The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis.

BACKGROUND: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. METHODS: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. RESULTS: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy. CONCLUSIONS: This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories.

Central Venous Access Devices for the Delivery of Systemic Anticancer Therapy: An Economic Evaluation.

OBJECTIVES: Patients undergoing long-term anticancer therapy typically require one of 3 venous access devices: Hickman-type device (HICK), peripherally inserted central catheter (PICC), or implantable chest wall port (PORT). Recent evidence has shown PORT is safer and improves patient satisfaction. However, PORT did not show improvement in quality-adjusted life-years and was more expensive. Decisions regarding cost-effectiveness in the United Kingdom are typically informed by a cost-per-quality-adjusted life-year metric. However, this approach is limited in its ability to capture the full range of relevant outcomes, especially in the context of medical devices. This study assessed the potential cost-effectiveness of HICK, PICC, and PORT in routine clinical practice. METHODS: This is a cost-consequence analysis to determine the trade-offs between the following outcomes: complication, infection, noninfection, chemotherapy interruption, unplanned device removals, health utilities, device insertion cost, follow-up cost, and total cost, using data from the Cancer and Venous Access clinical trial. We conducted value of implementation analysis of a PORT service. RESULTS: PORT was superior in terms of overall complication rate compared with both HICK (incidence rate ratio 0.422; 95% CI 0.286-0.622) and PICC (incidence rate ratio 0.295; 95% CI 0.189-0.458) and less likely to lead to an unplanned device removal. There was no difference in chemotherapy interruption or health utilities. Total cost with device in situ was lower on PORT than HICK (-£98.86; 95% CI -189.20 to -8.53) and comparable with PICC -£48.57 (95% CI -164.99 to 67.86). Value of implementation analysis found that PORT was likely to be considered cost-effective within the National Health Service. CONCLUSION: Decision makers should consider including PORT within the suite of venous access devices available within in the National Health Service.

Adding a Gene Expression Profile Test to Aid Differential Diagnosis and Treatment in Aggressive Large B-Cell Lymphoma: An Early Exploratory Economic Evaluation.

BACKGROUND AND OBJECTIVE: Adding gene expression profiles (GEPs) to the current diagnostic work-up of aggressive large B-cell lymphomas may lead to the reclassification of patients, treatment changes and improved outcomes. A GEP test is in development using TempO-Seq® technology to distinguish Burkitt lymphoma (BL) and primary mediastinal large B-cell lymphoma (PMBCL) from diffuse large B-cell lymphoma (DLBCL), and to classify patients with DLBLC and to predict the benefit of (e.g.) adding bortezomib to R-CHOP therapy (RB-CHOP). This study aims to estimate the potential impact of a GEP test on costs and health outcomes to inform pricing and evidence generation strategies. METHODS: Three decision models were developed comparing diagnostic strategies with and without GEP signatures over a lifetime horizon using a UK health and social care perspective. Inputs were taken from a recent clinical trial, literature and expert opinion. We estimated the maximum price of the test using a threshold of Great Britain Pound (GBP) 30,000 per quality-adjusted life-year (QALY). Sensitivity analyses were conducted. RESULTS: The estimated maximum threshold price for a combined test to be cost effective is GBP 15,352. At base-case values, the BL signature delivers QALY gains of 0.054 at an additional cost of GBP 275. This results in a net monetary benefit at a threshold of GBP 30,000 per QALY of GBP 1345. For PMBCL, the QALY gain was 0.0011 at a cost saving of GBP 406 and the net monetary benefit was GBP 437. The hazard ratio for the impact of treating BL less intensively must be at least 1.2 for a positive net monetary benefit. For identifying patients with the DLBCL subtype responsive to bortezomib, QALY gain was 0.2465 at a cost saving of GBP 6175, resulting in a net monetary benefit of GBP 13,570. In a probabilistic sensitivity analysis using 1000 simulations, a testing strategy was superior to a treat all with R-CHOP strategy in 81% of the simulations and with a cost saving in 92% assuming a cost price of zero. CONCLUSIONS: Our estimates show that the combined test has a high probability of being cost effective. There is good quality evidence for the benefit of subtyping DLBCL but the evidence on the number of patients reclassified to or from BL and PMBCL and the impact of a more precise diagnosis and the cost of treatment is weak. The developers can use the price estimate to inform a return on investment calculations. Evidence will be required of how well the TempO-Seq® technology performs compared to the testing GEP technology used for subtyping in the recent clinical trial. For BL and PMBCL elements of the test, evidence would be required of the number of patients reclassified and improved costing information would be useful. The diagnostic and therapeutic environment in haematological malignancies is fast moving, which increases the risk for developers of diagnostic tests.

The extent and quality of qualitative evidence included in health technology assessments: a review of submissions to NICE and CADTH.

OBJECTIVES: Qualitative methods allow in-depth exploration of patient experiences and can provide context for healthcare decision making. Frameworks for patient-based evidence in health technology assessment (HTA) are expanding; yet, how extensively qualitative methods are currently used is unclear. This review characterized the extent and quality of qualitative data submitted to National Institute for Health and Care Excellence (NICE) and Canadian Agency for Drugs and Technologies in Health (CADTH) for HTA. METHODS: NICE and CADTH submissions from September 2019 to August 2021 were reviewed. Submission characteristics and features of patient-based evidence included within submissions were extracted. The quality of qualitative reporting was assessed using the CASP checklist. RESULTS: Patient-based evidence was included in 83/107 NICE and 119/124 CADTH submissions. A small proportion described qualitative data collection (NICE=14; CADTH=24) and analysis (NICE=6; CADTH=9) methods. One-to-one interviews were the most common data collection method, and thematic analysis was exclusively used. Thirty-three percent of NICE submissions scored >7 yes responses on CASP, versus 78 percent of CADTH submissions. CONCLUSIONS: Although patient-based evidence was common in the submissions reviewed, only 14/107 NICE and 24/124 CADTH submissions involved formal qualitative data collection. Use of formal analysis methods was even rarer and reporting tended to be brief. At present, there is little guidance about qualitative evidence most likely to be informative and therefore to potentially impact decision making. Ensuring, however, that qualitative data are collected and analyzed in a systematic, rigorous way will maximize their usefulness and ensure that patient voices are clearly heard.

Overall survival in the UK in mycosis fungoides or Sézary syndrome cutaneous T-cell lymphoma: comparative effectiveness of mogamulizumab versus current standard of care.

Aim: Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with patients with previously treated advanced mycosis fungoides/Sézary syndrome (MF/SS) in real-world setting. Design, setting & participants: Data were from the Hospital Episode Statistics database (all patients in NHS secondary care system in 2009-2019). Patients were selected according to trial inclusion criteria, then trial and HES samples were matched on selected variables with significant imbalance. Outcomes: The analysis indicated significant improvement in OS for mogamulizumab treatment compared with UK clinical practice (hazard ratio: 0.36, 95% CI: 0.24, 0.53). Conclusion: Results suggest an OS advantage for patients with advanced MF/SS treated with mogamulizumab in MAVORIC trial compared with UK clinical practice.

Correlation between progression-free survival and overall survival in patients with ovarian cancer after cytoreductive surgery: a systematic literature review.

OBJECTIVES: This analysis aimed to better define the relationship between progression-free survival and overall survival in adult patients with ovarian cancer (including fallopian tube or primary peritoneal cancer) following primary cytoreductive surgery or interval cytoreductive surgery. METHODS: A systematic literature review was carried out across the Medline, Embase, and Cochrane Central databases on 7 July 2020 (date limits 1 January 2011 to 7 July 2020) to identify studies with the following eligibility criteria: clinical trials/observational studies including >200 patients with ovarian cancer aged ≥18 years, evaluating overall survival/progression-free survival following cytoreductive surgery by residual disease status in the United States, Europe, Japan, or China. Weighted linear regression models were used to assess any correlation between median progression-free survival and overall survival, and between logHR for progression-free survival and logHR for overall survival. Risk of bias was assessed for all included studies. RESULTS: Of the 50 studies reported, 43 were observational studies (41 retrospective and two prospective cohort studies), and seven were reporting for randomized clinical trials-of which four were retrospective data analyses. For analyses of the relationship between overall survival and progression-free survival, 21 studies were eligible. The weighted linear regression model showed a strong positive association between the two survival endpoints. Goodness-of-fit analysis measured the adjusted R2 as 0.84 (p<0.001); a positive association was also observed between logHRs for overall survival and progression-free survival in the included studies. CONCLUSIONS: Median progression-free survival was predictive of median overall survival. This correlation between progression-free survival and overall survival after primary treatment for ovarian cancer highlights the validity of progression-free survival as a primary endpoint. Observational studies contributed most data, with limited information on disease stage and histology.

Anticipated effects of burosumab treatment on long-term clinical sequelae in XLH: expert perspectives.

X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D ("conventional therapy") and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.

Determining the Relationship Between Seizure-Free Days and Other Predictors of Quality of Life in Patients with Dravet Syndrome and Their Carers from FFA Registration Studies.

INTRODUCTION: Dravet syndrome (DS) is a rare, lifelong epileptic encephalopathy characterised by frequent and severe seizures associated with premature mortality. Typically diagnosed in infancy, patients also experience progressive behavioural, motor-function and cognitive decline. Twenty percent of patients do not reach adulthood. Quality of life (QoL) is impaired for both patients and their carers. Reducing convulsive seizure frequency, increasing convulsive seizure-free days (SFDs) and improving patient/carer QoL are primary treatment goals in DS. This study explored the relationship between SFDs and patients' and carers' QoL to inform a cost-utility analysis of fenfluramine (FFA). METHODS: In FFA registration studies, patients (or their carer proxies) completed the Paediatric QoL inventory (PedsQL). These data were mapped to EuroQol-5 Dimensions Youth version (EQ-5D-Y) to provide patient utilities. Carer utilities were collected using EQ-5D-5L and mapped to EQ-5D-3L to align patient and carer QoL on the same scale. Linear mixed-effects and panel regression models were tested and Hausman tests identified the most appropriate approach for each group. On this basis, a linear mixed-effects regression model was used to examine the relationships between patient EQ-5D-Y and clinically relevant variables (age, frequency of SFDs per 28 days, motor impairments and treatment dose). A linear panel regression model examined the relationship between SFDs and carer QoL. RESULTS: After adjustment for age and underlying comorbidities, the patient regression model showed that SFDs per 28 days was a significant predictor of QoL. Each additional patient-SFD increased utility by 0.005 (p < 0.001). The carer linear panel model also showed that increasing SFDs per 28 days was a significant predictor of improved QoL. Each additional SFD increased carer utility by 0.014 (p < 0.001). CONCLUSION: This regression framework highlights that SFDs are significantly correlated with both patients' and carers' QoL. Treatment with effective antiseizure medications that increase SFDs directly improves QoL for patients and their carers.

Lipid Lowering in "Very High Risk" Patients Undergoing Coronary Artery Bypass Surgery and Its Projected Reduction in Risk for Recurrent Vascular Events: A Monte Carlo Stepwise Simulation Approach.

ABSTRACT: 2018 AHA guidelines provide criteria to identify patients at very high risk (VHR) for adverse vascular events and recommend an low density lipoprotein-C (LDL-C) level <1.8 mmol/L. Data regarding the 10-year risk for adverse vascular events in coronary artery bypass grafting (CABG) patients at VHR and the need for nonstatin therapies in the VHR cohort are limited. We queried a national cohort of CABG patients to answer these questions. The projected reduction of LDL-C from stepwise escalation of lipid-lowering therapy (LLT) was simulated; Monte Carlo methods were used to account for patient-level heterogeneity in treatment effects. Data on preoperative statin therapy and LDL-C levels were obtained. In the first scenario, all eligible patients not at target LDL-C received high-intensity statins, followed by ezetimibe and then alirocumab; alternatively, bempedoic acid was also used. The 10-year risk for an adverse vascular event was estimated using a validated risk score. Potential risk reduction was estimated after simulating maximal LLT. Before CABG, 8948 of 27,443 patients (median LDL-C 85 mg/dL) were at VHR. In the whole cohort, 31% were receiving high-intensity statins. With stepwise LLT escalation, the proportion of patients at target were 60%, 78%, 86%, and 97% after high-intensity statins, ezetimibe, bempedoic acid, and alirocumab, respectively. The projected 10-year risk to suffer a vascular event reduced by 4.6%. A large proportion of CABG patients who are at VHR for vascular events fail to meet 2018 AHA LDL-C targets. A stepwise approach, particularly with the use of bempedoic acid, can significantly reduce the need for more expensive proprotein convertase subtilisin kexin 9 inhibitors.

Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?: Insights and Perspectives From the National Institute for Health and Care Excellence and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) Addendum.

OBJECTIVES: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects. METHODS: We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE. RESULTS: IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials. CONCLUSIONS: The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders' research questions. Different estimands may serve to answer different relevant questions or decision problems.

Economic evaluation of genomic/genetic tests: a review and future directions.

It has been suggested that health economists need to improve their methods in order to meet the challenges of evaluating genomic/genetic tests. In this article, we set out twelve challenges identified from a rapid review of the literature and suggest solutions to the challenges identified. Two challenges were common to all economic evaluations: choice of perspective and time-horizon. Five challenges were relevant for all diagnostic technologies: complexity of analysis; range of costs; under-developed evidence base; behavioral aspects; and choice of outcome metrics. The final five challenges were pertinent for genomic tests and only these may require methodological development: heterogeneity of tests and platforms, increasing stratification, capturing personal utility; incidental findings; and spillover effects. Current methods of economic evaluation are generally able to cope with genomic/genetic tests, although a renewed focus on specific decision-makers' needs and a willingness to move away from cost-utility analysis may be required. Certain analysts may be constrained by reference cases developed primarily for the assessment of pharmaceuticals. The combined impact of multiple challenges may require analysts to be particularly careful in setting the scope of their analysis in order to ensure that feasibility is balanced with usefulness to the decision maker. A key issue is the under-developed evidence-base and it may be necessary to rethink translation processes to ensure sufficient, relevant evidence is available to support economic evaluation and adoption of genomic/genetic tests.

Adjusting for treatment crossover in the MAVORIC trial: survival in advanced mycosis fungoides and Sézary syndrome.

Background: Relative overall survival (OS) estimates reported in the MAVORIC trial are potentially confounded by a high proportion of patients randomized to vorinostat switching to mogamulizumab; furthermore, vorinostat is not used in clinical practice in the UK. Methods: Three methods were considered for crossover adjustment. Survival post-crossover adjustment was compared with data from the Hospital Episode Statistics (HES) to contextualize estimates. Results: Following adjustment, the OS hazard ratio for mogamulizumab versus vorinostat was 0.42 (95% CI: 0.18, 0.98) using the method considered most appropriate based on an assessment of assumptions and comparison with HES. Conclusions: OS of mogamulizumab relative to vorinostat may be underestimated in MAVORIC due to the presence of crossover. The HES database was used to validate this adjustment.

Health-related quality of life, fatigue and health utilities in lupus nephritis: A systematic literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by abnormal B-cell activation and the presence of autoantibodies, which can result in organ damage. Lupus nephritis (LN) is the most common severe organ manifestation of SLE and may result in impaired kidney function. However, there is limited research on the health-related quality of life (HRQoL) burden amongst patients with LN. The objective of this systematic literature review was to assess the HRQoL, fatigue and health utilities associated with LN. METHODS: A structured literature search (GSK Study 212980) of the MEDLINE and Embase databases was conducted in July 2019 and updated September 2021. Relevant international congress abstracts from 2016 to 2021 were searched, and gray literature searches and keyword-based searches in PubMed, Google, and Google Scholar were also conducted. Results were screened according to predefined criteria and data on the outcomes of interest were extracted. A quantitative analysis was conducted to supplement the narrative review, to provide 36-item Short Form survey (SF-36) estimates, and to determine variation by prognostic factors. RESULTS: Of 1155 articles identified, 26 studies for a total of 3440 patients were included. Patients with LN showed poorer HRQoL and more fatigue than healthy controls/the general population, although these were similar between patients with SLE with and without LN. HRQoL was worse in patients with LN Class III/IV or with active disease. Fatigue was generally reported as the most burdensome symptom and was associated with lower HRQoL and increased treatment dissatisfaction. During induction treatment, HRQoL and fatigue were improved with mycophenolate mofetil versus cyclophosphamide. HRQoL improved over time with treatment amongst patients with active LN. Very limited data were identified assigning utilities to health states for cost-effectiveness analysis. Nine studies were considered for quantitative analysis of baseline SF-36 scores. The analysis suggested that LN has a significant impact across all SF-36 domains, with the lowest scores in the general health perceptions and role-physical domains and physical component summary. CONCLUSIONS: There is a large HRQoL burden in patients with LN, in particular regarding symptoms of fatigue. Future research should focus on investigating fatigue severity and health utilities in LN.

Economic and Humanistic Burden of Cerebral Vasospasm and Its Related Complications after Aneurysmal Subarachnoid Hemorrhage: A Systematic Literature Review.

INTRODUCTION: Cerebral vasospasm (VSP) is the leading risk factor of neurological deterioration (i.e., delayed cerebral ischemia [DCI] and cerebral infarction) after aneurysmal subarachnoid hemorrhage (aSAH) and a cause of morbidity and mortality. The objective of this systematic literature review is to summarize the economic and humanistic burden of VSP and its related complications after aSAH. METHODS: A predefined protocol was designed, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Systematic searches were conducted in MEDLINE, Embase, and Cochrane (in January 2021) to identify studies reporting economic and/or humanistic (i.e., health-related quality of life [HRQoL]) outcomes for patients with asymptomatic and symptomatic VSP after aSAH. Related conferences and additional sources were searched manually. Dual screening, data extraction, and qualitative analysis were conducted. RESULTS: Of 3818 abstracts identified for review, 43 full-text articles representing 42 single studies met the inclusion criteria and were included. Most studies (33) were observational; nine were randomized clinical trials (RCTs). Economic outcomes were reported in 31 studies, and alongside HRQoL outcomes in 4 studies; 7 studies reported HRQoL outcomes only. Forty studies were conducted in single countries, while only 2 RCTs were conducted in multiple countries. Patients diagnosed with VSP or DCI spent between 2.1 and 7.4 days longer in intensive care and between 4.7 and 17 days longer in hospital (total) compared with patients without VSP or DCI. A significantly higher cost burden of US$33,945 (2021 £26,712) was identified for patients with VSP and £9370 (2021 £13,733) for patients with DCI compared with patients without. Patients with DCI were also disadvantaged by being employed for 62 fewer days (during 24-month follow-up), with an estimated mean cost of £3821 (2021 £5600) for days off work. Poor HRQoL was associated with ≥ 1 days with VSP symptoms (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.4-5.3), symptomatic VSP (OR: 1.9, 95% CI: 1.0-3.6), and DCI (OR: 2.3, 95% CI: 1.3-4.2), although this was not consistent across all studies. Symptomatic VSP and DCI were identified as significant risk factors for depressed mood (OR: 2.2, 95% CI: 1.0-4.9) and global cognitive impairment (OR: 2.3) at 12 months, respectively. The severity of VSP was a critical predictor of post-aSAH economic and humanistic burden. Similar trends in economic and humanistic burden were identified in the general aSAH patient population. Study design and patient heterogeneity precluded direct metaanalysis of the results. CONCLUSION: A substantial direct and indirect economic burden is linked to VSP and its related complications after aSAH. Although limited evidence was identified for humanistic burden, these patients seem to suffer from poor HRQoL with long-lasting burden. Overall, there is an urgent need to understand better the concept of "burden of illness" of VSP and its related complications after aSAH.

Aneurysmal subarachnoid hemorrhage is a sudden, life-threatening emergency caused by bleeding in the subarachnoid space between the brain and skull. Vasospasm of the arteries surrounding the hemorrhage occurs in most patients and may lead to permanent brain damage. This study summarizes the published literature to describe the burden that patients may experience due to vasospasm and its related complications after aneurysmal subarachnoid hemorrhage, focusing on financial and life quality aspects. We show that the burden of vasospasm, and its related complications, is huge. Patients often experience reduced quality of life due to their poor health and are more likely to suffer from depression and intellectual impairment. There is also a substantial financial burden linked to vasospasm and its related complications, driven by the need for more intensive care, hospitalization, and higher investigative costs associated with the treatment and management of these patients. In addition, days off work and unemployment can cause a substantial indirect financial burden. Our study highlights the need for additional research to understand further the "burden of illness" of vasospasm and its related complications after aneurysmal subarachnoid hemorrhage.

Precision rehabilitation for aphasia by patient age, sex, aphasia severity, and time since stroke? A prespecified, systematic review-based, individual participant data, network, subgroup meta-analysis.

BACKGROUND: Stroke rehabilitation interventions are routinely personalized to address individuals' needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias. AIM: We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database. METHODS: MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild-moderate/ moderate-severe based on language outcomes' median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness. RESULTS: 959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants' greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3-4 SLT-h/week; ⩾ 50 hours). For moderate-severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild-moderate participants' greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males' greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT (< 2 SLT-h/weekly). Consistencies across subgroups were also evident; greatest overall-language gains were associated with 20-to-50 SLT-h in total; auditory comprehension gains were generally observed when SLT > 9 h over ⩾ 4 days/week. CONCLUSIONS: We observed a treatment response in most subgroups' overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild-moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate-severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs.

Challenges of modelling approaches for network meta-analysis of time-to-event outcomes in the presence of non-proportional hazards to aid decision making: Application to a melanoma network.

BACKGROUND: Synthesis of clinical effectiveness from multiple trials is a well-established component of decision-making. Time-to-event outcomes are often synthesised using the Cox proportional hazards model assuming a constant hazard ratio over time. However, with an increasing proportion of trials reporting treatment effects where hazard ratios vary over time and with differing lengths of follow-up across trials, alternative synthesis methods are needed. OBJECTIVES: To compare and contrast five modelling approaches for synthesis of time-to-event outcomes and provide guidance on key considerations for choosing between the modelling approaches. METHODS: The Cox proportional hazards model and five other methods of estimating treatment effects from time-to-event outcomes, which relax the proportional hazards assumption, were applied to a network of melanoma trials reporting overall survival: restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models. RESULTS: All models fitted the melanoma network acceptably well. However, there were important differences in extrapolations of the survival curve and interpretability of the modelling constraints demonstrating the potential for different conclusions from different modelling approaches. CONCLUSION: The restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models can accommodate non-proportional hazards and differing lengths of trial follow-up within a network meta-analysis of time-to-event outcomes. We recommend that model choice is informed using available and relevant prior knowledge, model transparency, graphically comparing survival curves alongside observed data to aid consideration of the reliability of the survival estimates, and consideration of how the treatment effect estimates can be incorporated within a decision model.

How does risdiplam compare with other treatments for Types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison.

Aim: To conduct indirect treatment comparisons between risdiplam and other approved treatments for spinal muscular atrophy (SMA). Patients & methods: Individual patient data from risdiplam trials were compared with aggregated data from published studies of nusinersen and onasemnogene abeparvovec, accounting for heterogeneity across studies. Results: In Type 1 SMA, studies of risdiplam and nusinersen included similar populations. Indirect comparison results found improved survival and motor function with risdiplam versus nusinersen. Comparison with onasemnogene abeparvovec in Type 1 SMA and with nusinersen in Types 2/3 SMA was challenging due to substantial differences in study populations; no concrete conclusions could be drawn from the indirect comparison analyses. Conclusion: Indirect comparisons support risdiplam as a superior alternative to nusinersen in Type 1 SMA.

Improving the Estimation of Subgroup Effects for Clinical Trial Participants with Multimorbidity by Incorporating Drug Class-Level Information in Bayesian Hierarchical Models: A Simulation Study.

BACKGROUND: There is limited guidance for using common drug therapies in the context of multimorbidity. In part, this is because their effectiveness for patients with specific comorbidities cannot easily be established using subgroup analyses in clinical trials. Here, we use simulations to explore the feasibility and implications of concurrently estimating effects of related drug treatments in patients with multimorbidity by partially pooling subgroup efficacy estimates across trials. METHODS: We performed simulations based on the characteristics of 161 real clinical trials of noninsulin glucose-lowering drugs for diabetes, estimating subgroup effects for patients with a hypothetical comorbidity across related trials in different scenarios using Bayesian hierarchical generalized linear models. We structured models according to an established ontology-the World Health Organization Anatomic Chemical Therapeutic Classifications-allowing us to nest all trials within drugs and all drugs within anatomic chemical therapeutic classes, with effects partially pooled at each level of the hierarchy. In a range of scenarios, we compared the performance of this model to random effects meta-analyses of all drugs individually. RESULTS: Hierarchical, ontology-based Bayesian models were unbiased and accurately recovered simulated comorbidity-drug interactions. Compared with single-drug meta-analyses, they offered a relative increase in precision of up to 250% in some scenarios because of information sharing across the hierarchy. Because of the relative precision of the approaches, a large proportion of small subgroup effects was detectable only using the hierarchical model. CONCLUSIONS: By assuming that similar drugs may have similar subgroup effects, Bayesian hierarchical models based on structures defined by existing ontologies can be used to improve the precision of treatment efficacy estimates in patients with multimorbidity, with potential implications for clinical decision making.

Exploring the Impact of Treatment Switching on Overall Survival from the PROfound Study in Homologous Recombination Repair (HRR)-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BACKGROUND: In oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy. OBJECTIVE: This study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib. PATIENTS AND METHODS: The primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation. RESULTS: The RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5-0.97) to between 0.42 (0.18-0.90) and 0.52 (0.31-1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control. CONCLUSIONS: The magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.