Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence.Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362.Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow- up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2. 5% in each group for fatal or disabling stroke, and 5.3% with CAS versus 4.5% with CEA for any stroke (rate ratio [RR] 1.16, 95% CI 0.86-1.57; p=0 .33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1.11, 95% CI 0.91-1.32; p=0.21).Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable

The burden of traumatic brain injury from low-energy falls among patients from 18 countries in the CENTER-TBI Registry: A comparative cohort study.

BACKGROUND: Traumatic brain injury (TBI) is an important global public health burden, where those injured by high-energy transfer (e.g., road traffic collisions) are assumed to have more severe injury and are prioritised by emergency medical service trauma triage tools. However recent studies suggest an increasing TBI disease burden in older people injured through low-energy falls. We aimed to assess the prevalence of low-energy falls among patients presenting to hospital with TBI, and to compare their characteristics, care pathways, and outcomes to TBI caused by high-energy trauma. METHODS AND FINDINGS: We conducted a comparative cohort study utilising the CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) Registry, which recorded patient demographics, injury, care pathway, and acute care outcome data in 56 acute trauma receiving hospitals across 18 countries (17 countries in Europe and Israel). Patients presenting with TBI and indications for computed tomography (CT) brain scan between 2014 to 2018 were purposively sampled. The main study outcomes were (i) the prevalence of low-energy falls causing TBI within the overall cohort and (ii) comparisons of TBI patients injured by low-energy falls to TBI patients injured by high-energy transfer-in terms of demographic and injury characteristics, care pathways, and hospital mortality. In total, 22,782 eligible patients were enrolled, and study outcomes were analysed for 21,681 TBI patients with known injury mechanism; 40% (95% CI 39% to 41%) (8,622/21,681) of patients with TBI were injured by low-energy falls. Compared to 13,059 patients injured by high-energy transfer (HE cohort), the those injured through low-energy falls (LE cohort) were older (LE cohort, median 74 [IQR 56 to 84] years, versus HE cohort, median 42 [IQR 25 to 60] years; p < 0.001), more often female (LE cohort, 50% [95% CI 48% to 51%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001), more frequently taking pre-injury anticoagulants or/and platelet aggregation inhibitors (LE cohort, 44% [95% CI 42% to 45%], versus HE cohort, 13% [95% CI 11% to 14%]; p < 0.001), and less often presenting with moderately or severely impaired conscious level (LE cohort, 7.8% [95% CI 5.6% to 9.8%], versus HE cohort, 10% [95% CI 8.7% to 12%]; p < 0.001), but had similar in-hospital mortality (LE cohort, 6.3% [95% CI 4.2% to 8.3%], versus HE cohort, 7.0% [95% CI 5.3% to 8.6%]; p = 0.83). The CT brain scan traumatic abnormality rate was 3% lower in the LE cohort (LE cohort, 29% [95% CI 27% to 31%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001); individuals in the LE cohort were 50% less likely to receive critical care (LE cohort, 12% [95% CI 9.5% to 13%], versus HE cohort, 24% [95% CI 23% to 26%]; p < 0.001) or emergency interventions (LE cohort, 7.5% [95% CI 5.4% to 9.5%], versus HE cohort, 13% [95% CI 12% to 15%]; p < 0.001) than patients injured by high-energy transfer. The purposive sampling strategy and censorship of patient outcomes beyond hospital discharge are the main study limitations. CONCLUSIONS: We observed that patients sustaining TBI from low-energy falls are an important component of the TBI disease burden and a distinct demographic cohort; further, our findings suggest that energy transfer may not predict intracranial injury or acute care mortality in patients with TBI presenting to hospital. This suggests that factors beyond energy transfer level may be more relevant to prehospital and emergency department TBI triage in older people. A specific focus to improve prevention and care for patients sustaining TBI from low-energy falls is required.CENTER-TBI was supported by the European Union 7th Framework program (EC grant 602150), recipient A.I.R. Maas. Additional funding was obtained from the Hannelore Kohl Stiftung (Germany) - recipient A.I.R. Maas, from OneMind (USA) - recipient A.I.R. Maas and from Integra LifeSciences Corporation (USA) - recipient A.I.R. Maas. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study

BACKGROUND: Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies. OBJECTIVE: To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches. METHODS: This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20 000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months. EXPECTED OUTCOMES: Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research. DISCUSSION: Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management

Primary versus early secondary referral to a specialized neurotrauma center in patients with moderate/severe traumatic brain injury: a CENTER TBI study.

BackgroundPrehospital care for patients with traumatic brain injury (TBI) varies with some emergency medical systems recommending direct transport of patients with moderate to severe TBI to hospitals with specialist neurotrauma care (SNCs). The aim of this study is to assess variation in levels of early secondary referral within European SNCs and to compare the outcomes of directly admitted and secondarily transferred patients.MethodsPatients with moderate and severe TBI (Glasgow Coma Scale ResultsA total of 1347 moderate/severe TBI patients from 53 SNCs in 18 European countries were included. Of these 1347 patients, 195 (14.5%) were admitted after early secondary referral. Secondarily referred moderate/severe TBI patients presented more often with a CT abnormality: mass lesion (52% vs. 34%), midline shift (54% vs. 36%) and acute subdural hematoma (77% vs. 65%). After adjusting for case-mix, there was a large European variation in early secondary referral, with a median OR of 1.69 between countries. Early secondary referral was not associated with functional outcome (adjusted OR 1.07, 95% CI 0.78-1.69), nor with survival at discharge (1.05, 0.58-1.90).ConclusionsAcross Europe, substantial practice variation exists in the proportion of secondarily referred TBI patients at SNCs that is not explained by case mix. Within SNCs early secondary referral does not seem to impact functional outcome and survival after stabilisation in a non-specialised hospital. Future research should identify which patients with TBI truly benefit from direct transportation

Tracheal intubation in traumatic brain injury: a multicentre prospective observational study

Background We aimed to study the associations between pre- and in-hospital tracheal intubation and outcomes in traumatic brain injury (TBI), and whether the association varied according to injury severity. Methods Data from the international prospective pan-European cohort study, Collaborative European NeuroTrauma Effectiveness Research for TBI (CENTER-TBI), were used (n=4509). For prehospital intubation, we excluded self-presenters. For in-hospital intubation, patients whose tracheas were intubated on-scene were excluded. The association between intubation and outcome was analysed with ordinal regression with adjustment for the International Mission for Prognosis and Analysis of Clinical Trials in TBI variables and extracranial injury. We assessed whether the effect of intubation varied by injury severity by testing the added value of an interaction term with likelihood ratio tests. Results In the prehospital analysis, 890/3736 (24%) patients had their tracheas intubated at scene. In the in-hospital analysis, 460/2930 (16%) patients had their tracheas intubated in the emergency department. There was no adjusted overall effect on functional outcome of prehospital intubation (odds ratio=1.01; 95% confidence interval, 0.79–1.28; P=0.96), and the adjusted overall effect of in-hospital intubation was not significant (odds ratio=0.86; 95% confidence interval, 0.65–1.13; P=0.28). However, prehospital intubation was associated with better functional outcome in patients with higher thorax and abdominal Abbreviated Injury Scale scores (P=0.009 and P=0.02, respectively), whereas in-hospital intubation was associated with better outcome in patients with lower Glasgow Coma Scale scores (P=0.01): in-hospital intubation was associated with better functional outcome in patients with Glasgow Coma Scale scores of 10 or lower. Conclusion The benefits and harms of tracheal intubation should be carefully evaluated in patients with TBI to optimise benefit. This study suggests that extracranial injury should influence the decision in the prehospital setting, and level of consciousness in the in-hospital setting. Clinical trial registration NCT02210221

How do 66 European institutional review boards approve one protocol for an international prospective observational study on traumatic brain injury? Experiences from the CENTER-TBI study

Background The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency. Methods We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe. Results From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N = 11, 61%) or locally (N = 7, 39%) and primary IRB approval was obtained after one (N = 8, 44%), two (N = 6, 33%) or three (N = 4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional IRB approval was required in 55% of countries and could increase duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75-224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p = 0.0074). Conclusion We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.Peer reviewe

Health-related quality of life after traumatic brain injury : deriving value sets for the QOLIBRI-OS for Italy, The Netherlands and The United Kingdom

Purpose The Quality of Life after Brain Injury overall scale (QOLIBRI-OS) measures health-related quality of life (HRQoL) after traumatic brain injury (TBI). The aim of this study was to derive value sets for the QOLIBRI-OS in three European countries, which will allow calculation of utility scores for TBI health states. Methods A QOLIBRI-OS value set was derived by using discrete choice experiments (DCEs) and visual analogue scales (VAS) in general population samples from the Netherlands, United Kingdom and Italy. A three-stage procedure was used: (1) A selection of health states, covering the entire spectrum of severity, was defined; (2) General population samples performed the health state valuation task using a web-based survey with three VAS questions and an at random selection of sixteen DCEs; (3) DCEs were analysed using a conditional logistic regression and were then anchored on the VAS data. Utility scores for QOLIBRI-OS health states were generated resulting in estimates for all potential health states. Results The questionnaire was completed by 13,623 respondents. The biggest weight increase for all attributes is seen from "slightly" to "not at all satisfied", resulting in the largest impact on HRQoL. "Not at all satisfied with how brain is working" should receive the greatest weight in utility calculations in all three countries. Conclusion By transforming the QOLIBRI-OS into utility scores, we enabled the application in economic evaluations and in summary measures of population health, which may be used to inform decision-makers on the best interventions and strategies for TBI patients.Peer reviewe

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study

Background Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities. Methods Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subjective fatigue was measured by single item on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), administered at baseline, three and 6 months postinjury. Patients were categorized by clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU). Injury severity, preinjury somatic- and psychiatric conditions, depressive and sleep problems were registered at baseline. For prediction of fatigue changes, descriptive statistics and mixed effect logistic regression analysis are reported. Results Fatigue was experienced by 47% of patients at baseline, 48% at 3 months and 46% at 6 months. Patients admitted to ICU had a higher probability of experiencing fatigue than those in ER and ADM strata. Females and individuals with lower age, higher education, more severe intracranial injury, preinjury somatic and psychiatric conditions, sleep disturbance and feeling depressed postinjury had a higher probability of fatigue. Conclusion A high and stable frequency of fatigue was found during the first 6 months after TBI. Specific socio-demographic factors, comorbidities and injury severity characteristics were predictors of fatigue in this study

Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study

Background While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as ‘mild’, ‘moderate’ or ‘severe’ based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights. Methods We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation. Results Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with ‘moderate’ TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with ‘severe’ GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001). Conclusions Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care