Rate Of Severe Exacerbations Research Articles

Modeling severe uncontrolled asthma: transitioning away from health states

BackgroundModels developed to date to simulate long-term outcomes of asthma have been criticized for lacking granularity and ignoring disease heterogeneity. ObjectiveTo propose an alternative approach to modeling asthma and apply it to model long-term outcomes in a population with moderate-to-severe type 2 asthma (patients with raised fractional exhaled nitric oxide or eosinophils) and treated with conventional therapy. MethodsA discretely integrated condition event (DICE) approach was adopted, simulating individual profiles with asthma over patients’ lifetime in terms of exacerbations, asthma-related death, and death unrelated to asthma. The timing of these events is dependent on profile characteristics including lung function, asthma control, exacerbation history, and other baseline characteristics or contextual factors. Predictive equations were derived from a clinical trial to model time to exacerbation, change in asthma control, lung function, and utility. Real-world studies were used to supplement data gaps. Outcomes evaluated included life expectancy, quality-adjusted life-years (QALY), number of exacerbations, and lung function over time. ResultsAverage annual rates of severe and moderate exacerbations were 1.82 and 3.08 respectively, with rates increasing over time. Lung function declined at a higher rate compared with the general population. Average life expectancy was 75.2 years, compared with 82.4 years in a matched general population. The majority of life-years were spent with uncontrolled asthma and impaired lung function. ConclusionPatients with moderate-to-severe type 2 asthma and a history of exacerbations suffer from frequent exacerbations and reduced lung function and life expectancy. Capturing multiple conditions to simulate long-term outcomes in patients with asthma may provide more realistic projections of exacerbation rates.

Epidemiology of bronchiectasis at a single center in Japan: a retrospective cohort study

BackgroundThe characteristics of bronchiectasis (BE) in Asia, including Japan, remain largely unknown. We aimed to provide insights into the clinical characteristics and treatment outcomes of BE, especially regarding nontuberculous mycobacteria (NTM) infection and its poorly understood impact on prognosis. We also aimed to clarify the effect of long-term macrolide antibiotic use in patients with BE, who had no history of exacerbations.MethodsIn this single-center, retrospective study, the medical records of patients who satisfied the BE criteria between January 1, 2012, and August 31, 2023, were reviewed. Severe exacerbations and mortality during the observation period were recorded. Baseline characteristics and overall survival of patients with and without NTM infection, and factors influencing the time to the first exacerbation and death were analyzed. Additionally, the effects of long-term macrolide antibiotic use in patients without a history of severe exacerbations were estimated.ResultsIn a cohort of 1044 patients with BE, the rate of severe exacerbation was 22.3%, with mortality rates of 3.2% over 3 years. Notably, the high prevalence of NTM infection (n = 410, 39.3%) in this cohort was distinctive. NTM infection was not associated with either the time to first severe exacerbation (p = 0.5676, adjusted hazard ratio = 1.11) or mortality (p = 0.4139, adjusted hazard ratio = 0.78). Compared with the NTM group, the non-NTM group had a higher proportion of elevated inflammatory markers, with significant differences in C-reactive protein levels (p = 0.0301) and blood neutrophil counts (p = 0.0273). Pseudomonas aeruginosa colonization was more frequent in the non-NTM group (p = 0.0003). Among patients with non-NTM infection and without a history of exacerbation in the past 2 years, 38.2% received long-term macrolide antibiotics that did not invariably prolong the time to first severe exacerbation (p = 0.4517, IPW p = 0.3555).ConclusionsThis study highlights BE epidemiology in Japan, noting that the presence of NTM infection may not necessarily worsen the prognostic outcomes and advising caution in the casual use of macrolides for milder cases without a history of exacerbations.Clinical trial registrationUMIN Clinical Trials Registry Number: UMIN000054726 (Registered on 21 June 2024).

Exacerbation history and blood eosinophil count prior to diagnosis of COPD and risk of subsequent exacerbations.

Prior exacerbation history is used to guide initial maintenance therapy in COPD; however, the recommendations were derived from patients already diagnosed and treated. We assessed the rates of moderate (i.e. treated with antibiotics and/or systemic corticosteroids) and severe (i.e. hospitalised) exacerbations in the year following diagnosis in patients newly diagnosed with COPD according to their prior history of exacerbations, blood eosinophil count (BEC) and whether maintenance therapy was started. Data were extracted from the Optimum Patient Care Research Database. 73 189 patients were included. 61.9% had no exacerbations prior to diagnosis, 21.5% had 1 moderate, 16.5% had ≥2 moderate and 0.3% had ≥1 severe. 50% were started on maintenance therapy. In patients not started on maintenance therapy the rates of moderate exacerbations in the year after diagnosis in patients with no, 1 moderate, ≥2 moderate and ≥1 severe prior exacerbations were 0.34 (95% CI 0.33-0.35), 0.59 (95% CI 0.56-0.61), 1.18 (95% CI 1.14-1.23) and 1.21 (95% CI 0.73-1.69), respectively. Similar results were seen in patients started on maintenance therapy. BEC did not add significantly to the prediction of future exacerbation risk. A single moderate exacerbation in the year prior to diagnosis increases the risk of subsequent exacerbations, and more frequent or severe exacerbations prior to diagnosis are associated with a higher risk.

Trends in COPD severe exacerbations, and all-cause and respiratory mortality, before and after implementation of newer long-acting bronchodilators in a large population-based cohort

BackgroundLittle is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes.MethodsWe used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed.ResultsThere were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived).ConclusionsThe arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups.

Treatment patterns in patients with newly diagnosed COPD in the USA

BackgroundPrompt and effective management with maintenance therapy (single or dual bronchodilator therapy) is recommended after the initial diagnosis of chronic obstructive pulmonary disease (COPD) to maintain lung function and prevent exacerbations. Contrary to guideline-based recommendations, most patients are not prescribed maintenance treatment at initial diagnosis. The current study assessed the pharmacologic treatment patterns and outcomes of newly diagnosed patients with COPD in the USA.MethodsThis retrospective, noninterventional study used de-identified data from the Inovalon Insights’ database (Commercial, Medicaid Managed Care, and Medicare Advantage–insured individuals) between January 1, 2015, and December 31, 2021. The “patient journey” from initial diagnosis was followed over a 4-year period. The primary outcome measure was the number of moderate or severe exacerbations. Secondary outcome measures included the cumulative incidence of exacerbations, mean cumulative count of moderate and severe exacerbations, rates of moderate and severe exacerbations in patients who remained untreated after diagnosis in 12-month time periods for 4 years, sociodemographic and clinical characteristics, and pharmacologic treatment patterns.ResultsThe cohort consisted of 238,158 newly diagnosed patients with COPD (female [52.9%]; mean age 63.8 years). The majority of patients with COPD had Medicaid as their primary insurance (46.2%). Overall, during the 4-year follow-up period, 32.9% of the patients had at least one moderate or severe exacerbation, and 25.8% and 13.8% experienced moderate and severe exacerbations, respectively. At diagnosis, 86.2% of the patients were untreated and most remained untreated by the end of the follow-up (63.8%). Most patients (62.0%) received long-acting beta-agonist (LABA)/inhaled corticosteroids (ICS) as their initial treatment at diagnosis, and LABA/ICS continued to be the most common initial treatment during the 4-year period (64.0% at year 1; 58.0% at year 4).ConclusionsMost patients with COPD were not treated at initial diagnosis and remained untreated during follow-up. Our data highlight a lack of adherence to recommendations for clinical practice.

Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history

BackgroundJapanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count – focusing on blood EOS count 100 to < 300 cells/mm3 – as a function of exacerbation history and COPD severity.MethodsIn KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12–24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses.ResultsAmong patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD.ConclusionsThese post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations.Trial registrationClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

Dupilumab Efficacy in Children With Type 2 Asthma Receiving High- to Medium-Dose Inhaled Corticosteroid (VOYAGE)

In phase 3 VOYAGE (NCT02948959), dupilumab showed clinical efficacy with an acceptable safety profile in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb). We analyzed dupilumab's efficacy in children with type 2 asthma by high- or medium-dose inhaled corticosteroids (ICS) at baseline. Children were randomized to receive add-on dupilumab 100/200 mg (by body-weight ≤30 kg/>30 kg) every 2 weeks or placebo for 52 weeks and stratified by high- or medium-dose ICS at baseline. Endpoints were annualized severe exacerbation rate, changes from baseline in percent-predicted forced expiratory volume in 1 second (ppFEV1) and 7-item Asthma Control Questionnaire - Interviewer Administered (ACQ-7-IA) score, proportions of ACQ-7-IA responders (improvement ≥0.5), and biomarker changes. In children receiving high- (n = 152) or medium- (n = 195) dose ICS at baseline, dupilumab versus placebo reduced severe exacerbation rates by 63% (P < .001) and 59% (P = .003), respectively. At week 52, dupilumab improved ppFEV1 by least squares mean difference versus placebo of 5.7 percentage points (P = .02) and 9.35 points (P < .001), and reduced ACQ-7-IA scores by 0.53 points (P < .001) and 0.40 points (P < .001), respectively. No significant treatment interactions between ICS subgroups were detected at week 52. Significant improvements were observed in ACQ-7-IA responder rates and most type 2 biomarker levels. Dupilumab reduced severe exacerbation rates and improved lung function and asthma control in children with uncontrolled, moderate-to-severe type 2 asthma, regardless of ICS dose at baseline.

Longitudinal Changes in Maximal Forced Inspiratory Flow and Clinical Outcomes in Patients With COPD

BackgroundChronic obstructive pulmonary disease (COPD) primarily impairs expiratory flow due to progressive airflow obstruction and reduced lung elasticity. Increasing evidence underlines the importance of inspiratory flow as a biomarker for selecting inhaler devices and providing ancillary aerodynamic information. Research QuestionDoes the longitudinal changes in maximum forced inspiratory flow (FIFmax) influence acute exacerbations and lung function decline in COPD patients? Study Design and MethodsThis longitudinal study observed FIFmax in COPD patients over a 7-year period from 2004 to 2020. Eligible patients were categorized into two groups based on FIFmax trajectory: the increased FIFmax group and the decreased FIFmax group. Our study assessed the annual rate of acute exacerbations and the annual decline rate of forced expiratory volume in 1 second (FEV1). Subgroup analyses were conducted based on treatment status, with a focus on inhaled therapy and inhaler device usage. ResultsAmong the eligible 956 COPD patients, 56.5% belonged to the increased FIFmax group. After propensity score matching, the increased FIFmax group experienced lower rates of severe exacerbations (0.16/yr vs. 0.25/yr, P-value=0.017) and a slower decline in FEV1 (0 [interquartile range (IQR), -51–71] vs. -43 [IQR, -119–6] ml/yr, P-value<0.001) compared to the decreased FIFmax group. These associations were particularly prominent in patients using specific inhaler therapies, such as DPI therapies. InterpretationOur study revealed that the longitudinal changes in FIFmax are associated with clinical outcomes in COPD patients. Patients with increased FIFmax experienced a lower rate of severe exacerbations and a slower decline in lung function. These findings suggest the potential benefits of optimizing inspiratory flow in COPD management, though further studies are needed to confirm these observations due to potential confounding factors.

Real-world biomarker variability and effects of biologics on severe asthma in Alberta

Rationale: Guidelines recommend biomarker testing to phenotype patients with severe asthma (SA), to guide treatment. However, biomarker levels fluctuate, and individual responses to biologics are not fully understood. Objectives: This study estimated the proportion of patients experiencing biomarker variability and the real-world effectiveness of biologics in SA. Methods: A population-based retrospective cohort study was conducted using administrative data from Alberta, Canada (April 1, 2010 to March 31, 2020) for patients with SA. Year-to-year variability in biomarker levels was assessed using clinical thresholds (blood eosinophil count [EOS] ≥ 300 cells/µL; immunoglobin E [IgE] ≥ 30 IU/mL) to explore category switching. Incidence rate ratios of exacerbations were estimated by biomarker level. Associations between follow-up time with biologics exposure (bio-experience), biomarker levels and exacerbation rates were modeled. Results: Up to 28% of SA patients displayed year-over-year biomarker threshold switching for EOS and up to 12% for IgE. Severe exacerbation rates were higher with blood EOS count ≥300cells/µL or IgE ≥30 IU/mL. Bio-experience was associated with lower blood EOS versus pre-bio-experience (relative mean EOS: 0.53 [0.42-0.68]), persisting >1 year following discontinuation. Bio-experience was associated with a nearly 50% reduction in exacerbation risk after initiating biologics (IRR = 0.54 [0.48, 0.62]), regardless of comorbid status. Conclusions: Higher biomarker levels were associated with higher exacerbation rates, but a proportion of patients demonstrated variability, crossing clinical thresholds. Treatments with upstream agents targeting multiple pathways of inflammation may circumvent this issue. Biologics had real-world effectiveness in reducing SA biomarkers. Their persistent temporal effect provides a groundwork for exploring cost-effective biologics use.

Dupilumab 200 mg was efficacious in children (6-11 years) with moderate-to-severe asthma for up to 2 years: EXCURSION open-label extension study.

The phase 3 VOYAGE (NCT02948959) and open-label extension EXCURSION (NCT03560466) studies evaluated dupilumab in children (6-11 years) with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed the efficacy and safety of add-on dupilumab 200 mg every 2 weeks (q2w), the largest dose cohort in both studies, in children from VOYAGE who participated in EXCURSION. Annualized rate of severe asthma exacerbations (AERs), change in prebronchodilator percent predicted forced expiratory volume in 1 s (ppFEV1), and treatment-emergent adverse events were assessed in children with moderate-to-severe asthma who received dupilumab 200 mg q2w in VOYAGE and EXCURSION (dupilumab/dupilumab arm) and those who received placebo in VOYAGE and dupilumab 200 mg q2w in EXCURSION (placebo/dupilumab arm). These endpoints were also assessed in children with moderate-to-severe type 2 asthma (defined as blood eosinophil count ≥150 cells/µL or FeNO ≥20 ppb at the parent study baseline [PSBL]). In the overall population, dupilumab reduced AER and improved prebronchodilator ppFEV1 in the dupilumab/dupilumab arm (n = 158) for up to 2 years. Children receiving placebo/dupilumab (n = 85) showed similar reductions after initiation of dupilumab 200 mg q2w in EXCURSION. Similar results were observed for children with type 2 asthma at PSBL. The safety profile was consistent with the known safety profile of dupilumab. In children (6-11 years) with uncontrolled moderate-to-severe type 2 asthma, dupilumab 200 mg reduced exacerbation rates and improved lung function for up to 2 years and showed safety consistent with the known dupilumab safety profile.

Long-term Safety and Efficacy of Dupilumab in Patients With Uncontrolled, Moderate-to-Severe Asthma Recruited From Korean Centers: A Subgroup Analysis of the Phase 3 LIBERTY ASTHMA TRAVERSE Trial.

Long-term data are limited on the safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma from Korea. The current subgroup analysis was designed to evaluate the long-term safety and efficacy of dupilumab in patients enrolled from Korean centers in the parent studies (phase 2b and QUEST) and who participated in the TRAVERSE open-label extension (OLE) study. TRAVERSE was a global, multicenter, OLE study that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks for up to 96 weeks in patients (n = 2,282) with uncontrolled, moderate-to-severe asthma who completed prior dupilumab asthma clinical trials. The primary outcome was the incidence of any treatment-emergent adverse events (TEAEs); the secondary outcomes included annualized severe exacerbation rate, pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and 5-item Asthma Control Questionnaire (ACQ-5) score. Safety outcomes were consistent with the parent studies and the overall TRAVERSE population; out of 74 patients, 70 experienced ≥ 1 TEAE, and 6 (8.1%) discontinued because of adverse events. During the treatment period, the unadjusted annualized severe exacerbation rate was low (0.470). Improvement in pre-BD FEV1 was seen as early as Week 2 with a mean change from the parent study baseline (PSBL), standard deviation (SD) of 0.42 L (0.47), which was sustained until Week 96. Mean change from PSBL (SD) in ACQ-5 score was -1.32 (0.76) at Week 48. This subgroup analysis of TRAVERSE showed the long-term safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma enrolled from Korean centers. ClinicalTrials.gov Identifier: NCT02134028.

Prescription patterns and effectiveness of medications for chronic obstructive pulmonary disease: A retrospective study of real-world settings.

This study aimed to define real-world prescription patterns in Korea and compare the effectiveness of chronic obstructive pulmonary disease (COPD) medications. We used national claims data provided by the Health Insurance Review and Assessment Service in Korea and examined patients who were first diagnosed with COPD and started treatment between May 1, 2017, and April 30, 2018, with no change in drug regimen. Among 30,784 patients with COPD, long-acting β2 agonist (LABA) combined with long-acting muscarinic antagonist (LAMA) (32.7%), inhaled corticosteroid-LABA (ICS-LABA) (25.6%), LAMA (18.3%), ICS (5.8%), or LABA (4.6%) were prescribed as the first-choice inhalers. The use of LABA-LAMA (hazard ratio [HR], 0.248-0.584), LAMA (HR, 0.320-0.641), ICS-LABA (HR, 0.325-0.643), and xanthine (HR, 0.563-0.828) significantly reduced the total and severe exacerbation rates compared with no use of each medication. However, the use of ICS or LABA individually did not yield such effects. The continued use of LABA-LAMA, LAMA, and ICS-LABA showed a significant effect on exacerbation rate, whereas the long-term use of ICS, LABA, and xanthine did not. Moreover, some high doses of ICS-LABA did not show significant effects. This real-world study revealed that LAMA and/or LABA could be the first choice of therapy, as recommended by recent guidelines. However, ICS, xanthine, and high-dose ICS-LABA are still being prescribed frequently as first-line drugs in Korea.

Application of the Lancet Commission COPD classification to COPD Cohort Population in South Korea

The Lancet Commissions on COPD recommended a new classification based on five main risk factors.Patients with COPD were prospectively enrolled in a Korean COPD subgroup study cohort between April 2012 and June 2022. Patients were classified according to the etiologies (Type 1: Genetically determined (COPD-G), Type 2: Abnormal lung development (COPD-D), Type 3: Infections (COPD-I), Type 4: Cigarette smoking (COPD-C), Type 5: Biomass and pollution (COPD-P)).The database enrolled 3476 patients. Among 3392 patients, 52 (2 %), 1339 (39 %), 2930 (86 %), and 2221 (65 %) were compatible with type 2 (COPD-D), 3 (COPD-I), 4 (COPD-C), and 5 (COPD-P), respectively. Most patients (71 %, 2405) had multiple risk factors contributing to their COPD. However, 93, 712, and 182 patients had only type 3 (COPD-I), 4 (COPD-C), and 5 (COPD-P), respectively. Type 3 (COPD-I) only patients were significantly younger, more often female, and had lower lung function. Both the rate and frequency of severe exacerbations were significantly higher in type 3 (COPD-I) only patients (p = 0.038 and p = 0.048, respectively). Compared with type 5 (COPD-P) only, type 3 (COPD-I) only was significantly associated with the risk of severe exacerbation (Odds ratio, 5.7 [95 % CI, 1.0–32.4]; P = 0.049, incident rate ratio, 8.7 [95 % CI, 1.7–44.0]; P = 0.009).Many patients were affected by multiple factors. Therefore, it is important to consider not only smoking history, but also other potential risk factors when evaluating patients with COPD. Further research is needed to explore the implications of this new COPD classification system for clinical practice and treatment strategies.

Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation

BackgroundDupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear.MethodsIn a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George’s Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52.ResultsA total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P=0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab.ConclusionsIn patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.)

Differences in the effectiveness of single, dual, and triple inhaled corticosteroid therapy for reducing future risk of severe asthma exacerbation: A systematic review and network meta-analysis

ImportanceThe effectiveness of different combinations of inhaled corticosteroid (ICS) therapies in reducing severe exacerbations of adult asthma remains unclear. ObjectiveThis network meta-analysis (NMA) extensively evaluated the treatment effects of single ICS; dual ICS i.e., ICS/long-acting β2-adrenergic agonists (LABA); ICS/LABA as single maintenance and reliever therapy (SMART); and triple ICS, i.e., ICS/LABA/long-acting muscarinic antagonists (LAMA) in preventing severe asthma exacerbations. Data sourcesA systematic search of English databases, including PubMed and Web of Science, was conducted until December 31, 2022, using PRISMA-NMA. Study selectionUsing the PICOS criteria, the questions for this study were carefully selected so that the correct keywords could be identified. Data extraction and synthesisA pairwise meta-analysis was used to select trials based on the criteria for minimizing heterogeneity (I2). Subsequently, the “BUGSnet” package of R software was used to perform a Bayesian network meta-analysis. Main outcome measuresThe main outcome measures were risk rate and annualized rate ratio of severe asthma exacerbations. ResultsThis review included 56 randomized control trials (RCTs; n = 78,171 patients). As the pairwise meta-analysis demonstrated that the annualized rate ratio of severe asthma exacerbation had moderate heterogeneity, we analyzed the risk rate of severe asthma exacerbation using a network meta-analysis. In terms of direct/indirect comparisons with non-ICS, single ICS, dual ICS, SMART, and triple ICS reduced severe asthma exacerbations by 34 %, 47 %, 58 %, and 57 %, respectively. SMART and triple ICS showed high effectiveness in reducing severe exacerbations. ConclusionAND RELEVANCE: SMART and triple ICS were ranked higher in effectiveness in reducing severe asthma exacerbations in comparison with other therapies, indicating that these are the most effective treatments for reducing the future risk of severe asthma exacerbations.

AERIFY-1/2: two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD

BackgroundAccumulating data implicate interleukin (IL)-33, a proinflammatory cytokine released locally upon epithelial cell damage, in the pathogenesis of COPD. In a phase 2 study, itepekimab, a human monoclonal antibody against IL-33, reduced exacerbations and improved lung function in a subgroup analysis of former smokers with COPD with an acceptable safety profile.MethodsThe study designs of AERIFY-1 and AERIFY-2 are described in this article.DiscussionThe primary objective of AERIFY-1/2 (NCT04701983/NCT04751487), two phase 3 randomised, double-blind, placebo-controlled trials, is to assess the efficacy and safety of itepekimabversusplacebo in a population of former smokers with moderate-to-severe COPD over up to 52 weeks. An additional secondary population of current smokers are being enrolled in AERIFY-2. These two studies will enrol patients (aged 40–85 years) with COPD and chronic bronchitis who had ≥2 moderate or ≥ 1 severe exacerbations within the previous year despite standard-of-care triple or double background therapy. All participants are required to have ≥10-pack-year smoking history, and ≥6 months since smoking cessation for former smokers. The primary end-point is the annualised rate of moderate or severe acute exacerbation of COPD. Secondary end-points include change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 s, and annualised frequency of severe exacerbations. Symptomatic end-points include Evaluating Respiratory Symptoms in COPD and St. George's Respiratory Questionnaire, safety and anti-drug antibody responses.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: a retrospective US claims study

IntroductionDespite adherence to inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. MethodsRetrospective, longitudinal study analyzed data from Optum’s de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. ResultsIn the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p<0.001]). ConclusionsThis study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

Impact of Pharmacist-led Interventions on Medication Adherence and Inhalation Technique in Adult Patients with COPD and Asthma

Introduction: Inhalation technique and medication adherence are essential prerequisites for achieving optimal therapeutic effects in patients with chronic obstructive pulmonary disease (COPD) and asthma. Although there are various effective treatments for respiratory disorders, disease control in these patients is still sub-optimal because of incorrect inhalation techniques and poor medication adherence. Pharmacist-led interventions have demonstrated a positive impact on improving inhalation technique, better medication adherence, and thus subsequently improving the quality of life of patients. Methods: Search engines such as PubMed, Google Scholar, and Science Direct were used to identify the relevant information using keywords: Chronic Obstructive Pulmonary Disease, Asthma, Pharmaceutical care, Pharmacist Intervention, Medication Adherence and Inhalation Technique. The relevant articles that were published between 2005 to 2021 were included and reviewed for the Pharmacist-led interventions to improve medication adherence, inhalation technique, and quality of life of patients with COPD and asthma. Results: Of the 300 articles screened, a total of 14 articles met the inclusion criteria and were included for review. Pharmacist-led interventions help to improve the medication adherence, inhalation technique, and quality of life of patients with COPD and asthma. Similarly, the articles mentioned in this review found that the interventions provided by the pharmacist to COPD and asthma patients were cost-effective in terms of reducing hospitalization rates and severe exacerbation rates. Conclusion: Our review concluded that the pharmacists’ interventions have a significant improvement in medication adherence and inhalation techniques with the enhancement of therapeutic effects in adult patients with COPD and asthma.

Efficacy of bronchial thermoplasty in patients with severe asthma and frequent severe exacerbations: A randomized controlled study✰

BackgroundBronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe uncontrolled asthma, but randomized controlled studies of its efficacy in severe asthma with frequent exacerbations are lacking. The current aim was to assess BT efficacy in this patient population. MethodsThirty patients with asthma (GINA 5) who had experienced at least four severe exacerbations in the preceding year were randomized to BT (n = 15) or control groups (n = 15). All patients had four follow-up visits over the following 15 months, corresponding to 3, 6, 9, and 12 months after the last procedure for the BT group. The primary outcome was number of exacerbations at 15 months after inclusion (i.e. 12 months after bronchial thermoplasty). ResultsAll but three patients had received an asthma biologic without receiving benefit. In the year preceding enrollment, patients in the BT group had an average of five exacerbations, compared with six among controls. For patients in the BT group, oral steroid intake was 9.3 mg/d, compared with 11.0 mg/d among controls. The BT group had 1.58 fewer severe exacerbations (mean, 6.09) compared with controls (mean, 8.28) in the 12-month period after the therapy (p = 0.047). Oral steroid intake during follow-up after BT was significantly lower in the BT group (ratio vs controls: 0.61; p = 0.0002). Quality-of-life measures between inclusion and the last visit were significantly improved in the BT group, but not among controls. Few mild to moderate adverse events were reported, and all were controlled within days. ConclusionIn patients with severe asthma and frequent severe exacerbations, BT significantly decreased the rate of severe exacerbations and oral steroid intake and led to improved quality of life during the 15 months after inclusion. BT appears to offer a therapeutic option for severe asthma with frequent exacerbations.

Rate of severe exacerbations, healthcare resource utilisation and clinical outcomes in patients with COPD in low-income and middle-income countries: results from the EXACOS International Study

IntroductionThe EXAcerbations of Chronic obstructive lung disease (COPD) and their OutcomeS (EXACOS) International Study aimed to quantify the rate of severe exacerbations and examine healthcare resource utilisation (HCRU) and clinical...