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Abstract To optimize patient outcomes, healthcare decisions should be based on the most up-to-date high-quality evidence. Randomized controlled trials (RCTs) are vital for demonstrating the efficacy of interventions; however, information on how an intervention compares to already available treatments and/or fits into treatment algorithms is sometimes limited. Although different therapeutic classes are available for the treatment of chronic obstructive pulmonary disease (COPD), assessing the relative efficacy of these treatments is challenging. Synthesizing evidence from multiple RCTs via meta-analysis can help provide a comprehensive assessment of all available evidence and a “global summary” of findings. Pairwise meta-analysis is a well-established method that can be used if two treatments have previously been examined in head-to-head clinical trials. However, for some comparisons, no head-to-head studies are available, for example the efficacy of single-inhaler triple therapies for the treatment of COPD. In such cases, network meta-analysis (NMA) can be used, to indirectly compare treatments by assessing their effects relative to a common comparator using data from multiple studies. However, incorrect choice or application of methods can hinder interpretation of findings or lead to invalid summary estimates. As such, the use of the GRADE reporting framework is an essential step to assess the certainty of the evidence. With an increasing reliance on NMAs to inform clinical decisions, it is now particularly important that healthcare professionals understand the appropriate usage of different methods of NMA and critically appraise published evidence when informing their clinical decisions. This review provides an overview of NMA as a method for evidence synthesis within the field of COPD pharmacotherapy. We discuss key considerations when conducting an NMA and interpreting NMA outputs, and provide guidance on the most appropriate methodology for the data available and potential implications of the incorrect application of methods. We conclude with a simple illustrative example of NMA methodologies using simulated data, demonstrating that when applied correctly, the outcome of the analysis should be similar regardless of the methodology chosen.

Abstract The WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children’s lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry’s aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority.

Background Errors using inhaled delivery systems for COPD are common and it is assumed that these lead to worse clinical outcomes. Previous systematic reviews have included patients with both asthma and COPD and much of the evidence related to asthma. More studies in COPD have now been published. Through systematic review, the relationship between errors using inhalers and clinical outcomes in COPD, including the importance of specific errors, was assessed.MethodsElectronic databases were searched on 27 October 2023 to identify cohort, case–control or randomised controlled studies, which included patients with COPD, an objective assessment of inhaler errors and data on at least one outcome of interest (forced expiratory volume in 1 s, (FEV1), dyspnoea, health status and exacerbations). Study quality was assessed using the Newcastle and Ottawa scales. A narrative synthesis of the results was performed as there was insufficient detail in the publications to allow quantitative synthesis. There was no funding for the review.Results 19 publications were included (7 cohort and 12 case–control) reporting outcomes on 6487 patients. 15 were considered low quality, and most were confounded by the absence of adherence data. There was weak evidence that lower error rates are associated with better FEV1, symptoms and health status and fewer exacerbations. Only one considered the effects of individual errors and found that only some were related to worse outcomes.Conclusion Evidence about the importance of specific errors using inhalers and outcomes would optimise the education and training of patients with COPD. Prospective studies, including objective monitoring of inhalation technique and adherence, are needed.PROSPERO registration number CRD42023393120.

Abstract Background Triple therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite dual therapy. The optimal timing of triple therapy following an exacerbation of COPD is unknown. The outcomes of prompt (≤ 30 days) vs. delayed (31–180 days) initiation of single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) following an exacerbation of COPD were examined. Methods This was a retrospective cohort study of linked English primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data. Patients aged ≥ 35 years with COPD were indexed on the first and/or earliest date of exacerbation between November 15, 2017 and March 31, 2019 with subsequent FF/UMEC/VI initiation within 180 days. Patients were required to be continuously registered with a general practitioner for ≥ 12 months prior to and following index. Subsequent exacerbations, direct medical costs, and hospital readmissions were compared between prompt and delayed initiators. Inverse probability of treatment weighting was used to adjust for measured confounders between cohorts. Results Overall, 1599 patients were included (prompt: 393, delayed: 1206). After weighting, prompt initiators had numerically lower moderate/severe exacerbations compared with delayed initiators (rate ratio: 0.87, 95% confidence interval [CI]: 0.76–1.01, p = 0.0587). Both all-cause and COPD-related 30-day hospital readmissions were significantly lower among patients with prompt initiation compared with delayed initiators (all-cause: 23.6% vs. 34.6%, odds ratio [95% CI]: 0.58 [0.36–0.95], p = 0.0293; COPD-related: 20.3% vs. 30.6%, odds ratio [95% CI]: 0.58 [0.35–0.96], p = 0.0347). Prompt initiators also had numerically lower all-cause total costs and significantly lower COPD-related costs per-person-per year compared with delayed initiators (COPD-related: £742 vs. £801, p = 0.0016). Conclusion Prompt initiation of FF/UMEC/VI following a moderate/severe exacerbation was associated with fewer subsequent exacerbations, fewer hospital readmissions, and lower COPD-related medical costs compared with delayed initiation.

Background Compared with multiple-inhaler triple therapy (MITT), single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) demonstrated improved lung function and meaningful improvements in chronic obstructive pulmonary disease (COPD) Assessment Test score. This real-world study compared the effectiveness of switching patients with COPD in England from MITT to once-daily SITT with FF/UMEC/VI by evaluating rates of COPD exacerbation, healthcare resource use (HCRU) and associated direct medical costs.Methods Retrospective cohort pre-post study using linked primary care electronic health record and secondary care administrative datasets. Patients diagnosed with COPD at age ≥35 years, with smoking history, linkage to secondary care data and continuous GP registration for 12 months pre-switch and 6 months post-switch to FF/UMEC/VI were included. Index date was the first initiation of an FF/UMEC/VI prescription immediately following MITT use from 15 November 2017 to 30 September 2019. Baseline was 12 months prior to index, with outcomes assessed 6/12 months pre-switch and post-switch, and stratified by prior COPD exacerbation status.Results We included 2533 patients (mean [SD] age: 71.1 [9.9] years; 52.1% male). In the 6 months post-switch, there were significant decreases in the proportion of patients experiencing ≥1 moderate-to-severe (36.2%–28.9%), moderate only (24.4%–19.8%) and severe only (15.4%–11.8%) COPD exacerbation (each, p

Summary: Background: Asthma and chronic obstructive pulmonary disease (COPD) cause a considerable burden of morbidity and mortality in low-income and middle-income countries (LMICs). Access to safe, effective, quality-assured, and affordable essential medicines is variable. We aimed to review the existing literature relating to the availability, cost, and affordability of WHO's essential medicines for asthma and COPD in LMICs. Methods: A systematic review of the literature was done by searching seven databases to identify research articles published between Jan 1, 2010, and June 30, 2022. Studies on named essential medicines for asthma and COPD in LMICs were included and review articles were excluded. Two authors (MS and HT) screened and extracted data independently, and assessed bias using Joanna Briggs Institute appraisal tools. The main outcome measures were availability (WHO target of 80%), cost (compared with median price ratio [MPR]), and affordability (number of days of work of the lowest paid government worker). The study was registered with PROSPERO, CRD42021281069. Findings: Of 4742 studies identified, 29 met the inclusion criteria providing data from 60 LMICs. All studies had a low risk of bias. Six of 58 countries met the 80% availability target for short-acting beta-agonists (SABAs), three of 48 countries for inhaled corticosteroids (ICSs), and zero of four for inhaled corticosteroid–long-acting beta-agonist (ICS–LABA) combination inhalers. Costs were reported by 12 studies: the range of MPRs was 1·1–351 for SABAs, 2·6–340 for ICSs, and 24 for ICS–LABAs in the single study reporting this. Affordability was calculated in ten studies: SABA inhalers typically cost around 1–4 days’ wages, ICSs 2–7 days, and ICS–LABAs at least 6 days. The included studies showed heterogeneity. Interpretation: Essential medicines for treating asthma and COPD were largely unavailable and unaffordable in LMICs. This was particularly true for inhalers containing corticosteroids. Funding: WHO and Wellcome Trust.

Background The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time‐dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time‐to‐first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08–3.32]) or severe (HR, 21.84 [95% CI, 17.71–26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28–2.08]; severe: HR, 1.75 [95% CI, 0.99–3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53–3.97]; severe: HR, 41.29 [95% CI, 30.43–56.03]) and decreased in a similar time‐dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02164513; Unique identifier: NCT02164513

Abstract Background Fibrinogen is the first qualified prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This analysis used IMPACT trial data to examine the relationship between fibrinogen levels and exacerbation outcomes in patients with COPD. Methods 8094 patients with a fibrinogen assessment at Week 16 were included, baseline fibrinogen data were not measured. Post hoc analyses were performed by fibrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs). Results Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels

Abstract Background Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. Methods A composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 μg or placebo. Results The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George’s Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6–81.6%) and SGRQ (72.3–78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment. Conclusions Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. Trial registration ClinicalTrials.gov NCT00144339 . Graphical abstract

Abstract Background This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. Methods IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. Results Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments. Conclusions In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10–11% and 1–3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. Trial registration NCT02164513 (GSK study number CTT116855).

Plain Language Summary Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone’s breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

Abstract Background Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations. Methods This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18–80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non-high:

Abstract Background The primary lung function endpoint in clinical trials in adolescent and adult patients with asthma is usually forced expiratory volume in one second (FEV1). The objective of our analysis was to assess whether peak expiratory flow (PEF) is a suitable alternative primary lung function endpoint. Methods For this assessment, we calculated post hoc the correlation between pre-dose FEV1 and pre-dose PEF measured under supervision in the clinic and, for both lung function parameters, the correlations between supervised clinic and unsupervised home measurements, using the results from the 8 Phase III parallel-group trials of the global clinical development programme with tiotropium Respimat® in patients with asthma aged 12 to 75 years. Results Across all 8 trials included in this analysis, changes in lung function from baseline correlated well between pre-dose FEV1 and pre-dose PEF when both were measured under supervision in the clinic. Correlation between supervised in-clinic and unsupervised home measurements was stronger for pre-dose PEF than for pre-dose FEV1. Conclusions Pre-dose PEF measured at home could be an alternative primary lung function endpoint for trials in adolescent and adult patients with asthma. Using home-measured PEF could facilitate trial conduct and improve the convenience for patients by relocating scheduled assessments from the clinic to the patient’s home. Trial registration Adolescents aged 12 to 17 years: RubaTinA-asthma® (NCT01257230), PensieTinA-asthma® (NCT01277523). Adults aged 18 to 75 years: GraziaTinA-asthma® (NCT01316380), MezzoTinA-asthma® (NCT01172808/NCT01172821), CadenTinA-asthma® (NCT01340209), PrimoTinA-asthma® (NCT00772538/NCT00776984). All from Clinicaltrials.gov (https://clinicaltrials.gov/).

Abstract Background Use of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear. Methods A post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis). Results For the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study. Conclusion The results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk–benefit ratio of using ICS when making treatment decisions with their patients. Trial registration Post hoc analysis of UPLIFT®. ClinicalTrials.gov number: NCT00144339. Retrospectively registered September 2, 2005.