Performance metrics for models designed to predict treatment effect.

BACKGROUND: Measuring the performance of models that predict individualized treatment effect is challenging because the outcomes of two alternative treatments are inherently unobservable in one patient. The C-for-benefit was proposed to measure discriminative ability. However, measures of calibration and overall performance are still lacking. We aimed to propose metrics of calibration and overall performance for models predicting treatment effect in randomized clinical trials (RCTs). METHODS: Similar to the previously proposed C-for-benefit, we defined observed pairwise treatment effect as the difference between outcomes in pairs of matched patients with different treatment assignment. We match each untreated patient with the nearest treated patient based on the Mahalanobis distance between patient characteristics. Then, we define the Eavg-for-benefit, E50-for-benefit, and E90-for-benefit as the average, median, and 90th quantile of the absolute distance between the predicted pairwise treatment effects and local-regression-smoothed observed pairwise treatment effects. Furthermore, we define the cross-entropy-for-benefit and Brier-for-benefit as the logarithmic and average squared distance between predicted and observed pairwise treatment effects. In a simulation study, the metric values of deliberately "perturbed models" were compared to those of the data-generating model, i.e., "optimal model". To illustrate these performance metrics, different modeling approaches for predicting treatment effect are applied to the data of the Diabetes Prevention Program: 1) a risk modelling approach with restricted cubic splines; 2) an effect modelling approach including penalized treatment interactions; and 3) the causal forest. RESULTS: As desired, performance metric values of "perturbed models" were consistently worse than those of the "optimal model" (Eavg-for-benefit ≥ 0.043 versus 0.002, E50-for-benefit ≥ 0.032 versus 0.001, E90-for-benefit ≥ 0.084 versus 0.004, cross-entropy-for-benefit ≥ 0.765 versus 0.750, Brier-for-benefit ≥ 0.220 versus 0.218). Calibration, discriminative ability, and overall performance of three different models were similar in the case study. The proposed metrics were implemented in a publicly available R-package "HTEPredictionMetrics". CONCLUSION: The proposed metrics are useful to assess the calibration and overall performance of models predicting treatment effect in RCTs.

Instrumental variable analysis to estimate treatment effects: a simulation study showing potential benefits of conditioning on hospital.

BACKGROUND: Instrumental variable (IV) analysis holds the potential to estimate treatment effects from observational data. IV analysis potentially circumvents unmeasured confounding but makes a number of assumptions, such as that the IV shares no common cause with the outcome. When using treatment preference as an instrument, a common cause, such as a preference regarding related treatments, may exist. We aimed to explore the validity and precision of a variant of IV analysis where we additionally adjust for the provider: adjusted IV analysis. METHODS: A treatment effect on an ordinal outcome was simulated (beta - 0.5 in logistic regression) for 15.000 patients, based on a large data set (the IMPACT data, n = 8799) using different scenarios including measured and unmeasured confounders, and a common cause of IV and outcome. We compared estimated treatment effects with patient-level adjustment for confounders, IV with treatment preference as the instrument, and adjusted IV, with hospital added as a fixed effect in the regression models. RESULTS: The use of patient-level adjustment resulted in biased estimates for all the analyses that included unmeasured confounders, IV analysis was less confounded, but also less reliable. With correlation between treatment preference and hospital characteristics (a common cause) estimates were skewed for regular IV analysis, but not for adjusted IV analysis. CONCLUSION: When using IV analysis for comparing hospitals, some limitations of regular IV analysis can be overcome by adjusting for a common cause. TRIAL REGISTRATION: We do not report the results of a health care intervention.

Randomized trial of intravenous immunoglobulin maintenance treatment regimens in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: High peak serum immunoglobulin G (IgG) levels may not be needed for maintenance intravenous immunoglobulin (IVIg) treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and such high levels may cause side effects. More frequent lower dosing may lead to more stable IgG levels and higher trough levels, which might improve efficacy. The aim of this trial is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment. METHODS: In this randomized placebo-controlled crossover trial, we included patients with CIDP proven to be IVIg-dependent and receiving an individually established stable dose and interval of IVIg maintenance treatment. In the control arm, patients received their individual IVIg dose and interval followed by a placebo infusion at half the interval. In the intervention arm, patients received half their individual dose at half the interval. After a wash-out phase patients crossed over. The primary outcome measure was handgrip strength (assessed using a Martin Vigorimeter). Secondary outcome indicators were health-related quality of life (36-item Short-Form Health Survey), disability (Inflammatory Rasch-built Overall Disability Scale), fatigue (Rasch-built Fatigue Severity Scale) and side effects. RESULTS: Twenty-five patients were included and were treated at baseline with individually adjusted dosages of IVIg ranging from 20 to 80 g and intervals ranging from 14 to 35 days. Three participants did not complete the trial; the main analysis was therefore based on the 22 patients completing both treatment periods. There was no significant difference in handgrip strength change from baseline between the two treatment regimens (coefficient -2.71, 95% CI -5.4, 0.01). Furthermore, there were no significant differences in any of the secondary outcomes or side effects. CONCLUSIONS: More frequent lower dosing does not further improve the efficacy of IVIg in stable IVIg-dependent CIDP and does not result in fewer side effects.

Ordinal outcome analysis improves the detection of between-hospital differences in outcome.

BACKGROUND: There is a growing interest in assessment of the quality of hospital care, based on outcome measures. Many quality of care comparisons rely on binary outcomes, for example mortality rates. Due to low numbers, the observed differences in outcome are partly subject to chance. We aimed to quantify the gain in efficiency by ordinal instead of binary outcome analyses for hospital comparisons. We analyzed patients with traumatic brain injury (TBI) and stroke as examples. METHODS: We sampled patients from two trials. We simulated ordinal and dichotomous outcomes based on the modified Rankin Scale (stroke) and Glasgow Outcome Scale (TBI) in scenarios with and without true differences between hospitals in outcome. The potential efficiency gain of ordinal outcomes, analyzed with ordinal logistic regression, compared to dichotomous outcomes, analyzed with binary logistic regression was expressed as the possible reduction in sample size while keeping the same statistical power to detect outliers. RESULTS: In the IMPACT study (9578 patients in 265 hospitals, mean number of patients per hospital = 36), the analysis of the ordinal scale rather than the dichotomized scale ('unfavorable outcome'), allowed for up to 32% less patients in the analysis without a loss of power. In the PRACTISE trial (1657 patients in 12 hospitals, mean number of patients per hospital = 138), ordinal analysis allowed for 13% less patients. Compared to mortality, ordinal outcome analyses allowed for up to 37 to 63% less patients. CONCLUSIONS: Ordinal analyses provide the statistical power of substantially larger studies which have been analyzed with dichotomization of endpoints. We advise to exploit ordinal outcome measures for hospital comparisons, in order to increase efficiency in quality of care measurements. TRIAL REGISTRATION: We do not report the results of a health care intervention.

Between-centre differences in care for in-hospital cardiac arrest: a prospective cohort study.

BACKGROUND: Survival after in-hospital cardiac arrest is poor, but current literature shows substantial heterogeneity in reported survival rates. This study aims to evaluate care for patients suffering in-hospital cardiac arrest (IHCA) in the Netherlands by assessing between-hospital heterogeneity in outcomes and to explain this heterogeneity stemming from differences in case-mix or differences in quality of care. METHODS: A prospective multicentre study was conducted comprising 14 centres. All IHCA patients were included. The adjusted variation in structure and process indicators of quality of care and outcomes (in-hospital mortality and cerebral performance category [CPC] scale) was assessed with mixed effects regression with centre as random intercept. Variation was quantified using the median odds ratio (MOR), representing the expected odds ratio for poor outcome between two randomly picked centres. RESULTS: After excluding centres with less than 10 inclusions (2 centres), 701 patients were included of whom, 218 (32%) survived to hospital discharge. The unadjusted and case-mix adjusted MOR for mortality was 1.19 and 1.05, respectively. The unadjusted and adjusted MOR for CPC score was 1.24 and 1.19, respectively. In hospitals where personnel received cardiopulmonary resuscitation (CPR) training twice per year, 183 (64.7%) versus 290 (71.4%) patients died or were in a vegetative state, and 59 (20.8%) versus 68 (16.7%) patients showed full recovery (p < 0.001). CONCLUSION: In the Netherlands, survival after IHCA is relatively high and between-centre differences in outcomes are small. The existing differences in survival are mainly attributable to differences in case-mix. Variation in neurological outcome is less attributable to case-mix.

Path From Clinical Research to Implementation: Endovascular Treatment of Ischemic Stroke in the Netherlands.

Before 2015, endovascular treatment (EVT) for acute ischemic stroke was considered a promising treatment option. Based on limited evidence, it was performed in several dedicated stroke centers worldwide on selected patients. Since 2015, EVT for patients with intracranial large vessel occlusion has quickly been implemented as standard treatment in many countries worldwide, supported by the revised international guidelines based on solid evidence from multiple clinical trials. We describe the development in use of EVT in the Netherlands before, during, and after the pivotal EVT trials. We used data from all patients who were treated with EVT in the Netherlands from January 2002 until December 2018. We undertook a time-series analysis to examine trends in the use of EVT using Poisson regression analysis. Incidence rate ratios per year with 95% CIs were obtained to demonstrate the impact and implementation after the publication of the EVT trial results. We made regional observation plots, adjusted for stroke incidence, to assess the availability and use of the treatment in the country. In the buildup to the MR CLEAN (Multicenter Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands), a slow increase of EVT patients was observed, with 0.2% of all ischemic stroke patients receiving EVT. Before the trial results were formally announced, a statistically significant increase in EVT-treated patients per year was observed (incidence rate ratio, 1.72 [95% CI, 1.46-2.04]), and after the trial publication, an immediate steep increase was seen, followed by a more gradual increase (incidence rate ratio, 2.14 [95% CI, 1.77-2.59]). In 2018, the percentage of ischemic stroke patients receiving EVT increased to 5.8%. A well-developed infrastructure, a pragmatic approach toward the use of EVT in clinical practice, in combination with a strict adherence by the regulatory authorities to national evidence-based guidelines has led to successful implementation of EVT in the Netherlands. Ongoing efforts are directed at further increasing the proportion of stroke patients with EVT in all regions of the country.

Trauma models to identify major trauma and mortality in the prehospital setting.

BACKGROUND: Patients with major trauma might benefit from treatment in a trauma centre, but early identification of major trauma (Injury Severity Score (ISS) over 15) remains difficult. The aim of this study was to undertake an external validation of existing prognostic models for injured patients to assess their ability to predict mortality and major trauma in the prehospital setting. METHODS: Prognostic models were identified through a systematic literature search up to October 2017. Injured patients transported by Emergency Medical Services to an English hospital from the Trauma Audit and Research Network between 2013 and 2016 were included. Outcome measures were major trauma (ISS over 15) and in-hospital mortality. The performance of the models was assessed in terms of discrimination (concordance index, C-statistic) and net benefit to assess the clinical usefulness. RESULTS: A total of 154 476 patients were included to validate six previously proposed prediction models. Discriminative ability ranged from a C-statistic value of 0·602 (95 per cent c.i. 0·596 to 0·608) for the Mechanism, Glasgow Coma Scale, Age and Arterial Pressure model to 0·793 (0·789 to 0·797) for the modified Rapid Emergency Medicine Score (mREMS) in predicting in-hospital mortality (11 882 patients). Major trauma was identified in 52 818 patients, with discrimination from a C-statistic value of 0·589 (0·586 to 0·592) for mREMS to 0·735 (0·733 to 0·737) for the Kampala Trauma Score in predicting major trauma. None of the prediction models met acceptable undertriage and overtriage rates. CONCLUSION: Currently available prehospital trauma models perform reasonably in predicting in-hospital mortality, but are inadequate in identifying patients with major trauma. Future research should focus on which patients would benefit from treatment in a major trauma centre.

ANTECEDENTES: Los pacientes con traumatismo mayor pueden beneficiarse del tratamiento en un centro de trauma, pero la identificación precoz del traumatismo mayor (Injury Severity Score, ISS > 15) sigue siendo difícil. El objetivo de este estudio fue validar externamente los modelos pronósticos existentes para los pacientes con traumatismos con el fin de evaluar su capacidad para predecir el traumatismo mayor y la mortalidad en el entorno pre-hospitalario. MÉTODOS: Los modelos pronóstico se identificaron mediante una búsqueda sistemática de la literatura hasta octubre de 2017. Los pacientes incluidos fueron pacientes con traumatismos que fueron trasladados mediante los servicios de emergencia médica (emergency medical services, EMS) a un hospital inglés perteneciente a Trauma Audit and Research Network (TARN) entre 2013 y 2016. Las variables evaluadas fueron los traumatismos graves (ISS > 15) y la mortalidad hospitalaria. El rendimiento de los modelos se analizó en términos de discriminación (índice de concordancia, c) y de beneficio neto para evaluar la utilidad clínica. RESULTADOS: Se incluyeron un total de 154.476 pacientes para validar los seis modelos de predicción propuestos previamente. La capacidad discriminatoria osciló entre c = 0,602 (i.c. del 95%: 0,596-0,608) para el modelo que incluye mecanismo, escala de coma de Glasgow, edad y presión arterial (MGAP) hasta c = 0,793 (0,789-0,797) para la puntuación de medicina de emergencia rápida modificada (mREMS) en la predicción de la mortalidad hospitalaria (n = 11.882). Se identificó un traumatismo mayor en 52.818 pacientes, con una discriminación de c = 0,589 (0,586-0,592) para mREMS a c = 0,735 (0,733-0,737) para la puntuación de trauma de Kampala en la predicción de traumatismo mayor. Ninguno de los modelos de predicción cumplió con las tasas aceptables de subtriaje (undertriage) y sobretriaje (overtriage). CONCLUSIÓN: Los modelos de trauma pre-hospitalarios actualmente disponibles tienen un rendimiento razonable para predecir la mortalidad hospitalaria, pero son inadecuados para identificar a los pacientes con traumatismo mayor. En el futuro, las investigaciones deberían centrarse en identificar a los pacientes que se podrían beneficiar del tratamiento en un centro de trauma especializado.

Variation in the practice of tracheal intubation in Europe after traumatic brain injury: a prospective cohort study.

Traumatic brain injury patients frequently undergo tracheal intubation. We aimed to assess current intubation practice in Europe and identify variation in practice. We analysed data from patients with traumatic brain injury included in the prospective cohort study collaborative European neurotrauma effectiveness research in traumatic brain injury (CENTER-TBI) in 45 centres in 16 European countries. We included patients who were transported to hospital by emergency medical services. We used mixed-effects multinomial regression to quantify the effects on pre-hospital or in-hospital tracheal intubation of the following: patient characteristics; injury characteristics; centre; and trauma system characteristics. A total of 3843 patients were included. Of these, 1322 (34%) had their tracheas intubated; 839 (22%) pre-hospital and 483 (13%) in-hospital. The fit of the model with only patient characteristics predicting intubation was good (Nagelkerke R2 64%). The probability of tracheal intubation increased with the following: younger age; lower pre-hospital or emergency department GCS; higher abbreviated injury scale scores (head and neck, thorax and chest, face or abdomen abbreviated injury score); and one or more unreactive pupils. The adjusted median odds ratio for intubation between two randomly chosen centres was 3.1 (95%CI 2.1-4.3) for pre-hospital intubation, and 2.7 (95%CI 1.9-3.5) for in-hospital intubation. Furthermore, the presence of an anaesthetist was independently associated with more pre-hospital intubation (OR 2.9, 95%CI 1.3-6.6), in contrast to the presence of ambulance personnel who are allowed to intubate (OR 0.5, 95%CI 0.3-0.8). In conclusion, patient and injury characteristics are key drivers of tracheal intubation. Between-centre differences were also substantial. Further studies are needed to improve the evidence base supporting recommendations for tracheal intubation.

Systematic review of current randomised control trials in chronic subdural haematoma and proposal for an international collaborative approach.

BACKGROUND: Chronic subdural haematoma (CSDH) is a pathology that is frequently encountered by neurosurgeons. Nevertheless, there is a lack of guidelines based on solid evidence. There has been a recent and considerable increase in the interest on management and outcomes for CSDH. Therefore, we systematically reviewed all currently running randomised controlled trials (RCTs) in chronic subdural haematoma to understand the areas under investigation and plan future collaborative trials. METHODS: Clinical trials databases (Cochrane Controlled Register of Trials, WHO ICTRP and clinical trials.gov) were searched for trials relevant to chronic subdural haematoma. It was then established which trials were currently running and fulfilled robust research methodology for a RCT. RESULTS: There are 26 currently running RCTs in CSDH, with the most common topics covering application of steroids (7), surgical techniques (5) and tranexamic acid (5). Further to this, there are trials running on other pharmacological agents (4), middle meningeal artery (MMA) embolisation (2) and peri-operative management (3). CONCLUSIONS: Pharmacological agents are a particular focus of CSDH management currently, and a wealth of studies on steroids will hopefully lead to more harmonised, evidence-based practice regarding this in the near future. Surgical techniques and new procedures such as MMA embolisation are also important focuses for improving patient outcomes. There is an on-going need for future RCTs and evidence-based guidelines in CSDH, particularly including low- and middle-income countries, and it is hoped that the establishment of the iCORIC (International COllaborative Research Initiative on Chronic Subdural Haematoma) will help address this.

Prediction models for mortality in adult patients visiting the Emergency Department: a systematic review.

We provide a systematic overview of literature on prediction models for mortality in the Emergency Department (ED). We searched various databases for observational studies in the ED or similar setting describing prediction models for short-term mortality (up to 30 days or in-hospital mortality) in a non-trauma population. We used the CHARMS-checklist for quality assessment. We found a total of 14.768 articles and included 17 articles, describing 22 models. Model performance ranged from AUC 0.63-0.93. Most articles had a moderate risk of bias in one or more domains. The full model and PARIS model performed best, but are not yet ready for implementation. There is a need for validation studies to compare multiple prediction models and to evaluate their accuracy.

Patient-Reported Outcome Measures May Add Value in Breast Cancer Surgery.

PURPOSE: Considering the comparable prognosis in early-stage breast cancer after breast-conserving therapy (BCT) and mastectomy, quality of life should be a focus in treatment decision(s). We retrospectively collected PROs and analyzed differences per type of surgery delivered. We aimed to obtain reference values helpful in shared decision-making. PATIENTS AND METHODS: pTis-T3N0-3M0 patients operated between January 2005 and September 2016 were eligible if: (1) no chemotherapy was administered < 6 months prior to enrolment, and (2) identical surgeries were performed in case of bilateral surgery. After consent, EQ-5D-5L, EORTC-QLQ-C30/BR23, and BREAST-Q were administered. PROs were evaluated per baseline characteristics using multivariable linear regression models. Outcomes were compared for different surgeries as well as for primary (PBC) and second primary or recurrent (SBC) breast cancer patients using analyses of variance (ANOVAs). RESULTS: The response rate was 68%. PROs in 612 PBC patients were comparable to those in 152 SBC patients. Multivariable analyses showed increasing age to be associated with lower "physical functioning" [ß - 0.259, p < 0.001] and "sexual functioning" [ß - 0.427, p < 0.001], and increasing time since surgery with less "fatigue" [ß - 1.083, p < 0.001]. Mastectomy [ß - 13.596, p = 0.003] and implant reconstruction [ß - 13.040, p = 0.007] were associated with lower "satisfaction with breast" scores than BCT. Radiation therapy was associated with lower satisfaction scores than absence of radiotherapy. DISCUSSION: PRO scores were associated with age, time since surgery, type of surgery, and radiation therapy in breast cancer patients. The scores serve as a reference value for different types of surgery in the study population and enable prospective use of PROs in shared decision-making.

Use of surgical-site infection rates to rank hospital performance across several types of surgery.

BACKGROUND: Comparing and ranking hospitals based on health outcomes is becoming increasingly popular, although case-mix differences between hospitals and random variation are known to distort interpretation. The aim of this study was to explore whether surgical-site infection (SSI) rates are suitable for comparing hospitals, taking into account case-mix differences and random variation. METHODS: Data from the national surveillance network in the Netherlands, on the eight most frequently registered types of surgery for the year 2009, were used to calculate SSI rates. The variation in SSI rate between hospitals was estimated with multivariable fixed- and random-effects logistic regression models to account for random variation and case mix. 'Rankability' (as the reliability of ranking) of the SSI rates was calculated by relating within-hospital variation to between-hospital variation. RESULTS: Thirty-four hospitals reported on 13 629 patients, with overall SSI rates per surgical procedure varying between 0 and 15·1 per cent. Statistically significant differences in SSI rate between hospitals were found for colonic resection, caesarean section and for all operations combined. Rankability was 80 per cent for colonic resection but 0 per cent for caesarean section. Rankability was 8 per cent in all operations combined, as the differences in SSI rates were explained mainly by case mix. CONCLUSION: When comparing SSI rates in all operations, differences between hospitals were explained by case mix. For individual types of surgery, case mix varied less between hospitals, and differences were explained largely by random variation. Although SSI rates may be used for monitoring quality improvement within hospitals, they should not be used for ranking hospitals.

Clinical outcome of CIDP one year after start of treatment: a prospective cohort study.

OBJECTIVE: To assess clinical outcome in treatment-naive patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We included adult treatment-naive patients participating in the prospective International CIDP Outcome Study (ICOS) that fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for CIDP. Patients were grouped based on initial treatment with (1) intravenous immunoglobulin (IVIg), (2) corticosteroid monotherapy or (3) IVIg and corticosteroids (combination treatment). Outcome measures included the inflammatory Rasch-built overall disability scale (I-RODS), grip strength, and Medical Research Council (MRC) sum score. Treatment response, treatment status, remissions (improved and untreated), treatment changes, and residual symptoms or deficits were assessed at 1 year. RESULTS: Forty patients were included of whom 18 (45%) initially received IVIg, 6 (15%) corticosteroids, and 16 (40%) combination treatment. Improvement on ≥ 1 of the outcome measures was seen in 31 (78%) patients. At 1 year, 19 (48%) patients were still treated and fourteen (36%) patients were in remission. Improvement was seen most frequently in patients started on IVIg (94%) and remission in those started on combination treatment (44%). Differences between groups did not reach statistical significance. Residual symptoms or deficits ranged from 25% for neuropathic pain to 96% for any sensory deficit. CONCLUSIONS: Improvement was seen in most patients. One year after the start of treatment, more than half of the patients were untreated and around one-third in remission. Residual symptoms and deficits were common regardless of treatment.

Process of care partly explains the variation in mortality between hospitals after peripheral vascular surgery.

OBJECTIVES: The aim of this study is to investigate whether variation in mortality at hospital level reflects differences in quality of care of peripheral vascular surgery patients. DESIGN: Observational study. MATERIALS: In 11 hospitals in the Netherlands, 711 consecutive vascular surgery patients were enrolled. METHODS: Multilevel logistic regression models were used to relate patient characteristics, structure and process of care to mortality at 1 year. The models were constructed by consecutively adding age, sex and Lee index, then remaining risk factors, followed by structural measures for quality of care and finally, selected process of care parameters. RESULTS: Total 1-year mortality was 11%, ranging from 6% to 26% in different hospitals. Large differences in patient characteristics and quality indicators were observed between hospitals (e.g., age>70 years: 28-58%; beta-blocker therapy: 39-87%). Adjusted analyses showed that a large part of variation in mortality was explained by age, sex and the Lee index (Akaike's information criterion (AIC)=59, p<0.001). Another substantial part of the variation was explained by process of care (AIC=5, p=0.001). CONCLUSIONS: Differences between hospitals exist in patient characteristics, structure of care, process of care and mortality. Even after adjusting for the patient population at risk, a substantial part of the variation in mortality can be explained by differences in process measures of quality of care.

Statin treatment after a recent TIA or stroke: is effectiveness shown in randomized clinical trials also observed in everyday clinical practice?

AIM AND BACKGROUND: The benefit of statin treatment in patients with a previous ischemic stroke or transient ischemic attack (TIA) has been demonstrated in randomized clinical trials (RCT). However, the effectiveness in everyday clinical practice may be decreased because of a different patient population and less controlled setting. We aim to describe statin use in an unselected cohort of patients, identify factors related to statin use and test whether the effect of statins on recurrent vascular events and mortality observed in RCTs is also observed in everyday clinical practice. METHODS: In 10 centers in the Netherlands, patients admitted to the hospital or visiting the outpatient clinic with a recent TIA or ischemic stroke were prospectively and consecutively enrolled between October 2002 and May 2003. Statin use was determined at discharge and during follow-up. We used logistic regression models to estimate the effect of statins on the occurrence of vascular events (stroke or myocardial infarction) and mortality within 3 years. We adjusted for confounders with a propensity score that relates patient characteristics to the probability of using statins. RESULTS: Of the 751 patients in the study, 252 (34%) experienced a vascular event within 3 years. Age, elevated cholesterol levels and other cardiovascular risk factors were associated with statin use at discharge. After 3 years, 109 of 280 (39%) of the users at discharge had stopped using statins. Propensity score adjusted analyses showed a beneficial effect of statins on the occurrence of the primary outcome (odds ratio 0.8, 95% CI: 0.6-1.2). CONCLUSION: In our study, we found poor treatment adherence to statins. Nevertheless, after adjustment for the differences between statin users and non-statin users, the observed beneficial effect of statins on the occurrence of vascular events within 3 years, although not statistically significant, is compatible with the effect observed in clinical trials.

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT).

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

Prediction admission in the older population in the Emergency Department: the CLEARED tool.

BACKGROUND: Length of stay (LOS) in the Emergency Department (ED) is correlated with an extended in-hospital LOS and may even increase 30-day mortality. Older patients represent a growing population in the ED and they are especially at risk of adverse outcomes. Screening tools that adequately predict admission could help reduce waiting times in the ED and reduce time to treatment. We aimed to develop and validate a clinical prediction tool for admission, applicable to the aged patient population in the ED. METHODS: Data from 7,606 ED visits of patients aged 70 years and older between 2012 and 2014 were used to develop the CLEARED tool. Model performance was assessed with discrimination using logistic regression and calibration. The model was internally validated by bootstrap resampling in Erasmus Medical Center and externally validated at two other hospitals, Medisch Spectrum Twente (MST) and Leiden University Medical Centre (LUMC). RESULTS: CLEARED contains 10 predictors: body temperature, heart rate, diastolic blood pressure, systolic blood pressure, oxygen saturation, respiratory rate, referral status, the Manchester Triage System category, and the need for laboratory or radiology testing. The internally validated area under the curve (AUC) was 0.766 (95% CI [0.759;0.781]). External validation in MST showed an AUC of 0.797 and in LUMC, an AUC of 0.725. CONCLUSIONS: The developed CLEARED tool reliably predicts admission in elderly patients visiting the ED. It is a promising prompt, although further research is needed to implement the tool and to investigate the benefits in terms of reduction of crowding and LOS in the ED.

Low Socioeconomic Status Is Associated with Worse Outcomes After Curative Surgery for Colorectal Cancer: Results from a Large, Multicenter Study.

BACKGROUND: Socioeconomic status (SES) has been associated with early mortality in cancer patients. However, the association between SES and outcome in colorectal cancer patients is largely unknown. The aim of this study was to investigate whether SES is associated with short- and long-term outcome in patients undergoing curative surgery for colorectal cancer. METHODS: Patients who underwent curative surgery in the region of Rotterdam for stage I-III colorectal cancer between January 2007 and July 2014 were included. Gross household income and survival status were obtained from a national registry provided by Statistics Netherlands Centraal Bureau voor de Statistiek. Patients were assigned percentiles according to the national income distribution. Logistic regression and Cox proportional hazard regression were performed to assess the association of SES with 30-day postoperative complications, overall survival and cancer-specific survival, adjusted for known prognosticators. RESULTS: For 965 of the 975 eligible patients (99%), gross household income could be retrieved. Patients with a lower SES more often had diabetes, more often underwent an open surgical procedure, and had more comorbidities. In addition, patients with a lower SES were less likely to receive (neo) adjuvant treatment. Lower SES was independently associated with an increased risk of postoperative complications (Odds ratio per percent increase 0.99, 95%CI 0.99-0.998, p = 0.004) and lower cancer-specific mortality (Hazard ratio per percent increase 0.99, 95%CI 0.98-0.99, p = 0.009). CONCLUSION: This study shows that lower SES is associated with increased risk of postoperative complications, and poor cancer-specific survival in patients undergoing surgery for stage I-III colorectal cancer after correcting for known prognosticators.

Variation between hospitals in patient outcome after stroke is only partly explained by differences in quality of care: results from the Netherlands Stroke Survey.

BACKGROUND AND PURPOSE: Patient outcome is often used as an indicator of quality of hospital care. The aim of this study is to investigate whether there is a straightforward relationship between quality of care and outcome, and whether outcome measures could be used to assess quality of care after stroke. METHODS: In 10 centres in The Netherlands, 579 patients with acute stroke were prospectively and consecutively enrolled. Poor outcome was defined as a score on the modified Rankin scale >or=3 at 1 year. Quality of care was assessed by relating diagnostic, therapeutic and preventive procedures to indication. Multiple logistic regression models were used to compare observed proportions of patients with poor outcome with expected proportions, after adjustment for patient characteristics and quality of care parameters. RESULTS: A total of 271 (47%) patients were dead or disabled at 1 year. Poor outcome varied across the centres from 29% to 78%. Large differences between centres were also observed in clinical characteristics, prognostic factors and quality of care. For example, between hospital quartiles based on outcome, age >or=70 years varied from 50% to 65%, presence of vascular risk factors from 88% to 96%, intravenous fluids when indicated from 35% to 81%, and antihypertensive therapy when indicated from 60% to 85%. The largest part of variation in patient outcome between centres was explained by differences in patient characteristics (Akaike's Information Criterion (AIC) = 134.0). Quality of care parameters explained a small part of the variation in patient outcome (AIC = 5.5). CONCLUSIONS: Patient outcome after stroke varies largely between centres and is, for a substantial part, explained by differences in patient characteristics at time of hospital admission. Only a small part of the hospital variation in patient outcome is related to differences in quality of care. Unadjusted proportions of poor outcome after stroke are not valid as indicators of quality of care.

New approaches to increase statistical power in TBI trials: insights from the IMPACT study.

INTRODUCTION: None of the multi-centre phase III randomized controlled trials (RCTs) performed in TBI have convincingly demonstrated efficacy. Problems in clinical trial design and analysis may have contributed to these failures. Clinical trials in the TBI population pose several complicated methodological challenges, related especially to the heterogeneity of the population. In this paper we examine the issue of heterogeneity within the IMPACT (International Mission on Prognosis and Clinical Trial design in TBI) database and investigate the application of conventional and innovative methods for the statistical analysis of trials in TBI. METHODS AND RESULTS: Simulation studies in the IMPACT database (N = 9205) showed substantial gains in efficiency with covariate adjustment. Adjusting for 7 important predictors yielded up to a 28% potential reduction in trial size. Ongoing analyses on the potential benefit of ordinal analysis, such as proportional odds and sliding dichotomy, gave promising results with even larger potential reductions in trial size. CONCLUSION: The statistical power of RCTs in TBI can be considerably increased by applying covariate adjustment and by ordinal analysis methods of the GOS. These methods need to be considered for optimizing future TBI trials.