Publications by authors named "Geoffrey A Donnan"

449 Publications

Screening for post-stroke depression: who, when and how?

Med J Aust 2021 Sep 13. Epub 2021 Sep 13.

La Trobe University, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.51256DOI Listing
September 2021

Midline Shift Greater than 3 mm Independently Predicts Outcome After Ischemic Stroke.

Neurocrit Care 2021 Sep 7. Epub 2021 Sep 7.

Division of Neurocritical Care, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

Background: Cerebral edema is associated with worse outcome after acute stroke; however, the minimum clinically relevant threshold remains unknown. This study aimed to identify the minimal degree of midline shift (MLS) that predicts outcome in a cohort encompassing a broad range of patients with acute stroke.

Methods: Patient-level data from six acute stroke clinical trials were combined with endovascular thrombectomy registries from two academic referral centers, generating a combined cohort of 1977 patients. MLS was extracted from the original trial data or measured on computed tomography or magnetic resonance imaging that was obtained a median of 47.0 h (interquartile range 27.0-75.1 h) after stroke onset. Logistic regression was performed to identify predictors of poor outcome and the minimal clinically relevant MLS threshold.

Results: The presence of MLS was a predictor of poor outcome, independent of baseline clinical and demographic factors (adjusted odds ratio 4.46, 95% confidence interval 3.56-5.59, p < 0.001). Examining the full range of MLS values identified, a value of greater than 3 mm was the critical threshold that significantly predicted poor outcome (adjusted odds ratio 3.20 [1.31-7.82], p = 0.011).

Conclusions: These results show that the presence of MLS predicts poor outcome and, specifically, MLS value greater than 3 mm is an important threshold across a variety of clinical settings. These findings may have relevance for the design and interpretation of future trials for antiedema therapies.
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http://dx.doi.org/10.1007/s12028-021-01341-xDOI Listing
September 2021

Mobile Stroke Units Facilitate Prehospital Management of Intracerebral Hemorrhage.

Stroke 2021 Jun 30:STROKEAHA121034592. Epub 2021 Jun 30.

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Australia. (S.R.C., H.Z., B.C.V.C., L.C., S.C., D.E., F.L., B.Y., M.W.P., G.A.D., S.M.D., N.Y.).

Background And Purpose: Mobile stroke units (MSUs) improve reperfusion therapy times in acute ischemic stroke (AIS). However, prehospital management options for intracerebral hemorrhage (ICH) are less established. We describe the initial Melbourne MSU experience in ICH.

Methods: Consecutive patients with ICH and AIS treated by the Melbourne MSU were included. We describe demographics, proportions of patients receiving specific therapies, and bypass to comprehensive/neurosurgical centers. We also compare operational time metrics between patients with MSU-ICH and MSU-AIS.

Results: During a 2-year period, the Melbourne MSU managed 49 patients with ICH, mean (SD) age 74 (12) years, median (interquartile range) National Institutes of Health Stroke Scale 17 (12-20). Intravenous antihypertensives were the commonest treatment provided (46.9%). Bypass of a primary center to a comprehensive center with neurosurgical expertise occurred in 32.7% of patients with MSU-ICH compared with 20.5% of patients with MSU-AIS. Compared with patients with MSU-AIS, patients with MSU-ICH had faster onset-to-emergency-call, and onset-to-scene-arrival times at the median and 75th percentiles.

Conclusions: MSUs can facilitate ultra-early ICH diagnosis, management, and triage.
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http://dx.doi.org/10.1161/STROKEAHA.121.034592DOI Listing
June 2021

Utility of the Hospital Frailty Risk Score Derived From Administrative Data and the Association With Stroke Outcomes.

Stroke 2021 Aug 17;52(9):2874-2881. Epub 2021 Jun 17.

Stroke and Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia (M.F.K., H.T.P., J.K., L.L.D., R.G., A.G.T., N.E.A., D.A.C.).

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.033648DOI Listing
August 2021

Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population.

Stroke 2021 Aug 27;52(9):2882-2891. Epub 2021 May 27.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine (J.T.N., M.R., A. Bakshi, G.P., L.T.P.T., M.R.N., R.L.W., C.M.R., A.M.T., J.J.M., P.L.), Monash University, Melbourne, Australia.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.033670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384668PMC
August 2021

Association between pre-treatment perfusion profile and cerebral edema after reperfusion therapies in ischemic stroke.

J Cereb Blood Flow Metab 2021 May 17:271678X211017696. Epub 2021 May 17.

Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.

The relationship between reperfusion and edema is unclear, with experimental and clinical data yielding conflicting results. We investigated whether the extent of salvageable and irreversibly-injured tissue at baseline influenced the effect of therapeutic reperfusion on cerebral edema. In a pooled analysis of 415 patients with anterior circulation large vessel occlusion from the Tenecteplase-versus-Alteplase-before-Endovascular-Therapy-for-Ischemic-Stroke (EXTEND-IA TNK) part 1 and 2 trials, associations between core and mismatch volume on pre-treatment CT-Perfusion with cerebral edema at 24-hours, and their interactions with reperfusion were tested. Core volume was associated with increased edema (p < 0.001) with no significant interaction with reperfusion (p = 0.82). In comparison, a significant interaction between reperfusion and mismatch volume (p = 0.03) was observed: Mismatch volume was associated with increased edema in the absence of reperfusion (p = 0.009) but not with reperfusion (p = 0.27). When mismatch volume was dichotomized at the median (102 ml), reperfusion was associated with reduced edema in patients with large mismatch volume (p < 0.001) but not with smaller mismatch volume (p = 0.35). The effect of reperfusion on edema may be variable and dependent on the physiological state of the cerebral tissue. In patients with small to moderate ischemic core volume, the benefit of reperfusion in reducing edema is related to penumbral salvage.
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http://dx.doi.org/10.1177/0271678X211017696DOI Listing
May 2021

Factors associated with time to independent walking recovery post-stroke.

J Neurol Neurosurg Psychiatry 2021 Jul 17;92(7):702-708. Epub 2021 Mar 17.

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Heidelberg, Victoria, Australia

Background: Past studies have inconsistently identified factors associated with independent walking post-stroke. We investigated the relationship between pre-stroke factors and factors collected acutely after stroke and number of days to walking 50 m unassisted using data from A Very Early Rehabilitation Trial (AVERT).

Methods: The outcome was recovery of 50 m independent walking, tested from 24 hours to 3 months post-stroke. A set of a priori defined factors (participant demographics: age, sex, handedness; pre-stroke: hypertension, ischaemic heart disease, hypercholesterolaemia, diabetes mellitus, atrial fibrillation; stroke-related: stroke severity, stroke type, ischaemic stroke location, stroke hemisphere, thrombolysis) were investigated for association with independent walking using a cause-specific competing risk Cox proportional hazards model. Respective effect sizes are reported as cause-specific adjusted HR (caHR) adjusted for age, stroke severity and AVERT intervention.

Results: A total of 2100 participants (median age 73 years, National Institutes of Health Stroke Scale 7, <1% missing data) with stroke were included. The median time to walking 50 m unassisted was 6 days (IQR 2-63) and 75% achieved independent walking by 3 months. Adjusted Cox regression indicated that slower return to independent walking was associated with older age (caHR 0.651, 95% CI 0.569 to 0.746), diabetes (caHR 0.836, 95% CI 0.740 to 0.945), severe stroke (caHR 0.094, 95% CI 0.072 to 0.122), haemorrhagic stroke (caHR 0.790, 95% CI 0.675 to 0.925) and right hemisphere stroke (caHR 0.796, 95% CI 0.714 to 0.887).

Conclusion: Our analysis provides robust evidence for important factors associated with independent walking recovery. These findings highlight the need for tailored mobilisation programmes that target subgroups, in particular people with haemorrhagic and severe stroke.
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http://dx.doi.org/10.1136/jnnp-2020-325125DOI Listing
July 2021

Factors associated with arrival by ambulance for patients with stroke: a multicentre, national data linkage study.

Australas Emerg Care 2021 Sep 26;24(3):167-173. Epub 2021 Feb 26.

Stroke and Ageing Research, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia. Electronic address:

Background: Hospital arrival via ambulance influences treatment of acute stroke. We aimed to determine the factors associated with use of ambulance and access to evidence-based care among patients with stroke.

Methods: Patients with first-ever strokes from the Australian Stroke Clinical Registry (2010-2013) were linked with administrative data (emergency, hospital admissions). Multilevel, multivariable regression models were used to determine patient, clinical and system factors associated with arrival by ambulance.

Results: Among the 6,262 patients with first-ever stroke, 4,737 (76%) arrived by ambulance (52% male; 80% ischaemic). Patients who were older, frailer, with comorbidities or were unable to walk on admission (stroke severity) were more likely to arrive by ambulance to hospital. Compared to those using other means of transport, those who used ambulances arrived to hospital sooner after stroke onset (minutes, 124 vs 397) and were more likely to receive reperfusion therapy (adjusted odds ratio, 1.57, 95% CI: 1.09, 2.27).

Conclusion: Patients with stroke who use ambulances arrived faster and were more likely to receive reperfusion therapy compared to those using personal transport. Further public education about using ambulance services at all times, instead of personal transport when stroke is suspected is needed to optimise access to time critical care.
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http://dx.doi.org/10.1016/j.auec.2021.01.002DOI Listing
September 2021

Acute Stroke Biomarkers: Are We There Yet?

Front Neurol 2021 5;12:619721. Epub 2021 Feb 5.

Stroke Division, Melbourne Brain Centre, The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.

Distinguishing between stroke subtypes and knowing the time of stroke onset are critical in clinical practice. Thrombolysis and thrombectomy are very effective treatments in selected patients with acute ischemic stroke. Neuroimaging helps decide who should be treated and how they should be treated but is expensive, not always available and can have contraindications. These limitations contribute to the under use of these reperfusion therapies. An alternative approach in acute stroke diagnosis is to identify blood biomarkers which reflect the body's response to the damage caused by the different types of stroke. Specific blood biomarkers capable of differentiating ischemic from hemorrhagic stroke and mimics, identifying large vessel occlusion and capable of predicting stroke onset time would expedite diagnosis and increase eligibility for reperfusion therapies. To date, measurements of candidate biomarkers have usually occurred beyond the time window for thrombolysis. Nevertheless, some candidate markers of brain tissue damage, particularly the highly abundant glial structural proteins like GFAP and S100β and the matrix protein MMP-9 offer promising results. Grouping of biomarkers in panels can offer additional specificity and sensitivity for ischemic stroke diagnosis. Unbiased "omics" approaches have great potential for biomarker identification because of greater gene, protein, and metabolite coverage but seem unlikely to be the detection methodology of choice because of their inherent cost. To date, despite the evolution of the techniques used in their evaluation, no individual candidate or multimarker panel has proven to have adequate performance for use in an acute clinical setting where decisions about an individual patient are being made. Timing of biomarker measurement, particularly early when decision making is most important, requires urgent and systematic study.
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http://dx.doi.org/10.3389/fneur.2021.619721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902038PMC
February 2021

Posterior Circulation Stroke: Advances in Understanding and Management.

J Stroke 2021 Jan 31;23(1):144-145. Epub 2021 Jan 31.

Department of Neurology, Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.

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http://dx.doi.org/10.5853/jos.2020.04798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900395PMC
January 2021

Does Intravenous Thrombolysis Within 4.5 to 9 Hours Increase Clot Migration Leading to Endovascular Inaccessibility?

Stroke 2021 Mar 16;52(3):1083-1086. Epub 2021 Feb 16.

Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (A.B., H.M., B.C.V.C., M.W.P., S.M.D., G.A.D., B.Y.), University of Melbourne, Parkville, Australia.

Background And Purpose: Distal clot migration is a recognized event following intravenous thrombolysis (IVT) in the setting of acute ischemic stroke. Of note, clots that were initially retrievable by endovascular thrombectomy may migrate to a distal nonretrievable location and compromise clinical outcome. We investigated the incidence of clot migration leading to clot inaccessibility following IVT in the time window of 4.5 to 9 hours.

Methods: We performed a retrospective analysis of the EXTEND trial (Extending the Time for Thrombolysis in Emergency Neurological Deficits) data. Baseline and 12- to 24-hour follow-up clot location was determined on computed tomography angiogram or magnetic resonance angiogram. The incidence of clot migration leading to a change from retrievable to nonretrievable location was identified and compared between the two treatment groups (IVT versus placebo).

Results: Two hundred twenty patients were assessed. Clot migration from a retrievable to nonretrievable location occurred in 37 patients: 21 patients (19.3%) in the placebo group and 16 patients (14.4%) in the IVT group. No significant difference was identified in the incidence of clot migration leading to inaccessibility between groups (=0.336).

Conclusions: Our results did not show increased clot migration leading to clot inaccessibility in patients treated with IVT.
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http://dx.doi.org/10.1161/STROKEAHA.120.030661DOI Listing
March 2021

Patterns of Infarction on MRI in Patients With Acute Ischemic Stroke and Cardio-Embolism: A Systematic Review and Meta-Analysis.

Front Neurol 2020 8;11:606521. Epub 2020 Dec 8.

Melbourne Brain Centre at the Royal Melbourne Hospital, Parkville, VIC, Australia.

Cardioembolic strokes are common however atrial fibrillation, the most common cause, is often asymptomatic and difficult to detect. There is evidence that infarct topography and volume on magnetic resonance imaging may be associated with specific stroke etiologies. A systematic review and meta-analysis were undertaken to summarize the available evidence on the association between stroke etiology, infarct topography, and volume. A systematic review was conducted using Medline (OVID), Embase (OVID), and PubMed databases. Hand searches of the gray literature and of reference lists in relevant articles were also performed. A quality assessment was undertaken, based on the STROBE checklist. For each study, the number of patients with and without a CE source of stroke and infarct topography was collected and outcomes presented as odds ratios (OR) with 95% CI and -values. Four thousand eight hundred and seventy-three patients with ischemic stroke were included, of whom 1,559 were determined to have a CE source. Bilateral infarcts (OR 3.41; 95% CI 2.20-5.29; < 0.0001) and multiple territory infarcts (OR 1.57; 95% CI 1.12-2.21; = 0.009) were more common in patients with a CE source of stroke, than patients without a CE source. Lacunar infarcts (OR 0.49; 95% CI 0.31-0.80; = 0.004) were more likely to occur in patients without a CE source. No significant difference between the frequency of multiple infarcts (OR 0.96; 95% CI 0.57-1.61; = 0.87) anterior circulation (OR 1.45; 95% CI 0.83-2.53; = 0.19) or posterior circulation infarcts (OR 1.06; 95% CI 0.72-1.57; = 0.75), between the two groups were identified. Three out of four studies examining volume, found a significant association between increased infarct volume and CE source of stroke. A sensitivity analysis with cryptogenic and undetermined stroke sources assumed to be cardioembolic, did not alter the associations observed. The findings of this systematic review and meta-analysis are broadly consistent with previous literature and provide more robust evidence on the association between infarct topography, volume and stroke etiology. Our findings may assist with refining cardiac investigations for patients with cryptogenic stroke, based on infarct topography.
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http://dx.doi.org/10.3389/fneur.2020.606521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753023PMC
December 2020

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Fatal and non-fatal events within 14 days after early, intensive mobilization post stroke.

Neurology 2020 Nov 3. Epub 2020 Nov 3.

University of Melbourne, Melbourne Brain Centre, Parkville, Australia.

Objective: This tertiary analysis from AVERT examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days.

Method: AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced <24 hours post stroke, termed very early mobilization (VEM) to usual care (UC). Primary outcome was assessed at 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age.

Results: 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral haemorrhage and >80 years subgroups, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found.

Conclusion: While the overall case fatality at 14 days post-stroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM.

Classification Of Evidence: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke.

Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12606000185561.
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http://dx.doi.org/10.1212/WNL.0000000000011106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055346PMC
November 2020

Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.

JAMA Neurol 2021 Feb;78(2):236-240

Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.

Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain.

Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials.

Design, Setting, And Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020.

Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up.

Main Outcomes And Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more.

Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91).

Conclusions And Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.
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http://dx.doi.org/10.1001/jamaneurol.2020.4123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607491PMC
February 2021

Tranexamic acid in patients with intracerebral haemorrhage (STOP-AUST): a multicentre, randomised, placebo-controlled, phase 2 trial.

Lancet Neurol 2020 12 28;19(12):980-987. Epub 2020 Oct 28.

Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia.

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.

Methods: We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).

Findings: Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.

Interpretation: Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.

Funding: National Health and Medical Research Council, Royal Melbourne Hospital Foundation.
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http://dx.doi.org/10.1016/S1474-4422(20)30369-0DOI Listing
December 2020

Five-Year Prognosis After TIA or Minor Ischemic Stroke in Asian and Non-Asian Populations.

Neurology 2021 01 12;96(1):e54-e66. Epub 2020 Oct 12.

From the Department of Neurology and Stroke Center (T.H., H.C., J.L., P.C.L., P.-J.T., P.A.), Bichat Hospital, AP-HP and INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, France; Center for Brain and Cerebral Vessels (S.U.), Sanno Hospital and Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan; Department of Medicine and Therapeutics (L.K.S.W.), Chinese University of Hong Kong, Prince of Wales Hospital; Department of Neurology (T.H., K.K.), Tokyo Women's Medical University, Japan; Université Lille (J.L.), Centre Hospitalier Universitaire Lille, Équipe d'Accueil 2694-Santé Publique: Épidémiologie et Qualité des Soins, Lille, France; Stanford Stroke Center (G.W.A.), Department of Neurology and Neurological Sciences, Stanford University Medical Center, CA; Cerebrovascular Disease Service (L.R.C.), Beth Israel Deaconess Medical Center, Harvard University, Boston, MA; Melbourne Brain Centre (G.A.D.), Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Department of Neurosciences (J.M.F.), Service of Neurology, Hospital Santa Maria, University of Lisbon, Portugal; Department of Neurology (M.G.H.), Universitäts Medizin Mannheim, Heidelberg University, Germany; Stroke Unit, Department of Neurology (C.M.), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Spain; Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK; Department of Cardiology (P.G.S.), Bichat Hospital, AP-HP, Paris, France; National Heart and Lung Institute Imperial College (P.G.S.), Institute of Cardiovascular Medicine and Science Royal Brompton Hospital, London, UK; Department of Biostatistics (É.V.), Université Paris-Diderot, Sorbonne-Paris Cité, Fernand Widal Hospital, AP-HP, Paris, France.

Objective: To determine long-term vascular outcomes of Asian patients who experienced TIA or minor ischemic stroke and to compare the outcomes of Asian patients with those of non-Asian patients, in the context of modern guideline-based prevention strategies.

Methods: This is a subanalysis of the TIAregistry.org project, in which 3,847 patients (882 from Asian and 2,965 from non-Asian countries) with a recent TIA or minor ischemic stroke were assessed and treated by specialists at 42 dedicated units from 14 countries and followed for 5 years. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome.

Results: No differences were observed in the 5-year risk of the primary outcome (14.0% vs 11.7%; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.88-1.37; = 0.41) and stroke (10.7% vs 8.5%; HR, 1.17; 95% CI, 0.90-1.51; = 0.24) between Asian and non-Asian patients. Asian participants were at higher risk of intracranial hemorrhage (1.8% vs 0.8%; HR, 2.23; 95% CI, 1.09-4.57; = 0.029). Multivariable analysis showed that the presence of multiple acute infarctions on initial brain imaging was an independent predictor of primary outcome and modified Rankin Scale score of >1 in both Asian (HR, 1.91; 95% CI, 1.11-3.29; = 0.020) and non-Asian (HR, 1.39; 95% CI, 1.02-1.90; = 0.037) patients.

Conclusion: The long-term risk of vascular events in Asian patients was as low as that in non-Asian patients, while Asian participants had a 2.2-fold higher intracranial hemorrhage risk. Multiple acute infarctions were independently associated with future disability in both groups.

Classification Of Evidence: This study provides Class I evidence that among people who experienced TIA or minor stroke, Asian patients have a similar 5-year risk of cardiovascular death, stroke, and acute coronary syndrome as non-Asian patients.
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http://dx.doi.org/10.1212/WNL.0000000000010995DOI Listing
January 2021

Stroke incidence and subtypes in Aboriginal people in remote Australia: a healthcare network population-based study.

BMJ Open 2020 10 8;10(10):e039533. Epub 2020 Oct 8.

Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia

Objectives: We aimed to compare the incidence, subtypes and aetiology of stroke, and in-hospital death due to stroke, between Aboriginal and non-Aboriginal people in Central Australia, a remote region of Australia where a high proportion Aboriginal people reside (40% of the population). We hypothesised that the rates of stroke, particularly in younger adults, would be greater in the Aboriginal population, compared with the non-Aboriginal population; we aimed to elucidate causes for any identified disparities.

Design: A retrospective population-based study of patients hospitalised with stroke within a defined region from 1 January 2011 to 31 December 2014.

Setting: Alice Springs Hospital, the only neuroimaging-capable acute hospital in Central Australia, serving a network of 50 healthcare facilities covering 672 000 km.

Participants: 161 residents (63.4% Aboriginal) of the catchment area admitted to hospital with stroke.

Primary And Secondary Outcome Measures: Rates of first-ever stroke, overall (all events) stroke and in-hospital death.

Results: Of 121 residents with first-ever stroke, 61% identified as Aboriginal. Median onset-age (54 years) was 17 years younger in Aboriginal patients (p<0.001), and age-standardised stroke incidence was threefold that of non-Aboriginal patients (153 vs 51 per 100 000, incidence rate ratio 3.0, 95% CI 2 to 4). The rate ratios for the overall rate of stroke (first-ever and recurrent) were similar. In Aboriginal patients aged <55 years, the incidence of ischaemic stroke was 14-fold greater (95% CI 4 to 45), and intracerebral haemorrhage 19-fold greater (95% CI 3 to 142) than in non-Aboriginal patients. Crude prevalence of diabetes mellitus (70.3% vs 34.0%, p<0.001) and hypercholesterolaemia (68.9% vs 51.1%, p=0.049) was greater, and age-standardised in-hospital deaths were fivefold greater (35 vs 7 per 100 000, 95% CI 2 to 11) in Aboriginal patients than in non-Aboriginal patients.

Conclusions: Stroke incidence (both subtypes) and in-hospital deaths for remote Aboriginal Australians are dramatically greater than in non-Aboriginal people, especially in patients aged <55 years.
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http://dx.doi.org/10.1136/bmjopen-2020-039533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545633PMC
October 2020

Cost-Effectiveness of Tenecteplase Before Thrombectomy for Ischemic Stroke.

Stroke 2020 12 7;51(12):3681-3689. Epub 2020 Oct 7.

Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (L.C., N.Y., B.Y., M.W.P., G.A.D., S.M.D., B.C.V.C.), University of Melbourne, Parkville, Australia.

Background And Purpose: Tenecteplase improved functional outcomes and reduced the requirement for endovascular thrombectomy in ischemic stroke patients with large vessel occlusion in the EXTEND-IA TNK randomized trial. We assessed the cost-effectiveness of tenecteplase versus alteplase in this trial.

Methods: Post hoc within-trial economic analysis included costs of index emergency department and inpatient stroke hospitalization, rehabilitation/subacute care, and rehospitalization due to stroke within 90 days. Sources for cost included key study site complemented by published literature and government websites. Quality-adjusted life-years were estimated using utility scores derived from the modified Rankin Scale score at 90 days. Long-term modeled cost-effectiveness analysis used a Markov model with 7 health states corresponding to 7 modified Rankin Scale scores. Probabilistic sensitivity analyses were performed.

Results: Within the 202 patients in the randomized controlled trial, total cost was nonsignificantly lower in the tenecteplase-treated patients (40 997 Australian dollars [AUD]) compared with alteplase-treated patients (46 188 AUD) for the first 90 days(=0.125). Tenecteplase was the dominant treatment strategy in the short term, with similar cost (5412 AUD [95% CI, -13 348 to 2523]; =0.181) and higher benefits (0.099 quality-adjusted life-years [95% CI, 0.001-0.1967]; =0.048), with a 97.4% probability of being cost-effective. In the long-term, tenecteplase was associated with less additional lifetime cost (96 357 versus 106 304 AUD) and greater benefits (quality-adjusted life-years, 7.77 versus 6.48), and had a 100% probability of being cost-effective. Both deterministic sensitivity analysis and probabilistic sensitivity analyses yielded similar results.

Conclusions: Both within-trial and long-term economic analyses showed that tenecteplase was highly likely to be cost-effective for patients with acute stroke before thrombectomy. Recommending the use of tenecteplase over alteplase could lead to a cost saving to the healthcare system both in the short and long term. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388061.
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http://dx.doi.org/10.1161/STROKEAHA.120.029666DOI Listing
December 2020

Acute Routine Leukocyte and Neutrophil Counts Are Predictive of Poststroke Recovery at 3 and 12 Months Poststroke: An Exploratory Study.

Neurorehabil Neural Repair 2020 09;34(9):844-855

La Trobe University, College of Science, Health and Engineering, Bundoora, Victoria, Australia.

. White blood cell (WBC) and neutrophil counts (NC) are common markers of inflammation and neurological stroke damage and could be expected to predict poststroke outcomes. . The aim of this study was to explore the prognostic value of early poststroke WBC and NC to predict cognition, mood, and disability outcomes at 3 and 12 months poststroke. . Routine clinical analyses WBC and NC were collected at 3 time points in the first 4 days of hospitalization from 156 acute stroke patients. Correlations using hierarchical or ordinal regressions were explored between acute WBC and NC and functional recovery, depression, and cognition at 3 and 12 months poststroke, after covarying for age and baseline stroke severity. . We found significant increases in NC between <12 hours and 24 to 48 hours time points ( = .05). Hierarchical regressions, covaried for age and baseline stroke severity, found that 24 to 48 hours WBC ( = .05) and NC ( = .04) significantly predicted 3-month cognition scores. Similarly, 24 to 48 hours WBC ( = .05) and NC ( = .02) predicted cognition scores at 12 months. Increases in WBC and NC were predictive of increased cognition scores at both 3 and 12 months (positive recovery) though there were no significant associations between WBC and NC and disability or depression scores. . Routine acute stroke clinical laboratory tests such as WBC and NC taken between 24 and 48 hours poststroke are predictive of cognition poststroke. It is interpreted that higher rapid immunological activation in the acute phase is an indicator for the trajectory of positive stroke recovery.
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http://dx.doi.org/10.1177/1545968320948607DOI Listing
September 2020

Subgroup analysis of the ASPirin in Reducing Events in the Elderly randomized clinical trial suggests aspirin did not improve outcomes in older adults with chronic kidney disease.

Kidney Int 2021 02 10;99(2):466-474. Epub 2020 Sep 10.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Department of Nephrology, Monash Medical Centre, Monash Health, Melbourne, Victoria, Australia. Electronic address:

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.
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http://dx.doi.org/10.1016/j.kint.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957958PMC
February 2021

Look closer: The multidimensional patterns of post-stroke burden behind the modified Rankin Scale.

Int J Stroke 2021 06 27;16(4):420-428. Epub 2020 Aug 27.

NHMRC Centre for Research Excellence in Stroke Rehabilitation and Brain Recovery, Melbourne, Australia.

Background: The utility-weighted modified Rankin Scale, representing patient perspectives of quality of life, is a newly proposed measure to improve the interpretability of the modified Rankin Scale. Despite obvious advantages, such weighting imperfectly reflects the multidimensional patterns of post-stroke burden.

Aims: To investigate multidimensional patterns of post-stroke burden formed by individual domains of Assessment of Quality of Life and Barthel Index for each modified Rankin Scale category.

Methods: In the A Very Early Rehabilitation Trial (n = 2104), modified Rankin Scale scores and modified Rankin Scale-stratified Barthel Index scores of and , and Assessment of Quality of Life scores of , and were collected at three months. The multivariate relationship between individual Assessment of Quality of Life and Barthel Index domains, and modified Rankin Scale was investigated using random effects linear regression models with respective interaction terms.

Results: Of 2104 patients, simultaneously collected Assessment of Quality of Life, Barthel Index and modified Rankin Scale scores at three months were available in 1870 patients. While individual Assessment of Quality of Life and Barthel Index domain scores decreased significantly as modified Rankin Scale increased (p < 0.0001), the patterns of decrease differed by domains (p < 0.0001). Patients with modified Rankin Scale 0-1 had the largest post-stroke burden in the Mental Health and Relationship domains, while patients with modified Rankin Scale >3 showed the greatest burden in Independent Living, Mobility and Self-care domains.

Conclusions: Across the modified Rankin Scale, individual domains are varyingly impacted demonstrating unique patterns of post-stroke burden, which facilitates appropriate assessment, articulation and interpretation of the modified Rankin Scale and utility-weighted modified Rankin Scale.
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http://dx.doi.org/10.1177/1747493020951941DOI Listing
June 2021

Longitudinal Stroke Recovery Associated With Dysregulation of Complement System-A Proteomics Pathway Analysis.

Front Neurol 2020 28;11:692. Epub 2020 Jul 28.

Department of Occupational Therapy, La Trobe University, Bundoora, VIC, Australia.

Currently the longitudinal proteomic profile of post-ischemic stroke recovery is relatively unknown with few well-accepted biomarkers or understanding of the biological systems that underpin recovery. We aimed to characterize plasma derived biological pathways associated with recovery during the first year post event using a discovery proteomics workflow coupled with a topological pathway systems biology approach. Blood samples ( = 180, ethylenediaminetetraacetic acid plasma) were collected from a subgroup of 60 first episode stroke survivors from the Australian START study at 3 timepoints: 3-7 days (T1), 3-months (T2) and 12-months (T3) post-stroke. Samples were analyzed by liquid chromatography mass spectrometry using label-free quantification (data available at ProteomeXchange with identifier PXD015006). Differential expression analysis revealed that 29 proteins between T1 and T2, and 33 proteins between T1 and T3 were significantly different, with 18 proteins commonly differentially expressed across the two time periods. Pathway analysis was conducted using Gene Graph Enrichment Analysis on both the Kyoto Encyclopedia of Genes and Genomes and Reactome databases. Pathway analysis revealed that the significantly differentiated proteins between T1 and T2 were consistently found to belong to the complement pathway. Further correlational analyses utilized to examine the changes in regulatory effects of proteins over time identified significant inhibitory regulation of clusterin on complement component 9. Longitudinal post-stroke blood proteomics profiles suggest that the alternative pathway of complement activation remains in a state of higher activation from 3-7 days to 3 months post-stroke, while simultaneously being regulated by clusterin and vitronectin. These findings also suggest that post-stroke induced sterile inflammation and immunosuppression could inhibit recovery within the 3-month window post-stroke.
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http://dx.doi.org/10.3389/fneur.2020.00692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399641PMC
July 2020

Aeromedical Retrieval for Stroke in Australia.

Cerebrovasc Dis 2020 24;49(3):334-340. Epub 2020 Jun 24.

Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia.

Introduction: Rural, remote, and Indigenous stroke patients have worse stroke outcomes than urban Australians. This may be due to lack of timely access to expert facilities.

Objectives: We aimed to describe the characteristics of patients who underwent aeromedical retrieval for stroke, estimate transfer times, and investigate if flight paths corresponded with the locations of stroke units (SUs) throughout Australia.

Methods: Prospective review of routinely collected Royal Flying Doctor Service (RFDS) data. Patients who underwent an RFDS aeromedical retrieval for stroke, July 2014-June 2018 (ICD-10 codes: I60-I69), were included. To define the locations of SUs throughout Australia, we accessed data from the 2017 National Stroke Audit. The main outcome measures included determining the characteristics of patients with an in-flight diagnosis of stroke, their subsequent pickup and transfer locations, and corresponding SU and imaging capacity.

Results: The RFDS conducted 1,773 stroke aeromedical retrievals, consisting of 1,028 (58%) male and 1,481 (83.5%) non-Indigenous and 292 (16.5%) Indigenous patients. Indigenous patients were a decade younger, 56.0 (interquartile range [IQR] 45.0-64.0), than non-Indigenous patients, 66.0 (IQR 54.0-76.0). The most common diagnosis was "stroke not specified," reflecting retrieval locations without imaging capability. The estimated median time for aeromedical retrieval was 238 min (95% confidence interval: 231-244). Patients were more likely to be transferred to an area with SU and imaging capability (both p < 0.0001).

Conclusion: Stroke patients living in rural areas were younger than those living in major cities (75 years, Stroke Audit Data), with aeromedically retrieved Indigenous patients being a decade younger than non-Indigenous patients. The current transfer times are largely outside the time windows for reperfusion methods. Future research should aim to facilitate more timely diagnosis and treatment of stroke.
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http://dx.doi.org/10.1159/000508578DOI Listing
November 2020

Economic evaluation of the Melbourne Mobile Stroke Unit.

Int J Stroke 2021 06 14;16(4):466-475. Epub 2020 Jun 14.

Stroke & Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, 2541Monash University, Clayton, VIC, Australia.

Background: The Melbourne Mobile Stroke Unit (MSU) is the first Australian service to provide prehospital acute stroke treatment, including thrombolysis and facilitated triage for endovascular thrombectomy.

Aims: To estimate the cost-effectiveness of the MSU during the first full year of operation compared with standard ambulance and hospital stroke care pathways (standard care).

Methods: The costs and benefits of the Melbourne MSU were estimated using an economic simulation model. Operational costs and service utilization data were obtained from the MSU financial and patient tracking reports. The health benefits were estimated as disability-adjusted life years (DALYs) avoided using local data on reperfusion therapy and estimates from the published literature on their effectiveness. Costs were presented in Australian dollars. The robustness of results was assessed using multivariable (model inputs varied simultaneously: 10,000 Monte Carlo iterations) and various one-way sensitivity analyses.

Results: In 2018, the MSU was dispatched to 1244 patients during 200 days of operation. Overall, 167 patients were diagnosed with acute ischemic stroke, and 58 received thrombolysis, endovascular thrombectomy, or both. We estimated 27.94 DALYs avoided with earlier access to endovascular thrombectomy (95% confidence interval (CI) 15.30 to 35.93) and 16.90 DALYs avoided with improvements in access to thrombolysis (95% CI 9.05 to 24.68). The MSU was estimated to cost an additional $30,982 per DALY avoided (95% CI $21,142 to $47,517) compared to standard care.

Conclusions: There is evidence that the introduction of MSU is cost-effective when compared with standard care due to earlier provision of reperfusion therapies.
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http://dx.doi.org/10.1177/1747493020929944DOI Listing
June 2021

Pre-existing Comorbidity Burden and Patient Perceived Stroke Impact.

Int J Stroke 2021 04 23;16(3):273-279. Epub 2020 Apr 23.

Department of Occupational Therapy, Social Work and Social Policy, School of Allied Health, Human Services and Sport, La Trobe University, Bundoora, Australia.

Background: Pre-existing comorbidities can compromise recovery post-stroke. However, the association between comorbidity burden and patient-rated perceived impact has not been systematically investigated. To date, only observer-rated outcome measures of function, disability, and dependence have been used, despite the complexity of the impact of stroke on an individual.

Aim: Our aim was to explore the association between comorbidity burden and patient-rated perceived impact and overall recovery, within the first-year post-stroke, after adjusting for stroke severity, age, and sex.

Methods: The sample comprised 177 stroke survivors from 18 hospitals throughout Australia and New Zealand. Comorbidity burden was calculated using the Charlson Comorbidity Index. Perceived impact and recovery were measured by the Stroke Impact Scale index and Stroke Impact Scale overall recovery scale. Quantile regression models were applied to investigate the association between comorbidity burden and perceived impact and recovery.

Results: Significant negative associations between the Charlson Comorbidity Index and the Stroke Impact Scale index were found at three months. At the .25 quantile, a one-point increase on the Charlson Comorbidity Index was associated with 6.80-points decrease on the Stroke Impact Scale index (95%CI: -11.26, -2.34; p = .003). At the median and .75 quantile, a one-point increase on the Charlson Comorbidity Index was associated, respectively, with 3.58-points decrease (95%CI: -5.62, -1.54; p = .001) and 1.76-points decrease (95%CI: -2.80, -0.73; p = .001) on the Stroke Impact Scale index. At 12 months, at the .25 and .75 quantiles, a one-point increase on the Charlson Comorbidity Index was associated, respectively, with 6.47-points decrease (95%CI: -11.05, -1.89; p = .006) and 1.26-points decrease (95%CI: -2.11, -0.42; p = .004) on the Stroke Impact Scale index. For the Stroke Impact Scale overall recovery measure, significant negative associations were found only at the median at three months and at the .75 quantile at 12 months.

Conclusion: Comorbidity burden is independently associated with patient-rated perceived impact within the first-year post-stroke. The addition of patient-rated impact measures in personalized rehabilitation may enhance the use of conventional observer-rated outcome measures.
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http://dx.doi.org/10.1177/1747493020920838DOI Listing
April 2021

Improving acute stroke care in regional hospitals: clinical evaluation of the Victorian Stroke Telemedicine program.

Med J Aust 2020 05 7;212(8):371-377. Epub 2020 Apr 7.

Florey Institute of Neuroscience and Mental Health, Melbourne, VIC.

Objectives: To evaluate the impact of the Victorian Stroke Telemedicine (VST) program during its first 12 months on the quality of care provided to patients presenting with suspected stroke to hospitals in regional Victoria.

Design: Historical controlled cohort study comparing outcomes during a 12-month control period with those for the initial 12 months of full implementation of the VST program at each hospital.

Setting: 16 hospitals in regional Victoria that participated in the VST program between 1 January 2010 and 30 January 2016.

Participants: Adult patients with suspected stroke presenting to the emergency departments of the participating hospitals.

Main Outcome Measures: Indicators for key processes of care, including symptom onset-to-arrival, door-to-first medical review, and door-to-CT times; provision and timeliness of provision of thrombolysis to patients with ischaemic stroke.

Results: 2887 patients with suspected stroke presented to participating emergency departments during the control period, 3178 during the intervention period; the patient characteristics were similar for both periods. A slightly larger proportion of patients with ischaemic stroke who arrived within 4.5 hours of symptom onset received thrombolysis during the intervention than during the control period (37% v 30%). Door-to-CT scan time (median, 25 min [IQR, 13-49 min] v 34 min [IQR, 18-76 min]) and door-to-needle time for stroke thrombolysis (73 min [IQR, 56-96 min] v 102 min [IQR, 77-128 min]) were shorter during the intervention. The proportions of patients who received thrombolysis and had a symptomatic intracerebral haemorrhage (4% v 16%) or died in hospital (6% v 20%) were smaller during the intervention period.

Conclusions: Telemedicine has provided Victorian regional hospitals access to expert care for emergency department patients with suspected acute stroke. Eligible patients with ischaemic stroke are now receiving stroke thrombolysis more quickly and safely.
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http://dx.doi.org/10.5694/mja2.50570DOI Listing
May 2020

Lindsay Symon: A giant of stroke.

Int J Stroke 2020 06 3;15(4):356-360. Epub 2020 Apr 3.

Melbourne Brain Centre at Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.

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http://dx.doi.org/10.1177/1747493020913088DOI Listing
June 2020

Global Stroke Statistics 2019.

Int J Stroke 2020 10 9;15(8):819-838. Epub 2020 Mar 9.

Stroke and Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.

Background: Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning.

Aims: To provide the most current incidence, mortality and case-fatality data on stroke and describe current availability of stroke units around the world by country.

Methods: We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case-fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population.

Results: Since our last report in 2017, there were two countries with new incidence studies, China ( = 1) and India ( = 2) that met the ideal criteria. New data on case-fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries.

Conclusion: Up-to-date data on stroke incidence, case-fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low-middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.
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http://dx.doi.org/10.1177/1747493020909545DOI Listing
October 2020

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.

JAMA 2020 04;323(13):1257-1265

Department of Medicine, Ballarat Base Hospital, Ballarat, Victoria, Australia.

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.

Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.

Design, Setting, And Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.

Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.

Main Outcomes And Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.

Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]).

Conclusions And Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.

Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.
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http://dx.doi.org/10.1001/jama.2020.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139271PMC
April 2020
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