Outcomes of dostarlimab versus chemotherapy in post-platinum patients with recurrent/advanced endometrial cancer: data from the GARNET trial and the National Cancer Registration Service in England.

OBJECTIVES: Immune checkpoint inhibitors have emerged as novel treatment options in patients with endometrial cancer. In this study we aimed to compare the survival outcomes of patients with recurrent or advanced endometrial cancer. These patients had received dostarlimab after platinum-based chemotherapy in the single-arm, Phase I GARNET trial. We compared them with a matched indirect real-world cohort. METHODS: The real-world cohort was established using National Cancer Registration and Analysis Service data, with five treatment-specific real-world sub-cohorts identified. To compare clinical outcomes between the GARNET trial and real-world cohorts, we performed matching-adjusted indirect comparisons. We used prognostic variables to create matching scenarios, including scenario 1 that incorporated grade, histology, and platinum-based chemotherapy number; scenario 2 that considered histology and platinum-based chemotherapy number; and scenario 3 that included race/ethnicity, stage at diagnosis, histology, and prior surgery. Overall survival was defined as the time between the first dostarlimab dose or second-line real-world treatment and death. Adjusted hazard ratios for matching-adjusted indirect comparisons were estimated via weighted Cox proportional-hazards models. Progression-free survival, using time-to-next treatment as a proxy for real-world cohorts, was summarized descriptively. RESULTS: Distribution of baseline characteristics that were matched was similar between the GARNET cohort (n=153) and the real-world cohort (n=999). The most common International Federation of Gynecology and Obstetrics (FIGO) stage in both cohorts was stage III/IV (n=88; 57.5% and n=778; 77.9%, respectively), with endometroid histology predominating in the GARNET cohort (n=121; 79.1%) and non-endometrioid the predominant form in the real-world cohort (n=575; 57.6%). The median overall survival for dostarlimab was longer (range 27.1-40.5 months [95% confidence interval (CI) 6.4-non-estimable and 19.4-non-estimable]) both before and after matching for all scenarios compared with the real-world cohort (10.3 months). Across all matching scenarios, patients in the GARNET cohort had a decreased risk of death, with a HR for overall survival of 0.32 (p<0.0001) before matching, as compared with the overall real-world cohort and most treatment-specific real-world cohorts. For all three scenarios, progression-free survival rates at 12 and 18 months were higher for patients on dostarlimab compared with the real-world cohort (0.48 and 0.43 respectively before matching in the GARNET cohort vs 0.28 and 0.16 respectively in the real-world cohort; using time to next treatment as proxy). The effective sample size for scenario 1 was low when compared with the other scenarios (scenario 1: n=18; scenario 2: n=62; scenario 3: n=67). CONCLUSION: In this adjusted indirect dataset, patients with recurrent/advanced mismatch repair deficient/microsatellite instability-high endometrial cancer post-platinum-based chemotherapy who received dostarlimab in the GARNET trial had significantly improved overall survival compared with patients receiving current second-line treatment in England.

The Value of Federated Data Networks in Oncology: What Research Questions Do They Answer? Outcomes From a Systematic Literature Review.

OBJECTIVES: Real-world evidence (RWE) plays an important role in addressing key research questions of interest to healthcare decision makers. Federated data networks (FDNs) apply novel technology to enable the conduct of RWE studies with multiple partners, without the need to share the individual partner's data set. A systematic review of the published literature was performed to determine which types of research questions can best be addressed through FDNs, specifically in the field of oncology. METHODS: Systematic searches of MEDLINE and Embase were undertaken to identify the types of research questions that had been addressed in studies using FDNs. Additional information was retrieved about study characteristics, statistical methods, and the FDN itself. RESULTS: In total, 40 publications were included where research questions on the following had been addressed (multiple categories possible): disease natural history (58%), safety surveillance (18%), treatment pathways (15%), comparative effectiveness (10%), and cost/resource use studies (3%)-13% of studies had to be left uncategorized. A total of 50% of the studies were run with data partners in networks of ≤5. The size of the networks ranged from 227 patients to >5 million patients. Statistical methods used included distributed learning and distributed regression methods. CONCLUSIONS: Further work is needed to raise awareness of the important role that FDNs can play in leveraging readily available RWE to address key research questions of interest in cancer and the benefits to the research community in engaging in federated data initiatives with a long-term perspective.

[Appropriateness of Proton pump inhibitor (PPI) recommendation in discharge letters of a gastroenterological department]. / Untersuchung zur indikationsgerechten Empfehlung einer Protonenpumpeninhibitor (PPI)-Medikation in Entlassungsbriefen einer gastroenterologischen Klinik.

BACKGROUND AND STUDY AIMS: Proton pump inhibitors (PPI) are one of the most often prescribed drugs worldwide. They were thought to have a great safety profile before adverse effects in case of long-term medication were discussed recently. Undoubtedly, the use of PPI has to be based on a clear indication. In this retrospective analysis, we investigated the number of patients being discharged from a gastroenterological department with a PPI medication. We also analyzed if this recommendation was based on an established indication and if dose and duration of therapy were correct. PATIENTS AND METHODS: 1612 discharge letters from the period January 1st to June 30th 2011 were evaluated. Patients being discharged with a recommendation of PPI use were assigned to one of four groups: (1) PPI recommendation correct according to guidelines indication, dose and duration of treatment; (2) PPI recommendation correct according to guidelines indication, but with failing or false dose or duration of treatment; (3) PPI recommendation rational but not based on guidelines; (4) Failing indication, wrong recommendation. For a more detailed analysis the patients of group 1 to 4 were then assigned to various subgroups according to comorbidities and concomitant medication. RESULTS: 808 of 1612 discharge letters (50,1%) recommended a PPI use. Assignment to the four groups were as follows: (1) n=344 (42,6%); (2) n=115 (14,2%); (3) n=159 (19,7%); (4) n=190 (23,5%). CONCLUSIONS: At time of discharge, PPI are frequently and partially uncritically recommended. Therefore, there is a need for a more intensive education of training interns and for a more critical review of the discharge letters by senior physicians. Even in case of optimal realization of these needs about 20% of debatable recommendations are not based on current guidelines.

Health-related quality of life trajectory of treatment-naive patients with Merkel cell carcinoma receiving avelumab.

Aim: To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with avelumab (15-month follow-up). Materials & methods: Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Results: Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49-72% at 6 months, 40-58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). Conclusion: These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with avelumab. Clinical trial registration: NCT02155647 (ClinicalTrials.gov).

Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). METHODS: Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. RESULTS: Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse. CONCLUSIONS: Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.

Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial.

BACKGROUND: In the phase IIIb PROMID study, octreotide long-acting significantly extended time to tumor progression compared with placebo in treatment-naïve patients with well-differentiated metastatic midgut neuroendocrine tumors. We report post hoc analyses for health-related quality of life (HRQoL). METHODS: HRQoL was measured with EORTC QLQ-C30, a 30-item self-report questionnaire (5 functional, 1 global, 9 symptom scales). Assessments were completed at baseline and every 12 weeks until tumor progression. Time to definitive deterioration (TDD; worsening of ≥10 points without further improvement) was analyzed with the Kaplan-Meier method. Linear mixed models were fit to assess change from baseline in QLQ-C30 scores by treatment arm over time. RESULTS: Among 85 patients, 82 (96%) completed the QLQ-C30 at baseline. There were few events of definitive deterioration for many scales. Significantly longer TDD was reported for long-acting octreotide versus placebo for fatigue (median 18.5 months vs. 6.8; p = 0.0006), pain (not reached [NR] vs. 18.2; p = 0.0435) and insomnia (NR vs. 16.4; p = 0.0046). Change from baseline to week 24 fatigue scores were stable for long-acting octreotide (mean 0.78; 95% CI -6.3 to 7.8) but worsened for placebo (mean 9.1; 95% CI 1.9-16.4), and for diarrhea there were improvements for long-acting octreotide (mean -8.0; 95% CI -19.6 to 3.5) and worsening for placebo (mean 11.2; 95% CI -0.7 to 23.1). CONCLUSIONS: HRQoL was maintained with few deteriorations in long-acting octreotide patients, whereas there was earlier and/or more deterioration in placebo patients. In long-acting octreotide patients, HRQoL was maintained or improved for the clinically important neuroendocrine tumor symptoms such as fatigue, insomnia, diarrhea and pain, whereas placebo patients experienced a deterioration of HRQoL scores for these symptoms.

Psychometric Properties of EQ-5D-5L Scoring Algorithms for the United Kingdom in Metastatic Merkel Cell Carcinoma.

BACKGROUND: Currently, there are 4 EQ-5D-5L scoring algorithms available for the United Kingdom that can be used to derive a utility score. OBJECTIVES: To perform a psychometric validation of the EQ-5D utility score in patients with metastatic Merkel cell carcinoma (mMCC) and to compare 4 EQ-5D-5L value sets currently available for the United Kingdom. METHODS: Data collected in the phase 2 trial JAVELIN Merkel 200 were analyzed, in which 88 patients with mMCC were treated with avelumab. Utility scores were calculated using the EQ-5D-5L valuation set by Devlin et al and 3 further algorithms that are based on EQ-5D-3L valuations. Criterion validity was assessed by Pearson correlations between utility and other HRQoL scales. Responsiveness was assessed by correlating change in utility scores with change in HRQoL scales and percentage change in tumor size. Effect sizes for change from baseline in utility were calculated in subgroups of patients with improving and deteriorating health based on clinically relevant changes in various external anchors. RESULTS: Devlin utilities were up to 0.10 points higher than utilities calculated from EQ-5D-3L valuations. Large correlations (0.45-0.72; P < .01) between utility and the EuroQol Visual Analogue Scale and FACT-G total, physical, and functional scores were found for all 4 algorithms. Large correlations between these measures were also found for change from baseline scores. In patients with health improvements, effect sizes were larger for the 3 EQ-5D-3L-based algorithms, whereas the Devlin utilities had larger effect sizes for health deteriorations, probably because of different levels of baseline utility. CONCLUSIONS: The English National Institute for Health and Care Excellence currently recommends use of the 3L valuation sets. Our analyses show that all 4 scoring algorithms have good and similar psychometric properties in patients with mMCC.

Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma.

AIM: To assess the association between tumor response and health-related quality of life (HRQoL) in patients with metastatic Merkel cell carcinoma treated with the anti-PD-L1 avelumab. MATERIALS & METHODS: Phase II single-arm trial (NCT02155647) data of 88 patients were analyzed. Correlations between percentage reduction in tumor size and change from baseline in Functional Assessment of Cancer Therapy - General (FACT-G), FACT - Melanoma (FACT-M) and EuroQol-5 Dimension scores were calculated. HRQoL and utility by tumor response (per the Response Evaluation Criteria In Solid Tumors version 1.1) was estimated. RESULTS: Tumor shrinkage correlated positively with patients' change from baseline in the FACT-M total (0.364 [95% CI: 0.050-0.607]) and subscale scores. Differences in HRQoL and utility between nonprogressive disease and progressive disease were clinically relevant. CONCLUSION: In patients with metastatic Merkel cell carcinoma, nonprogression during treatment with avelumab correlated with gains in HRQoL.

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (±â€ˆ1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals.

Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States.

BACKGROUND: With several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving. The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies. METHODS: The current study is a physician survey followed by a retrospective chart review of patient medical records by physicians in the US between March and April 2015. One hundred three physicians were asked to complete an online survey aiming to understand their satisfaction and expectations with current available treatments and potential areas of unmet need for mBC patients. Medical records from 178 females were extracted for the chart review. Using these data from medical records, patient characteristics and treatment patterns were analyzed descriptively. Time to progression (TTP) on first line, and progression-free survival (PFS) on second and third line of therapy were analyzed using the Kaplan-Meier method. RESULTS: Sixty-seven percent (n = 119) of patients had metastatic disease at initial diagnosis of breast cancer. Mean age at chart data extraction was 65.8 (SD: 9.4) years. Aromatase inhibitors (AIs) were prescribed for 58% and around 13% of patients in first line and second line, respectively. Chemotherapy was prescribed to 14% in first line and 31% in second line. Median TTP on first line therapy was 12 months for patients receiving AIs as compared to 7.9 months for patients receiving chemotherapy. Across all treatment lines, bone pain and fatigue were reported as the main symptoms associated with disease progression which had an impact on patient quality of life. Physicians expressed that prolonging life was deemed the most important treatment goal, followed by preservation or improvement of quality of life. CONCLUSION: In this study the majority of patients received endocrine therapy as first line treatment and current therapies still resulted in a short time to progression in first line. Results from the chart review and the physician survey highlight a quantitative unmet need for more effective treatments which delay disease progression and improve survival outcomes while maintaining quality of life.

The 3-Year Cost-Effectiveness of a Nurse-Based Case Management versus Usual Care for Elderly Patients with Myocardial Infarction: Results from the KORINNA Follow-Up Study.

OBJECTIVES: To assess the 3-year cost-effectiveness of a nurse-based case management intervention in elderly patients with myocardial infarction from a societal perspective. METHODS: The intervention consisted of one home visit and quarterly telephone calls in the first year, and semi-annual calls in the following 2 years. The primary effect measures were quality-adjusted life-years (QALYs), on the basis of the EuroQol five-dimensional questionnaire (EQ-5D-3L) and adjusted life-years from patients' self-rated health states according to the visual analogue scale (VAS-ALs). A linear regression model was used for adjusted life-years and a gamma model for costs. Estimation uncertainty was addressed by cost-effectiveness acceptability curves, which indicate the likelihood of cost-effectiveness for a given value of willingness to pay. The secondary objective was to examine EQ-5D-3L utility scores and VAS scores among survivors using linear mixed models. RESULTS: Primary outcomes regarding QALY gains (+0.0295; P = 0.76) and VAS-AL gains (+0.1332; P = 0.09) in the intervention group were not significant. The overall cost difference was -€2575 (P = 0.30). The probability of cost-effectiveness of the case management at a willingness-to-pay value of €0 per QALY was 84% in the case of QALYs and 81% in the case of VAS-ALs. Secondary outcomes concerning survivors' quality of life were significantly better in the intervention group (EQ-5D-3L utilities: +0.104, P = 0.005; VAS: +8.15, P = 0.001) after 3 years. CONCLUSIONS: The case management was cost-neutral and led to an important and significant improvement in health status among survivors. It was associated with higher QALYs and lower costs but the differences in costs and QALYs were not statistically significant.

Costs of conservative management of early-stage prostate cancer compared to radical prostatectomy-a claims data analysis.

BACKGROUND: Due to widespread PSA testing incidence rates of localized prostate cancer increase but curative treatment is often not required. Overtreatment imposes a substantial economic burden on health care systems. We compared the direct medical costs of conservative management and radical therapy for the management of early-stage prostate cancer in routine care. METHODS: An observational study design is chosen based on claims data of a German statutory health insurance fund for the years 2008-2011. Three hundred fifty-three age-matched men diagnosed with prostate cancer and treated with conservative management and radical prostatectomy, are included. Individuals with diagnoses of metastases or treatment of advanced prostate cancer are excluded. In an excess cost approach direct medical costs are considered from an insured community perspective for in- and outpatient care, pharmaceuticals, physiotherapy, and assistive technologies. Generalized linear models adjust for comorbidity by Charlson comorbidity score and recycled predictions method calculates per capita costs per treatment strategy. RESULTS: After follow-up of 2.5 years per capita costs of conservative management are €6611 lower than costs of prostatectomy ([-9734;-3547], p < 0.0001). Complications increase costs of assistive technologies by 30% (p = 0.0182), but do not influence any other costs. Results are robust to cost outliers and incidence of prostate cancer diagnosis. The short time horizon does not allow assessing long-term consequences of conservative management. CONCLUSIONS: At a time horizon of 2.5 years, conservative management is preferable to radical prostatectomy in terms of costs. Claims data analysis is limited in the selection of comparable treatment groups, as clinical information is scarce and bias due to non-randomization can only be partly mitigated by matching and confounder adjustment.

The Burden of Diabetes Mellitus in Patients with Coronary Heart Disease: A Methodological Approach to Assess Quality-Adjusted Life-Years Based on Individual-Level Longitudinal Survey Data.

BACKGROUND: Reliable burden of disease (BOD) estimates are needed to support decision making in health care. OBJECTIVES: The objective of this study was to introduce an analysis approach based on individual-level longitudinal survey data that estimates the burden of diabetes in patients with coronary heart disease in terms of quality-adjusted life-years (QALYs) lost. METHODS: Data from two postal surveys (2006, N = 1022; 2010-2011, N = 716) of survivors from the KORA Myocardial Infarction Registry in Southern Germany were analyzed. Accumulated QALYs were calculated for each participant over a mean observation time of 4.1 years, considering the noninformative censoring structure of the follow-up study. Linear regression models were used to estimate the loss in (quality-unadjusted) life-years and QALYs between patients with and without diabetes, and generalized additive models were used to analyze the nonlinear association with age. The cross-sectional and longitudinal association with quality of life (QOL) and QOL change and the impact on mortality were analyzed to enhance the understanding of the observed results. RESULTS: Diabetes was associated with a reduced QOL at baseline (cross-sectional: ß = -0.069; P < 0.001), but not with a significant longitudinal QOL change. Mortality in patients with diabetes was increased (hazard ratio = 1.68; P < 0.005). This resulted in a loss of 0.14 life-years (P = 0.003) and 0.37 QALYs (P < 0.001). Results from generalized additive models indicated that the burden of diabetes is less pronounced in older subjects. CONCLUSIONS: The application of the proposed approach provides confounder-adjusted BOD estimates for the studied time horizon and can be used to compare the BOD across different chronic conditions. Curative efforts are needed to diminish the substantial diabetes-related QALY gap.

The association between physical activity and healthcare costs in children--results from the GINIplus and LISAplus cohort studies.

BACKGROUND: Physical inactivity in children is an important risk factor for the development of various morbidities and mortality in adulthood, physical activity already has preventive effects during childhood. The objective of this study is to estimate the association between physical activity, healthcare utilization and costs in children. METHODS: Cross-sectional data of 3356 children aged 9 to 12 years were taken from the 10-year follow-up of the birth cohort studies GINIplus and LISAplus, including information on healthcare utilization and physical activity given by parents via self-administered questionnaires. Using a bottom-up approach, direct costs due to healthcare utilization and indirect costs resulting from parental work absence were estimated for the base year 2007. A two-step regression model compared effects on healthcare utilization and costs for a higher (≥ 7 h/week) versus a lower (<7 h/week) level of moderate-to-vigorous physical activity (MVPA) adjusted for age, gender, BMI, education and income of parents, single parenthood and study region. Recycled predictions estimated adjusted mean costs per child and activity group. RESULTS: The analyses for the association between physical activity, healthcare utilization and costs showed no statistically significant results. Different directions of estimates were noticeable throughout cost components in the first step as well as the second step of the regression model. For higher MVPA (≥ 7 h/week) compared with lower MVPA (< 7 h/week) total direct costs accounted for 392 EUR (95% CI: 342-449 EUR) versus 398 EUR (95% CI: 309-480 EUR) and indirect costs accounted for 138 EUR (95% CI: 124-153 EUR) versus 127 EUR (95% CI: 111-146 EUR). CONCLUSIONS: The results indicate that childhood might be too early in life, to detect significant preventive effects of physical activity on healthcare utilization and costs, as diseases attributable to lacking physical activity might first occur later in life. This underpins the importance of clarifying the long-term effects of physical activity as it may strengthen the promotion of physical activity in children from a health economic perspective.

Competing-risks duration models with correlated random effects: an application to dementia patients' transition histories.

Multi-state transition models are widely applied tools to analyze individual event histories in the medical or social sciences. In this paper, we propose the use of (discrete-time) competing-risks duration models to analyze multi-transition data. Unlike conventional Markov transition models, these models allow the estimated transition probabilities to depend on the time spent in the current state. Moreover, the models can be readily extended to allow for correlated transition probabilities. A further virtue of these models is that they can be estimated using conventional regression tools for discrete-response data, such as the multinomial logit model. The latter is implemented in many statistical software packages and can be readily applied by empirical researchers. Moreover, model estimation is feasible, even when dealing with very large data sets, and simultaneously allowing for a flexible form of duration dependence and correlation between transition probabilities. We derive the likelihood function for a model with three competing target states and discuss a feasible and readily applicable estimation method. We also present the results from a simulation study, which indicate adequate performance of the proposed approach. In an empirical application, we analyze dementia patients' transition probabilities from the domestic setting, taking into account several, partly duration-dependent covariates.

The impact of preoperative patient characteristics on health states after total hip replacement and related satisfaction thresholds: a cohort study.

BACKGROUND: The aim of the study was to analyze the effect of preoperative patient characteristics on health outcomes 6 months after total hip replacement (THR), to support patient's decision making in daily practice with predicted health states and satisfaction thresholds. By giving incremental effects for different patient subgroups, we support comparative effectiveness research (CER) on osteoarthritis interventions. METHODS: In 2012, 321 patients participated in health state evaluation before and 6 months after THR. Health-related quality of life (HRQoL) was measured with the EQ-5D questionnaire. Hip-specific pain, function, and mobility were measured with the WOMAC in a prospective observation of a cohort. The predictive capability of preoperative patient characteristics - classified according to socio-demographic factors, medical factors, and health state variables - for changes in health outcomes is tested by correlation analysis and multivariate linear regressions. Related satisfaction thresholds were calculated with the patient acceptable symptom state (PASS) concept. RESULTS: The mean WOMAC and EQ-5D scores before operation were 52 and 60 respectively (0 worst, 100 best). At the 6-month follow-up, scores improved by 35 and 19 units. On average, patients reported satisfaction with the operation if postoperative (change) WOMAC scores were higher than 85 (32) and postoperative (change) EQ-5D scores were higher than 79 (14). CONCLUSIONS: Changes in WOMAC and EQ-5D scores can mainly be explained by preoperative scores. The lower the preoperative WOMAC or EQ-5D scores, the higher the change in the scores. Very good or very poor preoperative scores lower the probability of patient satisfaction with THR. Shared decision making using a personalized risk assessment approach provides predicted health states and satisfaction thresholds.

Longitudinal changes in health-related quality of life in normal glucose tolerance, prediabetes and type 2 diabetes: results from the KORA S4/F4 cohort study.

PURPOSE: The aim of this study was to examine how transition between normal glucose tolerance, prediabetes and diabetes over a 7 year period is associated with change in health-related quality of life (HRQL) in an elder German population-based cohort. METHODS: We used data from 1,046 participants of the KORA S4/F4 cohort study aged 55-74 years at baseline. Based on an oral glucose tolerance test, prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance. HRQL was assessed with the SF-12 questionnaire. Using linear regression, we estimated mean change in HRQL over time, depending on glucose status at baseline and follow-up, adjusted by demographic and lifestyle variables. RESULTS: Individuals progressing to prediabetes or diabetes experienced a greater loss in the physical component score than patients with persistent normal glucose tolerance (-2.31 and -7.44 vs. -1.08), but the difference was only significant for subjects converting to diabetes. Subjects with prediabetes at baseline and diabetes at follow-up had a significant loss in mental health compared to subjects with persistent prediabetes. CONCLUSIONS: There is first evidence that worsening of glucose metabolism over time is associated with deteriorating HRQL, however, further and larger longitudinal studies are needed to confirm these findings.

New potential determinants of disability in aged persons with myocardial infarction: results from the KORINNA-study.

BACKGROUND: Elderly individuals with coronary heart disease are a population particularly burdened by disability. However, to date many predictors of disability established in general populations have not been considered in studies examining disability in elderly acute myocardial infarction (AMI) survivors. Our study explores factors associated with the ability to perform basic activities of daily living in elderly patients with AMI. METHODS: Baseline data from 333 AMI-survivors older than 64 years included within the randomized controlled KORINNA-study were utilized to examine disability assessed by the Stanford Health Assessment Questionare Disability Index (HAQ-DI). Numerous potential determinants including demographic characteristics, clinical parameters, co-morbidities, interventions, lifestyle, behavioral and personal factors were measured.Disability was defined as a HAQ-DI ≥ 0.5. After bi-variate testing the probability of disability was modeled with logistic regression. Missing covariate values were imputed using a Markov Chain Monte Carlo method. RESULTS: Disability was significantly more frequent in older individuals (Odds Ratio (OR): 1.10, 95% Confidence Interval (CI): 1.05-1.16), patients with deficient nutrition (OR: 3.38, 95% CI: 1.60-7.15), coronary artery bypass graft (CABG) (OR: 3.26, 95% CI: 1.29-8.25), hearing loss in both ears (OR: 2.85, 95% CI: 1.41-5.74), diabetes mellitus (OR: 2.56, 95% CI: 1.39-4.72), and heart failure (OR: 3.32, 95% CI: 1.79-6.16). It was reduced in patients with percutaneous transluminal coronary angioplasty (PTCA) (OR: 0.41, 95% CI: 0.21-0.80) and male sex (OR: 0.48, 95% CI: 0.27-0.85). CONCLUSIONS: Effects of nutrition, hearing loss, and diametrical effects of PTCA and CABG on disability were identified as relevant for examination of causality in longitudinal trials. TRIAL REGISTRATION: ISRCTN02893746.

Health-related quality of life and chronic obstructive pulmonary disease in early stages - longitudinal results from the population-based KORA cohort in a working age population.

BACKGROUND: It is widely recognized that health-related quality of life (HRQL) is impaired in patients with Chronic Obstructive Pulmonary Disease (COPD), but there is a lack of research on longitudinal associations of COPD and HRQL. This study examined the effects of COPD in early stages of disease on HRQL over ten years in a working-age general population setting in Southern Germany while considering the influence of common comorbidities. METHODS: In the population-based KORA F4 study (2006-08) 1,321 participants aged 41-61 years performed spirometry and reported information on HRQL (measured by the generic SF-12) and comorbidities. For the same participants, HRQL information was available seven years before and three years after the lung function test from the previous S4 (1999-2001) and the F4L follow-up study (2010). Using linear mixed models, the physical and mental component summary scores (PCS-12 / MCS-12) of the SF-12 were compared over time between COPD groups. RESULTS: 7.8% of participants were classified as having COPD (according to the LLN definition and the Global Lungs Initiative), 59.4% of them in grade 1. Regression models showed a negative cross-sectional association of COPD grade 2+ with PCS-12 which persisted when comorbidities were considered. Adjusted mean PCS-12 scores for the COPD grade 2+ group were reduced (-3.5 (p=0.008) in F4, -3.3 (p=0.014) in S4 and -4.7 (p=0.003) in F4L) compared to the group without airflow limitation. The size of the COPD effect in grade 2+ was similar to the effect of myocardial infarction and cancer. Over ten years, a small decline in PCS-12 was observed in all groups. This decline was larger in participants with COPD grade 2+, but insignificant. Regarding MCS-12, no significant cross-sectional or longitudinal associations with COPD were found. CONCLUSION: Despite small HRQL differences between COPD patients in early disease stages and controls and small changes over ten years, our results indicate that it is important to prevent subjects with airflow limitation from progression to higher grades. Awareness of HRQL impairments in early stages is important for offering early interventions in order to maintain high HRQL in COPD patients.

Vaccine preparation time, errors, satisfaction, and preference of prefilled syringes versus RSV vaccines requiring reconstitution: randomized, time and motion study.

Aim: The current study compared preparation time, errors, satisfaction, and preference for a prefilled syringe (PFS) versus two RSV vaccines requiring reconstitution (VRR1 and VRR2) in a randomized, single-blinded time and motion study.Methods: Pharmacists, nurses, and pharmacy technicians were randomized to a preparation sequence of the three vaccines. Participants read instructions, then consecutively prepared the three vaccines with a 3- to 5-minute washout period in between. Preparations were video recorded and reviewed by a trained pharmacist for preparation time and errors using predefined, vaccine-specific checklists. Participant demographics, satisfaction with vaccine preparation, and vaccine preference were recorded. Within-subjects analysis of variance was used to compare preparation time. Mixed-effects Poisson and ordered logistic regression models were used to compare number of preparation errors and satisfaction scores, respectively.Results: 63 pharmacists (60%), nurses (35%), and pharmacy technicians (5%) participated at four sites in the United States. The least squares mean preparation time per dose for PFS was 141.8 seconds (95% CI:156.8, 126.7; p < 0.0001) faster than for VRR1, 103.6 seconds (118.7, 88.5; p < 0.0001) faster than for VRR2, and 122.7 seconds (95% CI: 134.2, 111.2; p < 0.0001) faster than the pooled VRRs. Overall satisfaction (combined 'Very' and 'Extremely') was 87.3% for PFS, 28.6% for VRR1, and 47.6% for VRR2. Most participants (81.0%) preferred the PFS vaccine.Limitations: The study is limited by the inability to completely blind observers. To minimize the effects of order, we utilized a 3-sequence block design, however, the order in which the vaccines were prepared may have affected outcomes. Participants were assessed once, whereas if repeated preparations were performed there may have been trained efficiencies gained for each vaccine.Conclusion: PFS vaccines can greatly simplify the vaccine preparation process, allowing administrators to prepare almost four times more doses per hour than with vial and syringe systems.