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Objective: to perform a cost-effectiveness analysis of asthma treatment with budesonide/formoterol against other treatment options used at Mexico's National Institute for Respiratory Diseases., Methods: A complete economic evaluation of cost-effectiveness from a public health perspective, comparing the use of budesonide/formoterol as maintenance therapy with fluticasone/vilanterol in 103 female asthma patients managed at INER between 2015 and 2021., Results: Average cost per patient was $743.23 USD, $733.36 USD for budesonide/formoterol and $767.24 USD for fluticasone/vilanterol. Pharmacological treatment represented over 70% of management costs for both groups, followed by follow-up visits and exacerbation management costs. LABA-ICS represented the highest proportion of pharmacologic management costs with a statistically significant difference amongst groups with an incremental cost of $80.17 USD for the fluticasone/vilanterol group. The budesonide/formoterol group showed an ICER of $613.31 USD for reducing the proportion of patients experiencing exacerbations during follow-up. Considering the willingness to pay threshold based on one GDP per capita ($10,902.98 USD in 2022), budesonide/formoterol represented a very cost-effective option., Conclusions: The ICER favored budesonide/formoterol over fluticasone/vilanterol in terms of cost-effectiveness. A 5.5% reduction in patient exacerbations indicated decreased disease burden. While not statistically significant, fewer exacerbations per patient might still cut costs by lowering emergency visits and hospitalizations.

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV 1 ) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of -0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference -0.001 L [95% CI: -0.025, 0.022], non-inferiority p  < 0.001) and intention-to-treat populations (-0.001 L [-0.024, 0.022]; non-inferiority p  < 0.001). There were no statistically significant BDP/FF-BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV 1 , supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD., Study Registration: China Centre for Drug Evaluation (CTR20180475).

Background/objective: To compare the efficacy of budesonide/formoterol (BF) versus fluticasone/salmeterol (FS) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)., Methods: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for studies comparing BF versus FS in the treatment of COPD from inception to July 17, 2023. Outcomes, including exacerbations, hospitalizations, pneumonia, emergency department (ED) visits for COPD, length of hospitalization, and number of exacerbations, were compared using risk ratio (RR) with corresponding 95% confidence interval (CI) or weighted mean difference (WMD) with 95% CI. All statistical analyses were performed using Stata version 12.0., Results: Ten studies comprising a total of 136,369 participants were included. Compared with those treated with FS, patients with COPD treated with BF experienced a reduced number of exacerbations (RR 0.91 [95% CI 0.83-1.00]; p  = 0.040), hospitalizations (RR 0.77 [95% CI 0.67-0.88]; p  < 0.001), and frequency of pneumonia (RR 0.77 [95% CI 0.64-0.92]; p  = 0.05). However, no significant difference was observed between BF and FS in terms of ED visits for COPD (RR 0.87 [95% CI 0.69-1.10]; p  = 0.243), length of hospitalization (WMD -0.18 [95% CI -0.62-0.27]; p  = 0.437), and number of exacerbations (WMD -0.06 [95% CI -0.28-0.16]; p  = 0.602). Notably, no significant heterogeneity was noted in length of hospitalization between the two groups, whereas clear heterogeneity was observed in other outcomes ( I 2 > 50%, p  < 0.05)., Conclusion: Compared with FS, BF therapy appears to be a more promising treatment strategy for patients with moderate-to-severe COPD; however, this should be verified in further high-quality studies.

Background: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event., Objective: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed., Methods: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV 1 ) were randomized to receive Salbutamol Easyhaler (2 × 200 μg), Ventoline Evohaler with spacer (4 × 100 μg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 μg) as a reliever. The treatment was repeated if FEV 1 did not recover to at least -10 % of baseline., Results: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV 1 %pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV 1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV 1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose., Conclusion: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. JK reports payment or honoraria for lectures, presentations or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Novartis and Orion Pharma and participation on an Advisory Board from GlaxoSmithKline and MSD. VV reports being former employee of Orion Pharma and having received personal consultation and lecture fees from Orion Pharma and having been in sustainability advisory board of Orion Pharma. AT reports payments for lectures or presentations from Chiesi and GlaxoSmithKline and participation on an Advisory Board from Chiesi. LPM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi and Orion Pharma. LV reports research grant from Tuberculosis foundation of Tampere. LL reports personal fees for lecturers and/or advisory board meetings from ALK, Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GSK, Menarini, Orion Pharma and Sanofi. SL, US and MV are employees of Orion Pharma., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The relationship between immediate symptom control, reliever medication use and exacerbation risk on treatment response and factors that modify it have not been assessed in an integrated manner. Here we apply simulation scenarios to evaluate the effect of individual baseline characteristics on treatment response in patients with moderate-severe asthma on regular maintenance dosing monotherapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)., Methods: Reduction in reliever medication use (puffs/24 h), change in symptom control scores (ACQ-5), and annualised exacerbation rate over 12 months were simulated in a cohort of patients with different baseline characteristics (e.g. time since diagnosis, asthma control questionnaire (ACQ-5) symptom score, smoking status, body mass index (BMI) and sex) using drug-disease models derived from large phase III/IV clinical studies., Results: Simulation scenarios show that being a smoker, having higher baseline ACQ-5 and BMI, and long asthma history is associated with increased reliever medication use (p < 0.01). This increase correlates with a higher exacerbation risk and higher ACQ-5 scores over the course of treatment, irrespective of the underlying maintenance therapy. Switching non-responders to ICS monotherapy to combination therapy after 3 months resulted in immediate reduction in reliever medication use (i.e. 1.3 vs. 1.0 puffs/24 h for FP/SAL and BUD/FOR, respectively). In addition, switching patients with ACQ-5 > 1.5 at baseline to FP/SAL resulted in 34% less exacerbations than those receiving regular dosing BUD/FOR (p < 0.01)., Conclusions: We have identified baseline characteristics of patients with moderate to severe asthma that are associated with greater reliever medication use, poor symptom control and higher exacerbation risk. Moreover, the effects of different inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combinations vary significantly when considering long-term treatment performance. These factors should be considered in clinical practice as a basis for personalised management of patients with moderate-severe asthma symptoms., (© 2024. The Author(s).)

Background: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control., Methods: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment., Results: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group., Conclusions: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART., (© 2024. The Author(s).)

To assess the impact of budesonide-formoterol on pulmonary ventilation function and prognosis in patients with mild-to-moderate acute exacerbations of bronchial asthma. A retrospective analysis was conducted on clinical data from 232 patients with acute exacerbations of bronchial asthma. These patients were divided into 2 groups based on their treatment: a control group (n=104) receiving budesonide dry powder inhalation and an observation group (n=107) receiving budesonide-formoterol dry powder inhalation. Clinical efficacy and safety indicators were compared. The results showed that the total treatment effectiveness rate in the observation group was significantly higher than that in the control group. Following treatment, the observation group exhibited significantly higher scores in the Asthma Quality of Life Questionnaire (AQLQ), as well as improved levels of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF), compared to the control group. Moreover, levels of tumor necrosis factor-alpha, interleukin-6, and C-reactive protein were significantly lower in the observation group. The incidence of adverse reactions between groups was comparable. Based on these findings, the application of budesonide-formoterol demonstrated significant effectiveness in patients with mild-to-moderate acute exacerbations of bronchial asthma. The combination therapy led to improved clinical outcomes, including enhanced pulmonary ventilation function and reduced inflammatory markers. Importantly, the safety profile of budesonide-formoterol was comparable to that of budesonide monotherapy. These results highlight the potential benefits of using budesonide-formoterol as an alternative treatment option for patients experiencing acute exacerbations of mild-to-moderate bronchial asthma.

Introduction: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma., Methods: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO 2 e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint., Results: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO 2 e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO 2 e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm., Conclusions: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI., Competing Interests: Conflict of interest: I.D. Pavord reports grants from Chiesi and Merck, lecture honoraria from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK, payment for expert testimony from AstraZeneca and Teva, travel support from GSK, Boehringer Ingelheim, AstraZeneca, Teva and Chiesi, patents from Merck, Bayer and Insmed, and advisory board participation with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp. H.K. Reddel reports grants from AstraZeneca, GlaxoSmithKline and Perpetual Philanthropy, consulting fees from Novartis, AstraZeneca and GlaxoSmithKline, lecture honoraria from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Sanofi, Getz, Chiesi and Alkem, advisory board participation for AstraZeneca, GlaxoSmithKline, Novartis, Chiesi and Sanofi, and is chair of the Science Committee and member of the Board of Directors of the Global Initiative for Asthma, and member of the Australian Asthma Guidelines Committee. R.J. Hancox reports funding for the present manuscript from AstraZeneca, and reports an unpaid leadership role with Asthma Foundation of New Zealand. A. Papi reports grants from Chiesi, AstraZeneca, GlaxoSmithKline and Sanofi, consulting fees from Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals and Moderna, lecture honoraria from Chiesi, AstraZeneca, GlaxoSmithKline, Menarini, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, MSD and Avillion, and advisory board participation with Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals and Moderna, outside the submitted work. R. Beasley reports support for the present manuscript from AstraZeneca and Health Research Council (NZ). In addition, outside the submitted work, R. Beasley reports grants from AstraZeneca, Genentech, HRC (NZ) and Cure Kids NZ, lecture honoraria and travel support from AstraZeneca, Avillion, Cipla, Teva and CSL Seqirus, leadership roles as chair of NZ asthma guidelines and board member of GOLD, and receipt of equipment from AstraZeneca. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data., Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori)., Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV 1 : 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting β 2 -agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period., Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days., Competing Interests: Hana Müllerová, Stefan Franzén, Johann Castaneda, and Jonathan Marshall are employees of, and own stock in, AstraZeneca. Jeffrey Shi Kai Chan, Heath Heatley, Victoria Carter, John Townend, and Derek Skinner are employees of Observational and Pragmatic Research Institute. David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy and lecture fees from Medscape, Inside Practice paid to Observational and Pragmatic Research Institute; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2024 Müllerová et al.)

Overuse of reliever as short-acting beta-agonist and associated underuse of controller as inhaled corticosteroid (ICS) administered via separate inhalers results in worse asthma outcomes. Such discordance can be obviated by combining both controller and reliever in the same inhaler. So-called anti-inflammatory reliever (AIR) therapy comprises the use of a single inhaler containing an ICS such as budesonide (BUD) in conjunction with a reliever as either albuterol (ALB) or formoterol (FORM), to be used on demand, with variable dosing driven by asthma symptoms in a flexible patient-centered regimen. Global guidelines now support the use of BUD-ALB as AIR therapy to reduce exacerbations, either on its own in mild asthma or in conjunction with fixed-dose maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Using BUD-FORM on its own allows patients to seamlessly move in an intuitive flexible fashion between AIR and maintenance and reliever therapy, by stepping up and down the dosing escalator across a spectrum of asthma severities. Head-to-head clinical studies are indicated to compare BUD-FORM versus BUD-ALB as AIR in mild asthma, and also BUD-FORM as maintenance and reliever therapy versus BUD-ALB as AIR plus maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Patients should be encouraged to make an informed decision in conjunction with their health care professional regarding the best therapeutic option tailored to their individual needs, which in turn is likely to result in long-term compliance and associated optimal asthma control., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Even though increased use of reliever medication, including short-acting beta agonists (SABA), provides an indirect measure of symptom worsening, there have been limited efforts to assess how different patterns of reliever use correlate with symptom control and future risk of exacerbations. Here, we evaluate the effect of individual baseline characteristics on reliever use in patients with moderate-severe asthma on regular maintenance therapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)., Methods: A drug-disease model describing the number of 24-h puffs and overnight occasions was developed with data from five clinical studies (N = 6212). The model was implemented using a nonlinear mixed effects approach and a Poisson function, considering clinical and demographic baseline characteristics. Goodness of fit and model predictive performance were assessed. Heatmaps were created to summarise the effect of concurrent baseline factors on reliever utilisation., Results: The final model accurately described individual patterns of reliever use, which is significantly increased with time since diagnosis, smoking, higher Asthma Control Questionnaire (ACQ-5) score and higher body mass index (BMI) at baseline. Whilst the number of puffs decreases slowly after an initial drop relative to the start of treatment, exacerbating patients utilise significantly more reliever than those who do not exacerbate. The mean effect of FP/SAL (median dose: 250/50 μg BID) on reliever use was slightly higher than that of BUD/FOR (median dose: 160/4.5 μg BID), i.e. a 75.3% vs 69.3% reduction in reliever use, respectively., Conclusions: The availability of individual-level patient data in conjunction with a parametric approach enabled the characterisation of interindividual differences in the patterns of reliever use in patients with moderate-severe asthma. Taken together, individual demographic and clinical characteristics, as well as exacerbation history, can be considered an indicator of the degree of asthma control. High SABA reliever use suggests suboptimal clinical management of patients on maintenance therapy., (© 2024. The Author(s).)

Background: The management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death., Objective: To compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine., Methods: We developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000)., Results: Inhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis., Conclusion: If made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving., Competing Interests: Disclosures Dr Shaker has participated in research that has received funding from DBV; is a member of the Joint Task Force on Practice Parameters; serves as an associated editor for Annals of Allergy, Asthma, and Immunology; and is an editorial board member for the Journal of Allergy and Clinical Immunology In Practice. Dr Greenhawt is a consultant for Aquestive; is a member of physician and medical advisory boards for DBV Technologies, Nutricia, Novartis, Aquestive, Allergy Therapeutics, AstraZeneca, ALK-Abello, Bryn, and Prota; is an unpaid member of the scientific advisory council for the National Peanut Board and the medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; is the senior associate editor for the Annals of Allergy, Asthma, and Immunology, and is member of the Joint Taskforce on Allergy Practice Parameters. Dr Sadatsafavi has received honoraria from GlaxoSmithKline and AstraZeneca for unrelated activities; and received funding from AstraZeneca and GlaxoSmithKline for unrelated projects. Dr Abrams is an employee of the Public Health Agency of Canada. Dr Oppenheimer is a consultant for Amgen, Aimmune, Aquestive, GSK, and Sanofi; is a member of the Adjudication or Data Safety Monitoring Board for AstraZeneca, Amgen, Abbvie, Novartis, and GlaxoSmithKline; is the Executive Editor for the Annals of Allergy Asthma and Immunology; and is a reviewer for UpToDate. Dr Mosnaim receives current research grant support from GlaxoSmithKline, Novartis, and Sanofi-Regeneron; and has received past research grant support from AstraZeneca, ALK-Abello, Teva, and Genentech. The remaining authors have no conflicts of interest to report., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: There is currently limited evidence for the optimal timing of triple therapy initiation in Japan, which is crucial for optimizing strategies for the effective treatment of chronic obstructive pulmonary disease (COPD). This study assessed the impact of prompt vs delayed initiation of triple therapy following a COPD exacerbation on clinical and economic outcomes in patients in Japan., Patients and Methods: Retrospective cohort study of patients in the Medical Data Vision Co., Ltd. database initiating triple therapy as single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol or budesonide/glycopyrronium/formoterol) or multiple-inhaler triple therapy within 180 days of a moderate-to-severe exacerbation (index). For the main analysis, patients were categorized as prompt or delayed initiators, initiating triple therapy within 0-30 days or 31-180 days of index, respectively. Inverse probability of treatment weighting based on propensity scores was used to adjust for measured confounders between prompt and delayed cohorts., Results: For the main analysis, 610 (60.3%) and 402 (39.7%) patients were prompt and delayed initiators, respectively. The rate of subsequent moderate-to-severe exacerbations following index exacerbation was numerically lower in prompt vs delayed initiators (weighted rate ratio 0.95, 95% confidence interval [CI]: 0.74-1.21; P = 0.6603). Time-to-first subsequent moderate-to-severe exacerbation increased significantly in prompt vs delayed initiators (weighted hazard ratio 0.77, 95% CI: 0.64-0.93; P = 0.0053). In patients indexed on a severe exacerbation, delayed initiation resulted in significantly higher 90-day all-cause readmissions vs prompt initiation (42.1% vs 30.6%; P = 0.0329 [weighted estimates]). Weighted healthcare resource utilization rates were numerically lower in prompt vs delayed initiators, and weighted direct costs (all cause and COPD-related) were significantly lower in prompt initiators., Conclusion: This real-world study demonstrated that earlier initiation of triple therapy resulted in several benefits in clinical outcomes for COPD and may also reduce the economic burden of COPD management in Japan., Competing Interests: Shoko Akiyama, Masao Yarita, Kenichi Hashimoto, Kieran J Rothnie, and Afisi S Ismaila are employees of, and/or hold stocks/shares in, GSK. Alexandrosz Czira and Takeo Ishii were employees of GSK at the time of the study. Robert P Wood, Lucinda J Camidge, Hannah Wallis, Thomas Jennison, and Rosie AC Wild are employees of Adelphi Real World. Adelphi Real World received funding from GSK to conduct the study only. The authors report no other conflicts of interest in this work., (© 2023 Czira et al.)

Introduction: The study aims to compare the real-world effectiveness and economy of the budesonide/formoterol reliever and maintenance therapy (SMART) with fixed-dose inhaled corticosteroids (ICS)/long-acting b-agonist (LABA) or ICS alone plus as-needed, short-acting β2 agonists (SABA) in pediatric patients., Methods: The outpatient data warehouse of a hospital in China was used. A total of 103 patients under 18 years old in the SMART group and 63 patients in the control group were included from January 1, 2020 to December 31, 2021. The effectiveness was assessed using asthma attacks and lung function at baseline, 6 months and 12 months follow-up. Cost-effectiveness analysis was performed with a three-state Markov model from the healthcare system perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to check the robustness of the results., Results: The SMART regimen was more effective than other strategies in reducing the risk of mild and severe attacks in the real-life management of childhood asthma. Patients in both groups showed significant improvement in lung function at 6 and 12 months in contrast to baseline. Compared with other strategies, the forced expiratory volume in 1 s (FEV 1 ) level in the SMART group was markedly improved at 6 months. The total cost of outpatient service using the SMART regimen was lower than that of other strategies, while the drug costs were similar in different groups. Incremental cost-effectiveness analysis results showed that using the SMART regimen reduced the total cost by approximately CNY 10,516.11 per year with a 0.12 quality-adjusted life year (QALYs) increase. Sensitive analyses supported that the SMART regimen was the dominant choice at the willingness-to-pay threshold of CNY 85,698, per capita GDP in China., Conclusions: Collectively, our findings indicate that the real-world effectiveness and economy of the SMART regimen are superior to the traditional strategies in pediatric asthma patients., (© 2023 Wiley Periodicals LLC.)

Background: A heavy financial burden is imposed on patients suffering from chronic diseases due to medicine out-of-pocket payments., Objectives: This study focuses on assessing the affordability of medications used for chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) in Iran, specifically on the category R medicines listed in the 2017 Iran drug list (IDL) that are used for the treatment of these diseases, based on the anatomical therapeutic chemical (ATC) drug code., Methods: The affordability of medicines in mono and combination therapy approaches was assessed in CRDs using the World Health Organization/Health Action International (WHO/HAI) methodology. Accordingly, if out-of-pocket payment for 30-days of pharmacotherapy exceeds one day for the lowest-paid unskilled government worker (LPGW), it's considered non-affordable., Results: Based on the monotherapy approach, our finding demonstrates that all generic medicines of category R were affordable. However, branded drugs such as Symbicort®, Pulmicort Respules®, Flusalmex®, Seretide®, Fluticort Plus®, Seroflo®, and Salmeflo® cost between 1.2 and 2.5 days' wage of LPGW and considered unaffordable despite 70% insurance coverage. Moreover, based on the affordability ratio in the combination therapy approach, all medicines used in asthma, COPD, and CF patients with mild respiratory problems are affordable except omalizumab (inj), which is non-affordable due to its high price and no insurance coverage., Conclusion: Results showed that the existing insurance coverage does not protect households from hardship, so more considerations are needed such as different insurance schedules and patient support programs., (© 2023. The Author(s).)

Background: Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS., Methods: Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled., Results: Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group., Conclusions: Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS., Competing Interests: Declaration of competing interest CK Rhee received consulting/lecture fees from MSD, AstraZeneca, GSK, Novartis, Takeda, Mundipharma, Boehringer-Ingelheim, Teva, Sanofi, and Bayer. All other authors also do not have competing interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Pharmacological asthma management focuses on the use of inhaled corticosteroid (ICS)-containing therapies, which reduce airway inflammation and provide bronchoprotection, improving symptom control and reducing exacerbation risk. ICS underuse due to poor adherence is common, leading to poor clinical outcomes including increased risk of mortality. This article reviews efficacy versus systemic activity profiles for various adherence patterns and dosing regimens of fluticasone furoate (FF)-containing and budesonide (BUD)-containing asthma therapies in clinical trials and real-world studies., Methods: We performed a structured literature review (1 January 2000-3 March 2022) and mathematical modelling analysis of FF-containing and BUD-containing regular daily dosing in patients with mild-to-severe asthma, as-needed BUD/formoterol (FOR) in mild asthma, and BUD/FOR maintenance and reliever therapy (MART) dosing in moderate-to-severe asthma, to assess efficacy (bronchoprotection) and systemic activity (cortisol suppression) profiles of dosing patterns of ICS use in multiple adherence scenarios., Results: A total of 22 manuscripts were included in full-text review and 18 in the model simulations. Focusing on FF-containing or BUD-containing treatments at comparable adherence rates, regular daily FF or FF/vilanterol (VI) dosing provided more prolonged bronchoprotection and fewer systemic effects than daily BUD, daily BUD/FOR, or BUD/FOR MART dosing, especially in low adherence scenarios. In model simulations and the real-world setting, FF/VI generally provided longer bronchoprotection, lower systemic activity, and greater clinical benefits over BUD/FOR as well as consistently higher adherence., Conclusion: In this literature review and modelling analysis, FF/VI was found to show clinical advantages on asthma control over BUD/FOR. These findings have implications for helping clinicians select the most suitable inhaled therapy for their patients with asthma., (© 2023. The Author(s).)

Background: In June 2020, the New Zealand (NZ) adolescent and adult asthma guidelines recommended budesonide/formoterol, taken as maintenance and/or reliever therapy, as the preferred therapeutic approach., Objective: To investigate whether these recommendations were associated with changes in clinical practice indicated by asthma medication use trends., Methods: NZ national dispensing data for inhaler medications from January 2010 to December 2021 were reviewed. Monthly "dispensings" of inhaled budesonide/formoterol, inhaled corticosteroid (ICS), other ICS/long-acting β 2 -agonists (LABA), and inhaled short-acting β 2 -agonists (SABA), for the 12+ age group, were displayed graphically with piecewise regression used to produce plots of rates by time with a July 1, 2020, break point. The number of dispensings in the last 6 months that data were available (July-December 2021) was compared with the corresponding period, July-December 2019., Results: Budesonide/formoterol dispensing increased markedly after July 1, 2020 (regression coefficient 41.1 inhalers dispensed/100,000 population per month [95% confidence interval (CI): 36.3-45.6, P < .0001]; 64.7% increase in the number of dispensings between July-December 2019 and July-December 2021), in contrast to "other ICS/LABA" (regression coefficient: -15.9 [95% CI: -22.2 to -9.6, P < .0001]; -1.7% decrease) and SABA (regression coefficient: -14.7 [95% CI: -29.7 to 0.3, P = .055]; -10.6% decrease), respectively., Conclusion: In NZ, a progressive increase in budesonide/formoterol dispensing, accompanied by a reduction in SABA and "other ICS/LABA" dispensing, occurred after publication of the 2020 NZ asthma guidelines. While acknowledging the limitations in the interpretation of temporal associations, these findings suggest that the transition to ICS/formoterol reliever-based therapy can be achieved if recommended and promoted as the preferred therapeutic approach in national guidelines., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The Global Initiative for Asthma and National Asthma Education and Prevention Program recently made paradigm-shifting recommendations regarding inhaler management in asthma. The Global Initiative for Asthma now recommends that combination inhaled corticosteroid (ICS)-formoterol inhalers replace short-acting β-agonists as the preferred reliever therapy at all steps of asthma management. Although the most recent guidelines of the National Asthma Education and Prevention Program did not review reliever ICS-formoterol usage in mild asthma, they similarly recommended single maintenance and reliever therapy (SMART) at steps 3 and 4 of asthma management. Despite these recommendations, many clinicians-particularly in the United States-are not prescribing new inhaler paradigms. Clinician-level reasons for this implementation gap remain largely unexplored., Objective: To gain an in-depth understanding of the facilitators and barriers to prescribing reliever ICS-formoterol inhalers and SMART in the United States., Methods: Community and academic primary care providers, pulmonologists, and allergists who reported regularly caring for adults with asthma were interviewed. Interviews were recorded, transcribed, qualitatively coded, and analyzed using the Consolidated Framework for Implementation Research. Interviews were continued until theme saturation., Results: Among 20 interviewed clinicians, only 6 clinicians described regularly prescribing ICS-formoterol inhalers as a reliever inhaler (either alone or within SMART). Significant barriers to new inhaler approaches included concerns surrounding a lack of Food and Drug Administration labeling for ICS-formoterol as a reliever therapy, a lack of awareness regarding a patient's formulary-preferred ICS-long-acting β-agonist choices, the high cost of combination inhalers, and time constraints. Facilitators to using new inhaler approaches included clinicians' beliefs that the latest inhaler recommendations are simpler and more congruent with real-world patients' behavior, and that a potential change in management strategy would offer a valuable opportunity for shared decision making., Conclusions: Although new guidelines exist in asthma, many clinicians described significant barriers to using them including medicolegal issues, pharmaceutical formulary confusion, and high drug costs. Nonetheless, most clinicians believed that the latest inhaler approaches would be more intuitive for their patients and would offer an opportunity for patient-centered collaboration and care. Stakeholders may find these results useful in future attempts to increase the real-world adoption of recent asthma recommendations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the clinical efficacy and safety of combining omalizumab with budesonide formoterol to treat children with moderate and severe allergic asthma, and investigate the effect of this combination therapy on pulmonary and immune functions., Methods: The data of 88 children with moderate and severe allergic asthma, who were admitted to our hospital between July 2021 and July 2022, were included in the study. The patients were randomly assigned either to control group (n = 44; received budesonide formoterol inhalation therapy) or experimental group (n = 44; received omalizumab subcutaneous injection + budesonide formoterol inhalation therapy) using computer-generated randomization. The clinical efficacy, asthma control (measured using childhood Asthma-Control Test [C-ACT] score), pulmonary function (forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow), immune function (cluster of differentiation 3 cells [CD3 + cells], cluster of differentiation 4 cells [CD4 + cells], immunoglobulin G, immunoglobulin A, and immunoglobulin E), and adverse reactions were observed and compared between both groups., Results: After treatment, the experimental group had improved levels of pulmonary function and immune function indexes, higher C-ACT scores, and a higher overall response rate than the control group (P < 0.05). In addition, the incidence of adverse reactions was not significantly different between both groups (P > 0.05)., Conclusion: The combination of omalizumab with budesonide formoterol for treating moderate and severe allergic asthma in children demonstrated promising clinical efficacy and improved their pulmonary and immune functions, leading to more rational asthma control. The combined regimen demonstrated satisfactory clinical safety and deserved clinical promotion.

Objective: To investigate the clinical efficacy of combining budesonide formoterol with tiotropium bromide for treating asthma-chronic obstructive pulmonary disease overlap syndrome (AOCS)., Methods: The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone). Patients' clinical efficacy, pulmonary function, fractioned exhaled nitric oxide (FeNO), immune function, endothelial function, serum lipid peroxidation injury indexes, adverse reactions, and quality of life scores were compared., Results: Prior to treatment, no significant differences were observed in various pulmonary function indicators, FeNO, immune function, endothelial function, and lipid peroxidation injury indexes between the two groups ( P > 0.05). However, after treatment, all observation indexes in both groups improved to different levels, with the experimental group -demonstrating -significantly superior improvement, compared to the conventional group ( P < 0.05). We also observed that adverse reactions in the experimental group were significantly lower than in the conventional group ( P < 0.05)., Conclusion: The combination of budesonide formoterol to tiotropium bromide in treating asthma-COPD overlap syndrome may significantly improve pulmonary function, endothelial function, and immune status of patients and encourage the recovery of serum lipid peroxidation injury; therefore, this may deserve widespread adoption and application., Competing Interests: The authors stated that there was no conflict of interest to disclose.

Aim: Inhaled corticosteroid (ICS)/long-acting β 2 agonist (LABA) combination therapy is used for the effective control of asthma. Aim of this study was to collect data on the effectiveness, safety, quality of life, and patient satisfaction from a fixed dose combination of budesonide/formoterol administered with the Elpenhaler ® device following 3-months' treatment. Methods: A 3-month real-life, multicentre, one-arm, prospective observational study (SKIRON study-NCT03055793) was conducted, using the following questionnaires: Asthma Control Questionnaire (ACQ-6) for asthma control assessment, MiniAQLQ questionnaire for QoL assessment, and Feeling of Satisfaction with Inhaler questionnaire (FSI-10) for patients' satisfaction with the inhaler device. Comorbidities and safety data were also recorded during the study. Results: We enrolled 1,174 asthmatic patients following standard clinical practice in primary care from 126 sites in urban and rural areas of Greece. The majority of patients (71.5%) had at least one comorbidity. A statistically significant improvement in the ACQ-6 score was noted at 3 months compared to the baseline evaluation (mean ± SD 2.19 ± 0.97 at baseline vs. 0.55 ± 0.56 at 3 months; mean change -1.64 (95%CI -1.69, -1.57), p  < 0.0001). MiniAQLQ score was statistically and clinically significantly improved, compared to baseline, (4.55 ± 1.04 at baseline vs. 6.37 ± 0.64 at 3 months; mean change 1.82 (95%CI 1.75, 1.87), p  < 0.0001). The mean FSI-10 score of 44.2 ± 5.4 indicated patient satisfaction and ease-of-use of the Elpenhaler ® device. Conclusions: In this large real-world study of inadequately-controlled asthma patients in primary care settings, the treatment with budesonide/formoterol FDC with the Elpenhaler ® device was associated with significant improvement in patients' asthma control and quality of life.

Background: Maintenance and reliever therapy (MART) with inhaled corticosteroid (ICS)/formoterol effectively reduces exacerbations in asthma. We aimed to investigate its efficacy compared with fixed-dose fluticasone/salmeterol in chronic obstructive pulmonary disease (COPD)., Methods: Patients with COPD and ≥1 exacerbation in the previous 2 years were randomly assigned to open-label MART (Spiromax budesonide/formoterol 160/4.5 µg 2 inhalations twice daily+1 prn) or fixed-dose therapy (Diskus fluticasone propionate/salmeterol combination (FSC) 500/50 µg 1 inhalation twice daily+salbutamol 100 µg prn) for 1 year. The primary outcome was rate of moderate/severe exacerbations, defined by treatment with oral prednisolone and/or antibiotics., Results: In total, 195 patients were randomised (MART Bud/Form n=103; fixed-dose FSC n=92). No significant difference was seen between MART and FSC therapy in exacerbation rates (1.32 vs 1.32 /year, respectively, rate ratio 1.05 (95% CI 0.79 to 1.39); p=0.741). No differences in lung function parameters or health status were observed. Total ICS dose was significantly lower with MART than FSC therapy (budesonide-equivalent 928 µg/day vs 1747 µg/day, respectively, p<0.05). Similar proportions of patients reported adverse events (MART Bud/Form: 73% vs fixed-dose FSC: 68%, p=0.408) and pneumonias (MART: 5% vs FSC: 1%, p=0.216)., Conclusions: This first study of MART in COPD found that budesonide/formoterol MART might be similarly effective to fluticasone/salmeterol fixed-dose therapy in moderate to severe patients with COPD, at a lower daily ICS dosage. Further evidence is needed about long-term safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: COPD is characterized by progressive and irreversible air flow limitations. Single-inhaler therapies (SITTs) incorporating an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β 2 -agonist have been shown to effectively alleviate symptoms and improve lung function. Fluticasone-furoate/umeclidinium/vilanterol (F/U/V) and budesonide/glycopyrronium/formoterol (B/G/F) are available as SITT in Japan. However, the clinical differences between these 2 combinations and the predictors of their proper use have not been established. This study aimed to identify the subject characteristics that could predict the effectiveness of inhaler therapy., Methods: We assessed the pulmonary function test results of subjects with COPD before and one month after using F/U/V and B/G/F as SITT. Subjects with a difference of 100 mL or more in the FEV 1 after treatment with pre-SITT were extracted and divided into the F/U/V effect and no-effect group and B/G/F effect and no-effect group to examine the factors associated with positive outcomes with each inhaler., Results: F/U/V and B/G/F significantly improved the inspiratory capacity (IC), %IC, FVC, and %FEV 1 when compared to pre-intervention values ( P < .001, P = .001, P = .007, P = .009, respectively, for F/U/V; and P = .006, P = .008, P = .038, P = .005, respectively, for B/G/F). Factors associated with FEV 1 improvement in F/U/V included lower %IC (odds ratio 0.97 [95% CI 0.94-0.99], P = .03) and a higher modified Medical Research Council (mMRC) dyspnea score (2.36 [1.27-4.70], P < .01). In addition, a higher %IC (1.03 [1.00-1.06], P = .02) and lower mMRC dyspnea score (0.55 [0.28-0.99], P = .041) were predictors for the effectiveness of B/G/F., Conclusions: Our results showed that SITT significantly improved the IC, %IC, FVC, and %FEV 1 when compared to pre-intervention and that F/U/V was more effective in subjects with severe symptoms, whereas B/G/F was more effective in subjects with mild symptoms., Competing Interests: The authors have disclosed no conflicts of interest. Clinical trial registration number: UMIN000041089., (Copyright © 2023 by Daedalus Enterprises.)

The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever"., Competing Interests: Declaration of competing interest RB and OS are former employees of Astra and/or AstraZeneca, Sweden, but retired many years ago. We have initiated and written this article independent of AstraZeneca. AstraZeneca was given the opportunity to review the final draft. The authors retained full editorial control. RB holds stocks with AstraZeneca., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases that remain uncontrolled in many patients, despite the wide range of therapeutic options available. This review analyzes the available clinical evidence on 3 budesonide/formoterol DPI devices, Spiromax ® , Turbuhaler ® , and Easyhaler ® , in terms of patient-reported outcomes (PROs), inhaler errors, and asthma and COPD control., Recent Findings: The effectiveness of dry powder inhalers (DPI) depends largely on the device and the patient's inhaler technique. Equally important are the patient's perception of the inhaler and adherence. Given the high burden of these diseases, it is important that efforts be made to select the best DPI for each patient and to analyze the impact of these variables to help improve the health and quality of life of our patients. This review provides a comprehensive overview of the present knowledge about PROs, inhaler handling errors, and asthma and COPD control achieved by Spiromax ® , Turbuhaler ® , and Easyhaler ® ., (© 2022. The Author(s).)

Background: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA., Methods: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 μg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis., Results: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV 1 /FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05)., Conclusions: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013., (© 2022. The Author(s).)

Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting beta-2 agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists., Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe., Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 y) from Canada, France, the Netherlands, Poland, Spain, the United Kingdom, and the United States. Negative binomial models (incidence rate ratio [IRR] [95% CI adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations., Results: Across severities, 40.2% of patients were prescribed/possessed 3 or more SABA canisters/y. Per the Global Initiative for Asthma (GINA) 2018 definitions, steps 3 to 5-treated patients prescribed/possessing 3 or more versus 1 or 2 SABAs experienced more severe exacerbations (IRR 1.08 [95% CI 1.04‒1.13], U.S. Medicare; IRR 2.11 [95% CI 1.96‒2.27], Poland). This association was not observed in all step 1 or 2-treated patients (the Netherlands, IRR 1.25 [95% CI 0.91‒1.71]; U.S. commercial, IRR 0.92 [95% CI 0.91‒0.93]; U.S. Medicare, IRR 0.74 [95% CI 0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the U.S. datasets was attributable to the large patient population possessing fewer than 3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face health care provider encounters. In U.S. SABA monotherapy-treated patients, 3 or more SABAs were associated with more emergency/outpatient visits and hospitalizations (IRR 1.31 [95% CI 1.29‒1.34]). Most GINA 2 to 5-treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of 3 or more SABAs and severe exacerbations persisted (IRR 1.32 [95% CI 1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when U.K. SABA data were analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications., Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: In mild asthma, as-needed budesonide-formoterol offers similar protection from severe exacerbations as daily inhaled corticosteroids (ICS), with lower ICS exposure but slightly increased symptoms. We sought to develop an electronic decision aid to guide discussions about the pros and cons of these first-line options, while identifying and integrating user preferences., Methods: Following International Patient Decision Aid Standards, we created a mild asthma decision aid prototype comparing convenience, clinical outcomes, cumulative ICS dose exposure, costs, and side-effects of each option. After face validation, the prototype was iteratively adapted through rapid-cycle development. Each cycle consisted of a patient focus group and a primary care physician interview. We made user preference-based improvements after each round, until reaching a pre-set stopping criterion (no new critical issues identified). We then performed a summative qualitative content analysis., Results: Over 5 cycles, we recruited 21 asthma patients (12/21 women, 10/21 ≥ 60 years old) and 5 physicians. Serial changes included simplification and reduction of text and reading level, inclusion of an ICS "myths" section and elaboration of patient-friendly infographics for numerical comparisons. User preferences fell within Content, Format, and tool use Process themes. In response to decision-making preferences, we created a complementary one-page conversation aid for patient-provider use at the point-of-care., Conclusions: We present preference-based electronic patient decision and conversation aids for treatment of mild asthma. Our user preference analyses offer useful insights for development of such tools in other chronic diseases. These tools now require integration into point-of-care workflows for measurement of real-world uptake and impact., Competing Interests: Declaration of competing interest MG, JLSC, AK, PMO, LPB, and AG declare that they have no competing interests in this work. JMF declares participating in advisory boards and receiving honoraria for lectures from AstraZeneca, GlaxoSmithKline, TEVA, Novartis, and Sanofi. JMF also reports the following research funding, paid directly to UBC: CIHR, NIH, AllerGen NCE and Astra Zeneca, GlaxoSmithKline, TEVA, Novartis, and Sanofi. SG owns the intellectual property for a practice-based asthma management decision support system called the Electronic Asthma Management System., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) in primary care in England., Methods: This is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015-December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy)., Results: Overall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally., Conclusion: Patient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history., Competing Interests: Competing interests: AC, GR, CC, MD and ASI are employees of GSK and hold stock and shares at GSK. ASI is also a part-time member of the McMaster University faculty. VB, TT, RWo and RWi are employees of Adelphi Real World (or were at the time of the study), which received funding from GSK to conduct the study. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government and non-government organisations. Adelphi Real World employees work with a variety of companies and organisations and are expressly prohibited from receiving any payment or honoraria directly from these organisations for services rendered., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting β 2 -agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD., Methods: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV 1 ), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible)., Results: The NMA was informed by five trials reporting FEV 1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV 1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6)., Conclusion: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available., (© 2022. The Author(s).)

Objective: Treatment with fluticasone furoate/vilanterol (FF/VI), an inhaled corticosteroid/long-acting β 2 -agonist therapy, reduces the risk of severe asthma exacerbations and improves lung function and symptom control in patients with asthma. However, real-world data remain limited among asthma patients in the United States (US)., Methods: This retrospective cohort study propensity score (PS) matched adult asthma patients initiating once-daily FF/VI 100/25 mcg with patients initiating twice-daily budesonide/formoterol (B/F) 160/4.5 mcg using a US claims database (January 1, 2015-December 31, 2018). Asthma control was measured by the mean number of short-acting β 2 -agonist (SABA) canisters dispensed per patient-year (PPY) during follow-up. Time to first, and rates of, overall and severe asthma exacerbations were also measured., Results: After PS matching, 18,531 patients receiving FF/VI were matched to 18,531 patients receiving B/F. Mean SABA canisters dispensed PPY was significantly lower for FF/VI users compared with B/F users (FF/VI: 1.47, B/F: 1.64; p  < 0.001). FF/VI use resulted in 13% significantly lower risk of having an overall asthma-related exacerbation and 22% lower risk of a severe exacerbation versus B/F use (overall exacerbation hazard ratio [HR] [95% confidence interval (CI)]: 0.87 [0.82-0.92], p  < 0.001; severe exacerbation HR [95% CI]: 0.78 [0.63-0.97], p  = 0.027). Asthma-related exacerbation rates per 100 patient-days were also significantly lower for the FF/VI group compared with the B/F group (overall: 0.0475 vs. 0.0558, p  < 0.001; severe: 0.0026 vs. 0.0033, p  = 0.020)., Conclusions: In real-world practice, initiation of once-daily FF/VI 100/25 mcg in adults with asthma was associated with lower use of SABA and fewer asthma-related exacerbations, which may indicate better asthma control, when compared with use of twice-daily B/F 160/4.5 mcg.

Background: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy., Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-treatment moderate/severe exacerbations up to Week 24, annual rate of on-treatment severe exacerbations up to Week 24, change from baseline in trough forced expiratory volume in 1 second at Week 24, and change from baseline in health status as measured by St George's respiratory questionnaire total score at Week 24., Results: Of the 1810 patients in the intent-to-treat population, 1180 (65%) had one or more moderate/severe exacerbation in the year prior to entry, while 630 (35%) patients did not. FF/UMEC/VI versus BUD/FOR significantly reduced moderate/severe exacerbation rates in the recent exacerbation subgroup (mean annualized rate: 0.19 vs 0.29; rate ratio [95% confidence interval [CI]]: 0.64: [0.45, 0.91]; p =0.014) and numerically reduced moderate/severe exacerbation rates in the no recent exacerbation subgroup (mean annualized rate: 0.29 vs 0.43; rate ratio [95% CI]: 0.67 [0.43, 1.04]; p =0.073). Severe exacerbation rates were numerically reduced with FF/UMEC/VI versus BUD/FOR treatment across both subgroups. FF/UMEC/VI conferred significant improvements in lung function and health status versus BUD/FOR, regardless of recent exacerbation history., Conclusion: FF/UMEC/VI reduced moderate/severe and severe exacerbation rates and improved lung function and health status versus BUD/FOR in patients with symptomatic COPD, regardless of recent exacerbation history., Competing Interests: RA Panettieri has received research support from Novartis, AstraZeneca, Genentech, Optikira, Medimmune, Maven, Evelobio, Johnson & Johnson, RIFM, Equillium, Theravance, TEVA, Origo, ACTIV-1, Janssen and Vault Health; has received consulting fees from AstraZeneca, RIFM, Equillium, Bayer and TEVA; is part of the speaking bureau for Sanofi/Regeneron, AstraZeneca, Merck & Co and Genentech; and is a member of the advisory committee for AstraZeneca, Genentech, RIFM, Equillium and Theravance. CA Camargo is a member of the scientific advisory board for AstraZeneca. T Cheema is part of the speaking bureau for BI, GSK, Regeneron and AstraZeneca, and is a consultant for Noveome Biotherapeutics. S El Bayadi is a speaker for GSK, Grifols, Sanofi Genzyme Regeneron, Mylan Theravance, Janssen, Bayer, Mallinckrodt Pharmaceuticals. S Fiel is a member of Speakers Bureau Gilead. T Vila, RG Jain, D Midwinter, DA Lipson are GSK employees and hold stock/shares at GSK. B Thomashow has taken part in advisory boards for AstraZeneca, Boehringer Ingelheim and GSK and performed consulting work for GSK. A Ludwig-Sengpiel is KLB Gesundheitsforschung Lübeck GmbH managing director. ELLIPTA is owned by or licensed to the GSK group of companies. Turbuhaler is owned by or licensed to the AstraZeneca group of companies, and BUD/FOR 400/12 mcg twice-daily is not a US Food and Drug Administration-approved formulation. The authors report no other conflicts of interest in this work., (© 2022 Panettieri Jr et al.)

Aim: To evaluate the budgetary impact of using budesonide + formoterol (Symbicort Turbuhaler) as maintenance therapy in real clinical practice compared with standard therapy for asthma of varying severity: for mild asthma with on-demand salbutamol; for moderate and severe asthma with the drug salmeterol + fluticasone and salbutamol on demand., Materials and Methods: A static mathematical model was built to assess the impact on the budget when introducing the drug budesonide + formoterol (Symbicort Turbuhaler) in the treatment of asthma into clinical practice from the point of view of the state. Demographic data was taken from the official data of the Federal State Statistics Service. Direct medical costs included the cost of medicines, the cost of hospitalization of patients associated with the development of asthma exacerbations, and the cost of scheduled outpatient visits. Indirect costs considered the loss of GDP due to hospitalization of patients against the background of asthma exacerbations. A one-way sensitivity analysis was performed to confirm the robustness of the study results., Results: Assessment of direct costs in the treatment of mild, moderate and severe asthma showed that a gradual increase in the proportion of patients receiving the drug budesonide + formoterol (Symbicort Turbuhaler) over the years to 5.5, 7.7 and 9.7% accordingly, led to an increase in the cost of pharmacotherapy over 3 years by 1.7 billion rubles, while direct non-drug costs associated with the treatment of complications that developed during the treatment of asthma decreased by 8.3 billion rubles. Thus, the reduction in total direct costs amounted to RUB 6.7 billion. At the same time, indirect costs decreased by 6.0 billion rubles. The total reduction in all costs (direct and indirect) when switching patients to budesonide + formoterol (Symbicort Turbuhaler) amounted to 12.5 billion rubles. In addition, the use of the drug budesonide + formoterol (Symbicort Turbuhaler) resulted in a decrease in the number of exacerbations: in the first year by 3137, in the second by 4393 and in the third by 5534 cases. A total of 13 064 asthma exacerbations were prevented over 3 years., Conclusion: Increasing the proportion of patients with asthma of varying severity receiving therapy with budesonide + formoterol (Symbicort Turbuhaler) will reduce the financial burden on both the healthcare system and the budgetary system.

Background: In randomised controlled trials, as-needed inhaled corticosteroid (ICS)-formoterol reliever therapy reduces severe exacerbation risk compared with maintenance ICS plus short-acting beta 2 -agonist (SABA) reliever in adolescent and adult asthma, but results in slightly worse control of asthma symptoms, as measured by mean Asthma Control Questionnaire-5 (ACQ-5) score., Objective: To assess the levels and changes in asthma control for as-needed budesonide-formoterol versus maintenance budesonide plus SABA in post hoc analyses from the Novel START and PRACTICAL clinical trials., Methods: The number and proportion of participants at study end in each ACQ-5 category ('well-controlled', 'partly controlled' or 'inadequately controlled' symptoms), and in each responder category based on the minimal clinically important difference for ACQ-5 of 0.5 (improved, no change and worse) with as-needed budesonide-formoterol and maintenance budesonide plus SABA treatment were calculated., Results: With last observation carried forwards, 189/214 (88.3%) and 354/434 (81.6%) of patients in the budesonide-formoterol group had 'well-controlled' or 'partly controlled' symptoms at the end of the study, vs 183/214 (85.5%) and 358/431 (83.1%) in the budesonide maintenance group, for Novel START and PRACTICAL, respectively. The proportion of patients whose symptom control was either improved or unchanged from baseline was 190/214 (88.8%) and 368/434 (84.8%) for budesonide-formoterol, vs 185/214 (86.4%) and 376/431 (87.2%) for maintenance budesonide, in Novel START and PRACTICAL respectively., Conclusions: There were no clinically important differences in the proportions of patients with 'well-controlled' or 'partly controlled' asthma symptoms, or proportions who improved or maintained their level of control, with as-needed budesonide-formoterol versus maintenance budesonide plus SABA., Competing Interests: Competing interests: LH, PB, CH, AE, RH, IB, MW, KO and MH have nothing to declare. IP reports speak fees from Aerocrine AB; speaker and consultant fees from Almirall and Novartis; speaker fees, payments for organisation of educational events, consultant fees, international scientific meeting sponsorship from AstraZeneca; speaker fees, consultant fees, international scientific meeting sponsorship from Boehringer Ingelheim; speaker fees, consultant fees, international scientific meeting sponsorship, research grant from Chiesi; speaker fees, payments for organisation of educational events, consultant fees, international scientific meeting sponsorship from GlaxoSmithKline, Regeneron Pharmaceuticals Inc, Sanofi, and Teva; consultant fees from Circassia, Dey Pharma, Genetech, Knopp Biosciences, Merk, MSD, RespiVert, and Schering-Plough; consultant fees and international scientific meeting sponsorship from Napp Pharmaceuticals. HKR reports support for the present manuscript from AstraZeneca (for Novel START) and the Health Research Council of New Zealand (for PRACTICAL); research grants from AstraZeneca, GlaxoSmithKline, Novartis; consulting fees from AstraZeneca and Novartis; independent medical education fees from AstraZeneca, GlaxoSmithKline, Teva, Boehringer-Ingelheim, Sanofi and Chiesi; participation on Advisory Boards for AstraZeneca, GlaxoSmithKline, Novartis, Chiesi and Sanofi; unpaid board roles for the Global Initiative for Asthma and the National Asthma Council (Australia). AP reports research grants from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Teva, and Sanofi; consulting fees from Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, IQVIA, Avillion, Elpen Pharmaceuticals, MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Menarini, Novartis, Zambon, Mundipharma, Teva, Sanofi, Edmond Pharma, IQIVA; Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, IQVIA, Avillion, Elpen Pharmaceuticals, MSD. RB reports support for the present manuscript from AstraZeneca (for Novel START) and the Health Research Council of New Zealand (for PRACTICAL); research grants from AstraZeneca, Genentech, the Health Research Council of New Zealand and Cure Kids NZ; fees and support from AstraZeneca, Cipla, Avillion, and the Asthma and Respiratory Foundation NZ for presentations, AdBoards, attending meetings and travel, participation on advisory boards., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression., Methods: We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes., Results: We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells., Conclusion: Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling., (© 2022. The Author(s).)

Background: Asthma is a chronic inflammatory disease of the airways that causes recurring episodes of wheezing, breathlessness, chest tightness and coughing. Inhaled drugs on a daily basis are the cornerstone of asthma treatment, therefore, patient adherence is very important., Methods: We performed a multicenter, open, non-interventional, observational, prospective study of 716 adult patients diagnosed with asthma receiving FDC (Fixed-dose combination) budesonide/formoterol via the Elpenhaler device. We assessed the adherence to treatment at 3 and 6 months (based on the MMAS-8: 8-item Morisky Medication Adherence Scale), the quality of life and change in forced expiratory volume in 1 s (FEV1) from baseline to follow-up., Results: Approximately 80% of the patients showed medium to high adherence throughout the study. The mean (SD) MMAS-8 score at 6 months was 6.85 (1.54) and we observed a statistically significant shift of patients from the low adherence group to the high adherence group at 6 months. Moreover, after 6 months of treatment with FDC budesonide/formoterol, we observed an increase in the patients' quality of life that as expressed by a change 2.01 (95%CI 1.93-2.10) units in Mini AQLQ (p < 0.0001) that was more pronounced in the high adherence group. The same trend was also observed in terms of spirometry (mean FEV1 2.58 L (0.85) at the end of the study, increased by 220 mL from baseline) with a higher improvement in the medium and high adherence groups., Conclusions: Treatment with FDC of budesonide/formoterol via the Elpenhaler device was associated with improvement in asthma-related quality of life and lung function over 6 months that were more prominent in patients with higher adherence., Trial Registration: 2017-HAL-EL-74 (ClinicalTrials.gov Identifier: NCT03300076)., (© 2022. The Author(s).)

Objective: Daily inhaled corticosteroid (ICS) and long-acting beta-2-agonist (LABA) combinations comprising either regular maintenance therapy with ICS/LABA plus as-needed short-acting beta-2-agonist (SABA) or ICS-formoterol combinations used as maintenance and reliever therapy (MART) are recommended for moderate asthma. This analysis compares the direct costs of twice-daily fluticasone propionate/salmeterol (FP/salm) and budesonide/formoterol MART in three Southeast Asian countries., Methods: A literature review identified three randomized trials in patients with asthma (≥ 12 years) comparing regular twice-daily FP/salm with as-needed SABA versus MART in moderate asthma: AHEAD (NCT00242775/17 countries/2309 patients), COMPASS (AstraZeneca study SD-039-0735/16 countries/3335 patients), and COSMOS (AstraZeneca study SD-039-0691/16 countries/2143 patients). Economic analyses, conducted from a healthcare sector perspective (medication costs + healthcare utilization costs), applied unit costs from countries where healthcare costs are publicly available: Indonesia, Thailand and Vietnam. Results are expressed in British pound sterling (GBP/patient/year)., Results: Annual exacerbation rates were low and differences between treatment strategies were small (range, FP/salm: 0.31-0.38, MART: 0.24-0.25) although statistically significant in favor of MART. Total average (minimum-maximum) direct costs (in GBP/patient/year) across the three studies were £187 (£137-£284), £158 (£125-£190), and £151 (£141-£164) for those who used FP/salm, and £242 (£217-£267), £284 (£237-£340) and £266 (£224-£315) for MART in Indonesia, Thailand and Vietnam, respectively. On average, total direct costs/patient/year with FP/salm were 22.8%, 44.6% and 43.0% lower than with MART for Indonesia, Thailand and Vietnam, respectively., Conclusions: In the three countries evaluated, total treatment costs with regular twice-daily FP/salm were consistently lower than with budesonide/formoterol MART due to lower direct healthcare costs.

Background: The emitted dose (ED) from most dry powder inhalers (DPIs) is almost independent of peak inspiratory flow (PIF) above a certain value, which is specific to the individual DPI. However, the ED of the Turbuhaler ® (TBH) increases linearly with PIF increments. This study investigated the powder clearance and clinical utility of TBH performance features by using the photo-reflection method (PRM), a type of laser photometry. Methods: Pulmicort ® (PLM) (containing budesonide only) and Symbicort ® (SMB) (drugs with lactose particles) were inspired with a ramp-up pattern of several PIF intensities using a vacuum pump. Time trajectories of particle release and PIF were then compared. Results: The particle-release trajectories from both types of DPIs were similar, consisting of a sharp increment phase (∼0.15 seconds) followed by exponential decay. Both onset to the peak of particle-release time and particle-release times were not affected by PIF changes when the PIF was >40 L/min. EDs from both TBHs were linearly related to PIFs, and the slope of the regression equation for SMB was 2.4-fold larger than that of PLM. The peak of the released particles (PK IED ) was also linearly related to PIF. A linear relationship was also observed between ED and PK IED in both TBHs, and these regression lines overlapped. Conclusion: EDs from the TBH were dependent on PK IED . Therefore, rapid, initially strong, and deep inhalation should be advised while using the TBH. PRM could measure the fine and small amount of particles released from the TBH.

Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a long-acting bronchodilator, depending on asthma severity, and may also be supplemented with short-acting bronchodilators for as-needed rescue medication. Adherence to asthma therapies is generally poor and characterized by underuse of ICS therapies and over-reliance on short-acting bronchodilators, which leads to poor clinical outcomes. This article reviews efficacy versus systemic activity profiles for various dosing regimens of budesonide (BUD) and fluticasone propionate (FP). We performed a structured literature review of BUD and FP regular daily dosing, and BUD/formoterol (FOR) as-needed dosing, to explore the relationship between various dosing patterns of ICS regimens and the risk-benefit profile in terms of the extent of bronchoprotection and cortisol suppression. In addition, we explored how adherence could potentially affect the risk-benefit profile, in patients with mild, moderate, and moderate-to-severe asthma. With a specific focus on BUD or FP-containing treatments, we found that regular daily ICS and ICS/long-acting β 2 -agonist (LABA) dosing had a greater degree of bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR maintenance and reliever therapy (MART) dosing, and still maintained low systemic activity. We also found that the benefits of regular daily ICS dosing regimens were diminished when adherence was low (50%); the shorter duration of bronchoprotection observed was similar to that seen with typical as-needed BUD/FOR usage. These findings have implications for aiding clinicians with selecting the most suitable treatment option for asthma management, and subsequent implications for the advice clinicians give their patients., (© 2022. The Author(s).)

Introduction: While mild asthma is generally better controlled than more severe disease, patients with mild asthma may experience severe exacerbations. Definite differences between countries in terms of asthma severity and control were described previously. Since SYGMA was a global study, this sub-analysis was conducted in geographic region to investigate potential regional specificities., Methods: The SYGMA2 trial is double-blind multicenter study involving patients ≥12 years of age with mild asthma ( n  = 4176), eligible for regular treatment with inhaled corticosteroid (ICS). We conducted an open-label descriptive subanalysis of the baseline characteristics of the Russian population ( n  = 579) comparing to rest of participants of SYGMA2 trial from other 24 countries. The subanalysis is solely descriptive and will be used for hypothesis generation., Results: The Russian population of patients with mild asthma hardly differs from the population in other countries in terms of baseline demographic and anthropometric characteristics, smoking status, and duration of asthma. At the study entry few patients from Russia received maintenance therapy with ICS and had symptom control, but the majority was uncontrolled on short-acting bronchodilators, thus the uncontrolled/controlled ratio was 52%/48% vs 45%/55% in other countries. More patients with mild asthma in the Russian group had faced at least one severe exacerbation in the previous year (30.1% vs 20.7%)., Conclusions: The subanalysis revealed a delayed prescription of controller (ICS) therapy and overuse of short-acting bronchodilators in the Russian population with mild asthma. These factors can lead to insufficient symptom control and higher risk of severe exacerbation in the Russian population with mild asthma.

Objective: To determine treatment persistence and exacerbations in patients initiating inhaler treatment with fixed-dose combinations of inhaled corticosteroids/long-acting beta-2-adrenergic agonists (ICS/LABA) for the treatment of asthma., Design: Retrospective observational study conducted by review of electronic medical records (database: Fundación RediSS)., Setting: Retrospective cohort study. The follow-up period was 1 year., Participants: The study included patients aged ≥18 years who started treatment with ICS/LABA and met the inclusion/exclusion criteria., Main Outcomes and Measures: The study groups were fluticasone propionate/salmeterol (FP/SAL), beclomethasone/formoterol (BDP/FORM), budesonide/formoterol (BUD/FORM), fluticasone furoate/vilanterol (FF/VI) and fluticasone propionate/formoterol (FP/FORM). The main measurements were persistence, medication possession ratio (MPR) and exacerbations. Statistical significance was established as p<0.05., Results: In total, 3203 patients were recruited for the study. By groups, 31.1% FP/SAL, 28.6% BDP/FORM, 25.0% BUD/FORM, 8.2% FF/VI and 7.0% FP/FORM. The mean age was 52.2 years, 60.8% were female and 44.9% had persistent-moderate asthma. Treatment persistence was 61.7% (95% CI 60.0% to 63.4%) and by study group it was FP/SAL: 60.7%, BDP/FORM: 61.2%, BUD/FORM: 60.3%, FF/VI: 66.7% and FP/FORM: 67.6% (p=0.046). MPR by study group was FP/SAL: 74.3%, BDP/FORM: 73.8%, BUD/FORM: 74.6%, FF/VI: 79.4% and FP/FORM: 80.6% (p=0.028). The mortality rate was 2.9%. By treatment group, exacerbations were FP/SAL: 21.9% (95% CI 19.3% to 24.5%), BDP/FORM: 22.2% (95% CI 19.5% to 24.9%), BUD/FORM: 22.8% (95% CI 19.9% to 25.7%), FF/VI: 17.9% (95% CI 14.9% to 20.7%) and FP/FORM: 16.0% (95% CI 12.2% to 19.3%), p=0.036., Conclusions: Patients undergoing treatment with FP/FORM and FF/VI versus FP/SAL, BDP/FORM and BUD/FORM were associated with greater treatment adherence (persistence, MPR) and lower rates of exacerbations. However, further studies will be needed to strengthen the consistency of the results., Competing Interests: Competing interests: AS-M is an independent consultant funded by Mundipharma with respect to this manuscript. ST-L and TF-S are employees of Mundipharma., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In asthma, treatment effectiveness is strongly influenced by the quality of inhaler use. New devices such as Spiromax® have been specifically developed to improve ease of use. It is crucial to determine whether switching to such a device improves inhaler technique and clinical outcomes, and to identify factors associated with handling errors. Methods: This observational study assessed inhaler device handling errors in 1435 asthma patients recruited via 135 participating physicians in France, before and after switching therapy from the Symbicort Turbuhaler® or Seretide® Diskus® to DuoResp® Spiromax®. Patients received training in the use of their new device at baseline and were re-assessed after three months. Results: After three months of use, 67% of patients were using the DuoResp® Spiromax® with no handling errors, and 88% with no critical errors. The presence of comorbidities was associated with handling errors overall. Concurrent illness potentially affecting device handling and previous training were associated with critical device handling errors. Most patients (85.4%) preferred DuoResp® Spiromax® over their previous device. Levels of inadequately controlled or uncontrolled asthma were reduced from baseline among patients using DuoResp® Spiromax® (8.6% versus 64.6%), and were higher in patients with critical handling errors. Conclusions: Effective patient education, correct inhaler technique, treatment adherence and devices associated with high patient satisfaction are interrelated factors key to the successful delivery of inhaled asthma therapy. Inhaler technique and patient device satisfaction should be routinely assessed in treated patients with uncontrolled asthma. Supplemental data for this article can be accessed at publisher's website.

Importance: The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting β2-agonist as maintenance plus short-acting β2-agonist as reliever., Objective: To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever among patients with poorly controlled asthma., Data Sources: For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever., Study Selection: Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher., Data Extraction and Synthesis: Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021., Main Outcomes and Measures: The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression., Results: Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting β2-agonist maintenance plus short-acting β2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85)., Conclusions and Relevance: In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever therapy.

Background: Recent asthma guidelines, such as the Global Initiative for Asthma (GINA), recommend in adult patients as-needed inhaled corticosteroids (ICS)-formoterol as an alternative to maintenance ICS in mild to moderate persistent asthma. The introduction of these recommendations concerns whether using as-needed budesonide-formoterol would be more cost-effective than to maintenance ICS. This study aimed to evaluate the cost-effectiveness of as-needed combination low-dose budesonide-formoterol compared to short-acting β2-agonist (SABA) reliever therapy in patients with mild asthma., Methods: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with mild asthma in Colombia. Total costs and QALYs of low-dose budesonide-formoterol compared to short-acting β2-agonist (SABA) were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000., Results: The model suggests a potential gain of 0.37 QALYs and per patient per year on as-needed ICS-formoterol and a reduction in the discounted cost per person-year, of as-needed ICS-formoterol to maintenance ICS, of US$40. This position of dominance of as-needed ICS-formoterol negates the need to calculate an incremental cost-effectiveness ratio. In the deterministic and probabilistic sensitivity analysis, our base-case results were robust to variations in all assumptions and parameters., Conclusion: Low-dose budesonide-formoterol as a reliever was cost-effective when added to usual care in patients with mild asthma. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries., (© 2021. The Author(s).)

Background: Previously evidence has demonstrated that as-needed combination low-dose budesonide-formoterol reduced the risk of severe exacerbations compared with short-acting β2-agonist (SABA) reliever therapy in an adolescent with mild asthma. Concerns as if the extra benefit offered by this drug outweighs the additional cost. This study aimed to evaluate the cost-effectiveness of as-needed combination low-dose budesonide-formoterol compared with short-acting β2-agonist (SABA) reliever therapy in adolescents with mild asthma in Colombia., Methods: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with mild asthma in Colombia. Total costs and QALYs of low-dose budesonide-formoterol compared with short-acting β2-agonist (SABA) were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000., Results: The model suggests a potential gain of 0.03 QALYs and per patient per year on low-dose budesonide-formoterol. The cost difference per person was US$-4 per patient per year in favor of budesonide- formoterol. The position of dominance negates the need to calculate an incremental cost-effectiveness ratio. In the one-way and probabilistic sensitivity analyses, our base-case results were robust to variations of all assumptions and parameters., Conclusion: In conclusion, low-dose budesonide-formoterol as a reliever was found to be cost-effective when added to usual care in adolescents with mild asthma. This evidence should promote economic evaluations in developed and developing countries for the inclusion of new drugs in health insurance plans., (© 2021 Wiley Periodicals LLC.)

Background: The efficacy of budesonide + formoterol therapy compared with high-dose salmeterol + fluticasone therapy plus short-acting β-agonist (SABA) has not been evaluated specifically in children. Objectives: To evaluate the efficacy and safety of budesonide + formoterol combination therapy two times a day plus as needed compared with salmeterol + fluticasone two times a day plus SABA (as needed) in children in China. Methods: This prospective cohort study included 164 children with persistent asthma (aged 12-17 years) who had experienced a minimum of one asthma exacerbation in 12 months prior to the study. The primary outcome was the time to the first severe exacerbation. Results: Eighty-two children were assigned to each of two groups. The exacerbation rate per 100 patients per year was not found to be significantly different. The number of patients with hospitalization/emergency room therapy was lower in budesonide + formoterol group, but the risk difference was not statistically significant. Asthma control measures showed comparable effects. Both treatments were well-tolerated. Conclusion: No significant differences were observed in the outcome measures between the groups. Budesonide + formoterol therapy is a favorable approach in terms of a low load of ICS, steroid exposure, need for multiple inhalers and cost.

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)-formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2). Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies. Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD-FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups. Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD-FORM (0.08 [95% confidence interval (CI), 0.06-0.10]) than with BUD maintenance (0.10 [95% CI, 0.09-0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56-0.98]; P  = 0.03), and similar results were shown in subgroup 2 with BUD-FORM (0.12 [95% CI, 0.10-0.14]) and BUD maintenance (0.10 [95% CI, 0.09-0.13]) (RR, 1.10 [95% CI, 0.86-1.41]; P  = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD-FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20-0.58]; P  < 0.001; subgroup 2: RR, 0.37 [95% CI, 0.25-0.54]; P  < 0.001). The number needed to treat to prevent one severe exacerbation with as-needed BUD-FORM and BUD maintenance versus as-needed terbutaline were 20 and 34 in subgroup 1 and 13 and 12 in subgroup 2, respectively. Conclusions: These findings suggest that, for patients with mild asthma currently receiving short-acting β 2 -agonists alone, as-needed low-dose ICS-FORM should be preferred over maintenance ICS as initial controller treatment. For patients whose asthma is controlled on maintenance low-dose ICS, as-needed BUD-FORM is an alternative to maintenance ICS without the need for daily treatment, and both of these options are safer than switching to short-acting β 2 -agonist-only treatment.