Systematic review of the effects of patient errors using inhaled delivery systems on clinical outcomes in COPD.

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.

Consideration and Assessment of Patient Factors When Selecting an Inhaled Delivery System in COPD.

Because guidelines and strategies for pharmacologic treatment of COPD focus on specific classes of inhaled medications, there is an unmet need for information to guide health care professionals for selecting an inhaled medication delivery system that matches the unique characteristics of individual patients. This article provides guidance for selecting an inhaled medication delivery system based on three "key" patient factors: cognitive function, manual dexterity/strength, and peak inspiratory flow. In addition, information is provided about specific tests to assess these patient factors. Cognitive impairment with an estimated prevalence of 25% among patients with COPD adversely affects patients' ability to correctly use a handheld device. To our knowledge, the prevalence of impaired manual dexterity/strength has not been reported in those with COPD. However, 79% of patients with COPD have reported one or more physical impediments that could influence their ability to manipulate an inhaler device. The measurement of peak inspiratory flow against the simulated resistance (PIFr) of a dry powder inhaler establishes whether the patient has the inhalation ability for creating optimal turbulent energy within the device. A suboptimal PIFr for low to medium-high resistance dry powder inhalers has been reported in 19% to 84% of stable outpatients with COPD. Health care professionals should consider cognitive function, manual dexterity/strength, and PIFr in their patients with COPD when prescribing inhaled pharmacotherapy. Impairments in these patient factors are common among those with COPD and can affect the individual's competency and effectiveness of using inhaled medications delivered by handheld devices.

Impact of exacerbation history on long-term efficacy of dupilumab in patients with asthma.

Background: The phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies demonstrated the efficacy of dupilumab 200/300 mg versus placebo every 2 weeks for 52 weeks (QUEST) and dupilumab 300 mg up to an additional 96 weeks (TRAVERSE) in patients ≥12 years of age with uncontrolled, moderate-to-severe asthma. Overall, safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed long-term dupilumab efficacy for up to 3 years by exacerbation history. Patients and methods: Unadjusted annualised severe exacerbation rates (AER) and change from parent study baseline (PSBL) in pre-bronchodilator forced expiratory volume in 1 s (FEV1) and 5-item Asthma Control Questionnaire (ACQ-5) score were assessed in patients with PSBL eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥20 ppb and 1 (n=624), 2 (n=344), or ≥3 (n=311) exacerbations in the year before enrolment in QUEST. Results: In all three groups, dupilumab treatment progressively reduced AER range to 0.17-0.30 during TRAVERSE (Weeks 48-96), increased pre-bronchodilator FEV1 range by 0.28-0.49 L by Week 96 and improved asthma control (reduced ACQ-5 score range by 1.51-2.03 by Week 48). For patients who first received dupilumab upon TRAVERSE enrolment, AER decreased, and lung function and asthma control improved rapidly, as was observed upon initiation of dupilumab in QUEST. Dupilumab was efficacious regardless of exacerbation history. Conclusion: For patients with uncontrolled, moderate-to-severe asthma with elevation of at least one type 2 biomarker, dupilumab treatment provides sustained, long-term reduction of exacerbation rates and improvements in lung function and asthma control irrespective of exacerbation history.

Benefit of prompt initiation of single-inhaler fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) in patients with COPD in England following an exacerbation: a retrospective cohort study.

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.

Triple therapy with an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) who still experience symptoms while taking dual therapy (LABA/LAMA or ICS/LABA). Triple therapy can be taken using single or multiple inhalers. The best time to start triple therapy for patients who may benefit from it following a short-term worsening (flare-up) of their COPD symptoms is unknown. This study assesses the effect of starting treatment with triple therapy sooner compared with later in patients with COPD.Patients who experienced a flare-up of their COPD symptoms were split into two groups ­ those who started taking triple therapy (via a single inhaler) within 30 days of their symptom flare-up and those who started taking triple therapy 31­180 days following their symptom flare-up. Over the 12 months following the initial flare-up, patients who started triple therapy earlier (within 30 days) had fewer subsequent symptom flare-ups, fewer hospital admissions, and lower healthcare costs compared with patients who started triple therapy later (31­180 days). These findings suggest that doctors should consider prescribing triple therapy (via a single inhaler) to their patients with COPD straight away if they experience a flare-up of their symptoms.

Clinical Management of COPD in the Real World: Can Studies Reveal Errors in Management and Pathways to Improve Patient Care?

Real world data comprise information on health care that is derived from multiple sources outside typical clinical research settings. This review focuses on what real world evidence tells us about problems with the diagnosis of chronic obstructive pulmonary disease (COPD), problems with the initial and follow-up pharmacological and non-pharmacological management, problems with the management of exacerbations and problems with palliative care. Data from real world studies show errors in the management of COPD with delays to diagnosis, lack of confirmation of the diagnosis with spirometry, lack of holistic assessment, lack of attention to smoking cessation, variable adherence to management guidelines, delayed implementation of appropriate interventions, under-recognition of patients at higher risk of adverse outcomes, high hospitalisation rates for exacerbations and poor implementation of palliative care. Understanding that these problems exist and considering how and why they occur is fundamental to developing solutions to improve the diagnosis and management of patients with COPD.

Personalizing Selection of Inhaled Delivery Systems in Chronic Obstructive Pulmonary Disease.

It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the multiple individual and combinations of inhaled medications available in numerous delivery systems. Guidance on the selection of an inhaled delivery system has received limited attention compared with the emphasis on prescribing the class of the inhaled molecule(s). Although numerous recommendations and algorithms have been proposed to guide the selection of an inhaled delivery system for patients with COPD, no specific approach has been endorsed in COPD guidelines/strategies or by professional organizations. To provide recommendations for an inhaler selection strategy at initial and follow-up appointments, we examined the impact of patient errors using handheld inhalers on clinical outcomes and performed a focused narrative review to consider patient factors (continuity of the inhaled delivery system, cognitive function, manual function/dexterity, and peak inspiratory flow) when selecting an inhaled delivery system. On the basis of these findings, five questions are proposed for HCPs to consider in the initial selection of an inhaler delivery system and three questions to consider at follow-up. We propose that HCPs consider the inhaled medication delivery system as a unit and to match appropriate medication(s) with the unique features of the delivery system to individual patient factors. Assessment of inhaler technique and adherence together with patient outcomes/satisfaction at each visit is essential to determine whether the inhaled medication delivery system is providing benefits. Continued and repeated education on device features and correct technique is warranted to optimize efficacy.

Identification of key opportunities for optimising the management of high-risk COPD patients in the UK using the CONQUEST quality standards: an observational longitudinal study.

Background: This study compared management of high-risk COPD patients in the UK to national and international management recommendations and quality standards, including the COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST). The primary comparison was in 2019, but trends from 2000 to 2019 were also examined. Methods: Patients identified in the Optimum Patient Care Research Database were categorised as newly diagnosed (≤12 months after diagnosis), already diagnosed, and potential COPD (smokers having exacerbation-like events). High-risk patients had a history of ≥2 moderate or ≥1 severe exacerbations in the previous 12 months. Findings: For diagnosed patients, the median time between diagnosis and first meeting the high-risk criteria was 617 days (Q1-Q3: 3246). The use of spirometry for diagnosis increased dramatically after 2004 before plateauing and falling in recent years. In 2019, 41% (95% CI 39-44%; n = 550/1343) of newly diagnosed patients had no record of spirometry in the previous year, and 45% (95% CI 43-48%; n = 352/783) had no record of a COPD medication review within 6 months of treatment initiation or change. In 2019, 39% (n = 6893/17,858) of already diagnosed patients had no consideration of exacerbation rates, 46% (95% CI 45-47%; n = 4942/10,725) were not offered or referred for pulmonary rehabilitation, and 41% (95% CI 40-42%; n = 3026/7361) had not had a COPD review within 6 weeks of respiratory hospitalization. Interpretation: Opportunities for early diagnosis of COPD patients at high risk of exacerbations are being missed. Newly and already diagnosed patients at high-risk are not being assessed or treated promptly. There is substantial scope to improve the assessment and treatment optimisation of these patients. Funding: This study is conducted by the Observational & Pragmatic Research International Ltd and was co-funded by Optimum Patient Care and AstraZeneca. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution.

Mortality Risk and Serious Cardiopulmonary Events in Moderate-to-Severe COPD: Post Hoc Analysis of the IMPACT Trial.

Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time-to-first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p<0.001) but not significantly different at 1-90 days post-severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Conclusion: Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

Cost-Effectiveness of Single- versus Multiple-Inhaler Triple Therapy in a UK COPD Population: The INTREPID Trial.

Purpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective. Patients and Methods: The analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George's Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions. Results: Over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £1764 (95% CI: -£2600, -£678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses. Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.

Comparative Adherence and Persistence of Single- and Multiple-Inhaler Triple Therapies Among Patients with Chronic Obstructive Pulmonary Disease in an English Real-World Primary Care Setting.

Purpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting ß2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥35 years and had a forced expiratory volume in 1 second/forced vital capacity <0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days' supply of SITT or MITT prescriptions. Persistence was measured with a gap of >30 days between the end of a prescription and the following refill used to determine non-persistence. Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference <10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p<0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months). Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.

Dupilumab efficacy in subgroups of type 2 asthma with high-dose inhaled corticosteroids at baseline.

BACKGROUND AND OBJECTIVE: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV1), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS). METHODS: Adjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV1, and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 µg) ICS with baseline blood eosinophils ≥150 cells/µL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV1/forced vital capacity (<70%/≥70%), blood eosinophil level, exacerbation history, median baseline pre-bronchodilator FEV1, age at asthma onset (≤40/>40 years), median FEV1 reversibility, body mass index (<30/≥30 kg/m2), and sex. RESULTS: Dupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS. CONCLUSION: Dupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline. CLINICAL TRIAL REGISTRATION NUMBER: NCT02414854.

The availability, cost, and affordability of essential medicines for asthma and COPD in low-income and middle-income countries: a systematic review.

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.