Evaluating the strength and quality of evidence in american heart association/American stroke association's guidelines for aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage.

BACKGROUND: Clinical practice recommendations guide healthcare decisions. This study aims to evaluate the strength and quality of evidence supporting the American Heart Association (AHA)/American Stroke Association (ASA) guidelines for aneurysmal subarachnoid hemorrhage (aSAH) and spontaneous intracerebral hemorrhage (ICH). METHODS: We reviewed the current AHA/ASA guidelines for aSAH and spontaneous ICH and compared with previous guidelines. Guidelines were classified based on the Class of recommendation (COR) and Level of evidence (LOE). COR signifies recommendation strength (COR 1: Strong; COR 2a: Moderate; COR 2b: Weak; COR 3: No Benefit/Harm), while LOE denotes evidence quality (LOE A: High-Quality; LOE B-NR: Moderate-Quality, Not Randomized; LOE B-R: Moderate-Quality, Randomized; LOE C-EO: Expert Opinion; LOE C-LD: Limited Data). RESULTS: For aSAH, we identified 84 recommendations across 15 guideline categories. Of these, 31% were classified as COR I, 30% as COR 2a, 17% as COR 2b, and 18% as COR 3. In terms of LOE, 7% were based on LOE A, 10% on LOE B-R, 65% on LOE B-NR, 14% on LOE C-LD, and 5% on LOE C-EO. Compared to previous guidelines, there was a 46% decrease in LOE A, a 45% increase in LOE B, and an 11% decrease in LOE C. For spontaneous ICH, 124 guidelines were identified across 31 guideline categories. Of these, 28% were COR I, 32% COR 2b, and 9% COR 3. For LOE, 4% were based on LOE A, 35% on LOE B-NR, and 42% on LOE C-LD. Compared to previous guidelines, there was a 78% decrease in LOE A, an 82% increase in LOE B, and a 14% increase in LOE C. This analysis highlights that less than a third of AHA/ASA guidelines are classified as the highest class of recommendation, with less than 10% based on the highest LOE. CONCLUSION: Less than a third of AHA/ASA guidelines on aSAH and spontaneous ICH are classified as the highest class of recommendation with less than 10% based on highest LOE. There appears to be a decrease in proportion of guidelines based on highest LOE in most recent guidelines.

Optimal Randomization Designs for Large Multicenter Clinical Trials: From the National Institutes of Health Stroke Trials Network Funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke Experience.

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization.

Designing a phase-III time-to-event clinical trial using a modified sample size formula and Poisson-Gamma model for subject accrual that accounts for the lag in site initiation using the PERT distribution.

A priori estimation of sample size and subject accrual in multi-site, time-to-event clinical trials is often challenging. Such trials are powered based on the number of events needed to detect a clinically significant difference. Sample size based on number of events relates to the expected duration of observation time for each subject. Temporal patterns in site initiation and subject enrollment ultimately affect when subjects can be accrued into the study. Lag times are common as the site start-up process optimizes, resulting in delays that may curtail observational follow-up and therefore undermine power. The proposed method introduces a Program Evaluation and Review Technique (PERT) model into the sample size estimation which accounts for the lag in site start-up. Additionally, a PERT model is introduced into a Poisson-Gamma subject accrual model to predict the quantity of study sites needed. The introduction of the PERT model provides greater flexibility in both a priori power assessment and planning the number of sites, as it specifically allows for the inclusion of anticipated delays in site start-up time. This model results in minimal power loss even when PERT distribution inputs are misspecified compared to the traditional assumption of simultaneous start-up for all sites. Together these updated formulations for sample size and subject accrual models offer an improved method for designing a multi-site time-to-event clinical trial that accounts for a flexible site start-up process.

Selection of a statistical analysis method for the Glasgow Outcome Scale-Extended endpoint for estimating the probability of favorable outcome in future severe TBI clinical trials.

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.

Effect of Cilostazol in Animal Models of Cerebral Ischemia and Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, appears to be a promising agent for preventing cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Here, the authors perform a systematic review and meta-analysis to quantitatively assess the effects of cilostazol on brain structural and functional outcomes in animal models of cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm. METHODS: By using the PRISMA guidelines, a search of the PubMed, Scopus, and Web of Science was conducted to identify relevant studies. Study quality of each included study for both systematic reviews were scored by using an adapted 15-item checklist from the Collaborative Approach to Meta-Analysis of Animal Data from Experimental Studies. We calculated a standardized mean difference as effect size for each comparison. For each outcome, comparisons were combined by using random-effects modeling to account for heterogeneity, with a restricted maximum likelihood estimate of between-study variance. RESULTS: A total of 22 (median [Q1, Q3] quality score of 7 [5, 8]) and 6 (median [Q1, Q3] quality score of 6 [6, 6]) studies were identified for cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm, respectively. Cilostazol significantly reduced the infarct volume in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.88 (95% confidence interval [CI] [- 1.07 to - 0.70], p < 0.0001). Cilostazol significantly reduced neurofunctional deficits in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.66 (95% CI [- 1.06 to - 0.28], p < 0.0001). Cilostazol significantly improved the basilar artery diameter in subarachnoid hemorrhage-induced cerebral vasospasm with a pooled standardized mean difference estimate of 2.30 (95% CI [0.94 to 3.67], p = 0.001). Cilostazol also significantly improved the basilar artery cross-section area with a pooled standardized mean estimate of 1.88 (95% CI [0.33 to 3.43], p < 0.05). Overall, there was between-study heterogeneity and asymmetry in the funnel plot observed in all comparisons. CONCLUSIONS: Published animal data support the overall efficacy of cilostazol in reducing infarct volume and neurofunctional deficits in cerebral ischemia models and cerebral vasospasm in subarachnoid hemorrhage models.

Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.

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-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. 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.

Early Hyperchloremia is Independently Associated with Death or Disability in Patients with Intracerebral Hemorrhage.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

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.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 ).

Correction to: Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials.

An amendment to this paper has been published and can be accessed via the original article.