Robot-Assisted Transcranial Doppler Versus Transthoracic Echocardiography for Right to Left Shunt Detection.

BACKGROUND: Right to left shunt (RLS), including patent foramen ovale, is a recognized risk factor for stroke. RLS/patent foramen ovale diagnosis is made by transthoracic echocardiography (TTE), which is insensitive, transesophageal echocardiography, which is invasive, and transcranial Doppler (TCD), which is noninvasive and accurate but scarce. METHODS: We conducted a prospective, single-arm device clinical trial of robot-assisted TCD (raTCD) versus TTE for RLS diagnosis at 6 clinical sites in patients who presented with an event suspicious for embolic cerebrovascular ischemia from October 6, 2020 to October 20, 2021. raTCD was performed with standard TCD bubble study technique. TTE bubble study was performed per local standards. The primary outcome was rate of RLS detection by raTCD versus TTE. RESULTS: A total of 154 patients were enrolled, 129 evaluable (intent to scan) and 121 subjects had complete data per protocol. In the intent to scan cohort, mean age was 60±15 years, 47% were women, and all qualifying events were diagnosed as ischemic stroke or transient ischemic attack. raTCD was positive for RLS in 82 subjects (64%) and TTE was positive in 26 (20%; absolute difference 43.4% [95% CI, 35.2%-52.0%]; P<0.001). On prespecified secondary analysis, large RLS was detected by raTCD in 35 subjects (27%) versus 13 (10%) by TTE (absolute difference 17.0% [95% CI, 11.5%-24.5%]; P<0.001). There were no serious adverse events. CONCLUSIONS: raTCD was safe and ≈3 times more likely to diagnose RLS than TTE. TTE completely missed or underdiagnosed two thirds of large shunts diagnosed by raTCD. The raTCD device, used by health professionals with no prior TCD training, may allow providers to achieve the known sensitivity of TCD for RLS and patent foramen ovale detection without the need for an experienced operator to perform the test. Pending confirmatory studies, TCD appears to be the superior screen for RLS compared with TTE (funded by NeuraSignal). REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04604015.

Telestroke: Maintaining Quality Acute Stroke Care During the COVID-19 Pandemic.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted acute stroke care globally. Decreased stroke presentations and concern for delays in acute stroke care have been identified. This study evaluated the impact of COVID-19 on the timely treatment of patients with thrombolytics at hospitals utilizing telestroke acute stroke services. Methods: Acute stroke consultations seen in 171 hospitals (19 states) via telestroke from December 1, 2019, to June 27, 2020, were extracted from the TeleCare™ database. The consults were divided into pre-COVID and COVID groups (March 15, 2020, start of COVID group). The consults were reviewed for age, sex, hospital, state, date seen, last known normal, arrival time, consult call time, needle time, thrombolytic candidate, and National Institutes of Health Stroke Scale (NIHSS) score. The total number of consults, median door to needle (DTN) time for emergency department (ED) patients, and call to needle (CTN) time for inpatients were calculated. Results: Pre-COVID, 15,226 stroke consults were evaluated compared with 11,105 in the COVID group, a 27% decrease. Pre-COVID, 1,071 ED patients (7.9%) received thrombolytics and 66 inpatients (4.0%), while COVID, 813 ED patients (8.2%) and 70 inpatients (5.7%). The median DTN time for ED patients pre-COVID was 42 (32, 55) versus 40 (31, 52) in the COVID group, with no statistically significant difference between groups. CTN time pre-COVID was 53 (35, 67) versus 46 (35, 61) in the COVID group, with no statistically significant difference between groups. Conclusions: Telestroke assessments allowed for uninterrupted acute stroke care and treatment stability despite nursing and other resource realignments triggered by the COVID-19 pandemic.

Epidemiological Surveillance of the Impact of the COVID-19 Pandemic on Stroke Care Using Artificial Intelligence.

BACKGROUND AND PURPOSE: The degree to which the coronavirus disease 2019 (COVID-19) pandemic has affected systems of care, in particular, those for time-sensitive conditions such as stroke, remains poorly quantified. We sought to evaluate the impact of COVID-19 in the overall screening for acute stroke utilizing a commercial clinical artificial intelligence platform. METHODS: Data were derived from the Viz Platform, an artificial intelligence application designed to optimize the workflow of patients with acute stroke. Neuroimaging data on suspected patients with stroke across 97 hospitals in 20 US states were collected in real time and retrospectively analyzed with the number of patients undergoing imaging screening serving as a surrogate for the amount of stroke care. The main outcome measures were the number of computed tomography (CT) angiography, CT perfusion, large vessel occlusions (defined according to the automated software detection), and severe strokes on CT perfusion (defined as those with hypoperfusion volumes >70 mL) normalized as number of patients per day per hospital. Data from the prepandemic (November 4, 2019 to February 29, 2020) and pandemic (March 1 to May 10, 2020) periods were compared at national and state levels. Correlations were made between the inter-period changes in imaging screening, stroke hospitalizations, and thrombectomy procedures using state-specific sampling. RESULTS: A total of 23 223 patients were included. The incidence of large vessel occlusion on CT angiography and severe strokes on CT perfusion were 11.2% (n=2602) and 14.7% (n=1229/8328), respectively. There were significant declines in the overall number of CT angiographies (-22.8%; 1.39-1.07 patients/day per hospital, P<0.001) and CT perfusion (-26.1%; 0.50-0.37 patients/day per hospital, P<0.001) as well as in the incidence of large vessel occlusion (-17.1%; 0.15-0.13 patients/day per hospital, P<0.001) and severe strokes on CT perfusion (-16.7%; 0.12-0.10 patients/day per hospital, P<0.005). The sampled cohort showed similar declines in the rates of large vessel occlusions versus thrombectomy (18.8% versus 19.5%, P=0.9) and comprehensive stroke center hospitalizations (18.8% versus 11.0%, P=0.4). CONCLUSIONS: A significant decline in stroke imaging screening has occurred during the COVID-19 pandemic. This analysis underscores the broader application of artificial intelligence neuroimaging platforms for the real-time monitoring of stroke systems of care.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Bronchoalveolar Tregs are associated with duration of mechanical ventilation in acute respiratory distress syndrome.

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4+ T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples. METHODS: We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48-96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4+ T cells that were Tregs. RESULTS: The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood. CONCLUSION: Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4+ cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.

Sphenopalatine Ganglion Stimulation to Augment Cerebral Blood Flow: A Randomized, Sham-Controlled Trial.

Background and Purpose- Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy. Methods- In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial. Results- Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64-79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9-15), and time from last known well median 18.6 hours (interquartile range, 14.5-22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89-2.47); P=0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted, P=0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08-6.73); P=0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed. Conclusions- SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03767192.

Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke.

BACKGROUND AND PURPOSE: This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke. METHODS: We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0-2) at day 90 and radiographic outcomes at day 5. RESULTS: Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (P=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49-166] versus 43 [18-81] mL; P=0.006) and larger final infarct volumes (110 [61-155] versus 48 [21-99] mL; P=0.001). CONCLUSIONS: Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.

Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke.

BACKGROUND: Among patients with acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, less than 40% regain functional independence when treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy with the use of a stent retriever, in addition to intravenous t-PA, increases reperfusion rates and may improve long-term functional outcome. METHODS: We randomly assigned eligible patients with stroke who were receiving or had received intravenous t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The primary outcome was the severity of global disability at 90 days, as assessed by means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]). RESULTS: The study was stopped early because of efficacy. At 39 centers, 196 patients underwent randomization (98 patients in each group). In the intervention group, the median time from qualifying imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at 90 days over the entire range of scores on the modified Rankin scale (P<0.001). The rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, P=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P=0.12). CONCLUSIONS: In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461.).

Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke.

OBJECTIVE: To assess the utility of computed tomographic (CT) perfusion for selection of patients for endovascular therapy up to 18 hours after symptom onset. METHODS: We conducted a multicenter cohort study of consecutive acute stroke patients scheduled to undergo endovascular therapy within 90 minutes after a baseline CT perfusion. Patients were classified as "target mismatch" if they had a small ischemic core and a large penumbra on their baseline CT perfusion. Reperfusion was defined as >50% reduction in critical hypoperfusion between the baseline CT perfusion and the 36-hour follow-up magnetic resonance imaging. RESULTS: Of the 201 patients enrolled, 190 patients with an adequate baseline CT perfusion study who underwent angiography were included (mean age = 66 years, median NIH Stroke Scale [NIHSS] = 16, median time from symptom onset to endovascular therapy = 5.2 hours). Rate of reperfusion was 89%. In patients with target mismatch (n = 131), reperfusion was associated with higher odds of favorable clinical response, defined as an improvement of ≥8 points on the NIHSS (83% vs 44%; p = 0.002, adjusted odds ratio [OR] = 6.6, 95% confidence interval [CI] = 2.1-20.9). This association did not differ between patients treated within 6 hours (OR = 6.4, 95% CI = 1.5-27.8) and those treated > 6 hours after symptom onset (OR = 13.7, 95% CI = 1.4-140). INTERPRETATION: The robust association between endovascular reperfusion and good outcome among patients with the CT perfusion target mismatch profile treated up to 18 hours after symptom onset supports a randomized trial of endovascular therapy in this patient population. Ann Neurol 2017;81:849-856.

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial.

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02072226.

Early Trajectory of Stroke Severity Predicts Long-Term Functional Outcomes in Ischemic Stroke Subjects: Results From the ESCAPE Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

BACKGROUND AND PURPOSE: The trajectory of neurological improvement after stroke treatment is clinically likely to be an important prognostic signal. We compared the accuracy of early longitudinal National Institutes of Health Stroke Scale (NIHSS) measurement versus other early markers of stroke severity post treatment in predicting subjects' 90-day stroke outcome. METHODS: Data are from the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). Stroke severity was assessed at baseline, 1, 2, 5, 30, and 90 days. Subjects' functional outcome was assessed using the modified Rankin Scale at baseline, 30 days, and 90 days. Group-based trajectory model was used to identify distinct subgroups of longitudinal trajectories of NIHSS measured over the first 2, 5, and 30 days. The accuracy of baseline NIHSS, infarct volume, 24-hour change in NIHSS, infarct volume, and disease severity trajectory subgroups in predicting 90-day stroke outcome were assessed using logistic regression analysis. RESULTS: Group-based trajectory model of the 2-day longitudinal NIHSS data revealed 3 distinct subgroups of NIHSS trajectories-large improvement (41.6%), minimal improvement (31.1%), and no improvement (27.3%) subgroups. Individuals in the large improvement group were more likely were more likely to exhibit good outcomes after 90 days than those in the minimal improvement or no improvement subgroup. Among candidate predictors, the 2-day trajectory subgroup variable was the most accurate in predicting 90-day modified Rankin Scale at 84.5%. CONCLUSIONS: Early trajectory of neurological improvement defined by 2-day longitudinal NIHSS data predicts functional outcomes with greater accuracy than other common variables. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator (SST+tPA) compared with tPA. Previous studies suggested that this strategy may be cost-effective, but models were derived from pooled data and older assumptions. METHODS: In this prospective economic substudy conducted alongside the SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), in-trial costs were measured for patients using detailed medical resource utilization and hospital billing data. Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension questionnaire. Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors. RESULTS: Index hospitalization costs were $17 183 per patient higher for SST+tPA than for tPA ($45 761 versus $28 578; P<0.001), driven by initial procedure costs. Between discharge and 90 days, costs were $4904 per patient lower for SST+tPA than for tPA ($11 270 versus $16 174; P=0.014); total 90-day costs remained higher with SST+tPA ($57 031 versus $44 752; P<0.001). Higher utility values for SST+tPA led to higher in-trial quality-adjusted life years (0.131 versus 0.105; P=0.005). In lifetime projections, SST+tPA was associated with substantial gains in quality-adjusted life years (6.79 versus 5.05), cost savings of $23 203 per patient and was economically dominant when compared with tPA in 90% of bootstrap replicates. CONCLUSIONS: Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial, SST increased initial treatment costs, but was projected to improve quality-adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657461.

Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME.

OBJECTIVE: 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. METHODS: Baseline ischemic core and hypoperfusion volumes were assessed prior to randomized treatment with intravenous (IV) tissue plasminogen activator (tPA) alone versus IV tPA + endovascular therapy (Solitaire stent-retriever) using RAPID automated postprocessing software. Reperfusion was assessed with angiographic Thrombolysis in Cerebral Infarction scores at the end of the procedure (endovascular group) and Tmax > 6-second volumes at 27 hours (both groups). Infarct volume was assessed at 27 hours on noncontrast CT or magnetic resonance imaging (MRI). RESULTS: A total of 151 patients with baseline imaging with CT perfusion (79%) or multimodal MRI (21%) were included. The median baseline ischemic core volume was 6 ml (interquartile range= 0-16). Ischemic core volumes correlated with 27-hour infarct volumes in patients who achieved reperfusion (r = 0.58, p < 0.0001). In patients who did not reperfuse (<10% reperfusion), baseline Tmax > 6-second lesion volumes correlated with 27-hour infarct volume (r = 0.78, p = 0.005). In target mismatch patients, the union of baseline core and early follow-up Tmax > 6-second volume (ie, predicted infarct volume) correlated with the 27-hour infarct volume (r = 0.73, p < 0.0001); the median absolute difference between the observed and predicted volume was 13 ml. INTERPRETATION: Ischemic core and hypoperfusion volumes, obtained primarily from CT perfusion scans, predict 27-hour infarct volume in acute stroke patients who were treated with reperfusion therapies.

Telephone-supported computerised cognitive-behavioural therapy: REEACT-2 large-scale pragmatic randomised controlled trial.

BackgroundComputerised cognitive-behavioural therapy (cCBT) for depression has the potential to be efficient therapy but engagement is poor in primary care trials.AimsWe tested the benefits of adding telephone support to cCBT.MethodWe compared telephone-facilitated cCBT (MoodGYM) (n = 187) to minimally supported cCBT (MoodGYM) (n = 182) in a pragmatic randomised trial (trial registration: ISRCTN55310481). Outcomes were depression severity (Patient Health Questionnaire (PHQ)-9), anxiety (Generalized Anxiety Disorder Questionnaire (GAD)-7) and somatoform complaints (PHQ-15) at 4 and 12 months.ResultsUse of cCBT increased by a factor of between 1.5 and 2 with telephone facilitation. At 4 months PHQ-9 scores were 1.9 points lower (95% CI 0.5-3.3) for telephone-supported cCBT. At 12 months, the results were no longer statistically significant (0.9 PHQ-9 points, 95% CI -0.5 to 2.3). There was improvement in anxiety scores and for somatic complaints.ConclusionsTelephone facilitation of cCBT improves engagement and expedites depression improvement. The effect was small to moderate and comparable with other low-intensity psychological interventions.

Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

BACKGROUND AND PURPOSE: Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). METHODS: The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I-III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days. RESULTS: From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [P=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11-0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09-0.74; adjusted for age, type of treatment, and follow-up scan). CONCLUSIONS: INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis.

IMPORTANCE: Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. OBJECTIVE: To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS: Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES: Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS: Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, -6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, -5.2% [95% CI, -8.3% to -2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, -0.9% to 4.2%]). CONCLUSIONS AND RELEVANCE: In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.

Computed tomography perfusion imaging in the selection of acute stroke patients to undergo emergent carotid endarterectomy.

Severe acute stroke patients with critical carotid stenosis or occlusion without intracranial thrombus typically do not undergo emergent carotid thromboendarterectomy (CEA) because of the risk of reperfusion-related intracranial hemorrhage. Past studies have not consistently demonstrated benefit of early operative intervention. Cerebral computed tomography (CT), cervical and cerebral CT angiography (CTA), and cerebral CT perfusion (CTP) imaging may identify a subset of acute stroke patients without intracranial thrombus who may benefit from emergent CEA. Acute stroke patients underwent unenhanced brain CT imaging to exclude pathology that would contraindicate emergent therapy. Emergent CTAs of the intracranial and extracranial vessels were utilized to identify patients who presented with stroke symptoms based on the presence of isolated extracranial carotid disease in the absence of intracranial thromboembolism. CTP was then used to assess the extent of potentially reversible cerebral ischemia (penumbral tissue). Patients with isolated extracranial carotid lesions with significant reversible ischemia in the absence of large areas of irreversible cerebral damage underwent emergent CEA to salvage ischemic penumbra. In 1 year, 3 patients presented with large acute strokes in which CTA disclosed symptomatic extracranial internal carotid artery preocclusive or occlusive lesions without intracranial thromboembolic occlusions. CTP indicated a large area of ischemic penumbra with limited permanent injury. Mean age, time to presentation, and National Institutes of Health stroke score (NIHSS) were 66 years, 4.2 hr, and 19.3. All patients underwent emergent CEA with cervical carotid thrombectomy. Average time from stroke symptom onset to revascularization was 12.5 (range 5.9-19.0) hr. There were no perioperative deaths. At day 5, the mean NIHSS decreased to 7.6 and at day 30 was 4.7. The modified Rankin scale score dropped from a poststroke, preoperative level of 5 to 2.3 by day 30. Emergent CEA should be considered in patients presenting with large acute strokes based on favorable CT, CTA, and CTP findings. Emergent clot localization and physiological assessment of brain "tissue at risk" relative to irreversible cerebral infarction using CT, CTA, and CTP is now available. Utilization of this information by an experienced stroke team of neurologists, radiologists, and surgeons may aid in the recognition of a select group of patients in which emergent CEA may drive to improved outcomes.

Predictors of functional dependence despite successful revascularization in large-vessel occlusion strokes.

BACKGROUND AND PURPOSE: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy. METHODS: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization. RESULTS: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence. CONCLUSIONS: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867.

Severe bronchospasm and acute respiratory failure associated with inhaled prostacyclin therapy.

Prostacyclin therapy is a mainstay of the management of pulmonary arterial hypertension (PAH). Inhaled prostacyclins present safe and effective options for the management of PAH that limit systemic side effects. We describe the first reported case of life-threatening bronchospasm and acute respiratory failure associated with inhaled prostacyclin administration.

Intravenous Odatroltide for Acute Ischemic Stroke Within 24 Hours of Onset: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Purpose: Odatroltide (LT3001), a novel small synthetic peptide molecule designed to recanalize occluded blood vessels and reduce reperfusion injury, is safe and efficacious in multiple embolic stroke animal models. This study aimed to investigate the safety and tolerability of intravenous administration of odatroltide in patients with acute ischemic stroke within 24 hours of onset. Patients and Methods: Patients with National Institutes of Health Stroke Scale (NIHSS 4-30) who were untreated with intravenous thrombolysis or endovascular thrombectomy were randomized (2:1) to receive a single dose of odatroltide (0.025 mg/kg) or placebo within 24 hours of stroke symptom onset. The primary safety outcome was symptomatic intracranial hemorrhage (sICH) occurrence within 36 hours. Results: Twenty-four patients were enrolled and randomized; of these 16 and 8 received intravenous odatroltide infusion and placebo, respectively. sICH did not occur in both groups, and other safety measures were comparable between the groups. The rate of excellent functional outcome (modified Rankin Scale score, 0-1, at 90 days) was 21% and 14% in the odatroltide and placebo groups, respectively. Furthermore, 47% and 14% of patients in the odatroltide and placebo groups, respectively, showed major neurological improvement (NIHSS improvement ≥4 points from baseline to 30 days). Among the 9 odatroltide-treated patients with baseline NIHSS ≥6, 78% showed major neurological improvement. Conclusion: Compared with placebo, treatment with intravenous odatroltide within 24 hours following onset of ischemic stroke appears to be safe and may be associated with better neurological and functional outcomes. However, the efficacy and safety of odatroltide requires further confirmation in the next phase of clinical trials. Clinical Trial Registration: Clinicaltrials.gov identifier: NCT04091945.