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BACKGROUND: Neurodevelopmental impairment is a significant consequence for survivors of surgery for critical congenital heart disease. This study sought to determine if intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes. METHODS: A planned secondary analysis of a two-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery was performed. A brain injury biomarker was measured perioperatively. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two sample t-tests and generalized linear models were used. RESULTS: There were 129 participants (n=61 methylprednisolone, n=68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between the two treatment groups. Participants who underwent a palliative (vs. corrective) procedure had lower mean BSID-III cognitive (101±15 vs. 106±14, p=0.03) and motor scores (85±18 vs. 94±16, p

Vaccinations are reported at the state level, but services are delivered at the county level through health departments (HD). This research contributes statistical models to predict county level HPV vaccination.Using a cross sectional study design, secondary data were analyzed for the years 2016-2018 for all counties of GA. Study population was male and female adolescents aged 13-17 who received the tetanus, diphtheria and pertussis (Tdap) vaccine. The number of administered HPV vaccine doses and HPV vaccination coverage rate were modeled using indicators of HD clinic access, age, sex, race/ethnicity, socioeconomic status, education, median household income, health insurance, and urban/rural residence.By county the number of administered HPV vaccine doses showed a statistically significant positive association with indicators of HD clinic access: public transit and the number of HD private clinics. HPV vaccination coverage showed a statistically significant negative association with White race and rural residency.Examining Tdap vaccinated adolescents conservatively predicted HPV vaccination and controlled for multiple confounders such as vaccination ineligibility, vaccine exemption, and vaccine opposition. Within this population, public health professionals and clinicians could use these statistical models to target HPV vaccination efforts among non-Hispanic whites and rural communities at the county level.

Background: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. Methods: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL— Results: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1–2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2–2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P =0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0–3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1–3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. Conclusions: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01176565.

To characterize counties in GA by quantifying administered doses of the HPV and Tdap vaccines collected by the state health department immunization registry and indicators of Health Department (HD) clinic access.Using a cross sectional study design, secondary data were collected from public health data sources for the years 2016 to 2018 for 159 counties of Georgia. The study population was male and female adolescents aged 13-17. The number of administered HPV and Tdap vaccine doses were modeled in relation to number of private and public HD clinics, number of HD clinics registered in the VFC program and the availability of public transportation using Poisson regression, negative binomial regression, and Bayesian spatial analysis.Choropleth maps showed similar clustering patterns between administered doses of the HPV vaccine and Tdap vaccine and increased counts of administered vaccine doses in counties with both public and private clinics. Administered doses of HPV and Tdap vaccines were found to exhibit spatial dependence across counties. Accounting for spatial dependence, the availability of public transit had a significant positive effect on administered HPV vaccine doses, while the number of private HD clinics had a significant positive effect on administered Tdap vaccine doses.Maps at the county level show vaccination variability, clustering patterns and provide additional insights on the access to health care. Bayesian spatial models are needed to accurately identify and estimate factors associated with administering doses of the HPV and Tdap vaccines. Future work is needed to further examine the utilization of HPV vaccination services among urban groupings.

Aim: Missing data cause problems through decreasing sample size and the potential for introducing bias. We tested four missing data methods on the Sequential Organ Failure Assessment (SOFA) score, an intensive care research severity adjuster. Methods: Simulation study using 2015–2017 electronic health record data, where the complete dataset was sampled, missing SOFA score elements imposed and performance examined of four missing data methods – complete case analysis, median imputation, zero imputation (recommended by SOFA score creators) and multiple imputation (MI) – on the outcome of in-hospital mortality. Results: MI performed well, whereas other methods introduced varying amounts of bias or decreased sample size. Conclusion: We recommend using MI in analyses where SOFA score component values are missing in administrative data research.

Background and aims Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. Methods A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4–6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Summary of review Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00–1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02–1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00–1.05 per hour). Conclusions Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110–139 mm Hg versus 140–179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00–5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71–1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Background We performed this meta-analysis of randomized clinical trials to compare the outcomes in patients treated with endovascular thrombectomy who receive prior intravenous thrombolysis with those who do not receive such treatment. Recently, one randomized trial reported outcomes to address this issue, so timely update of meta-analysis is needed to determine the value of administering intravenous thrombolysis before endovascular thrombectomy. Materials and methods Four randomized clinical trials are included in our meta-analysis. We calculated pooled odds ratios and 95% CIs using random-effects models. The primary efficacy endpoint was a favorable outcome defined by a modified Rankin Scale score of 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) at 90 days post-randomization. Secondary endpoints analyzed were any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality. Results Of the 1633 patients randomized, the proportion of patients who achieved a favorable outcome was similar between endovascular thrombectomy alone and combined approach with intravenous thrombolysis and endovascular thrombectomy (1631 patients analyzed; odds ratio 1.02; CI 0.84–1.25; p = 0.83). Risk of any intracerebral hemorrhage was significantly lower among those randomized to endovascular thrombectomy alone (1633 patients analyzed; odds ratio 0.75; CI 0.57–0.99; p = 0.04). Rates of symptomatic intracerebral hemorrhage (p = 0.36) and mortality (p = 0.62) were not significantly different between the two groups. Conclusions Compared with endovascular thrombectomy preceded by intravenous thrombolysis, endovascular thrombectomy resulted in similar rates of favorable outcome with a lower rate of intracerebral hemorrhage. A large phase 3 trial is required to conclusively demonstrate equivalency of both approaches to guide future practice.

Objective: The aim of this study was to better define the shape of association between the degree (“magnitude”) of early (Methods: Association of the continuous magnitude of SBP reduction described using cubic splines and an ordinal measure of the functional outcome on the modified Rankin scale (mRS) scores at 90 days were analyzed in generalized linear mixed models. Models were adjusted for achieved (mean) and variability (standard deviation, SD) of SBP between 1 and 24 h, various baseline covariates, and trial as a random effect. Results: Among 3796 patients (mean age 63.1 (SD = 13.0) years; female 37.4%), with a mean magnitude ( 70 mmHg. Similar J-shape associations were evident across various time epochs across 24 h and consistent according to baseline hematoma volume and SBP and history of hypertension. Interpretation: A moderate degree of rapid SBP lowering is associated with improved functional outcome after ICH, but large SBP reductions over 1 h (e.g. from > 200 to target

On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH).We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders.Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders.The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH.ClinicalTrials.gov: NCT01176565.

Introduction: Optimal management of neonates with tetralogy of Fallot and pulmonary atresia (TOF/PA) with confluent pulmonary arteries is unknown. We sought to compare outcomes for patients who underwent primary complete repair vs. initial surgical palliation followed by delayed repair. Methods: We conducted a retrospective study at 20 centers within CoRe-PCICS (Collaborative Research from the Pediatric Cardiac Intensive Care Society). Data were collected on infants undergoing initial surgical intervention at 0 - 60 days of age with TOF/PA from 2009 to 2018, excluding patients with MAPCAs or those undergoing ductal stenting (n=22). The primary outcome was days alive and out of hospital in first year of life (DAOH). Secondary outcomes were 1 year mortality and a composite major complication outcome (similar to that in prior STS-CHSD studies), defined as occurrence of ≥ 1 of the following: renal failure requiring dialysis, stroke/seizure, permanent pacemaker, ECMO, or diaphragm paralysis during a palliation and/or repair hospitalization, or unplanned reoperation in the first year. Multivariable modeling with generalized estimating equations were utilized to compare outcomes between groups. Results: Of 210 subjects, 79 underwent primary complete repair and 131 underwent surgical palliation. Patients who underwent palliation had greater use of preoperative mechanical ventilation at first procedure (26% vs. 8%, p = 0.002). Other baseline characteristics were similar between groups (p > 0.05 for all). There was no statistically significant difference in DAOH between the palliation and primary repair groups [median (25%,75% IQR): 319 (280,336) vs. 338 (314,348 days), adjusted p = 0.20]. Nine (7%) patients who underwent palliation died in the first year of life vs. 4 (6 %) who underwent primary repair (adjusted OR: 1.1, 95% CI: 0.3-4.5; p = 0.9). At least one major complication occurred in 35% of patients who underwent palliation vs. 18% of patients who underwent primary repair (adjusted OR: 2.5, 95% CI: 1.4-4.4, p = 0.001). Conclusions: For infants with TOF/PA with confluent pulmonary arteries, a strategy of surgical palliation or primary complete repair resulted in similar DAOH and early mortality, whereas the morbidity incidence favored primary repair.

OBJECTIVE: Acute kidney injury is a frequent complication following neonatal cardiac surgery and is associated with significant morbidity and mortality. The objectives of this study were to determine if plasma neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury and clinical outcomes in neonates with congenital heart disease undergoing cardiopulmonary bypass. DESIGN: Retrospective single-center observational study SETTING: A pediatric cardiac intensive care unit within a tertiary-care academic hospital. PATIENTS: Patients age less than 30 days undergoing cardiac surgery requiring cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Plasma neutrophil gelatinase-associated lipocalin peaked at 12 hours post-cardiopulmonary bypass and more than doubled compared to preoperative levels. Higher preoperative and 24 hour postoperative neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury (r = 0.30, r = 0.49), longer duration of mechanical ventilation (r = 0.40, r = 0.51), intensive care unit (r = 0.32, r = 0.33) and hospital lengths of stay (r = 0.28, r = 0.32) and total hospital charges (r = 0.35, r = 0.30; all p values < 0.05). CONCLUSIONS: Both preoperative and 24 hour postoperative plasma neutrophil gelatinase-associated lipocalin levels are associated with acute kidney injury and worse clinical outcomes in neonates undergoing cardiac surgery. Plasma neutrophil gelatinase-associated lipocalin levels may have a role in risk stratification for predicting postoperative renal dysfunction as well as providing a potential clinical trajectory in the postoperative period.

Background The efficacy of intraoperative corticosteroids to improve outcomes following congenital cardiac operations remains controversial. Objectives The purpose of this study was to determine whether intraoperative methylprednisolone improves post-operative recovery in neonates undergoing cardiac surgery. Methods Neonates undergoing cardiac surgery with cardiopulmonary bypass at 2 centers were enrolled in a double-blind randomized controlled trial of methylprednisolone (30 mg/kg) or placebo after the induction of anesthesia. The primary outcome was a previously validated morbidity-mortality composite that included any of the following events following surgery before discharge: death, mechanical circulatory support, cardiac arrest, hepatic injury, renal injury, or rising lactate level (>5 mmol/l). Results Of the 190 subjects enrolled, 176 (n = 81 methylprednisolone, n = 95 placebo) were included in this analysis. A total of 27 (33%) subjects in the methylprednisolone group and 40 (42%) in the placebo group reached the primary study endpoint (odds ratio [OR]: 0.63; 95% confidence interval [CI]: 0.31 to 1.3; p = 0.21). Methylprednisolone was associated with reductions in vasoactive inotropic requirements and in the incidence of the composite endpoint in subjects undergoing palliative operations (OR: 0.38; 95% CI: 0.15 to 0.99; p = 0.048). There was a significant interaction between treatment effect and center. In this analysis, methylprednisolone was protective at 1 center, with an OR: 0.35 (95% CI: 0.15 to 0.84; p = 0.02), and not so at the other center, with OR: 5.13 (95% CI: 0.85 to 30.90; p = 0.07). Conclusions Intraoperative methylprednisolone failed to show an overall significant benefit on the incidence of the composite primary study endpoint. There was, however, a benefit in patients undergoing palliative procedures and a significant interaction between treatment effect and center, suggesting that there may be center or patient characteristics that make prophylactic methylprednisolone beneficial.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Domain-specific endpoints are assessments that correspond to the output of individual neural systems and are useful for capturing treatment effects on specific behaviors. By contrast, global endpoints combine several attributes into a single score and are useful for capturing broad treatment effects in a summary way. While global endpoints have become the de facto mechanism required to define benefit in stroke trials, they also have important limitations, some of which might be addressed by simultaneously measuring domain-specific endpoints. Substantial opportunity remains to identify quantifiable patient benefit that would otherwise not be captured by global endpoints. Potential advantages of incorporating domain-specific endpoints in acute stroke trials are discussed, such as increased granularity of measurement, improved understanding of how therapies affect the brain between acute treatment and day 90, and optimized therapeutic translation. Potential disadvantages are also considered, including time and cost of administering domain-specific endpoints, as well as statistical implications. Domain-specific endpoints and global endpoints are not mutually exclusive, and both capture clinical benefits to patients. Incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific endpoints, is warranted.

Background Hematoma volume in chronic subdural hematoma (CSDH) may predict neurologic deterioration and need for surgical evacuation. Several computer software–assisted methods exist for accurate volume measurements of intracerebral hemorrhage, but no reliable method has been identified for measurement of CSDH volume. Methods A total of 30 consecutive patients with CSDH from 2018–2019 admitted to our institution were selected. The noncontrast computed tomography head studies were reviewed by 2 residents. The region of interest method on a Horos Open Source Medical Image Viewer (version 3.3.6) was utilized for volume measurement by each resident (resident-1 and resident-2) independently. Resident-1 repeated the protocol on the same studies 1 month later. We calculated the intra- and interobserver reliability of hematoma volume measurements using the Bland–Altman method. Results Mean age of the patients was 79 years (range, 50–92 years). For interobserver analysis, resident-1 mean hematoma volume was 85.46 cm3 (range, 6.40–178.63 cm3) and was 87.15 cm3 (range, 8.79–165.97 cm3) for resident-2. The Bland–Altman coefficient of variation was 13.15% (range, 0.07%–46.29%, 97% within the limits of acceptance). For intraobserver analysis, the initial average volume measured by resident-1 was 85.46 cm3 (range, 6.40–178.63 cm3) and subsequent was 95.26 cm3 (range, 10.48–182.99 cm3). The Bland–Altman coefficient of variation was 13.76% (range, 0.81%–48.34%, 97% within the limits of acceptance). Conclusions We are reporting inter- and intraobserver reliability for a novel volumetric analysis of CSDH volume using Horos Medical Image Viewer region of interest generated volume calculation. This method is accurate and efficient and could have important clinical and research implications for risk stratification.

Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis.In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data.Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios.The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.

With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial.We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days.Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume 30 cmRandomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Background Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis. Methods In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data. Results Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios. Conclusions The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

Background: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure (SBP) levels achieved with intravenous nicardipine immediately after onset of intracerebral haemorrhage (ICH) on clinical outcomes were determined. Methods: A systematic review and individual patient data analysis of articles before October 1, 2020 identified on PubMed were performed. Prospective studies involving hyperacute ICH adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale (mRS) were eligible. Outcomes included death or disability at 90 days, defined as an mRS score of 4-6, and haematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Findings: Three studies met the eligibility criteria. Of 1,271 patients overall, 1,265 (age 62.6±13.0 years, 484 women) with available SBP data were included. Death or disability occurred in 38.2%, and haematoma expansion occurred in 17.4%. Mean hourly SBP during the initial 24 h was positively associated with death or disability [adjusted odds ratio (aOR) 1.12, 95% CI 1.00–1.26 per 10 mmHg] and haematoma expansion (1.16, 1.02–1.32). The association of SBP with death or disability was modified by race, baseline diastolic BP, and study population (higher SBP increased the risk in Asians, aOR 1.26, 95% CI 1.10–1.43). Mean hourly SBP from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Slower lowering of SBP to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00–1.05, per hour). Interpretation: Rapid lowering of SBP by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute ICH decreased early haematoma expansion and 90-day death or disability without increasing serious adverse events. Funding: Japan Agency for Medical Research and Development. Conflict of Interest: All of the following conflicts are outside the submitted work.Toyoda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, Bristol-Myers-Squibb (BMS), and Nippon Boehringer-Ingelheim (NBI). Ihara reports grants from Panasonic, Shimadzu Corporation, BMS, Otsuka Pharmaceutical, and personal fees from Daiichi-Sankyo, Eisai, and Bayer Yakuhin.Itabashi reports grants from Tohoku Fukushi University and NBI. Yamagami reports research grants from BMS; lecturer’s fees from Stryker, Terumo, Medtronic, Medico’s Hirata, Johnson and Johnson, Bayer, Daiichi-Sankyo, BMS, NBI, Takeda, and Otsuka Pharmaceutical; and membership of the advisory boards for Daiichi-Sankyo. Itabashi reports honoraria from Bayer, Eisai, BMS, Daiichi Sankyo, NBI, Takeda, Otsuka Pharmaceutical, Tanabe-Mitsubishi Parma, Pfizer, GE Healthcare Japan, Stryker, Medtronic, and Johnson and Johnson, and research support from Tohoku Fukushi University and NBI. Sakai reports grants from Daiichi-Sankyo, Jimro, Medtronic, Terumo, and honoraria from Asahi-Intec, Biomedical Solutions, Daiichi-Sankyo, Medtronic, and Stryker. Inoue reports personal fees from Daiichi-Sankyo, Bayer, BMS, and Medtronic. Minematsu reports personal fees and other from Bayer Yakuhin and AstraZeneca, personal fees from Otsuka Pharmaceutical, NBI, Mitsubishi Tanabe Pharma, BMS, Pfizer, Japan Stryker, Daiichi-Sankyo, Astellas Pharma, Nippon Chemiphar, and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico’s Hirata, EPS Corporation, HEALIOS K.K., and T-PEC Corporation. Koga reports honoraria from Bayer Yakuhin, Otsuka, Daiichi-Sankyo, and NBI, scientific advisory board from Ono, and research support from Takeda, Daiichi-Sankyo, NBI, and Shionogi.None of the other authors has any conflicts of interest to declare. Ethical Approval: The study design followed PRISMA guidelines for IPD systematic reviews. Ethical approval to perform the present IPD analysis was obtained from the site of the corresponding author. The study is registered with PROSPERO (CRD42020213857).

Additional file 1.

Background There is persistent uncertainty over the benefits of early intensive systolic blood pressure lowering in acute intracerebral hemorrhage. In particular, over the timing, target, and intensity of systolic blood pressure control for optimum balance of potential benefits (i.e. functional recovery) and risks (e.g. cerebral ischemia). Aims To determine associations of early systolic blood pressure lowering parameters and outcomes in patients with a hypertensive response in acute intracerebral hemorrhage. Secondary aims are to identify the modifying effects of patient characteristics and an optimal systolic blood pressure lowering profile. Methods Individual participant data pooled analyses of two large, multicenter, randomized controlled trials specifically undertaken to assess the effects of early intensive systolic blood pressure reduction on clinical outcomes in acute intracerebral hemorrhage: the Intensive Blood Pressure in Acute Intracerebral Hemorrhage Trial (INTERACT2) and the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. Combined data will include baseline characteristics; systolic blood pressure in the first 24 h; process of care measures; and key efficacy and safety outcomes. Outcomes The primary outcome is functional recovery, defined by an ordinal distribution of scores on the modified Rankin scale at 90 days post-randomization. Secondary outcomes include various standard binary cut-points for disability-free survival on the modified Rankin scale, and health-related quality of life at 90 days. Safety outcomes include symptomatic hypotension requiring corrective therapy and early neurologic deterioration within 24 h, and deaths, any serious adverse event, and cardiac and renal serious adverse events, within 90 days. Discussion A pre-determined protocol was developed to facilitate successful collaboration and reduce analysis bias arising from prior knowledge of the findings. Clinical trial registration URL: http://www.clinicaltrials.gov . Unique identifiers for INTERACT2 (NCT00716079) and ATACH-II (NCT01176565).

Background Obesity and diabetes mellitus, or diabetes, are independently associated with post-ischemic stroke outcomes (e.g., functional disability and all-cause mortality). Although obesity and diabetes are also associated with post-ischemic stroke outcomes, the joint effect of obesity and diabetes on these post-ischemic stroke outcomes has not been explored previously. The purpose of the current study was to explore whether the effect of obesity on post-ischemic stroke outcomes differed by diabetes status in a cohort of acute ischemic stroke subjects with at least a moderate stroke severity. Methods Data from the Interventional Management of Stroke (IMS) III clinical trial was analyzed for this post-hoc analysis. A total of 656 subjects were enrolled in IMS III and were followed for one year. The joint effects of obesity and diabetes on functional disability at 3-months and all-cause mortality at 1-year were examined. Results Of 645 subjects with complete obesity and diabetes information, few were obese (25.74%) or had diabetes (22.64%). Obese subjects with diabetes and non-obese subjects without diabetes had similar odds of functional disability at 3-months following an ischemic stroke (adjusted common odds ratio, 1.038, 95% CI: 0.631, 1.706). For all-cause mortality at 1-year following an ischemic stroke, obese subjects with diabetes had a similar hazard compared with non-obese subjects without diabetes (adjusted hazard ratio, 1.005, 95% CI: 0.559, 1.808). There was insufficient evidence to declare a joint effect between obesity and diabetes on either the multiplicative scale or the additive scale for both outcomes. Conclusions In this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on post-ischemic stroke outcomes. Additionally, there was not sufficient evidence to determine that either factor was independently associated with all-cause mortality. Future studies could differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories to determine if the effect of obesity on post-stroke outcomes differs by diabetes status.

The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p

Ordinal outcomes collected at multiple follow-up visits are common in clinical trials. Sometimes, one visit is chosen for the primary analysis and the scale is dichotomized amounting to loss of information. Multistate Markov models describe how a process moves between states over time. Here, simulation studies are performed to investigate the type I error and power characteristics of multistate Markov models for panel data with limited non-adjacent state transitions. The results suggest that the multistate Markov models preserve the type I error and adequate power is achieved with modest sample sizes for panel data with limited non-adjacent state transitions.

Background Oxidized low-density lipoprotein (OxLDL) is a contributor to atherosclerosis development. OxLDL formation increases in the postprandial state due to oxidative stress in subjects with coronary artery disease (CAD) and diabetes, but has not been studied in patients with atherosclerotic stroke. We aimed to determine differences in postprandial OxLDL in patients with atherosclerotic stroke compared to stroke from other causes. Methods Patients with ischemic stroke but no history of CAD (n = 42) were enrolled and categorized by stroke subtype as extracranial atherosclerosis (EC), n = 12; intracranial atherosclerosis (IC), n = 16; or other cause, n = 14. After fasting overnight, subjects consumed a standardized fat meal. OxLDL levels were measured at t = 0 and t = 4 hours postprandial using enzyme-linked immunosorbent assay. Comparisons between the mean changes in OxLDL between the groups were performed using the analysis of variance procedure. Results The IC group had the highest mean baseline level of OxLDL and the greatest decline during the postprandial period. There was a trend toward a difference in the mean change in OxLDL between the 3 groups (P = .0553). Subjects with atherosclerotic stroke (EC and IC groups) had higher fasting OxLDL and had a significant decline in OxLDL compared to those with stroke from other causes (P = .0164). Conclusions Subjects with stroke due to atherosclerosis, particularly intracranially, demonstrated high fasting OxLDL and a decline in OxLDL during the postprandial period. This decline in OxLDL may indicate an accelerated clearance of OxLDL resulting from meal-induced oxidative stress.

BACKGROUND: Previous studies have reported that different locations of intracranial atherosclerosis (ICAS) are associated with different demographic features and vascular risk factors. We aimed to examine this observation in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial population. METHODS: SAMMPRIS was a randomized controlled trial that enrolled 451 patients with recent transient ischemic attack or stroke-related due to severe (70-99%) stenosis of a major intracranial artery. We compared the baseline demographic features and vascular risk factors between the symptomatic artery locations. Wilcoxon test was used to compare continuous variables, and chi-square test was used for categorical variables. RESULTS: Of 449 patients included in the analysis; 289 (64.4%) had ICAS in the anterior circulation and 160 (35.6%) in the posterior circulation. Features that were significantly different between patients with anterior versus posterior ICAS were: median age (58.3 years vs. 64.0 years, P

Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study.We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality.We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47).PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality.

Uncertainty persists over the effects of blood pressure lowering in acute intracerebral haemorrhage. We aimed to combine individual patient-level data from the two largest randomised controlled trials of blood pressure lowering strategies in patients with acute intracerebral haemorrhage to determine the strength of associations between key measures of systolic blood pressure control and safety and efficacy outcomes.We did a preplanned pooled analysis of individual patient-level data acquired from the main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. These trials included adult patients aged 19-99 years with spontaneous (non-traumatic) intracerebral haemorrhage and elevated systolic blood pressure, without a clear indication or contraindication to treatment. Patients were excluded if they had a structural cerebral cause for the intracerebral haemorrhage, had a low score (3-5) on the Glasgow Coma Scale, or required immediate neurosurgery. Our primary analysis assessed the independent associations between three post-randomisation systolic blood pressure summary measures-magnitude of reduction in 1 h, mean achieved systolic blood pressure, and variability in systolic blood pressure between 1 h and 24 h-and the primary outcome of functional status, as defined by the distribution of scores on the modified Rankin Scale at 90 days post-randomisation. We analysed the systolic blood pressure measures as continuous variables using generalised linear mixed models, adjusted for baseline covariables and trial. The primary and safety analyses were done in a modified intention-to-treat population, which only included patients with sufficient data on systolic blood pressure.3829 patients (mean age 63·1 years [SD 12·9], 1429 [37%] women, and 2490 [65%] Asian ethnicity) were randomly assigned in INTERACT2 and ATACH-II, with a median neurological impairment defined by scores on the National Institutes of Health Stroke Scale of 11 (IQR 6-16) and median time from the onset of symptoms of intracerebral haemorrhage to randomisation of 3·6 h (2·7-4·4). We excluded 20 patients with insufficient or no systolic blood pressure data, and we imputed missing systolic blood pressure data in 23 (1%) of the remaining 3809 patients. Overall, the mean magnitude of early systolic blood pressure reduction was 29 mm Hg (SD 22), and subsequent mean systolic blood pressure achieved was 147 mm Hg (15) and variability in systolic blood pressure was 14 mm Hg (8). Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio [OR] 0·90 [95% CI 0·87-0·94], p0·0001). Symptomatic hypotension occurred in 28 (1%) patients, renal serious adverse events occurred in 26 (1%) patients, and cardiac serious adverse events occurred in 99 (3%) patients.Our pooled analyses indicate that achieving early and stable systolic blood pressure seems to be safe and associated with favourable outcomes in patients with acute intracerebral haemorrhage of predominantly mild-to-moderate severity.None.

Background: The significance of early neurological improvement (ENI) and deterioration (END) in patients with primary intracerebral hemorrhage (ICH) is unclear. We sought to determine the prevalence and predictors of ENI and END and their impact on long term clinical outcome in patients with primary ICH recruited within 4.5 hours after symptom onset. Methods: We analyzed data from Antihypertensive Treatment at Acute Cerebral Hemorrhage (ATACH)-2 trial. ENI and END were defined by ≥ 4 points decrease or increase in NIHSS score within 24 hours post randomization, respectively. Baseline characteristics of patients that predicted ENI and END were identified. The association between ENI and END with favorable 90-day outcome (defined as modified Rankin Scale (mRS) Results: Ninety five of 1000 patients with ICH had END (9.5%). END was more common among non-Asians compared to Asians (55% vs 42%), patients with hematoma volume >=30 cc (26% vs 8%, p= Conclusions: We found a relatively high prevalence of early neurological improvement or deterioration in ICH patients. Both ENI and END are independent predictors of 90-day functional outcome.

Background and Purpose— The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. Methods— The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). Results— The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87–15.57). Conclusions— Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00235495.

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Background Neurodevelopmental disability is the most significant complication for survivors of infant surgery for congenital heart disease. In this study we sought to determine if perioperative circulating brain injury biomarker levels are associated with neurodevelopmental outcomes at 12 months. Methods A secondary analysis of a randomized controlled trial of neonates who underwent cardiac surgery was performed. Glial fibrillary acidic protein (GFAP) was measured: (1) before skin incision; (2) immediately after bypass; (3) 4 and (4) 24 hours postoperatively. Linear regression models were used to determine an association with the highest levels of GFAP and Bayley Scales of Infant and Toddler Development third edition (BSID) composite scores. Results There were 97 subjects who had cardiac surgery at a mean age of 9 ± 6 days and completed a BSID at 12.5 ± 0.6 months of age. Median (25th-75th percentile) levels of GFAP were 0.01 (0.01-0.02), 0.85 (0.40-1.55), 0.07 (0.05-0.11), and 0.03 (0.02-0.04) ng/mL at the 4 time points, respectively. In univariate analysis GFAP was negatively associated with cognitive, language, and motor composite scores. GFAP levels immediately after bypass differed between institutions; 1.57 (0.92-2.48) versus 0.77 (0.36-1.21) ng/mL (P = .01). After adjusting for center and potential confounders, GFAP was independently associated with BSID motor score (P = .04). Conclusions Higher GFAP levels at the time of neonatal cardiac operations were independently associated with decreased BSID motor scores at 12 months. GFAP might serve as a diagnostic means to acutely identify perioperative brain-specific injury and serve as a benchmark of therapeutic efficacy for investigational treatments, discriminate center-specific effects, and provide early prognostic information for intervention.

In clinical trials, longitudinally assessed ordinal outcomes are commonly dichotomized and only the final measure is used for primary analysis, partly for ease of clinical interpretation. Dichotomization of the ordinal scale and failure to utilize the repeated measures can reduce statistical power. Additionally, in certain emergent settings, the same measure cannot be assessed at baseline prior to treatment. For such a data set, a piecewise-constant multistate Markov model that incorporates a latent model for the unobserved baseline measure is proposed. These models can be useful in analyzing disease history data and are advantageous in clinical applications where a disease process naturally moves through increasing stages of severity. Two examples are provided using acute stroke clinical trials data. Conclusions drawn in this article are consistent with those from the primary analysis for treatment effect in both of the motivating examples. Use of these models allows for a more refined examination of treatment effect and describes the movement between health states from baseline to follow-up visits which may provide more clinical insight into the treatment effect.

Supplemental Material for Statistical analysis plan for pooled individual patient data from two landmark randomized trials (INTERACT2 and ATACH-II) of intensive blood pressure lowering treatment in acute intracerebral hemorrhage by Tom J Moullaali, Xia Wang, Renee' H Martin, Virginia B Shipes, Adnan I Qureshi, Craig S Anderson and Yuko Y Palesch in International Journal of Stroke

Although obesity and diabetes mellitus, or diabetes, are independently associated with mortality-related events (e.g., all-cause mortality and cardiovascular-related mortality) following an ischemic stroke, little is known about the joint effect of obesity and diabetes on mortality-related events following an ischemic stroke. The aim of this study is to evaluate the joint effect of obesity and diabetes on mortality-related events in subjects with a recent ischemic stroke. Data from the multicenter Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial was analyzed for this study. The joint effect of obesity and diabetes on mortality-related events was estimated via Cox proportional hazards regression models. No difference in the hazard of all-cause mortality following an ischemic stroke was observed between obese subjects with diabetes and underweight/normal-weight subjects without diabetes. In contrast, obese subjects with diabetes had an increased hazard of cardiovascular-related mortality following an ischemic stroke compared with underweight/normal-weight subjects without diabetes. Additionally, there was evidence of an attributable proportion due to interaction as well as evidence of a highly statistically significant interaction on the multiplicative scale for cardiovascular-related mortality. In this clinical trial cohort of ischemic stroke survivors, obesity and diabetes synergistically interacted to increase the hazard of cardiovascular-related mortality.

Objective:To validate various noncontrast CT (NCCT) predictors of hematoma expansion in a large international cohort of ICH patients and investigate whether intensive blood pressure (BP) treatment reduces ICH growth and improves outcome in patients with these markers.Methods:We analyzed patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized controlled trial. Participants were assigned to intensive (systolic BP 33% and unfavorable outcome was defined as modified Rankin Scale score >3 at 90 days. Logistic regression was used to identify predictors of ICH expansion and explore the association between NCCT signs and clinical benefit from intensive BP treatment.Results:A total of 989 patients were included (mean age 62 years, 61.9% male), of whom 186/869 experienced hematoma expansion (21.4%) and 361/952 (37.9%) had unfavorable outcome. NCCT markers independently predicted ICH expansion (all p < 0.01) with overall accuracy ranging from 61% to 78% and good interrater reliability (k > 0.6 for all markers). There was no evidence of an interaction between NCCT markers and benefit from intensive BP reduction (all p for interaction >0.10).Conclusions:NCCT signs reliably identify ICH patients at high risk of hematoma growth. However, we found no evidence that patients with these markers specifically benefit from intensive BP reduction.Clinicaltrials.gov identifier:NCT01176565.

Historically, ordinal measures of functional outcome have been dichotomized for the primary analysis in acute stroke therapy trials. A number of alternative methods to analyze the ordinal scales have been proposed, with an emphasis on maintaining the ordinal structure as much as possible. In addition, despite the availability of longitudinal outcome data in many trials, the primary analysis consists of a single endpoint. Inclusion of information about the course of disease progression allows for a more complete understanding of the treatment effect. Multistate Markov modeling, which allows for the full ordinal scale to be analyzed longitudinally, is compared with previously suggested analytic techniques for the ordinal modified Rankin Scale (dichotomous-logistic regression; continuous-linear regression; ordinal- shift analysis, proportional odds model, partial proportional odds model, adjacent categories logit model; sliding dichotomy; utility weights; repeated measures). In addition, a multistate Markov model utilizing an estimate of the unobservable baseline outcome derived from principal component analysis is compared Each of the methods is used to re-analyze the National Institute of Neurological Diseases and Stroke tissue plasminogen activator study which showed a consistently significant effect of tissue plasminogen activator using a global test of four dichotomized outcomes in the analysis of the primary outcome at 90 days post-stroke in the primary analysis. All methods detected a statistically significant treatment effect except the multistate Markov model without predicted baseline (p = 0.053). This provides support for the use of the estimated baseline in the multistate Markov model since the treatment effect is able to be detected with its inclusion. Multistate Markov modeling allows for a more refined examination of treatment effect and describes the movement between modified Rankin Scale states over time which may provide more clinical insight into the treatment effect. Multistate Markov models are feasible and desirable in describing treatment effect in acute stroke therapy trials.

Background and Purpose: the computed tomography angiography (CTA) spot sign is a strong predictor of intracerebral hemorrhage (ICH) expansion, and may mark those most likely to benefit from intensive blood pressure (BP) reduction. The Spot Sign score in restricting ICH growth (SCORE-IT) study analyzed whether intensive BP reduction improved outcome in Spot Sign positive patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) clinical trial. Methods: In ATACH-2, patients with ICH were randomly assigned to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment within 4.5 h from stroke onset. This analysis included patients with a CTA performed within 8 hours from onset. The association between intensive BP lowering, ICH expansion and functional outcome was investigated with a multivariable logistic regression model. Results: 133 subjects met the inclusion criteria, of whom 53 (39.9%) had a spot sign and 24/123 (19.5%) experienced ICH expansion. A total of 56/123 patients had a 90 day modified Rankin scale (mRS) >3 (45.5%). Among Spot positive patients, 74.1% of those in the intensive BP lowering group had poor outcome, compared with 50.0% of those in the standard group (p=0.31). After adjustment for potential confounders, intensive BP lowering was not associated with a significant reduction of ICH expansion (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.27 - 2.51, p = 0.74) or improved functional outcome (OR for mRS>3 1.24, 95% CI 0.53 - 2.91, p = 0.62) in spot sign positive ICH patients. Conclusions: We found no evidence that ICH patients with a spot sign specifically benefit from intensive BP reduction.

Background Interventional Management of Stroke III did not show that combining IV recombinant tissue plasminogen activator (rt-PA) with endovascular therapies (EVTs) is better than IV rt-PA alone. Objective To report efficacy and safety results for EVT of intracranial internal carotid artery (ICA) and middle cerebral artery trunk (M1) occlusion. Methods Five revascularization methods for persistent occlusions after IV rt-PA treatment were evaluated for prespecified primary and secondary endpoints, after accounting for differences in key baselines variables using propensity scores. Revascularization was scored using the arterial occlusive lesion (AOL) and the modified Thrombolysis in Cerebral Ischemia (mTICI) scores. Results EVT of 200 subjects with intracranial ICA or M1 occlusion resulted in 81.5% AOL 2–3 recanalization, in addition to 76% mTICI 2–3 and 42.5% mTICI 2b–3 reperfusion. Adverse events included symptomatic intracranial hemorrhage (SICH) (8.0%), vessel perforations (1.5%), and new emboli (14.9%). EVT techniques used were standard microcatheter n=51; EKOS n=14; Merci n=77; Penumbra n=39; Solitaire n=4; multiple n=15. Good clinical outcome was associated with both TICI 2–3 and TICI 2b–3 reperfusion. Neither modified Rankin scale (mRS) 0–2 (28.5%), nor 90-day mortality (28.5%), nor asymptomatic ICH (36.0%) differed among revascularization methods after propensity score adjustment for subjects with intracranial ICA or M1 occlusion. Conclusions Good clinical outcome was associated with good reperfusion for ICA and M1 occlusion. No significant differences in efficacy or safety among revascularization methods were demonstrated after adjustment. Lack of high-quality reperfusion, adverse events, and prolonged time to treatment contributed to lower-than-expected mRS 0–2 outcomes and study futility compared with IV rt-PA. Trial registration number NCT00359424.

ObjectiveHigh blood pressure (BP) is commonly not diagnosed, and patients do not achieve target values when treated. Among 20 000 patients encompassing most races-ethnicities, we evaluated BP measurements and treatment response in a stroke prevention trial. Our goal was to identify BP measurement di

Oftentimes valid statistical analyses for clinical trials involve adjustment for known influential covariates, regardless of imbalance observed in these covariates at baseline across treatment groups. Thus, it must be the case that valid interim analyses also properly adjust for these covariates. There are situations, however, in which covariate adjustment is not possible, not planned, or simply carries less merit as it makes inferences less generalizable and less intuitive. In this case, covariate imbalance between treatment groups can have a substantial effect on both interim and final primary outcome analyses. This paper illustrates the effect of influential continuous baseline covariate imbalance on unadjusted conditional power (CP), and thus, on trial decisions based on futility stopping bounds. The robustness of the relationship is illustrated for normal, skewed, and bimodal continuous baseline covariates that are related to a normally distributed primary outcome. Results suggest that unadjusted CP calculations in the presence of influential covariate imbalance require careful interpretation and evaluation.

Background and Purpose— Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue-type plasminogen activator followed by endovascular treatment with intravenous tissue-type plasminogen activator alone in patients with acute ischemic stroke presenting Methods— Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. Results— The futility boundary was crossed at the trial’s fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. Conclusions— Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00359424.