Symptomatic hemorrhage after alteplase therapy not due to silent ischemia

BACKGROUND: Stroke thrombolysis-related intracerebral hemorrhage may occur remotely from the anatomical site of ischemia. One postulated mechanism for this is simultaneous multiple embolization with hemorrhage into a "silent" area of ischemia. RESULTS: A patient suffered a disabling stroke affecting the right cerebral hemisphere. He was treated with intravenous alteplase and underwent extensive early imaging with multimodal MRI. Several hours after treatment he developed a brainstem hemorrhage despite having no evidence of ischemia on DWI MRI in the brainstem. CONCLUSION: Not all occurrences of remote ICH after stroke thrombolysis are secondary to multiple emboli with silent ischemia

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

Background Positioning 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/Design We 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. Discussion HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. Trial registration ClinicalTrials.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

Associations of Early Systolic Blood Pressure Control and Outcome after Thrombolysis-Eligible Acute Ischemic Stroke: Results from the ENCHANTED Study

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. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616

Assessment and Implication of Prognostic Imbalance in Randomized Controlled Trials with a Binary Outcome – A Simulation Study

Chance imbalance in baseline prognosis of a randomized controlled trial can lead to over or underestimation of treatment effects, particularly in trials with small sample sizes. Our study aimed to (1) evaluate the probability of imbalance in a binary prognostic factor (PF) between two treatment arms, (2) investigate the impact of prognostic imbalance on the estimation of a treatment effect, and (3) examine the effect of sample size (n) in relation to the first two objectives.We simulated data from parallel-group trials evaluating a binary outcome by varying the risk of the outcome, effect of the treatment, power and prevalence of the PF, and n. Logistic regression models with and without adjustment for the PF were compared in terms of bias, standard error, coverage of confidence interval and statistical power.For a PF with a prevalence of 0.5, the probability of a difference in the frequency of the PF≥5% reaches 0.42 with 125/arm. Ignoring a strong PF (relative risk = 5) leads to underestimating the strength of a moderate treatment effect, and the underestimate is independent of n when n is >50/arm. Adjusting for such PF increases statistical power. If the PF is weak (RR = 2), adjustment makes little difference in statistical inference. Conditional on a 5% imbalance of a powerful PF, adjustment reduces the likelihood of large bias. If an absolute measure of imbalance ≥5% is deemed important, including 1000 patients/arm provides sufficient protection against such an imbalance. Two thousand patients/arm may provide an adequate control against large random deviations in treatment effect estimation in the presence of a powerful PF.The probability of prognostic imbalance in small trials can be substantial. Covariate adjustment improves estimation accuracy and statistical power, and hence should be performed when strong PFs are observed

Association of follow-up infarct volume with functional outcome in acute ischemic stroke: a pooled analysis of seven randomized trials.

BACKGROUND: Follow-up infarct volume (FIV) has been recommended as an early indicator of treatment efficacy in patients with acute ischemic stroke. Questions remain about the optimal imaging approach for FIV measurement. OBJECTIVE: To examine the association of FIV with 90-day modified Rankin Scale (mRS) score and investigate its dependency on acquisition time and modality. METHODS: Data of seven trials were pooled. FIV was assessed on follow-up (12 hours to 2 weeks) CT or MRI. Infarct location was defined as laterality and involvement of the Alberta Stroke Program Early CT Score regions. Relative quality and strength of multivariable regression models of the association between FIV and functional outcome were assessed. Dependency of imaging modality and acquisition time (≤48 hours vs >48 hours) was evaluated. RESULTS: Of 1665 included patients, 83% were imaged with CT. Median FIV was 41 mL (IQR 14-120). A large FIV was associated with worse functional outcome (OR=0.88(95% CI 0.87 to 0.89) per 10 mL) in adjusted analysis. A model including FIV, location, and hemorrhage type best predicted mRS score. FIV of ≥133 mL was highly specific for unfavorable outcome. FIV was equally strongly associated with mRS score for assessment on CT and MRI, even though large differences in volume were present (48 mL (IQR 15-131) vs 22 mL (IQR 8-71), respectively). Associations of both early and late FIV assessments with outcome were similar in strength (ρ=0.60(95% CI 0.56 to 0.64) and ρ=0.55(95% CI 0.50 to 0.60), respectively). CONCLUSIONS: In patients with an acute ischemic stroke due to a proximal intracranial occlusion of the anterior circulation, FIV is a strong independent predictor of functional outcome and can be assessed before 48 hours, oneither CT or MRI