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Background and ObjectivesThe safety and efficacy of tenecteplase (TNK) in patients with tandem lesion (TL) stroke is unknown. We performed a comparative analysis of TNK and alteplase in patients with TLs.MethodsWe first compared the treatment effect of TNK and alteplase in patients with TLs using individual patient data from the EXTEND-IA TNK trials. We evaluated intracranial reperfusion at initial angiographic assessment and 90-day modified Rankin scale (mRS) with ordinal logistic and Firth regression models. Because 2 key outcomes, mortality and symptomatic intracranial hemorrhage (sICH), were few in number among those who received alteplase in the EXTEND-IA TNK trials, we generated pooled estimates for these outcomes by supplementing trial data with estimates of incidence obtained through a meta-analysis of studies identified in a systematic review. We then calculated unadjusted risk differences to compare the pooled estimates for those receiving alteplase with the incidence observed in the trial among those receiving TNK.ResultsSeventy-one of 483 patients (15%) in the EXTEND-IA TNK trials possessed a TL. In patients with TLs, intracranial reperfusion was observed in 11/56 (20%) of TNK-treated patients vs 1/15 (7%) alteplase-treated patients (adjusted odds ratio 2.19; 95% CI 0.28–17.29). No significant difference in 90-day mRS was observed (adjusted common odds ratio 1.48; 95% CI 0.44–5.00). A pooled study-level proportion of alteplase-associated mortality and sICH was 0.14 (95% CI 0.08–0.21) and 0.09 (95% CI 0.04–0.16), respectively. Compared with a mortality rate of 0.09 (95% CI 0.03–0.20) and an sICH rate of 0.07 (95% CI 0.02–0.17) in TNK-treated patients, no significant difference was observed.DiscussionFunctional outcomes, mortality, and sICH did not significantly differ between patients with TLs treated with TNK and those treated with alteplase.Classification of EvidenceThis study provides Class III evidence that TNK is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and sICH compared with alteplase in patients with acute stroke due to TLs. However, the CIs do not rule out clinically important differences.Trial Registration Informationclinicaltrials.gov/ct2/show/NCT02388061;clinicaltrials.gov/ct2/show/NCT03340493.

Background: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke). Methods: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015–2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models. Results: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03–4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50–10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16–2.06]; P interaction =0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00–8.05] versus absent: aOR, 1.98 [95% CI, 0.65–6.03]; P interaction =0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25–11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01–3.83]; P interaction =0.16). Conclusions: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship.In a pooled, patient-level analysis of EXTEND-IA trials and SELECT study, we employed a mediation analysis framework to quantify infarct growth and cerebral edema(midline shift) mediation effect on successful reperfusion(mTICI≥2b) association with functional outcome(mRS distribution). Further, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift.542/665(81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful vs unsuccessful reperfusion. Median(IQR) infarct growth was 12.3(1.8-48.4)ml and median(IQR) midline shift was 0(0,2.2)mm. Of 249(37%) demonstrating a midline shift of ≥1mm, median(IQR) shift was 2.75(1.89, 4.21)mm). Successful reperfusion was associated with reductions in both predefined mediators; infarct growth (β, -1.19; 95%CI, -1.51to-0.88;p0.001) and midline shift (aOR:0.36,95%CI:0.23-0.57,p0.001). Successful reperfusion association with improved functional outcome (acOR:2.68; 95%CI:1.86-3.88,p0.001), became insignificant (acOR:1.39, 95%CI:0.95-2.04,p=0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect. Analysis considering alternative hypothesis demonstrated consistent results.In this mediation analysis from a pooled, patient-level cohort, a significant proportion(~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect and identify novel therapeutic targets to further enhance reperfusion benefits. This article is protected by copyright. All rights reserved.

Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates.Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND-IA and EXTEND-IA TNK trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or 50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90-day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression.Among 893 patients included in the primary analysis, thrombolytic-induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09-2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93-2.14) and second segment (aIRR = 2.07, 95% CI = 0.98-4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04-1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00-1.13). No significant treatment-by-time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90-day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54-3.01) compared to patients who achieved reperfusion following endovascular therapy.Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2022.

The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy).DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants.Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84).We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment.Australian National Health and Medical Research Council and Stryker USA.

Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase.The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed.Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61-83), and the median NIHSS at baseline was 8 (5-14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3-28]) than with alteplase (35 mL [18-76]; adjusted incidence rate ratio 0·55, 95% CI 0·37-0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23-2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26-4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase.Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care.Melbourne Academic Centre for Health.

Background Trials of tranexamic acid (TXA) in acute intracerebral hemorrhage (ICH) have focused on the imaging outcomes of intraparenchymal hematoma growth. However, intraventricular hemorrhage (IVH) growth is also strongly associated with outcome after ICH. Revised definitions of hematoma expansion incorporating IVH growth have been proposed. Aims We sought to evaluate the effect of TXA on IVH growth. Methods We analyzed data from the STOP-AUST trial, a prospective randomized trial comparing TXA to placebo in ICH patients presenting ≤ 4.5 h from symptom onset with a CT-angiography spot sign. New IVH development at follow-up, any interval IVH growth, and IVH growth ≥ 1 mL were compared between the treatment groups using logistic regression. The treatment effect of TXA against placebo using conventional (> 6 mL or 33%), and revised definitions of hematoma expansion (> 6 mL or 33% or IVH expansion ≥ 1 mL, > 6 mL or 33%, or any IVH expansion, and > 6 mL or 33% or new IVH development) were also assessed. Treatment effects were adjusted for baseline ICH volume. Results The analysis population consisted of 99 patients (50 placebo, 49 TXA). New IVH development at follow-up was observed in 6/49 (12%) who received TXA and 13/50 (26%) who received placebo (aOR: 0.38 [95% CI: 0.13–1.13]). Any interval IVH growth was observed in 12/49 (25%) who received TXA versus 26/50 (32%) receiving placebo (aOR: 0.69 [95% CI: 0.28–1.66]). IVH growth ≥ 1 mL did not differ between the two groups. Using revised definitions of hematoma expansion, no significant difference in treatment effect was observed between TXA and placebo. Conclusions IVH may be attenuated by TXA following ICH; however, studies with larger cohorts are required to investigate this further. Registration http://www.clinicaltrials.gov ; Unique identifier: NCT01702636.

Background and ObjectivesDetailed study of tenecteplase (TNK) in patients older than 80 years is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients older than 80 years with large vessel occlusion.MethodsWe performed a pooled analysis of the EXTEND-IA TNK randomized controlled trials (n = 502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase 0.90 mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin Scale (mRS) score, all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIH Stroke Score, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.ResultsIn patients >80 years (n = 137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, adjusted common odds ratio (acOR) 2.70, 95% CI 1.23–5.94) and reduced mortality (acOR 0.34, 95% CI 0.13–0.91) vs 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, acOR 2.28, 95% CI 1.03–5.05) vs alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg. In patients ≤80 years, no differences in 90-day mRS, mortality, or symptomatic ICH were observed among TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg.DiscussionTNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients older than 80 years. No differences among the doses were observed in younger patients.Trial Registration InformationNCT02388061, NCT03340493.Classification of EvidenceThis study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.

ObjectiveThe concept of the ‘self-fulfilling prophecy’ is well established in intracerebral haemorrhage (ICH). The ability to improve prognostication and prediction of long-term outcomes during the first days of hospitalisation is important in guiding conversations around goals of care. We previously demonstrated that incorporating delayed imaging into various prognostication scores for ICH improves the predictive accuracy of 90-day mortality. However, delayed prognostication scores have not been used to predict long-term functional outcomes beyond 90 days.Design, setting and participantsWe analysed data from the ICH Deferoxamine trial to see if delaying the use of prognostication scores to 96 hours after ICH onset will improve performance to predict outcomes at 180 days. 276 patients were included.Interventions and measurementsWe calculated the original ICH score (oICH), modified-ICH score (MICH), max-ICH score and the FUNC score on presentation (baseline), and on day 4 (delayed). Outcomes assessed were mortality and poor functional outcome in survivors (defined as modified Rankin Scale of 4–5) at 180 days. We generated receiver operating characteristic curves, and measured the area under the curve values (AUC) for mortality and functional outcome. We compared baseline and delayed AUCs with non-parametric methods.ResultsAt 180 days, 21 of 276 (7.6%) died. Out of the survivors, 54 of 255 had poor functional outcome (21.2%). The oICH, MICH and max-ICH performed significantly better at predicting 180-day mortality when calculated 4 days later compared with their baseline equivalents ((0.74 vs 0.83, p=0.005), (0.73 vs 0.80, p=0.036), (0.74 vs 0.83, p=0.008), respectively). The delayed calculation of these scores did not significantly improve our accuracy for predicting poor functional outcomes.ConclusionDelaying the calculation of prognostication scores in acute ICH until day 4 improved prediction of 6-month mortality but not functional outcomes.Trial registration numberClinicalTrials.gov Registry (NCT02175225).

We reviewed stroke care delivery during the COVID-19 pandemic at our stroke center and provincial telestroke system. We counted referrals to our prevention clinic, code strokes, thrombolysis, endovascular thrombectomies, and activations of a provincial telestroke system from February to April of 2017–2020. In April 2020, there was 28% reduction in prevention clinic referrals, 32% reduction in code strokes, and 26% reduction in telestroke activations compared to prior years. Thrombolysis and endovascular thrombectomy rates remained constant. Fewer patients received stroke services across the spectrum from prevention, acute care to telestroke care in Ontario, Canada, during the COVID-19 pandemic.

A 73-year-old man presented with sudden right-sided weakness, aphasia, and low-grade headache. Medical history was pertinent for obstructive sleep apnea, hypertension, diabetes, and dyslipidemia, for which he was appropriately treated, in addition to taking aspirin for primary prevention. Initial bloodwork, head CT, and vessel imaging were normal. MRI showed a nonenhancing, nonrestricting T2 hyperintensity in the left temporal lobe, in addition to multiple microhemorrhages (figure 1, A and B). Symptoms resolved within 24 hours and he was discharged on a second antiplatelet agent (clopidogrel). Three weeks later, a second episode of aphasia and right-sided weakness occurred, resolving within hours. He returned to the hospital the following day as symptoms recurred again. He had had been continually complaining of headaches, and his family had noted a gradual cognitive decline over the past month. Repeat bloodwork and erythrocyte sedimentation rate were normal. MRI demonstrated persistent microhemorrhages and superficial siderosis, worsening of the left temporal lobe subcortical changes, as well as diffuse leptomeningeal enhancement.

Background and Purpose— Definitions of significant hematoma expansion traditionally focus on changes in intraparenchymal volume. The presence of intraventricular hemorrhage (IVH) is a predictor of poor outcome, but current definitions of hematoma expansion do not include IVH expansion. We evaluated whether including IVH expansion to current definitions of hematoma expansion improves the ability to predict 90-day outcome. Methods— Using data from the PREDICT-ICH study (Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT), we compared a standard definition of hematoma expansion (≥6 mL or ≥33%) to revised definitions that includes new IVH development or expansion (≥6 mL or ≥33% or any IVH; ≥6 mL or ≥33% or IVH expansion ≥1 mL). The primary outcome was poor clinical outcome (modified Rankin Scale score, 4–6) at 90 days. Diagnostic accuracy measures were calculated for each definition, and C statistics for each definition were compared using nonparametric methods. Results— Of the 256 patients eligible for primary analysis, 127 (49.6%) had a modified Rankin Scale score of 4 to 6. Sensitivity and specificity for the standard definition (n=80) were 45.7% (95% CI, 36.8–54.7) and 82.9% (95% CI, 75.3–88.9), respectively. The revised definition, ≥6 mL or ≥33% or any IVH (n=113), possessed a sensitivity of 63.8% (95% CI, 54.8–72.1) and specificity of 75.2% (95% CI, 66.8–82.4). Overall accuracy was significantly improved with the revised definition ( P =0.013) and after adjusting for relevant covariates, was associated with a 2.55-fold increased odds (95% CI, 1.31–4.94) of poor outcome at 90 days. A second revised definition, ≥6 mL or ≥33% or IVH expansion ≥1 mL, performed similarly (sensitivity, 56.7% [95% CI, 47.6–65.5]; specificity, 78.3% [95% CI, 40.2–85.1]; aOR, 2.40 [95% CI, 1.23–4.69]). Conclusions— In patients with mild-to-moderate ICH, including IVH expansion to the definition of hematoma expansion improves sensitivity with only minimal decreases to specificity and improves overall prediction of 90-day outcome.

Background and Purpose— Patients with intracerebral hemorrhage (ICH) are often subject to rapid deterioration due to hematoma expansion. Current prognostic scores are largely based on the assessment of baseline radiographic characteristics and do not account for subsequent changes. We propose that calculation of prognostic scores using delayed imaging will have better predictive values for long-term mortality compared with baseline assessments. Methods— We analyzed prospectively collected data from the multicenter PREDICT study (Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign). We calculated the ICH Score, Functional Outcome in Patients With Primary Intracerebral Hemorrhage (FUNC) Score, and modified ICH Score using imaging data at initial presentation and at 24 hours. The primary outcome was mortality at 90 days. We generated receiver operating characteristic curves for all 3 scores, both at baseline and at 24 hours, and assessed predictive accuracy for 90-day mortality with their respective area under the curve. Competing curves were assessed with nonparametric methods. Results— The analysis included 280 patients, with a 90-day mortality rate of 25.4%. All 3 prognostic scores calculated using 24-hour imaging were more predictive of mortality as compared with baseline: the area under the curve was 0.82 at 24 hours (95% CI, 0.76–0.87) compared with 0.78 at baseline (95% CI, 0.72–0.84) for ICH Score, 0.84 at 24 hours (95% CI, 0.79–0.89) compared with 0.76 at baseline (95% CI, 0.70–0.83) for FUNC, and 0.82 at 24 hours (95% CI, 0.76–0.88) compared with 0.74 at baseline (95% CI, 0.67–0.81) for modified ICH Score. Conclusions— Calculation of the ICH Score, FUNC Score, and modified ICH Score using 24-hour imaging demonstrated better prognostic value in predicting 90-day mortality compared with those calculated at presentation.

Objective: We sought to map the landscape of trials investigating hydroxychloroquine (HCQ) for SARS-CoV-2 in order to draw conclusions about how clinical trials have been conducted in the pandemic environment and offer potential regulatory recommendations. Study Design and Setting: We identified and captured data related to registered studies using HCQ to treat SARS-CoV-2 registered with the publicly available National Institutes of Health (NIH) Clinical Trials Registry between February and November 2020. Results: Between February and November 2020, 206 studies investigating HCQ in SARS-CoV-2 were registered with the NIH Clinical Trials Registry. As of November 2020, 135 studies were listed as ongoing, 22 have been completed, and 46 are either suspended or have been terminated. Reasons for suspension or termination included difficulties with patient recruitment (n=9), emerging evidence showing a lack of benefit of HCQ (n=7), and recommendations by regulatory boards to discontinue (n=10). Conclusion: Many clinical trials of HCQ were launched in the first months of the pandemic, and a significant proportion of them remained active as of November 2020. The medical community appears to have responded very quickly to political interest in HCQ, while responding much more slowly to the evolving medical evidence of its lack of efficacy.

RationaleHaematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth.Methods and designStopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework.HypothesisIn patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo.Sample size estimatesA sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients.InterventionParticipants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo.Primary efficacy measureThe primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan.DiscussionWe describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments.

The Modified Intracerebral Hemorrhage (MICH) score is a simple tool created to provide prognostication in basal ganglia hemorrhages. Current prognostic scores, including the MICH, are based on the assessment of baseline patient characteristics, failing to account for significant developments, such as intraventricular extension and clinical deterioration, which may occur over the first 72 hours. We propose to validate the MICH in all hemorrhage locations and hypothesize that its calculation at 72 hours will outperform its baseline counterpart with respect to predicting mortality and functional outcome. We performed a retrospective analysis of collated data from the Virtual International Stroke Trials Archive database. Primary outcome was 90-day mortality. Secondary outcome was poor outcome (modified Rankin Scale 4-6) at 90 days. Receiver operating characteristic curves were generated looking at the predictive ability of the MICH score for mortality and poor outcome, at baseline and at 72 hours. Competing curves were assessed with nonparametric methods. A total of 226 patients were included, with a 90-day mortality of 22.5%. The MICH scores calculated at 72 hours were more predictive of mortality than at baseline (area under the curve [AUC]: 0.89 [95% confidence interval [CI]: 0.83-0.94] vs 0.78 [95% CI: 0.70-0.85]), P < .01. The MICH scores at 72 hours similarly better predicted functional outcome (AUC: 0.78 [95% CI: 0.72-0.84] vs AUC: 0.72 [95% CI: 0.66-0.78]), P = .047. The MICH score has positive prognostic value for mortality and poor functional outcome in all hemorrhage locations. Delaying its calculation resulted in higher predictive values for both and suggests that delaying discussions around withdrawal of care may result in more accurate prognostication in acute intracerebral hemorrhage.

The computed tomography angiography (CTA) spot sign is widely used to assess the risk of hematoma expansion following acute intracerebral hemorrhage (ICH). However, not all patients can receive intravenous contrast nor are all hospital systems equipped with this technology. We aimed to independently validate the Hematoma Expansion Prediction (HEP) Score, an 18-point non-contrast prediction scale, in an external cohort and compare its diagnostic capability to the CTA spot sign. We performed a retrospective analysis of the predicting hematoma growth and outcome in intracerebral hemorrhage using contrast bolus CT (PREDICT) Cohort Study. Primary outcome was significant hematoma expansion (≥ 6 mL or ≥ 33%). We generated a receiver operating characteristic (ROC) curve comparing the HEP score to significant expansion. We calculated sensitivity, specificity, positive and negative predictive values (PPV/NPV) for each score point. We determined independent predictors of significant hematoma expansion via logistic regression. A total of 292 patients were included in primary analysis. Hematoma growth of ≥ 6 mL or ≥ 33% occurred in 94 patients (32%). The HEP score was associated with significant expansion (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.01–1.30). ROC curves comparing HEP score to significant expansion had an area under the curve of 0.64 (95% CI 0.57–0.71). Youden’s method showed an optimum score of 4. HEP Scores ≥ 4 (n = 100, sensitivity 49%, specificity 73%, PPV 46%, NPV 75%, aOR 1.99, 95% CI 1.09–3.64) accurately predicted significant expansion. PPV increased with higher HEP scores, but at the cost of lower sensitivity. The diagnostic characteristics of the spot sign (n = 82, Sensitivity 49%, Specificity 81%, PPV 55%, NPV 76%, aOR 2.95, 95% CI 1.61–5.42) were similar to HEP scores ≥ 4. The HEP score is predictive of significant expansion (≥ 6 mL or ≥ 33%) and is comparable to the spot sign in diagnostic accuracy. Non-contrast prediction tools may have a potential role in the recruitment of patients in future intracerebral hemorrhage trials.

Background and purpose Recovery after intracerebral haemorrhage (ICH) is often slower than ischemic stroke. Despite this, ICH research often quantifies recovery using the same outcome measures obtained at the same timepoints as ischemic stroke. The primary objective of this scoping review is to map the existing literature to determine when and how outcomes are being measured in prospective studies of recovery after ICH. Methods We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science from inception to November 2019, for prospective studies that included patients with ICH. Two investigators independently screened the studies and extracted data around timing and type of outcome assessment. Results Among the 9761 manuscripts reviewed, 395 met inclusion criteria, of which 276 were observational studies and 129 were interventional studies that enrolled 66274 patients. Mortality was assessed in 93% of studies. Functional outcomes were assessed in 85% of studies. The most frequently used functional assessment tool was the modified Rankin Scale (mRS) (60%), followed by the National Institute of Health Stroke Severity Scale (22%) and Barthel Index (21%). The most frequent timepoint at which mortality was assessed was 90 days (41%), followed by 180 days (18%) and 365 days (12%), with 2% beyond 1 year. The most frequent timepoint used for assessing mRS was 90 days (62%), followed by 180 days (21%) and 365 days (17%). Conclusion While most prospective ICH studies report mortality and functional outcomes only at 90 days, a significant proportion do so at 1 year and beyond. Our results support the feasibility of collecting long-term outcome data to optimally assess recovery in ICH.

Background and Purpose: It is unclear whether it is clinically necessary or cost-effective to routinely obtain a transthoracic echocardiogram (TTE) during inpatient admission for ischemic stroke. Methods: We assessed consecutive patients presenting with acute ischemic stroke at a comprehensive stroke center from 2015 to 2017 who underwent TTE. We assessed for findings on TTE that would warrant urgent intervention including cardiac thrombus, atrial myxoma, mitral stenosis, valve vegetation, valve dysfunction requiring surgery, and low ejection fraction. Subsequent changes in management included changes in anticoagulation, antibiotics, or valve surgery. We calculated in-hospital resource utilization and associated costs for inpatient TTE using individual direct cost details within a case-costing system. Results: Of 695 patients admitted with acute ischemic stroke, 516 (74%) had a TTE and were included in our analysis. TTE findings were potentially clinically significant in 30 patients (5.8%) and changed management in 17 patients (3.3%). Inpatient admission was prolonged to expedite TTE in 24 patients, while TTE occurred after discharge in 76 patients. After correcting for the cost of TTE, the mean difference in cost to prolong an admission for TTE was $555.52 (USD), or $16 832 per change in management. Conclusions: Given the low clinical utility of inpatient TTE after acute ischemic stroke and the costs associated with prolonging admission, discharge from hospital should not be delayed solely to obtain TTE.

ObjectiveNo systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in female patients. In this scoping review, we aimed to identify all randomised controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularisation, and determine whether sufficient information is reported within these studies to assess short-term and long-term outcomes in female patients.Design, setting and participantsWe systematically searched Medline, Embase, Pubmed and Cochrane libraries for RCTs published between 1991 and 2020 that included female patients and compared either endarterectomy with stenting, or any revascularisation (endarterectomy or stenting) with medical therapy in patients with symptomatic high-grade (>50%) carotid stenosis.ResultsFrom 1537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled female patients were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however, there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment are largely limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex.ConclusionsOnly half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analyses on the results of carotid artery intervention for female patients with symptomatic stenosis are limited.

Background: Hematoma expansion (HE) is an important therapeutic target in intracerebral hemorrhage. Recently proposed HE definitions have not been validated, and no previous definition has accounted for withdrawal of care (WOC). Objective: To compare conventional and revised definitions of hematoma expansion (HE), while accounting for WOC. Methods: We analyzed data from the ATACH-2 trial, comparing revised definitions of HE incorporating intraventricular hemorrhage (IVH) expansion to the conventional definition of “≥6 mL or ≥33%”. The primary outcome was modified Rankin Scale of 4-6 at 90-days. We calculated the incidence, sensitivity, specificity, positive and negative predictive values, and c- statistic for all definitions of HE. Definitions were compared using non-parametric methods. Secondary analyses were performed after removing patients who experienced WOC. Results: Primary analysis included 948 patients. Using the conventional definition, the sensitivity was 37.1% and specificity was 83.2% for the primary outcome. Sensitivity improved with all three revised definitions (53.3%, 48.7%, and 45.3%, respectively), with minimal change to specificity (78.4%, 80.5%, and 81.0%, respectively). The greatest improvement was seen with the definition “≥6 mL or ≥33% or any IVH”, with increased c -statistic from 60.2% to 65.9% (p < 0.001). Secondary analysis excluded 46 participants who experienced WOC. The revised definitions outperformed the conventional definition in this population as well, with the greatest improvement in c -statistic using “≥6 mL or ≥33% or any IVH” (58.1% vs 64.1%, p < 0.001). Conclusions: HE definitions incorporating intraventricular expansion outperformed conventional definitions for predicting poor outcome, even after accounting for care limitations.

Background and Purpose: In present-day intracerebral hemorrhage (ICH) trials, hematoma expansion (HE) is often analyzed as a binary variable - present or absent. However, dichotomizing intrinsically wide-ranging variables discards substantial information reflective of treatment effect and can reduce the ability to detect relationships between the exposure and outcome of interest. We explored the concept of a “HE shift analysis” as a novel analytic mode for ICH treatment trials using previously published clinical trial data. Methods: Using data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial, patients were stratified by treatment status (intensive vs. standard blood pressure lowering with IV nicardipine) and HE shift was evaluated by generating strata based on a) previously established HE definitions, b) quartiles of 24-hour total hematoma volume, and c) quartiles of 24-hour total hematoma volume (THV) change. The relationship between blood pressure treatment and hematoma expansion shift was explored using proportional odds models and adjusted Wilcoxon testing. Results: The primary analysis population included 863 patients. In both treatment groups, approximately one-third of patients exhibited no hematoma growth. Using a conventional threshold, significant intraparenchymal expansion (≥33%) was reduced by 5.8% in those assigned to the intensive therapy arm (aOR: 0.77 [95% CI: 0.60-0.99], Figure 1A). The stratified quartiles of 24-hour total hematoma volumes were associated with a 5% shift within the highest and lowest strata in the intensive arm, (aOR: 0.83 [0.66-1.05], Figure 1B). Intensive therapy was associated with a 5.2% reduction from > 3 mL to 0.5-3 mL (aOR: 0.86 [0.68-1.09], Figure 1C). Conclusions: A shift analysis model of HE provides additional insights into the biological effects of a given therapy and may be an alternate way to assess hemostatic agents in future hemorrhage trials.

Background and Purpose: No systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in women. In this scoping review, we aimed to identify all randomized controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularization, and determine whether sufficient information is reported within these studies to assess women’s short and long-term outcomes. Methods: We systematically searched Medline, Embase, Pubmed, and Cochrane libraries for RCTs published between 1991 and 2020 that included women and compared either endarterectomy with stenting, or any revascularization (endarterectomy or stenting) with medical therapy in patients with symptomatic high grade (greater than 50%) carotid stenosis. Results: From 1,537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled women were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment were limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex. Conclusions: Half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analysis on the benefits of carotid artery intervention for women with symptomatic stenosis is limited . Further analysis with individual patient data and a network meta-analysis is the necessary next step to better assess the treatment effects of carotid management in women.

ObjectiveHematoma expansion (HE) is commonly analyzed as a dichotomous outcome in intracerebral hemorrhage (ICH) trials. In this proof-of-concept study, we propose an HE shift analysis model as a method to improve the evaluation of candidate ICH therapies.MethodsUsing data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial, we performed HE shift analysis in response to intensive blood pressure lowering by generating polychotomous strata based on previously established HE definitions, percentile/absolute quartiles of hematoma volume change, and quartiles of 24-hour follow-up hematoma volumes. The relationship between blood pressure treatment and HE shift was explored with proportional odds models.ResultsThe primary analysis population included 863 patients. In both treatment groups, approximately one-third of patients exhibited no HE. With the use of a trichotomous HE stratification, the highest strata of ≥33% revealed a 5.8% reduction in hematoma growth for those randomized to intensive therapy (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.60–0.99). Using percentile quartiles of hematoma volume change, we observed a favorable shift to reduce growth in patients treated with intensive therapy (aOR 0.73, 95% CI 0.57–0.93). Similarly, in a tetrachotomous analysis of 24-hour follow-up hematoma volumes, shifts in the highest stratum (>21.9 mL) were most notable.ConclusionsOur findings suggest that intensive blood pressure reduction may preferentially mitigate growth in patients at risk of high volume HE. A shift analysis model of HE provides additional insights into the biological effects of a given therapy and may be an additional way to assess hemostatic agents in future studies.Trial Registration InformationClinicalTrials.govIdentifier:NCT01176565.

Background Hematoma expansion is an important therapeutic target in intracerebral hemorrhage. Recently proposed hematoma expansion definitions have not been validated, and no previous definition has accounted for withdrawal of care. Aims To externally validate revised definitions of hematoma expansion that incorporate intraventricular hemorrhage, and to test their validity in the context of withdrawal of care. Methods We analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II trial, comparing revised definitions of hematoma expansion incorporating intraventricular hemorrhage expansion to the conventional definition of “≥6 mL or ≥33%.” Primary outcome was modified Rankin Scale of 4–6 at 90 days. We calculated the incidence, sensitivity, specificity, positive and negative predictive values, and c-statistic for all definitions of hematoma expansion. Definitions were compared using nonparametric methods. Secondary analyses were performed after removing patients with withdrawal of care. Results Primary analysis included 948 patients. Using the conventional definition, the sensitivity was 37.1% and specificity was 83.2% for the primary outcome. Sensitivity improved with all three revised definitions (53.3%, 48.7%, and 45.3%, respectively), with minimal change to specificity (78.4%, 80.5%, and 81.0%, respectively). The greatest improvement was seen with the definition “≥6 mL or ≥33% or any intraventricular hemorrhage,” with increased c-statistic from 60.2% to 65.9% ( p Conclusions Revised hematoma expansion definitions incorporating intraventricular hemorrhage expansion outperformed conventional definitions for predicting poor outcome, even after accounting for care limitations.

IntroductionClinical trials for intracerebral haemorrhage typically measure outcomes in the same way and at the same time points as trials for ischaemic stroke. However, there is growing evidence that the trajectory of recovery following intracerebral haemorrhage may differ significantly from that following ischaemic stroke. A better understanding of current approaches to outcome assessment is essential to ensure that future trials examining treatments for intracerebral haemorrhage are designed appropriately.ObjectiveTo determine when and how outcomes are measured in patients with intracerebral haemorrhage.Methods and analysisWith the assistance of an information specialist, we will conduct a scoping review by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science for prospective studies of adults with primary intracerebral haemorrhage and documented outcomes with specified times. Two reviewers will independently collect data on included studies pertaining to publication data, study population information, timing of outcome and details of the outcome measurement tools used. The extracted data will be used to demonstrate the type and timing of outcome measures.Ethics and disseminationPrimary data will not be collected therefore formal ethics is not required. The findings of this study will be disseminated through peer-reviewed publications and through presentation at academic conferences.

Evidence of spinal cord involvement in Powassan virus infection is largely limited to mouse models. We report a case of a polio-like illness caused by Powassan virus infection in a 62-year-old man in Canada. Magnetic resonance imaging showed T2 hyperintensities in the anterior horns of the cervical spinal cord.

Background and Purpose— In acute spontaneous intracerebral hemorrhage, multiple hematoma expansion scores have been proposed for use in clinical trial environments. We performed a systematic scoping review to identify all existing hematoma expansion scores and describe their development, validation, and relative performance. Methods— Two reviewers searched MEDLINE, PUBMED, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) for studies that derived or validated a hematoma expansion prediction score in adults presenting with spontaneous intracerebral hemorrhage. A descriptive analysis of the extracted data was performed, focusing on score development techniques and predictive capabilities. Results— Of the 14 434 records retrieved, 15 studies met inclusion criteria and 10 prediction scores were identified. Validation analysis using independent samples was performed in 9 studies on 5 scores. All derivation studies reported high performance with C statistics ranging from 0.72 to 0.93. In validation, the C-statistic range was broader with studies reporting 0.62 to 0.77. For every score, the risk of expansion increased with each point increase, although patients with high scores were rare. Conclusions— At present, 10 hematoma expansion scores have been developed, of which 5 have been externally validated. Real-world performance in validation studies was lower than performance in derivation studies. Data from the current literature are insufficient to support a meaningful meta-analysis.

Supplemental material, sj-pdf-1-wso-10.1177_1747493020967255 for Revised intracerebral hemorrhage expansion definitions: Relationship with care limitations by Ronda Lun, Vignan Yogendrakumar, Greg Walker, Michel Shamy, Robert Fahed, Adnan Qureshi and Dar Dowlatshahi in International Journal of Stroke