Browsing by Author "Anderson, Craig S."
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Item Acute Treatment of Stroke (Except Thrombectomy)(2018) Muñoz, Paula; Appleton, Jason P.; Anderson, Craig S.; Bath, Philip M.Purpose of Review The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials. Recent Findings Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this everexpanding area. Summary Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the individual.Publication Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis- Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study(2022) Wang, Xia; Minhas, Jatinder S.; Moullaali, Tom J.; Di Tanna, Gian Luca; Lindley, Richard I.; Chen, Xiaoying; Arima, Hisatomi; Chen, Guofang; Delcourt, Candice; Bath, Philip M.; Broderick, Joseph P.; Demchuk, Andrew M.; Donnan, Geoffrey A.; Durham, Alice C.; Lavados, Pablo; Lee, Tsong-Hai; Levi, Christopher; Martins, Sheila O.; Olavarría, Verónica V.; Pandian, Jeyaraj D.; Parsons, Mark W.; Pontes-Neto, Octavio M.; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay K.; Silva, Federico; Thang, Nguyen H.; Wang, Ji-Guang; Woodward, Mark; Chalmers, John; Song, Lili; Anderson, Craig S.; Robinson, Thompson G.BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150–180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130–140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1–24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71–0.82]; P<0.001 and 0.86 [95% CI, 0.76–0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93– 1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06–1.31]; P=0.002 and 1.34 [1.11–1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98–1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients.Publication Bundled care to optimize outcome after intracerebral hemorrhage: action for effective implementation(2023) Ouyang, Menglu; Anderson, Craig S.Patients who experience acute intracerebral hemorrhage (ICH) are not managed with urgency or level of coordinated care as those with acute ischemic stroke. This is largely due to the lack of any proven treatment for ICH, which has led to therapeutic nihilism and a low threshold for the withdrawal of active care in these patients. The third Intensive Care Bundle with Blood Pres sure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3) is a landmark study which used a novel, quality improvement, implementation design across 122 hospitals in 10 countries, to show that the early intervention of bundled care with time- and target-based metrics, can substantially improve outcomes for patients who suffer ICH. We advocate the widespread adoption of an early bundle of care focused on urgent time-based metrics for the control of elevated blood pressure and other abnormal physiological parameters, and the emergency reversal of anticoagulation, for patients with ICH. Such coordinated interdisciplinary stroke care will optimise the chances of patients all over the world surviving free of major disability after suffering an ICH.Item Ethnicity and Other Determinants of Quality of Functional Outcome in Acute Ischemic Stroke(2020) Chen, Xiaoying; Wang, Xia; Delcourt, Candice; Li, Jingwei; Arima, Hisatomi; Hackett, Maree L; Lavados, Pablo; Lindley, Richard I.; Chalmers, John; Robinson, Thompson; Anderson, Craig S.Background and Purpose— Patient-centered outcomes are important. We aimed to determine predictors of health-related quality of life (HRQoL) and develop utility-weighted modified Rankin Scale (mRS) scores in thrombolyzed acute ischemic stroke patients from both arms of ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods— ENCHANTED was an international quasi-factorial clinical trial of different doses of intravenous alteplase and intensities of blood pressure control in acute ischemic stroke patients, with outcomes on the 5-Dimensional European Quality of Life Scale and mRS assessed at 90 days post-randomization. Logistic regression models were used to identify baseline predictors of poor HRQoL (≤mean 5-Dimensional European Quality of Life Scale utility scores). Ordinary least squares regression derived utility-weighted mRS scores. Results— In 4016 acute ischemic stroke patients with complete 5-Dimensional European Quality of Life Scale and mRS data, independent predictors of poor HRQoL were older age (odds ratio, 1.19 [95% CI, 1.12–1.27], per 10-year increase), non-Asian ethnicity (1.91 [1.61–2.27]), greater stroke severity on the National Institutes of Health Stroke Scale (1.11 [1.09–1.12]), diabetes mellitus (1.41 [1.18–1.69]), premorbid disability (mRS score 1 versus 0; 1.62 [1.33–1.97]), large vessel atheromatous pathogenesis (1.32 [1.12–1.54]), and proxy respondent (2.35 [2.01–2.74]). Sensitivity analyses indicate the ethnicity influence on HRQoL was driven by the high proportion of Chinese (62.9% of Asian) participants with better HRQoL compared with non-Chinese or other Asian groups. Derived utility values across mRS scores 0 to 5 were 0.977, 0.885, 0.748, 0.576, 0.194, and −0.174, respectively. Correlations between mRS and 5-Dimensional European Quality of Life Scale scores were stronger in Asians. Conclusions— HRQoL is worse after thrombolyzed acute ischemic stroke in the elderly, non-Asians, with greater initial severity, diabetes mellitus, premorbid disability, due to large vessel atheroma, and proxy assessment. The broader significance of better HRQoL in Asians is tempered by Chinese participants dominating analyses. From utility-weighted mRS scores indicating the greatest steps in mRS scores are between 5 and 3, treatments to avoid major disability provide the greatest benefits for patients.Item Influence of Including Patients with Premorbid Disability in Acute Stroke Trials: The HeadPoST Experience(2021) Wang, Xia; Moullaali, Tom J.; Ouyang, Menglu; Billot, Laurent; Sandset, Else Charlotte; Song, Lili; Delcourt, Candice; Hackett, Maree L.; Watkins, Caroline L.; Robinson, Thompson G.; Yang, Jie; Lavados, Pablo; Brunser, Alejandro; Muñoz Venturelli, Paula; Olavarría, Verónica; Arima, Hisatomi; Middleton, Sandy; Pontes-Neto, Octávio M.; Pandian, Jeyaraj Durai; Rogers; Rogers, Kris; Anderson, Craig S.Background: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. Methods: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 ("early ΔmRS"), and poor outcome (mRS score 3-6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0-1 versus 2-5. Results: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2-5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14-1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. Conclusions: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect.Item INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge clusterrandomized controlled trial(2021) Song, Lili; Hu, Xin; Ma, Lu; Chen, Xiaoying; Ouyang, Menglu; Billot, Laurent; Li, Qiang; Muñoz Venturelli, Paula; Abanto, Carlos; Pontes-Neto, Octavio M.; Arauz, Antonio; Wasay, Mohammad; Silva, Asita de; Nguyen, Huy Thang; Pandian, Jeyaraj Durai; Wahab, Kolawole Wasiu; You, Chao; Anderson, Craig S.; INTERACT3 investigatorsBackground: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH. Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), clusterrandomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1–7.8 mmol/L and 7.8– 10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7- day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions. Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established. Trial registration: ClinicalTrials.gov NCT03Item Low blood pressure and adverse outcomes in acute stroke: HeadPoSTstudy explanations(2021) Muñoz Venturelli, Paula; Billota, Laurent; Wang, Xia; Ouyang, Menglu; Song, Lili; Arima, Hisatomi; Lavados, Pablo; Hackett, Maree L.; Olavarría, Verónica V.; Brunser, Alejandro; Middleton, Sandy; Pontes-Neto, Octavio M.; Lee, Tsong-Hai; Watkins, Caroline L.; Robinson, Thompson; Anderson, Craig S.Objective: As uncertainties exist over underlying causes, we aimed to define the characteristics and prognostic significance of low blood pressure (BP) early after the onset of acute stroke. Methods: Post hoc analyzes of the international Head Positioning in acute Stroke Trial (HeadPoST), a pragmatic cluster-crossover randomized trial of lying flat versus sitting up in stroke patients from nine countries during 2015-2016. Associations of baseline BP and death or dependency [modified Rankin scale (mRS) scores 3-6] and serious adverse events (SAEs) at 90 days were assessed in generalized linear mixed models with adjustment for multiple confounders. SBP and DBP was analysed as continuous measures fitted with a cubic spline, and as categorical measures with low (<10th percentile) and high (≥140 and ≥90 mmHg, respectively) levels compared with a normal range (≥10th percentile; 120-139 and 70-89 mmHg, respectively). Results: Among 11 083 patients (mean age 68 years, 39.9% women) with baseline BP values, 7.2 and 11.7% had low SBP (<120 mmHg) and DBP (<70 mmHg), respectively. Patients with low SBP were more likely to have preexisting cardiac and ischemic stroke and functional impairment, and to present earlier with more severe neurological impairment than other patients. Nonlinear 'J-shaped' relationships of BP and poor outcome were apparent: compared with normal SBP, those with low SBP had worse functional outcome (adjusted odds ratio 1.27, 95% confidence interval 1.02-1.58) and more SAEs, particularly cardiac events, with adjustment for potential confounders to minimize reverse causation. The findings were consistent for DBP and were stronger for ischemic rather than hemorrhagic stroke. Conclusion: The prognostic significance of low BP on poor outcomes in acute stroke was not explained by reverse causality from preexisting cardiovascular disease, and propensity towards greater neurological deficits and cardiac events. These findings provide support for the hypothesis that low BP exacerbates cardiac and cerebral ischemia in acute ischemic stroke.Item Quantifying regional variations in components of acute stroke unit (ASU) care in the international HeadPoST study(2020) Ouyang, Menglu; Zhang, Yao; Wang, Xia; Song, Lili; Billot, Laurent; Robinson, Thompson; Lavados, Pablo; Arima, Hisatomi; Hackett, Maree L.; Olavarría, Verónica; Muñoz Venturelli, Paula; Middleton, Sandy; Watkins, Caroline L.; Pontes-Neto, Octavio M.; Lee, Tsong-Hai; Brunser, Alejandro; Anderson, Craig S.Objective: Access to acute stroke unit (ASU) care is known to vary worldwide. We aimed to quantify regional variations in the various components of ASU care. Method: Secondary analysis of the Head Positioning in acute Stroke Trial (HeadPoST), an international, multicentre, cluster crossover trial of head-up versus head-down positioning in 11,093 acute stroke patients at 114 hospitals in 9 countries. Patients characteristics and 11 standard components of processes of care were described according to ASU admission within and across four economically-defined regional groups (Australia/UK, China [includes Taiwan], India/Sri Lanka, and South America [Brazil/Chile/Colombia]). Variations in process of ASU care estimates were obtained in hierarchical mixed models, with adjustment for study design and potential patient- and hospital-level confounders. Results: Of 11,086 patients included in analyses, 59.7% (n = 6620) had an ASU admission. In China, India/Sri Lanka and South America, ASU patients were older, had greater neurological severity and more premorbid conditions than non-ASU patients. ASU patients were more likely to receive reperfusion therapy and multidisciplinary care within regions, but the components of care varied across regions. With Australia/UK as reference, patients in other regions had a lower probability of receiving reperfusion therapy, especially in India/Sri Lanka (adjusted odds ratio [aOR] 0.27, 95% confidence interval [CI] 0.12–0.63) and multidisciplinary care (mainly in formal dysphagia assessment, physiotherapy and occupational therapy). Conclusion: There is significant variation in the components of stroke care across economically-defined regions of the world. Ongoing efforts are required to reduce disparities and optimise health outcomes, especially in resource poor areas.Item Withdrawal of active treatment after intracerebral haemorrhage in the INTERACT2 study(2017) Muñoz Venturelli, Paula; Wang, Xia; Zahuranec, Darin B.; Lavados, Pablo; Stapf, Christian; Lindley, Richard; Delcourt, Candice; Chalmers, John; Anderson, Craig S.; Robinson, Thompson G.; THOMPSON G. ROBINSON8, THOMPSON G. ROBINSON8 , FOR THE INTERACT2 INVESTIGATORSBackground: in the second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2), a minority of patients received withdrawal of active treatment (WAT). We wished to determine the characteristics of these patients, and the relation of this decision-making to subsequent management and final outcome. Methods: the INTERACT2 cohort of acute intracerebral haemorrhage (ICH) patients had a decision of WAT within 7 days after hospital admission recorded. Multivariable logistic regression was used to identify the determinants of WAT and poor outcome at 90 days, defined by modified Rankin scale (mRS) scores 3–6. Results: of 2,779 participants with available data, WAT occurred in 121 (4%) and this was significantly associated with increasing age, greater neurological severity, larger haematoma volume, intraventricular extension and randomisation to intensive BP lowering. Compared to other patients, those with WAT had greater mortality (81/121 [67%] versus 205/2624 [8%]; P < 0.001) and survivors were more likely to be severely disabled (mRS score 4–5, 19/39 [49%] versus 695/2419 [29%]; P = 0.006). Conclusions: WAT was undertaken in patients with recognised predictors of poor prognosis, who subsequently were more likely to die or be left with severe disability. Improved understanding of specific factors determining WAT in ICH patients might improve care delivery and outcomes. Clinical Trial Registration: the INTERACT2 study is registered with ClinicalTrials.gov (NCT00716079).