurocritical care team was an independent predictor of decreased mortality (odds ratio, 0.7 [0.5–1.0], p = .044). Admission after the neurocritical care team was implemented was associated with reduced length of stay in both the neurosciences critical care unit (4.2 ± 4.0 vs. 3.7 ± 3.4, p < .001) and the hospital (9.9 ± 8.0 vs. 8.4 ± 6.9, p < .0001). There was no difference in readmission rates to the intensive care unit or discharge disposition to home before and after the neurocritical care team was established. The availability of the neurocritical care team was not associated with significant changes in long-term mortality. Factors independently associated with long-term mortality included female gender, admission from another intensive care unit, APACHE III score, and being moderately disabled before admission. Conclusion:Introduction of a neurocritical care team, including a full-time neurointensivist who coordinated care, was associated with significantly reduced in-hospital mortality and length of stay without changes in readmission rates or long-term mortality.

Conscious Sedation Versus General Anesthesia During Endovascular Therapy for Acute Anterior Circulation Stroke: Preliminary Results From a Retrospective, Multicenter Study

Background and Purpose— Patients undergoing intra-arterial therapy (IAT) for acute ischemic stroke receive either general anesthesia (GA) or conscious sedation. GA may delay time to treatment, whereas conscious sedation may result in patient movement and compromise the safety of the procedure. We sought to determine whether there were differences in safety and outcomes in GA patients before initiation of IAT. Methods— A cohort of 980 patients at 12 stroke centers underwent IAT for acute stroke between 2005 and 2009. Only patients with anterior circulation strokes due to large-vessel occlusion were included in the study. A binary logistic-regression model was used to determine independent predictors of good outcome and death. Results— The mean age was 66±15 years and median National Institutes of Health Stroke Scale score was 17 (interquartile range, 13–20). The overall recanalization rate was 68% and the symptomatic hemorrhage rate was 9.2%. GA was used in 44% of patients with no differences in intracranial hemorrhage rates when compared with the conscious sedation group. The use of GA was associated with poorer neurologic outcome at 90 days (odds ratio=2.33; 95% CI, 1.63–3.44; P<0.0001) and higher mortality (odds ratio=1.68; 95% CI, 1.23–2.30; P<0.0001) compared with conscious sedation. Conclusions— Patients placed under GA during IAT for anterior circulation stroke appear to have a higher chance of poor neurologic outcome and mortality. There do not appear to be differences in hemorrhagic complications between the 2 groups. Future clinical trials with IAT can help elucidate the etiology of the differences in outcomes.

Vertebrobasilar dolichoectasia diagnosed by magnetic resonance angiography and risk of stroke and death: a cohort study

Correspondence to: Professor Neil J Scolding, Institute of Clinical Neurosciences, Department of Neurology, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, UK; n.j.scolding@bristol.ac.uk _________________________ P ost-infectious and inflammatory encephalomyelitis are broadly represented by the syndrome acute disseminated encephalomyelitis (ADEM). ADEM forms one of several categories of primary inflammatory demyelinating disorders of the central nervous system. Others include multiple sclerosis (MS), acute transverse myelitis, and Devic’s disease. It should be remembered that these are syndromically defined diseases at present. There are no diagnostic tests presently available short of brain biopsy, but future advances may reveal diagnostic biological markers of disease and in so doing dramatically advance the pathophysiological and therapeutic understanding of these conditions. A wholesale change in classification and nomenclature may well follow. In the meantime clinicians must remain keenly appreciative of subtle shades of grey: ADEM, first MS relapse, or ultimately benign clinically isolated syndrome? The answers are relevant to prognosis and, more recently, selection of the correct therapeutic strategy.

Response to Intra-Arterial and Combined Intravenous and Intra-Arterial Thrombolytic Therapy in Patients With Distal Internal Carotid Artery Occlusion

Background and Purpose— The objective of this study was to determine the clinical features, angiographic findings, and response to treatment with thrombolytic therapy in patients with ischemic stroke caused by acute occlusion of the distal internal carotid artery. Methods— This is a retrospective case series from a prospectively collected stroke database for patients with acute internal carotid occlusion presenting within 6 hours of stroke onset to evaluate safety, feasibility, and response to thrombolytic therapy. The University Hospital–based brain attack database was reviewed over a 5-year period. Demographics, clinical features, stroke mechanisms, severity, imaging findings, type of thrombolysis, treatment responses, mortality, and long-term outcome using modified Rankin Scale and Barthel Index were determined. The short-term outcome was assessed using the National Institutes of Health Stroke Scale (NIHSS). Acute thrombolytic therapy was administered using recombinant tissue plasminogen activator or urokinase given intra-arterially or in combination with intravenous (IV) routes. Results— Two hundred seven patients treated with thrombolysis between 1995 and 2000 were reviewed, and of these, 101 were studied with cerebral angiography. Eighteen patients were identified with acute ischemic stroke and ipsilateral occlusion of the distal internal carotid artery. Time to treatment was the most powerful predictor of response to thrombolytic therapy (P <0.001). The response to therapy also correlated well with the severity of the initial clinical deficit as judged by the NIHSS (P <0.001). There was no difference in recanalization rate, symptomatic hemorrhage, and NIHSS for IV/intra-arterial (IA) versus IA alone (P =NS). Complete angiographic recanalization was accomplished in 80% of those who received combined IV/IA thrombolysis and in 62% of those who received IA therapy (P =NS). Those with distal occlusions extending to the middle and anterior cerebral arteries were the least likely to respond to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 20% of the patients receiving IV/IA therapy, and in 15% of the IA only (P =NS). At 24 hours, the NIHSS dropped by 3 points in the IA group and 4 points in the IV/IA group (P =NS). Mild disability with independence was found in 77% of the survivors at 3-month follow-up. The mortality rate was 50% in this group despite thrombolysis. Conclusions— Thrombolytic therapy using a combination of IV and IA routes and using the IA-only route may be effective in improving outcome for the patients suffering from occlusion of the distal internal carotid artery. Shorter intervals between onset and treatment seem to be correlated with higher rate of recanalization and improved outcome.