Publications by authors named "Jeffrey L Saver"

566 Publications

Endovascular treatment with versus without tirofiban for stroke patients with large vessel occlusion: The multicenter, randomized, placebo-controlled, double-blind RESCUE BT study protocol.

Int J Stroke 2022 Jan 27:17474930211069510. Epub 2022 Jan 27.

Neurology, Xinqiao Hospital and The Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

Background: Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, has been shown to reduce the risk of thrombotic complications during percutaneous coronary intervention. However, it remains unknown whether tirofiban improves outcomes in large vessel occlusion stroke patients undergoing endovascular treatment.

Objective: This trial aims to assess whether additional intravenous tirofiban therapy can improve the clinical outcomes in large vessel occlusion stroke patients who undergo endovascular treatment within 24 h of symptom onset.

Methods And Design: The Endovascular Treatment With versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) Trial is an investigator-initiated, randomized, placebo-controlled, double-blind, multicenter trial. Up to 930 eligible patients will be consecutively randomized to intravenous tirofiban or placebo in 1:1 ratio over 3 years across 50 endovascular-capable stroke centers in China.

Outcomes: The primary end point is the disability level as measured by overall distribution of the 90-day modified Rankin Scale scores. Primary safety end points include symptomatic intracerebral hemorrhage at 48 h and mortality at 90 days.

Trial Registry Number: ChiCTR-INR-17014167 (www.chictr.org.cn).
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http://dx.doi.org/10.1177/17474930211069510DOI Listing
January 2022

Prolonged migraine aura resembling ischemic stroke following CoronaVac vaccination: an extended case series.

J Headache Pain 2022 Jan 21;23(1):13. Epub 2022 Jan 21.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: After the initiation of the COVID-19 vaccination program in Thailand, thousands of patients have experienced unusual focal neurological symptoms. We report 8 patients with focal neurological symptoms after receiving inactivated virus vaccine, CoronaVac.

Case Series: Patients were aged 24-48 years and 75% were female. Acute onset of focal neurological symptoms occurred within the first 24 h after vaccination in 75% and between 1-7d in 25%. All presented with lateralized sensory deficits, motor deficits, or both, of 2-14 day duration. Migraine headache occurred in half of the patients. Magnetic resonance imaging of the brain during and after the attacks did not demonstrate any abnormalities suggesting ischemic stroke. All patients showed moderately large regions of hypoperfusion and concurrent smaller regions of hyperperfusion on SPECT imaging while symptomatic. None developed permanent deficits or structural brain injury.

Discussions: Here, we present a case series of transient focal neurological syndrome following Coronavac vaccination. The characteristic sensory symptoms, history of migraine, female predominant, and abnormal functional brain imaging without structural changes suggest migraine aura as pathophysiology. We propose that pain related to vaccine injection, component of vaccine, such as aluminum, or inflammation related to vaccination might trigger migraine aura in susceptible patients.
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http://dx.doi.org/10.1186/s10194-022-01385-0DOI Listing
January 2022

Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke.

JAMA 2021 12;326(22):2277-2286

Department of Neurology, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts.

Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear.

Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems.

Design, Setting, And Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017.

Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable.

Main Outcomes And Measures: Ischemic stroke.

Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively.

Conclusions And Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.
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http://dx.doi.org/10.1001/jama.2021.20956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672231PMC
December 2021

Ischemic Stroke and Pulmonary Arteriovenous Malformations: A Review.

Neurology 2021 Dec 8. Epub 2021 Dec 8.

Department of Clinical and Molecular Medicine, Imperial College London, London, UK.

The potential of covert pulmonary arteriovenous malformations (PAVMs) to cause early onset, preventable ischemic strokes is not well known to neurologists. This is evident by their lack of mention in serial American Heart Association/ American Stroke Association (AHA/ASA) Guidelines, and the single case-report biased literature of recent years. To inform, we performed PubMed and Cochrane database searches for major studies on ischemic stroke and PAVMs published from January 1, 1974 through April 3, 2021. This identified twenty-four major observational studies, three societal guidelines, one nationwide analysis, three systematic reviews, twenty-one other review/opinion articles, and eighteen recent (2017-2021) case-reports/series that were synthesized. Key points are that patients with PAVMs suffer ischemic stroke a decade earlier than routine stroke, losing nine extra healthy-life-years per patient in the recent US nationwide analysis (2005-2014). Large-scale thoracic CT screens of the general population in Japan estimate PAVM prevalence to be 38/100,000 (95% confidence interval 18-76), with ischemic stroke rates exceeding 10% across PAVM series dating back to the 1950s, with most PAVMs remaining undiagnosed until the time of clinical stroke. Notably, the rate of PAVM diagnoses doubled in US ischemic stroke hospitalizations between 2005-2014. The burden of silent cerebral infarction approximates to twice that of clinical stroke. Over 80% patients have underlying hereditary hemorrhagic telangiectasia (HHT). The predominant stroke mechanism is paradoxical embolization of platelet-rich emboli, with iron-deficiency emerging as a modifiable risk-factor. PAVM related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Single antiplatelet therapy maybe effective for secondary stroke prophylaxis, with dual antiplatelet or anticoagulation therapy requiring nuanced risk-benefit analysis given their risk of aggravating iron deficiency. In conclusion, this review summarizes the current ischemic stroke burden from PAVMs, the implicative pathophysiology, and relevant diagnostic and treatment overviews to facilitate future incorporation into AHA/ASA guidelines.
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http://dx.doi.org/10.1212/WNL.0000000000013169DOI Listing
December 2021

Trial of Mobile Stroke Units. Reply.

N Engl J Med 2021 12;385(24):2302-2303

Memorial Hermann Hospital-Texas Medical Center, Houston, TX.

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http://dx.doi.org/10.1056/NEJMc2116124DOI Listing
December 2021

INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): study protocol for a randomized controlled trial.

Trials 2021 Dec 6;22(1):885. Epub 2021 Dec 6.

The George Institute China, Peking University Health Science Center, Room 052A, Unit 1, Tayuan Diplomatic Office Building, No. 14 Liangmahe Nan Lu, Chaoyang District, Beijing, China.

Background: Early pre-hospital initiation of blood pressure (BP) lowering could improve outcomes for patients with acute stroke, by reducing hematoma expansion in intracerebral hemorrhage (ICH), and time to reperfusion treatment and risk of intracranial hemorrhage in ischemic stroke (IS). We present the design of the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4).

Methods: A multi-center, ambulance-delivered, prospective, randomized, open-label, blinded endpoint (PROBE) assessed trial of pre-hospital BP lowering in 3116 hypertensive patients with suspected acute stroke at 50+ sites in China. Patients are randomized through a mobile phone digital system to intensive BP lowering to a target systolic BP of < 140 mmHg within 30 min, or guideline-recommended BP management according to local protocols. After the collection of in-hospital clinical and management data and 7-day outcomes, trained blinded assessors conduct telephone or face-to-face assessments of physical function and health-related quality of life in participants at 90 days. The primary outcome is the physical function on the modified Rankin scale at 90 days, analyzed as an ordinal outcome with 7 categories. The sample size was estimated to provide 90% power (α = 0.05) to detect a 22% reduction in the odds of a worse functional outcome using ordinal logistic regression.

Discussion: INTERACT4 is a pragmatic clinical trial to provide reliable evidence on the effectiveness and safety of ambulance-delivered hyperacute BP lowering in patients with suspected acute stroke.

Trial Registration: ClinicalTrials.gov NCT03790800. Registered on 2 January 2019; Chinese Trial Registry ChiCTR1900020534. Registered on 7 January 2019. All items can be found in this protocol paper.
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http://dx.doi.org/10.1186/s13063-021-05860-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646007PMC
December 2021

Machine Learning Automated Detection of Large Vessel Occlusion From Mobile Stroke Unit Computed Tomography Angiography.

Stroke 2021 Dec 6:STROKEAHA121036091. Epub 2021 Dec 6.

Department of Neurology, UTHealth McGovern Medical School, Houston TX (A.L.C., S.P., Y.K., R.A., S.S.-M., K.P., R.B., S.A.S.).

Background And Purpose: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO.

Methods: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics.

Results: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5-196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80-0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71-0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts.

Conclusions: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.
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http://dx.doi.org/10.1161/STROKEAHA.121.036091DOI Listing
December 2021

Thrombectomy With and Without Computed Tomography Perfusion Imaging in the Early Time Window: A Pooled Analysis of Patient-Level Data.

Stroke 2021 Nov 30:STROKEAHA121034331. Epub 2021 Nov 30.

Neurological Institute, Cooper University Hospital, Camden, New Jersey (T.G.J.).

Background And Purpose: The optimal imaging paradigm for endovascular thrombectomy (EVT) patient selection in early time window (0-6 hours) treated acute ischemic stroke patients remains uncertain. We aimed to compare post-EVT outcomes between patients who underwent prerandomization basic (noncontrast computed tomography [CT], CT angiography only) versus additional advanced imaging (computed tomography perfusion [CTP] imaging) and to determine the association of performance of prerandomization CTP imaging with clinical outcomes.

Methods: The HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) pooled patient-level data from randomized controlled trials comparing EVT with usual care for acute ischemic stroke due to anterior circulation large vessel occlusion. Good functional outcome, defined as modified Rankin Scale score 0 to 2 at 90 days, was compared between randomized patients with and without CTP baseline imaging. Univariable and multivariable binary logistic regression analysis was performed to determine the association of baseline CTP imaging and good functional outcome.

Results: We analyzed 1348 patients 610 (45.3%) of whom underwent CTP prerandomization. The benefit of EVT compared with best medical management was maintained irrespective of the baseline imaging paradigm (90-day modified Rankin Scale score 0-2 in EVT versus control patients: with CTP: 46.0% (137/298) versus 28.9% (88/305), without CTP: 44.1% (162/367) versus 27.3% (100/366). Performance of CTP baseline imaging compared with baseline noncontrast CT and CT angiography only yielded similar rates of good outcome (odds ratio, 1.05 [95% CI, 0.82-1.33], adjusted odds ratio, 1.04, [95% CI, 0.80-1.35]).

Conclusions: Rates of good functional outcome were similar among patients in whom CTP was or was not performed, and EVT treatment effect in the 0- to 6-hour time window was similar in patients with and without baseline CTP imaging.
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http://dx.doi.org/10.1161/STROKEAHA.121.034331DOI Listing
November 2021

Achieving More Rapid Door-to-Needle Times and Improved Outcomes in Acute Ischemic Stroke in a Nationwide Quality Improvement Intervention.

Stroke 2021 Nov 22:STROKEAHA121035853. Epub 2021 Nov 22.

Division of Cardiology, University of California at Los Angeles (G.C.F.).

Background And Purpose: The benefits of tPA (tissue-type plasminogen activator) in acute ischemic stroke are time-dependent. However, delivery of thrombolytic therapy rapidly after hospital arrival was initially occurring infrequently in hospitals in the United States, discrepant with national guidelines.

Methods: We evaluated door-to-needle (DTN) times and clinical outcomes among patients with acute ischemic stroke receiving tPA before and after initiation of 2 successive nationwide quality improvement initiatives: Target: Stroke Phase I (2010-2013) and Target: Stroke Phase II (2014-2018) from 913 Get With The Guidelines-Stroke hospitals in the United States between April 2003 and September 2018.

Results: Among 154 221 patients receiving tPA within 3 hours of stroke symptom onset (median age 72 years, 50.1% female), median DTN times decreased from 78 minutes (interquartile range, 60-98) preintervention, to 66 minutes (51-87) during Phase I, and 50 minutes (37-66) during Phase II (<0.001). Proportions of patients with DTN ≤60 minutes increased from 26.4% to 42.7% to 68.6% (<0.001). Proportions of patients with DTN ≤45 minutes increased from 10.1% to 17.7% to 41.4% (<0.001). By the end of the second intervention, 75.4% and 51.7% patients achieved 60-minute and 45-minute DTN goals. Compared with the preintervention period, hospitals during the second intervention period (2014-2018) achieved higher rates of tPA use (11.7% versus 5.6%; adjusted odds ratio, 2.43 [95% CI, 2.31-2.56]), lower in-hospital mortality (6.0% versus 10.0%; adjusted odds ratio, 0.69 [0.64-0.73]), fewer bleeding complication (3.4% versus 5.5%; adjusted odds ratio, 0.68 [0.62-0.74]), and higher rates of discharge to home (49.6% versus 35.7%; adjusted odds ratio, 1.43 [1.38-1.50]). Similar findings were found in sensitivity analyses of 185 501 patients receiving tPA within 4.5 hours of symptom onset.

Conclusions: A nationwide quality improvement program for acute ischemic stroke was associated with substantial improvement in the timeliness of thrombolytic therapy start, increased thrombolytic treatment, and improved clinical outcomes.
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http://dx.doi.org/10.1161/STROKEAHA.121.035853DOI Listing
November 2021

Early lowering of blood pressure after acute intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

J Neurol Neurosurg Psychiatry 2022 01 3;93(1):6-13. Epub 2021 Nov 3.

Stroke Trials Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.

Objective: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH).

Methods: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect.

Results: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (p=0.031) and agent (p<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth.

Interpretation: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent.

Prospero Registration Number: CRD42019141136.
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http://dx.doi.org/10.1136/jnnp-2021-327195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685661PMC
January 2022

Collateral Circulation in Thrombectomy for Stroke After 6 to 24 Hours in the DAWN Trial.

Stroke 2021 Nov 3:STROKEAHA121034471. Epub 2021 Nov 3.

Emory University School of Medicine/ Grady Memorial Hospital, Atlanta, GA (D.C.H., R.G.N.).

Background And Purpose: Collaterals govern the pace and severity of cerebral ischemia, distinguishing fast or slow progressors and corresponding therapeutic opportunities. The fate of sustained collateral perfusion or collateral failure is poorly characterized. We evaluated the nature and impact of collaterals on outcomes in the late time window DAWN trial (Diffusion-Weighted Imaging or Computed Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo).

Methods: The DAWN Imaging Core Lab prospectively scored collateral grade on baseline computed tomography angiography (CTA; endovascular and control arms) and digital subtraction angiography (DSA; endovascular arm only), blinded to all other data. CTA collaterals were graded with the Tan scale and DSA collaterals were scored by ASITN grade (American Society of Interventional and Therapeutic Neuroradiology collateral score). Descriptive statistics characterized CTA collateral grade in all DAWN subjects and DSA collaterals in the endovascular arm. The relationship between collateral grade and day 90 outcomes were separately analyzed for each treatment arm.

Results: Collateral circulation to the ischemic territory was evaluated on CTA (n=144; median 2, 0-3) and DSA (n=57; median 2, 1-4) before thrombectomy in 161 DAWN subjects (mean age 69.8±13.6 years; 55.3% women; 91 endovascular therapy, 70 control). CTA revealed a broad range of collaterals (Tan grade 3, n=64 [44%]; 2, n=45 [31%]; 1, n=31 [22%]; 0, n=4 [3%]). DSA also showed a diverse range of collateral grades (ASITN grade 4, n=4; 3, n=22; 2, n=27; 1, n=4). Across treatment arms, baseline demographics, clinical variables except atrial fibrillation (41.6% endovascular versus 25.0% controls, =0.04), and CTA collateral grades were balanced. Differences were seen across the 3 levels of collateral flow (good, fair, poor) for baseline National Institutes of Health Stroke Scale, blood glucose <150, diabetes, previous ischemic stroke, baseline and 24-hour core infarct volume, baseline and 24-hour Alberta Stroke Program Early CT Score, dramatic infarct progression, final Thrombolysis in Cerebral Infarction 2b+, and death. Collateral flow was a significant predictor of 90-day modified Rankin Scale score of 0 to 2 in the endovascular arm, with 43.7% (31/71) of subjects with good collaterals, 30.8% (16/52) of subjects with fair collaterals, and 17.7% (6/34) of subjects with poor collaterals reaching modified Rankin Scale score of 0 to 2 at 90 days (=0.026).

Conclusions: DAWN subjects enrolled at 6 to 24 hours after onset with limited infarct cores had a wide range of collateral grades on both CTA and DSA. Even in this late time window, better collaterals lead to slower stroke progression and better functional outcomes.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.
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http://dx.doi.org/10.1161/STROKEAHA.121.034471DOI Listing
November 2021

Predictors of unfavorable outcomes despite substantial reperfusion: Insights from Analysis of Revascularization in Ischemic Stroke With EmboTrap II Study.

Interv Neuroradiol 2021 Oct 30:15910199211051553. Epub 2021 Oct 30.

Mercy St Vincent Medical Center, Toledo, OH, USA.

Background: A considerable proportion of stroke patients have unfavorable outcomes despite substantial reperfusion during mechanical thrombectomy for large vessel occlusion. This study aimed to determine predictors of unfavorable outcomes despite substantial reperfusion (modified thrombolysis in cerebral infarction score of ≥2b).

Methods: We conducted a post hoc analysis of Analysis of Revascularization in Ischemic Stroke With EmboTrap, a prospective, multicenter study on the efficacy of the EmboTrap revascularization device. We included patients with anterior large vessel occlusion, substantial reperfusion within three passes, and 3-month follow-up. Univariate and multivariate logistic regression analyses were performed to determine independent predictors of dependency or death (modified Rankin Score 3-6) at 90 days.

Results: Of the 176 patients included in the study, 124 (70.45%) achieved modified Rankin Score of 0-2 at 90 days and 52 (29.6%) had modified Rankin Score of 3-6. On univariate analysis, patient age and initial National Institutes of Health Stroke Scale score were significantly higher in the modified Rankin Score of 3-6 groups (71.4 ± 11.3 years vs. 66.0 ± 13.1 years, 0.01; 18.9 ± 4.13 vs. 14.6 ± 4.36,  < 0.01, respectively). Mean number of passes and symptomatic intracranial hemorrhage were also higher in patients with modified Rankin Score of 3-6 (2.46 ± 1.42 vs. 1.65 ± 0.9, p < 0.01; 13.5% vs. 2.4%,  = 0.008). On multivariate analysis, initial National Institutes of Health Stroke Scale score and mean number of passes and were independent predictors of modified Rankin Score of 3-6 at 90 days.

Conclusion: More severe initial neurologic deficit and higher number of passes in patients with substantial reperfusion were independent predictors of dependency or death. These findings highlight a reduction in the number of passes required to achieve reperfusion as a therapeutic target to improve the outcome after thrombectomy.
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http://dx.doi.org/10.1177/15910199211051553DOI Listing
October 2021

Endovascular Treatment for Acute Stroke Patients With a Pre-stroke Disability: An International Survey.

Front Neurol 2021 4;12:714594. Epub 2021 Oct 4.

Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, United States.

It is unclear what factors clinicians consider when deciding about endovascular thrombectomy (EVT) in acute ischemic stroke patients with a pre-existing disability. We aimed to explore international practice patterns and preferences for EVT in patients with a pre-stroke disability, defined as a modified Rankin score (mRS) ≥ 2. Electronic survey link was sent to principal investigators of five major EVT trials and members of a professional interventional neurology society. Of the 81 survey-responding clinicians, 57% were neuro-interventionalists and 33% were non-interventional stroke clinicians. Overall, 64.2% would never or almost never consider EVT for a patient with pre-stroke mRS of 4-5, and 49.3% would always or almost always offer EVT for a patient with pre-stroke mRS 2-3. Perceived benefit of EVT (89%) and severity of baseline disability (83.5%) were identified as the most important clinician-level and patient-level factors that influence EVT decisions in these patients. In this survey of 80 respondents, we found that EVT practice for patients with pre-stroke disability across the world is heterogenous and depends upon patient characteristics. Individual clinician opinions substantially alter EVT decisions in pre-stroke disabled patients.
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http://dx.doi.org/10.3389/fneur.2021.714594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520928PMC
October 2021

Heterogeneity between proximal and distal aspects of occlusive thrombi on pretreatment imaging in acute ischemic stroke.

Neuroradiol J 2021 Oct 5:19714009211049713. Epub 2021 Oct 5.

Department of Neurology, University of California, Los Angeles, USA.

Background: The potential heterogeneity in occlusive thrombi caused by in situ propagation by secondary thrombosis after embolic occlusion could obscure the characteristics of original thrombi, preventing the clarification of a specific thrombus signature for the etiology of ischemic stroke. We aimed to investigate the heterogeneity of occlusive thrombi by pretreatment imaging.

Methods: Among consecutive stroke patients with acute embolic anterior circulation large vessel occlusion treated with thrombectomy, we retrospectively reviewed 104 patients with visible occlusive thrombi on pretreatment non-contrast computed tomography admitted from January 2015 to December 2018. A region of interest was set on the whole thrombus on non-contrast computed tomography under the guidance of computed tomography angiography. The region of interest was divided equally into the proximal and distal segments and the difference in Hounsfield unit densities between the two segments was calculated.

Results: Hounsfield unit density in the proximal segment was higher than that in the distal segment (mean difference 4.45;  < 0.001), regardless of stroke subtypes. On multivariate analysis, thrombus length was positively correlated (β = 0.25;  < 0.001) and time from last-known-well to imaging was inversely correlated (β = -0.0041;  = 0.002) with the difference in Hounsfield unit densities between the proximal and distal segments.

Conclusions: The difference in density between the proximal and distal segments increased as thrombi became longer and decreased as thrombi became older after embolic occlusion. This time/length-dependent thrombus heterogeneity between the two segments is suggestive of secondary thrombosis initially occurring on the proximal side of the occlusion.
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http://dx.doi.org/10.1177/19714009211049713DOI Listing
October 2021

Automated Final Lesion Segmentation in Posterior Circulation Acute Ischemic Stroke Using Deep Learning.

Diagnostics (Basel) 2021 Sep 4;11(9). Epub 2021 Sep 4.

Department of Biomedical Engineering and Physics, Amsterdam UMC, Location AMC, 1105 Amsterdam, The Netherlands.

Final lesion volume (FLV) is a surrogate outcome measure in anterior circulation stroke (ACS). In posterior circulation stroke (PCS), this relation is plausibly understudied due to a lack of methods that automatically quantify FLV. The applicability of deep learning approaches to PCS is limited due to its lower incidence compared to ACS. We evaluated strategies to develop a convolutional neural network (CNN) for PCS lesion segmentation by using image data from both ACS and PCS patients. We included follow-up non-contrast computed tomography scans of 1018 patients with ACS and 107 patients with PCS. To assess whether an ACS lesion segmentation generalizes to PCS, a CNN was trained on ACS data (ACS-CNN). Second, to evaluate the performance of only including PCS patients, a CNN was trained on PCS data. Third, to evaluate the performance when combining the datasets, a CNN was trained on both datasets. Finally, to evaluate the performance of transfer learning, the ACS-CNN was fine-tuned using PCS patients. The transfer learning strategy outperformed the other strategies in volume agreement with an intra-class correlation of 0.88 (95% CI: 0.83-0.92) vs. 0.55 to 0.83 and a lesion detection rate of 87% vs. 41-77 for the other strategies. Hence, transfer learning improved the FLV quantification and detection rate of PCS lesions compared to the other strategies.
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http://dx.doi.org/10.3390/diagnostics11091621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466415PMC
September 2021

Prestroke Disability and Outcome After Thrombectomy for Emergent Anterior Circulation Large Vessel Occlusion Stroke.

Neurology 2021 11 20;97(19):e1914-e1919. Epub 2021 Sep 20.

From the Department of Neurology (A.d.H.), University of Utah, Salt Lake City; Department of Neurology (A.C.), University of Toledo, OH; Department of Neurology, Neurosurgery, and Radiology (R.N.), Emory University, Atlanta, GA; Department of Neurology, Neurosurgery, and Radiology (T.N.N.), Boston Medical Center, MA; California Pacific Medical Center (J.E.), San Francisco; Department of Neurointerventional Surgery (S.R.S.), Christiana Care Health System, Newark, DE; Department of Neurosurgery (E.V.), Drexel Neurosciences Institute, Philadelphia, PA; Department of Neurology (J.L.S.), University of California, Los Angeles; Department of Neurosurgery (J.M.), Mt. Sinai, New York, NY; Department of Neurology (P.K.), University of Cincinnati, OH; Department of Neurology (E.M.), Vanderbilt Medical Center, Nashville, TN; and Department of Neurology (O.O.Z.), Mercy Health-St. Vincent Medical Center, Toledo, OH.

Background And Objectives: To determine the impact of endovascular therapy for large vessel occlusion stroke in patients with vs those without premorbid disability.

Methods: We performed a post hoc analysis of the TREVO Stent-Retriever Acute Stroke (TRACK) Registry, which collected data on 634 consecutive patients with stroke treated with the Trevo device as first-line endovascular thrombectomy (EVT) at 23 centers in the United States. We included patients with internal carotid or middle cerebral (M1/M2 segment) artery occlusions, and the study exposure was patient- or caregiver-reported premorbid modified Rank Scale (mRS) score ≥2 (premorbid disability [PD]) vs premorbid mRS score of 0 to 1 (no PD [NPD]). The primary outcome was no accumulated disability, defined as no increase in 90-day mRS score from the patient's premorbid mRS score.

Results: Of the 634 patients in TRACK, 407 patients were included in our cohort, of whom 53 (13.0%) had PD. The primary outcome of no accumulated disability was achieved in 37.7% (20 of 53) of patients with PD and 16.7% (59 of 354) of patients with NPD ( < 0.001), while death occurred in 39.6% (21 of 53) and 14.1% (50 of 354) ( < 0.001), respectively. The adjusted odds ratio of no accumulated disability for patients with PD was 5.2 (95% confidence interval [CI] 2.4-11.4, < 0.001) compared to patients with NPD. However, the adjusted odds ratio for death in patients with PD was 2.90 (95% CI 1.38-6.09, = 0.005).

Discussion: In this study of patients with anterior circulation acute ischemic stroke treated with EVT, we found that PD was associated with a higher probability of not accumulating further disability compared to patients with NPD but also with higher probability of death.

Classification Of Evidence: This study provides Class II evidence that in anterior circulation acute ischemic stroke treated with EVT, patients with PD compared to those without disability were more likely not to accumulate more disability but were more likely to die.
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http://dx.doi.org/10.1212/WNL.0000000000012827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601211PMC
November 2021

Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial.

Eur Heart J 2021 12;42(47):4821-4829

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Suite 7022, Boston, MA 02115, USA.

Aims: We assessed the impact of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD).

Methods And Results: In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74-0.88]; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75-0.91]), cerebrovascular (HR 0.77 [0.65-0.92]), and peripheral vascular (HR 0.58 [0.38-0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69-0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75-0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67-0.85]) thereafter.

Conclusion: The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.
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http://dx.doi.org/10.1093/eurheartj/ehab604DOI Listing
December 2021

Stent Retriever Thrombectomy for Anterior vs. Posterior Circulation Ischemic Stroke: Analysis of the STRATIS Registry.

Front Neurol 2021 23;12:706130. Epub 2021 Aug 23.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

The benefits of mechanical thrombectomy (MT) in vertebrobasilar artery occlusions have not been well-studied. We compared clinical, procedural, and safety outcomes of MT for posterior circulation (PC) vs. anterior circulation (AC) occlusions among patients in the STRATIS registry. Data from STRATIS including patient demographics, procedural characteristics, and outcomes including symptomatic intracranial hemorrhage (sICH) at 24 h, serious adverse events (SAE), substantial reperfusion [modified thrombolysis in cerebral infarction (mTICI) 2b/3], 90-day functional independence [modified Rankin Scale (mRS) 0-2], and 90-day mortality were analyzed. Univariate logistic regression was used to calculate predictors of good clinical outcome. Of 984 STRATIS patients, 43 (4.4%) patients with PC occlusions [mean age 63.0 ± 13.6, 25.6% (11/43) female] and 932 (94.7%) with AC occlusions [mean age 68.5 ± 14.8, 46.9% (437/932) female] were included for analysis. Median National Institutes of Health Stroke Scale (NIHSS) scores at baseline were 17.0 (13.0, 12.0) for the AC group and 12.0 (11.0, 24.0) for the PC group. Time from onset to procedure end was longer for the PC group [median (IQR): 322.0 min (255.0-421.0) vs. 271.0 min (207.0-360.0); = 0.007]. PC and AC groups had similar rates of substantial reperfusion [89.2% (33/37) vs. 87.7% (684/780)], procedure-related SAE [0.0% (0/43) vs. 1.7% (16/932)], sICH [0.0% (0/38) vs. 1.5% (12/795)], 90-day functional independence [66.7% (26/39) vs. 55.9% (480/858)] and mortality [12.8% (5/39) vs. 15.8% (136/861)]. National Institutes of Health Stroke Scale score and patient sex were significant univariate predictors of good clinical outcome ( < 0.05). Despite longer reperfusion times, MT in PC stroke has similar rates of 90-day functional independence with no significant difference in procedure-related SAE, sICH, or mortality, supporting the use of MT in PC acute ischemic stroke (AIS). https://www.clinicaltrials.gov, Identifier: NCT02239640.
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http://dx.doi.org/10.3389/fneur.2021.706130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421856PMC
August 2021

Thrombolysis in Mild Stroke: A Comparative Analysis of the PRISMS and MaRISS Studies.

Stroke 2021 10 9;52(10):e586-e589. Epub 2021 Sep 9.

Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.).

Background And Purpose: Mild ischemic stroke patients enrolled in randomized controlled trials of thrombolysis may have a different symptom severity distribution than those treated in routine clinical practice.

Methods: We compared the distribution of the National Institutes of Health Stroke Scale (NIHSS) scores, neurological symptoms/severity among patients enrolled in the PRISMS (Potential of r-tPA for Ischemic Strokes With Mild Symptoms) randomized controlled trial to those with NIHSS score ≤5 enrolled in the prospective MaRISS (Mild and Rapidly Improving Stroke Study) registry using global P values from χ2 analyses.

Results: Among 1736 participants in MaRISS, 972 (56%) were treated with alteplase and 764 (44%) were not. These participants were compared with 313 patients randomized in PRISMS. The median NIHSS scores were 3 (2–4) in MaRISS alteplase-treated, 1 (1–3) in MaRISS non–alteplase-treated, and 2 (1–3) in PRISMS. The percentage with an NIHSS score of 0 to 2 was 36.3%, 73.3%, and 65.2% in the 3 groups, respectively (P<0.0001). The proportion of patients with a dominant neurological syndrome (≥1 NIHSS item score of ≥2) was higher in MaRISS alteplase-treated (32%) compared with MaRISS nonalteplase-treated (13.8%) and PRISMS (8.6%; P<0.0001).

Conclusions: Patients randomized in PRISMS had comparable deficit and syndromic severity to patients not treated with alteplase in the MaRISS registry and lesser severity than patients treated with alteplase in MaRISS. The PRISMS trial cohort is representative of mild patients who do not receive alteplase in current broad clinical practice.
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http://dx.doi.org/10.1161/STROKEAHA.120.033466DOI Listing
October 2021

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

N Engl J Med 2021 09;385(11):971-981

From the Mobile Stroke Unit, Memorial Hermann Hospital-Texas Medical Center (J.C.G., J. McCarthy, T.F.), the Departments of Biostatistics and Data Science (J.-M.Y., A.P.J., M.W., N.S., M.G.) and Management, Policy, and Community Heath (S.S.R.), University of Texas School of Public Health, the Departments of Neurology (S.A.P., N.R.G., P.L.B., N.R.-G., E.L., J.S., K.P., Y.S., E.A.N., R.B.) and Emergency Medicine (D.P.), University of Texas McGovern Medical School, the Departments of Emergency Medicine (D.P.) and Neurology (C.P.V.R.), Baylor College of Medicine, the Department of Neurology, Houston Methodist Hospital (D.C., J.V., V.M.), the Department of Neurology, Harris Health-Ben Taub General Hospital (J.S.K.), and HCA Houston Healthcare (L.G.) - all in Houston; the Department of Neurology, University of Colorado, UCHealth Anschutz Medical Campus, Aurora (W.J.J., B.D.S., K.A., M.E., D.O.), and the Department of Neurology, UCHealth Memorial Hospital, Colorado Springs (J. Miller) - both in Colorado; the Department of Neurology, University of Tennessee Health Science Center, Memphis (A.W.A., A.V.A., J.P.R.); the Department of Neurology, Weill Cornell Medicine (B.B.N., M.E.F., C.S., M.L., S.M.), and the Department of Neurology, Columbia University Irving Medical Center (J.Z.W.) - both in New York; the Department of Neurology, Ronald Reagan UCLA Medical Center, Los Angeles (M.N., J.L.S., K.M.B., B.M.V.), the Department of Neurology, Mills Peninsula Medical Center, Burlingame (I.S., J.E., N. Barazangi, J.I.), Los Angeles County Emergency Medical Services, Santa Fe Springs (M.G.-H., N. Bosson), and San Mateo County Emergency Medical Services, South San Francisco (G.G.) - all in California; and the Department of Neurology, Indiana University School of Medicine, Indianapolis (J. Mackey, S.Q.C., K.S.).

Background: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied.

Methods: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients.

Results: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group.

Conclusions: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).
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http://dx.doi.org/10.1056/NEJMoa2103879DOI Listing
September 2021

Value of infarct location in the prediction of functional outcome in patients with an anterior large vessel occlusion: results from the HERMES study.

Neuroradiology 2021 Sep 3. Epub 2021 Sep 3.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.

Purpose: Follow-up infarct volume (FIV) is moderately associated with functional outcome. We hypothesized that accounting for infarct location would strengthen the association of FIV with functional outcome.

Methods: We included 252 patients from the HERMES collaboration with follow-up diffusion weighted imaging. Patients received endovascular treatment combined with best medical management (n = 52%) versus best medical management alone (n = 48%). FIV was quantified in low, moderate and high modified Rankin Scale (mRS)-relevant regions. We used binary logistic regression to study the relation between the total, high, moderate or low mRS-relevant FIVs and favorable outcome (mRS < 2) after 90 days. The strength of association was evaluated using the c-statistic.

Results: Small lesions only occupied high mRS-relevant brain regions. Lesions additionally occupied lower mRS-relevant brain regions if FIV expanded. Higher FIV was associated with a higher risk of unfavorable outcome, as were volumes of tissue with low, moderate and high mRS relevance. In multivariable modeling, only the volume of high mRS-relevant infarct was significantly associated with favorable outcome. The c-statistic was highest (0.76) for the models that included high mRS-relevant FIV or the combination of high, moderate and low mRS-relevant FIV but was not significantly different from the model that included only total FIV (0.75).

Conclusion: This study confirms the association of FIV and unfavorable functional outcome but showed no strengthened association if lesion location was taken into account.
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http://dx.doi.org/10.1007/s00234-021-02784-xDOI Listing
September 2021

Outcomes Among Patients With Reversible Cerebral Vasoconstriction Syndrome: A Nationwide United States Analysis.

Stroke 2021 12 2;52(12):3970-3977. Epub 2021 Sep 2.

Neurology Department, Montpellier University Hospital, France (A.D.).

Background And Purpose: Reversible cerebral vasoconstriction syndrome (RCVS) is a well-established cause of stroke, but its demographics and outcomes have not been well delineated.

Methods: Analysis of the United States Nationwide Inpatient Sample database (2016-2017) to characterize the frequency of hospitalizations for RCVS, demographic features, inpatient mortality, and discharge outcomes.

Results: During the 2-year study period, 2020 patients with RCVS were admitted to Nationwide Inpatient Sample hospitals, representing 0.02 cases per 100 000 national hospitalizations. The mean age at admission was 47.6 years, with 85% under 65 years of age, and 75.5% women. Concomitant neurological diagnoses during hospitalization included ischemic stroke (17.1%), intracerebral hemorrhage (11.0%), subarachnoid hemorrhage (32.7%), seizure disorders (6.7%), and reversible brain edema (13.6%). Overall, 70% of patients were discharged home, 29.7% discharged to a rehabilitation facility or nursing home and 0.3% died before discharge. Patient features independently associated with the poor outcome of discharge to another facility or death were advanced age (odds ratio [OR], 1.04 [95% CI, 1.03-1.04]), being a woman (OR, 2.45 [1.82-3.34]), intracerebral hemorrhage (OR, 2.91 [1.96-4.31]), ischemic stroke (OR, 5.72 [4.32-7.58]), seizure disorders (OR, 2.61 [1.70-4.00]), reversible brain edema (OR, 6.26 [4.41-8.89]), atrial fibrillation (OR, 2.97 [1.83-4.81]), and chronic kidney disease (OR, 3.43 [2.19-5.36]).

Conclusions: Projected to the entire US population, >1000 patients with RCVS are hospitalized each year, with the majority being middle-aged women, and about 300 required at least some rehabilitation or nursing home care after discharge. RCVS-related inpatient mortality is rare.
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http://dx.doi.org/10.1161/STROKEAHA.121.034424DOI Listing
December 2021

Cerebral Edema in Patients With Large Hemispheric Infarct Undergoing Reperfusion Treatment: A HERMES Meta-Analysis.

Stroke 2021 11 13;52(11):3450-3458. Epub 2021 Aug 13.

Department of Medicine and Neurology, Melbourne Brain Centre (F.C.N., N.Y., G.S., S.M.D., B.C.V.C.), Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.

Background And Purpose: Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline.

Methods: In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool.

Results: Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98]; reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08]).

Conclusions: In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.
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http://dx.doi.org/10.1161/STROKEAHA.120.033246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545835PMC
November 2021

Standardized Nomenclature for Modified Rankin Scale Global Disability Outcomes: Consensus Recommendations From Stroke Therapy Academic Industry Roundtable XI.

Stroke 2021 08 29;52(9):3054-3062. Epub 2021 Jul 29.

Division of Stroke and Neurocritical Care, Department of Neurology and Neurological Sciences and the Stanford Stroke Center, Stanford University (C.V., G.W.A.).

The modified Rankin Scale (mRS), a 7-level, clinician-reported, measure of global disability, is the most widely employed outcome scale in acute stroke trials. The scale's original development preceded the advent of modern clinimetrics, but substantial subsequent work has been performed to enable the mRS to meet robust contemporary scale standards. Prior research and consensus recommendations have focused on modernizing 2 aspects of the mRS: operationalized assignment of scale scores and statistical analysis of scale distributions. Another important characteristic of the mRS still requiring elaboration and specification to contemporary clinimetric standards is the Naming of scale outcomes. Recent clinical trials have used a bewildering variety, often mutually contradictory, of rubrics to describe scale states. Understanding of the meaning of mRS outcomes by clinicians, patients, and other clinical trial stakeholders would be greatly enhanced by use of a harmonized, uniform set of labels for the distinctive mRS outcomes that would be used consistently across trials. This statement advances such recommended rubrics, developed by the Stroke Therapy Academic Industry Roundtable collaboration using an iterative, mixed-methods process. Specific guidance is provided for health state terms (eg, Symptomatic but Nondisabled for mRS score 1; requires constant care for mRS score 5) and valence terms (eg, excellent for mRS score 1; very poor for mRS score 5) to employ for 23 distinct numeric mRS outcomes, including: all individual 7 mRS levels; all 12 positive and negative dichotomized mRS ranges, positive and negative sliding dichotomies; and utility-weighted analysis of the mRS.
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http://dx.doi.org/10.1161/STROKEAHA.121.034480DOI Listing
August 2021

Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis?

Stroke 2021 08 28;52(9):3075-3080. Epub 2021 Jul 28.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Finland (J.P., M.K.).

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http://dx.doi.org/10.1161/STROKEAHA.121.034244DOI Listing
August 2021

Endovascular Treatment Effect Diminishes With Increasing Thrombus Perviousness: Pooled Data From 7 Trials on Acute Ischemic Stroke.

Stroke 2021 11 20;52(11):3633-3641. Epub 2021 Jul 20.

Radiology and Nuclear Medicine (M.K., M.L.T., K.M.T., B.G.D., H.A., G.Z., H.A.M., C.B.L.M.M.).

Background And Purpose: Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness.

Methods: We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL).

Results: Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly (P=0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction.

Conclusions: Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.
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http://dx.doi.org/10.1161/STROKEAHA.120.033124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547583PMC
November 2021

Serial ASPECTS in the DAWN Trial: Infarct Evolution and Clinical Impact.

Stroke 2021 10 20;52(10):3318-3324. Epub 2021 Jul 20.

University of Pittsburgh Medical Center, PA (A.P.J., T.G.J.).

Background And Purpose: The impact of baseline ischemia on Alberta Stroke Program Early CT Score (ASPECTS) and evolution over 24 hours may be distinct in late thrombectomy. We analyzed predictors of serial ASPECTS and clinical outcomes in the DAWN trial (Diffusion-Weighted Imaging or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo).

Methods: The DAWN Imaging Core Laboratory independently scored ASPECTS at baseline and 24 hours. Descriptive statistics characterized ASPECTS on computed tomography/magnetic resonance imaging at baseline and 24 hours, delineating ASPECTS change over 24 hours.

Results: 206 subjects (mean age 70.0±13.7 years; 54.9% (n=113) female; baseline National Institutes of Health Stroke Scale median (interquartile range) 17 (13, 21) were included. Baseline ASPECTS was median (interquartile range) 8.0 (7–8), with 92/205 (44.9%) between 0 and 7 and 113/205 (55.1%) 8 and 10. 24-hour ASPECTS was median 6.0 (4–8), with ASPECTS change or infarct evolution having median −1, ranging from −8 to +2. Multivariable logistic regression showed older age (odds ratio [OR] for 10-year interval, 1.26 [95% CI, 1.02–1.55], P=0.030) and dyslipidemia (OR, 1.84 [95% CI, 1.06–3.19], P=0.031) were independently associated with higher baseline ASPECTS. Higher 24-hour ASPECTS was predicted by endovascular treatment (OR, 2.76 [95% CI, 1.58–4.81], P=0.0004), baseline glucose <150 mg/dL (OR, 2.86 [95% CI, 1.50–5.46], P=0.001), lower baseline National Institutes of Health Stroke Scale (OR, 0.93 [95% CI, 0.89–0.98], P=0.010), and older age (OR for 10-year interval, 1.25 [95% CI, 1.01–1.55], P=0.041). Internal carotid artery lesion location (OR, 0.47 [95% CI, 0.24–0.89], P=0.021) was inversely related to 24-hour ASPECTS. Good clinical outcome (day 90 modified Rankin Scale score 0–2) was predicted by 24-hour ASPECTS (OR, 1.46 [95% CI, 1.08–1.96], P=0.014). Extensive infarct evolution (ASPECTS decrease ≥6) occurred in 14/201 (7.0%). Elevated baseline serum glucose ≥150 mg/dL was a predictor of ASPECTS decrease of ≥4 points (OR, 2.78 [95% CI, 1.21–6.35] P=0.016) as was internal carotid artery occlusion (OR, 2.49 [95% CI, 1.05–5.88]; P=0.038). ASPECTS change was influenced by treatment arm (P=0.001 by Wilcoxon), including 0 ASPECTS change in 42/105 (40.0%) of the endovascular arm and only 20/96 (20.8%) of the medical arm.

Conclusions: DAWN subjects enrolled with small infarct cores had a broad range of baseline ASPECTS. Twenty-four-hour ASPECTS, strikingly influenced by endovascular therapy, predicted good clinical outcomes.

Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.
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http://dx.doi.org/10.1161/STROKEAHA.120.033477DOI Listing
October 2021

Endovascular thrombectomy without versus with intravenous thrombolysis in acute ischemic stroke: a non-inferiority meta-analysis of randomized clinical trials.

J Neurointerv Surg 2021 Jul 15. Epub 2021 Jul 15.

Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi, Taiwan

Objective: To conduct a meta-analysis of randomized trials to comprehensively compare the effect of endovascular thrombectomy (EVT) versus intravenous thrombolysis (IVT) plus EVT on functional independence (modified Rankin Scale (mRS) 0-2) after acute ischemic stroke due to large vessel occlusions (AIS-LVO).

Methods: We searched Pubmed, EMBASE, CENTRAL, and clinicaltrials.gov from January 2000 to February 2021 and abstracts presented at the International Stroke Conference in March 2021 to identify trials comparing EVT alone versus IVT plus EVT in AIS-LVO. Five non-inferiority margins established in the literature were assessed: -15%, -10%, -6.5%, -5%, and -1.3% for the risk difference for functional independence at 90 days.

Results: Four trials met the selection criteria, enrolling 1633 individuals, with 817 participants randomly assigned to EVT alone and 816 to IVT plus EVT. Crude cumulative rates of 90-day functional independence were 46.0% with EVT alone versus 45.5% with IVT plus EVT. Pooled results showed the risk difference of functional independence was 1% (95% CI -4% to 5%) between EVT alone versus IVT plus EVT. The lower 95% CI bound of -4% fell within the non-inferiority margins of -15%, -10%, -6.5%, and -5%, but not -1.3%. Pooled results also showed the risk difference between EVT alone versus IVT plus EVT was 1% (95% CI -3% to 5%) for mRS 0-1, and 1% (95% CI -1% to 3%) for symptomatic intracranial hemorrhage.

Conclusions: This meta-analysis suggests that EVT alone is non-inferior to IVT plus EVT for several, but not the most stringent, non-inferiority margins.
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http://dx.doi.org/10.1136/neurintsurg-2021-017667DOI Listing
July 2021

Prediction of Outcome and Endovascular Treatment Benefit: Validation and Update of the MR PREDICTS Decision Tool.

Stroke 2021 08 16;52(9):2764-2772. Epub 2021 Jul 16.

Department of Public Health (E.V., E.W.S., H.F.L.), Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Background And Purpose: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice.

Methods: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0–2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic.

Results: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72–0.77) in HERMES and, after model updating, 0.80 (0.78–0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%–14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at www.mrpredicts.com.

Conclusions: Because of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center.
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http://dx.doi.org/10.1161/STROKEAHA.120.032935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378416PMC
August 2021
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