Understanding why restrictive trial eligibility criteria are inappropriate.

BACKGROUND: An important difference between explanatory and pragmatic clinical trials concerns eligibility criteria. Eligibility criteria are restrictive in explanatory trials, while pragmatic trials are more inclusive or even all-inclusive. METHODS: To better understand the diverging views regarding eligibility criteria, we examine the contrast between theoretical and clinical medicine, and 3 different research contexts: laboratory research, population studies and clinical trials. In each context we review the purpose for selecting study subjects or research material, as well as the type of inductive inference or generalization that is sought by such selection. RESULTS: In each context, selection concerns different things and serves different purposes: In the laboratory, selection concerns the homogenous research material that will help isolate a causal signal. In the epidemiological context selection concerns the (random) sampling method, designed to produce a representative sample of the population. In the clinical trial setting, selection concerns patients in need of care. Restrictive eligibility criteria become inappropriate in the care setting because the aim of the trial is not to represent a population nor to isolate a causal signal, but to find out which patients benefit from treatment. CONCLUSION: The idea of selecting patients comes from methods that belong to theoretical medicine. In the care setting, most clinical trials should be pragmatic and as inclusive as possible.

Trial selection criteria should not be used for clinical decisions and recommendations: the thrombectomy trials example.

BACKGROUND: Despite multiple calls for more inclusive studies, most clinical trial eligibility criteria remain too restrictive. Thrombectomy trials have been no exception. METHODS: We review the landmark trials that have shown the benefits of thrombectomy, their eligibility criteria, and consequences on clinical practice. We discuss the rationale behind various reasons for exclusions. We also examine the logical problem involved in using eligibility criteria as indications for treatment. RESULTS: Most thrombectomy trials have been too restrictive. This has been shown by a plethora of follow-up studies that have refuted most of the previously recommended trial eligibility restrictions. Meanwhile, the effect of clinical recommendations based on restrictive eligibility criteria is that treatment has been denied to the majority of patients who could have benefitted. Trial eligibility criteria cannot be used to make clinical decisions or recommendations unless, like any other medical diagnosis, they have been shown capable of reliably differentiating patients into those that will, and those that will not benefit from treatment. This goal can only be achieved with all-inclusive pragmatic trials. CONCLUSION: Restrictive eligibility criteria render clinical trials incapable of guiding medical decisions or recommendations.

Basilar artery occlusion management: An international survey of gender influence on management.

BACKGROUND: The superiority of endovascular thrombectomy (EVT) over medical management was not established in two early basilar artery occlusion (BAO) randomized controlled trials. Despite this, many clinicians recommended EVT for acute BAO under certain circumstances. This paper aims to compare physicians' diagnostic and management strategies of BAO according to gender. METHODS: From January to March 2022 an international survey was conducted regarding management strategies in acute BAO. We compared responses between clinicians by identifying gender. Questions were designed to examine clinical and imaging parameters influencing management of patients with BAO. RESULTS: Among the 1245 respondents from 73 countries, 311 (25.0%) identified as female. This figure was 13.6% amongst interventionists. Geographically, female respondents were lowest in Asia (14.5%) and North America (23.9%). The proportion of respondents identifying as female was consistent regardless of their years of experience. Female respondents were more likely to choose time of onset as time of first estimated stroke like symptom (48.0% vs. 38.5%, p < .01), were less likely to favor thrombectomy in the V4 segment of vertebrobasilar artery occlusions (31.5% vs. 43.3%, p < .01), and were less likely to find it acceptable to enroll all patients who met trial criteria in the standard medical treatment arm of a clinical trial (41.2% vs. 47.0%, p = .01). Male respondents were more likely to agree that thrombolysis would not alter their decision on proceeding with EVT (93.7% vs. 88.3%, p < .01). CONCLUSIONS: Female clinicians appear to be significantly underrepresented in stroke medicine. This is most pronounced amongst interventionists and in Asia. Although male and female opinions were closely aligned on many aspects of BAO management, differences in opinion were observed in a number of significant areas which influence decision making.

Ethical Problems of Observational Studies and Big Data Compared to Randomized Trials.

The temptation to use prospective observational studies (POS) instead of conducting difficult trials (RCTs) has always existed, but with the advent of powerful computers and large databases, it can become almost irresistible. We examine the potential consequences, were this to occur, by comparing two hypothetical studies of a new treatment: one RCT, and one POS. The POS inevitably submits more patients to inferior research methodology. In RCTs, patients are clearly informed of the research context, and 1:1 randomized allocation between experimental and validated treatment balances risks for each patient. In POS, for each patient, the risks of receiving inferior treatment are impossible to estimate. The research context and the uncertainty are down-played, and patients and clinicians are at risk of becoming passive research subjects in studies performed from an outsider's view, which potentially has extraneous objectives, and is conducted without their explicit, autonomous, and voluntary involvement and consent.

Reliability of study endpoint adjudication in a pragmatic trial on brain arteriovenous malformations.

BACKGROUND: The results of a clinical trial are given in terms of primary and secondary outcomes that are obtained for each patient. Just as an instrument should provide the same result when the same object is measured repeatedly, the agreement of the adjudication of a clinical outcome between various raters is fundamental to interpret study results. The reliability of the adjudication of study endpoints determined by examination of the electronic case report forms of a pragmatic trial has not previously been tested. METHODS: The electronic case report forms of 62/434 (14%) patients selected to be observed in a study on brain AVMs were independently examined twice (4 weeks apart) by 8 raters who judged whether each patient had reached the following study endpoints: (1) new intracranial hemorrhage related to AVM or to treatment; (2) new non-hemorrhagic neurological event; (3) increase in mRS ≥1; (4) serious adverse events (SAE). Inter and intra-rater reliability were assessed using Gwet's AC1 (κG) statistics, and correlations with mRS score using Cramer's V test. RESULTS: There was almost perfect agreement for intracranial hemorrhage (92% agreement; κG = 0.84 (95%CI: 0.76-0.93), and substantial agreement for SAEs (88% agreement; κG = 0.77 (95%CI: 0.67-0.86) and new non-hemorrhagic neurological event (80% agreement; κG = 0.61 (95%CI: 0.50-0.72). Most endpoints correlated (V = 0.21-0.57) with an increase in mRS of ≥1, an endpoint which was itself moderately reliable (76% agreement; κG = 0.54 (95%CI: 0.43-0.64). CONCLUSION: Study endpoints of a pragmatic trial were shown to be reliable. More studies on the reliability of pragmatic trial endpoints are needed.

The use and abuse of survival analysis and Kaplan-Meier curves in surgical trials.

BACKGROUND: Survival analysis based on Cox regression and Kaplan-Meier curves, initially devised for oncology trials, have frequently been used in other contexts where fundamental statistical assumptions (such as a constant hazard ratio) are not satisfied. This is almost always the case in trials that compare surgery with medical management. METHODS: We review a trial that compared extracranial-intracranial bypass surgery (EC-IC bypass) with medical management (MM) of patients with symptomatic occlusion of the carotid or middle cerebral artery, where it was claimed that surgery was of no benefit. We discuss a hypothetical study and review other neurovascular trials which have also used survival analysis to compare results. RESULTS: The trial comparing EC-IC bypass and MM did not satisfy the fundamental proportional hazard assumption necessary for valid analyses. This was also the case for two prior EC-IC bypass trials, as well as for other landmark neurovascular studies, such as the trials comparing endarterectomy with MM for carotid stenoses, or for the trial that compared intervention and MM for unruptured brain arteriovenous malformations. While minor deviations may have little effect on large trials, it may be impossible to show the benefits of surgery when trial size is small and deviations large. CONCLUSION: Survival analyses are inappropriate in RCTs comparing surgery with conservative management, unless survival is calculated after the postoperative period. Alternative ways to compare final clinical outcomes, using for example a fixed follow-up period, should be planned for preventive surgical trials that compare intervention with conservative management.

Noncontrast CT Selected Thrombectomy vs Medical Management for Late-Window Anterior Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: There is uncertainty whether patients with large vessel occlusion (LVO) presenting in the late 6-hour to 24-hour time window can be selected for endovascular therapy (EVT) by noncontrast CT (NCCT) and CT angiography (CTA) for LVO detection. We evaluated the clinical outcomes of patients selected for EVT by NCCT compared with those medically managed in the extended time window. METHODS: This multinational cohort study was conducted at 66 sites across 10 countries. Consecutive patients with proximal anterior LVO stroke selected for EVT by NCCT or medically managed and presenting within 6-24 hours of time last seen well (TSLW) from January 2014 to May 2022 were included. The primary end point was the 90-day ordinal shift in the modified Rankin Scale (mRS) score. Inverse probability treatment weighting (IPTW) and multivariable methods were used. RESULTS: Of 5,098 patients screened, 839 patients were included, with a median (interquartile range) age of 75 (64-83) years; 455 (54.2%) were women. There were 616 patients selected to undergo EVT by NCCT (73.4%) and 223 (26.6%) who were medically managed. In IPTW analyses, there was a more favorable 90-day ordinal mRS shift in patients selected by NCCT to EVT vs those who were medically managed (odds ratio [OR] 1.99, 95% CI 1.53-2.59; p < 0.001). There were higher rates of 90-day functional independence (mRS 0-2) in the EVT group (40.1% vs 18.4%, OR 3.31, 95% CI 2.11-5.20; p < 0.001). sICH was nonsignificantly higher in the EVT group (8.5% vs 1.4%, OR 3.77, 95% CI 0.72-19.7, p = 0.12). Mortality at 90 days was lower in the EVT vs MM group (23.9% vs 32.3%, OR 0.61, 95% CI 0.45-0.83, p = 0.002). DISCUSSION: In patients with proximal anterior LVO in the extended time window, there was a lower rate of disability and mortality in patients selected with NCCT and CTA to EVT compared with those who were medically managed. These findings support the use of NCCT as a simpler and more inclusive approach to patient selection in the extended window. TRIAL REGISTRATION INFORMATION: This study was registered at ClinicalTrials.gov under NCT04096248. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with proximal anterior circulation occlusion presenting with ischemic stroke from 6 to 24 hours, compared with medical management, those undergoing thrombectomy based on NCCT have reduced disability and mortality at 90 days.

Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke.

INTRODUCTION: The benefit of endovascular therapy (EVT) among stroke patients with large ischemic core (ASPECTS 0-5) in the extended time window outside of trial settings remains unclear. We analyzed the effect of EVT among these stroke patients in real-world settings. PATIENTS AND METHODS: The CT for Late Endovascular Reperfusion (CLEAR) study recruited patients from 66 centers in 10 countries between 01/2014 and 05/2022. The extended time-window was defined as 6-24 h from last-seen-well to treatment. The primary outcome was shift of the 3-month modified Rankin scale (mRS) score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. Outcomes were analyzed with ordinal and logistic regressions. RESULTS: Among 5098 screened patients, 2451 were included in the analysis (median age 73, 55% women). Of patients with ASPECTS 0-5 (n = 310), receiving EVT (n = 209/310) was associated with lower 3-month mRS when compared to medical management (median 4 IQR 3-6 vs 6 IQR 4-6; aOR 0.4, 95% CI 0.2-0.7). Patients undergoing EVT had higher sICH (11.2% vs 4.0%; aOR 4.1, 95% CI 1.2-18.8) and lower mortality (31.6% vs 58.4%, aOR 0.4; 95% CI 0.2-0.9) compared to medically managed patients. The relative benefit of EVT was comparable between patients with ASPECTS 0 and 5 and 6-10 in the extended time window (interaction aOR 0.9; 95% CI 0.5-1.7). CONCLUSION: In the extended time window, patients with ASPECTS 0-5 may have preserved relative treatment benefit of EVT compared to patients with ASPECTS 6-10. These findings are in line with recent trials showing benefit of EVT among real-world patients with large ischemic core in the extended time window. TRIAL REGISTRATION NUMBER: clinicaltrials.gov; Unique identifier: NCT04096248.

Endovascular Parent Vessel Occlusion Versus Flow Diversion in the Treatment of Large and Giant Aneurysms: A Randomized Comparison.

OBJECTIVE: Parent vessel occlusion (PVO) is a time-honored treatment for unclippable or uncoilable intracranial aneurysms. Flow diversion (FD) is a recent endovascular alternative that can occlude the aneurysm and spare the parent blood vessel. Our aim was to compare outcomes of FD with endovascular PVO. METHODS: This is a prespecified treatment subgroup analysis of the Flow diversion in Intracranial Aneurysms trial (FIAT). FIAT was an investigator-led parallel-group all-inclusive pragmatic randomized trial. For each patient, clinicians had to prespecify an alternative management option to FD before stratified randomization. We report all patients for whom PVO was selected as the best alternative treatment to FD. The primary outcome was a composite of core-lab determined angiographic occlusion or near-occlusion at 3-12 months combined with an independent clinical outcome (mRS<3). Primary analyses were intent-to-treat. There was no blinding. RESULTS: There were 45 patients (16.2% of the 278 FIAT patients randomized between 2011 and 2020 in 3 centers): 22 were randomly allocated to FD and 23 to PVO. Aneurysms were mainly large or giant (mean 22 mm) anterior circulation (mainly carotid) aneurysms. A poor primary outcome was reached in 11/22 FD (50.0%) compared to 9/23 PVO patients (39.1%) (RR: 1.28, 95% CI [0.66-2.47]; P = 0.466). Morbidity (mRS >2) at 1 year occurred in 4/22 FD and 6/23 PVO patients. Angiographic results and serious adverse events were similar. CONCLUSIONS: The comparison between PVO and FD was inconclusive. More randomized trials are needed to better determine the role of FD in large aneurysms eligible for PVO.

Influence of Growth, Maturation, and Sex on Maximal Power, Force, and Velocity During Overground Sprinting.

ABSTRACT: Sudlow, A, Galantine, P, Del Sordo, G, Raymond, J-J, Dalleau, G, Peyrot, N, and Duché, P. Influence of growth, maturation, and sex on maximal power, force, and velocity during overground sprinting. J Strength Cond Res 38(3): 491-500, 2024-In pediatric populations maximal anaerobic power, force, and velocity capabilities are influenced by changes in body dimensions and muscle function. The aim of this study was to investigate the influences of growth, maturation, and sex on short-term anaerobic performance. One hundred forty children pre-, mid-, and postpeak height velocity performed two 30-m sprints concurrently measured using a radar device. Maximal power (Pmax), force (F0), and velocity (v0) were calculated from sprint velocity-time data and normalized using sex-specific, multiplicative, allometric models containing body mass, fat-free mass (FFM), or height, and chronological age. Absolute values for Pmax, F0, and v0 were higher with increasing maturity (p < 0.01; d ≥ 0.96), and boys had greater outputs than girls (p < 0.01; d ≥ 1.19). When Pmax and v0 were scaled all maturity-related and sex-related differences were removed. When F0 was scaled using models excluding age, all maturity-related differences were removed except for the least mature group (p < 0.05; d ≥ 0.88) and boys maintained higher values than girls (p < 0.05; d ≥ 0.92). All maturity-related and sex-related differences were removed when F0 was scaled using models including age. Maturity-related and sex-related variance in Pmax and v0 can be entirely explained when FFM, height, and chronological age are accounted for. Regarding F0, there seems to be a threshold after which the inclusion of age is no longer necessary to account for maturity-related differences. In young prepubertal children, the inclusion of age likely accounts for deficits in neuromuscular capacities and motor skills, which body dimensions cannot account for. Practitioners should focus on eliciting neural adaptations and enhancing motor coordination in prepubertal children to improve anaerobic performance during overground sprinting.

Real-World Management Strategies of Anticoagulated Atrial Fibrillation Patients After a Clinically Significant Bleeding Episode.

BACKGROUND: Systemic anticoagulation for stroke prevention in patients with atrial fibrillation (AF) carries inherent bleeding risks, and determining whether and when to resume anticoagulation after significant bleeding is a common dilemma. We aimed to describe the clinical characteristics of AF patients discharged after a bleeding event, document real-life thromboembolic prevention strategy (TPS), and analyse their associated clinical outcomes. METHODS: We retrospectively reviewed the charts of anticoagulated AF patients admitted for bleeding from 2017 to 2019. RESULTS: A total of 140 patients were included, with a mean age of 78.6 years. Four discharge groups were defined: 75 patients (53.5%) had optimal anticoagulation (OA), 37 (26.4%) had a suboptimal antithrombotic regimen (SAR; low-dose direct oral anticoagulants without dose-reduction criteria or antiplatelet therapy), 10 (7.1%) were referred for left atrial appendage occlusion (LAAO), and 18 (12.9%) left without any TPS. All-cause mortality at 2 years was high (28.6%) but not statistically different between groups (P = 0.71). Patients discharged with a TPS (OA/SAR/LAAO referral) were more likely to be readmitted for bleeding at 2 years (34% vs 0%; P = 0.002), and those discharged without a TPS had higher rates of stroke (16.6% vs 1.4%; P = 0.003). SAR yielded readmission rates for bleeding similar to resumption of OA (27% vs 34.7%; P = 0.41) but was associated with high rates of death or readmission at 2 years. CONCLUSIONS: This real-life cohort reveals that clinicians frequently downgrade or discontinue long-term thromboembolic protection after a bleeding event despite current guideline recommendations to the contrary, and downgrading resulted in bleeding risk similar to OA.

Energy and Macronutrient Intakes in Young Athletes: A Systematic Review and Meta-analysis.

The aim of this study was to conduct a systematic review and meta-analysis of differences in energy and macronutrient intakes between young athletes and non-athletes, considering age, gender and sport characteristics. The study included original research articles that compared energy and macronutrient intakes of 8 to 18-year-old athletes to non-athletes. Mean difference (MD) meta-analyses were performed to quantify energy and macronutrient intake differences between athletes and non-athletes. Eighteen observational studies were included. Results revealed that the energy and carbohydrate consumption of athletes was higher than that of non-athletes (MD=4.65kcal/kg/d, p<0.01 and MD=1.65% of total energy intake, p<0.01, respectively). Subgroup analyses revealed a significant effect of total training time on the observed mean differences between athletes and non-athletes. As practice time increased, the differences between athletes and non-athletes increased for carbohydrate and decreased for protein. Sport type analysis revealed a higher protein intake by mixed sport athletes compared to endurance and power sports. Analyses also indicated an age effect: the older the athletes, the smaller the differences between athletes and non-athletes for energy intake. However, the methods used to match groups and estimate dietary intakes forced us to moderate the results. More rigorous research methods are needed to define the dietary intakes of athletes and non-athletes.

Understanding the role of randomization in clinical research and practice.

BACKGROUND: The scientific role randomization plays in clinical research is universally recognized, but poorly understood. In stark contrast, the ethical role randomization plays in the proper care of patients in the presence of uncertainty has been almost completely ignored. METHODS: We review the introduction of randomization in the design of experiments, its first use in Britain, and its essential role in analysis of statistical results. We also review Thomas Chalmers' argument from 1975 that showed the ethical role randomization can play in the care of patients. We discuss how Chalmers' vision can be generalized to all contexts of clinical uncertainty. DISCUSSION: Randomization is not only essential to the validity of statistical tests, it is also the best way to learn from experience. Although Chalmers' admonition to 'Randomize the first patient' pertained to the use of innovations, the notion that randomized allocation can be done in the best interest of patients is generalizable to all medical or surgical interventions that have yet to be proven beneficial, opening the perspective that care research can be integrated into practice in the best medical interest of patients. CONCLUSION: Randomized allocation plays crucial scientific and ethical roles both in research and practice. It is the most efficient way to learn from experience. Prior to this gain in knowledge, it is the way to optimize care in the presence of uncertainty.

Understanding categories or subgroups and a common clinical reasoning error: the example of aneurysm size and neck width.

BACKGROUND: Individualized clinical decisions are often made by considering some patient or lesion characteristics that are thought to have an impact on the efficacy or safety of treatment. For example, aneurysm size and neck width have often been determinants of treatment choices in neurovascular practice. METHODS: We review observational and randomized data on the influence of aneurysm or neck size on angiographic results of coiling, stent-assisted coiling, or surgical clipping. New RCT data are used to demonstrate the shortcomings of managing patients using clinical judgment regarding patient or lesion characteristics. We discuss why clinical decisions should not be based on comparisons of different patients treated by the same treatment. Clinical decision making requires a comparison between the same patients treated with different treatments in a randomized trial. RESULTS: The results of endovascular treatment of large or wide-necked aneurysms are always inferior to those of small or narrow-necked aneurysms, in observational as well as in randomized studies. However, this fact alone is not sufficient to infer that patients with small aneurysms should be coiled, while those with large aneurysms should be managed with stenting or surgical clipping. The purported superiority of clipping for large aneurysms could not be demonstrated in recent RCTs (while surgery was found superior for small aneurysms). Similarly, the superiority of stent-assisted coiling for wide-necked aneurysms was not shown in another recent RCT. CONCLUSION: Clinical experience and observational studies alone can mislead practice. Proper clinical decisions for individuals requires randomized evidence.

History of Neurointervention.

In this review article, we aim to provide a summary of the discoveries and developments that were instrumental in the evolution of the Neurointerventional field. We begin with developments in the advent of Diagnostic Cerebral Angiography and progress to cerebral aneurysm treatment, embolization in AVMs and ischemic stroke treatment. In the process we discuss many persons who were key in the development and maturation of the field. A pivotal aspect to rapid growth in the field has been the multidisciplinary involvement of the different neuroscience specialties and therefore we close out our discussion with excitement about ongoing and future developments in the field with a focus on treatments in the non-cerebrovascular disease realm.