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.

Incidence, risk factors, prognosis, and health-related quality of life after stroke in a low-resource community in Chile (ÑANDU): a prospective population-based study.

BACKGROUND: Stroke is a leading cause of disability and death worldwide. The best estimates of local, national, and global burden of stroke are derived from prospective population-based studies. We aimed to investigate the incidence, risk factors, long-term prognosis, care, and quality of life after stroke in the Ñuble region of Chile. METHODS: We did a prospective community-based study with use of multiple overlapping sources of hospitalised, ambulatory, and deceased cases. Standardised diagnostic criteria were used to identify and follow up all cases occurring in the resident population of the Ñuble region, Chile (in a low-income rural-urban population including predominantly people of Indigenous-European heritage), for 1 year. Participants were included if they had a clinical diagnosis of stroke confirmed according to the study criteria. All cases were adjudicated by vascular neurologists. Incidence rates of first-ever stroke were calculated from the population of Ñuble according to the 2017 national census. FINDINGS: From April 1, 2015, to March 31, 2016, we ascertained 1103 stroke cases, of which 890 (80·7%) were first-ever incident cases. The mean age of patients with first-ever stroke was 70·3 years (SD 14·1) and 443 (49·8%) were women. A CT scan was obtained in 801 (90%) of 890 patients (mean time from symptom onset to scan of 13·4 h (SD 29·8). The incidence of first-ever stroke age-adjusted to the world population was 121·7 (95% CI 113·7-130·1) per 100 000. The age-adjusted incidence rates, per 100 000 inhabitants, by main pathological subtypes were as follows: ischaemic stroke (101·5 [95% CI 90·9-113·0]); intracerebral haemorrhage (17·9 [13·5-23·4]), and subarachnoid haemorrhage (4·2 [2·1-7·3]). The 30-day case-fatality rate was 24·6% (21·9-27·6). At 6 months after the stroke, 55·9% (432 of 773) of cases had died or were disabled, which increased to 61·0% (456 of 747) at 12 months. Health-related quality of life in survivors was low at 6 months, improving slightly at 12 months after the stroke. INTERPRETATION: The incidence of stroke in this low-resource population was higher than our previous finding in northern Chile and within the mid-range of most population-based stroke studies. This result was due mainly to a higher incidence of ischaemic stroke, probably associated with increasing age and a high prevalence of cardiometabolic risk factors in the population studied. Our findings suggest that more should be done for the prevention and care of stroke in communities like the Ñuble population. FUNDING: The National Agency for Research and Development and the Technology-Health Research Fund, Clínica Alemana de Santiago, Boehringer Ingelheim, Bristol Meyers Squibb, The Herminda Martin Clinical Hospital of Chillán, Universidad Mayor, and Universidad de Concepción.

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.

Prevention of stroke: a global perspective.

Along with the rising global burden of disability attributed to stroke, costs of stroke care are rising, providing the impetus to direct our research focus towards effective measures of stroke prevention. In this Series paper, we discuss strategies for reducing the risk of the emergence of disease (primordial prevention), preventing the onset of disease (primary prevention), and preventing the recurrence of disease (secondary prevention). Our focus includes global strategies and campaigns, and measurements of the effectiveness of worldwide preventive interventions, with an emphasis on low-income and middle-income countries. Our findings reveal that effective tobacco control, adequate nutrition, and development of healthy cities are important strategies for primordial prevention, whereas polypill strategies, use of mobile technology (mHealth), along with salt reduction and other dietary interventions, are effective in the primary prevention of stroke. An effective collaboration between various health-care sectors, government policies, and campaigns can successfully implement secondary prevention strategies, through surveillance and registries, such as the WHO's non-communicable diseases programmes, across high-income and low-income countries.

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.

Impact of living and socioeconomic characteristics on cardiovascular risk in ischemic stroke patients.

OBJECTIVE: We aimed to stratify the risk of vascular event recurrence in patients with cerebral infarction according to living and socioeconomic characteristics and geographic region. METHOD: The Outcomes in Patients with TIA and Cerebrovascular Disease (OPTIC) study is an international prospective study of patients aged 45 years or older who required secondary prevention of stroke [following either an acute transient ischemic attack, minor ischemic strokes, or recent (less than six-months previous), stable, first-ever, nondisabling ischemic stroke]. A total 3635 patients from 245 centers in 17 countries in four regions (Latin America, Middle East, North Africa, South Africa) were enrolled between 2007 and 2008. The outcome measure was the two-year rate of a composite of major vascular events (vascular death, myocardial infarction and stroke). RESULTS: During the two-year follow-up period, 516 patients experienced at least one major cardiovascular event, resulting in an event rate of 15·6% (95% confidence interval 14·4-16·9%). Event rates varied across geographical region (P < 0·001), ranging from 13·0% in Latin America to 20·7% in North Africa. Unemployment status, living in a rural area, not living in fully serviced accommodation (i.e., house or apartment with its own electricity, toilet and water supply), no health insurance coverage, and low educational level (less than two-years of schooling) were predictors of major vascular events. Major vascular event rates steeply increased with the number of low-quality living/socioeconomic conditions (from 13·4% to 47·9%, adjusted P value for trend <0·001). CONCLUSION: Vascular risk in stroke patients in low- and middle-income countries varies not only with the number of arterial beds involved but also with socioeconomic variables.

Short- and long-term survival after stroke in hospitalized patients in Chile: a nationwide 5-year study.

BACKGROUND: Short- and long-term stroke survival is a key indicator of hospital performance in stroke care. Our aim was to estimate short- and long-term survival rates in discharged patients diagnosed with ischemic stroke in Chile in a 5-year period and identify associated variables. MATERIALS AND METHODS: We included all discharged patients from all hospitals in Chile with main diagnosis of ischemic stroke from 2003 to 2007, which were identified through the National Hospital Discharge Registry. To establish survival, discharges were linked to deaths in the Deaths Registry. Kaplan-Meier survival curves were used to estimate the cumulative 7-day, 30-day, 1-year, and 3-year survival rates. Independent predictors of death (sex, age, geographical regions, and status insurance) were assessed by Cox proportional hazard regression model. RESULTS: A total of 51,130 with first-ever ischemic stroke patients were identified. Overall survival rate decreased from 88.9% (95% confidence interval [CI] 88.6-89.2) 7 days after hospital admission to 81.9% (95% CI 81.6-82.3), 69.9% (95% CI 69.5-70.3), and 61.2% (95% CI 60.7-61.6) after 30-day, 1-year, and 3-year, respectively. The multivariable model showed that the elderly patients (>80 years; hazard ratio [HR] 4.07; 95% CI 3.89-4.26) and hospital admission in the North (HR 1.14; 95% CI 1.09-1.20) and South area (HR 1.06; 95% CI 1.03-1.110) were associated with lower survival after stroke. Patients with private health insurance have a higher probability of survival than patients with public insurance (private insurance, HR .53; 95% CI .49-.56). CONCLUSIONS: Short- and long-term survival after ischemic stroke was heterogeneous by geographic regions and type of health insurance, regardless age and sex were the strongest predictors. This suggests an impact of socioeconomic factors and access to acute management of strokes on survival.

Demographics, socio-economic characteristics, and risk factor prevalence in patients with non-cardioembolic ischaemic stroke in low- and middle-income countries: the OPTIC registry.

BACKGROUND: There is a paucity of data on patients with stroke/transient ischaemic attack in low- and middle-income countries. We sought to describe the characteristics and management of patients with an ischaemic stroke and recent transient ischaemic attack or minor ischaemic strokes in low- or middle-income countries. METHODS: The Outcomes in Patients with TIA and Cerebrovascular disease registry is an international, prospective study. Patients ≥ 45 years who required secondary prevention of stroke (either following an acute transient ischaemic attack or minor ischaemic strokes (National Institutes of Health Stroke Scale <4) of <24 h duration, or recent (<6 months), stable, first-ever, non-disabling ischaemic stroke) were enrolled in 17 countries in Latin America, the Middle East, and Africa. The main measures of interest were risk factors, comorbidities, and socio-economic variables. RESULTS: Between January 2007 and December 2008, 3635 patients were enrolled in Latin America (n = 1543), the Middle East (n = 1041), North Africa (n = 834), and South Africa (n = 217). Of these, 63% had a stable, first-ever ischaemic stroke (median delay from symptom onset to inclusion, 25 days interquartile range, 7-77); 37% had an acute transient ischaemic attack or minor ischaemic stroke (median delay, two-days; interquartile range, 0-6). Prevalence of diabetes was 46% in the Middle East, 29% in Latin America, 35% in South Africa, and 38% in North Africa; 72% had abdominal obesity (range, 65-78%; adjusted P < 0.001); prevalence of metabolic syndrome was 78% (range, 72-84%, P < 0.001). Abnormal ankle brachial index (<0.9) was present in 22%, peripheral artery disease in 7.6%, and coronary artery disease in 13%. Overall, 24% of patients had no health insurance and 27% had a low educational level. INTERPRETATION: In this study, patients in low- and middle-income countries had a high burden of modifiable risk factors. High rates of low educational level and lack of health insurance in certain regions are potential obstacles to risk factor control. FUNDING: The Outcomes in Patients with TIA and Cerebrovascular disease registry is supported by Sanofi-Aventis, Paris, France.

Stroke epidemiology, prevention, and management strategies at a regional level: Latin America and the Caribbean.

Stroke is a major health problem in Latin American and Caribbean countries. In this paper, we review the epidemiology, aetiology, and management of stroke in the region based on a systematic search of articles published in Spanish, Portuguese, and English. Stroke mortality is higher than in developed countries but rates are declining. Population-based studies show variations in incidence of strokes: lower rates of ischaemic stroke and similar rates of intracranial haemorrhages, compared with other regions. A significant proportion of strokes in these populations can be attributed to a few preventable risk factors. Some countries have published national clinical guidelines, although much needs to be done in the organisation of care and rehabilitation. Even though the burden of stroke is high, there is a paucity of information for implementing evidence-based management. The Global Stroke Initiative, the WHO STEPS Stroke surveillance, and WHO-PREMISE projects provide opportunities for surveillance at institutional and community levels.