Comparing binary efficacy outcomes for systemic immunomodulatory treatments for atopic dermatitis in a living systematic review and network meta-analysis.

BACKGROUND: Systemic treatments for atopic dermatitis (AD) are evaluated primarily in placebo-controlled trials with binary efficacy outcomes. In a living systematic review and network meta-analysis (NMA), we previously analysed continuous efficacy measures. OBJECTIVES: To compare binary efficacy outcomes of systemic treatments for AD. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Science Information (LILACS) database, Global Resource for Eczema Trials (GREAT) database and trial registries up to 1 March 2023. We included randomized trials examining ≥ 8 weeks of treatment with systemic immunomodulatory medications for moderate-to-severe AD. We screened titles, abstracts and full texts and abstracted data independently, in duplicate. Outcomes included the proportion of patients achieving at least 50%, 75% and 90% improvements in Eczema Area and Severity Index (EASI 50, EASI 75 and EASI 90, respectively) and Investigator Global Assessment (IGA) success. We performed random-effects Bayesian NMAs to calculate odds ratios (OR) and 95% credible intervals (CrIs) between each intervention for each outcome. RESULTS: Eighty-three trials with 22 122 participants were included in the systematic review. In analyses limited to trials of 8-16 weeks' duration with predominantly adult populations, abrocitinib 200 mg daily (OR 1.5, 95% CrI 1.1-2.2) and upadacitinib 15 mg daily (OR 1.7, 95% CrI 0.9-3.3) and 30 mg daily (OR 2.5, 95% CrI 1.3-5.0) were associated with higher odds of achieving EASI 50 vs. dupilumab. Abrocitinib 100 mg daily (OR 0.7, 95% CrI 0.5-1.0), baricitinib 2 mg daily (OR 0.4, 95% CrI 0.3-0.5) and 4 mg daily (OR 0.5, 95% CrI 0.3-0.7), and tralokinumab (OR 0.4, 95% CrI 0.3-0.6) were associated with lower odds of achieving EASI 50 vs. dupilumab. Results were similar for EASI 75, EASI 90 and IGA success. CONCLUSIONS: Supporting results for continuous outcome measures, upadacitinib 30 mg daily and abrocitinib 200 mg daily are the most efficacious with regard to binary efficacy endpoints up to 16 weeks in adults with moderate-to-severe AD, followed by upadacitinib 15 mg daily, dupilumab and abrocitinib 100 mg daily. Dupilumab and both doses of upadacitinib and abrocitinib are more efficacious than baricitinib 4 and 2 mg daily and tralokinumab.

Cost-effectiveness of ropeginterferon alfa-2b-njft for the treatment of polycythemia vera.

Aim: Patients with polycythemia vera (PV), a rare and chronic blood cancer, are at a higher risk for thromboembolic events, progression to myelofibrosis, and leukemic transformation. In 2021, ropeginterferon alfa-2b-njft (BESREMi®) was approved in the US to treat adults with PV. The purpose of this study is to estimate the cost-effectiveness of ropeginterferon alfa-2b-njft, used as a first- or second-line treatment, for the treatment of patients with PV in the US. Materials & methods: A Markov cohort model was developed from the healthcare system perspective in the United States. Model inputs were informed by the PROUD-PV and CONTINUATION-PV studies and published literature. The model population included both low-risk and high-risk patients with PV. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. Results: Over the modeled lifetime, ropeginterferon alfa-2b-njft provided an additional 0.4 higher quality-adjusted life years (QALYs) and 0.4 life-years with an added cost of USD60,175, resulting in a cost per QALY of USD141,783. The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates. A younger patient age at baseline and a higher percentage of patients with low-risk disease improved the cost-effectiveness of ropeginterferon alfa-2b-njft. Conclusion: Ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea.

Systemic Immunomodulatory Treatments for Atopic Dermatitis: Update of a Living Systematic Review and Network Meta-analysis.

Importance: Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head. Objective: To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021. Study Selection: Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate. Data Extraction and Synthesis: Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021. Main Outcomes and Measures: Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS). Results: Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, -2.1; 95% CrI, -4.1 to -0.3; high certainty), baricitinib, 4 mg daily (MD, -3.2; 95% CrI, -5.7 to -0.8; high certainty), baricitinib, 2 mg daily (MD, -5.2; 95% CrI, -7.5 to -2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, -3.5; 95% CrI, -5.8 to -1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, -1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS. Conclusions and Relevance: In this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores.

Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States.

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an ultra-rare progressive neurodegenerative disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes that lead to premature death, with most individuals dying between 10 and 25 years of age. NPC can present at any age and many individuals with NPC may be misdiagnosed or undiagnosed. A key challenge with recognizing NPC is the heterogeneous and nonspecific clinical presentation. Currently, there are no approved treatments for NPC in the United States; miglustat, an FDA-approved treatment for Gaucher disease, is used off-label for NPC and GM1 gangliosidosis. OBJECTIVES: To estimate the number of people in the United States that 1) have an NPC diagnosis 2) have an NPC diagnosis and/or are treated off-label with miglustat for NPC and 3) are likely to have NPC. METHODS: For the first two objectives, patients were identified using the Symphony Integrated DataVerse database (Oct 2015-Jan 2020). To identify the number of people with NPC for Objective 1, cases of NPC were defined as any patients with an ICD-10 code of E75.242 (NPC) during the study period. Objective 2 expands upon Objective 1, including (a) patients from Objective 1 and (b) patients with documented miglustat use (NDC 43975-0310 or 10,148-0201) who did not have any claim with Gaucher disease (ICD-10 E75.22) or GM1 gangliosidosis (ICD-10 E75.1) during the study period. For the third objective, published NPC incidence (1 per 89,000 live births) and expected mortality estimates were applied to the 2018 United States birth rate (11.6 per 1000) and population size (326.7 million). RESULTS: A total of 308 million unique individuals were represented in the database. Of these, 294 individuals had an NPC diagnosis, yielding an identified NPC prevalence of 0.95 per million people in the United States. 305 individuals were diagnosed with NPC and/or were treated with miglustat without having a diagnosis for either Gaucher or GM1 gangliosidosis, yielding an NPC diagnosed or treated prevalence of 0.99 per million people in the United States. Based on the published literature, there are an estimated 42 new NPC cases per year. Applying this number to the distribution of NPC type (based on age of neurologic symptom onset) and corresponding mortality estimates generates an estimated 943 prevalent cases of NPC, or 2.9 cases of NPC per million people in the United States. CONCLUSIONS: NPC is an ultra-rare, progressive neurodegenerative disease with approximately 1 per million people in the United States diagnosed with or treated off-label for NPC. Given that NPC is often misdiagnosed or undiagnosed, the estimated prevalence from the epidemiology calculations (2.9 per million) approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.

Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US.

BACKGROUND: Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA. OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US. METHODS: A de novo economic model was developed with the following health states: "permanent ventilation", "not sitting", "sitting", "walking", and "death". Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan-Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters. RESULTS: In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of $590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the "not sitting" and "sitting" health states. CONCLUSIONS: The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended.

Active learning for efficiently training emulators of computationally expensive mathematical models.

An emulator is a fast-to-evaluate statistical approximation of a detailed mathematical model (simulator). When used in lieu of simulators, emulators can expedite tasks that require many repeated evaluations, such as sensitivity analyses, policy optimization, model calibration, and value-of-information analyses. Emulators are developed using the output of simulators at specific input values (design points). Developing an emulator that closely approximates the simulator can require many design points, which becomes computationally expensive. We describe a self-terminating active learning algorithm to efficiently develop emulators tailored to a specific emulation task, and compare it with algorithms that optimize geometric criteria (random latin hypercube sampling and maximum projection designs) and other active learning algorithms (treed Gaussian Processes that optimize typical active learning criteria). We compared the algorithms' root mean square error (RMSE) and maximum absolute deviation from the simulator (MAX) for seven benchmark functions and in a prostate cancer screening model. In the empirical analyses, in simulators with greatly varying smoothness over the input domain, active learning algorithms resulted in emulators with smaller RMSE and MAX for the same number of design points. In all other cases, all algorithms performed comparably. The proposed algorithm attained satisfactory performance in all analyses, had smaller variability than the treed Gaussian Processes, and, on average, had similar or better performance as the treed Gaussian Processes in six out of seven benchmark functions and in the prostate cancer model.

Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis: A Systematic Review and Network Meta-analysis.

Importance: Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. Objective: To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. Study Selection: English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. Data Extraction and Synthesis: Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Main Outcomes and Measures: Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. Results: A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. Conclusions and Relevance: Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.

Propensity Score-Based Methods in Comparative Effectiveness Research on Coronary Artery Disease.

This review examines the conduct and reporting of observational studies using propensity score-based methods to compare coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or medical therapy for patients with coronary artery disease. A systematic selection process identified 48 studies: 20 addressing CABG versus PCI; 21 addressing bare-metal stents versus drug-eluting stents; 5 addressing CABG versus medical therapy; 1 addressing PCI versus medical therapy; and 1 addressing drug-eluting stents versus balloon angioplasty. Of 32 studies reporting information on variable selection, 7 relied exclusively on statistical criteria for the association of covariates with treatment, and 5 used such criteria to determine whether product or nonlinear terms should be included in the propensity score model. Twenty-five (52%) studies reported assessing covariate balance using the estimated propensity score, but only 1 described modifications to the propensity score model based on this assessment. The over 400 variables used in the 48 propensity score models were classified into 12 categories and 60 subcategories; only 17 subcategories were represented in at least half of the propensity score models. Overall, reporting of propensity score-based methods in observational studies comparing CABG, PCI, and medical therapy was incomplete; when adequately described, the methods used were often inconsistent with current methodological standards.

Advanced Age and Post-Acute Care Outcomes After Subarachnoid Hemorrhage.

BACKGROUND: Older patients with aneurysmal subarachnoid hemorrhage (aSAH) are unique, and determinants of post-acute care outcomes are not well elucidated. The primary objective was to identify hospital characteristics associated with 30-day readmission and mortality rates after hospital discharge among older patients with aSAH. METHODS AND RESULTS: This cohort study used Medicare patients ≥65 years discharged from US hospitals from January 1, 2008, to November 30, 2010, after aSAH. Medicare data were linked to American Hospital Association data to describe characteristics of hospitals treating these patients. Using multivariable logistic regression to adjust for patient characteristics, hospital factors associated with (1) hospital readmission and (2) mortality within 30 days after discharge were identified. A total of 5515 patients ≥65 years underwent surgical repair for aSAH in 431 hospitals. Readmission rate was 17%, and 8.5% of patients died within 30 days of discharge. In multivariable analyses, patients treated in hospitals with lower annualized aSAH volumes were more likely to be readmitted 30 days after discharge (lowest versus highest quintile, 1-2 versus 16-30 cases; adjusted odds ratio, 2.10; 95% confidence interval, 1.56-2.84). Patients treated in hospitals with lower annualized aSAH volumes (lowest versus highest quintile: adjusted odds ratio, 1.52; 95% confidence interval, 1.05-2.19) had a greater likelihood of dying 30 days after discharge. CONCLUSIONS: Older patients with aSAH discharged from hospitals treating lower volumes of such cases are at greater risk of readmission and dying within 30 days. These findings may guide clinician referrals, practice guidelines, and regulatory policies influencing which hospitals should care for older patients with aSAH.

Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture: a network meta-analysis.

OBJECTIVE: To compare the efficacy of bazedoxifene and oral bisphosphonates for the prevention of nonvertebral fractures (NVFs) in women with higher risk of postmenopausal osteoporosis (i.e., the Fracture Risk Assessment Tool [FRAX] score ≥ 20%), based on currently available evidence from randomized controlled trials. METHODS: Randomized controlled trials evaluating the NVF relative risk reduction (RRR) with oral bisphosphonates or bazedoxifene were identified by a systematic literature review and combined by means of a network meta-analysis. A subgroup of patients with a FRAX score of 20% or more in the bazedoxifene phase III osteoporosis study was selected as the population of interest on the basis of the bazedoxifene label. In one analysis (analysis 1), the placebo response of the subgroup with a FRAX score of 20% or more was the benchmark to select comparable bisphosphonate trials. Additional analyses incorporated the aggregate data from the bisphosphonate trials with all the FRAX subgroups (analysis 2) or with the individual patient data from the bazedoxifene trial (analysis 3). RESULTS: Nine identified bisphosphonate trials (alendronate, ibandronate, risedronate; N = 23,440 patients) with a similar placebo response as observed for the subgroup of high risk patients in the bazedoxifene trial were included in analysis 1. The results of the network meta-analysis of this study set suggest that bazedoxifene is expected to have an RRR of 0.43 (95% credible interval [CrI] -0.19 to 0.72) versus alendronate, 0.58 (95% CrI 0.05-0.81) versus ibandronate, and 0.39 (95% CrI -0.29 to 0.70) versus risedronate. Analyses in which treatment effects with bisphosphonates were projected to a population with a FRAX score of 20% or more with meta-regression approaches (analysis 2 and analysis 3) provide similar findings. CONCLUSION: Based on an indirect comparison of randomized trials, bazedoxifene is expected to have at least a comparable RRR of NVF as alendronate, ibandronate, and risedronate in women with higher risk of postmenopausal osteoporosis.

Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women.

OBJECTIVE: Compare the efficacy of bazedoxifene with oral bisphosphonates for reduction of vertebral fracture risk in postmenopausal osteoporotic (PMO) women and in higher-risk patients based on evidence from randomized controlled trials (RCTs). METHODS: Eight RCTs assessing vertebral fracture risk reduction with oral bisphosphonates (n = 7) or bazedoxifene (n = 1) were identified by a systematic literature review. Individual study results were pooled in a network meta-analysis (NMA) to indirectly compare treatment effects for overall PMO women and a higher-risk subgroup (FRAX ≥ 20%). Three sets of NMA analyses were conducted: aggregate data (AD) from the bisphosphonate RCTs and bazedoxifene RCT for the full population or the FRAX ≥20% subgroup (NMA AD); bisphosphonate AD and bazedoxifene AD from each FRAX subgroup adjusted for baseline risk (NMA AD meta-regression); and bisphosphonate AD and bazedoxifene individual patient data (IPD) adjusted for baseline risk/FRAX (NMA AD/IPD meta-regression). RESULTS: For the overall population, bisphosphonates had lower fracture risks versus bazedoxifene although there is considerable uncertainty in supporting one intervention over another. The relative risk reduction (RRR) for bazedoxifene was -0.23 (95% CrI: -1.11, 0.27) versus ibandronate, -0.17 (-0.76, 0.22) versus alendronate, and -0.06 (-0.62, 0.30) versus risedronate. RESULTS from the meta-regression analyses were similar. For the FRAX ≥20% population, estimated fracture rates with bazedoxifene were lower than with bisphosphonates, but again the uncertainty limits strong interpretation. The RRR for bazedoxifene was 0.51 (-0.31, 0.83) versus ibandronate, 0.53 (-0.18, 0.83) versus alendronate, and 0.57 (-0.07, 0.85) versus risedronate. The meta-regression analyses showed comparable findings. CONCLUSION: The analyses only considered vertebral fractures for oral bisphosphonates versus bazedoxifene, and IPD was available only for bazedoxifene. In light of this, bazedoxifene is comparable to bisphosphonates in the overall PMO population and at least as effective as bisphosphonates for preventing vertebral fractures among higher-risk PMO patients. The findings suggest bazedoxifene performs better in higher-risk PMO than in the overall PMO.