Novel hormonal therapy versus standard of care-A registry-based comparative effectiveness evaluation for mCRPC-patients.

BACKGROUND: This paper presents results from one of the few comparative effectiveness evaluations of novel antiandrogen medications (NHT) against standard of care (SoC) for patients suffering from metastatic castrate-resistant prostate cancer (mCRPC). METHODS: The design and the analysis are published in a protocol before accessing outcome data. Two groups of patients are balanced on hundreds of important covariates measured before the prostate cancer diagnosis and up to the date of the prescription. While the design yields balance on the observed covariates, one cannot discard the possibility that unobserved confounders are not balanced. The unconfoundedness assumption is assessed by estimating placebo regressions on two health measures, not included in the design but added together with the outcome data after protocol publication. RESULTS: We find a substantial (64 percent) increase in mortality for patients prescribed with NHT rather than SoC. However, based on the results from one of the two placebo regressions, we cannot rule out that the difference in mortality may be due to confounding. Using a bounding strategy of the effect, we can, however, rule out that NHT reduces mortality compared to SoC. Under an empirical valid assumption that most mCRPC patients who die suffer from bone metastases, we have a strong indication of increased skeleton-related events in patients if prescribed NHT against SoC. CONCLUSIONS: Generally, the SoC for this group of patients is docetaxel. Given the substantially higher costs of many of the NHT, the finding of no positive effects from NHT on both mortality and SRE is important. More comparative studies, including studies analysing quality of life outcomes, are thus needed.

Causal inferences and real-world evidence: A comparative effectiveness evaluation of abiraterone acetate against enzalutamide.

Regulatory authorities are recognizing the need for real-world evidence (RWE) as a complement to randomized controlled trials in the approval of drugs. However, RWE needs to be fit for regulatory purposes. There is an ongoing discussion regarding whether pre-publication of a protocol on appropriate repositories, e.g. ClinicalTrials.gov, would increase the quality of RWE or not. This paper illustrates that an observational study based on a pre-published protocol can entail the same level of detail as a protocol for a randomized experiment. The strategy is exemplified by designing a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice. These two cancer drugs are prescribed to patients with advanced prostate cancer. Two complementary designs, including pre-analysis plans, were published before data on outcomes and proxy-outcomes were obtained. The underlying assumptions are assessed and both analyses show an increased mortality risk from being prescribed abiraterone acetate compared to enzalutamide.

Economic Consequences of Surgery for Adhesive Small Bowel Obstruction: A Population-Based Study.

Background and Aims: Most patients develop adhesions after abdominal surgery, some will be hospitalized with small bowel obstruction (SBO), and some also require surgery. The operations and follow-up are expensive, but recent data of costs are scarce. The aim of this study was to describe the direct costs of SBO-surgery and follow-up, in a population-based setting. The association between cost of SBO and peri- and postoperative data was also studied. Methods: In a retrospective cohort study, all patients (n = 402) operated for adhesive SBO in Gävleborg and Uppsala counties (2007-2012) were studied. The median follow-up was 8 years. Costs were calculated according to the pricelist of Uppsala University Hospital, Uppsala, Sweden. Results: Overall total costs were €16.267 million, corresponding to a mean total cost per patient of €40,467 during the studied period. Diffuse adhesions and postoperative complications were associated with increased costs for SBO in a multivariable analysis (P < 0.001). Most costs, about €14 million (85%), arouse in conjunction with the SBO-index surgery period. In-hospital stay was the dominating cost, accounting for 70% of the total costs. Conclusion: Surgery for SBO generates substantial economic burden for healthcare systems. Measures that reduce the incidence of SBO, the frequency of postoperative complication, or the length of stay have the potential to reduce this economic burden. The cost estimates from this study may be valuable for future cost-benefit analyses in intervention studies.

Study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide: a longitudinal study based on Swedish administrative registers.

INTRODUCTION: This paper presents a study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice, two cancer drugs given to patients suffering from advanced prostate cancer. METHOD AND ANALYSIS: The protocol designs a comparative-effectiveness analysis of abiraterone acetate against enzalutamide. With the substantial number of covariates a two-step procedure is suggested in choosing relevant covariates in the matching design. In the first step, an exploratory factor analysis reduces the dimension of a large set of continuous covariates to nine factors. In the second step, we reduce the dimension of the covariates, interactions and second order terms for the continuous covariates using propensity score estimation. The final design makes use of a genetic matching algorithm. The study protocol provides a detailed statistical analysis plan of the analysis sample derived from the matching design. The analysis will make use of linear regression and robust inference adjusted for multisignificance testing. DISCUSSION: As in a randomised experiment the focus is on the design of the assignment to treatment. This allows the publication of this preanalysis plan before having access to outcome data. This means that the p values will be correct if the maintained assumption of uncounfoundedness is valid. Given that is p-hacking is substantial problem in empirical research, this is a substantial strength of this study. However, while design yields, balance on the observed covariates one cannot discard the possibility that unobserved confounders are not balanced. For that reason, sensitivity tests for the maintained assumption of uncounfoundedness are presented. ETHICS AND DISSEMINATION: The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2017/482). Results will be published in a peer-reviewed journal and distributed to relevant stakeholders in healthcare.

Routine Oxygen Therapy Does Not Improve Health-Related Quality of Life in Patients With Acute Myocardial Infarction-Insights From the Randomized DETO2X-AMI Trial.

Background: After decades of ubiquitous oxygen therapy in all patients with acute myocardial infarction (MI), recent guidelines are more restrictive based on lack of efficacy in contemporary trials evaluating hard clinical outcomes in patients without hypoxemia at baseline. However, no evidence regarding treatment effects on health-related quality of life (HRQoL) exists. In this study, we investigated the impact of routine oxygen supplementation on HRQoL 6-8 weeks after hospitalization with acute MI. Secondary objectives included analyses of MI subtypes, further adjustment for infarct size, and oxygen saturation at baseline and 1-year follow-up. Methods: In the DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial, 6,629 normoxemic patients with suspected MI were randomized to oxygen at 6 L/min for 6-12 h or ambient air. In this prespecified analysis, patients younger than 75 years of age with confirmed MI who had available HRQoL data by European Quality of Life Five Dimensions questionnaire (EQ-5D) in the national registry were included. Primary endpoint was the EQ-5D index assessed by multivariate linear regression at 6-10 weeks after MI occurrence. Results: A total of 3,086 patients (median age 64, 22% female) were eligible, 1,518 allocated to oxygen and 1,568 to ambient air. We found no statistically significant effect of oxygen therapy on EQ-5D index (-0.01; 95% CI: -0.03-0.01; p = 0.23) or EQ-VAS score (-0.57; 95% CI: -1.88-0.75; p = 0.40) compared to ambient air after 6-10 weeks. Furthermore, no significant difference was observed between the treatment groups in EQ-5D dimensions. Results remained consistent across MI subtypes and at 1-year follow-up, including further adjustment for infarct size or oxygen saturation at baseline. Conclusions: Routine oxygen therapy provided to normoxemic patients with acute MI did not improve HRQoL up to 1 year after MI occurrence. Clinical Trial Registration: ClinicalTrials.gov number, NCT01787110.

Avoiding Routine Oxygen Therapy in Patients With Myocardial Infarction Saves Significant Expenditure for the Health Care System-Insights From the Randomized DETO2X-AMI Trial.

Background: Myocardial infarction (MI) occurs frequently and requires considerable health care resources. It is important to ensure that the treatments which are provided are both clinically effective and economically justifiable. Based on recent new evidence, routine oxygen therapy is no longer recommended in MI patients without hypoxemia. By using data from a nationwide randomized clinical trial, we estimated oxygen therapy related cost savings in this important clinical setting. Methods: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial randomized 6,629 patients from 35 hospitals across Sweden to oxygen at 6 L/min for 6-12 h or ambient air. Costs for drug and medical supplies, and labor were calculated per patient, for the whole study population, and for the total annual care episodes for MI in Sweden (N = 16,100) with 10 million inhabitants. Results: Per patient, costs were estimated to 36 USD, summing up to a total cost of 119,832 USD for the whole study population allocated to oxygen treatment. Applied to the annual care episodes for MI in Sweden, costs sum up to between 514,060 and 604,777 USD. In the trial, 62 (2%) patients assigned to oxygen and 254 (8%) patients assigned to ambient air developed hypoxemia. A threshold analysis suggested that up to a cut-off of 624 USD spent for hypoxemia treatment related costs per patient, avoiding routine oxygen therapy remains cost saving. Conclusions: Avoiding routine oxygen therapy in patients with suspected or confirmed MI without hypoxemia at baseline saves significant expenditure for the health care system both with regards to medical and human resources. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT01787110.

Cost-effectiveness of an indicated preventive intervention for depression in adolescents: a model to support decision making.

BACKGROUND: Adolescent depression has negative health and economic outcomes in the short- and long-term. Indicated preventive interventions, in particular group based cognitive behavioural therapy (GB-CBT), are effective in preventing depression in adolescents with subsyndromal depression. However, little is known about the cost-effectiveness of these interventions. METHODS: A Markov cohort model was used to conduct cost-effectiveness analyses comparing a GB-CBT indicated preventive intervention for depression, to a no-intervention option in a Swedish setting. Taking a time horizon of 5- and 10 years, incremental differences in societal costs and health benefits expressed as differences in the proportion of cases of depression prevented, and as quality adjusted life years (QALYs) gained were estimated. Through univariate and probabilistic sensitivity analyses, the robustness of the results was explored. Costs, presented in 2018 USD, and effects were discounted at a yearly rate of 3%. RESULTS: The base-case analysis showed that GB-CBT indicated preventive intervention incurred lower costs, prevented a larger proportion of cases of depression and generated higher QALYs compared to the no-intervention option for both time horizons. Offering the intervention was even a cost saving strategy and demonstrated a probability of being cost-effective of over 95%. In the sensitivity analyses, these results were robust to the modelling assumptions. LIMITATIONS: The study considered a homogeneous cohort and assumed a constant annual decay rate of the relative treatment effect. CONCLUSIONS: GB-CBT indicated preventive interventions for depression in adolescence can generate good value for money compared to leaving adolescents with subsyndromal depression untreated.

Influence of elicitation procedure and phrasing on health state valuations in experience-based time trade-off tasks among diabetes patients in China.

PURPOSE: Open-ended and iteration-based time trade-off (TTO) tasks can both be used for valuation of health states. It has so far not been examined how the elicitation procedure affects the valuation of experience-based health states. The purpose of this study is to investigate the influence of elicitation procedure on experience-based health state values elicited by the TTO method. METHODS: 156 Chinese adults with type 2 diabetes participated in face-to-face interviews with an open-ended or an iteration-based TTO task. The association between the type of TTO task and the valuation of health states was investigated through multiple linear regression analyses. A modified open-ended TTO task was also developed (n = 33) to test whether different phrasings of open-ended TTO tasks influence TTO values. RESULTS: Higher TTO values were observed in the original open-ended TTO task compared to the iteration-based task, which indicates that the elicitation procedure influences the valuation of health states. When the modified open-ended task was introduced, the difference between the two elicitation procedures was no longer statistically significant, suggesting that the phrasing and/or visual presentation of the TTO task may influence the valuation of health states. CONCLUSIONS: The choice of elicitation procedure as well as the description of experience-based TTO tasks may influence the valuation of health states. Further research is warranted, also in other cultural contexts, to further explore these findings.

Depressive disorders in adolescence, recurrence in early adulthood, and healthcare usage in mid-adulthood: A longitudinal cost-of-illness study.

BACKGROUND: Depression in adolescence is associated with increased healthcare consumption in adulthood, but prior research has not recognized the heterogeneity of depressive disorders. This paper investigated the additional healthcare usage and related costs in mid-adulthood for individuals with adolescent depression, and examined the mediating role of subsequent depression in early adulthood. METHODS: This study was based on the Uppsala Longitudinal Adolescent Depression Study, initiated in Sweden in the early 1990s. Depressive disorders were assessed in adolescence (age 16-17) and early adulthood (age 19-30). Healthcare usage and related costs in mid-adulthood (age 31-40) were estimated using nationwide population-based registries. Participants with specific subtypes of adolescent depression (n = 306) were compared with matched non-depressed peers (n = 213). RESULTS: Women with persistent depressive disorder (PDD) in adolescence utilized significantly more healthcare resources in mid-adulthood. The association was not limited to psychiatric care, and remained after adjustment for individual and parental characteristics. The total additional annual cost for a single age group of females with a history of PDD at a population level was estimated at 3.10 million USD. Depression recurrence in early adulthood mediated the added costs for psychiatric care, but not for somatic care. LIMITATIONS: Primary health care data were not available, presumably resulting in an underestimation of the true healthcare consumption. Estimates for males had limited precision due to a relatively small male proportion. CONCLUSIONS: On a population level, the additional healthcare costs incurred in mid-adulthood in females with a history of adolescent PDD are considerable. Early treatment and prevention should be prioritized.

Research participants' preferences for receiving genetic risk information: a discrete choice experiment.

PURPOSE: This study aims to determine research participants' preferences for receiving genetic risk information when participating in a scientific study that uses genome sequencing. METHODS: A discrete choice experiment questionnaire was sent to 650 research participants (response rate 60.5%). Four attributes were selected for the questionnaire: type of disease, disease penetrance probability, preventive opportunity, and effectiveness of the preventive measure. Panel mixed logit models were used to determine attribute level estimates and the heterogeneity in preferences. Relative importance of the attribute and the predicted uptake for different information scenarios were calculated from the estimates. In addition, this study estimates predicted uptake for receiving genetic risk information in different scenarios. RESULTS: All characteristics influenced research participants' willingness to receive genetic risk information. The most important characteristic was the effectiveness of the preventive opportunity. Predicted uptake ranged between 28% and 98% depending on what preventive opportunities and levels of effectiveness were presented. CONCLUSION: Information about an effective preventive measure was most important for participants. They valued that attribute twice as much as the other attributes. Therefore, when there is an effective preventive measure, risk communication can be less concerned with the magnitude of the probability of developing disease.

How psychological distance of a study sample in discrete choice experiments affects preference measurement: a colorectal cancer screening case study.

PURPOSE: The purpose of this study was to investigate to what extent the outcomes of a discrete choice experiment (DCE) differ based on respondents' psychological distance to the decision at hand. METHODS: A DCE questionnaire regarding individuals' preferences for genetic screening for colorectal cancer (CRC) within the Dutch national CRC screening program was created. The DCE contained nine D-efficient designed choice tasks and was distributed among two populations that differ in their psychological distance to the decision at hand: 1) a representative sample of the Dutch general population aged 55-65 years, and 2) a sample of Dutch individuals who attended an information appointment regarding colonoscopies following the detection of blood in their stool sample in the CRC screening program. The DCE consisted of four attributes related to the decision whether to participate in genetic screening for CRC: 1) risk of being genetically predisposed, 2) risk of developing CRC, 3) frequency of follow-up colonoscopies, and 4) survival. Direct attribute ranking, dominant decision-making behavior, and relative importance scores (based on panel MIXL) were compared between the two populations. Attribute level estimates were compared with the Swait and Louviere test. RESULTS: The proportion of respondents who both ranked survival as the most important attribute, and showed dominant decision-making behavior for this attribute, was significantly higher in the screened population compared to the general population. The relative importance scores of the attributes significantly differed between populations. Finally, the Swait and Louviere test also revealed significant differences in attribute level estimates in both the populations. CONCLUSION: The study outcomes differed between populations depending on their psychological distance to the decision. This study shows the importance of adequate sample selection; therefore, it is advocated to increase attention to study sample selection and reporting in DCE studies.

Indicated preventive interventions for depression in children and adolescents: A meta-analysis and meta-regression.

Depression contributes about 2% to the global burden of disease. A first onset of depressive disorder or subsyndromal depressive symptoms is common in adolescence, indicating that early prevention is a priority. However, trials of preventive interventions for depression in youths show conflicting results. This systematic review and meta-analysis investigated the effectiveness of group-based cognitive behavioral therapy (GB-CBT) as a preventive intervention targeting subsyndromal depression in children and adolescents. In addition, the impact of different covariates (type of comparator and use of booster sessions) was assessed. Relevant articles were identified from previous systematic reviews, and supplemented with an electronic search spanning from 01/09/2014 to 28/02/2018. The retrieved articles were assessed for eligibility and risk of bias. Relevant data were extracted. Intervention effectiveness was pooled using a random-effects model and the impact of covariates assessed using meta-regression. 38 eligible articles (34 trials) were obtained. The analysis showed GB-CBT to significantly reduce the incidence (relative risk 0.43, 95% CI 0.21-0.87) and symptoms (Cohen's d -0.22, 95% CI -0.32 to -0.11) of depression at post-test compared to all controls. Comparisons with passive comparators suggested that the effect decayed over time. However, compared to active controls, a significant intervention effect was evident only after 12 month or more. Our results suggest that the preventive effect of GB-CBT wears off, but still lasts longer than the effect of active comparators. Only a few studies included booster sessions, precluding firm conclusions. Future studies should clarify to what extent maintenance strategies can prolong the preventive effect of GB-CBT.

Nurse-led clinic for patients with liver cirrhosis-effects on health-related quality of life: study protocol of a pragmatic multicentre randomised controlled trial.

INTRODUCTION: Liver cirrhosis affects health-related quality of life (HRQoL) even in its early stages. Morbidity is especially high when the disease decompensates and self-care actions become essential. Nurse involvement in secondary prevention in other chronic diseases has contributed to better symptom control, less need of inpatient care and improved HRQoL. In order to evaluate the impact of nurse involvement in the follow-up of patients with liver cirrhosis, we decided to compare structured nurse-led clinics, inspired by Dorothea Orem's nursing theory and motivational strategies, with a group of patients receiving standard care. The primary outcome is HRQoL and the secondary outcomes are quality of care, visits to outpatient clinics or hospitals, disease progress and health literacy. METHODS AND ANALYSIS: This is a pragmatic, multicentre randomised controlled study conducted at six Swedish hepatology departments. Eligible patients are adults with diagnosed cirrhosis of the liver (n=500). Participants are randomised into either an intervention with nurse-led follow-up group or into a standard of care group. Recruitment started in November 2016 and is expected to proceed until 2020. Primary outcomes are physical and mental HRQoL measured by RAND-36 at enrolment, after 1 and 2 years. ETHICS AND DISSEMINATION: The study is ethically approved by the Regional Ethical Review Board in Uppsala. The results shall be disseminated in international conferences and peer-reviewed articles. TRIAL REGISTRATION NUMBER: NCT02957253; Pre-results.

Making sense of genetic risk: A qualitative focus-group study of healthy participants in genomic research.

OBJECTIVE: It is well known that research participants want to receive genetic risk information that is about high risks, serious diseases and potential preventive measures. The aim of this study was to explore, by qualitative means, something less well known: how do healthy research participants themselves make sense of genetic risk information? METHOD: A phenomenographic approach was chosen to explore research participants' understanding and assessment of genetic risk. We conducted four focus-group (N=16) interviews with participants in a research programme designed to identify biomarkers for cardiopulmonary disease. RESULTS: Among the research participants, we found four ways of understanding genetic risk: as a binary concept, as an explanation, as revealing who I am (knowledge of oneself) and as affecting life ahead. CONCLUSION: Research participants tend to understand genetic risk as a binary concept. This does not necessarily imply a misunderstanding of, or an irrational approach to, genetic risk. Rather, it may have a heuristic function in decision-making. PRACTICAL IMPLICATIONS: Risk communication may be enhanced by tailoring the communication to the participants' own lay conceptions. For example, researchers and counselors should address risk in binary terms, maybe looking out for how individual participants search for threshold figures.

Freedom of Choice About Incidental Findings Can Frustrate Participants' True Preferences.

Ethicists, regulators and researchers have struggled with the question of whether incidental findings in genomics studies should be disclosed to participants. In the ethical debate, a general consensus is that disclosed information should benefit participants. However, there is no agreement that genetic information will benefit participants, rather it may cause problems such as anxiety. One could get past this disagreement about disclosure of incidental findings by letting participants express their preferences in the consent form. We argue that this freedom of choice is problematic. In transferring the decision to participants, it is assumed that participants will understand what they decide about and that they will express what they truly want. However, psychological findings about people's reaction to probabilities and risk have been shown to involve both cognitive and emotional challenges. People change their attitude to risk depending on what is at stake. Their mood affects judgments and choices, and they over- and underestimate probabilities depending on whether they are low or high. Moreover, different framing of the options can steer people to a specific choice. Although it seems attractive to let participants express their preferences to incidental findings in the consent form, it is uncertain if this choice enables people to express what they truly prefer. In order to better understand the participants' preferences, we argue that future empirical work needs to confront the participant with the complexity of the uncertainty and the trade-offs that are connected with the uncertain predictive value of genetic risk information.

Milk intake and risk of mortality and fractures in women and men: cohort studies.

OBJECTIVE: To examine whether high milk consumption is associated with mortality and fractures in women and men. DESIGN: Cohort studies. SETTING: Three counties in central Sweden. PARTICIPANTS: Two large Swedish cohorts, one with 61,433 women (39-74 years at baseline 1987-90) and one with 45,339 men (45-79 years at baseline 1997), were administered food frequency questionnaires. The women responded to a second food frequency questionnaire in 1997. MAIN OUTCOME MEASURE: Multivariable survival models were applied to determine the association between milk consumption and time to mortality or fracture. RESULTS: During a mean follow-up of 20.1 years, 15,541 women died and 17,252 had a fracture, of whom 4259 had a hip fracture. In the male cohort with a mean follow-up of 11.2 years, 10,112 men died and 5066 had a fracture, with 1166 hip fracture cases. In women the adjusted mortality hazard ratio for three or more glasses of milk a day compared with less than one glass a day was 1.93 (95% confidence interval 1.80 to 2.06). For every glass of milk, the adjusted hazard ratio of all cause mortality was 1.15 (1.13 to 1.17) in women and 1.03 (1.01 to 1.04) in men. For every glass of milk in women no reduction was observed in fracture risk with higher milk consumption for any fracture (1.02, 1.00 to 1.04) or for hip fracture (1.09, 1.05 to 1.13). The corresponding adjusted hazard ratios in men were 1.01 (0.99 to 1.03) and 1.03 (0.99 to 1.07). In subsamples of two additional cohorts, one in males and one in females, a positive association was seen between milk intake and both urine 8-iso-PGF2α (a biomarker of oxidative stress) and serum interleukin 6 (a main inflammatory biomarker). CONCLUSIONS: High milk intake was associated with higher mortality in one cohort of women and in another cohort of men, and with higher fracture incidence in women. Given the observational study designs with the inherent possibility of residual confounding and reverse causation phenomena, a cautious interpretation of the results is recommended.

Incidental findings: the time is not yet ripe for a policy for biobanks.

Incidental findings (IFs) are acknowledged to be among the most important ethical issues to consider in biobank research. Genome-wide association studies and disease-specific genetic research might reveal information about individual participants that are not related to the research purpose, but may be relevant to those participants' future health. In this article, we provide a synopsis of arguments for and against the disclosure of IFs in biobank research. We argue that arguments that do not distinguish between communications about pathogenic conditions and complex genetic risk for diseases fail, as preferences and decisions may be far more complex in the latter case. The principle of beneficence, for example, often supports the communication of incidentally discovered diseases, but if communication of risk is different, the beneficence of such communication is not equally evident. By conflating the latter form of communication with the former, the application of ethical principles to IFs in biobank research sometimes becomes too easy and frictionless. Current empirical surveys of people's desire to be informed about IFs do not provide sufficient guidance because they rely on the same notion of risk communication as a form of communication about actual health and disease. Differently designed empirical research and more reflection on biobank research and genetic risk information is required before ethical principles can be applied to support the adoption of a reasonable and comprehensive policy for handling IFs.