Handling Missing Data in Health Economics and Outcomes Research (HEOR): A Systematic Review and Practical Recommendations.

BACKGROUND: Missing data in costs and/or health outcomes and in confounding variables can create bias in the inference of health economics and outcomes research studies, which in turn can lead to inappropriate policies. Most of the literature focuses on handling missing data in randomized controlled trials, which are not necessarily always the data used in health economics and outcomes research. OBJECTIVES: We aimed to provide an overview on missing data issues and how to address incomplete data and report the findings of a systematic literature review of methods used to deal with missing data in health economics and outcomes research studies that focused on cost, utility, and patient-reported outcomes. METHODS: A systematic search of papers published in English language until the end of the year 2020 was carried out in PubMed. Studies using statistical methods to handle missing data for analyses of cost, utility, or patient-reported outcome data were included, as were reviews and guidance papers on handling missing data for those outcomes. The data extraction was conducted with a focus on the context of the study, the type of missing data, and the methods used to tackle missing data. RESULTS: From 1433 identified records, 40 papers were included. Thirteen studies were economic evaluations. Thirty studies used multiple imputation with 17 studies using multiple imputation by chained equation, while 15 studies used a complete-case analysis. Seventeen studies addressed missing cost data and 23 studies dealt with missing outcome data. Eleven studies reported a single method while 20 studies used multiple methods to address missing data. CONCLUSIONS: Several health economics and outcomes research studies did not offer a justification of their approach of handling missing data and some used only a single method without a sensitivity analysis. This systematic literature review highlights the importance of considering the missingness mechanism and including sensitivity analyses when planning, analyzing, and reporting health economics and outcomes research studies.

Meta-analysis of pazopanib and trabectedin effectiveness in previously treated metastatic synovial sarcoma (second-line setting and beyond).

Background: This study examined the efficacy/effectiveness of pazopanib and trabectedin in previously treated metastatic synovial sarcoma (mSS). Materials & methods: A literature search identified studies (2002-2019) reporting outcomes of pazopanib and trabectedin in previously treated mSS, including median overall survival (mOS) and overall response rate (ORR). A meta-analysis was conducted and sensitivity analyses examined outcomes by agent (pazopanib/trabectedin), study type (clinical trial [CT] or real-world [RW]) and sample size. Results: Sixteen studies were included (pazopanib: n = 7; trabectedin: n = 9). Pooled mOS was 10.4 months and was consistent across agents and in RW and CT (pazopanib: 10.3; trabectedin: 10.4; CT: 10.8; RW: 9.9). ORR results were more variable (pooled ORR: 14.7%). ORR was consistently higher for RW (17.7%) than for CT (9.5%) and for pazopanib (18.9%) compared with trabectedin (12.3%). Conclusion: Poor outcomes across agents and settings highlight a need for novel treatments with improved efficacy. This study serves as a benchmark for efficacy estimates in this rare disease.

Synovial sarcoma (SS) is a rare and aggressive type of soft tissue sarcoma. SS frequently spreads to other locations, referred to as metastatic SS (mSS) and is associated with a high death rate. Patients treated with first-line chemotherapy (1L setting), may need further lines of treatment (≥2L setting), which commonly involve the drugs pazopanib and trabectedin. This study assessed how well pazopanib and trabectedin work in people with ≥2L mSS, by examining both clinical trial (CT) and real-world (RW) studies. Overall, findings across 16 studies showed that mSS patients lived approximately 10 months after treatment with pazopanib or trabectedin in the ≥2L setting, and this was similar across both agents (10.3 months for pazopanib; 10.4 months for trabectedin) and between the CT (10.8 months) and the RW (9.9 months) settings. In terms of response to treatment, a higher percentage of people appeared to respond in RW settings (17.7%) than in CTs (9.5%), and to pazopanib (18.9%) compared with trabectedin (12.3%). These results show there is a need for better treatments for patients with previously treated mSS. These findings are useful benchmarks for the development of future treatment approaches for this rare disease.

Single-Inhaler Triple Therapy in Patients with Advanced COPD: Bayesian Modeling of the Healthcare Resource Utilization Data and Associated Costs from the IMPACT Trial.

Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting. Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs. Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals. Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.

Mepolizumab improves work productivity, activity limitation, symptoms, and rescue medication use in severe eosinophilic asthma.

Patients with severe eosinophilic asthma experience daily activity limitations and reduced productivity at work. Using anonymized individual patient-level data from two previously conducted randomized, double-blind, placebo-controlled studies (MENSA [GSK ID:115588/NCT01691521]; MUSCA [GSK ID:200862/NCT02281318]), we investigated the effect of mepolizumab on work productivity, activity limitation, symptoms, and rescue medication use. Patient-reported outcomes including Work Productivity and Activity Impairment-General Health (WPAI-GH) scores (impairment percentages, 0%-100%), global activity limitation (scale 1-4), and perceived change in activity limitation (Likert scale 1-7) since the start of the study were analyzed. WPAI-GH scores from MENSA were analyzed post hoc for employed patients using mixed model repeated measures; global activity limitation and perceived change in activity limitation from MUSCA were analyzed by ordinal logistic regression. Mean changes from baseline in daily asthma symptom scores (scale 0-5) and rescue medication use (occasions/day) were also assessed, via a post hoc meta-analysis of MENSA and MUSCA. At study end, WPAI-GH scores indicative of overall work impairment, impairment while working, and activity impairment consistently improved with mepolizumab versus placebo. Overall, 76% versus 54% of patients rated their activity as "much better," "better," or "slightly better" since the start of the study with mepolizumab versus placebo. Mepolizumab was associated with numerically larger improvements from baseline in asthma symptoms (treatment difference 0.21-0.29 points) and rescue medication use (treatment difference -0.08 to -0.22 occasions/day) versus placebo. Our results indicate that patients with severe eosinophilic asthma may experience improved activity limitation, work productivity, symptoms, and rescue medication use with mepolizumab.

Clinical characteristics and burden of illness among adolescent and adult patients with severe asthma by asthma control: the IDEAL study.

OBJECTIVES: Severe asthma (SA) can be uncontrolled despite guideline-directed treatment. We described SA characteristics and identified factors associated with uncontrolled disease and frequent exacerbations. METHODS: Post hoc analysis of the observational IDEAL study (201722/NCT02293265) included patients with SA aged ≥12 years receiving high-dose inhaled corticosteroids plus additional controller(s) for ≥12 months. Uncontrolled SA was defined by Asthma Control Questionnaire (ACQ)-5 scores ≥1.5 or ≥1 exacerbations (prior year), and further stratified by exacerbation frequency (no/infrequent [0-1] vs frequent [≥2]; prior year); associated factors were determined using multivariate logistic regression. RESULTS: Of 670 patients with SA, 540 (81%) were uncontrolled (ACQ-5 scores ≥1.5: 80%; ≥1 exacerbations [prior year]: 71%). Uncontrolled patients had lower lung function and worse health-related quality of life (HRQoL) than controlled patients; 197/540 (37%) experienced frequent exacerbations (prior year). Worse St George's Respiratory Questionnaire (SGRQ) total score, comorbid sinusitis, or eczema were significantly associated with uncontrolled SA; younger age, never smoker status, exacerbation requiring hospitalization (previous year), worse SGRQ symptom score, comorbid nasal polyps, COPD, or osteoporosis were significantly associated with uncontrolled SA with frequent exacerbations. CONCLUSIONS: In IDEAL, one-fifth of patients with SA were controlled, based on symptoms. Uncontrolled, exacerbating SA was associated with specific comorbidities, frequent exacerbations, a lower lung function, and compromised HRQoL, although inference from this analysis is limited by the selective cross-sectional nature of the cohort. Nonetheless, these data highlight the need for more effective precision treatments in this population.

Treatment Preferences of Patients with Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups in the United Kingdom, United States, and Germany.

BACKGROUND: A wide range of therapeutic regimens, including single-inhaler triple therapies (SITTs), are now available for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Thus, an improved understanding of patient preferences may be valuable to inform physician prescribing decisions. This study was performed to assess the factors considered by patients when making decisions about their COPD treatments using qualitative techniques. METHODS: In the United Kingdom, United States and Germany, individual qualitative interviews (n=10 per country) and focus groups (1 per country; [United Kingdom, n=4; United States, n=6; Germany, n=6 participants]) were conducted. Interviews and focus groups were semi­structured, lasting approximately 60 minutes, and focused on treatment preferences. Data were analyzed according to emerging themes identified from the interviews; qualitative thematic analysis of the data was performed using specialist software. RESULTS: In interviews and focus groups, efficacy, ease of use, and lower frequency of use were favored attributes for current treatment, while side effects, medication taste, and more complex administration techniques were key dislikes. In interviews, most participants would consider a switch in medication, mainly for improved efficacy, but also to reduce medication frequency or following physician advice. Overall, efficacy and ease of use were the 2 most important attributes reported in interviews in all 3 countries. CONCLUSION: Patients with COPD have preferences for certain attributes of medication, highlighting the multi-faceted nature of treatment effectiveness and the importance of the delivery device.These results were subsequently used to inform the design of a discrete choice experiment.

Evaluating Patient Preferences of Maintenance Therapy for the Treatment of Chronic Obstructive Pulmonary Disease: A Discrete Choice Experiment in the UK, USA and Germany.

Introduction: With increasing availability of different treatments for chronic obstructive pulmonary disease (COPD), we sought to understand patient preferences for COPD treatment in the UK, USA, and Germany using a discrete choice experiment (DCE). Methods: Qualitative research identified six attributes associated with COPD maintenance treatments: ease of inhaler use, exacerbation frequency, frequency of inhaler use, number of different inhalers used, side effect frequency, and out-of-pocket costs. A DCE using these attributes, with three levels each, was designed and tested through cognitive interviews and piloting. It comprised 18 choice sets, selected using a D-efficient experimental design. Demographics and disease history were collected and the final DCE survey was completed online by participants recruited from panels in the UK, USA and Germany. Responses were analyzed using mixed logit models, with results expressed as odds ratios (ORs). Results: Overall, 450 participants (150 per country) completed the DCE; most (UK and Germany, 97.3%; USA, 98.0%) were included in the final analysis. Based on relative attribute importance, avoidance of side effects was found to be most important (UK: OR 11.65; USA: OR 7.17; Germany: OR 11.45; all p<0.0001), followed by the likelihood of fewer exacerbations (UK: OR 2.22; USA: OR 1.63; Germany: OR 2.54; all p<0.0001) and increased ease of use (UK: OR 1.84; USA: OR 1.84; Germany: OR 1.60; all p<0.0001). Number of inhalers, out-of-pocket costs, and frequency of inhaler use were found to be less important. Preferences were relatively consistent across the three countries. All participants required a reduction in exacerbations to accept more frequent inhaler use or use of more inhalers. Conclusion: When selecting COPD treatment, individuals assigned the highest value to the avoidance of side effects, experiencing fewer exacerbations, and ease of inhaler use. Ensuring that patients' preferences are considered may encourage treatment compliance.

Impact of exacerbations on St George's Respiratory Questionnaire score in patients with severe asthma: post hoc analyses of two clinical trials and an observational study.

Objective: To assess the effect of asthma exacerbations and mepolizumab treatment on health status of patients with severe asthma using the St George's Respiratory Questionnaire (SGRQ).Methods: Post hoc analyses were conducted using data from two randomized controlled trials in patients ≥12 years old with severe eosinophilic asthma randomized to receive placebo or mepolizumab 75 mg intravenously (32-week MENSA study) or 100 mg subcutaneously (MENSA/24-week MUSCA studies), and an observational single-visit study in patients with severe asthma (IDEAL). Linear regression models assessed the impact of historical exacerbations on baseline SGRQ total and domain scores (using data from each of the three studies), and within-study severe exacerbations and mepolizumab treatment on end-of-study SGRQ scores (using data from MENSA/MUSCA).Results: Overall, 1755 patients were included (MENSA, N = 540; MUSCA, N = 551; IDEAL, N = 664). In all studies, higher numbers of historical exacerbations were associated with worse baseline SGRQ total scores. Each additional historical exacerbation (beyond the second [MENSA/MUSCA]) or first [IDEAL] was associated with worsening mean total SGRQ scores of +1.5, +1.1 at baseline and +2.3 within the year prior to study enrollment. During MENSA and MUSCA, each within-study severe exacerbation was associated with a worsening in total SGRQ score of +2.4 and +3.4 points at study end. Independent of exacerbation reduction, mepolizumab accounted for an improvement in total SGRQ score of -5.3 points (MENSA) and -6.2 points (MUSCA).Conclusions: These findings support an association between a higher number of exacerbations and worse health status in patients with severe (eosinophilic) asthma.

Long-term cost and utility consequences of short-term clinically important deterioration in patients with chronic obstructive pulmonary disease: results from the TORCH study.

Purpose: Clinically important deterioration (CID) in chronic obstructive pulmonary disease (COPD) is a novel composite endpoint that assesses disease stability. The association between short-term CID and future economic and quality of life (QoL) outcomes has not been previously assessed. This analysis considers 3-year data from the TOwards a Revolution in COPD Health (TORCH) study, to examine this question. Patients and methods: This post hoc analysis of TORCH (NCT00268216) compared costs and utilities at 3 years among patients without CID (CID-) and with CID (CID+) at 24 weeks. A positive CID status was defined as either: a deterioration in forced expiratory volume in 1 second (FEV1) of ≥100 mL from baseline; or a ≥4-unit increase from baseline in St George's Respiratory Questionnaire (SGRQ) total score; or the incidence of a moderate/severe exacerbation. Patients from all treatment arms were included. Utility change was based on the EQ-5D utility index. Costs were based on healthcare resource utilization from 24 weeks to end of follow-up combined with unit costs for the UK (2016 GBP), and reported as per patient per year (PPPY). Adjusted estimates were generated controlling for baseline characteristics, treatment assignment, and number of CID criteria met. Results: Overall, 3,769 patients completed the study and were included in the analysis (stable CID- patients, n=1,832; unstable CID+ patients, n=1,937). At the end of follow-up, CID- patients had higher mean (95% confidence interval [CI]) utility scores than CID+ patients (0.752 [0.738, 0.765] vs 0.697 [0.685, 0.71]; difference +0.054; P<0.001), and lower costs PPPY (£538 vs £916; difference: £378 [95% CI: £244, £521]; P<0.001). The cost differential was primarily driven by the difference in general hospital ward days (P=0.003). Conclusion: This study demonstrated that achieving early stability in COPD by preventing short-term CID is associated with better preservation of future QoL alongside reduced healthcare service costs.

Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison.

BACKGROUND: Three anti-IL-5 pathway-directed therapies are approved for use in patients with severe eosinophilic asthma (SEA); however, no head-to-head comparison data are available. OBJECTIVE: We sought to compare the efficacy of licensed doses of mepolizumab, benralizumab, and reslizumab in patients with SEA, according to baseline blood eosinophil counts. METHODS: This indirect treatment comparison (ITC) used data from a Cochrane review and independent searches. Eligible studies were randomized controlled trials in patients aged 12 years or greater with SEA. End points included annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire score and FEV1. An ITC was performed in patients with Asthma Control Questionnaire scores of 1.5 or greater and stratified by baseline blood eosinophil count. RESULTS: Eleven studies were included. All treatments significantly reduced the rate of clinically significant exacerbations and improved asthma control versus placebo in all blood eosinophil count subgroups. Mepolizumab reduced clinically significant exacerbations by 34% to 45% versus benralizumab across subgroups (rate ratio ≥400 cells/µL: 0.55 [95% CI, 0.35-0.87]; ≥300 cells/µL: 0.61 [95% CI, 0.37-0.99]; and ≥150 cells/µL: 0.66 [95% CI, 0.49-0.89]; all P < .05) and by 45% versus reslizumab in the 400 cells/µL or greater subgroup (rate ratio, 0.55 [95% CI, 0.36-0.85]; P = .007). Asthma control was significantly improved with mepolizumab versus benralizumab (all subgroups: P < .05) and versus reslizumab in the 400 cells/µL or greater subgroup (P = .004). Benralizumab significantly improved lung function versus reslizumab in the 400 cells/µL or greater subgroup (P = .025). CONCLUSIONS: This ITC of the licensed doses suggests that mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts.

Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma.

BACKGROUND: Limited data describe the association between the frequency of asthma exacerbations and the decline in lung function in severe asthma. OBJECTIVE: To determine whether asthma exacerbations are associated with enhanced decline in lung function. METHODS: Changes in lung function were analyzed retrospectively using data from the DREAM and MENSA studies of mepolizumab intervention in patients with severe asthma. Patients were either nonsmokers or former smokers. A linear regression model was used to analyze the relationship between the number of exacerbations and decline in FEV1 across treatment groups. RESULTS: In a combined post hoc analysis, 57% (n = 572) of patients had no exacerbations and experienced an improvement in postbronchodilator FEV1 of 143 mL. In contrast, in patients who experienced 3 or more exacerbations, there was a decrease in postbronchodilator FEV1 of 77 mL in the combined analysis. The linear modeling analysis estimated that for each exacerbation seen during the observational period, there was a decrease of 50 mL in FEV1 (P < .001). CONCLUSIONS: A direct relationship between the number of exacerbations in patients with severe eosinophilic asthma and decline in lung function was observed. Repeated exacerbations may be associated with accelerated loss of lung function.

Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma.

BACKGROUND: Mepolizumab significantly reduces exacerbations in patients with severe eosinophilic asthma. The early identification of patients likely to receive long-term benefit from treatment could ensure effective resource allocation. OBJECTIVE: To assess potential continuation rules for mepolizumab in addition to initiation criteria defined as 2 or more exacerbations in the previous year and blood eosinophil counts of 150 cells/µL or more at initiation or 300 cells/µL or more in the previous year. METHODS: This post hoc analysis included data from 2 randomized, double-blind, placebo-controlled studies (NCT01000506 and NCT01691521) of mepolizumab in patients with severe eosinophilic asthma (N = 1,192). Rules based on blood eosinophils, physician-rated response to treatment, FEV1, Asthma Control Questionnaire (ACQ-5) score, and exacerbation reduction were assessed at week 16. To assess these rules, 2 key metrics accounting for the effects observed in the placebo arm were developed. RESULTS: Patients not meeting continuation rules based on physician-rated response, FEV1, and the ACQ-5 score still derived long-term benefit from mepolizumab. Nearly all patients failing to reduce blood eosinophils had counts of 150 cells/µL or less at baseline. For exacerbations, assessment after 16 weeks was potentially premature for predicting future exacerbations. CONCLUSION: There was no evidence of a reliable physician-rated response, ACQ-5 score, or lung function-based continuation rule. The added value of changes in blood eosinophils at week 16 over baseline was marginal. Initiation criteria for mepolizumab treatment provide the best method for assessing patient benefit from mepolizumab treatment, and treatment continuation should be reviewed on the basis of a predefined reduction in long-term exacerbation frequency and/or oral corticosteroid dose.

Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study.

OBJECTIVES: Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. METHODS: This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. RESULTS: The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31-41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7-21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27-37% were omalizumab-eligible and 18% were reslizumab-eligible. CONCLUSIONS: Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Comparative effectiveness of mepolizumab and omalizumab in severe asthma: An indirect treatment comparison.

BACKGROUND: Severe asthma is a heterogeneous disease. Patients with both eosinophilic and allergic asthma phenotypes may be eligible for treatment with mepolizumab and omalizumab. Evidence on the relative effectiveness of these treatments in this 'overlap' population would be informative for clinical and payer decision making. METHODS: A systematic literature review and indirect treatment comparison (Bayesian framework) were performed to assess the comparative effectiveness and tolerability of mepolizumab and omalizumab, as add-ons to standard of care. Studies included in the primary analysis were double-blind, randomized controlled trials, ≥12 weeks' duration enrolling patients with severe asthma with a documented exacerbation history and receiving high-dose inhaled corticosteroids plus ≥1 additional controller. Two populations were examined: patients potentially eligible for 1) both treatments (Overlap population) and 2) either treatment (Trial population). RESULTS: In the Overlap population, no differences between treatments in clinically significant exacerbations and exacerbations requiring hospitalization were found, although trends favored mepolizumab (rate ratio [RR]:0.66 [95% credible intervals (Crl):0.37,1.19]; 0.19[0.02,2.32], respectively). In the Trial population, mepolizumab treatment produced greater reductions in clinically significant exacerbations (RR:0.63 [95% CrI:0.45,0.89]) but not exacerbations requiring hospitalization compared with omalizumab (RR:0.58 [95% Crl: 0.16,2.13]), although the trend favored mepolizumab. Both treatments had broadly comparable effects on lung function, and similar tolerability profiles. CONCLUSIONS: Whilst this analysis has limitations due to a restricted evidence base and residual heterogeneity, it showed that in patients with severe asthma, mepolizumab seems to be at least as effective as omalizumab and that the tolerability profiles of the two treatments did not meaningfully differentiate.

Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma.

BACKGROUND: Studies show that mepolizumab can reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, compared with placebo. However, important events such as hospitalizations and emergency room visits are rare and difficult to characterize in single studies. OBJECTIVE: We sought to compare hospitalization or hospitalization and/or emergency room visit rates in patients with severe eosinophilic asthma treated with mepolizumab or placebo in addition to standard of care for at least 24 weeks. METHODS: This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. PubMed and the GSK Clinical Study Register were searched for suitable studies. The primary end points were the rate of exacerbations requiring hospitalization and the rate of exacerbations requiring hospitalization/emergency room visit. The proportion of patients with 1 or more event was also assessed. All mepolizumab doses were combined and individual patient-level data were analyzed. RESULTS: Four studies (n = 1388) were eligible for inclusion. Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30-0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33-0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively. CONCLUSIONS: Mepolizumab approximately halved exacerbations requiring hospitalization and/or emergency room visits compared with placebo in patients with severe eosinophilic asthma. This treatment addresses a key outcome in a patient population with a high unmet need (GSK Study 204664).

Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.

BACKGROUND: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds. METHODS: We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab ( DREAM: 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per µL, ≥300 cells per µL, ≥400 cells per µL, and ≥500 cells per µL) and baseline blood eosinophil ranges (<150 cells per µL, ≥150 cells per µL to <300 cells per µL, ≥300 cells per µL to <500 cells per µL, and ≥500 cells per µL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis. FINDINGS: Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per µL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per µL. At a baseline count less than 150 cells per µL, predicted efficacy of mepolizumab was reduced. INTERPRETATION: Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per µL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab. FUNDING: GlaxoSmithKline.

Modelling the overdiagnosis of breast cancer due to mammography screening in women aged 40 to 49 in the United Kingdom.

INTRODUCTION: Overdiagnosis of breast cancer due to mammography screening, defined as the diagnosis of screen-detected cancers that would not have presented clinically in a women's lifetime in the absence of screening, has emerged as a highly contentious issue, as harm caused may question the benefit of mammographic screening. Most studies included women over 50 years old and little information is available for younger women. METHODS: We estimated the overdiagnosis of breast cancer due to screening in women aged 40 to 49 years using data from a randomised trial of annual mammographic screening starting at age 40 conducted in the UK. A six-state Markov model was constructed to estimate the sensitivity of mammography for invasive and in situ breast cancer and the screen-detectable mean sojourn time for non-progressive in situ, progressive in situ, and invasive breast cancer. Then, a 10-state simulation model of cancer progression, screening, and death, was developed to estimate overdiagnosis attributable to screening. RESULTS: The sensitivity of mammography for invasive and in situ breast cancers was 90% (95% CI, 72 to 99) and 82% (43 to 99), respectively. The screen-detectable mean sojourn time of preclinical non-progressive and progressive in situ cancers was 1.3 (0.4 to 3.4) and 0.11 (0.05 to 0.19) years, respectively, and 0.8 years (0.6 to 1.2) for preclinical invasive breast cancer. The proportion of screen-detected in situ cancers that were non-progressive was 55% (25 to 77) for the first and 40% (22 to 60) for subsequent screens. In our main analysis, overdiagnosis was estimated as 0.7% of screen-detected cancers. A sensitivity analysis, covering a wide range of alternative scenarios, yielded a range of 0.5% to 2.9%. CONCLUSION: Although a high proportion of screen-detected in situ cancers were non-progressive, a majority of these would have presented clinically in the absence of screening. The extent of overdiagnosis due to screening in women aged 40 to 49 was small. Results also suggest annual screening is most suitable for women aged 40 to 49 in the United Kingdom due to short cancer sojourn times.