A Simulation Study of the Effect of Clinical Characteristics and Treatment Choice on Reliever Medication Use, Symptom Control and Exacerbation Risk in Moderate-Severe Asthma.

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.

In this study we looked at how different factors affect the response to asthma treatment in people with moderate to severe asthma who are taking regular medication. Specifically, we wanted to quantify how much asthma duration, differences in the degree of symptom control and lung function, as well as smoking habit, body weight, and sex influence how well someone responds to regular maintenance therapy. Using computer simulations based on models obtained from data in a large patient population with moderate­severe asthma, we explored scenarios that reflect real-life management of patients undergoing treatment with inhaled corticosteroids alone or in combination with long-acting beta agonists over a 12-month period. We looked at how much reliever inhaler they use, how well they rate their asthma control, and how often they have asthma attacks. By considering these results together, we evaluated how well the treatments work on ongoing symptoms and/or reduce the risk of future asthma attacks. Our simulations showed that smokers, people with higher asthma symptom scores, who are obese, and have a longer history of asthma tend to use their reliever inhalers more often. This was linked to a higher risk of having asthma attacks and worse symptom control. Switching those patients who do not respond well to their initial treatment with corticosteroid to combination therapy reduced how much reliever inhaler they need. Also, the effects of fluticasone propionate/salmeterol combination therapy were greater than budesonide/formoterol. In conclusion, our study found that certain patient characteristics can predict how well someone responds to asthma treatment.

[Diagnosis and therapy of patients with asthma in Germany. Results of the care study RELEVANT]. / Diagnostik und Therapie von Patienten mit Asthma in Deutschland : Ergebnisse der Versorgungsstudie RELEVANT.

BACKGROUND: Diagnostic and therapeutic options for asthma have improved with asthma control and remission being of central importance. The RELEVANT study aimed for a nationwide snapshot of current asthma diagnosis and treatment in general practice and specialty care for identification of further aspects for optimization. METHOD: RELEVANT is a nationwide cross-sectional study using a structured questionnaire. This comprised 14 questions on asthma-related topics covering diagnostics and therapy. Participants were general practitioners/internal medicine specialists and pulmonologists. RESULTS: A total of 1,558 persons took part in the survey. Regarding relevant specific diagnostic procedures for asthma, GPs/internists almost exclusively mentioned pulse oximetry. Among the pulmonologists, fractional exhaled nitric oxide (FeNO) measurement was mentioned, among others. FeNO and blood eosinophils were only mentioned by the pulmonologists as diagnostic and treatment-relevant markers. A total of more than 60% of the GPs/internists surveyed stated that only around 25% or fewer of their patients would voluntarily report restrictions in their everyday lives. Regarding drug treatment, the majority stated that they recognized differences between various ICS/LABA combination therapies. CONCLUSIONS: The results indicate a need for optimization, particularly regarding asthma control. This involves both a better assessment by patients' everyday life restrictions and modern ways of assessing asthma control in cooperation between GPs/internal medicine specialists and pulmonologists. One fifth of respondents do not see any differences between various ICS/LABA combinations in daily practice, although there are pharmacodynamic and pharmacokinetic differences.

Outcomes of Patients with COPD Treated with ICS/LABA Before and After Initiation of Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI).

INTRODUCTION: Triple therapy (fluticasone furoate/umeclidinium/vilanterol; FF/UMEC/VI) has been shown to improve symptoms and reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. This real-world study compared exacerbation rates and healthcare resource utilization (HCRU) before and after initiation of FF/UMEC/VI in patients with COPD previously treated with inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA). METHODS: This retrospective cohort study included commercial and Medicare Advantage with Part D administrative claims data from September 01, 2016, to March 31, 2020, of patients diagnosed with COPD. The index date was the date of the first FF/UMEC/VI claim (September 2017-March 2019). The 12 months prior to index (baseline) were used to assess patient characteristics and outcomes; the 12 months following index (follow-up) were used to assess study outcomes. All patients had ≥ 30 consecutive days' supply of any ICS/LABA dual therapy during the 12 months prior to FF/UMEC/VI initiation. Subgroup analyses included patients with ≥ 30 consecutive days' supply of budesonide/formoterol (BUD/FORM) during baseline. Analyses of patients with ≥ 1 COPD exacerbation during baseline were reported as well. RESULTS: The overall population included 1449 patients (mean age 70.75 years; 54.18% female), of whom 540 were patients in the BUD/FORM subgroup. Significantly fewer patients experienced any exacerbation during follow-up versus baseline (overall population 53.49% vs 62.59%; p < 0.001; BUD/FORM subgroup 55.00% vs 62.41%; p = 0.004). Effects on exacerbation reduction were more pronounced among patients with ≥ 1 exacerbation during baseline. Lower COPD-related HCRU was observed during the follow-up compared with baseline for both the overall population and the BUD/FORM subgroup. CONCLUSION: Patients with COPD treated with ICS/LABA during baseline, including patients specifically treated with BUD/FORM and those with a history of ≥ 1 exacerbation, had fewer COPD exacerbations and lower COPD-related HCRU after initiating FF/UMEC/VI.

Effect of Individual Patient Characteristics and Treatment Choices on Reliever Medication Use in Moderate-Severe Asthma: A Poisson Analysis of Randomised Clinical Trials.

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.

In this study, we tried to understand how patients with moderate to severe asthma use their quick-relief inhalers (like albuterol), how it relates to their symptoms and the risk of having asthma attacks. To evaluate whether differences in reliever inhaler use between patients are associated with factors like smoking or their asthma symptoms at the beginning of treatment, we gathered data from five clinical studies (n = 6212 patients). These data allowed us to create a model that predicts how often patients use their reliever inhalers (expressed as number of puffs in 24 h) during maintenance therapy with inhaled corticosteroids alone or in combination with long-acting beta agonists. The final model showed that reliever inhaler use is higher in patients who have been diagnosed with asthma for > 10 years, are smokers, have higher asthma symptom scores, and are obese or extremely obese. Patients who had asthma attacks also used their reliever inhalers more often. In addition, to understand how relief inhalers are used in real-life situations, we also created heatmaps that include a wide range of patient characteristics. By using individual patient data together with this model, we have learned that smoking, asthma control, BMI, long history of asthma and previous asthma attacks significantly influence reliever use. This information can help physicians and healthcare professionals understand know how well someone's asthma is managed. A patient who uses their reliever inhaler often is likely not to have their asthma well controlled by their regular medications.

Relationship Between Asthma Control Status and Health-Related Quality of Life in Japan: A Cross-Sectional Mixed-Methods Study.

INTRODUCTION: There is limited information regarding multidimensional relationships between asthma control and health-related quality of life (HRQoL), work productivity, and asthma symptom burden in Japan. Furthermore, systematic qualitative investigations about asthma burden have not been performed. METHODS: This cross-sectional, mixed-methods study included Japanese patients (≥ 20 years) with asthma adherent to inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA). The primary endpoint was impact of asthma on HRQoL, measured using the Asthma Health Questionnaire-33 (AHQ-33). Secondary endpoints were cough burden (Japanese-adapted Leicester Cough Questionnaire [J-LCQ]) and impact of asthma on work/activities (asthma-specific Work Productivity and Activity Impairment Questionnaire [WPAI:Asthma]). Quantitative data were assessed for the overall population and for well-controlled (WC) and not well-controlled (NWC) asthma subgroups. Qualitative verbal interviews further assessed the impact of NWC asthma on patients' HRQoL; emergent themes were extracted using thematic analyses. RESULTS: Of 454 patients, 45.2% (n = 205) had NWC asthma. Patients with NWC asthma had significantly worse asthma- and cough-related HRQoL across all AHQ-33 and J-LCQ domains and significantly greater work and activity impairment versus patients with WC asthma, across all assessed WPAI:Asthma domains. AHQ-33 total score was highly correlated with J-LCQ total and domain scores (r = - 0.8132 to r = - 0.7407). Nine themes emerged from qualitative interviews and confirmed that patients with NWC asthma had considerable HRQoL impairment due to asthma symptoms. CONCLUSIONS: Patients with NWC asthma had higher symptom burden and worse HRQoL than patients with WC asthma, despite ICS/LABA adherence. Cough burden correlated with HRQoL, suggesting cough may be one of the key markers to inform treatment strategy for patients with asthma.

Triple Therapy with Mometasone/Indacaterol/Glycopyrronium or Doubling the ICS/LABA Dose in GINA Step 4: IRIDIUM Analyses.

INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate-Severe Symptoms.

INTRODUCTION: The assessment of future risk has become an important feature in the management of patients with asthma. However, the contribution of patient-specific characteristics and treatment choices to the risk of exacerbation is poorly understood. Here we evaluated the effect of interindividual baseline differences on the risk of exacerbation and treatment performance in patients receiving regular maintenance doses of inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABA) combination therapy. METHODS: Exacerbations and changes to asthma symptoms 5-item Asthma Control Questionnaire (ACQ-5) were simulated over a 12-month period using a time-to-event and a longitudinal model developed from phase III/IV studies in patients with moderate-severe asthma (N = 16,282). Simulations were implemented to explore treatment performance across different scenarios, including randomised designs and real-world settings. Treatment options included regular dosing with ICS monotherapy [fluticasone propionate (FP)] and combination therapy [fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)]. Exacerbation rate was analysed using the log-rank test. The cumulative incidence of events was summarised stratified by treatment. RESULTS: Being a woman, smoker, having higher baseline ACQ-5 and body mass index (BMI) and lower forced expiratory volume in the first second (FEV1) are associated with increased exacerbation risk (p < 0.01). This risk is bigger in winter because of the seasonal variation effect. Across the different scenarios, the use of FP/SAL resulted in a 10% lower annual incidence of exacerbations relative to FP or regular dosing BUD/FOR, independently of baseline characteristics. Similar differences in the annual incidence of exacerbations were also observed between treatments in obese patients (BMI ≥ 25-35 kg/m2) (p < 0.01) and in patients who do not achieve symptom control on FP monotherapy. CONCLUSIONS: Individual baseline characteristics and treatment choices affect future risk. Achieving comparable levels of symptom control whilst on treatment does not imply comparable risk reduction, as shown by the lower exacerbation rates in FP/SAL vs. BUD/FOR-treated patients. These factors should be considered as a basis for personalised clinical management of patients with moderate-severe asthma.

The goal of this project was to demonstrate that individual baseline characteristics can affect the risk of exacerbation as well as the overall treatment response in patients receiving regular maintenance doses of inhaled corticosteroids, given as monotherapy or in combination with long-acting beta-agonists. Using computer simulations based on a drug­disease model previously developed from a large pool of patients with moderate­severe asthma symptoms (N = 16,282), we describe how demographic and clinical baseline patient characteristics at the time of treatment start correlate with the risk of exacerbation. Our results indicate that poor symptom control, limited lung function, obesity, smoking and sex are associated with significant increase in the incidence of asthma attacks. Such an effect is augmented in winter because of the contribution of seasonal variation. This analysis also allowed us to assess how different treatments modify or reduce the annual incidence of moderate to severe attacks. In addition, simulated scenarios showed that combination therapy with fluticasone propionate/salmeterol results in 10% fewer asthma attacks relative to budesonide/formoterol combination therapy. Such a difference may be associated with corticosteroid-specific properties, which vary between inhaled corticosteroids. Consequently, even though comparable level of immediate relief and symptom control may be achieved whilst on treatment, these effects do not imply the same long-term reduction in the risk of exacerbation. These factors should be considered as a basis for personalised clinical management of patients with moderate­severe asthma.

Defined daily dose definition in medication adherence assessment in asthma.

Adherence to inhaled corticosteroids (ICS) has been described as poor. In adherence studies, if the actual prescribed dosing is not available, generic defined daily doses (DDD) are applied instead when assessing adherence. We evaluated asthma patients' adherence in a large prospective follow-up survey. We also analysed whether World Health Organization (WHO) and Global Initiative for Asthma (GINA) reference doses give different results. The current study was cross-sectional and included respondents attending to HeSSup follow-up questionnaire in 2012. Altogether 1,141 of 12,854 adult participants answered positively to the question about having asthma. According to the Finnish Social Insurance Institutions' medication register, 686 of them had purchased ICS medication during 2011. DDDs for ICS by WHO as well as medium doses from GINA report were used as reference doses to evaluate adherence. To estimate adherence to ICS, the proportion of days covered (PDC) over one year was calculated for every patient. If the lower limit of GINA medium ICS dose was used as a reference, 65% of the patients were adherent (PDC ≥ 80%). Use of WHO's DDD as reference halved the proportion of adherent patients. Adherence was higher among those using a combination inhaler of corticosteroid and long-acting ß2-agonist compared to those using steroid only inhalers. Use of WHO's daily defined doses as reference values may lead to underestimation of adherence to inhaled corticosteroids. Thus, attention should be paid when choosing the reference doses for the evaluation of adherence to inhaled corticosteroids in asthma.

Comparative Effectiveness of Umeclidinium/Vilanterol versus Inhaled Corticosteroid/Long-Acting ß2-Agonist in Patients with Chronic Obstructive Pulmonary Disease in a Primary Care Setting in England.

Purpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England. Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as >0% difference between treatment groups. Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p<0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied. Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.

Characteristics of Oral Corticosteroid Users Among Persons with Asthma on GINA Step 3 Therapy and Above: A Cross-Sectional Study in Portuguese Community Pharmacies.

Purpose: Oral corticosteroids (OCS) are frequently used in asthma management but have an important risk-profile. The aim of the study is to characterize and compare the sociodemographic and clinical characteristics, treatment regimen and asthma control between OCS users and non-users among the population of asthma patients (≥18 years) at GINA step 3 and above treated with a fixed combination of an inhaled corticosteroid and a long-acting beta-agonist (ICS/LABA). Methods: Cross-sectional study in Portuguese community pharmacies. Data was collected via paper-based interview delivered at the pharmacy (sociodemographic characteristics and asthma treatment regimen, namely ICS/LABA and OCS utilization), followed by a telephonic interview collecting smoking history, comorbidities, body mass index (BMI), history of exacerbations and asthma-related healthcare resource utilization (HCRU) in the previous 12 months, as well as asthma control using the Control of Allergic Rhinitis and Asthma Test (CARAT®). Results: A total of 347 patients recruited in 98 pharmacies were included in the analysis. Of those, 328 had completed both questionnaires. A quarter of the individuals reported OCS use in the previous 12 months (OCS users), either as add-on therapy (6%) or exacerbation treatment (19%). Patients were mostly females (72%), with an average age of 59.5 years (SD=15.4). OCS users were significantly older and reported more frequently having conjunctivitis (25.9% vs 15.0%), osteoporosis (25.9% vs 13.4%), arthritis (14.6% vs 6.9%), and gastrointestinal disease (16.1% vs 8.1%). OCS users also reported greater urgent HCRU: unscheduled consultations (33.3% vs 9.3%) and emergency department (ED) visits (32.1% vs 12.1%). Both groups presented poor disease control (85.2% of OCS users vs 72.9% of non-OCS users). Conclusion: These results highlight the burden of OCS therapy to asthma patients and the need to improve asthma management, by adopting OCS sparing strategies in this subgroup of patients.

Impact of inhaled fluticasone propionate/salmeterol on health-related quality of life in asthma: A network meta-analysis.

OBJECTIVE: This network meta-analysis (NMA) compared fixed-dose, twice daily fluticasone propionate/salmeterol (FP/Sal) vs. inhaled corticosteroid (ICS) and other ICS/long-acting beta-agonists (LABA) treatments, including when administered using maintenance and reliever therapy (MART) regimens, in terms of improvements in health-related quality of life (HRQoL). The relationship between changes in asthma control and HRQoL was assessed. METHODS: Articles published between 2001 and 2021, reporting change from baseline (CFB) in Asthma Quality of Life Questionnaire (AQLQ) in patients with moderate-to-severe asthma, were identified by a systematic review. Random effects Bayesian NMAs derived estimates of the mean difference in CFB in AQLQ vs. other interventions connected to the network (included 15 studies). Sensitivity analyses explored the impacts of differences in follow-up duration, baseline asthma control, the inclusion of observational studies, adjusting for baseline FEV1, and low-medium ICS dose arms only. Linear regression analysis compared CFBs in AQLQ and Asthma Control Questionnaire (ACQ) score. RESULTS: Mean CFB in AQLQ with FP/Sal vs. comparators demonstrated expected ranked effects: mean difference 0.65 [95% credible interval: 0.54, 0.78] versus placebo, 0.58 [ 0.33, 0.84] versus LABA, 0.21 [ 0.13, 0.31] versus ICS alone, 0.06 [-0.04, 0.19] versus other ICS/LABA, and 0.00 [-0.13, 0.14] versus ICS/formoterol MART. Sensitivity analyses largely showed consistent results. Improvements in AQLQ and ACQ were strongly correlated (R = 0.94). CONCLUSIONS: This NMA demonstrates that HRQoL is responsive to treatment, is strongly related to asthma control and that it can be well-managed in patients with moderate-to-severe asthma using regular treatment with inhaled FP/Sal.

Effect of Recent Exacerbation History on the Efficacy of Once-Daily Single-Inhaler Fluticasone Furoate/Umeclidinium/Vilanterol Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease in the FULFIL Trial.

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.

Assessment of Real-World Escalation to Biologics in US Patients With Asthma.

BACKGROUND: Previous studies indicate that suboptimal medication adherence may contribute to uncontrolled asthma. Global Initiative for Asthma (GINA) guidelines recommend treatment escalation to biologics for patients with uncontrolled asthma despite adherence to high-dose maintenance medication and who have eosinophilic/allergic biomarkers or require maintenance oral corticosteroids. OBJECTIVE: This study aimed to describe the clinical status of patients with asthma escalated to biologic therapy. METHODS: This retrospective claims database analysis enrolled US patients with asthma who were escalated to biologics between January 2016 and June 2020. Exacerbations, control status, GINA step, and maintenance medication adherence during the 12 months before biologic therapy initiation were analyzed. Asthma control was assessed using both the European Respiratory Society/American Thoracic Society (ERS/ATS) and Stempel criteria. Adherence was defined as the proportion of days covered (PDC) by maintenance medication claims. RESULTS: Of 1786 patients escalated to biologics, 506 were included for analysis. During the 12 months before escalation, 346 patients had confirmed exacerbations. Uncontrolled asthma status was estimated in 55% and 70% of patients (ERS/ATS and Stempel criteria, respectively). GINA step was inferred for 395 patients: 154 were at step 2, 11 at step 3, 104 at step 4, and 126 at step 5. Of 403 patients with maintenance medication claims, 63% had suboptimal maintenance medication adherence (PDC <80%). CONCLUSION: In this study, most patients initiating biologic therapy had mild-to-moderate asthma or suboptimal maintenance medication adherence, possibly indicating inappropriate escalation. Incorporating objective medication adherence monitoring into existing guidelines may reduce inappropriate escalation to biologics.

Assessment of Symptoms Control, Pulmonary Function and Related Quality of Life in Asthmatic Patients Treated with Extrafine Beclomethasone Dipropionate/Formoterol Fumarate 100/6 µg pMDI: Results of a Multicenter Observational Study in Romania (ALFRESCO Study).

Introduction: Asthma treatment guidelines advocate the use of long-acting beta2-agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone. This is the first study done in Romania, which collected the real-world data on the effects of Foster® (extrafine beclomethasone dipropionate/formoterol fumarate BDP/FF in a pressurized metered-dose inhaler pMDI 100/6 µg formulation) in adult asthmatic population. Objective: We aimed to assess the asthma symptoms control, pulmonary function and quality of life parameters in a heterogeneous Romanian asthmatic adult outpatient population, treated with extrafine BDP/FF 100/6 µg pMDI. Methods: This was a prospective, multicenter, observational study involving 30 pulmonologists randomly selected from the Romanian healthcare system, which did not declare any competing interests. Recruitment period was Oct 2018 - Feb 2019, while the patients' observational period was 24 weeks. The study included poorly controlled and uncontrolled adult asthma outpatients treated with non-extrafine formulations medication, for which the treatment indication, according to Global Initiative for Asthma (GINA) 2018, was the use of an ICS-LABA combination. The study collected demographic data, smoking habits, comorbidities, data regarding asthma diagnosis, the evolution of asthma symptoms, spirometry, Asthma Control Questionnaire (ACQ-7) scoring test, current and concomitant treatment. Results: Of 302 included patients, 290 completed the study. Pulmonary function parameters assessed during the trial (forced expiratory volume in one second - FEV1 and forced vital capacity - FVC) showed a significant improvement versus baseline (p<0.001). ACQ-7 score decreased significantly from 3.09±0.83 (visit 1) to 1.56±0.89 (visit 2) and to 1.09±0.81 (visit 3) (p<0.001). At the end of the study, 127 (43.79%) patients were well controlled (ACQ-7 score < 0.75). Conclusion: This observational study demonstrates the effectiveness and safety of extrafine fixed combination of BDP/FF (100/6 µg) pMDI in Romanian adult asthma patients uncontrolled with non-extrafine medication in a real-world setting, leading to clinically and statistically improvements in asthma control and pulmonary function.

A review of the efficacy and safety of fluticasone propionate/formoterol fixed-dose combination.

INTRODUCTION: Fluticasone propionate/formoterol fumarate (FP/FORM) is one of the newer combinations among inhaled corticosteroid (ICS) and long-acting ß2-agonist (LABA) combination formulations currently available. To evaluate the efficacy and safety of this FP/FORM combination, it is important to review all the available evidence and take a comprehensive look at the current and relevant data in the patient population suffering from asthma and chronic obstructive pulmonary disease (COPD). AREAS COVERED: In this focused review, we summarize the available literature published until January 2021 using the PubMed/Medline and Cochrane Controlled Trials Register databases on the efficacy and safety of FP/FORM with its mono-components; concurrent administration of FP+FORM; and with other ICS/LABA combinations in asthma and COPD patients. EXPERT OPINION: FP/FORM combination therapy is a strong alternative in the treatment of persistent asthma and moderate-severe COPD. Extensive study of several trials has established the superior efficacy of FP/FORM combination therapy over FP or FORM monotherapy, comparable efficacy with FP+FORM and non-inferiority to other ICS/LABA fixed-dose combinations. The safety profile of FP/FORM has also been found to be comparable with respect to its mono-components and their concurrent use, and also other ICS/LABA combinations such as formoterol/budesonide and fluticasone/salmeterol.

Expert Opinion on Practice Patterns in Mild Asthma After the GINA 2019 Updates: A Major Shift in Treatment Paradigms from a Long-Standing SABA-Only Approach to a Risk Reduction-Based Strategy with the Use of Symptom-Driven (As-Needed) Low-Dose ICS/LABA.

PURPOSE OF REVIEW: This expert opinion, prepared by a panel of chest disease specialists, aims to review the current knowledge on practice patterns in real-life management of mild asthma and to address the relevant updates in asthma treatment by The Global Initiative for Asthma (GINA) to guide clinicians for the best clinical practice in applying these new treatment paradigms. RECENT FINDINGS: On the basis of the emerging body of evidence suggesting the non-safety of short-acting ß2-agonists (SABA)-only therapy and comparable efficacy of the as-needed inhaled corticosteroids (ICS)-formoterol combinations with maintenance ICS regimens, GINA recently released their updated Global Strategy for Asthma Management and Prevention Guide (2019). The new GINA 2019 recommendations no longer support the SABA-only therapy in mild asthma but instead includes new off-label recommendations such as symptom-driven (as-needed) low-dose ICS-formoterol and "low dose ICS taken whenever SABA is taken." The GINA 2019 asthma treatment recommendations include a major shift from long-standing approach of clinical practice regarding the use of symptom-driven SABA treatment alone in the management of mild asthma. This expert opinion supports the transition from a long-standing SABA-only approach to a risk reduction-based strategy, with the use of symptom-driven (as-needed) low-dose ICS/LABA in mild asthma patients, particularly in those with poor adherence to controller medications. The thoughtful and comprehensive approach of clinicians to these strategies is important, given that the exact far-reaching impact of this major change in management of mild asthma in the real-world settings will only be clarified over time.

A Pilot Randomized Trial of As-Needed Budesonide-Formoterol for Stepping Down Controller Treatment in Moderate Asthma with Complete Remission.

BACKGROUND: The use of low-dose inhaled corticosteroid-formoterol as reliever monotherapy has recently been recommended in the asthma treatment guidelines. However, the efficacy of this treatment strategy has not yet been determined during the stepping-down period in moderate asthma. This study aimed to evaluate the feasibility of reducing treatment to as-needed budesonide-formoterol (BFM) in moderate asthma with complete remission. METHODS: We randomly assigned 31 patients (8 males and 23 females with a mean age of 57.2 years) with complete remission of asthma by inhaled BFM (160/4.5 µg) twice daily to receive BFM (160/4.5 µg) as needed (16 patients), or budesonide (BUD) (200 µg) twice daily (15 patients). The study was an open-label study done for 48 weeks, with the primary outcome as the cumulative percentages of patients with treatment failure (asthma exacerbation or loss of asthma control or lack of satisfaction after using medications) in the two groups. RESULTS: Six patients (42%) using as-needed BFM had treatment failure, as compared with three patients (21.4%) using BUD maintenance (hazards ratio for as-needed BFM, 1.77; 95% confidential interval, 0.44-7.12; p=0.41). The changes in forced expiratory volume in 1 second were -211.3 mL with as-needed BFM versus -97.8 mL with BUD maintenance (difference, 113.5 mL; p=0.75) and the change in fractional exhaled nitric oxide was significantly higher in both groups, at 8.68 parts per billion (ppb) in the as-needed BFM group and 2.5 ppb. in the BUD maintenance group (difference, 6.18 ppb; p=0.049). CONCLUSION: Compared with BUD maintenance, there were no significant differences in treatment failure rate in patients who received as-needed BFM during the stepping down period in moderate asthma. However, they showed reduced lung function and relapsed airway inflammation. The results are limited by imprecision, and further large RCTs are needed.

Direct healthcare costs associated with management of asthma: comparison of two treatment regimens in Indonesia, Thailand and Vietnam.

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.

A Practical Guide to Implementing SMART in Asthma Management.

The use of a single inhaler containing the combination of an inhaled corticosteroid (ICS) and formoterol, a specific long-acting bronchodilator, for both maintenance and quick relief therapy (single maintenance and reliever therapy [SMART or MART]) is recommended by both the Global Initiative for Asthma and the National Asthma Education and Prevention Program Coordinating Committee in steps 3 and 4 of asthma management. This article provides practical advice about implementing SMART in clinical practice based on evidence and clinical experience. Fundamental to SMART is that ICS-formoterol provides quick relief of asthma symptoms similar to that of short-acting ß2-agonists such as albuterol, while reducing the risk for severe asthma exacerbations and at an overall lower ICS exposure. Most SMART clinical trials were in adults and adolescents (aged ≥12 years), using budesonide-formoterol 160/4.5 µg (delivered dose), one inhalation once or twice daily (step 3) and two inhalations twice daily (step 4). For both steps 3 and 4, patients take additional inhalations of budesonide-formoterol 160/4.5 µg, one inhalation whenever needed for symptom relief, up to a maximum for adults and adolescents of 12 total inhalations in any single day (delivering 54 µg formoterol). The efficacy and safety of SMART with budesonide-formoterol and beclometasone-formoterol have been confirmed, but other ICS-long-acting bronchodilator combinations have not been studied. The SMART regimen should be introduced with a careful explanation of its role in self-management, preferably with a customized written asthma action plan. The cost to patients and the availability of SMART treatment will depend on the prescribed dose and national or local payer agreements.

Management of patients with severe asthma: results from a survey among allergists and clinical immunologists of the Central Italy Inter-Regional Section of SIAAIC.

BACKGROUND: Asthma, and severe asthma in particular, is often managed within a specialized field with allergists and clinical immunologists playing a leading role. In this respect, the National Scientific Society SIAAIC (Società Italiana di Allergologia, Asma ed Immunologia Clinica), structured in Regional and Inter-Regional sections, interviewed a large number of specialists involved in the management of this respiratory disease. METHODS: A survey entitled "Management of patients with asthma and severe asthma" based on 17 questions was conducted through the SIAAIC newsletter in 2019 thanks to the collaboration between GlaxoSmithKline S.p.A. and the Inter-Regional Section of SIAAIC of Central Italy. RESULTS: Fifty-nine allergists and clinical immunologists participated to the survey, and 40 of them completed the entire questionnaire. Almost all of the specialists (88%) reported that asthma control was achieved in above 50% of their patients, even if only one third (32%) actually used validated clinical tools such as asthma control test (ACT). Poor adherence to inhaled therapy was recognized as the main cause of asthma control failure by 60% of respondents, and 2-5 min on average is dedicated to the patient inhaler technique training by two-thirds of the experts (65%). Maintenance and as-needed therapy (SMART/MART) is considered an appropriate approach in only a minority of the patients (25%) by one half of the respondents (52%). A high number of exacerbations despite the maximum inhalation therapy were recognized as highly suspicious of severe asthma. Patients eligible for biological therapies are 3-5% of the patients, and almost all the responders (95%) agreed that patients affected by severe asthma need to be managed in specialized centers with dedicated settings. Biological drugs are generally prescribed after 3-6 months from the initial access to the center, and once started, the follow-up is initially programmed monthly, and then every 3-6 months after the first year of treatment (96% of responders). After phenotyping and severity assessment, comorbidities (urticaria, chronic rhinosinusitis with or without nasal polyps, vasculitis, etc.) are the drivers of choice among the different biological drugs. In the management of severe asthma, general practitioners (GPs) should play a central role in selecting patients and referring them to specialized centers while Scientific Societies should train GPs to appropriately recognize difficult asthma and promote public disease awareness campaigns. CONCLUSIONS: This survey which collects the point of view of allergists and clinical immunologists from Central Italy highlights that asthma control is still not measured with validated instruments. There is a general consensus that severe asthma should be managed only in dedicated centers and to this aim it is essential to encourage patient selection from a primary care setting and develop disease awareness campaigns for patients.