Value-Based Integrated Care: A Systematic Literature Review.

BACKGROUND: Healthcare services worldwide are transforming themselves into value-based organizations. Integrated care is an important aspect of value-based healthcare (VBHC), but practical evidence-based recommendations for the successful implementation of integrated care within a VBHC context are lacking. This systematic review aims to identify how value-based integrated care (VBIC) is defined in literature, and to summarize the literature regarding the effects of VBIC, and the facilitators and barriers for its implementation. METHODS: Embase, Medline ALL, Web of Science Core Collection, and Cochrane Central Register of Controlled Trails databases were searched from inception until January 2022. Empirical studies that implemented and evaluated an integrated care intervention within a VBHC context were included. Non-empirical studies were included if they described either a definition of VBIC or facilitators and barriers for its implementation. Theoretical articles and articles without an available full text were excluded. All included articles were analysed qualitatively. The Rainbow Model of Integrated Care (RMIC) was used to analyse the VBIC interventions. The quality of the articles was assessed using the Mixed Methods Appraisal Tool (MMAT). RESULTS: After screening 1328 titles/abstract and 485 full-text articles, 24 articles were included. No articles were excluded based on quality. One article provided a definition of VBIC. Eleven studies reported-mostly positive- effects of VBIC, on clinical outcomes, patient-reported outcomes, and healthcare utilization. Nineteen studies reported facilitators and barriers for the implementation of VBIC; factors related to reimbursement and information technology (IT) infrastructure were reported most frequently. CONCLUSION: The concept of VBIC is not well defined. The effect of VBIC seems promising, but the exact interpretation of effect evaluations is challenged by the precedence of multicomponent interventions, multiple testing and generalizability issues. For successful implementation of VBIC, it is imperative that healthcare organizations consider investing in adequate IT infrastructure and new reimbursement models. Systematic Review Registration: PROSPERO (CRD42021259025).

Impact of Intracranial Volume and Brain Volume on the Prognostic Value of Computed Tomography Perfusion Core Volume in Acute Ischemic Stroke.

BACKGROUND: Computed tomography perfusion (CTP)-estimated core volume is associated with functional outcomes in acute ischemic stroke. This relationship might differ among patients, depending on brain volume. MATERIALS AND METHODS: We retrospectively included patients from the MR CLEAN Registry. Cerebrospinal fluid (CSF) and intracranial volume (ICV) were automatically segmented on NCCT. We defined the proportion of the ICV and total brain volume (TBV) affected by the ischemic core as ICVcore and TBVcore. Associations between the core volume, ICVcore, TBVcore, and functional outcome are reported per interquartile range (IQR). We calculated the area under the curve (AUC) to assess diagnostic accuracy. RESULTS: In 200 patients, the median core volume was 13 (5-41) mL. Median ICV and TBV were 1377 (1283-1456) mL and 1108 (1020-1197) mL. Median ICVcore and TBVcore were 0.9 (0.4-2.8)% and 1.7 (0.5-3.6)%. Core volume (acOR per IQR 0.48 [95%CI 0.33-0.69]), ICVcore (acOR per IQR 0.50 [95%CI 0.35-0.69]), and TBVcore (acOR per IQR 0.41 95%CI 0.33-0.67]) showed a lower likelihood of achieving improved functional outcomes after 90 days. The AUC was 0.80 for the prediction of functional independence at 90 days for the CTP-estimated core volume, the ICVcore, and the TBVcore. CONCLUSION: Correcting the CTP-estimated core volume for the intracranial or total brain volume did not improve the association with functional outcomes in patients who underwent EVT.

Performance of the IMPACT and CRASH prognostic models for traumatic brain injury in a contemporary multicenter cohort: a TRACK-TBI study.

OBJECTIVE: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization After Significant Head Injury (CRASH) prognostic models for mortality and outcome after traumatic brain injury (TBI) were developed using data from 1984 to 2004. This study examined IMPACT and CRASH model performances in a contemporary cohort of US patients. METHODS: The prospective 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years 2014-2018) enrolled subjects aged ≥ 17 years who presented to level I trauma centers and received head CT within 24 hours of TBI. Data were extracted from the subjects who met the model criteria (for IMPACT, Glasgow Coma Scale [GCS] score 3-12 with 6-month Glasgow Outcome Scale-Extended [GOSE] data [n = 441]; for CRASH, GCS score 3-14 with 2-week mortality data and 6-month GOSE data [n = 831]). Analyses were conducted in the overall cohort and stratified on the basis of TBI severity (severe/moderate/mild TBI defined as GCS score 3-8/9-12/13-14), age (17-64 years or ≥ 65 years), and the 5 top enrolling sites. Unfavorable outcome was defined as GOSE score 1-4. Original IMPACT and CRASH model coefficients were applied, and model performances were assessed by calibration (intercept [< 0 indicated overprediction; > 0 indicated underprediction] and slope) and discrimination (c-statistic). RESULTS: Overall, the IMPACT models overpredicted mortality (intercept -0.79 [95% CI -1.05 to -0.53], slope 1.37 [1.05-1.69]) and acceptably predicted unfavorable outcome (intercept 0.07 [-0.14 to 0.29], slope 1.19 [0.96-1.42]), with good discrimination (c-statistics 0.84 and 0.83, respectively). The CRASH models overpredicted mortality (intercept -1.06 [-1.36 to -0.75], slope 0.96 [0.79-1.14]) and unfavorable outcome (intercept -0.60 [-0.78 to -0.41], slope 1.20 [1.03-1.37]), with good discrimination (c-statistics 0.92 and 0.88, respectively). IMPACT overpredicted mortality and acceptably predicted unfavorable outcome in the severe and moderate TBI subgroups, with good discrimination (c-statistic ≥ 0.81). CRASH overpredicted mortality in the severe and moderate TBI subgroups and acceptably predicted mortality in the mild TBI subgroup, with good discrimination (c-statistic ≥ 0.86); unfavorable outcome was overpredicted in the severe and mild TBI subgroups with adequate discrimination (c-statistic ≥ 0.78), whereas calibration was nonlinear in the moderate TBI subgroup. In subjects ≥ 65 years of age, the models performed variably (IMPACT-mortality, intercept 0.28, slope 0.68, and c-statistic 0.68; CRASH-unfavorable outcome, intercept -0.97, slope 1.32, and c-statistic 0.88; nonlinear calibration for IMPACT-unfavorable outcome and CRASH-mortality). Model performance differences were observed across the top enrolling sites for mortality and unfavorable outcome. CONCLUSIONS: The IMPACT and CRASH models adequately discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to update prognostic models to incorporate contemporary changes in TBI management and case-mix. Investigations to elucidate the relationships between increased survival, outcome, treatment intensity, and site-specific practices will be relevant to improve models in specific TBI subpopulations (e.g., older adults), which may benefit from the inclusion of blood-based biomarkers, neuroimaging features, and treatment data.

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy.

INTRODUCTION: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). PATIENTS AND METHODS: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. RESULTS: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73-1.00). CBS was similar between sexes (median 6, IQR 4-8). Intracranial (aOR 0.73;95% CI:0.62-0.87) and extracranial (aOR 0.64;95% CI:0.43-0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39-2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00-1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09-0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:-0.02-0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29-1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8-10vs 9-10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83-1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53-0.86). DISCUSSION AND CONCLUSION: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.

Improving shared decision-making about cancer treatment through design-based data-driven decision-support tools and redesigning care paths: an overview of the 4D PICTURE project.

Background: Patients with cancer often have to make complex decisions about treatment, with the options varying in risk profiles and effects on survival and quality of life. Moreover, inefficient care paths make it hard for patients to participate in shared decision-making. Data-driven decision-support tools have the potential to empower patients, support personalized care, improve health outcomes and promote health equity. However, decision-support tools currently seldom consider quality of life or individual preferences, and their use in clinical practice remains limited, partly because they are not well integrated in patients' care paths. Aim and objectives: The central aim of the 4D PICTURE project is to redesign patients' care paths and develop and integrate evidence-based decision-support tools to improve decision-making processes in cancer care delivery. This article presents an overview of this international, interdisciplinary project. Design methods and analysis: In co-creation with patients and other stakeholders, we will develop data-driven decision-support tools for patients with breast cancer, prostate cancer and melanoma. We will support treatment decisions by using large, high-quality datasets with state-of-the-art prognostic algorithms. We will further develop a conversation tool, the Metaphor Menu, using text mining combined with citizen science techniques and linguistics, incorporating large datasets of patient experiences, values and preferences. We will further develop a promising methodology, MetroMapping, to redesign care paths. We will evaluate MetroMapping and these integrated decision-support tools, and ensure their sustainability using the Nonadoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) framework. We will explore the generalizability of MetroMapping and the decision-support tools for other types of cancer and across other EU member states. Ethics: Through an embedded ethics approach, we will address social and ethical issues. Discussion: Improved care paths integrating comprehensive decision-support tools have the potential to empower patients, their significant others and healthcare providers in decision-making and improve outcomes. This project will strengthen health care at the system level by improving its resilience and efficiency.

Improving the cancer patient journey and respecting personal preferences: an overview of the 4D PICTURE project The 4D PICTURE project aims to help cancer patients, their families and healthcare providers better undertstand their options. It supports their treatment and care choices, at each stage of disease, by drawing on large amounts of evidence from different types of European data. The project involves experts from many different specialist areas who are based in nine European countries. The overall aim is to improve the cancer patient journey and ensure personal preferences are respected.

Personalized decision-making for aneurysm treatment of aneurysmal subarachnoid hemorrhage: development and validation of a clinical prediction tool.

BACKGROUND: In patients with aneurysmal subarachnoid hemorrhage suitable for endovascular coiling and neurosurgical clip-reconstruction, the aneurysm treatment decision-making process could be improved by considering heterogeneity of treatment effect and durability of treatment. We aimed to develop and validate a tool to predict individualized treatment benefit of endovascular coiling compared to neurosurgical clip-reconstruction. METHODS: We used randomized data (International Subarachnoid Aneurysm Trial, n = 2143) to develop models to predict 2-month functional outcome and to predict time-to-rebleed-or-retreatment. We modeled for heterogeneity of treatment effect by adding interaction terms of treatment with prespecified predictors and with baseline risk of the outcome. We predicted outcome with both treatments and calculated absolute treatment benefit. We described the patient characteristics of patients with ≥ 5% point difference in the predicted probability of favorable functional outcome (modified Rankin Score 0-2) and of no rebleed or retreatment within 10 years. Model performance was expressed with the c-statistic and calibration plots. We performed bootstrapping and leave-one-cluster-out cross-validation and pooled cluster-specific c-statistics with random effects meta-analysis. RESULTS: The pooled c-statistics were 0.72 (95% CI: 0.69-0.75) for the prediction of 2-month favorable functional outcome and 0.67 (95% CI: 0.63-0.71) for prediction of no rebleed or retreatment within 10 years. We found no significant interaction between predictors and treatment. The average predicted benefit in favorable functional outcome was 6% (95% CI: 3-10%) in favor of coiling, but 11% (95% CI: 9-13%) for no rebleed or retreatment in favor of clip-reconstruction. 134 patients (6%), young and in favorable clinical condition, had negligible functional outcome benefit of coiling but had a ≥ 5% point benefit of clip-reconstruction in terms of durability of treatment. CONCLUSIONS: We show that young patients in favorable clinical condition and without extensive vasospasm have a negligible benefit in functional outcome of endovascular coiling - compared to neurosurgical clip-reconstruction - while at the same time having a substantially lower probability of retreatment or rebleeding from neurosurgical clip-reconstruction - compared to endovascular coiling. The SHARP prediction tool ( https://sharpmodels.shinyapps.io/sharpmodels/ ) could support and incentivize a multidisciplinary discussion about aneurysm treatment decision-making by providing individualized treatment benefit estimates.

Between-hospital variation in indicators of quality of care: a systematic review.

BACKGROUND: Efforts to mitigate unwarranted variation in the quality of care require insight into the 'level' (eg, patient, physician, ward, hospital) at which observed variation exists. This systematic literature review aims to synthesise the results of studies that quantify the extent to which hospitals contribute to variation in quality indicator scores. METHODS: Embase, Medline, Web of Science, Cochrane and Google Scholar were systematically searched from 2010 to November 2023. We included studies that reported a measure of between-hospital variation in quality indicator scores relative to total variation, typically expressed as a variance partition coefficient (VPC). The results were analysed by disease category and quality indicator type. RESULTS: In total, 8373 studies were reviewed, of which 44 met the inclusion criteria. Casemix adjusted variation was studied for multiple disease categories using 144 indicators, divided over 5 types: intermediate clinical outcomes (n=81), final clinical outcomes (n=35), processes (n=10), patient-reported experiences (n=15) and patient-reported outcomes (n=3). In addition to an analysis of between-hospital variation, eight studies also reported physician-level variation (n=54 estimates). In general, variation that could be attributed to hospitals was limited (median VPC=3%, IQR=1%-9%). Between-hospital variation was highest for process indicators (17.4%, 10.8%-33.5%) and lowest for final clinical outcomes (1.4%, 0.6%-4.2%) and patient-reported outcomes (1.0%, 0.9%-1.5%). No clear pattern could be identified in the degree of between-hospital variation by disease category. Furthermore, the studies exhibited limited attention to the reliability of observed differences in indicator scores. CONCLUSION: Hospital-level variation in quality indicator scores is generally small relative to residual variation. However, meaningful variation between hospitals does exist for multiple indicators, especially for care processes which can be directly influenced by hospital policy. Quality improvement strategies are likely to generate more impact if preceded by level-specific and indicator-specific analyses of variation, and when absolute variation is also considered. PROSPERO REGISTRATION NUMBER: CRD42022315850.

Predicting outcome in acute stroke with large vessel occlusion-application and validation of MR PREDICTS in the ESCAPE-NA1 population.

BACKGROUND: Predicting outcome after endovascular treatment for acute ischemic stroke is challenging. We aim to investigate differences between predicted and observed outcomes in patients with acute ischemic stroke treated with endovascular treatment and to evaluate the performance of a validated outcome prediction score. PATIENTS AND METHODS: MR PREDICTS is an outcome prediction tool based on a logistic regression model designed to predict the treatment benefit of endovascular treatment based on the MR CLEAN and HERMES populations. ESCAPE-NA1 is a randomized trial of nerinetide vs. placebo in patients with acute stroke and large vessel occlusion. We applied MR PREDICTS to patients in the control arm of ESCAPE-NA1. Model performance was assessed by calculating its discriminative ability and calibration. RESULTS: Overall, 556/1105 patients (50.3%) in the ESCAPE-NA1-trial were randomized to the control arm, 435/556 (78.2%) were treated within 6 h of symptom onset. Good outcome (modified Rankin scale 0-2) at 3 months was achieved in 275/435 patients (63.2%), the predicted probability of good outcome was 52.5%. Baseline characteristics were similar in the study and model derivation cohort except for age (ESCAPE-NA1: mean: 70 y vs. HERMES: 66 y), hypertension (72% vs. 57%), and collaterals (good collaterals, 15% vs. 44%). Compared to HERMES we observed higher rates of successful reperfusion (TICI 2b-3, ESCAPE-NA1: 87% vs. HERMES: 71%) and faster times from symptom onset to reperfusion (median: 201 min vs. 286 min). Model performance was good, indicated by a c-statistic of 0.76 (95%confidence interval: 0.71-0.81). CONCLUSION: Outcome-prediction using models created from HERMES data, based on information available in the emergency department underestimated the actual outcome in patients with acute ischemic stroke and large vessel occlusion receiving endovascular treatment despite overall good model performance, which might be explained by differences in quality of and time to reperfusion. These findings underline the importance of timely and successful reperfusion for functional outcomes in acute stroke patients.

Prioritization of surgical patients during the COVID-19 pandemic and beyond: A qualitative exploration of patients' perspectives.

INTRODUCTION: During the COVID-19 pandemic, prioritizing certain surgical patients became inevitable due to limited surgical capacity. This study aims to identify which factors patients value in priority setting, and to evaluate their perspective on a decision model for surgical prioritization. METHODS: We enacted a qualitative exploratory study and conducted semi-structured interviews with N = 15 patients. Vignettes were used as guidance. The interviews were transcribed and iteratively analyzed using thematic analysis. RESULTS: We unraveled three themes: 1) general attitude towards surgical prioritization: patients showed understanding for the difficult decisions to be made, but demanded greater transparency and objectivity; 2) patient-related factors that some participants considered should, or should not, influence the prioritization: age, physical functioning, cognitive functioning, behavior, waiting time, impact on survival and quality of life, emotional consequences, and resource usage; and 3) patients' perspective on a decision model: usage of such a model for prioritization decisions is favorable if the model is simple, uses trustworthy data, and its output is supervised by physicians. The model could also be used as a communication tool to explain prioritization dilemmas to patients. CONCLUSION: Support for the various factors and use of a decision model varied among patients. Therefore, it seems unrealistic to immediately incorporate these factors in decision models. Instead, this study calls for more research to identify feasible avenues and seek consensus.

Patient-relevant health outcomes for von Willebrand disease, platelet function disorders, and rare bleeding disorders: a Delphi study.

Background: To assess patient value, it is essential to regularly measure health outcomes that matter to patients. It is currently unknown which health outcomes are important for patients with autosomal inherited bleeding disorders. Objectives: This study aimed to assess which health outcomes are important for patients with autosomal inherited bleeding disorders, consisting of von Willebrand disease, platelet function disorders, and rare bleeding disorders, as seen from the patients', caregivers', and healthcare professionals' perspectives. Methods: Two panels, one consisting of patients and caregivers, and one consisting of healthcare professionals participated in a Delphi process. A list of 146 health outcomes was identified from the literature. During 3 rounds, both panels rated the importance of health outcomes on a 5-point Likert scale. A health outcome was considered important by a panel if it received a median score of 5 with an IQR of ≤1. Results: In total, 13 patients, 10 caregivers, and 19 healthcare professionals participated in the Delphi study. Both panels reached consensus on the importance of health outcomes related to bleeding episodes, life-threatening complications, and the intensity and impact of menstruation. Patients and caregivers additionally reached consensus on the importance of health outcomes related to menstruation and the impact of the bleeding disorder on their daily lives. Healthcare professionals reached consensus on the importance of health outcomes related to treatment, joint health, and pain. Conclusion: In this study, health outcomes were identified that should be considered when implementing value-based health care in the care of patients with autosomal inherited bleeding disorders.

Standardized mortality ratios for regionalized acute cardiovascular care.

BACKGROUND: Standardized Mortality Ratios (SMRs) are case-mix adjusted mortality rates per hospital and are used to evaluate quality of care. However, acute care is increasingly organized on a regional level, with more severe patients admitted to specialized hospitals. We hypothesize that the current case-mix adjustment insufficiently captures differences in case-mix between non-specialized and specialized hospitals. We aim to improve the SMR by adding proxies of disease severity to the model and by calculating a regional SMR (RSMR) for acute cerebrovascular disease (CVD) and myocardial infarction (MI). METHODS: We used data from the Dutch National Basic Registration of Hospital Care. We selected all admissions from 2016 to 2018. SMRs and RSMRs were calculated by dividing the observed in-hospital mortality by the expected in-hospital mortality. The expected in-hospital mortality was calculated using logistic regression with adjustment for age, sex, socioeconomic status, severity of main diagnosis, urgency of admission, Charlson comorbidity index, place of residence before admission, month/year of admission, and in-hospital mortality as outcome. RESULTS: The IQR of hospital SMRs of CVD was 0.85-1.10, median 0.94, with higher SMRs for specialized hospitals (median 1.12, IQR 1.00-1.28, 71%-SMR > 1) than for non-specialized hospitals (median 0.92, IQR 0.82-1.07, 32%-SMR > 1). The IQR of RSMRs was 0.92-1.09, median 1.00. The IQR of hospital SMRs of MI was 0.76-1.14, median 0.98, with higher SMRs for specialized hospitals (median 1.00, IQR 0.89-1.25, 50%-SMR > 1 versus median 0.94, IQR 0.74-1.11, 44%-SMR > 1). The IQR of RSMRs was 0.90-1.08, median 1.00. Adjustment for proxies of disease severity mostly led to lower SMRs of specialized hospitals. CONCLUSION: SMRs of acute regionally organized diseases do not only measure differences in quality of care between hospitals, but merely measure differences in case-mix between hospitals. Although the addition of proxies of disease severity improves the model to calculate SMRs, real disease severity scores would be preferred. However, such scores are not available in administrative data. As a consequence, the usefulness of the current SMR as quality indicator is very limited. RSMRs are potentially more useful, since they fit regional organization and might be a more valid representation of quality of care.

Handling missing values in the analysis of between-hospital differences in ordinal and dichotomous outcomes: a simulation study.

Missing data are frequently encountered in registries that are used to compare performance across hospitals. The most appropriate method for handling missing data when analysing differences in outcomes between hospitals with a generalised linear mixed model is unclear. We aimed to compare methods for handling missing data when comparing hospitals on ordinal and dichotomous outcomes. We performed a simulation study using data from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry, a prospective cohort study in 17 hospitals performing endovascular therapy for ischaemic stroke in the Netherlands. The investigated methods for handling missing data, both case-mix adjustment variables and outcomes, were complete case analysis, single imputation, multiple imputation, single imputation with deletion of imputed outcomes and multiple imputation with deletion of imputed outcomes. Data were generated as missing completely at random (MCAR), missing at random and missing not at random (MNAR) in three scenarios: (1) 10% missing data in case-mix and outcome; (2) 40% missing data in case-mix and outcome; and (3) 40% missing data in case-mix and outcome with varying degree of missing data among hospitals. Bias and reliability of the methods were compared on the mean squared error (MSE, a summary measure combining bias and reliability) relative to the hospital effect estimates from the complete reference data set. For both the ordinal outcome (ie, the modified Rankin Scale) and a common dichotomised version thereof, all methods of handling missing data were biased, likely due to shrinkage of the random effects. The MSE of all methods was on average lowest under MCAR and with fewer missing data, and highest with more missing data and under MNAR. The 'multiple imputation, then deletion' method had the lowest MSE for both outcomes under all simulated patterns of missing data. Thus, when estimating hospital effects on ordinal and dichotomous outcomes in the presence of missing data, the least biased and most reliable method to handle these missing data is 'multiple imputation, then deletion'.

Cost-effectiveness of CT perfusion for the detection of large vessel occlusion acute ischemic stroke followed by endovascular treatment: a model-based health economic evaluation study.

OBJECTIVES: CT perfusion (CTP) has been suggested to increase the rate of large vessel occlusion (LVO) detection in patients suspected of acute ischemic stroke (AIS) if used in addition to a standard diagnostic imaging regime of CT angiography (CTA) and non-contrast CT (NCCT). The aim of this study was to estimate the costs and health effects of additional CTP for endovascular treatment (EVT)-eligible occlusion detection using model-based analyses. METHODS: In this Dutch, nationwide retrospective cohort study with model-based health economic evaluation, data from 701 EVT-treated patients with available CTP results were included (January 2018-March 2022; trialregister.nl:NL7974). We compared a cohort undergoing NCCT, CTA, and CTP (NCCT + CTA + CTP) with a generated counterfactual where NCCT and CTA (NCCT + CTA) was used for LVO detection. The NCCT + CTA strategy was simulated using diagnostic accuracy values and EVT effects from the literature. A Markov model was used to simulate 10-year follow-up. We adopted a healthcare payer perspective for costs in euros and health gains in quality-adjusted life years (QALYs). The primary outcome was the net monetary benefit (NMB) at a willingness to pay of €80,000; secondary outcomes were the difference between LVO detection strategies in QALYs (ΔQALY) and costs (ΔCosts) per LVO patient. RESULTS: We included 701 patients (median age: 72, IQR: [62-81]) years). Per LVO patient, CTP-based occlusion detection resulted in cost savings (ΔCosts median: € - 2671, IQR: [€ - 4721; € - 731]), a health gain (ΔQALY median: 0.073, IQR: [0.044; 0.104]), and a positive NMB (median: €8436, IQR: [5565; 11,876]) per LVO patient. CONCLUSION: CTP-based screening of suspected stroke patients for an endovascular treatment eligible large vessel occlusion was cost-effective. CLINICAL RELEVANCE STATEMENT: Although CTP-based patient selection for endovascular treatment has been recently suggested to result in worse patient outcomes after ischemic stroke, an alternative CTP-based screening for endovascular treatable occlusions is cost-effective. KEY POINTS: • Using CT perfusion to detect an endovascular treatment-eligible occlusions resulted in a health gain and cost savings during 10 years of follow-up. • Depending on the screening costs related to the number of patients needed to image with CT perfusion, cost savings could be considerable (median: € - 3857, IQR: [€ - 5907; € - 1916] per patient). • As the gain in quality adjusted life years was most affected by the sensitivity of CT perfusion-based occlusion detection, additional studies for the diagnostic accuracy of CT perfusion for occlusion detection are required.

Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study.

Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]). Interpretation: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. Funding: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.

Value of intravenous thrombolysis in endovascular treatment for large-vessel anterior circulation stroke: individual participant data meta-analysis of six randomised trials.

BACKGROUND: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. METHODS: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986. FINDINGS: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly. INTERPRETATION: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment. FUNDING: Stryker and Amsterdam University Medical Centers, University of Amsterdam.

Development and Validation of a Postprocedural Model to Predict Outcome After Endovascular Treatment for Ischemic Stroke.

Importance: Outcome prediction after endovascular treatment (EVT) for ischemic stroke is important to patients, family members, and physicians. Objective: To develop and validate a model based on preprocedural and postprocedural characteristics to predict functional outcome for individual patients after EVT. Design, Setting, and Participants: A prediction model was developed using individual patient data from 7 randomized clinical trials, performed between December 2010 and December 2014. The model was developed within the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration and external validation in data from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry of patients treated in clinical practice between March 2014 and November 2017. Participants included patients from multiple centers throughout different countries in Europe, North America, East Asia, and Oceania (derivation cohort), and multiple centers in the Netherlands (validation cohort). Included were adult patients with a history of ischemic stroke from an intracranial large vessel occlusion in the anterior circulation who underwent EVT within 12 hours of symptom onset or last seen well. Data were last analyzed in July 2022. Main Outcome(s) and Measure(s): A total of 19 variables were assessed by multivariable ordinal regression to predict functional outcome (modified Rankin Scale [mRS] score) 90 days after EVT. Variables were routinely available 1 day after EVT. Akaike information criterion (AIC) was used to optimize model fit vs model complexity. Probabilities for functional independence (mRS 0-2) and survival (mRS 0-5) were derived from the ordinal model. Model performance was expressed with discrimination (C statistic) and calibration. Results: A total of 781 patients (median [IQR] age, 67 [57-76] years; 414 men [53%]) constituted the derivation cohort, and 3260 patients (median [IQR] age, 72 [61-80] years; 1684 men [52%]) composed the validation cohort. Nine variables were included in the model: age, baseline National Institutes of Health Stroke Scale (NIHSS) score, prestroke mRS score, history of diabetes, occlusion location, collateral score, reperfusion grade, NIHSS score at 24 hours, and symptomatic intracranial hemorrhage 24 hours after EVT. External validation in the MR CLEAN Registry showed excellent discriminative ability for functional independence (C statistic, 0.91; 95% CI, 0.90-0.92) and survival (0.89; 95% CI, 0.88-0.90). The proportion of functional independence in the MR CLEAN Registry was systematically higher than predicted by the model (41% vs 34%), whereas observed and predicted survival were similar (72% vs 75%). The model was updated and implemented for clinical use. Conclusion and relevance: The prognostic tool MR PREDICTS@24H can be applied 1 day after EVT to accurately predict functional outcome for individual patients at 90 days and to provide reliable outcome expectations and personalize follow-up and rehabilitation plans. It will need further validation and updating for contemporary patients.

Dexamethasone versus Surgery for Chronic Subdural Hematoma.

BACKGROUND: The role of glucocorticoids without surgical evacuation in the treatment of chronic subdural hematoma is unclear. METHODS: In this multicenter, open-label, controlled, noninferiority trial, we randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary end point was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary end points included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale. RESULTS: From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively. CONCLUSIONS: In a trial that involved patients with chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be noninferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.).

Intramural Healthcare Consumption and Costs After Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

Traumatic brain injury (TBI) is a global public health problem and a leading cause of mortality, morbidity, and disability. The increasing incidence combined with the heterogeneity and complexity of TBI will inevitably place a substantial burden on health systems. These findings emphasize the importance of obtaining accurate and timely insights into healthcare consumption and costs on a multi-national scale. This study aimed to describe intramural healthcare consumption and costs across the full spectrum of TBI in Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective observational study conducted in 18 countries across Europe and in Israel. The baseline Glasgow Coma Scale (GCS) was used to differentiate patients by brain injury severity in mild (GCS 13-15), moderate (GCS 9-12), or severe (GCS ≤8) TBI. We analyzed seven main cost categories: pre-hospital care, hospital admission, surgical interventions, imaging, laboratory, blood products, and rehabilitation. Costs were estimated based on Dutch reference prices and converted to country-specific unit prices using gross domestic product (GDP)-purchasing power parity (PPP) adjustment. Mixed linear regression was used to identify between-country differences in length of stay (LOS), as a parameter of healthcare consumption. Mixed generalized linear models with gamma distribution and log link function quantified associations of patient characteristics with higher total costs. We included 4349 patients, of whom 2854 (66%) had mild, 371 (9%) had moderate, and 962 (22%) had severe TBI. Hospitalization accounted for the largest part of the intramural consumption and costs (60%). In the total study population, the mean LOS was 5.1 days at the intensive care unit (ICU) and 6.3 days at the ward. For mild, moderate, and severe TBI, mean LOS was, respectively, 1.8, 8.9, and 13.5 days at the ICU and 4.5, 10.1, and 10.3 days at the ward. Other large contributors to the total costs were rehabilitation (19%) and intracranial surgeries (8%). Total costs increased with higher age and greater trauma severity (mild; €3,800 [IQR €1,400-14,000], moderate; €37,800 [IQR €14,900-€74,200], severe; €60,400 [IQR €24,400-€112,700]). The adjusted analysis showed that female patients had lower costs than male patients (odds ratio (OR) 0.80 [CI 0.75-1.85]). Increasing TBI severity was associated with higher costs, OR 1.46 (confidence interval [CI] 1.31-1.63) and OR 1.67 [CI 1.52-1.84] for moderate and severe patients, respectively. A worse pre-morbid overall health state, increasing age and more severe systemic trauma, expressed in the Injury Severity Score (ISS), were also significantly associated with higher costs. Intramural costs of TBI are significant and are profoundly driven by hospitalization. Costs increased with trauma severity and age, and male patients incurred higher costs. Reducing LOS could be targeted with advanced care planning, in order to provide cost-effective care.

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.

Importance: Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. Design, Setting, and Participants: This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. Interventions: Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). Main Outcomes and Measures: The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. Results: A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ß = 65 mg/dL; 95% CI, 26-105 mg/dL). Conclusions and Relevance: In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04256473.

Number of life-years lost at the time of diagnosis and several years post-diagnosis in patients with solid malignancies: a population-based study in the Netherlands, 1989-2019.

Background: Loss of life expectancy (LOLE) may provide more intuitive information on the impact of cancer than relative survival over a fixed time horizon (e.g., 5-year relative survival). We aimed to assess the evolution of the LOLE using a nationwide, population-based cohort including patients diagnosed with one of 17 most frequent solid malignancies. Methods: From the Netherlands Cancer Registry, we selected adult patients diagnosed with one of the 17 most frequent solid malignancies in the Netherlands during 1989-2019, with survival follow-up until 2022. We used flexible parametric survival models to estimate the LOLE at diagnosis and the LOLE after surviving several years post-diagnosis (conditional LOLE; CLOLE) by cancer type, calendar year, age, sex, and disease stage. Findings: For all cancers combined, the LOLE consistently decreased from 1989 to 2019. This decrease was most pronounced for males with prostate cancer (e.g., from 6.9 [95% confidence interval [CI], 6.7-7.1] to 2.7 [95% CI, 2.5-3.0] for 65-year-olds) and females with breast cancer (e.g., from 6.6 [95% CI, 6.4-6.7] to 1.9 [95% CI, 1.8-2.0] for 65-year-olds). The LOLE among patients with cancers of the head and neck or the central nervous system remained constant over time. Overall, the CLOLE showed that the life years lost among patients with cancer decreased with each additional year survived post-diagnosis. For example, the LOLE at diagnosis for 65-year-old females diagnosed with breast cancer in 2019 was 1.9 [95% CI, 1.8-2.0] compared with 1.7 [95% CI, 1.6-1.8], 1.0 [95% CI, 0.9-1.1], and 0.5 [95% CI, 0.5-0.6] when surviving one, five, and ten years post-diagnosis, respectively. Estimates for other combinations of patient and tumour characteristics are available in a publicly available web-based application. Interpretation: Our findings suggested that the evolution of LOLE substantially varies across cancer type, age, and disease stage. LOLE estimates help patients better understand the impact of their specific cancer diagnosis on their life expectancy. Funding: None.