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BACKGROUND AND PURPOSE: Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known. METHODS: We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders. RESULTS: A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p = .30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823 vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction. CONCLUSIONS: Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization.
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Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that ß-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 ß-adrenoceptor (ß-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of ß-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32âmg salbutamol, 160µg clenbuterol, 60âmg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20µg on Day 1, 40µg on Day 2, 80µg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral ß 2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of ß2-ARs in the CNS.
Aims and Purpose of the Research:This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease.Background of the Research:Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease.Methods and Research Design:The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs salbutamol, clenbuterol, and pindolol as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days.Results and Importance:In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain.These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings.
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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.
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AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.
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Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research.
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Teorema de Bayes , Ensaios Clínicos Fase II como Assunto , Modelos Estatísticos , Humanos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Simulação por Computador , Ensaios Clínicos Controlados Aleatórios como Assunto , Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fatores de TempoRESUMO
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.
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Tamanho da Amostra , Humanos , Avaliação de Programas e Projetos de Saúde , Fatores de TempoRESUMO
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.
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Lesões Encefálicas Traumáticas , Humanos , Teorema de Bayes , Lesões Encefálicas Traumáticas/terapia , Escala de Resultado de Glasgow , Probabilidade , Prognóstico , Ensaios Clínicos como AssuntoRESUMO
Adrenoceptors (ARs) throughout the brain are stimulated by noradrenaline originating mostly from neurons of the locus coeruleus, a brainstem nucleus that is ostensibly the earliest to show detectable pathology in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The α1-AR, α2-AR, and ß-AR subtypes expressed in target brain regions and on a range of cell populations define the physiological responses to noradrenaline, which includes activation of cognitive function in addition to modulation of neurometabolism, cerebral blood flow, and neuroinflammation. As these heterocellular functions are critical for maintaining brain homeostasis and neuronal health, combating the loss of noradrenergic tone from locus coeruleus degeneration may therefore be an effective treatment for both cognitive symptoms and disease modification in neurodegenerative indications. Two pharmacologic approaches are receiving attention in recent clinical studies: preserving noradrenaline levels (e.g., via reuptake inhibition) and direct activation of target adrenoceptors. Here, we review the expression and role of adrenoceptors in the brain, the preclinical studies which demonstrate that adrenergic stimulation can support cognitive function and cerebral health by reversing the effects of noradrenaline depletion, and the human data provided by pharmacoepidemiologic analyses and clinical trials which together identify adrenoceptors as promising targets for the treatment of neurodegenerative disease.
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Studies that investigate the performance of prognostic and predictive biomarkers are commonplace in medicine. Evaluating the performance of biomarkers is challenging in traumatic brain injury (TBI) and other conditions when both the time factor (i.e. time from injury to biomarker measurement) and different levels or doses of treatments are in play. Such factors need to be accounted for when assessing the biomarker's performance in relation to a clinical outcome. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial seeks to determine the dose of hyperbaric oxygen therapy (HBOT) for treating severe TBI that has the highest likelihood of demonstrating efficacy in a phase III trial. Hyperbaric Oxygen in Brain Injury Treatment will study up to 200 participants with severe TBI. This paper discusses the statistical approaches to assess the prognostic and predictive performance of the biomarkers studied in this trial, where prognosis refers to the association between a biomarker and the clinical outcome while the predictiveness refers to the ability of the biomarker to identify patient subgroups that benefit from therapy. Analyses based on initial biomarker levels accounting for different levels of HBOT and other baseline clinical characteristics, and analyses of longitudinal changes in biomarker levels are discussed from a statistical point of view. Methods for combining biomarkers that are of complementary nature are also considered and the relevant algorithms are illustrated in detail along with an extensive simulation study that assesses the performance of the statistical methods. Even though the discussed approaches are motivated by the HOBIT trial, their applications are broader. They can be applied in studies assessing the predictiveness and prognostic ability of biomarkers in relation to a well-defined therapeutic intervention and clinical outcome.
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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.
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National Institute of Neurological Disorders and Stroke (USA) , Acidente Vascular Cerebral , Humanos , Hemorragia Cerebral/terapia , Estudos Multicêntricos como Assunto , National Institutes of Health (U.S.) , Distribuição Aleatória , Acidente Vascular Cerebral/tratamento farmacológico , Estados Unidos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: We sought to compare outcomes for infants with tetralogy of Fallot with pulmonary atresia (TOF/PA) and confluent pulmonary arteries who underwent staged or primary complete surgical repair. METHODS: This retrospective study included infants undergoing initial surgical intervention between 0 and 60 days of age with TOF/PA without aortopulmonary collaterals from 2009 to 2018 at 20 centers. The primary outcome was days alive and out of the hospital in the first year of life (DAOH365). Secondary outcomes were mortality at 1 year of age and a composite major complication outcome. Multivariable modeling with generalized estimating equations were used to compare outcomes between groups. RESULTS: Of 221 subjects, 142 underwent staged repair and 79 underwent primary complete repair. There was no significant difference in median DAOH365 between the staged and primary repair groups (317 days [interquartile range, 278-336] vs 338 days [interquartile range, 314-348], respectively; adjusted P = .13). Nine staged repair patients (7%) died in the first year of life vs 5 primary repair patients (6%; adjusted odds ratio, 1.00; 95% CI, 0.25-3.95). At least 1 major complication occurred in 37% of patients who underwent staged repair vs 41% of patients who underwent primary complete repair (P = .75), largely driven by the need for unplanned cardiac reinterventions. CONCLUSIONS: For infants with TOF/PA with confluent pulmonary arteries, a surgical strategy of staged or primary complete repair resulted in statistically similar DAOH365, early mortality, and morbidity.
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Procedimentos Cirúrgicos Cardíacos , Atresia Pulmonar , Tetralogia de Fallot , Lactente , Humanos , Tetralogia de Fallot/complicações , Estudos Retrospectivos , Procedimentos Cirúrgicos Cardíacos/métodos , Resultado do Tratamento , Artéria Pulmonar/cirurgia , Artéria Pulmonar/anormalidadesRESUMO
BACKGROUND: Symptomatic intracranial atherosclerotic disease (sICAD) is estimated to cause 10% of strokes annually in the United States. However, treatment remains a challenge with several different stenting options studied in the past with unfavorable results. OBJECTIVE: To report the 30-day stroke and/or death rate associated with intracranial stent placement for sICAD using Resolute Onyx Zotarolimus-Eluting Stent (RO-ZES) and provide a comparison with the results of Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: Prospectively maintained databases across 8 stroke centers were used to identify adult patients treated with RO-ZES for sICAD between January 2019 and December 2021. Primary end point was composite of 30-day stroke, intracerebral hemorrhage, and/or death. Propensity score matching was performed using age, hypertension, lipid disorder, cigarette smoking, and symptomatic target vessel to create a matched group for comparison between RO-ZES and the SAMMPRIS medical management and treatment groups (SAMMPRIS percutaneous angioplasty and stenting [S-PTAS]). RESULTS: A total of 132 patients met the inclusion criteria for analysis (mean age: 64.2 years). Mean severity of stenosis was 81.4% (±11.4%). A total of 4 (3.03%) stroke and/or deaths were reported within 30 days of treatment in the RO-ZES group compared with 6.6% in the SAMMPRIS medical management group (OR [odds ratio] 2.26, 95% CI 0.7-9.56, P = .22) and 15.6% in the S-PTAS group (OR 5.9, 95% CI 2.04-23.4, P < .001). Propensity score match analysis of 115 patients in each group demonstrated 30-day stroke and/or death rate of 2.6% in the RO-ZES group and 15.6% in the S-PTAS group (OR 6.88, 95% CI 1.92-37.54, P < .001). CONCLUSION: Patients treated with RO-ZES had a relatively low 30-day stroke and/or death rate compared with the S-PTAS group. Further large-scale prospective studies are warranted to evaluate the safety and efficacy of RO-ZES for the treatment of sICAD.
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Stents Farmacológicos , Acidente Vascular Cerebral , Adulto , Humanos , Pessoa de Meia-Idade , Constrição Patológica/cirurgia , Stents Farmacológicos/efeitos adversos , Pontuação de Propensão , Resultado do Tratamento , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/etiologia , Stents/efeitos adversos , Infarto Cerebral/etiologiaRESUMO
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.
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Isquemia Encefálica , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/cirurgia , Acidente Vascular Cerebral/etiologia , Isquemia Encefálica/cirurgia , Resultado do Tratamento , Procedimentos Endovasculares/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombectomia/métodos , Terapia Trombolítica/métodos , Hemorragia Cerebral/terapia , Fibrinolíticos/uso terapêuticoRESUMO
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.
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Isquemia Encefálica , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Animais , Cilostazol/farmacologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Funções Verossimilhança , Infarto Cerebral , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Modelos AnimaisRESUMO
BACKGROUND: A resurgence of research into phase II trial design in the mid-2000s led to the use of futility designs in a wide variety of disease areas. Phase II futility studies differ from efficacy studies in that their null hypothesis is that treatment, relative to control, does not meet or exceed the level of benefit required to justify additional study. A rejection of the null hypothesis indicates that the treatment should not proceed to a larger confirmatory trial. METHODS: Bayesian approaches to the design of phase II futility clinical trials are presented and allow for the quantification of key probabilities, such as the predictive probability of current trial success or even the predictive probability of a future trial's success. RESULTS: We provide an illustration of the design and interpretation of a phase II futility study constructed in a Bayesian framework. We focus on the operating characteristics of our motivating trial based on a simulation study, as well as the general interpretation of trial outcomes, type I, and type II errors in this framework. CONCLUSIONS: Phase II futility clinical trials, when designed under in a Bayesian framework, offer an alternative approach to the design of mid-phase studies which provide unique benefits relative to trials designed in a frequentist framework and designs which focus on treatment efficacy.
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Futilidade Médica , Projetos de Pesquisa , Humanos , Teorema de Bayes , Probabilidade , Simulação por ComputadorRESUMO
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.
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Nicardipino , Acidente Vascular Cerebral , Anti-Hipertensivos/uso terapêutico , Hemorragia Cerebral , Cloretos/uso terapêutico , Humanos , Nicardipino/uso terapêuticoRESUMO
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Difteria , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Tétano , Coqueluche , Adolescente , Estudos Transversais , Feminino , Georgia , Humanos , Masculino , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/uso terapêutico , Vacinação , Coqueluche/prevenção & controleRESUMO
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Vacinas contra Difteria, Tétano e Coqueluche Acelular , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adolescente , Teorema de Bayes , Estudos Transversais , Feminino , Georgia , Humanos , Masculino , Infecções por Papillomavirus/prevenção & controle , VacinaçãoRESUMO
OBJECTIVE: The aim of this study was to better define the shape of association between the degree ("magnitude") of early (< 1 h) reduction in systolic blood pressure (SBP) and outcomes in patients with acute intracerebral hemorrhage (ICH) through pooled analysis of the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) and second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) datasets. 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 (< 1 h) of SBP reduction of 28.5 (22.8) mmHg, those with larger magnitude were more often non-Asian and female, had higher baseline SBP, received multiple blood pressure (BP) lowering agents, and achieved lower SBP levels in 1-24 h. Compared to those patients with no SBP reduction within 1 h (reference), the adjusted odds of unfavorable functional outcome, according to a shift in mRS scores, were lower for SBP reductions up to 60 mmHg with an inflection point between 32 and 46 mmHg, but significantly higher for SBP reductions > 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 < 140 mmHg) were associated with reduction, or reversal, of any such benefit.
Assuntos
Hipertensão , Acidente Vascular Cerebral , Humanos , Feminino , Pessoa de Meia-Idade , Pressão Sanguínea , Hemorragia Cerebral/complicações , Hemorragia Cerebral/terapia , Hematoma , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Resultado do TratamentoRESUMO
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.