Medicine (RMH) - Research Publications
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ItemVenous thromboembolism management in Northeast Melbourne: how does it compare to international guidelines and data?(WILEY, 2017-09)BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality with significant heterogeneity in its management, both within our local practice and in international guidelines. AIMS: To provide a holistic evaluation of 'real-world' Australian experience in the warfarin era, including how we compare to international guidelines. METHODS: Retrospective evaluation of VTE from July 2011 to December 2012 at two major hospitals in Melbourne, Australia. These results were compared to recommendations in the international guidelines. RESULTS: A total of 752 episodes involving 742 patients was identified. Contrary to international guidelines, an unwarranted heritable thrombophilia screen was performed in 22.0% of patients, amounting to a cost of AU$29 000. The duration of anticoagulation was longer compared to international recommendations, although the overall recurrence (3.2/100 person-years) and clinically significant bleeding rates (2.4/100 person-years) were comparable to 'real-world' data. Unprovoked VTE (hazard ratio 2.06; P = 0.01) was a risk factor for recurrence, and there was no difference in recurrence between major VTE (proximal deep vein thrombosis (DVT) and/or pulmonary embolism) and isolated distal DVT (3.02 vs 3.94/100 person-years; P = 0.25). Fourteen patients were subsequently diagnosed with malignancy, and patients with recurrent VTE had increased risk of prospective cancer diagnosis (relative risk 6.68; P < 0.001). CONCLUSIONS: While our 'real-world' VTE experience during the warfarin era largely correlates with international guidelines, there remains heterogeneity in the management strategies, including excessive thrombophilia screening and longer duration of anticoagulation. This audit highlights the need for national VTE guidelines, as well as prospective auditing of VTE management, in the direct oral anticoagulant era for future comparison.
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ItemImpact of heart rate on admission on mortality and morbidity in acute ischaemic stroke patients - results from VISTA(WILEY-BLACKWELL, 2016-12)BACKGROUND AND PURPOSE: Elevated heart rate (HR) is associated with worse outcomes in patients with cardiovascular disease. Its predictive value in acute stroke patients is less well established. We investigated the effects of HR on admission in acute ischaemic stroke patients. METHODS: Using the Virtual International Stroke Trials Archive (VISTA) database, the association between HR in acute stroke patients without atrial fibrillation and the pre-defined composite end-point of (recurrent) ischaemic stroke, transient ischaemic attack (TIA), myocardial infarction (MI) and vascular death within 90 days was analysed. Pre-defined secondary outcomes were the composite end-point components and any death, decompensated heart failure and degree of functional dependence according to the modified Rankin Scale after 90 days. HR was analysed as a categorical variable (quartiles). RESULTS: In all, 5606 patients were available for analysis (mean National Institutes of Health Stroke Scale 13; mean age 67 years; mean HR 77 bpm; 44% female) amongst whom the composite end-point occurred in 620 patients (11.1%). Higher HR was not associated with the composite end-point. The frequencies of secondary outcomes were 3.2% recurrent stroke (n = 179), 0.6% TIA (n = 35), 1.8% MI (n = 100), 6.8% vascular death (n = 384), 15.0% any death (n = 841) and 2.2% decompensated heart failure (n = 124). Patients in the highest quartile (HR> 86 bpm) were at increased risk for any death [adjusted hazard ratio (95% confidence interval) 1.40 (1.11-1.75)], decompensated heart failure [adjusted hazard ratio 2.20 (1.11-4.37)] and worse modified Rankin Scale [adjusted odds ratio 1.29 (1.14-1.52)]. CONCLUSIONS: In acute stroke patients, higher HR (>86 bpm) is linked to mortality, heart failure and higher degree of dependence after 90 days but not to recurrent stroke, TIA or MI.
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ItemMaximising data value and avoiding data waste: a validation study in stroke research(AUSTRALASIAN MED PUBL CO LTD, 2019-01-14)OBJECTIVES: To determine the feasibility of linking data from the Australian Stroke Clinical Registry (AuSCR), the National Death Index (NDI), and state-managed databases for hospital admissions and emergency presentations; to evaluate data completeness and concordance between datasets for common variables. DESIGN, SETTING, PARTICIPANTS: Cohort design; probabilistic/deterministic data linkage of merged records for patients treated in hospital for stroke or transient ischaemic attack from New South Wales, Queensland, Victoria, and Western Australia. MAIN OUTCOME MEASURES: Descriptive statistics for data matching success; concordance of demographic variables common to linked databases; sensitivity and specificity of AuSCR in-hospital death data for predicting NDI registrations. RESULTS: Data for 16 214 patients registered in the AuSCR during 2009-2013 were linked with one or more state datasets: 15 482 matches (95%) with hospital admissions data, and 12 902 matches (80%) with emergency department presentations data were made. Concordance of AuSCR and hospital admissions data exceeded 99% for sex, age, in-hospital death (each κ = 0.99), and Indigenous status (κ = 0.83). Of 1498 registrants identified in the AuSCR as dying in hospital, 1440 (96%) were also recorded by the NDI as dying in hospital. In-hospital death in AuSCR data had 98.7% sensitivity and 99.6% specificity for predicting in-hospital death in the NDI. CONCLUSION: We report the first linkage of data from an Australian national clinical quality disease registry with routinely collected data from several national and state government health datasets. Data linkage enriches the clinical registry dataset and provides additional information beyond that for the acute care setting and quality of life at follow-up, allowing clinical outcomes for people with stroke (mortality and hospital contacts) to be more comprehensively assessed.
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ItemComparative Analysis of Markers of Mass Effect after Ischemic Stroke(WILEY, 2018-09)BACKGROUND AND PURPOSE: Midline shift determined on magnetic resonance imaging (MRI) or computed tomography (CT) images is a well-validated marker of mass effect after large hemispheric infarction and associated with mortality. In this study, we targeted a population with moderately sized strokes. We compared midline shift to other imaging markers and determined their ability to predict long-term outcome. METHODS: MRI scans were studied from the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) cohort. Midline shift, acute stroke lesion volume, lesional swelling volume, change in ipsilateral hemisphere volume, the ratio of ipsilateral to contralateral hemisphere volume, and the reduction in lateral ventricle volume were measured. The relationships of these markers with poor outcome (modified Rankin scale score 3-6 at day 90) were assessed. Receiver-operating characteristic (ROC) curves were generated to compare the performance of each metric. RESULTS: Of the 71 included patients, 59.2% had a poor outcome that was associated with significantly larger values for midline shift, lesional swelling volume, and ratio of hemisphere volumes. Lesional swelling volume, change in hemisphere volume, ratio of hemisphere volumes, and lateral ventricle displacement were each correlated with midline shift (Spearman r = .60, .49, .61, and -.56, respectively; all P < .0001). ROC curve analysis showed that lesional swelling volume (area under the curve [AUC] = .791) predicted poor outcome better than midline shift (AUC = .682). For predicting mortality, ROC curve analysis showed that these three markers were equivalent. CONCLUSION: The ratio of ipsilateral to contralateral hemisphere volume, baseline lesion volume and lesional swelling volume best predicted poor outcome across a spectrum of stroke sizes.
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ItemDifferentiating arterial ischaemic stroke from migraine in the paediatric emergency department(WILEY, 2018-11)AIM: To estimate the strengths of association between clinical features and migraine or arterial ischaemic stroke (AIS) in children presenting to the emergency department. METHOD: Eighty-four children with migraine, prospectively recruited from 2009 to 2010, were compared with 55 children with AIS, prospectively/retrospectively recruited from 2003 to 2010. Odds ratios were calculated via logistic regression to measure associations between clinical features and process-of-care factors, and migraine and AIS. RESULTS: Median age was 13 years 5 months (interquartile range 12y 11mo-13y 10mo) for migraine and 5 years (interquartile range 3y 7mo-8y) for patients with AIS. All cases of AIS and 30% of migraine cases underwent neuroimaging. Over 40% of children with migraine had vomiting, numbness, or visual disturbance; other symptoms were uncommon. Fifty-five per cent had no signs on physician assessment. Weakness or speech disturbance were common in patients with AIS. Significant clinical features associated with increased odds of AIS included sudden symptom onset, weakness, seizures, speech disturbance, and ataxia, and signs of face, arm, or leg weakness, inability to walk, dysarthria, dysphasia, and altered consciousness (p<0.05). Significant features associated with decreased odds of AIS included older age, vomiting, visual, sensory, other symptoms, and absent focal signs on assessment (p<0.05). INTERPRETATION: Presenting features can discriminate childhood AIS from migraine. These differences inform decisions about urgency and type of neuroimaging in children presenting to the emergency department with brain attack symptoms. WHAT THE PAPER ADDS: Weakness, seizures, ataxia, speech, or walking difficulties are more frequent in arterial ischaemic stroke (AIS). Vomiting, visual, or sensory disturbance and absent focal signs are more frequent in migraine. Identifying features of AIS and migraine guides neuroimaging in children with brain attack symptoms.
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ItemAntibiotic Class and Outcome in Post-stroke Infections: An Individual Participant Data Pooled Analysis of VISTA-Acute(FRONTIERS MEDIA SA, 2019-05-14)Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection. Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression. Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus β-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002]. Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.
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ItemDependency and health utilities in stroke: Data to inform cost-effectiveness analyses(SAGE PUBLICATIONS LTD, 2017-03)INTRODUCTION: Health utilities (HU) assign preference weights to specific health states and are required for cost-effectiveness analyses. Existing HU for stroke inadequately reflect the spectrum of post-stroke disability. Using international stroke trial data, we calculated HU stratified by disability to improve precision in future cost-effectiveness analyses. MATERIALS AND METHODS: We used European Quality of Life Score (EQ-5D-3L) data from the Virtual International Stroke Trials Archive (VISTA) to calculate HU, stratified by modified Rankin Scale scores (mRS) at 3 months. We applied published value sets to generate HU, and validated these using ordinary least squares regression, adjusting for age and baseline National Institutes of Health Stroke Scale (NIHSS) scores. RESULTS: We included 3858 patients with acute ischemic stroke in our analysis (mean age: 67.5 ± 12.5, baseline NIHSS: 12 ± 5). We derived HU using value sets from 13 countries and observed significant international variation in HU distributions (Wilcoxon signed-rank test p < 0.0001, compared with UK values). For mRS = 0, mean HU ranged from 0.88 to 0.95; for mRS = 5, mean HU ranged from -0.48 to 0.22. OLS regression generated comparable HU (for mRS = 0, HU ranged from 0.9 to 0.95; for mRS = 5, HU ranged from -0.33 to 0.15). Patients' mRS scores at 3 months accounted for 65-71% of variation in the generated HU. CONCLUSION: We have generated HU stratified by dependency level, using a common trial endpoint, and describing expected variability when applying diverse value sets to an international population. These will improve future cost-effectiveness analyses. However, care should be taken to select appropriate value sets.
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ItemDiscovery and Longitudinal Evaluation of Candidate Biomarkers for Ischaemic Stroke by Mass Spectrometry-Based Proteomics(SAGE PUBLICATIONS LTD, 2017-12-20)Application of acute therapies such as thrombolysis for ischaemic stroke (IS) is constrained because of diagnostic uncertainty and the dynamic nature of stroke biology. To investigate changes in blood proteins after stroke and as a result of thrombolysis treatment we performed label-free quantitative proteomics on serum samples using high-resolution mass spectrometry and long high-performance liquid chromatography gradient (5 hours) combined with a 50-cm column to optimise the peptide separation. We identified (false discovery rate [FDR]: 1%) and quantified a total of 574 protein groups from a total of 92 samples from 30 patients. Ten patients were treated by thrombolysis as part of a randomised placebo-controlled trial and up to 5 samples were collected from each individual at different time points after stroke. We identified 26 proteins differently expressed by treatment group (FDR: 5%) and significant changes of expression over time for 23 proteins (FDR: 10%). Molecules such as fibrinogen and C-reactive protein showed expression profiles with a high-potential clinical utility in the acute stroke setting. Protein expression profiles vary acutely in the blood after stroke and have the potential to allow the construction of a stroke clock and to have an impact on IS treatment decision making.
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ItemNo Preview AvailableTreating the acute stroke patient as an emergency: current practices and future opportunities(WILEY, 2006-04)Developments in acute stroke therapy have followed advances in the understanding of the evolving pathophysiology in both ischaemic stroke and intracerebral haemorrhage (ICH). In ischaemic stroke, rapid reperfusion of the ischaemic penumbra with thrombolysis within 3 h of symptom onset is of proven benefit, but few patients currently receive therapy, mainly due to the short-time window and lack of stroke expertise. In ICH, a recent study indicated that a haemostatic agent can limit ongoing bleeding and improve outcomes when administered within 4 h of stroke onset. These advances in acute stroke therapy underlie the concept that 'time is brain' and that urgent intervention can limit cerebral damage. Neuroprotective therapy could offer the prospect of a greater proportion of stroke patients receiving treatment, potentially before imaging and even in the ambulance setting. Virtually all stroke patients would benefit from receiving multidisciplinary care in acute stroke units.
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ItemWhere Will the Next Generation of Stroke Treatments Come From?(PUBLIC LIBRARY SCIENCE, 2010-03)Remarkable progress has occurred over the last two decades in stroke interventions. Many have been developed on the basis of their efficacy in other disorders. This "inheritance" approach should continue, but two areas where completely novel therapeutic targets might emerge are the stimulation of neuroplasticity and unraveling the genetic code of stroke heterogeneity (Table 2). For the former, the next steps are to identify small-molecule, nontoxic compounds that most effectively enhance plasticity in animal models, and then subject them to clinical trial in humans. For the latter, more and larger-scale cooperative GWASs in carefully phenotyped stroke populations are required to better understand the polygenic nature of cerebrovascular disease. Then, the physiological relevance of genetic abnormalities can be determined in in vitro and in vivo systems before candidate compounds are developed.
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