CT Perfusion Map Synthesis from CTP Dynamic Images Using a Learned LSTM Generative Adversarial Network for Acute Ischemic Stroke Assessment.

Computed tomography perfusion (CTP) is a dynamic 4-dimensional imaging technique (3-dimensional volumes captured over approximately 1 min) in which cerebral blood flow is quantified by tracking the passage of a bolus of intravenous contrast with serial imaging of the brain. To diagnose and assess acute ischemic stroke, the standard method relies on summarizing acquired CTPs over the time axis to create maps that show different hemodynamic parameters, such as the timing of the bolus arrival and passage (Tmax and MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). However, producing accurate CTP maps requires the selection of an arterial input function (AIF), i.e. a time-concentration curve in one of the large feeding arteries of the brain, which is a highly error-prone procedure. Moreover, during approximately one minute of CT scanning, the brain is exposed to ionizing radiation that can alter tissue composition, and create free radicals that increase the risk of cancer. This paper proposes a novel end-to-end deep neural network that synthesizes CTP images to generate CTP maps using a learned LSTM Generative Adversarial Network (LSTM-GAN). Our proposed method can improve the precision and generalizability of CTP map extraction by eliminating the error-prone and expert-dependent AIF selection step. Further, our LSTM-GAN does not require the entire CTP time series and can produce CTP maps with a reduced number of time points. By reducing the scanning sequence from about 40 to 9 time points, the proposed method has the potential to minimize scanning time thereby reducing patient exposure to CT radiation. Our evaluations using the ISLES 2018 challenge dataset consisting of 63 patients showed that our model can generate CTP maps by using only 9 snapshots, without AIF selection, with an accuracy of 84.37 % .

The Impact of Atherosclerotic Burden on Vascular Outcomes in Patients with Stroke and Atrial Fibrillation: The ATHENA study.

Introduction: Patients with ischemic stroke (IS) and atrial fibrillation (AF) face a higher risk of recurrent vascular events. This study evaluates the impact of atherosclerotic vascular disease burden across different vascular territories on the risk of vascular events in patients with recent ischemic stroke and AF within 90 days. Patients and Methods: We included patients with IS and AF from the International RAF network in a prospective 90-day follow-up. Atherosclerotic vascular disease was identified by at least one of the following: Symptomatic ischemic heart disease, symptomatic peripheral artery disease, internal carotid stenosis ≥50%, or the presence of plaques in the aorta. The primary outcome was a composite of stroke, transient ischemic attack, systemic embolism, cerebral bleeding, and major extracranial bleeding within 90 days postacute stroke. Patients were categorized into 5 groups based on the number of affected atherosclerotic vascular territories, with those with no atherosclerotic vascular disease as the reference. Kaplan-Meier curves were generated and compared using the log-rank test to determine the predictive value of the number of diseased territories for the risk of events. Data analysis was performed with SPSS/PC Win Package 25.0. Results: Of the 2148 patients (mean age 77.59; 53.86% female), 744 (34.60%) had atherosclerosis. Multivariable analysis revealed that involvement of 3 (hazard ratio [HR] 2.80, 95% confidence interval [CI]: 1.20-6.53) or 4 (HR 6.81, 95% CI: 1.02-36.24) vascular territories was significantly associated with the risk of combined events. Conclusions: In patients with recent ischemic stroke and AF, atherosclerosis across multiple territories correlates with a higher risk of future vascular events.

Intraoperative intensive blood pressure management strategy and the outcome of patients who had an acute ischaemic stroke undergoing endovascular treatment under general anaesthesia: study protocol for a prospective randomised controlled trial.

BackgroundEndovascular thrombectomy is the recommended treatment for acute ischaemic stroke, but the optimal blood pressure management strategy during the procedure under general anaesthesia remains controversial. In this study protocol, we propose an intraoperative intensive blood pressure range (110-140 mm Hg systolic blood pressure) based on a retrospective analysis and extensive literature review. By comparing the outcomes of patients who had an acute ischaemic stroke undergoing mechanical thrombectomy under general anaesthesia with standard blood pressure management (140-180 mm Hg systolic blood pressure) versus intensive blood pressure management, we aim to determine the impact of intraoperative intensive blood pressure management strategy on patient prognosis. METHODS AND ANALYSIS: The study is a double-blinded, randomised, controlled study, with patients randomised into either the standard blood pressure management group or the intensive blood pressure management group. The primary endpoint of the study will be the sequential analysis of modified Rankin Scale scores at 90 days after mechanical thrombectomy. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of Shanghai Changhai Hospital with an approval number CHEC2023-015. The results of the study will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: ChiCTR2300070764.

[Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options]. / Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva.

Background and purpose:

The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.

We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo­gical and cardiovascular findings compared to those in the thrombolysis project. 

Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 
2 pa­tients had improved visual acuity, 2 pa­tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.

CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.

Personalised stroke evaluation and management: tailoring individualised patient care for hereditary haemorrhagic telangiectasia.

SummaryHereditary haemorrhagic telangiectasia (HHT) has an estimated prevalence of 1 in 5000-8000 individuals globally with pulmonary arteriovenous malformations (PAVMs) affecting approximately 15%-50% of HHT patients. Ischaemic stroke is a known complication of PAVMs that affects ≤30% of patients with PAVMs. Studies have shown that patients with PAVMs have ischaemic stroke a decade earlier than routine stroke. The predominant mechanism of ischaemic stroke in HHT patients is paradoxical embolism due to PAVMs, but most HHT-related PAVMs are asymptomatic. Additionally, HHT is often underdiagnosed in patients and poses a challenge to physicians due to its rarity. We present a case of a patient with ischaemic stroke who was subsequently diagnosed with HHT and found to have a PAVM on further evaluation. This case highlights the importance of using an individualised patient-centred stroke evaluation and screening for PAVMs in patients who had a stroke with possible or suspected HHT and definite HHT.

Predictive value of admission D-dimer levels in patient with acute ischaemic stroke and COVID-19: a second-wave prospective cohort study.

OBJECTIVES: This study aimed to evaluate the predictive value of admission D-dimer levels for in-hospital mortality in patients with COVID-19 and acute ischaemic stroke. DESIGN: Cohort (prospective). SETTING: Tertiary referral hospital in the capital city of Indonesia conducted from June to December 2021. PARTICIPANTS: 60 patients with acute ischaemic stroke and COVID-19 were included. Patients were classified into D-dimer groups (low and high) according to a 2 110 ng/mL cut-off value, determined via receiver operating characteristic analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was in-hospital mortality, with admission D-dimer levels as the major predictor. Secondary outcomes included associations between other demographic and clinical variables and the admission D-dimer value. Kaplan-Meier method was used to carry out survival analysis, with univariable and multivariable Cox regression performed to assess the association of D-dimer levels and other confounding variables (including demographic, clinical and laboratory parameters) with in-hospital mortality. RESULTS: The findings demonstrated an association between elevated admission D-dimer levels (≥2 110 ng/mL) and an increased likelihood of death during hospitalisation. The adjusted HR was 14.054 (95% CI 1.710 to 115.519; p=0.014), demonstrating an increase in mortality risk after accounting for confounders such as age and diabetes history. Other significant predictors of mortality included a history of diabetes and increased white blood cell count. CONCLUSIONS: Admission D-dimer levels may be a useful predictive indicator for the likelihood of death during hospitalisation in individuals with COVID-19 and acute ischaemic stroke.

Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy.

AIMS: Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB-PTPIP51 in experimental cerebral ischemia. METHODS: We simulated cerebral ischemia-reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model. RESULTS: We observed a decrease in VAPB-PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria-ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator. CONCLUSIONS: Our findings suggest that the downregulation of VAPB-PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS.

Socioeconomic disparities in the association of age at first live birth with incident stroke among Chinese parous women: A prospective cohort study.

Background: Stroke has become a significant public health issue in China. Although studies have shown that women's age at first live birth (AFLB) might be associated with incident stroke, there is limited evidence on this relationship among Chinese parous women. Likewise, the nature of this association across urban-rural socioeconomic status (SES) has yet to be explored. In this prospective study, we sought to investigate the associations of women's AFLB with the risk of incident stroke and its subtypes (ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage) and to explore the differences of these associations as well as the population-level impacts across SES classes. Methods: We used data on 290 932 Chinese parous women from the China Kadoorie Biobank who were recruited in the baseline survey between 2004 and 2008 and followed up until 2015. We used latent class analysis to identify urban-rural SES classes and Cox proportional hazard regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for AFLB's association with incident stroke. We then calculated population attributable fraction (PAF) to demonstrate the population-level impact of later AFLB on stroke. Results: Around 8.9% of parous women developed stroke after AFLB. Compared with women with AFLB <22 years, those with older AFLB had a higher risk of total stroke, with fully adjusted HRs (95% CI) of 1.71 (95% CI = 1.65-1.77) for 22-24 years and 3.37 (95% CI = 3.24-3.51) for ≥25 years. The associations of AFLB with ischaemic stroke were stronger among rural-low-SES participants. We found the highest PAFs of ischaemic stroke (60.1%; 95% CI = 46.2-70.3) associated with later AFLB for urban-high-SES individuals. Conclusions: Older AFLB was associated with higher risks of incident stroke and its subtypes among Chinese parous women, with stronger associations between AFLB and ischaemic stroke among rural-low-SES participants. Targeted medical advice for pregnant women of different ages could have long-term benefits for stroke prevention.

Causal effects of immune cell surface antigens and functional outcome after ischemic stroke: a Mendelian randomization study.

Objective: While observational studies link immune cells with post-stroke functional outcome, the underlying immune mechanisms are not well understood. Immune cell surface antigens are actively involved in the biological behavior of immune cells, investigating immune cell surface antigens could deepen our comprehension of their role and biological processes in stroke recovery. Therefore, we aimed to investigate the immunological basis of stroke outcome by exploring the causal relationship between immune cell surface antigens and functional outcome after ischemic stroke in a Mendelian randomization study. Methods: Genetic variants related to immune cell surface antigens and post-stroke functional outcome were selected for two-sample Mendelian randomization (MR) analysis. 389 fluorescence intensities (MFIs) with surface antigens were included. Inverse variance weighted (IVW) modeling was used as the primary MR method to estimate the causal effect of exposure on the outcome, followed by several alternative methods and sensitivity analyses. Additional analysis of the association between immune cell surface antigens and risk of ischemic stroke for assessment of collider bias. Results: We found that suggestive associations between CD20 on switched memory B cell (OR = 1.16, 95% CI: 1.01-1.34, p = 0.036) and PDL-1 on monocyte (OR = 1.32, 95% CI: 1.04-1.66, p = 0.022) and poor post-stroke functional outcome, whereas CD25 on CD39+ resting Treg (OR = 0.77, 95% CI: 0.62-0.96, p = 0.017) was suggestively associated with good post-stroke functional outcome. Conclusion: The elevated CD20 on switched memory B cell, PDL-1 on monocyte, and CD25 on CD39+ resting Treg may be novel biomarkers and potential causal factors influencing post-stroke functional outcome.

Development of insomnia in patients with stroke: A systematic review and meta-analysis.

BACKGROUND AND AIM: Stroke is a serious threat to human life and health, and post-stroke insomnia is one of the common complications severely impairing patients' quality of life and delaying recovery. Early understanding of the relationship between stroke and post-stroke insomnia can provide clinical evidence for preventing and treating post-stroke insomnia. This study was to investigate the prevalence of insomnia in patients with stroke. METHODS: The Web of Science, PubMed, Embase, and Cochrane Library databases were used to obtain the eligible studies until June 2023. The quality assessment was performed to extract valid data for meta-analysis. The prevalence rates were used a random-efect. I2 statistics were used to assess the heterogeneity of the studies. RESULTS: Twenty-six studies met the inclusion criteria for meta-analysis, with 1,193,659 participants, of which 497,124 were patients with stroke.The meta-analysis indicated that 150,181 patients with stroke developed insomnia during follow-up [46.98%, 95% confidence interval (CI): 36.91-57.18] and 1806 patients with ischemic stroke (IS) or transient ischemic attack (TIA) developed insomnia (47.21%, 95% CI: 34.26-60.36). Notably, 41.51% of patients with the prevalence of nonclassified stroke developed insomnia (95% CI: 28.86-54.75). The incidence of insomnia was significantly higher in patients with acute strokes than in patients with nonacute strokes (59.16% vs 44.07%, P < 0.0001).Similarly, the incidence of insomnia was significantly higher in the patients with stroke at a mean age of ≥65 than patients with stroke at a mean age of <65 years (47.18% vs 40.50%, P < 0.05). Fifteen studies reported the follow-up time. The incidence of insomnia was significantly higher in the follow-up for ≥3 years than follow-up for <3 years (58.06% vs 43.83%, P < 0.05). Twenty-one studies used the Insomnia Assessment Diagnostic Tool, and the rate of insomnia in patients with stroke was 49.31% (95% CI: 38.59-60.06). Five studies used self-reporting, that the rate of insomnia in patients with stroke was 37.58% (95% CI: 13.44-65.63). CONCLUSIONS: Stroke may be a predisposing factor for insomnia. Insomnia is more likely to occur in acute-phase stroke, and the prevalence of insomnia increases with patient age and follow-up time. Further, the rate of insomnia is higher in patients with stroke who use the Insomnia Assessment Diagnostic Tool.

The factors influencing the occurrence of post-ischemic stroke depression and its relationship with the burden score of cerebral small vessel disease.

OBJECTIVE: This study explored the determinants of post-stroke depression (PSD) in ischemic stroke (AIS) patients and its association with the burden score of cerebral small vessel disease (CSVD). PATIENTS AND METHODS: We analyzed 374 AIS patients treated between January 2020 and January 2022. Patients were categorized into 90 with PSD and 284 without PSD, enabling an investigation into PSD risk factors and the CSVD-PSD relationship. RESULTS: There was no significant difference in health factors between PSD and non-PSD patients (p>0.05). However, significant disparities were noted in age, gender, initial Barthel Index (BI), Mini-Mental State Examination (MMSE) score, plasma fibrinogen, homocysteine, red cell distribution width, National Institutes of Health Stroke Scale (NIHSS) score, and CSVD burden score (p<0.05). Regression analysis indicated that these variables were pivotal PSD predictors (OR>1, p<0.05). Surprisingly, a positive correlation with PSD occurrence was found for age, NIHSS score, plasma fibrinogen, homocysteine levels, red cell distribution width, CSVD burden score (r=0.565, 0.615, 0.482, 0.514, 0.572, 0.608, respectively; p<0.05). Meanwhile, the MMSE score and BI index were inversely related to PSD onset (r=-0.604, -0.590; p<0.05). The ROC curve analysis of the combination model based on MMSE, NIHSS and CSVD score revealed an AUC of 0.926 and Youden's index of 0.744. CONCLUSIONS: Age, MMSE score, BI index, NIHSS score, plasma fibrinogen concentration, homocysteine level, red blood cell distribution width, and CSVD burden score are all major influencing factors in the occurrence of PSD. The combination model based on MMSE, NIHSS, and CSVD scores presented a valuable approach to predicting PSD.

Leukocyte counts and ratios as potential predictors of large vessel occlusion in acute ischemic stroke: A retrospective cohort study.

Leukocyte counts and ratios are independent biomarkers to determine the severity and prognosis of acute ischemic stroke (AIS). In AIS, the connection between leukocytes and large vessel occlusion (LVO) is uncertain. This study aims to determine the relationship between the existence of LVO and leukocyte counts and ratios on admission to AIS. Patients were retrospectively evaluated within six hours of AIS starting between January 2019 and April 2023. On admission, blood specimens were collected, and leukocyte subtype counts were promptly analyzed. Computed tomography or digital subtraction angiography were utilized to verify the existence of LVO. Regression analysis and receiver operating characteristic (ROC) curves were employed to investigate the connections between the counts and ratios of leukocytes and the existence of LVO, as well as the discriminatory ability of these variables in predicting LVO. Total white blood cell (WBC) count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR) were substantially higher in the LVO existence group compared to the LVO absence group, whereas the ratio of eosinophils to neutrophils (ENR × 102) was lower (P < .001, respectively). Significant associations were observed between total WBC counts, neutrophil counts, NLR, and ENR × 102 and the existence of LVO (P < .001, respectively). Total WBC counts, neutrophil counts, NLR, and ENR × 102 had respective areas under the curves (AUC) of 0.730, 0.748, 0.704, and 0.680 for identifying LVO. Our results show that in AIS patients, the existence of LVO is independently associated with elevated total WBC and neutrophil counts, high NLR, and low ENR × 102 levels. Neutrophil and total WBC counts, as well as NLR and levels of ENR × 102, may serve as potential biomarkers for predicting LVO. Neuroinflammation, based on the existence of LVO, should be given particular attention in future investigations.

Contrast extravasation mimicking intracerebral and intraventricular hemorrhage after intravenous thrombolytic treatment of ischemic stroke: a case report.

BACKGROUND: Although contrast extravasation on follow-up head computed tomography (CT) is frequently visualized after endovascular treatment, this phenomenon is rare after intravenous thrombolytic treatment in patients with acute ischemic stroke (AIS). Here, we report a case of contrast extravasation mimicking intracerebral hemorrhage (ICH) with intraventricular extension after intravenous thrombolytic treatment and computed tomography angiography (CTA). CASE PRESENTATION: A 52-year-old man presented with right-sided hemiparesis and hypoesthesia. Initial non-contrast head CT was negative for intracranial hemorrhage and acute ischemic changes. He received intravenous treatment with tenecteplase 3.8 h after the onset of stroke. CTA of the head and neck was performed at 4.3 h after stroke onset. It showed no stenosis or occlusion of the carotid and major intracranial arteries. At about 1.5 h after CTA, the right-sided hemiparesis deteriorated, accompanied by drowsiness, aphasia, and urinary incontinence. Immediate head CT showed hyperdense lesions with mild space-occupying effect in the left basal ganglia and both lateral ventricles. The hyperdense lesions were reduced in size on follow-up CT after 5 h. Two days later, CT showed that the hyperdense lesions in the lateral ventricles almost completely disappeared and only a small amount remained in the infarcted area. CONCLUSIONS: Contrast extravasation into the brain tissue and lateral ventricles, mimicking ICH with intraventricular extension, could occur after intravenous thrombolytic treatment and CTA in a patient with AIS, which might lead to misdiagnosis and wrong treatment of the patient. The rapid resolution of intracranial hyperdense lesions is key to differentiate contrast extravasation from ICH on serial non-enhanced CT.

CT Imaging Computed Tomography/Computed Tomography Angiography/Perfusion in Acute Ischemic Stroke and Vasospasm.

Computed tomography (CT), CT angiography (CTA), and CT perfusion (CTP) play crucial roles in the comprehensive evaluation and management of acute ischemic stroke, aneurysmal subarachnoid hemorrhage (SAH), and vasospasm. CTP provides functional data about cerebral blood flow, allowing radiologists, neurointerventionalists, and stroke neurologists to more accurately delineate the volume of core infarct and ischemic penumbra allowing for patient-specific treatment decisions to be made. CTA and CTP are used in tandem to evaluate for vasospasm associated with aneurysmal SAH and can help provide an insight into the physiologic impact of angiographic vasospasm, better triaging patients for medical and interventional treatment.

Metabolic Imaging of Acute Ischemic Stroke (PET, 1Hydrogen Spectroscopy, 17Oxygen Imaging, 23Sodium MRI, pH Imaging).

Acute stroke imaging plays a vital and time-sensitive role in therapeutic decision-making. Current clinical workflows widely use computed tomography (CT) and magnetic resonance (MR) techniques including CT and MR perfusion to estimate the volume of ischemic penumbra at risk for infarction without acute intervention. The use of imaging techniques aimed toward evaluating the metabolic derangements underlying a developing infarct may provide additional information for differentiating the penumbra from benign oligemia and infarct core. The authors review several modalities of metabolic imaging including PET, hydrogen and oxygen spectroscopy, sodium MRI, and pH-weighted MRI.

MR Imaging Techniques for Acute Ischemic Stroke and Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage.

Acute ischemic stroke (AIS) is a leading cause of death and disability worldwide, and its prevalence is expected to increase with global population aging and the burgeoning obesity epidemic. Clinical care for AIS has evolved during the past 3 decades, and it comprises of 3 major tenants: (1) timely recanalization of occluded vessels with intravenous thrombolysis or endovascular thrombectomy, (2) prompt initiation of antithrombotic agents to prevent stroke recurrences, and (3) poststroke supportive care and rehabilitation. In this article, we summarize commonly used MR sequences for AIS and DCI and highlight their clinical applications.

Dual-Energy Computed Tomography in the Evaluation and Management of Subarachnoid Hemorrhage, Intracranial Hemorrhage, and Acute Ischemic Stroke.

Dual-energy computed tomography (DECT) has emerged as a valuable imaging modality in the diagnosis and management of various cerebrovascular pathologies, including subarachnoid hemorrhage, intracranial hemorrhage, and acute ischemic stroke. This article reviews the principles of DECT and its applications in the evaluation and management of these conditions. The authors discuss the advantages of DECT over conventional computed tomography, as well as its limitations, and provide an overview of current research and future directions in the field.

Factors Associated With Premature Termination of Hyperacute Stroke Trials: A Review.

BACKGROUND: We performed a review of acute stroke trials to determine features associated with premature termination of trial enrollment, defined by the authors as not meeting preplanned sample size. METHODS AND RESULTS: MEDLINE was searched for randomized clinical stroke trials published in 9 major clinical journals between 2013 and 2022. We included randomized clinical trials that were phase 2 or 3 with a preplanned sample size ≥100 and a time-to-treatment within 24 hours of onset for transient ischemic attack, ischemic stroke, or intracerebral hemorrhage. Data were abstracted on trial features including trial design, inclusion criteria, imaging, location and number of sites, masking, treatment complexity, control group (standard therapy, placebo), industry involvement, and preplanned stopping rules (futility and efficacy). Least absolute shrinkage and selection operator regression was used to select the most important factors associated with premature termination; then, a multivariable logistic regression was fit including only the least absolute shrinkage and selection operator selected variables. Of 1475 studies assessed, 98 trials met eligibility criteria. Forty-five (46%) trials were prematurely terminated, of which 27% were stopped for benefit/efficacy, 20% for lack of money/slow enrollment, 18% for futility, 16% for newly available evidence, 17% for other reasons, and 4% due to harm. Complex trials (adjusted odds ratio [aOR], 2.76 [95% CI, 1.13-7.49]), presence of a futility rule (aOR, 4.43 [95% CI, 1.62-17.91]), and exclusion of prestroke dependency (none/slight disability only; aOR, 2.19 [95% CI, 0.84-6.72] versus dependency allowed) were identified as the strongest predictors. CONCLUSIONS: Nearly half of acute stroke trials were terminated prematurely. Broadening inclusion criteria and simplifying trial design may decrease the likelihood of unplanned termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.