Paula Muñoz-Venturelli

Prognostic Significance of Hyperglycemia in Acute Intracerebral Hemorrhage: The INTERACT2 Study

Background and Purpose— We aimed to determine associations of baseline blood glucose and diabetes mellitus with clinical outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods— INTERACT2 was an international prospective, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure randomly assigned to intensive (target systolic blood pressure <140 mm Hg) or guideline-based (systolic blood pressure <180 mm Hg) BP management. Associations of hyperglycemia at presentation (>6.5 mmol/L) and combined and separate poor outcomes of death and major disability (scores of 3–6, 3–5, and 6, respectively, on the modified Rankin scale) at 90 days were determined in logistic regression models. Results— In 2653 patients with available data, there were 1348 (61%) with hyperglycemia and 292 (11%) with diabetes mellitus. Associations of baseline blood glucose and poor outcome were strong and near continuous. After adjustment for baseline variables, the highest fourth (7.9–25.0 mmol/L) of blood glucose was significantly associated with combined poor outcome (adjusted odds ratio 1.35, 95% confidence interval 1.01–1.80; P trend 0.015). Diabetes mellitus also predicted poor outcome (adjusted odds ratio 1.46, 95% confidence interval 1.05–2.02; P=0.023), though more important for residual disability than death on separate analysis. Conclusions— Hyperglycemia and diabetes mellitus are independent predictors of poor outcome in patients with predominantly mild to moderate severity of intracerebral hemorrhage. These data support guideline recommendations for good glycemic control in patients with intracerebral hemorrhage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.

Mannitol and Outcome in Intracerebral Hemorrhage Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results

Background and Purpose— Mannitol is often used to reduce cerebral edema in acute intracerebral hemorrhage but without strong supporting evidence of benefit. We aimed to determine the impact of mannitol on outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods— INTERACT2 was an international, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure allocated to intensive (target systolic blood pressure, <140 mm Hg within 1 hour) or guideline-recommended (target systolic blood pressure, <180 mm Hg) blood pressure–lowering treatment. Propensity score and multivariable analyses were performed to investigate the relationship between mannitol treatment (within 7 days) and poor outcome, defined by death or major disability on the modified Rankin Scale score (3–6) at 90 days. Results— There was no significant difference in poor outcome between mannitol (n=1533) and nonmannitol (n=993) groups: propensity score–matched odds ratio of 0.90 (95% confidence interval, 0.75–1.09; P=0.30) and multivariable odds ratio of 0.87 (95% confidence interval, 0.71–1.07; P=0.18). Although a better outcome was suggested in patients with larger (≥15 mL) than those with smaller (<15 mL) baseline hematomas who received mannitol (odds ratio, 0.52 [95% confidence interval, 0.35–0.78] versus odds ratio, 0.91 [95% confidence interval, 0.72–1.15]; P homogeneity <0.03 in propensity score analyses), the association was not consistent in analyses across other cutoff points (≥10 and ≥20 mL) and for differing grades of neurological severity. Mannitol was not associated with excess serious adverse events. Conclusions— Mannitol seems safe but might not improve outcome in patients with acute intracerebral hemorrhage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.

Head Position in Stroke Trial (HeadPoST)--sitting-up vs lying-flat positioning of patients with acute stroke : study protocol for a cluster randomised controlled trial

BackgroundPositioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke.Methods/DesignWe plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period.DiscussionHeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke.Trial registrationClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014.

Prophylactic heparin in acute intracerebral hemorrhage: a propensity score-matched analysis of the INTERACT2 study:

Background Indication and timing of pharmacological venous thromboembolism prophylaxis in intracerebral hemorrhage patients is controversial. Aims To determine whether use of subcutaneous heparin during the first 7 days after spontaneous intracerebral hemorrhage increases risks of death and disability. Methods Data are from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) study. Patients with acute intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure were included; patients received subcutaneous heparin following local best practice standards of care. Multivariable logistic regression and propensity score matched analysis were used to determine associations of heparin use on death and disability (modified Rankin scale) at 90 days. Results In 2525 patients with available data, there were 465 (22.5%) who received subcutaneous heparin. They had higher death or major disability at 90 days in crude (odds ratio 2.29, 95% confidence interval 1.85–2.84; p < 0.001), adjusted (odds ratio 1.62, 95% confidence interval 1.26–2.09; p < 0.001) and propensity score matched (odds ratio 2.06, 95% confidence interval 1.53–2.77; p < 0.001) analyses. In propensity score matched analysis, heparin-treated patients had significant lower mortality (odds ratio 0.55, 95% CI 0.35–0.87; p = 0.01) but greater major disability (odds ratio 1.68, 95% confidence interval 1.25–2.28; p < 0.001) at 90 days. However, no mortality difference was found in analysis restricted to 48-hour survivors. Conclusions Use of subcutaneous heparin is associated with poor outcome in acute intracerebral hemorrhage, driven by increased residual disability. Despite the limitations of this study, and no clear relation of heparin with bleeding risk, we recommend careful consideration of the need for venous thromboembolism prophylaxis with heparin in intracerebral hemorrhage patients. Trial registration http://www.clinicaltrials.gov NCT00716079.

Long-term Adherence to National Guidelines for Secondary Prevention of Ischemic Stroke: A Prospective Cohort Study in a Public Hospital in Chile

BACKGROUND Clinical guidelines for the secondary prevention of ischemic stroke have been developed, but their publication is insufficient to make them effective. Our aim was to investigate adherence to Chilean guidelines, its associated variables, and to determine prognosis at follow-up. METHODS We prospectively included all consecutive patients discharged with a diagnosis of ischemic stroke from Valparaíso Regional Hospital between July 15, 2007 and January 15, 2008. Patient follow-up was performed at 5, 10, and 15 months using a standardized questionnaire. We used the Chi-square and Fisher exact tests to compare discrete variables and multivariate logistic regression analysis to adjust for potential confounding factors. A Cox regression model was fitted. RESULTS We included 156 patients; 128 patients (82%) completed follow-up. Adherence to oral anticoagulation decreased significantly compared to all other medications during follow-up (P = .004). This was not associated with any of the studied variables. Adherence to antihypertensives, statins, and hypoglycemic medications remained >65% without a significant variation. Patients with cardioembolic stroke had greater mortality (P = .003) and recurrence rates. CONCLUSIONS The observed significant decrease in adherence to oral anticoagulation in patients with cardioembolic stroke suggests a need for the implementation of specific strategies to achieve the desired secondary prevention goals in these patients. Future research into the evaluation of other factors that could be associated with the lack of adherence to these guidelines, measurements of therapeutic goals, and new therapeutic strategies that are easier to use and that are associated with less risk could improve the prognosis of these patients.

Transcranial Doppler as a Predictor of Ischemic Events in Carotid Artery Dissection.

We aim to evaluate clinical features and transcranial Doppler (TCD) elements, as predictors of the development of ischemic events (IEs) in patients suffering from spontaneous carotid arterial dissection without stroke (CCADW).

Statistical analysis plan of the head position in acute ischemic stroke trial pilot (HEADPOST pilot)

Background The HEADPOST Pilot is a proof-of-concept, open, prospective, multicenter, international, cluster randomized, phase IIb controlled trial, with masked outcome assessment. The trial will test if lying flat head position initiated in patients within 12 h of onset of acute ischemic stroke involving the anterior circulation increases cerebral blood flow in the middle cerebral arteries, as measured by transcranial Doppler. The study will also assess the safety and feasibility of patients lying flat for ≥24 h. The trial was conducted in centers in three countries, with ability to perform early transcranial Doppler. A feature of this trial was that patients were randomized to a certain position according to the month of admission to hospital. Objective To outline in detail the predetermined statistical analysis plan for HEADPOST Pilot study. Methods All data collected by participating researchers will be reviewed and formally assessed. Information pertaining to the baseline characteristics of patients, their process of care, and the delivery of treatments will be classified, and for each item, appropriate descriptive statistical analyses are planned with comparisons made between randomized groups. For the outcomes, statistical comparisons to be made between groups are planned and described. Results This statistical analysis plan was developed for the analysis of the results of the HEADPOST Pilot study to be transparent, available, verifiable, and predetermined before data lock. Conclusions We have developed a statistical analysis plan for the HEADPOST Pilot study which is to be followed to avoid analysis bias arising from prior knowledge of the study findings. Trial registration The study is registered under HEADPOST-Pilot, ClinicalTrials.gov Identifier NCT01706094.

Flat-head positioning increases cerebral blood flow in anterior circulation acute ischemic stroke. A cluster randomized phase IIb trial

Background Whether lying-flat improves blood flow in patients with acute ischemic stroke is unknown. Our aim was to investigate if lying-flat “changes” cerebral blood flow velocities assessed by transcranial Doppler in acute ischemic stroke patients. Methods In a multicenter cluster clinical trial, we randomly assigned patients within 12 h from onset of a neurological deficit due to cerebral ischemia of the anterior circulation to lying-flat or upright head positioning. The primary outcome was a change of 8 cm/s or more in mean cerebral blood flow velocities on transcranial Doppler to the middle cerebral artery at 1 and 24 h post-randomization, adjusted for imbalance in baseline variables. Secondary outcomes included serious adverse events and physical functioning at 90 days. Results Ninety-four of 304 patients screened were recruited. The primary outcome occurred in 11 (26%) of 43 patients in the lying-flat group and in 6 (12%) of 51 in the upright group at 1 h (adjusted odds ratio, 3.81; 95% CI, 1.07 to 13.54), and in 23 (53%) and 18 (36%) patients in these respective groups at 24 h (adjusted odds ratio, 3.04; 95% CI, 1.08 to 8.53). There were no between-group differences in serious adverse events, including pneumonia, heart failure or mortality, nor in functional outcome at 3 months (adjusted common odds ratio, 1.38; 95% CI 0.64 to 3.00). Conclusion The lying-flat head position was associated with a significant increase in cerebral blood flow velocities at one and 24 h within the ipsilateral hemisphere of anterior circulation acute ischemic stroke, without serious safety concerns. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01706094.

The distribution of the modified Rankin scale scores change according to eligibility criteria in acute ischemic stroke trials: A consideration for sample size calculations when using ordinal regression analysis

Background Distribution shifts of the modified Rankin scale (mRs) is used as outcome measure in acute ischemic stroke (AIS) randomized controlled trials (RCT). Distribution across strata of mRs is relevant for sample size calculations and may be affected by eligibility criteria. Aim We aimed to assess the distribution of mRs scores across its different strata in AIS according to usual eligibility criteria. Methods We computed follow-up mRs strata distribution between an unselected cohort and samples with (a) time from symptom onset < 6 h (b) National Institutes of Health Stroke Scale (NIHSS) scores > 3 and < 25, and (c) both criteria combined. We compared distributions with the Mann-Whitney U Test and calculated sample sizes for each distribution. Results We included 5849 AIS patients. The unselected sample had a non-normal distribution with a median of 2. All selection criteria yielded significantly different distributions of mRs (p = 004, 0.02 and 0.02 respectively). This resulted in a significant variation in the calculated sample size when applying different selection criteria, with smaller numbers when RCT selection criteria are used (3616 versus 1553). Conclusions The use of usual RCT eligibility criteria result in significant differences in mRs distribution and smaller sample sizes compared to unselected AIS samples.