Analyses of quality of life in cancer drug trials - a review of measurements and analytical choices in post-reimbursement studies.

OBJECTIVES: For drugs reimbursed with limited evidence of patient benefits, confirmatory evidence of overall survival (OS) and quality of life (QoL) benefits is important. For QoL data to serve as valuable input to patients and decision-makers, it must be measured and analyzed using appropriate methods. We aimed to assess the measurement and analyses of post-reimbursement QoL data for cancer drugs introduced in Swedish healthcare with limited evidence at the time of reimbursement. METHODS: We reviewed any published post-reimbursement trial data on QoL for cancer drugs reimbursed in Sweden between 2010 and 2020 with limited evidence of improvement in QoL and OS benefits at the time of reimbursement. We extracted information on the instruments used, frequency of measurement, extent of missing data, statistical approaches, and the use of pre-registration and study protocols. RESULTS: Out of 22 drugs satisfying our inclusion criteria, we identified published QoL data for 12 drugs in 22 studies covering multiple cancer types. The most frequently used QoL instruments were EORTC QLQ-C30 and EQ-5D-3/5L. We identified three areas needing improvement in QoL measurement and analysis: (i) motivation for the frequency of measurements, (ii) handling of the substantial missing data problem, and (iii) inclusion and adherence to QoL analyses in clinical trial pre-registration and study protocols. CONCLUSIONS: Our review shows that the measurements and analysis of QoL data in our sample of cancer trials covering drugs initially reimbursed without any confirmed QoL or OS evidence have significant room for improvement. The increasing use of QoL assessments must be accompanied by a stricter adherence to best-practice guidelines to provide valuable input to patients and decision-makers.

The impact of multimorbidity among adults with cardiovascular diseases on healthcare costs in Indonesia: a multilevel analysis.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death in Indonesia, accounting for 38% of the total mortality in 2019. Moreover, healthcare spending on CVDs has been at the top of the spending under the National Health Insurance (NHI) implementation. This study analyzed the association between the presence of CVDs with or without other chronic disease comorbidities and healthcare costs among adults (> 30 years old) and if the association differed between NHI members in the subsidized group (poorer) and non-subsidized households group (better-off) in Indonesia. METHODS: This retrospective cohort study analyzed the NHI database from 2016-2018 for individuals with chronic diseases (n = 271,065) ascertained based on ICD-10 codes. The outcome was measured as healthcare costs in USD value for 2018. We employed a three-level multilevel linear regression, with individuals at the first level, households at the second level, and districts at the third level. The outcome of healthcare costs was transformed with an inverse hyperbolic sine to account for observations with zero costs and skewed data. We conducted a cross-level interaction analysis to analyze if the association between individuals with different diagnosis groups and healthcare costs differed between those who lived in subsidized and non-subsidized households. RESULTS: The mean healthcare out- and inpatient costs were higher among patients diagnosed with CVDs and multimorbidity than patients with other diagnosis groups. The predicted mean outpatient costs for patients with CVDs and multimorbidity were more than double compared to those with CVDs but no comorbidity (USD 119.5 vs USD 49.1, respectively for non-subsidized households and USD 79.9 vs USD 36.7, respectively for subsidized households). The NHI household subsidy status modified relationship between group of diagnosis and healthcare costs which indicated a weaker effect in the subsidized household group (ß = -0.24, 95% CI -0.29, -0.19 for outpatient costs in patients with CVDs and multimorbidity). At the household level, higher out- and inpatient costs were associated with the number of household members with multimorbidity. At the district level, higher healthcare costs was associated with the availability of primary healthcare centres. CONCLUSIONS: CVDs and multimorbidity are associated with higher healthcare costs, and the association is stronger in non-subsidized NHI households. Households' subsidy status can be construed as indirect socioeconomic inequality that hampers access to healthcare facilities. Efforts to combat cardiovascular diseases (CVDs) and multimorbidity should consider their distinct impacts on subsidized households. The effort includes affirmative action on non-communicable disease (NCD) management programs that target subsidized households from the early stage of the disease.

Myxomatous Mitral Valve Disease in Large Breed Dogs: Survival Characteristics and Prognostic Variables.

Myxomatous mitral valve disease (MMVD) is the most common acquired heart disease in dogs and its occurrence in small-and medium-sized dogs has been extensively investigated. MMVD has been described in large breed dogs as well, but substantial knowledge gaps remain. The aim of this study was to provide characteristics, survival times, and prognostic variables in large breed dogs with MMVD. Medical records of dogs diagnosed with MMVD, between 2012 and 2021, were retrospectively reviewed and 202 dogs were analyzed. Median survival time (MST) for all-cause mortality was 800 days for stage B1 dogs, 274 days for stage B2 dogs, and 184 days for stage C dogs. The MST for cardiac-related death for B1 dogs could not be calculated (because survival was greater than 50% at the last timepoint) and for stage B2 and C dogs the MST were 484 and 252 days, respectively. These findings suggest that the frequency of cardiac-related death is low in large breed dogs with stage B1 MMVD. In addition, increased left atrial and ventricular size, evidence of systolic dysfunction, a thrilling murmur, and increased early trans-mitral peak velocity are predictors of cardiac-related death. Data also suggest that the risk of a negative outcome increases profoundly when large breed dogs advance from ACVIM stage B1 into stage B2 or C.

A Review of the Cost-Effectiveness Evidence for FDA-Approved Cell and Gene Therapies.

Cell and gene therapy (CGT) innovations have provided several significant breakthroughs in recent years. However, CGTs often come with a high upfront cost, raising questions about patient access, affordability, and long-term value. This study reviewed cost-effectiveness analysis (CEA) studies that have attempted to assess the long-term value of Food and Drug Administration (FDA)-approved CGTs. Two reviewers independently searched the Tufts Medical Center CEA Registry to identify all studies for FDA-approved CGTs, per January 2023. A data extraction template was used to summarize the evidence in terms of the incremental cost-effectiveness ratio expressed as the cost per quality-adjusted life year (QALY) and essential modeling assumptions, combined with a template to extract the adherence to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. The review identified 26 CEA studies for seven CGTs. Around half of the base-case cost-effectiveness results indicated that the cost per QALY was below $100,000-$150,000, often used as a threshold for reasonable cost-effectiveness in the United States. However, the results varied substantially across studies for the same treatment, ranging from being considered very cost-effective to far from cost-effective. Most models were based on data from single-arm trials with relatively short follow-ups, and different long-term extrapolations between studies caused large differences in the modeled cost-effectiveness results. In sum, this review showed that, despite the high upfront costs, many CGTs have cost-effectiveness evidence that can support long-term value. Nonetheless, substantial uncertainty regarding long-term value exists because so much of the modeling results are driven by uncertain extrapolations beyond the clinical trial data.

Place or patient as the driver of regional variation in healthcare spending - Discrepancies by category of care.

We study how much regional variation in healthcare spending is driven by place- and patient-specific factors using a random sample of 53,620 regional migrants in Sweden. We find notable differences depending on the category of care, with place-specific factors having a significantly larger impact on specialized outpatient care compared to inpatient and pharmaceutical care. The place effect is estimated to 75% of variation in specialized outpatient care, but 26% or less in variations in inpatient care, and 5% in prescription drug spending. We also find that the empirical estimator has a substantial impact on the estimates of the place-specific effect. The results based on the traditional approach in the literature with two-way fixed effects and event-study models produce much larger estimates of the place-specific effect compared to results based on recently developed heterogeneity-robust models. For total healthcare spending, the traditional two-way fixed effects model estimates a place effect of 78%, while the heterogeneity-robust estimator finds a place effect around 10%. This finding indicates that previous results in this literature, all based on traditional two-way fixed-effects regressions, should be interpreted with care.

Systematic review of cost-effectiveness in breast reconstruction: deep inferior epigastric perforator flap vs. implant-based breast reconstruction.

BACKGROUND: There are several techniques for reconstructing breasts after mastectomy, but little scientific evidence for which technique is superior. The aim of this systematic review was to compare the cost-effectiveness of implant-based and autologous reconstruction and to evaluate the overall certainty of evidence, as well as the quality of reporting of the included studies. METHODS: Studies investigating the cost-effectiveness of breast reconstruction with a deep inferior epigastric perforator (DIEP) flap compared to implant-based reconstruction, meeting criteria defined in a PICO (population, intervention, comparison, and outcome), were included. Medline, PubMed, Embase, Cochrane library, CinahL, EconLit, and NHS EED databases were searched. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence, and the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) 2022 was used to evaluate the quality of reporting. RESULTS AND CONCLUSIONS: A total of 256 abstracts were retrieved from the search, and after scrutiny, seven studies were included. The findings of this present systematic review should be interpreted with caution as the overall certainty of evidence is low (GRADE ƟƟОО). The included studies suggest that DIEP-flaps are cost-effective compared with implant-based breast reconstruction when the applied cost-effectiveness thresholds of $50,000 to $100,000 per quality-adjusted life years are used. It is noteworthy that no high level evidence exists regarding cost-effeciency, to support recommendations and decision in breast reconstruction. Methodological issues that can be improved in future studies are presented.

Effects of the COVID-19 pandemic on healthcare utilization among older adults with cardiovascular diseases and multimorbidity in Indonesia: an interrupted time-series analysis.

BACKGROUND: The COVID-19 pandemic has disrupted healthcare utilization globally, but little is known about the effects among patients with cardiovascular diseases (CVDs) and other multimorbidities. This study analyzed the impacts of COVID-19 on healthcare utilization for patients aged 30 years and older with cardiovascular diseases (CVDs) with or without other chronic disease comorbidities in Indonesia. METHODS: We designed a retrospective cohort study based on the Indonesian National Health Insurance (NHI) sample data from 2016-2020. We defined healthcare utilization as monthly outpatient and inpatient visits related to chronic diseases at the hospital and primary healthcare levels per 10,000 NHI members. We used interrupted time series analysis to evaluate how the healthcare utilization patterns had changed due to the COVID-19 pandemic. RESULTS: Overall, hospital outpatient visits decreased by 39% when the pandemic occurred (95% Confidence Interval (CI): 0.48,0.76), inpatient visits by 28% (95% CI: 0.62,0.83), and primary healthcare visits by 34% (95% CI:0.55, 0.81). For patients with CVDs and multimorbidity, hospital outpatient and inpatient visit rates were reduced by 36% and 38%, respectively and primary healthcare visits by 32%. Some insignificant differences in the reduction of out-and inpatient visits were observed across diagnosis groups and regions. CONCLUSION: Healthcare utilization among patients with chronic diseases decreased significantly during COVID-19 and consistently across different chronic diseases and regions. To cope with the unmet needs of healthcare utilization in the context of the pandemic, the healthcare system needs to be strengthened to cater to the needs of the population-at-risk, especially for patients with CVDs and multimorbidity.

Absolute Contusion Expansion Is Superior to Relative Expansion in Predicting Traumatic Brain Injury Outcomes: A Multi-Center Observational Cohort Study.

Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6-12 months post-injury, dichotomized into unfavorable (GOS ≤3) or favorable (GOS ≥4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1-8.3 mL) and 100% (IQR 10-530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p = 0.003). For dichotomized CE, absolute cutoffs of 1-10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.

Long-term effects on healthcare utilisation among spouses of persons with stroke.

BACKGROUND: Stroke is a common and costly disease affecting the person with stroke and their relatives. If the negative effect on the health of informal caregivers to a person with stroke translates into an increased healthcare consumption has not yet been studied. Further, the importance of including costs and health consequences of informal caregiving in health economic evaluation supporting decision-making is an ongoing discussion. Therefore, this study aims to estimate the long-term effect on healthcare utilisation among spouses of persons with a first-ever stroke. METHOD: The study population consists of spouses of persons with first-ever stroke events in 2010-2011 and a reference population matched on age, sex and municipality of residence. We have access to information on healthcare utilisation five years before and five years after the stroke event for the whole study population. Using a difference-in-difference approach, the main analysis estimates the effects on primary and specialist outpatient care visits and days with inpatient care per year. Further, we analyse the healthcare utilisation among spouses depending on the modified Rankin Scale (mRS) of the person with stroke. RESULTS: Our main analysis indicates that spouses have slightly more days with inpatient care five years after the stroke event than the reference population (p = 0.03). In contrast, spouses have fewer primary and specialist outpatient care visits than the reference population following the stroke event. In the analysis where spouses' healthcare utilisation is analysed according to the mRS status of the person with stroke, we identify the most notable change in the number of visits to specialist outpatient and days with inpatient care among spouses of persons with mRS 3 (dependency in daily activities). CONCLUSION: Our study suggests that being the spouse of a person with stroke has minor effects on healthcare utilisation. Further, healthcare utilisation is most affected among the spouses of persons with stroke and dependency in daily activities (mRS 3). According to our results, it does not seem vital to include spouses of persons with stroke healthcare utilisation in health economic evaluations.

Adverse events during endovascular treatment of ruptured aneurysms: A prospective nationwide study on subarachnoid hemorrhage in Sweden.

Introduction: A range of adverse events (AEs) may occur in patients with subarachnoid hemorrhage (SAH). Endovascular treatment is commonly used to prevent aneurysm re-rupture. Research question: The aim of this study was to identify AEs related to endovascular treatment, analyze risk factors for AEs and how AEs affect patient outcome. Material and methods: Patients with aneurysmal SAH admitted to all neurosurgical centers in Sweden during a 3.5-year period (2014-2018) were prospectively registered. AEs related to endovascular aneurysm treatment were thromboembolic events, aneurysm re-rupture, vessel dissection and puncture site hematoma. Potential risk factors for the AEs were analyzed using multivariate logistic regression. Functional outcome was assessed at one year using the extended Glasgow outcome scale. Results: In total, 1037 patients were treated for ruptured aneurysms. Of which, 715 patients were treated with endovascular occlusion. There were 115 AEs reported in 113 patients (16%). Thromboembolic events were noted in 78 patients (11%). Aneurysm re-rupture occurred in 28 (4%), vessel dissection in 4 (0.6%) and puncture site hematoma in 5 (0.7%). Blister type aneurysm, aneurysm smaller than 5 mm and endovascular techniques other than coiling were risk factors for treatment-related AEs. At follow-up, 230 (32%) of the patients had unfavorable outcome. Patients suffering intraprocedural aneurysm re-rupture were more likely to have unfavorable outcome (OR 6.9, 95% CI 2.3-20.9). Discussion and conclusion: Adverse events related to endovascular occlusion of a ruptured aneurysm were seen in 16% of patients. Aneurysm re-rupture during endovascular treatment was associated with increased risk of unfavorable functional outcome.

The impact of stroke on spousal and family income: a difference-in-difference study from Swedish national registries.

AIM: To investigates the financial consequences in the overall population spouses of persons with stroke in Sweden as well as for subgroups based on spouses age, sex and modified Rankin Scale (mRS) of the person with stroke. METHODS: The study population consists of spouses aged ≤ 60 during the year of their partner's stroke event. Each spouse was matched to four reference individuals. This longitudinal registry data covers spouses and a reference population between 2005 and 2016. We use difference-in-differences to estimate the impact on individual income from paid work, disposable individual income, and disposable family income. RESULTS: The primary analysis shows a small and statistically insignificant decrease on spouses' individual income from paid work and disposable individual income. In the subgroup analysis based on mRS, the largest effect is seen in mRS 4-5, where spouses' individual income from paid work and disposable individual income increases after their partner's stroke. Further, younger female spouses' individual income from paid work decreases by 1 614 EUR (p = 0.008) on average. CONCLUSION: The financial consequences are small in the overall population of spouses. However, for some subgroups, younger women, and spouses of persons with stroke and mRS 4-5, the financial consequences are more prominent.

Molecular anatomy of adult mouse leptomeninges.

Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.

Cost-Effectiveness of Exercise Therapy in Patients with Intermittent Claudication-A Comparison of Supervised Exercise, Home-Based Structured Exercise, and Walk Advice from the SUNFIT Trial.

Hospital-based supervised exercise (SEP) is a guideline-recommended intervention for patients with intermittent claudication (IC). However, due to the limited availability of SEP, home-based structured exercise programs (HSEP) have become increasingly popular alongside the "go home and walk" advice. We evaluated the cost-effectiveness of walk advice (WA) with Nordic pole walking vs. SEP combined with WA or HSEP combined with WA. We used data from the SUNFIT RCT (NCT02341716) to measure quality-adjusted life-years (QALYs) over a 12-month follow-up, and economic costs were obtained from a hospital cost-per-patient accounting system. Incremental cost-effectiveness ratios (ICERs) were calculated, and uncertainty was assessed using nonparametric bootstrapping. The average health-care-cost per patient was similar in the WA (EUR 1781, n = 51) and HSEP (EUR 1820, n = 48) groups but higher in the SEP group (EUR 4619, n = 50, p-value < 0.01). Mean QALYs per patient during the follow-up were similar with no statistically significant differences. The findings do not support SEP as a cost-effective treatment for IC, as it incurred significantly higher costs without providing additional health improvements over WA with or without HSEP during the one-year observation period. The analysis also suggested that HSEP may be cost-effective compared to WA, but only with a 64% probability.

Lifetime healthcare expenditures across socioeconomic groups in Sweden.

BACKGROUND: Individuals of lower socioeconomic status generally have higher healthcare expenditures than individuals of higher socioeconomic status. However, little is known about how expenditures are distributed across socioeconomic groups over a lifetime, once accounting for differences in life expectancy. This study describes how lifetime healthcare expenditures are distributed across age, sex and socioeconomic groups in Sweden while adjusting for differences in life expectancy. METHODS: Healthcare utilization from 2016 were linked to demographic and socioeconomic data for a random sample of individuals aged 20 and above in the four largest Swedish regions (n = 440 659). Mortality data were used to estimate income- and sex-specific survival rates. Expected lifetime healthcare expenditures were estimated by combining survival rates with mean healthcare expenditures over age, by sex, and income quintile. RESULTS: We find that expected lifetime healthcare expenditures are highest among the first (lowest) income quintile despite their evident lower life expectancy. Expected lifetime expenditures were 17.9% (16.8%) higher in the first income quintile compared to the fifth (highest) quintile for women (men). Individuals in the first income quintile had higher expected lifetime expenditures for all care categories except for primary care. CONCLUSION: We conclude that despite a lower life expectancy, the quintile of the lowest socioeconomic status still had higher lifetime healthcare expenditures.

Economic Burden of Sanfilippo Syndrome in the United States.

Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. Design and Setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Main Outcome Measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death. Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome. Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.

Cost-effectiveness analysis of monthly, 3-monthly, and 6-monthly long-acting injectable and oral paliperidone in adults with schizophrenia.

BACKGROUND: Paliperidone is among the most cost-effective antipsychotics in adults with schizophrenia, and it has different formulations, including oral paliperidone extended-release (ER) and long-acting injectable (LAI) paliperidone formulations administered every month (PP1M), 3 months (PP3M), or 6 months (PP6M). However, cost-effectiveness analyses comparing different paliperidone formulations were limited. OBJECTIVE: To compare the cost-effectiveness across different paliperidone formulations. METHODS: A Markov model was developed to simulate 1,000 adults aged 40 years with stable schizophrenia transitioning among stable disease-medication adherent, stable disease-medication nonadherent, relapse with hospitalization, relapse with ambulatory care, and death states every 3 months for 5 years. Drug costs were estimated using the prices listed in the Veterans Affairs Federal Supply Schedule, and costs for treating complications were estimated from published studies. All costs were estimated from the US health care system perspective and standardized to 2022 US dollars using the Consumer Price Index Inflation Calculator. Quality-adjusted life-years (QALYs) were estimated using relapse rates from randomized clinical trials and health-related quality of life scores from observational studies. The estimated future costs and QALYs were discounted at 3%. We reported incremental net monetary benefits between alternative formulations at the $50,000 willingness-to-pay (WTP) threshold with a positive value indicating cost-effectiveness. The impact of parameter uncertainty on study outcomes was assessed using 1-way deterministic and probabilistic sensitivity analyses. RESULTS: In adults with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was associated with increased QALY (PP1M = 0.05, PP3M = 0.14, PP6M = 0.15) and increased cost (PP1M = 49,433, PP3M = 26,698, PP6M = 26,147), leading to a negative incremental net monetary benefit (PP1M = -$46,804, PP3M = -$19,508, PP6M = -$18,886) compared with continuing ER. Among LAI formulations, PP6M was cost-saving with the most QALYs gained (cost = $63,277, QALY = 3.731), followed by PP3M (cost = $63,828, QALY = 3.729) and PP1M (cost = $86,563, QALY = 3.638). At the $50,000 WTP threshold, the probabilities for PP1M, PP3M, and PP6M being cost-effective compared with paliperidone ER were 0.4%, 10.2%, and 9.8%, respectively. The probability of PP6M being cost-effective was 92.6% for the PP6M-PP1M pair and 55.2% for the PP6M-PP3M pair, and 91.1% of PP3M use was cost-effective in the PP3M-PP1M pair. The results were generally robust in the sensitivity analyses, even at the $190,000 WTP threshold. CONCLUSIONS: For patients with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was not cost-effective, suggesting the high drug costs for LAI may not justify the improved quality of life within 5 years. Among LAI formulations, PP6M was cost-effective over PP1M and PP3M.

Cancer Drugs Reimbursed with Limited Evidence on Overall Survival and Quality of Life: Do Follow-Up Studies Confirm Patient Benefits?

BACKGROUND AND OBJECTIVE: Cancer drug costs have increased considerably within healthcare systems, but many drugs lack quality-of-life (QoL) and overall survival (OS) data at the time of reimbursement approval. This study aimed to review the extent of subsequent literature documenting improvements in OS and QoL for cancer drug indications where no such evidence existed at the time of reimbursement approval. METHODS: Drug indications with claims of added therapeutical value but a lack of evidence on OS and QoL that were reimbursed between 2010 and 2020 in Sweden were included for review. Searches were conducted in PubMed and ClinicalTrial.gov for randomized controlled trials examining OS and QoL. RESULTS: Of the 22 included drug indications, seven were found to have at least one trial with conclusive evidence of improvements in OS or QoL after a mean follow-up of 6.6 years. The remaining 15 drug indications either lacked subsequent randomized controlled trial data on OS or QoL (n = 6) or showed no statistically significant improvements (n = 9). Only one drug demonstrated evidence of improvement in both OS and QoL for its indication. CONCLUSIONS: A considerable share of reimbursed cancer drug indications continue to lack evidence of improvement in both OS and QoL. With limited healthcare resources and an increasing cancer burden, third-party payers have strong incentives to require additional post-reimbursement data to confirm any improvements in OS and QoL.

Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation.

BACKGROUND: Astrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. METHODS: We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. RESULTS: We confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1ß and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC. CONCLUSIONS: Ventral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.

Healthcare cost and survival in patients with non-functioning pituitary adenoma.

OBJECTIVE: Pituitary adenomas and their consequences impact mortality and morbidity. We studied the healthcare costs, survival, and cost-effectiveness of growth hormone (GH) vs no GH replacement in patients with non-functioning pituitary adenoma (NFPA). DESIGN AND METHODS: A cohort study including all NFPA patients followed from 1987 or the date of diagnosis until the time of death or December 31, 2019, in the Västra Götaland region, Sweden. Data to assess resource use, costs, survival, and cost-effectiveness were collected from patient records and regional/national healthcare registries. RESULTS: A total of 426 patients with NFPA (274 men) with a follow-up of 13.6 ± 6.8 years (mean ± SD) were included. The total annual healthcare cost was higher in patients receiving GH (€9287) than those without GH (€6770), mainly driven by a higher pharmaceutical cost. Glucocorticoid replacement therapy (P = .02), diabetes insipidus (P = .04), body mass index (BMI) (P < .01), and hypertension (P < .01) were all individually associated with a higher total annual cost. The survival rate was higher in the GH group (HR [hazard ratio] 0.60; P = .01) and reduced in patients with glucocorticoid replacement (HR 2.02; P < .01) or diabetes insipidus (HR 1.67; P = .04). The cost per gained life-year for GH vs no GH replacement was about €37 000. CONCLUSIONS: This healthcare utilization study identified several factors driving the cost of care in NFPA patients, such as GH replacement, adrenal insufficiency, and diabetes insipidus. Life expectancy was increased in those with GH replacement and reduced in patients with adrenal insufficiency and diabetes insipidus.

Disease Specific Health Related Quality of Life in Patients With Chronic Limb Threatening Ischaemia Undergoing Revascularisation of Femoropopliteal Lesions.

OBJECTIVE: Patients with chronic limb threatening ischaemia (CLTI) suffer from pain and non-healing ulcers, which impact negatively on both their physical and mental health. While maintaining and improving quality of life is a principal aim with all treatments, little is known about the health related quality of life (HRQoL) of CLTI patients and how revascularisation procedures impact on HRQoL endpoints. The aim of this study was to investigate disease specific HRQoL before and after revascularisation in patients with CLTI undergoing femoropopliteal revascularisation. METHODS: HRQoL was prospectively analysed in 190 CLTI patients with main atherosclerotic target lesions in the femoropopliteal segment, who were planned for endovascular or open revascularisation. The choice of revascularisation method was made by the vascular team, represented by both open and endovascular expertise. The Vascular Quality of Life (VascuQoL) questionnaire was used to assess disease specific HRQoL before revascularisation and one month, one year, and two years after the procedure. Main endpoints were mean VascuQoL score changes, effect sizes of observed changes and the proportion reaching a minimally important difference (half a standard deviation change from baseline) during two years after revascularisation. RESULTS: Patient reported VascuQoL scores were low at baseline (mean 2.68, 95% CI 1.18 - 4.17). After revascularisation, the mean VascuQoL score improved statistically significantly over time, with the largest improvement observed after one year (difference from baseline 2.02, 95% CI 1.75 - 2.29; p < .001). No differences in HRQoL change over time were observed between patients treated with endovascular approaches compared with bypass surgery. Approximately half the patients reached the minimally important threshold at one year (53%), which was largely maintained also at two years (41%). CONCLUSION: While CLTI profoundly affected HRQoL, a large and clinically meaningful HRQoL increase was observed after revascularisation. This confirms the value of CLTI revascularisation on HRQoL and underlines the importance of including patient reported outcomes when evaluating revascularisation procedures in CLTI patients.