Pablo M. Lavados

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage

BACKGROUND Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. METHODS We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physicians choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. RESULTS Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. CONCLUSIONS In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

Incidence, 30-day case-fatality rate, and prognosis of stroke in Iquique, Chile: a 2-year community-based prospective study (PISCIS project)

BACKGROUND The epidemiology of stroke in Latin-American populations and variation of subtypes between communities are unclear. Our aim was to ascertain prospectively the incidence of first-ever stroke in the predominantly Hispanic-Mestizo population of Iquique, a city in the northern desert region of Chile. METHODS We prospectively identified all possible cases of stroke and transient ischaemic attacks between July 1, 2000, and June 30, 2002, from several overlapping sources. Patients were rapidly assessed by two field neurologists. Standard definitions for incident cases, stroke, transient ischaemic attack, pathological type, and infarction subtype were used. All cases identified were adjudicated by at least two stroke neurologists and followed up at 6 months. Incidence rates of first-ever strokes were calculated from the population of Iquique (214 526) according to the national census of 2002. FINDINGS Of 380 cases of stroke identified, 292 were incident. CT scans were done in 267 (91%) patients and the mean time to scan was 2.2 days. The hospital admission rate was 71% (207/292). The overall age-adjusted incidence rate of first-ever stroke was 140.1 per 100,000 (95% CI 124.0-156.2). The incidence rates per 100,000 according to pathological type were: infarcts 87.3, intracerebral haemorrhage 27.6, and subarachnoid haemorrhage 6.2. The 30 day and 6-month case-fatality rates were 23.3% and 33.0%, respectively. INTERPRETATION Our results show incidence rates of stroke similar to those reported in other community studies. Although the proportion of intracerebral haemorrhages was higher than reported in previous studies, the overall incidence was not, which could indicate a slightly lower incidence of ischaemic strokes in this population than in other countries. The prognosis was similar to that found in other population-based studies.

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.

Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial

Summary Background Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. Methods We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome—defined as a score of 4–5 on the modified Rankin Scale—3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). Findings 1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85–1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86–1·08). Interpretation Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. Funding Netherlands Heart Foundation, UK Medical Research Council.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

BACKGROUND Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial

BACKGROUND High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079). METHODS INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150-220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2-7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. FINDINGS We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05-1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14-2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14-1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13-1·88; ptrend=0·0044). INTERPRETATION Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. FUNDING National Health and Medical Research Council of Australia.

Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study

BACKGROUND Incidence of ischaemic stroke subtypes, classified by cause, seems to vary between communities. We aimed to prospectively ascertain the incidence of first-ever ischaemic stroke in a predominantly Hispanic-Mestizo population in the northern desertic region of Chile. METHODS Between July, 2000, and June, 2002, all patients with possible stroke or transient ischaemic attacks were identified from multiple overlapping sources and were rapidly assessed by two field neurologists. All identified patients were diagnosed by at least two stroke neurologists according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) definitions and were followed up at 6 months. Annual incidence rates were age adjusted to WHO, European, and US populations by the direct method to allow comparisons. FINDINGS A total of 239 ischaemic strokes were identified, of which 185 (77%) were first-ever cases. 151 (82%) patients were hospitalised, of whom only 70 (38%) were assessed within 6 h of symptom onset. The mean age of patients was 66.4 years (SD 14.9) and 56% were men. The crude annual incidence rates (per 100 000) according to stroke subtype were: cardioembolic, 9.3; large-artery disease, 2.0; small-vessel disease, 15.8; other determined cause, 0.2; and undetermined cause, 17.4. Hypertension was the most common cardiovascular risk factor in all subtypes and atrial fibrillation was the most common cause of cardioembolic stroke. Case fatality at 30 days was highest in cardioembolic strokes (28%) and lowest in small-vessel disease (0%). Dependency or death at 6 months was also highest in cardioembolic strokes (62%) and lowest in small-vessel disease (21%). INTERPRETATION Incidence and prognosis of small vessel and cardioembolic infarction was similar to that in other populations and incidence of large-artery atherothrombotic infarction was lower than in most previous reports. Hypertension and atrial fibrillation were the most common risk factor and cause, respectively, of ischemic stroke in this population. These findings should help the national stroke programme in the prevention of cardioembolic stroke, increase access to specialists and acute brain imaging and vascular studies, and improve stroke care.

Rationale, Design, and Progress of the ENhanced Control of Hypertension ANd Thrombolysis Stroke Study (ENCHANTED) Trial: An International Multicenter 2 × 2 Quasi-Factorial Randomized Controlled Trial of Low- vs. Standard-Dose rt-PA and Early Intensive vs. Guideline-Recommended Blood Pressure Lowering in Patients with Acute Ischaemic Stroke Eligible for Thrombolysis Treatment

Rationale Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of iv rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. Aims The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) iv rt-PA; and (ii) early intensive BP lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). Design The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent, 2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] ‘rt-PA dose’ and/or Arm [B] ‘BP control’, using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. Study outcomes The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2–6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Results Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Conclusions Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Optimal achieved blood pressure in acute intracerebral hemorrhage INTERACT2

Objectives: To investigate the effects of intensive blood pressure (BP) lowering according to baseline BP levels and optimal achieved BP levels in patients with acute intracerebral hemorrhage (ICH). Methods: INTERACT2 was an open, blinded endpoint, randomized controlled trial in 2,839 patients with ICH within 6 hours of onset and elevated systolic BP (SBP) (150–220 mm Hg) who were allocated to receive intensive (target SBP <140 mm Hg within 1 hour, with lower limit of 130 mm Hg for treatment cessation) or guideline-recommended (target SBP <180 mm Hg) BP-lowering treatment. Outcome was physical function across all 7 levels of the modified Rankin Scale at 90 days. Results: Analysis of the randomized comparisons showed that intensive BP lowering produced comparable benefits on physical function at 90 days in 5 subgroups defined by baseline SBP of <160, 160–169, 170–179, 180–189, and ≥190 mm Hg (p homogeneity = 0.790). Analyses of achieved BP showed linear increases in the risk of physical dysfunction for achieved SBP above 130 mm Hg for both hyperacute (1–24 hours) and acute (2–7 days) phases while modest increases were also observed for achieved SBP below 130 mm Hg. Conclusions: Intensive BP lowering appears beneficial across a wide range of baseline SBP levels, and target SBP level of 130–139 mm Hg is likely to provide maximum benefit in acute ICH. Classification of evidence: This study provides Class I evidence that the effect of intensive BP lowering on physical function is not influenced by baseline BP.

Sex Differences in Stroke Incidence, Prevalence, Mortality and DALYs: Results from the Global Burden of Disease Study 2013

Background: Accurate information on stroke burden in men and women are important for evidence-based healthcare planning and resource allocation. Previously, limited research suggested that the absolute number of deaths from stroke in women was greater than in men, but the incidence and mortality rates were greater in men. However, sex differences in various metrics of stroke burden on a global scale have not been a subject of comprehensive and comparable assessment for most regions of the world, nor have sex differences in stroke burden been examined for trends over time. Methods: Stroke incidence, prevalence, mortality, disability-adjusted life years (DALYs) and healthy years lost due to disability were estimated as part of the Global Burden of Disease (GBD) 2013 Study. Data inputs included all available information on stroke incidence, prevalence and death and case fatality rates. Analysis was performed separately by sex and 5-year age categories for 188 countries. Statistical models were employed to produce globally comprehensive results over time. All rates were age-standardized to a global population and 95% uncertainty intervals (UIs) were computed. Findings: In 2013, global ischemic stroke (IS) and hemorrhagic stroke (HS) incidence (per 100,000) in men (IS 132.77 (95% UI 125.34-142.77); HS 64.89 (95% UI 59.82-68.85)) exceeded those of women (IS 98.85 (95% UI 92.11-106.62); HS 45.48 (95% UI 42.43-48.53)). IS incidence rates were lower in 2013 compared with 1990 rates for both sexes (1990 male IS incidence 147.40 (95% UI 137.87-157.66); 1990 female IS incidence 113.31 (95% UI 103.52-123.40)), but the only significant change in IS incidence was among women. Changes in global HS incidence were not statistically significant for males (1990 = 65.31 (95% UI 61.63-69.0), 2013 = 64.89 (95% UI 59.82-68.85)), but was significant for females (1990 = 64.892 (95% UI 59.82-68.85), 2013 = 45.48 (95% UI 42.427-48.53)). The number of DALYs related to IS rose from 1990 (male = 16.62 (95% UI 13.27-19.62), female = 17.53 (95% UI 14.08-20.33)) to 2013 (male = 25.22 (95% UI 20.57-29.13), female = 22.21 (95% UI 17.71-25.50)). The number of DALYs associated with HS also rose steadily and was higher than DALYs for IS at each time point (male 1990 = 29.91 (95% UI 25.66-34.54), male 2013 = 37.27 (95% UI 32.29-45.12); female 1990 = 26.05 (95% UI 21.70-30.90), female 2013 = 28.18 (95% UI 23.68-33.80)). Interpretation: Globally, men continue to have a higher incidence of IS than women while significant sex differences in the incidence of HS were not observed. The total health loss due to stroke as measured by DALYs was similar for men and women for both stroke subtypes in 2013, with HS higher than IS. Both IS and HS DALYs show an increasing trend for both men and women since 1990, which is statistically significant only for IS among men. Ongoing monitoring of sex differences in the burden of stroke will be needed to determine if disease rates among men and women continue to diverge. Sex disparities related to stroke will have important clinical and policy implications that can guide funding and resource allocation for national, regional and global health programs.