Factors leading to discontinuation of biologic therapy in patients with severe asthma.

OBJECTIVE: To assess patient- and physician-reported reasons for discontinuing biologic therapy among patients with severe asthma from a real-world US cohort. METHODS: This retrospective analysis surveyed US physicians and their patients with severe asthma who were receiving/had previously received biologic therapy between August and December 2019. Physicians managing ≥3 patients with asthma per month completed surveys on disease management, demographics, exacerbation history, and biologic adherence for eligible patients. Patients could voluntarily complete a questionnaire, providing perceptions of their disease and treatment. RESULTS: 117 physicians completed case reports for 285 patients; 85 patients had discontinued biologic therapy. Physicians (n = 85) and patients (n = 64) reported patient request (28.2% and 46.9%), shortness of breath (45.9% and 23.4%), other chronic respiratory symptoms (29.4% and 10.9%), cost/reimbursement (17.7%/9.4% and 20.3%/7.8%), and exacerbations (25.9% and 10.9%) among the main reasons for biologic discontinuation. Patients who continued biologic therapy were older (mean age 47.6 years) than those who discontinued (43.8 years), and were more likely to have ≥2 exacerbations in the previous year (52.5% vs 35.3%), allergic rhinitis (70.0% vs 62.4%), or chronic rhinosinusitis (30.0% vs 12.9%). Side effects were cited as reasons by only 15.3% and 7.8% of physicians and patients, respectively. CONCLUSIONS: The most common reasons given for discontinuation of biologic therapy were lack of symptom control, exacerbations, cost, and patient request. These data highlight the complexity of care for this patient group and the need for ongoing, regular assessment of common challenges to biologic continuation and reasons for discontinuation, including both clinical and non-clinical factors.

Time-to-first exacerbation, adherence, and medical costs among US patients receiving umeclidinium/vilanterol or tiotropium as initial maintenance therapy for chronic obstructive pulmonary disease: a retrospective cohort study.

BACKGROUND: Adherence to chronic obstructive pulmonary disease (COPD) maintenance medication is important for managing symptoms and exacerbation risk, and is associated with reduced mortality, hospitalizations, and costs. This study compared on-treatment exacerbations, medical costs, and medication adherence in patients with COPD initiating treatment with umeclidinium/vilanterol (UMEC/VI) or tiotropium (TIO). METHODS: This retrospective matched cohort study selected patients from Optum's de-identified Clinformatics Data Mart database who initiated maintenance treatment with UMEC/VI or TIO between 01/01/2014 and 12/31/2017 (index date defined as the first dispensing). Eligible patients were ≥ 40 years of age and had ≥ 12 months continuous health plan coverage pre- and post-index; ≥ 1 medical claim for COPD pre-index or on the index date; no moderate/severe COPD-related exacerbations on the index date; no asthma diagnosis pre- or post-index; no maintenance medication fills containing inhaled corticosteroids, long-acting ß2-agonists, or long-acting muscarinic antagonists pre-index or on the index date; and no fills for both UMEC/VI and TIO on the index date. Outcomes included time-to-first (Kaplan-Meier analysis) and rates of on-treatment COPD-related moderate/severe exacerbations, medication adherence (proportion of days covered [PDC] and proportion of adherent patients [PDC ≥ 0.8]), and COPD-related medical costs per patient per month (PPPM). Propensity score matching was used to adjust for potential confounders. RESULTS: Each cohort included 3929 matched patients. Kaplan-Meier rates of on-treatment COPD-related exacerbations were similar between cohorts (hazard ratio at 12 months; overall: 0.93, moderate: 0.92, severe: 1.07; all p > 0.05). UMEC/VI versus TIO initiators had significantly higher adherence (mean PDC: 0.44 vs 0.37; p < 0.001; proportion with PDC ≥ 0.8: 22.0% vs 16.4%; p< 0.001) and significantly lower mean on-treatment COPD-related total medical costs ($867 vs $1095 PPPM; p = 0.028), driven by lower outpatient visit costs. CONCLUSIONS: These findings provide valuable information for physicians considering UMEC/VI or TIO as initial maintenance therapy options for patients with COPD.

Umeclidinium/Vilanterol Compared with Fluticasone Propionate/Salmeterol, Budesonide/Formoterol, and Tiotropium as Initial Maintenance Therapy in Patients with COPD Who Have High Costs and Comorbidities.

BACKGROUND: Comorbidities in patients with chronic obstructive pulmonary disease (COPD) are associated with increased medical costs and risk of exacerbations. This study compared COPD-related medical costs and exacerbations in high-cost, high-comorbidity patients with COPD receiving initial maintenance treatment (IMT) with umeclidinium/vilanterol (UMEC/VI) versus fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (B/F), or tiotropium (TIO). METHODS: This retrospective, matched cohort study identified patients from Optum's de-identified Clinformatics Data Mart database who initiated UMEC/VI, FP/SAL, B/F, or TIO between January 1, 2014 and December 31, 2018 (index date defined as date of the first fill). Eligibility criteria included age ≥40 years at index, ≥1 pre-index COPD diagnosis, no pre-index asthma diagnosis, 12 months of continuous insurance coverage pre-index, and high pre-index costs (≥80th percentile of IMT population) and comorbidities (Quan-Charlson comorbidity index ≥3). Propensity score matching was used to control for potential confounders. On-treatment COPD-related medical costs (primary endpoint) and exacerbations were evaluated. RESULTS: Matched cohorts were well balanced on baseline characteristics (UMEC/VI vs FP/SAL: n=1194 each; UMEC/VI vs B/F: n=1441 each; UMEC/VI vs TIO: n=1277 each). Patients receiving UMEC/VI had significantly lower COPD-related medical costs versus FP/SAL (difference: $6587 per patient per year; P=0.048), and numerically lower costs versus B/F and TIO. Patients initiating UMEC/VI had significantly lower risk of COPD-related severe exacerbation versus FP/SAL (hazard ratio [95% CI]: 0.78 [0.62, 0.98]; P=0.032), B/F (0.77 [0.63, 0.95]; P=0.016), and TIO (0.79 [0.64, 0.98]; P=0.028). The rate of COPD-related severe exacerbations was significantly lower with UMEC/VI versus FP/SAL (rate ratio [95% CI]: 0.73 [0.59, 0.91]; P=0.008) and B/F (0.73 [0.59, 0.93]; P=0.012), and numerically lower versus TIO (0.83 [0.68, 1.04]; P=0.080). CONCLUSION: These findings suggest that high-cost, high-comorbidity patients with COPD receiving UMEC/VI compared with FP/SAL, B/F, and TIO as IMT may have lower medical costs and exacerbation risk.

Hospital Admission and Readmission Among US Patients Receiving Umeclidinium/Vilanterol or Tiotropium as Initial Maintenance Therapy for Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations are at risk of further readmissions, increased treatment costs, and excess mortality. This study evaluated inpatient admissions and readmissions in patients receiving initial maintenance therapy with umeclidinium/vilanterol (UMEC/VI) versus tiotropium (TIO). METHODS: This retrospective, matched cohort study identified patients with COPD who initiated maintenance therapy with UMEC/VI or TIO from Optum's de-identified Clinformatics Data Mart database between January 1, 2013, and December 31, 2018 (index date defined as earliest dispensing). Eligibility criteria included: ≥ 1 medical claim for COPD pre-index or on the index date; ≥ 12 months of continuous eligibility pre-index; age ≥ 40 years at index; no pre- or post-index asthma diagnosis; and no pre-index claims for medications containing inhaled corticosteroids, long-acting ß2-agonists, or long-acting muscarinic antagonists. Outcomes included time to first on-treatment COPD-related inpatient admission, rate of on-treatment COPD-related admissions, and rate of all-cause and COPD-related readmissions within 30 and 90 days. Propensity score matching was used to adjust for potential confounders. RESULTS: Matched UMEC/VI and TIO cohorts each included 7997 patients and were balanced on baseline characteristics (mean age 70.9 years; female 47.1-47.6%). Over 12 months, patients initiating UMEC/VI had significantly reduced risk (hazard ratio [95% CI]: 0.87 [0.79, 0.96]; p = 0.006) and rates (rate ratio [95% CI]: 0.80 [0.72, 0.92]; p = 0.008) of COPD-related inpatient admissions compared with TIO. While all-cause readmission rates were similar between treatment cohorts, readmission rates among patients with an initial admission length of stay of 1-3 days were numerically lower for UMEC/VI versus TIO (30-day readmissions: 10.5% vs. 12.4%; 90-day readmissions: 15.5% vs. 19.8%). Similar patterns were observed for COPD-related readmissions. CONCLUSIONS: These findings highlight the real-world benefits of dual therapy with UMEC/VI versus TIO in reducing inpatient admissions and readmissions in patients with COPD, which may translate to lower healthcare costs.

Patients with chronic obstructive pulmonary disease (COPD) who are admitted to the hospital are more likely to be readmitted in the future, have higher healthcare costs, and are more likely to die from their illness. Patients who are readmitted to hospital have even higher treatment costs. Identifying which treatments are best at reducing the number of patients with COPD who are admitted to the hospital may help to improve outcomes and reduce the cost of COPD treatment. We used US healthcare claims data to compare two daily treatments for COPD, umeclidinium/vilanterol and tiotropium. We aimed to find out which treatment was more effective at reducing hospital admissions due to COPD. We also compared how many patients on each treatment were readmitted within 30 or 90 days of their original hospital admission for COPD. We found that patients who started treatment with umeclidinium/vilanterol were less likely to be admitted to the hospital for COPD than patients who started treatment with tiotropium. Similar numbers of patients on each treatment were readmitted to the hospital within 30 or 90 days after they were discharged. However, among patients whose initial hospital stay was short (1­3 days), readmissions within 30 or 90 days were less common with umeclidinium/vilanterol than tiotropium. These findings suggest that umeclidinium/vilanterol may be more effective than tiotropium at reducing the number of patients with COPD who need to be admitted or readmitted to hospital. Starting COPD treatment with umeclidinium/vilanterol may lead to better health outcomes and lower costs than tiotropium.

Symptom Burden and GOLD Classification in Medicare Advantage Patients with COPD Initiating Umeclidinium/Vilanterol or Fluticasone Propionate/Salmeterol Therapy.

Background: Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) provide greater improvements in lung function and symptoms than inhaled corticosteroid (ICS)/LABA in patients with chronic obstructive pulmonary disease (COPD). This study evaluated symptom burden and Global Initiative for Obstructive Lung Disease (GOLD) categorization among patients who recently initiated umeclidinium/vilanterol (UMEC/VI; LAMA/LABA) or fluticasone propionate/salmeterol (FP/SAL; ICS/LABA) single-inhaler dual therapy. Methods: COPD-diagnosed Medicare Advantage enrollees aged ≥65 years were identified from the Optum Research Database (ORD). Eligible patients had ≥1 pharmacy claim for UMEC/VI or FP/SAL in the 6-month period before sample identification, with no evidence of triple therapy (ICS/LAMA/LABA), asthma, or lung cancer. Symptom burden was assessed via cross-sectional surveys using the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Patients were classified into GOLD categories using patient-reported symptoms and claims-based exacerbation history. Treatment groups were balanced on potential confounders using inverse probability of treatment weighting (IPTW). CAT and mMRC scores were analyzed with generalized linear regression models using IPTW propensity scores. Results: The final analytic sample included 789 respondents (UMEC/VI: N=392; FP/SAL: N=397). Approximately 66% patients were classified as GOLD B when assessing symptoms with CAT and mMRC together, or CAT alone; more patients were classified as GOLD A (~40%) than GOLD B (~36%) using mMRC alone. Proportions of patients in each GOLD group were similar between treatment cohorts. Post-IPTW multivariable modeling showed similar symptom burden between treatment groups. Conclusion: After controlling for baseline characteristics, symptom burden was similar between patients receiving UMEC/VI or FP/SAL. GOLD classification using mMRC produced more conservative results compared with CAT, potentially underestimating patient symptoms. Many patients receiving FP/SAL were classified as GOLD A or B, despite GOLD recommending non-ICS-containing therapy in these patients. These findings support the need for routine assessment of symptoms in patients with COPD.

Evaluation of Medication Adherence and Rescue Medication Use in Non-Exacerbating Patients with COPD Receiving Umeclidinium/Vilanterol or Budesonide/Formoterol as Initial Maintenance Therapy.

Background: Adherence to inhaled maintenance therapy is critical to managing chronic obstructive pulmonary disease (COPD), while increasing rescue medication usage may indicate worsening symptoms. This study evaluated adherence and rescue medication use in patients with COPD without a history of exacerbation who initiated combination therapy with budesonide/formoterol (B/F) or umeclidinium/vilanterol (UMEC/VI). Methods: Retrospective observational study of commercially insured and Medicare Advantage with Part D enrollees who initiated UMEC/VI or B/F between January 1, 2014 and December 31, 2017 (earliest fill defined as index date). Eligibility criteria included age ≥40 years, 12 months continuous enrollment pre- and post-index, ≥1 pre-index COPD diagnosis, no pre-index asthma diagnosis, COPD-related exacerbations, or medication fills containing inhaled corticosteroids, long-acting ß2-agonists, or long-acting muscarinic antagonists. Inverse probability of treatment weighting (IPTW) was used to balance treatment groups on potential confounders. Medication adherence (primary endpoint) was evaluated by the proportion of days covered (PDC). Rescue medication use (secondary endpoint) was standardized to canister equivalents (1 metered dose inhaler [200 puffs] or ~100 nebulized doses of short-acting ß2-agonist- and/or short-acting muscarinic agonist-containing medication). Results: After IPTW, covariates were balanced between cohorts (UMEC/VI: N=4082; B/F: N=9529). UMEC/VI initiators had a significantly greater mean PDC (UMEC/VI: 0.47 [0.33]; B/F: 0.38 [0.30]; P<0.001) and significantly higher rates of adherence (PDC≥0.80) than B/F initiators (UMEC/VI: n=1004 [25%], B/F: n=1391 [15%]; relative risk: 1.68, 95% CI: 1.57, 1.81; P<0.001). In the year following initiation, UMEC/VI initiators filled significantly fewer rescue medication canister equivalents than B/F initiators (predicted mean [95% CI]: 1.78 [1.69, 1.88] vs 2.15 [2.08, 2.23]; mean difference [95% CI]: -0.37 [-0.50, -0.24]; P<0.001), corresponding to 17% less (estimated) rescue medication use (incidence rate ratio [95% CI]: 0.83 [0.78, 0.88]). Conclusion: Among non-exacerbating patients with COPD initiating dual therapy, UMEC/VI demonstrated improved adherence and reduced rescue medication use compared with B/F.

Real-world effectiveness of umeclidinium/vilanterol versus fluticasone propionate/salmeterol as initial maintenance therapy for chronic obstructive pulmonary disease (COPD): a retrospective cohort study.

Background and objective: Retrospective claims data in patients with chronic obstructive pulmonary disease (COPD) initiating maintenance therapy with inhaled fixed-dose combinations of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) versus inhaled corticosteroid (ICS)/LABA have not been reported. Methods: Retrospective observational study in a COPD-diagnosed population of commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years from a US health insurer database. Patients initiated umeclidinium/vilanterol (UMEC/VI [62.5/25 µg]) or fluticasone propionate/salmeterol (FP/SAL [250/50 µg]) between April 1, 2014 and August 31, 2016 (index date) and had 12 months continuous enrollment pre- and post-index. Exclusion criteria included an asthma diagnosis in the pre-index period/index date; ICS-, LABA-, or LAMA-containing therapy during the pre-index period; or pharmacy fills for both UMEC/VI and FP/SAL, multiple-inhaler triple therapy, a non-index therapy, or COPD exacerbation on the index date. Adherence (proportion of days covered [PDC] ≥80%) was modeled using weighted logistic regression following inverse probability of treatment weighting (IPTW). Weighted Kaplan-Meier and Cox proportional hazards regression following IPTW were performed for incidence of COPD exacerbation and escalation to multiple-inhaler triple therapy. Results: The study population included 5306 patients (1386 initiating UMEC/VI and 3920 initiating FP/SAL). Adjusted odds of adherence were 2.00 times greater among UMEC/VI than FP/SAL initiators (95% confidence interval [CI]: 1.62─2.46; P<0.001). The adjusted hazard ratio (HR) for first exacerbation was 0.87 (95% CI: 0.74-1.01; P=0.067) among UMEC/VI versus FP/SAL initiators. UMEC/VI initiators had 35% lower adjusted risk of escalation to multiple-inhaler triple therapy (HR 0.65; 95% CI: 0.47-0.89; P=0.008) versus FP/SAL. On-treatment, UMEC/VI initiators had an adjusted 30% reduced risk of a first moderate/severe COPD exacerbation (HR 0.70; 95% CI: 0.54-0.90; P=0.006). Conclusion: Patients with COPD initiating UMEC/VI had higher adherence and longer time before escalation to multiple-inhaler triple therapy than FP/SAL initiators.

Systematic literature review and meta-analysis of US-approved LAMA/LABA therapies versus tiotropium in moderate-to-severe COPD.

Dual bronchodilator maintenance therapy may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) versus long-acting muscarinic antagonist (LAMA) monotherapy. The efficacy and safety of US-approved LAMA/long-acting beta-agonist (LABA) combinations versus tiotropium (TIO), a LAMA, were assessed. This systematic review and meta-analysis (GSK: 206938), conducted in MEDLINE, MEDLINE In-process, and EMBASE following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, identified randomized clinical trials (>8 weeks) in moderate-to-severe COPD (per Global Initiative for Chronic Obstructive Lung Disease guidelines), receiving LAMA/LABA or TIO. ENDPOINTS: difference in change from baseline in lung function (forced expiratory volume in 1 s [FEV1]; trough, peak, area under the curve 0-3 h post-dose (AUC0-3), St George's Respiratory Questionnaire (SGRQ) responder rate (≥4-unit improvement), SGRQ total score, and rescue medication use at 12 and 24 weeks. Safety was also assessed. From 5683 citations, the meta-analysis included eight clinical trials. LAMA/LABA significantly improved FEV1 trough (Week 12: 63.0 mL, 95% confidence intervals [CI]: 39.2, 86.8; Week 24: 66.1 mL, 95% CI: 40.0, 92.3), peak (Week 12: 91.5 mL, 95% CI: 70.5, 112.4; Week 24: 92.4 mL, 95% CI: 72.9, 111.9), AUC0-3 (Week 12: 126.8 mL, 95% CI: 108.1, 145.4), SGRQ responder rate at Week 12 (risk ratio: 1.19; 95% CI: 1.09, 1.28), mean SGRQ total score (Week 12: -1.87, 95% CI: -2.72, -1.02; Week 24: -1.05, 95% CI: -2.02, -0.09), and rescue medication use (Week 24: -0.47 puffs/day, 95% CI: -0.64, -0.30) versus TIO (all p ≤ 0.03). The SGRQ responder rate at 24 weeks and adverse events were not significantly different between treatments. US-approved LAMA/LABA therapies improved lung function, SGR,Q and rescue medication use versus TIO, without compromising safety.

Rates of escalation to triple COPD therapy among incident users of LAMA and LAMA/LABA.

BACKGROUND: Improved outcomes have been reported for patients with chronic obstructive pulmonary disease (COPD) receiving combination long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) therapy compared with LAMA monotherapy. However, little is known about the relative characteristics of these patients and their rates of escalation to triple therapy (TT, combining a LAMA, LABA, and inhaled corticosteroid). This study aimed to characterize patients initiating treatment with the LAMA tiotropium (TIO) and the fixed-dose LAMA/LABA combination therapy umeclidinium/vilanterol (UMEC/VI), and to compare rates of escalation to TT between patients receiving these therapies. METHODS: Retrospective study of patients with COPD enrolled in a US health insurance plan during 2013-2015 and newly initiated on TIO or UMEC/VI. Patients were ≥40 years of age at index (date of therapy initiation) with continuous enrollment for 12 months pre-index and ≥30 days post-index. LAMA users were propensity score matched 1:1 to LAMA/LABA users, with TT initiation rates reported by cohort using pharmacy claims. RESULTS: 35,357 patients initiating on TIO and 2407 patients initiating on UMEC/VI were identified. After propensity score matching, the rate of TT initiation was significantly higher in new TIO users (n = 1320) than in new UMEC/VI users (n = 1320) (0.92 vs 0.49 per 100 months of exposure, respectively; p < 0.001). Relative to the UMEC/VI cohort, the TIO cohort had an 87% higher risk of TT initiation (hazard ratio: 1.87; 95% confidence interval: 1.4-2.5; p = 0.001). CONCLUSIONS: Patients receiving UMEC/VI progressed to TT more slowly, and were at lower risk of progressing to TT, than patients receiving TIO.

Effect of prolonged fluconazole treatment on Candida albicans in diffusion chambers implanted into mice.

Fluconazole is an azole agent with primarily fungistatic activity in standard in vitro susceptibility tests. The present study was undertaken to develop a diffusion chamber model system in mice in order to study the in vivo effects of prolonged fluconazole treatment on Candida albicans. Chambers containing 100 C. albicans yeast cells were implanted subcutaneously on the flanks of C57BL/6 mice and were then retrieved 6 or 14 weeks later (after fluconazole treatment for 4 or 12 weeks, respectively). Leukocyte counts demonstrated that implantation of the chambers did elicit an inflammatory response but that only small numbers of inflammatory cells were able to enter the chamber interior. Treatment with fluconazole at 10 mg/kg of body weight/day for 12 weeks not only reduced the numbers of viable organisms within the chambers compared to those in untreated mice (mean +/- standard deviation of log(10) CFU of 0.7 +/- 1.2 versus 2.3 +/- 2.0; P < 0.001 by the Bonferroni test) but also increased the numbers of chambers that became sterile over the treatment period (14 of 16 versus 6 of 19; P = 0.0009 by the chi-square test). However, treatment for only 4 weeks had minimal effects on the numbers of chamber CFU, and none of the chambers became sterile during this period. Distribution of retrieved organisms between interior fluid and the chamber filters was approximately equal in all the treatment groups. This model system appears to be useful for evaluating the effects of antifungal drugs over prolonged periods in vivo. Its use in the present study demonstrates that fluconazole can increase the rate of sterilization of C. albicans foci that are protected from the host's inflammatory response.