Development and internal validation of a prediction model for long-term opioid use-an analysis of insurance claims data.

ABSTRACT: In the United States, a public-health crisis of opioid overuse has been observed, and in Europe, prescriptions of opioids are strongly increasing over time. The objective was to develop and validate a multivariable prognostic model to be used at the beginning of an opioid prescription episode, aiming to identify individual patients at high risk for long-term opioid use based on routinely collected data. Predictors including demographics, comorbid diseases, comedication, morphine dose at episode initiation, and prescription practice were collected. The primary outcome was long-term opioid use, defined as opioid use of either >90 days duration and ≥10 claims or >120 days, independent of the number of claims. Traditional generalized linear statistical regression models and machine learning approaches were applied. The area under the curve, calibration plots, and the scaled Brier score assessed model performance. More than four hundred thousand opioid episodes were included. The final risk prediction model had an area under the curve of 0.927 (95% confidence interval 0.924-0.931) in the validation set, and this model had a scaled Brier score of 48.5%. Using a threshold of 10% predicted probability to identify patients at high risk, the overall accuracy of this risk prediction model was 81.6% (95% confidence interval 81.2% to 82.0%). Our study demonstrated that long-term opioid use can be predicted at the initiation of an opioid prescription episode, with satisfactory accuracy using data routinely collected at a large health insurance company. Traditional statistical methods resulted in higher discriminative ability and similarly good calibration as compared with machine learning approaches.

Financial Toxicity in Swiss Cancer Patients Treated with Proton Therapy: An Observational Cross-Sectional Study on Self-Reported Outcome.

BACKGROUND: Proton therapy is indicated for cancers that would be difficult to treat with conventional radiotherapy. Compulsory healthcare insurance covers the costs of this therapy in Switzerland, but this does not mean that proton therapy is cost-neutral for every cancer patient. Significant out-of-pocket (OOP) costs may arise due to expenses associated with proton therapy, and patients may experience treatment-related financial distress-an effect known as "financial toxicity." This study investigates the financial toxicity of patients undergoing proton therapy in a high-income country with a compulsory health insurance policy. METHODS: Between September 2019 and November 2021, 146 Swiss cancer patients treated with proton therapy participated in this study, of whom 90 (62%) were adults and 56 (38%) were caregivers of child cancer patients. Financial toxicity was assessed using the FACIT Comprehensive Score for Financial Toxicity (COST). OOP costs during proton therapy were recorded weekly, and financial coping strategies were captured at the end of treatment. FINDINGS: The median COST score, indicating financial toxicity, was 29.9 (IQR 21.0; 36.0) for all patients, 30.0 (IQR 21.3; 37.9) for adults, and 28.0 (IQR 20.5; 34.0) for children's caregivers. Higher income (estimate 8.1, 95% CI 3.7 to 12.4, p ≤ 0.001) was significantly associated with higher COST scores, indicating less financial toxicity. Further distance from home to the treatment centre per 100 km (estimate -3.7, 95% CI -5.7 to -1.9, p ≤ 0.001) was significantly associated with lower COST scores, indicating increased financial toxicity. Married adult patients had substantially lower COST scores than single patients (estimate: -9.1, 95% CI -14.8 to -3.4, p ≤ 0.001). The median OOP cost was 2050 Swiss francs (CHF) and was spent mainly on travel, accommodation, and eating out. Sixty-three (43%) patients used their savings; 54 (37%) cut spending on leisure activities; 21 (14.4%) cut living expenses; 14 (9.6%) borrowed money; nine (6.2%) worked more; and four (2.7%) sold property. Patients with high COST scores used significantly fewer coping strategies such as saving on leisure activities (estimate -9.5, 95% CI -12.4 to -6.6, p ≤ 0.001), spending savings (estimate -3.9, 95% CI -6.3 to -1.4, p = 0.002), borrowing money (estimate -6.3, 95% CI -10.4 to -2.2, p = 0.003), and increasing workload (estimate -5.5, 95% CI -10.5 to -0.4, p = 0.035). INTERPRETATION: A substantial number of cancer patients treated with proton therapy experience financial toxicity in Switzerland. Long travel distances to the proton therapy centre and low income negatively affect the financial well-being of these patients during proton therapy.

Long-term neurodevelopmental outcome and serial cerebral magnetic resonance imaging assessment in Fontan patients at school age.

OBJECTIVES: Children with univentricular congenital heart disease undergoing staged surgical palliation are at risk for impaired neurodevelopmental (ND) outcome. Little is known about the long-term effects on brain growth until school age. METHODS: In a prospective two-centre study, consecutive patients undergoing stage I (Hybrid or Norwood) to stage III (Fontan procedure) were evaluated by 2 serial cerebral magnetic resonance imaging examinations, somatic growth and ND testing before Fontan procedure at 2 years of age (Bayley-III) and after Fontan at 6-8 years of age (Wechsler Intelligence Scale for Children-third edition). Magnetic resonance imaging findings were compared with 8 healthy controls. Medical and sociodemographic characteristics were documented and related to cerebral and ND findings. RESULTS: We examined 33 children (16 female) at a mean age of 2.3 (0.35) and 6.8 (± 0.7) years. The mean Bayley-III cognitive scales were 99.1 (9.9), language scales 98.4 (11.9) and motor scales 98.5 (13.8) at the first examination. Follow-up at school age showed a mean total IQ of 86.7 (13.6). The rate of structural brain lesions increased from 39% at 2 years to 58% at school age. Bayley-III language scale (P = 0.021) and mean Wechsler Intelligence Scale for Children-third edition (P = 0.019) were lower in children with pathological MR findings. Total brain volume (P < 0.001), total grey matter volume (P = 0.002), deep grey matter volume (P = 0.001) and white matter volume (P < 0.001) were smaller in patients compared to age- and gender-matched healthy controls. CONCLUSIONS: Smaller brain volumes and structural brain lesions in complex congenital heart defect patients at school age are associated with impaired ND outcome. For the evaluation of predictive surgical or clinical factors, larger multicentre studies are needed.

The incremental value of the contribution of a biostatistician to the reporting quality in health research-A retrospective, single center, observational cohort study.

BACKGROUND: The reporting quality in medical research has recently been critically discussed. While reporting guidelines intend to maximize the value from funded research, and initiatives such as the EQUATOR network have been introduced to advance high quality reporting, the uptake of the guidelines by researchers could be improved. The aim of this study was to assess the contribution of a biostatistician to the reporting and methodological quality of health research, and to identify methodological knowledge gaps. METHODS: In a retrospective, single center, observational cohort study, two groups of publications were compared. The group of exposed publications had an academic biostatistician on the author list, whereas the group of non-exposed publications did not include a biostatistician of the evaluated group. Rating of reporting quality was done in blinded fashion and in duplicate. The primary outcome was a sum score based on six dimensions, ranging between 0 (worst) and 11 (best). The study protocol was reviewed and approved as a registered report. RESULTS: There were 131 publications in the exposed group published between 2017 and 2018. Of these, 95 were either RCTs, observational, or prediction / prognostic studies. Corresponding matches in the group of non-exposed publications were identified in a reproducible manner. Comparison of reporting quality overall revealed a 1.60 (95%CI from 0.92 to 2.28, p <0.0001) units higher reporting quality for exposed publications. A subgroup analysis within study types showed higher reporting quality across all three study types. CONCLUSION: Our study is the first to report an association of a higher reporting quality and methodological strength in health research publications with a biostatistician on the author list. The higher reporting quality persisted through subgroups of study types and dimensions. Methodological knowledge gaps were identified for prediction / prognostic studies, and for reporting on statistical methods in general and missing values, specifically.

Increased risk of adverse events in non-cancer patients with chronic and high-dose opioid use-A health insurance claims analysis.

BACKGROUND: Chronic and high dose opioid use may result in adverse events. We analyzed the risk associated with chronic and high dose opioid prescription in a Swiss population. METHODS: Using insurance claims data covering one-sixth of the Swiss population, we analyzed recurrent opioid prescriptions (≥2 opioid claims with at least 1 strong opioid claim) between 2006 and 2014. We calculated the cumulative dose in milligrams morphine equivalents (MED) and treatment duration. Excluded were single opioid claims, opioid use that was cancer treatment related, and opioid use in substitution programs. We assessed the association between the duration of opioid use, prescribed opioid dose, and benzodiazepine use with emergency department (ED) visits, urogenital and pulmonary infections, acute care hospitalization, and death at the end of the episode. RESULTS: In 63,642 recurrent opioid prescription episodes (acute 38%, subacute 7%, chronic 25.8%, very chronic (>360 days) episodes 29%) 18,336 ED visits, 30,209 infections, 19,375 hospitalizations, and 9,662 deaths occurred. The maximum daily MED dose was <20 mg in 15.8%, 20-<50 mg in 16.6%, 50-<100 mg in 21.6%, and ≥100 mg in 46%. Compared to acute episodes (<90 days), episode duration was an independent predictor of ED visits (chronic OR 1.09 (95% CI 1.03-1.15), very chronic (>360 days) OR 1.76 (1.67-1.86)) for adverse effects; infections (chronic OR 1.74 (1.66-1.82), very chronic 4.16 (3.95-4.37)), and hospitalization (chronic: OR 1.22 (1.16-1.29), very chronic OR 1.82 (1.73-1.93)). The risk of death decreased over time (very chronic OR 0.46 (0.43-0.50)). A dose dependent increased risk was observed for ED visits, hospitalization, and death (≥100mg daily MED OR 1.21 (1.13-1.29), OR 1.29 (1.21-1.38), and OR 1.67, 1.50-1.85, respectively). A concomitant use of benzodiazepines increased the odds for ED visits by 46% (OR 1.46, 1.41-1.52), infections by 44% (OR 1.44, 1.41-1.52), hospitalization by 12% (OR 1.12, 1.07-1.1), and death by 45% (OR 1.45, 1.37-1.53). CONCLUSION: The length of opioid use and higher prescribed morphine equivalent dose were independently associated with an increased risk for ED visits and hospitalizations. The risk for infections, ED visits, hospitalizations, and death also increased with concomitant benzodiazepine use.

[Care Management for Polytrauma Patients in a Level-1 Trauma Centre]. / Care Management für Polytrauma-Patientinnen und -Patienten in einem überregionalen Level-1- Traumazentrum.

Care Management for Polytrauma Patients in a Level-1 Trauma Centre Abstract. In our level-1 trauma institution, polytrauma patients with an Injury Severity Score of 16 or higher are facing waiting times for transfer to a rehabilitation facility, causing a negative financial outcome for our institution. The purpose of this study is to stimulate rapid transfer to a rehabilitation facility. In a single-centre case study, care management for (poly)trauma patients was started to ensure time-directed treatment for trauma patients related to Diagnosis-Related Groups (DRG). In the period of 2013-2018 there was an increase in trauma admissions up to 14 % (n = 16 157) with a mean length of hospital stay of 6.4 days, together with a reduction in the number of trauma bed capacity from 50 to 42. In relation to the DRGs, regular trauma patients who were not in need of a stationary rehabilitation facility stayed in line with the expected time of hospital stay. But (poly)trauma patients (n = 1831) with the need of a stationary stay in a rehabilitation centre were faced with waiting times before they could be transferred. The average excess waiting time in relation to DRG for polytrauma patients was 5.1 days. Trauma patients for a rehabilitation centre have a higher Case Mix Index (CMI) compared to those who do not require inpatient rehabilitation (4.22 versus 1.04, p <0.0001). With about 280 trauma patients annually waiting an extra 5.1 days for transfer to a rehabilitation facility, the financial burden for our department amounts to Swiss francs 885,360 without reimbursement. Since no extra bed capacities in rehabilitation facilities are available in our area, it may be advised to set up an early in-hospital trauma rehabilitation program in a level-1 trauma centre in order to reduce financial loss.

Executive function deficits mediate the association between very preterm birth and behavioral problems at school-age.

BACKGROUND & AIMS: Children and adolescents born very preterm are at increased risk to develop executive function deficits and to suffer from social, emotional and attentional problems. This study investigated whether executive function deficits contribute to behavioral problems in children and adolescents born very preterm at school-age. STUDY DESIGN: Thirty-eight children and adolescents born very preterm and 41 age-matched term-born peers were assessed at a mean age of 12.9 (±1.8) years with a comprehensive battery of executive function tests, including working memory, planning, cognitive flexibility, and verbal fluency. A composite score was calculated to reflect overall executive function abilities. To assess behavioral problems, parents completed the Strengths and Difficulties Questionnaire (SDQ). Mediation analysis was applied to quantify the effect of preterm birth on behavioral problems with executive function abilities as a mediating variable. RESULTS: Executive function abilities were poorer in the very preterm compared to the term-born group (d = 0.62, p = .005) and the parents of very preterm children reported more behavioral problems on the SDQ Total Difficulties Score (d = 0.54, p = .01). The effect of birth status on behavioral problems was significantly mediated by executive function abilities while adjusting for age at assessment, sex, and socioeconomic status (F(2, 76) = 6.42, p = .002, R2 = 0.14). CONCLUSION: Results from this study suggest that the increase in behavioral symptoms in very preterm children at school-age compared to term-born peers may partly be explained by their executive function deficits. These findings highlight the importance of continuously monitoring the development of children born very preterm to provide optimal care as they grow up.

Opioid Prescription in Switzerland: Appropriate Comedication use in Cancer and Noncancer Pain.

BACKGROUND: In Europe, limited information on the use of opioids is available. OBJECTIVES: To assess how guideline recommendations to manage opioid-related adverse events were followed in cancer- and noncancer-related opioid use. STUDY DESIGN: Analysis of health insurance data of one of the major health insurers in Switzerland. SETTING: All opioid claims between 2006 and 2014. METHODS: Opioid episodes were cancer-related when cancer treatments were used within ± 3 months of the first opioid claim. Recurrent strong episodes were defined as >/= 2 opioid claims with at least one strong opioid claim. Episode duration were acute (< 90 days), subacute, or chronic (>/= 120 days >/= 90 days +>/= 10 claims). RESULTS: Out of 591,633 opioid episodes 76,968 (13%) were recurrent episodes: 94% were noncancer related (83% in recurrent episodes) and 6% cancer related (17% recurrent). Chronic opioid use was observed in 55% (noncancer) and 58% (cancer) recurrent episodes. Recommended laxatives were used in 50% noncancer and in 67% cancer episodes. Antiemetic drugs were used in 54% noncancer and in 83% cancer episodes. Not recommended coprescription of benzodiazepines was observed in 34% recurrent noncancer and 46% cancer episodes. LIMITATIONS: No clinical information was available to assess the indication for opioid use. CONCLUSIONS: In this study, opioids were primarily used outside the context of cancer-related treatment. In noncancer-related opioid use, we found a substantial higher proportion without recommended laxative and antiemetic medications. Coprescription of benzodiazepines may increase the risk for opioid overdose and was present in one-third of the noncancer episodes and in almost every second cancer episode. KEY WORDS: Pain medications, opioids, nonopioids, benzodiazepines, health insurance claims data, cancer pain, noncancer pain, chronic opioid use, adverse events prevention, guideline recommendations.

Changes over time in prescription practices of pain medications in Switzerland between 2006 and 2013: an analysis of insurance claims.

BACKGROUND: In Europe, scant information is available about prescription practices for pain medications. The aim of this research was to assess changes in prescription rates of non-opioid, weak opioid, and strong opioid medications between 2006 and 2013 in the Swiss population. METHODS: Using insurance claims data covering one-sixth of the Swiss population, we analyzed the numbers of reimbursed pain medications, the number of reimbursements per persons, and the cumulative dose in milligrams. For opioids, the morphine equivalent dose and treatment days were calculated. Data were extrapolated to the dose per day per 100'000 population stratified by age, gender, and canton. RESULTS: In total, 4'746'942 paracetamol, 2'156'620 NSAIDs or Coxibs, 931'129 metamizole, 1'322'272 weak opioid, and 807'835 strong opioid claims were analyzed. Between 2006 and 2013, the increase in claims per 100'000 persons was 32% for paracetamol, 242% for metamizole, 107% for NSAIDS, 86% for Coxibs, 13% for weak opioids, and 121% for strong opioids. For strong opioids the total MED in mg /100'000 increased by 117%, the treatment days /100'000 by 101%. For strong opioids, fentanyl was most frequently used (increase between 2006 and 2013 by 91% for MED/100'000 persons and 94% treatment days / 100'000) followed by buprenorphine and oxycodone. The highest proportional increase in MED / 100'000 was observed for methadone (+1414%) and oxycodone (+313%). Marked geographical variation was detected in the use of metamizole, paracetamole, and strong opioids in different cantons. CONCLUSION: The analysis of insurance claims data provides evidence that the prescription rates for pain medications increased in Switzerland within the last ten years, in particular for metamizole and strong opioids. Furthermore, the prescription rates for metamizole, paracetamol, and strong opioids varied substantially between different cantons in Switzerland.

The chronic care for age-related macular degeneration study (CHARMED): study protocol for a randomized controlled trial.

BACKGROUND: Neovascular age-related macular degeneration is the leading cause of irreversible blindness in people 50 years of age or older in the developed world. As in other chronic diseases, several effective treatments are available, but in clinical daily practice there is an evidence performance gap. The Chronic Care Model represents an evidence-based framework for the care of chronically ill patients and aims at closing that gap. However, no data are available regarding patients with neovascular age-related macular degeneration. METHODS/DESIGN: CHARMED is a multicenter randomized controlled trial. The study challenges the hypothesis that the implementation of core elements of the Chronic Care Model (patient empowerment, delivering evidence based information, clinical information system, reminder system with structured follow up and frequent monitoring) via a specially trained Chronic Care Coach in Swiss centres for neovascular age-related macular degeneration results in better visual acuity (primary outcome) and an increased disease specific quality of life (secondary outcome) in patients with neovascular age-related macular degeneration. According to the power calculation, a total sample size of 352 patients is needed (drop out rate of 25%). 14 specialised medical doctors from leading ophtalmologic centres in Switzerland will include 25 patients. In each centre, a Chronic Care Coach will provide disease specific care according to the Chronic Care Model for intervention group. Patients from the control group will be treated as usual. Baseline measurements will be taken in month III - XII, starting in March 2011. Follow-up data will be collected after 6 months and 1 year. DISCUSSION: Multiple studies have shown that implementing Chronic Care Model elements improve clinical outcomes as well as process parameters in different chronic diseases as osteoarthritis, depression or e.g. the cardiovascular risk profile of diabetes patients. This study will be the first to assess this approach in neovascular age-related macular degeneration. If our hypothesis will be confirmed, the implementation of this approach in routine care for patients with with neovascular age-related macular degeneration should be considered. TRIAL REGISTRATION: Current controlled trials ISRCTN32507927.

Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index.

BACKGROUND: The BODE index (including body-mass index, airflow obstruction, dyspnoea, and exercise capacity) was an important contribution to the prognostic assessment of patients with chronic obstructive pulmonary disease (COPD). However, no study has assessed whether the risk of mortality predicted by the BODE index matches the observed mortality in different populations. We assessed the calibration of the BODE index, updated it to improve its calibration, and developed and validated a simplified index for use in primary-care settings. METHODS: We included 232 patients from the Swiss Barmelweid cohort with longstanding and severe COPD and 342 patients from the Spanish Phenotype and Course of COPD cohort study who had had their first hospital admission due to moderate-to-severe COPD. In both cohorts we compared the observed 3-year risk of all-cause mortality with the risk predicted by the BODE index. We then updated the BODE index and developed a simplified ADO index (including age, dyspnoea, and airflow obstruction) from the Swiss cohort, and validated both in the Spanish cohort. FINDINGS: Calibration of the BODE index was poor, with relative underprediction of 3-year risk of mortality by 36% in the Swiss cohort (median predicted risk 21.7% [IQR 12.7-31.7] vs 34.1% observed risk; p=0.013) and relative overprediction by 39% in the Spanish cohort (16.7% [12.7-31.7] vs 12.0%; p=0.035). The 3-year risk of mortality predicted by both the updated BODE (median 10.7% [8.1-13.8]) and ADO indices (11.8% [9.1-14.3]) matched the observed mortality in the Spanish cohort well (p=0.99 and p=0.98, respectively). INTERPRETATION: Both the updated BODE and ADO indices could lend support to the prognostic assessment of patients with COPD in specialised and primary-care settings. Such assessment enhances the targeting of treatments to individual patients. FUNDING: Swiss National Science Foundation; Klinik Barmelweid; Fondo de Investigación Sanitaria Ministry of Health, Spain; Agència d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA; Red RCESP; Fondo de Investigación Sanitaria; Fondo de Investigación Sanitaria; Fundació La Marató de TV3; Novartis Farmacèutica, Spain.

Robotic-assisted versus laparoscopic cholecystectomy: outcome and cost analyses of a case-matched control study.

OBJECTIVE: To compare safety and costs of robotic-assisted and laparoscopic cholecystectomy in patients with symptomatic cholecystolithiasis. BACKGROUND: Technical benefits of robotic-assisted surgery are well documented. However, pressure is currently applied to decrease costs, leading to restriction of development, and implementation of new technologies. So far, no convincing data are available comparing outcome or costs between computer assisted and conventional laparoscopic cholecystectomy. METHODS: A prospective case-matched study was conducted on 50 consecutive patients, who underwent robotic-assisted cholecystectomy (Da Vinci Robot, Intuitive Surgical) between December 2004 and February 2006. These patients were matched 1:1 to 50 patients with conventional laparoscopic cholecystectomy, according to age, gender, American Society of Anesthesiologists score, histology, and surgical experience. Endpoints were complications after surgery (mean follow-up of 12.3 months [SD 1.2]), conversion rates, operative time, and hospital costs (ClinicalTrial.gov ID: NCT00562900). RESULTS: No minor, but 1 major complication occurred in each group (2%). No conversion to open surgery was needed in either group. Operation time (skin-to-skin, 55 minutes vs. 50 minutes, P < 0.85) and hospital stay (2.6 days vs. 2.8 days) were similar. Overall hospital costs were significantly higher for robotic-assisted cholecystectomy $7985.4 (SD 1760.9) versus $6255.3 (SD 1956.4), P < 0.001, with a raw difference of $1730.1(95% CI 991.4-2468.7) and a difference adjusted for confounders of $1606.4 (95% CI 1076.7-2136.2). This difference was mainly related to the amortization and consumables of the robotic system. CONCLUSIONS: Robotic-assisted cholecystectomy is safe and, therefore, a valuable approach. Costs of robots, however, are high and do not justify the use of this technology considering the lack of benefits for patients. A reduction of acquisition and maintenance costs for the robotic system is a prerequisite for large-scale adoption and implementation.