Inhaled Corticosteroid/long-acting Beta2-agonist Research Articles

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n=2216) and IRIDIUM (n=3092), 24-week study ARGON (n=1426), and 12-week study QUARTZ (n=802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S+Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND =2.35%, pooled-dose MF =2.18%, RD=0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY=3.65%, pooled-dose MF/IND=3.77%, RD=-0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND=3.69%, medium-dose MF/IND=3.35%, RD=0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY=2.84%, medium-dose MF/IND/GLY=2.02%, RD=0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND=3.69%, F/S=2.82%, RD=0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY=1.26%, F/S+TIO=1.05%, RD=0.21% (-1.26%, 1.68%). There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S±TIO.

Adherence and usage patterns of inhaled corticosteroids-long-acting beta-agonists by using inhaler-monitoring technology.

Background: Results of previous research indicate that adherence to prescribed inhaled corticosteroid-long-acting beta2-agonist (ICS-LABA) asthma controller medications is suboptimal, yet actual daily-use patterns are unclear and may be influenced by regimen complexity or dosing frequency. Objective: To investigate real-world use of asthma medications by using inhaler sensors for the ICS-LABA controllers: twice-daily fluticasone propionate (FP) plus salmeterol (SAL) and once-daily fluticasone furoate (FF) plus vilanterol (VI); and albuterol rescue medication. Methods: This longitudinal, two-phase, observational study included adults with asthma-prescribed FP-SAL (phase I) or FF-VI (phase II), and albuterol metered-dose inhalers. The participants completed baseline and follow-up surveys, and used clip-on inhaler sensors to monitor real-time inhaler use over the 6-month study period. Pharmacy claims data for the 6-month follow-up period were used to assess refills of ICS-LABA and albuterol inhalers. Results: Patients who used twice-daily FP-SAL received a sufficient dose (≥2 actuations/day) approximately one third of the time, those on once-daily FF-VI received a sufficient dose (≥1 actuation/day) ∼60% of the time. Patients who used once-daily FF-VI were more likely to take their medication as prescribed versus those who used twice-daily FP-SAL. There were no significant differences in the percentage of albuterol-free days (FP-SAL, 68.06% [n = 241]; FF-VI, 72.67% [n = 127]; p = 0.230). Exploratory outcomes are reported in this article's Online Supplemental Material. Claims-based measures of adherence were higher than sensor-based measures, hence claims data may have overestimated adherence, whereas sensors may have more accurately measured patients' medication use. Conclusion: These data supported the use of inhaler sensors as tools to directly and accurately measure ICS-LABA adherence and rescue medication use, and the adherence benefits of once-daily versus twice-daily ICS-LABA regimens.

PRS14 COST-EFECTIVENESS ANALYSIS OF AN INTERVENTION TO REDUCE THE CRITICAL HANDLING ERRORS OF FIXED-DOSE ICS/LABA COMBINATIONS IN ASTHMA PATIENTS IN SPAIN

This study explores the cost-effectiveness of an error-targeted intervention, in asthma patients treated with fixed-dose inhaled corticosteroid/long-acting beta-2 agonist (ICS/LABA) devices, consisting in the use of the new breath-activated inhaler (K-Haler®) in comparison with the most used ICS/LABA combination devices: Fluticasone/Saltemerol pMDI (FS-MDI), Fluticasone/Salmeterol Accuhaler® (ACCU), Budesonide/Formoterol Turbuhaler® (TURBU). A probabilistic Markov cost-utility model was developed, based on the CRITIKAL study findings (Price et al. 2017). Patients with moderate-severe asthma, according to Global Initiative for Asthma (GINA) criteria, transitioned between controlled and uncontrolled health states, on weekly cycles over a 5-year period. Estimated asthma exacerbations were also included in the model. Spanish costs and resources were accounted, based on literature review and an expert panel opinion. Effectiveness outcome measure were Quality-Adjusted Life Years (QALYs). Model analysis was carried out, primary, from the perspective of the Spanish National Health System (SNHS) and, secondarily, from the societal perspective. A 3% discount rate, was reckoned, affecting costs (€2019) and effects. The intervention (K-Haler® device) dominated pMDI as well as the two DPI devices compared over 5 years. Direct cost savings of €207.44/€421.68/€957.12 vs FS-MDI, ACCU and TURBU respectively, alongside additional 0.03/0.05/0.02 QALY gains. Furthermore, it showed the highest probability of being cost-effective at a €30,000/QALY threshold. Key factors driving variance were weekly utilities per state and RR of moving to an uncontrolled state, and its impact on exacerbations. The robustness of the model was validated with both deterministic and probabilistic sensitivity analysis. Handling error minimization due to K-Haler® device utilization resulted in an improved asthma control, improving treatment effectiveness as quality of life of patients. K-Haler® is a dominant therapeutic alternative in comparison with the other inhaler devices analyzed from the SNHS perspective. Study funded by Mundipharma Pharmaceuticals, S.L.

Does a Patient-Directed Financial Incentive Affect Patient Choices About Controller Medicines for Asthma? A Discrete Choice Experiment and Financial Impact Analysis.

In Australia, many patients who are initiated on asthma controller inhalers receive combination inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) despite having asthma of sufficiently low severity that ICS-alone would be equally effective and less costly for the government. We conducted a discrete choice experiment (DCE) in a nationally representative sample of adults (n = 792) and parents of children (n = 609) with asthma. Mixed multinomial models were estimated and calibrated to reflect the estimated market shares of ICS-alone, ICS/LABA and no controller. We then simulated the impact of varying patient co-payment on demand and the financial impact on government pharmaceutical expenditure. Preference for inhaler decreased with increasing costs to the patient or government, increasing chance of a repeat visit to the doctor, and if fewer symptoms were present. Adults preferred high-strength controllers, but parents preferred low-strength inhalers for children (general beneficiaries only). The DCE predicted a higher proportion choosing controller treatment (89%) compared to current levels (57%) at the current co-payment level, with proportionately higher uptake of ICS-alone and a lower average cost per patient [32.73 Australian dollars (AU$) c.f. AU$38.54]. Reducing the co-payment on ICS-alone by 50% would increase its market share to 50%, whilst completely removing the co-payment would only have a small marginal impact on market share, but increased average cost of treatment to the government to AU$41.04 per person. Patient-directed financial incentives are unlikely to encourage much switching of medicines, and current levels of under-treatment are not explained by patient preferences. Interventions directed at prescribers are more likely to promote better use of asthma medicines.

AN EVALUATION OF PATIENT AGE ON THE EFFICACY AND SAFETY OF ONCE DAILY FLUTICASONE FUROATE/VILANTEROL 100/25 IN COPD FROM TWO LUNG FUNCTION TRIALS

SESSION TITLE: Obstructive Lung Diseases 3 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Elderly patients with chronic obstructive pulmonary disease (COPD) may be perceived to have increased difficulty using inhaled medications and decreased efficacy relative to younger patients with COPD. We investigated the consistency of the lung function benefit observed with the once daily inhaled corticosteroid/long acting beta2-agonist (ICS/LABA) fluticasone furoate/vilanterol (FF/VI) 100/25 delivered via the ELLIPTA dry powder inhaler in patients under or over 65 years of age relative to placebo or VI alone. METHODS: A preplanned analysis of the intent-to-treat (ITT) population <65 years and ≥65 years from two 24-week lung function trials (HZC112206, HZC112207) evaluated the two co-primary endpoints, weighted mean (WM) forced expiratory volume in 1 second (FEV1) 0-4 hours post-dose and trough FEV1, at the end of the studies. Subjects with COPD in these multicenter, double blind trials were randomized to treatment with FF/VI (200/25, 100/25, or 50/25 mcg), FF (200 or 100 mcg), VI 25 mcg, or placebo once daily via the ELLIPTA inhaler. Lung function was evaluated via spirometry at each study visit. Safety was evaluated by summaries of adverse events reported by age group. RESULTS: A total of 2254 subjects were randomized to treatment and received at least one dose, 1339 subjects <65 years (mean age=56) and 915 subjects ≥65 years (mean age=71). In each subgroup, improvements from baseline in lung function were observed in subjects treated with FF/VI 100/25 or VI compared with placebo. At day 168, WM FEV1 0-4 hours mean change from baseline for subjects <65 years treated with FF/VI 100/25, VI, and placebo was 220, 161, and 9 mL respectively; subjects ≥65 years demonstrated 177, 143, and 8 mL respectively. At day 169, trough FEV1 mean change from baseline for subjects <65 years treated with FF/VI 100/25, VI, and placebo was 173, 113, and 30 mL respectively; subjects ≥65 years demonstrated 116, 92, and 6 mL respectively. Subjects in both subgroups treated with FF/VI 100/25 had significant treatment differences from placebo (p≤0.002) at all time points assessed for each co-primary endpoint. The safety profile of each treatment group was similar and consistent between the age subgroups. CONCLUSIONS: In patients with COPD from both age subgroups, FF/VI 100/25 was well tolerated, provided numerical improvements in lung function compared with the LABA VI alone, and demonstrated consistently significant improvements in lung function compared with placebo throughout the study. CLINICAL IMPLICATIONS: These data provide evidence of consistent and clinically meaningful lung function response in patients treated with FF/VI 100/25 delivered via the ELLIPTA inhaler regardless of age. DISCLOSURES: Employee relationship with GlaxoSmithKline Please note: >$100000 Added 02/27/2018 by Scott Caveney, source=Web Response, value=Shareholder Employee relationship with GlaxoSmithKline Please note: >$100000 Added 02/27/2018 by Scott Caveney, source=Web Response, value=Salary Employee relationship with GlaxoSmithKline, LLC Please note: >$100000 Added 02/28/2018 by Courtney Crim, source=Web Response, value=Restricted shares Employee relationship with GlaxoSmithKline Please note: >$100000 Added 02/28/2018 by Sally Lettis, source=Web Response, value=Salary Employee relationship with GlaxoSmithKline Please note: >$100000 Added 02/27/2018 by Tedi Soule, source=Web Response, value=Salary Employee relationship with GlaxoSmithKline Please note: $5001 - $20000 Added 02/27/2018 by Tedi Soule, source=Web Response, value=stock holder My spouse/partner as a stock holder relationship with gl Please note: $5001 - $20000 Added 02/27/2018 by Tedi Soule, source=Web Response, value=stock Removed 02/27/2018 by Tedi Soule, source=Web Response My spouse/partner as a stockholder relationship with GlaxoSmithKline Please note: $5001 - $20000 Added 02/27/2018 by Tedi Soule, source=Web Response, value=stock

Burden of asthma among patients adherent to ICS/LABA: A real-world study

ABSTRACTObjectives: Asthma is a chronic respiratory condition with a U.S. prevalence of 7.4%. Despite numerous treatment options, asthma remains poorly controlled in some patients. Uncontrolled asthma is associated with high healthcare resource utilization (HCRU) and reduced productivity. This study assessed symptoms, productivity, and HCRU of patients adherent to medium/high-dosage inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) treatment, and the relationship of asthma control with these parameters. Methods: Data were collected in the U.S. in 2013–2016 in the Adelphi Respiratory Disease Specific Programme, a cross-sectional survey. Participating physicians (n = 258) each completed a record form for eligible patients, who were receiving medium/high-dosage ICS/LABA treatment with self-reported moderate/high adherence, completed the Asthma Control Test (ACT) and the Work Productivity and Activity Impairment (WPAI) questionnaire, and were included in the analyses. Results: Patients (n = 428) had a mean of 59% symptom-free days in the past month. Wheezing was the most troublesome symptom for 25% of patients. In the previous 12 months, the mean number of exacerbations was 1.3; 15% of exacerbations required emergency room treatment and/or hospitalization. Mean physician visits for asthma was 5.7. Asthma impacted leisure/personal time frequently/constantly for 11% of patients, with 20% overall work impairment. Asthma was poorly controlled (ACT score ≤15) in 18% of patients; poorer asthma control was associated with higher rates of exacerbations, work impairment, and HCRU. Conclusion: Given the substantial burden described, greater attention to asthma monitoring and management is necessary. Identification of novel treatments may be important for patients not responding to medium/high-dosage ICS/LABA treatment.

Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients

Fluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL). Three 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged ≥40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0-24 h weighted mean FEV(1) (wmFEV(1)) on Day 84. Safety was also assessed. In Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0-24 h wmFEV(1) was significantly greater with FF/VI than FP/SAL (Δ80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0-24 h wmFEV(1) was not significantly greater with FF/VI than FP/SAL (Δ29 mL, P = 0.267; Δ25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (Δ41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments. Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar. clinicaltrials.gov: NCT01323634; NCT01323621; NCT01706328. GlaxoSmithKline study codes: HZC113109; HZC112352; RLV116974.

Treatment Comparison of Budesonide/Formoterol with Salmeterol/Fluticasone Propionate in Adults Aged ≥16 Years with Asthma

Three fixed maintenance-dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) combinations for the treatment of asthma are currently available: salmeterol/fluticasone propionate (Seretide/Advair/Adoair) budesonide/formoterol (Symbicort) and beclometasone/formoterol (Foster). All of these combinations have proven efficacy in terms of controlling symptoms, improving lung function and reducing the rate of exacerbations compared with ICSs and LABAs administered separately. Budesonide/formoterol is also approved for use as maintenance and reliever therapy in a number of countries (Symbicort SMART). Many of the studies supporting the use of budesonide/formoterol combination therapies have included populations of adolescents and adults aged >11 years. This post hoc analysis compared the efficacy of ICS/LABA fixed maintenance-dose treatment with budesonide/formoterol and salmeterol/fluticasone propionate versus budesonide/formoterol maintenance and reliever therapy in patients with persistent asthma aged > or =16 years. Following 2-weeks' run-in, 2866 adults aged > or =16 years were randomized to: fixed maintenance-dose budesonide/formoterol 640 microg/18 microg per day, salmeterol/fluticasone propionate 100 microg/500 microg per day plus terbutaline as needed, or budesonide/formoterol 320 microg/9 microg per day plus additional inhalations as needed (budesonide/formoterol maintenance and reliever therapy). Outcome measures included time to first severe asthma exacerbation (primary outcome) and number of severe asthma exacerbations. Budesonide/formoterol maintenance and reliever therapy prolonged time to first severe exacerbation versus budesonide/formoterol and salmeterol/fluticasone propionate fixed maintenance dose (p = 0.037 and p = 0.0089, respectively). Compared with salmeterol/fluticasone propionate fixed maintenance-dose treatment, fixed maintenance-dose budesonide/formoterol reduced the risk of hospitalizations/emergency-room visits by 28% (relative rate [RR] 0.72; 95% CI 0.53, 0.98; p = 0.034) and budesonide/formoterol maintenance and reliever therapy by 37% (RR 0.63; 95% CI 0.46, 0.87; p = 0.0043). All treatments provided similar improvements in lung function, asthma control days and asthma-related quality of life. Budesonide/formoterol fixed maintenance dose or maintenance and reliever therapy provides similar improvements in current asthma control and reduces the future risk of hospitalizations/emergency-room treatments versus salmeterol/fluticasone propionate fixed maintenance-dose treatment, providing additional clinical benefit to asthma patients aged > or =16 years.

Cost‐effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark – Cost‐effectiveness analysis based on five randomised controlled trials

Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) is an effective asthma-management regime where patients use budesonide/formoterol both as maintenance treatment and as additional doses as needed to improve overall asthma control by reducing symptoms and exacerbations. The aim of this study was to determine the cost-effectiveness of the Symbicort SMART regime in Denmark vs higher dose inhaled corticosteroid (ICS) plus reliever medication, similar dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) combination therapy plus reliever medication or higher dose of inhaled ICS/LABA combination therapy plus reliever medication. The cost-effectiveness analyses were based on effectiveness and resource utilisation data, which were prospectively collected during the treatment period in five randomised clinical trials (duration: 24 weeks, 26 weeks or 1 year). Economic analyses were conducted from both a health care sector (direct costs) and a societal perspective [total costs, i.e direct costs + indirect costs (sick leave)]. The time horizon for the economic analyses was 1 year. The effectiveness measure used was the number of avoided severe exacerbations per patient per year. Patients treated with budesonide/formoterol maintenance and reliever therapy showed statistically significant fewer severe exacerbations per patient compared with the alternative treatment regimes in all comparisons. Budesonide/formoterol maintenance and reliever therapy was a dominant treatment option when compared with higher dose ICS or higher dose ICS/LABA, i.e. it was more effective at a lower total cost. In two of the three comparisons with a similar ICS/LABA dose, Symbicort SMART was dominant. Cost-effectiveness analyses of budesonide/formoterol maintenance and reliever therapy show that the significant reduction in the number of severe exacerbations observed in all the included clinical studies is predominately obtained at lower costs compared with alternative treatment regimes. This indicates that budesonide/formoterol maintenance and reliever therapy is a cost-effective treatment option in a Danish setting.

Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone

Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) improves asthma control compared with fixed-dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) regimens, but its efficacy has not been assessed in comparison with sustained high-dose salmeterol/fluticasone (Seretide) plus a short-acting beta(2)-agonist (SABA). Patients (N=2309) with symptomatic asthma (aged 12 years; forced expiratory volume in 1s 50% predicted), who had experienced an asthma exacerbation in the previous year, were randomised to receive budesonide/formoterol 160/4.5 microg two inhalations twice daily and as needed, or one inhalation of salmeterol/fluticasone 50/500 microg twice daily plus terbutaline as needed, for 6 months. Time to first severe exacerbation, the pre-specified primary outcome, was not significantly prolonged (risk ratio 0.82; 95% confidence interval 0.63, 1.05). Budesonide/formoterol maintenance and reliever therapy reduced total exacerbations from 31 to 25 events/100 patients/year (P=0.039), and exacerbations requiring hospitalisation/emergency room (ER) treatment from 13 to 9 events/100 patients/year (P=0.046). The treatments showed no difference in measures of lung function or asthma symptoms. The mean dose of ICS received was lower using budesonide/formoterol maintenance and reliever therapy (792 microg/day budesonide [1238 microg/day beclomethasone dipropionate (BDP) equivalent] versus 1000 microg/day fluticasone [2000 microg/day BDP equivalent] with salmeterol/fluticasone therapy; P<0.0001). Both treatments were well tolerated. In the treatment of uncontrolled asthma, budesonide/formoterol maintenance and reliever therapy reduces the incidence of severe asthma exacerbations and hospitalisation/ER treatment with similar daily symptom control compared with sustained high-dose salmeterol/fluticasone plus SABA. This benefit is achieved with substantially less ICS exposure.

Pharmacological strategies for self-management of asthma exacerbations: Table 1—

Written action plans are effective within asthma self-management, but there are few guidelines about the specific medication adjustments which can be recommended for self-treatment of exacerbations. This review examines pharmacological strategies for self-management of asthma exacerbations in adults, including those for inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) users. Oral corticosteroids are well-established in clinical practice and clinical trials for the treatment of severe exacerbations, including during combination therapy. Evidence supports 7-10 days treatment, with no need to taper except to reduce side-effects. Doubling the dose of ICS is not effective. Several studies have shown benefit from high-dose ICS (2,400-4,000 microg beclomethasone equivalent) for 1-2 weeks. This may be achieved by adding a high-dose ICS inhaler to maintenance ICS or ICS/LABA therapy. There is inconclusive evidence about acutely increasing the dose of maintenance budesonide/formoterol for exacerbations, and no studies of this approach with fluticasone/salmeterol. For patients taking maintenance budesonide/formoterol, use of the same medication as-needed reduces exacerbations. Short-acting beta2-agonists are still effective in producing bronchodilation during combination therapy; however, a higher dose may be required. There is a need for further studies to clarify remaining issues about self-management of asthma exacerbations, particularly with regard to side-effects of treatment and patient acceptability.