Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Cost-effectiveness of mechanical thrombectomy for acute ischemic stroke in Brazil: Results from the RESILIENT trial.

BACKGROUND: The RESILIENT trial demonstrated the clinical benefit of mechanical thrombectomy in patients presenting acute ischemic stroke secondary to anterior circulation large vessel occlusion in Brazil. AIMS: This economic evaluation aims to assess the cost-utility of mechanical thrombectomy in the RESILIENT trial from a public healthcare perspective. METHODS: A cost-utility analysis was applied to compare mechanical thrombectomy plus standard medical care (n = 78) vs. standard medical care alone (n = 73), from a subset sample of the RESILIENT trial (151 of 221 patients). Real-world direct costs were considered, and utilities were imputed according to the Utility-Weighted modified Rankin Score. A Markov model was structured, and probabilistic and deterministic sensitivity analyses were performed to evaluate the robustness of results. RESULTS: The incremental costs and quality-adjusted life years gained with mechanical thrombectomy plus standard medical care were estimated at Int$ 7440 and 1.04, respectively, compared to standard medical care alone, yielding an incremental cost-effectiveness ratio of Int$ 7153 per quality-adjusted life year. The deterministic sensitivity analysis demonstrated that mRS-6 costs of the first year most affected the incremental cost-effectiveness ratio. After 1000 simulations, most of results were below the cost-effective threshold. CONCLUSIONS: The intervention's clear long-term benefits offset the initially higher costs of mechanical thrombectomy in the Brazilian public healthcare system. Such therapy is likely to be cost-effective and these results were crucial to incorporate mechanical thrombectomy in the Brazilian public stroke centers.

Contrast optimization in arterial spin labeling with multiple post-labeling delays for cerebrovascular assessment.

OBJECTIVE: Improving the readout for arterial spin labeling with multiple post-labeling delays (multi-PLD ASL) through a flip angle (FA) sweep towards increasing contrast-to-noise ratio for long PLD images. METHODS: Images were acquired from 20 healthy subjects and 14 patients with severe, asymptomatic carotid artery stenosis (ACAS) in a 3T MRI scanner. Multi-PLD ASL images with conventional and proposed (FA sweep) readouts were acquired. For patients, magnetic resonance angiography was used to validate the multi-PLD ASL results. Perfusion values were calculated for brain regions irrigated by the main cerebral arteries and compared by analysis of variance. RESULTS: For healthy subjects, better contrast was obtained for long PLDs when using the proposed multi-PLD method compared to the conventional. For both methods, no hemispheric difference of perfusion was observed. For patients, the proposed method facilitated the observation of delayed tissue perfusion, which was not visible for long PLD using the conventional multi-PLD ASL. CONCLUSION: We successfully assessed brain perfusion of patients with asymptomatic CAS using multi-PLD ASL with FA sweep. We were able to show subtle individual differences. Moreover, prolonged arterial transit time in patients was observed, although they were considered asymptomatic, suggesting that it may not be an adequate term to characterize them.

Clinical swallowing assessment in the diagnosis of silent aspiration / Avaliação clínica da deglutição no diagnóstico da aspiração silente

ABSTRACT Purpose: to identify, in the clinical assessment of swallowing, signs indicating silent aspiration in ischemic stroke patients. Methods: forty-six patients were assessed, 17 days being the mean time elapsed from the stroke to the swallowing assessment. The clinical assessment encompassed structural and functional aspects, oximetry monitoring, and cervical auscultation. During the videofluoroscopy examination, the patients were also monitored with pulse oximetry. In both assessments, the patients were given 100 ml of liquid. In the statistical analysis, the exact logistic regression test and odds ratio calculation were used, with a 0.05 significance level. Results: seven, out of the 46 patients, presented aspiration, which was silent in six of them. Change in the cervical auscultation, in the clinical assessment (OR: 18.8; 95% CI: 1.2 - 1000, p = 0.03), was associated with silent aspiration, as detected in the videofluoroscopy. The hawking present in the analysis of the recording (OR: 12.2; 95% CI: 1.23 - ∞, p = 0.03), was associated with possible non-silent laryngotracheal penetrations and aspirations. No change was identified regarding oxygen saturation in patients presented with silent aspiration. Conclusion: the change in cervical auscultation observed in the clinical assessment can indicate silent aspiration in patients affected by an ischemic stroke.

RESUMO Objetivo: identificar sinais na avaliação clínica da deglutição que indiquem aspiração silente em pacientes com acidente vascular cerebral isquêmico. Métodos: foram avaliados 46 pacientes. O tempo médio entre a ocorrência do acidente e a avaliação da deglutição foi de 17 dias. A avaliação clínica abarcou aspectos estruturais e funcionais, monitoração da oximetria e ausculta cervical. Durante o exame de videofluoroscopia os pacientes foram monitorados por meio da oximetria de pulso. Em ambas avaliações os pacientes ingeriram 100 ml de líquido. Na análise estatística foi utilizado o teste de regressão logística exata e o cálculo do Odds Ratio (OR), com nível de significância de 0,05. Resultados: dos 46 pacientes, sete apresentaram aspiração, sendo silente em seis. A alteração da ausculta cervical na avaliação clínica (OR: 18,8; IC 95%: 1,2 - 1000, p=0,03) associou-se à aspiração silente detectada na videofluoroscopia. O pigarro presente na análise da filmagem (OR: 12,2; IC 95%: 1,23 - ∞, p=0,03) foi associado a possíveis penetrações e aspiração laringotraqueais não silentes. Não foi identificada alteração no nível de saturação de oxigênio nos pacientes com aspiração silente. Conclusão: alteração da ausculta cervical observada na avaliação clínica pode indicar aspiração silente em pacientes acometidos por acidente vascular cerebral isquêmico.

Priorities to reduce the burden of stroke in Latin American countries.

The large and increasing burden of stroke in Latin American countries, and the need to meet the UN and WHO requirements for reducing the burden from non-communicable disorders (including stroke), brought together stroke experts and representatives of the Ministries of Health of 13 Latin American countries for the 1st Latin American Stroke Ministerial meeting in Gramado, Brazil, to discuss the problem and identify ways of cooperating to reduce the burden of stroke in the region. Discussions were focused on the regional and country-specific activities associated with stroke prevention and treatment, including public stroke awareness, prevention strategies, delivery and organisation of care, clinical practice gaps, and unmet needs. The meeting culminated with the adoption of the special Gramado Declaration, signed by all Ministerial officials who attended the meeting. With agreed priorities for stroke prevention, treatment, and research, an opportunity now exists to translate this Declaration into an action plan to reduce the burden of stroke.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Assessment of the Predictive Validity of Etiologic Stroke Classification.

Importance: The ability of present-day etiologic stroke classification systems to generate subtypes with discrete stroke characteristics is not known. Objective: To test the hypothesis that etiologic stroke subtyping identifies different disease processes that can be recognized through their different clinical courses. Design, Setting, and Participants: We performed a head-to-head evaluation of the ability of the Causative Classification of Stroke (CCS), Trial of Org 10172 in Acute Stroke Treatment (TOAST), and ASCO (A for atherosclerosis, S for small-vessel disease, C for cardiac source, and O for other cause) classification systems to generate etiologic subtypes with different clinical, imaging, and prognostic characteristics in 1816 patients with ischemic stroke. This study included 2 cohorts recruited at separate periods; the first cohort was recruited between April 2003 and June 2006 and the second between June 2009 and December 2011. Data analysis was performed between June 2014 and May 2016. Main Outcomes and Measures: Separate teams of stroke-trained neurologists performed CCS, TOAST, and ASCO classifications based on information available at the time of hospital discharge. We assessed the association between etiologic subtypes and stroke characteristics by computing receiver operating characteristic curves for binary variables (90-day stroke recurrence and 90-day mortality) and by calculating the ratio of between-category to within-category variability from the analysis of variance for continuous variables (admission National Institutes of Health Stroke Scale score and acute infarct volume). Results: Among the 1816 patients included, the median age was 70 years (interquartile range, 58-80 years) (830 women [46%]). The classification systems differed in their ability to assign stroke etiologies into known subtypes; the size of the undetermined category was 33% by CCS, 53% by TOAST, and 42% by ASCO (P < .001 for all binary comparisons). All systems provided significant discrimination for the validation variables tested. For the primary validation variable (90-day recurrence), the area under the receiver operating characteristic curve was 0.71 (95% CI, 0.66-0.75) for CCS, 0.61 (95% CI, 0.56-0.67) for TOAST, and 0.66 (95% CI, 0.60-0.71) for ASCO (P = .01 for CCS vs ASCO; P < .001 for CCS vs TOAST; P = .13 for ASCO vs TOAST). The classification systems exhibited similar discrimination for 90-day mortality. For admission National Institutes of Health Stroke Scale score and acute infarct volume, CCS generated more distinct subtypes with higher between-category to within-category variability than TOAST and ASCO. Conclusions and Relevance: Our findings suggest that the major etiologic stroke subtypes are distinct categories with different stroke characteristics irrespective of the classification system used to identify them. We further show that CCS generates discrete etiologic categories with more diverse clinical, imaging, and prognostic characteristics than either TOAST or ASCO.

Regional variation in acute stroke care organisation.

BACKGROUND: Few studies have assessed regional variation in the organisation of stroke services, particularly health care resourcing, presence of protocols and discharge planning. Our aim was to compare stroke care organisation within middle- (MIC) and high-income country (HIC) hospitals participating in the Head Position in Stroke Trial (HeadPoST). METHODS: HeadPoST is an on-going international multicenter crossover cluster-randomized trial of 'sitting-up' versus 'lying-flat' head positioning in acute stroke. As part of the start-up phase, one stroke care organisation questionnaire was completed at each hospital. The World Bank gross national income per capita criteria were used for classification. RESULTS: 94 hospitals from 9 countries completed the questionnaire, 51 corresponding to MIC and 43 to HIC. Most participating hospitals had a dedicated stroke care unit/ward, with access to diagnostic services and expert stroke physicians, and offering intravenous thrombolysis. There was no difference for the presence of a dedicated multidisciplinary stroke team, although greater access to a broad spectrum of rehabilitation therapists in HIC compared to MIC hospitals was observed. Significantly more patients arrived within a 4-h window of symptoms onset in HIC hospitals (41 vs. 13%; P<0.001), and a significantly higher proportion of acute ischemic stroke patients received intravenous thrombolysis (10 vs. 5%; P=0.002) compared to MIC hospitals. CONCLUSIONS: Although all hospitals provided advanced care for people with stroke, differences were found in stroke care organisation and treatment. Future multilevel analyses aims to determine the influence of specific organisational factors on patient outcomes.

Validation of a structured interview for telephone assessment of the modified Rankin Scale in Brazilian stroke patients.

BACKGROUND: The modified Rankin Scale (mRS) is a commonly used scale to assess the functional outcome after stroke. Several studies on mRS showed good reliability, feasibility, and interrater agreement of this scale using a face-to-face assessment. However, telephone assessment is a more time-efficient way to obtain an mRS grade than a face-to-face interview. The aim of this study was to validate the telephone assessment of mRS among the Portuguese using a structured interview in a sample of Brazilian stroke patients. METHODS: We evaluated 50 stroke outpatients twice. The first interview was face-to-face and the second was made by telephone and the time between the two assessments ranged between 7 and 14 days. Four certified raters evaluated the patients using a structured interview based on a questionnaire previously published in the literature. Raters were blinded for the Rankin score given by the other rater. For both assessments, the rater could also interview a caregiver if necessary. RESULTS: The patients' mean age was 62.8 ± 14.7, mean number of years of study 5.2 ± 3.4, 52% were males, 55.2% of patients needed a caregiver's help to answer the questions. The majority of caregivers were female (85%), mean age 49.1 ± 15, and mean number of years of study 8.3 ± 3.4. Perfect agreement between the telephone and face-to-face assessments was obtained for 27 (54%) patients, corresponding to an unweighted Kappa of 0.44 (95% CI 0.27-0.61) and a weighted Kappa of 0.89. The median of telephone assessment mRS was 3.5 (interquartile range = 2-4) and of face-to-face assessment was 4 (interquartile range = 2-5). There was no difference between the two assessments (Wilcoxon test, p = 0.35). CONCLUSIONS: Despite the low education level of our sample, the telephone assessment of functional impairment of stroke patients using a translated and culturally adapted Brazilian Portuguese version of the mRS showed good validity and reliability. Therefore, the telephone assessment of mRS can be used in clinical practice and scientific studies in Brazil.

Past, present, and future of stroke in middle-income countries: the Brazilian experience.

BACKGROUND: Stroke is one of the major public health challenges in middle-income countries. Brazil is the world's sixth largest economy but was clearly behind the milestones in the fight against stroke, which is the leading cause of death and disability in the country. Nevertheless, many initiatives are now reshaping stroke prevention, care, and rehabilitation in the country. AIMS: The present article discusses the evolution of stroke care in Brazil over the last decade. METHODS: We describe the main characteristics of stroke care before 2008; a pilot study in a Southern Brazilian city between 2008 and 2010, the Brazilian Stroke Project initiative; and the 2012 National Stroke Policy Act. RESULTS: The National Stroke Project was followed by a major increased on the number of stroke center in the country. The key elements of the 2012 National Stroke Policy Act included: definition of the requirements and levels of stroke centers; improved reimbursement for stroke care; promotion of stroke telemedicine; definition of the Line of Stroke Care (to integrate available resources and other health programs); increased funding for stroke rehabilitation; funding for training of healthcare professionals and initiatives to increase awareness about stroke within the population. CONCLUSIONS: The evolution of stroke care in Brazil over the last decade is a pathway that exemplifies the challenges that middle-income countries have to face in order to improve stroke prevention, treatment and rehabilitation. The reported Brazilian experience can be extrapolated to understand the past, present, and future of stroke care in middle-income countries.