Dual Bronchodilator Research Articles

Study on the Management of the Health Status of Patients with Stable Chronic Obstructive Pulmonary Disease Treated with Double Bronchodilator.

Objective To investigate the patients with stable chronic obstructive pulmonary disease (COPD) to understand the use of double bronchodilator therapy and influencing factors. Methods The patients with stable COPD who used double bronchodilators were continuously enrolled in our hospital. The information of demographic characteristics, medical history, physical examination, drug use, and correct treatment methods after using inhaled drugs were collected by standardized questionnaire. Measurement data between groups were compared by using the independent sample t-test, and counting data between groups were compared by using the chi-square test. Results A total of 102 patients were included in the analysis. The proportion of patients with stable COPD who correctly used dual bronchodilators was 59.8% (61 patients). In the GOLD classification, the correct use rate of C-level patients was 69.8%, which was significantly higher than the used correct rate of D-level patients (49.0%) (P=0.032). In the age group, the correct use rate of patients <65 years old was 72.1%, which was significantly higher than that of patients ≥65 years old (50.8%) (P=0.031). In addition, education level, duration of drug use, and drug type may also affect the correct use of drugs, but no significant statistical significance was found between the groups of these three factors (P > 0.05). Conclusion There is still a gap between the treatment of dual bronchodilators in patients with stable COPD and the guidelines, so the management of COPD should be strengthened. Besides, the correct use rate could be affected by the GOLD classification and age.

Dual bronchodilation for the treatment of COPD: From bench to bedside.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting β-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator.

Impact of switching from triple therapy to dual bronchodilation in COPD: the DACCORD \u2018real world\u2019 study

IntroductionChronic obstructive pulmonary disease (COPD) guidelines recommend reserving triple therapy of inhaled corticosteroid (ICS), long-acting β2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) for patients with exacerbations despite dual therapy. However, many patients receive triple therapy without a clear indication. For these patients, it would be useful to know whether ICS can be withdrawn.MethodsDACCORD was a longitudinal, non-interventional ‘real-world’ study in three cohorts. This manuscript describes the results of Cohort 3, which recruited patients with COPD who had received triple therapy for ≥ 6 months. Prior to entry, each patient’s physician decided to continue triple therapy, or switch to a LABA/LAMA; patients were then followed for 12 months, with exacerbations and COPD Assessment Test (CAT) data recorded every 3 months. The primary endpoint was the time until COPD worsening, defined as the occurrence of a moderate/severe exacerbation or clinically relevant CAT worsening.ResultsOf the 1192 patients recruited into the study, 967 completed the end-of-study visit and ≥ 2 of the three interim visits, 292 and 675 receiving LABA/LAMA and triple therapy, respectively. Most baseline demographics were similar between the two groups. A lower proportion of patients in the LABA/LAMA group had COPD worsening than with triple therapy (32.5% vs 55.7% at 12 months), with the time to worsening extended in the LABA/LAMA group (hazard ratio 2.004, p < 0.001). In addition, a significantly lower proportion of patients in the LABA/LAMA group exacerbated (18.5% vs 28.7%; p < 0.001), accompanied by a greater improvement from baseline in CAT total score. Overall, fewer patients in the LABA/LAMA group reported adverse events than in the triple therapy group (12.9% vs 15.1%).ConclusionsThese results suggest that in a real world setting physicians are able to identify patients who can be ‘stepped down’ from triple therapy to LABA/LAMA. Following step down, there was no overall decline in COPD—indeed, some patients had better outcomes.

New insights into the optimal management of COPD: extracts from CHEST 2021 annual meeting (October 17–20, 2021)

ABSTRACT Introduction Discordance between real-world prescribing patterns and global treatment guidelines for the treatment of chronic obstructive pulmonary disease (COPD) with inhaled single or dual long-acting bronchodilator maintenance therapy is increasingly being reported in the literature, particularly with regard to addition of inhaled corticosteroids (ICS). Patient-related factors, e.g. inhalation technique and inspiratory flow, are key to disease control in COPD. Treatment discordance and patient-related factors can lead to high-cost side effects and sub-optimal treatment benefit; furthermore, the COVID-19 pandemic has led to new challenges in COPD management. Areas Covered This article summarizes a series of presentations sponsored by Boehringer Ingelheim and delivered at the annual CHEST congress 2021 (October 17–20, 2021) that explored new insights into the optimal management of COPD. Expert Opinion/Commentary There is a concerning high degree of discordance with GOLD recommendations. Dual therapy without addition of ICS does not increase exacerbation risk and could reduce pneumonia risk, and unnecessary prescription of triple therapy has financial implications. Clinic-based spirometry may not reflect the home setting, and training is required; inhalers that operate independently of users’ inhalation profiles should be considered. Integration of digital healthcare solutions into clinical studies is suggested in the post-COVID setting, although further evaluation is required.

Treatment Patterns for Chronic Obstructive Pulmonary Disease (COPD) in the United States: Results from an Observational Cross-Sectional Physician and Patient Survey.

PurposeThere is a high prevalence of chronic obstructive pulmonary disease (COPD) in the United States (US). Although guidelines are available for the treatment of COPD, evidence suggests that management of COPD in clinical practice is not always aligned with this guidance. This study aimed to further understand the current use of COPD maintenance medication in the US.Patients and MethodsThis study was an analysis of data from the Adelphi Respiratory Disease Specific Programme (DSP™) 2019. Point-in-time data were collected from participating US physicians and their COPD patients. Physicians were either primary care physicians (PCPs) or pulmonologists, with a minimum workload of ≥3 COPD patients per month. Patients were aged ≥18 years with a physician-confirmed diagnosis of COPD.ResultsIn total, 171 physicians completed the survey (92 PCPs and 79 pulmonologists). Mean patient age was 66.4 years, 45% were female, with moderate COPD in 49.4% of patients and severe/very severe in 19.3%. Pulmonologists more frequently prescribed dual bronchodilation and triple therapy than PCPs, whereas inhaled corticosteroid/long-acting β2-agonist was more frequently prescribed by PCPs than pulmonologists. For both physician types, the most common reason for prescribing their patients’ current treatment was 24-hour symptom relief. The majority of PCPs (70.1%) and pulmonologists (71.9%) reported referring to COPD guidelines when making treatment decisions.ConclusionPrescribing patterns for COPD patients were found to differ between PCPs and pulmonologists. Improved physician understanding of how to tailor treatment for each patient, based on current symptoms and exacerbation risk, could help optimize patient care in COPD.

PREFUL MRI Depicts Dual Bronchodilator Changes in COPD: A Retrospective Analysis of a Randomized Controlled Trial.

PurposeTo assess whether dynamic ventilation and perfusion (Q) biomarkers derived by phase-resolved functional lung (PREFUL) MRI can measure treatment response to 14-day therapy with indacaterol-glycopyrronium (IND-GLY) and correlate to clinical outcomes including lung function, symptoms, and cardiac function in patients with chronic obstructive pulmonary disease (COPD), as determined by spirometry, body plethysmography, cardiac MRI, and dyspnea score measurements.Materials and MethodsThe cardiac left ventricular function in COPD (CLAIM) study enrolled patients aged 40 years or older with COPD, stable cardiovascular function, and hyperinflation (residual volume > 135% predicted). Dynamic MRI data of these patients were retrospectively analyzed using the PREFUL technique to assess the effect of 14-day IND-GLY treatment versus placebo on regional measurements of ventilation dynamics. After manual segmentation of the lung parenchyma, flow-volume loops of each voxel were correlated to an individualized reference flow-volume loop, creating a two-dimensional flow-volume loop correlation map (FVL-CM) as a measure of ventilation dynamics. Ventilation-perfusion match (VQM) was evaluated in combination with perfusion and regional ventilation (VQMRVent) and with perfusion and the FVL-CM measurement (VQMCM). For image and statistical analysis, the lung parenchyma was segmented as a region of interest by manually delineating the lung boundary and excluding the large (central) vessels for each section. Differences in ventilation, perfusion, and VQM between IND-GLY and placebo were compared using analysis of variance, with study treatment, patient, and period included as factors.ResultsFifty patients (mean age, 64.3 years ± 7.65 [SD]; 35 men) were included in this analysis. IND-GLY significantly increased mean correlation as measured with FVL-CM versus that of placebo (least squares [LS] means treatment difference: 0.05 [95% CI: 0.03, 0.07]; P < .0001). Compared with placebo, IND-GLY increased mean Q (LS means treatment difference: 9.27 mL/min/100 mL [95% CI: 0.05, 18.49]; P = .049) and improved both VQMCM and VQMRVent (LS means treatment difference: 0.06 [95% CI: 0.03, 0.08]; P < .0001 and 0.05 [95% CI: 0.02, 0.08]; P = .001, respectively).ConclusionRegional ventilation dynamics and VQM measured by PREFUL MRI show treatment response in COPD. Supplemental material is available for this article. Clinical trial registration no. NTR6831Keywords: MRI, COPD, Perfusion, Ventilation, Lung, PulmonaryPublished under a CC BY 4.0 license

A Pooled Analysis of Mortality in Patients with COPD Receiving Dual Bronchodilation with and without Additional Inhaled Corticosteroid.

BackgroundRecent studies report a lower mortality rate during treatment with long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations.ObjectiveWe compared time to all-cause mortality with LAMA/LABA versus LAMA/LABA/ICS in patients with mild-to-very-severe COPD and a predominantly low exacerbation risk.MethodsData were pooled from six randomized controlled trials (TONADO 1/2, DYNAGITO, WISDOM, UPLIFT and TIOSPIR; LAMA/LABA: n = 3156, LAMA/LABA/ICS: n = 11,891). Analysis was on-treatment and data were censored at 52 weeks. Patients on LAMA/LABA/ICS received ICS prior to study entry, which was not withdrawn at randomization. Patients on LAMA/LABA/ICS were propensity score (PS)-matched to patients on LAMA/LABA who had not previously received ICS; covariates included age, sex, geographical region, smoking status, post-bronchodilator forced expiratory volume in 1 second percent predicted, exacerbation history in previous year, body mass index and time since diagnosis. Time to all-cause mortality was assessed using Cox proportional hazard regression models.ResultsAfter PS matching, 3133 patients on LAMA/LABA and 3133 patients on LAMA/LABA/ICS were analyzed. Fewer than 20% of patients reported ≥2 exacerbations in the prior year (LAMA/LABA: 19.1%; LAMA/LABA/ICS: 19.0%). There were 41 (1.3%) deaths on LAMA/LABA and 45 (1.4%) deaths on LAMA/LABA/ICS. No statistically significant difference in time to death was observed between treatment arms (hazard ratio for LAMA/LABA 1.06; 95% confidence intervals 0.68, 1.64; P = 0.806). Sensitivity analyses conducted using different covariates or in an intent-to-treat population showed similar results.ConclusionThis pooled analysis of over 6000 patients with mild-to-very-severe COPD and predominantly low exacerbation risk showed no differences in mortality with LAMA/LABA versus LAMA/LABA/ICS, suggesting that the survival benefit of triple therapy seen in some recent studies may be specific to a high-risk population. This supports current Global Initiative for Chronic Obstructive Lung Disease recommendations that triple therapy should be reserved for the subpopulations of patients who need it the most (eg, those with an eosinophilic phenotype and a high risk of exacerbations) to avoid ICS overuse.

Cost-Effectiveness of Umeclidinium/Vilanterol versus Salmeterol/Fluticasone in Elderly Patients with Chronic Obstructive Pulmonary Diseases in China.

BackgroundFixed dose dual bronchodilators such as long-acting muscarinic antagonists (LAMAs) plus long-acting β2-agonists (LABAs) are a new and important inhaled preparation for COPD treatment in China. Among these, umeclidinium/vilanterol (UMEC/VIL) is increasingly being used in China, especially among the elderly.PurposeThis study aimed to assess the cost-effectiveness of maintenance treatment with UMEC/VIL compared with salmeterol/fluticasone (FSC) as one of the main therapeutic drugs for moderate to very severe COPD in China.MethodsA Markov model was developed to estimate the costs and outcomes from a societal perspective in a 10-year time horizon. Patients with moderate-to-very severe COPD were treated with UMEC/VIL (62.5/25µg) or FSC (50/500ug). Data concerning clinical efficacy, costs, utilities, transition probability, exacerbation rate, and mortality were obtained from the published literature and official government datasets. The costs were presented in US dollars based on 2021 prices. The indicators of total costs, life years (LYs), quality-adjusted life-years (QALYs), and mortality were used as the model output. Costs and outcomes were discounted at a 5% annual rate. Incremental cost-effectiveness ratios were calculated considering the threshold recommended by WHO. One-way and probabilistic sensitivity analyses were conducted to assess the stability of results.ResultsCompared with FSC, treatment with UMEC/VIL could save $1947.18, with a gain of 0.12 life-years and 0.05 QALYs. Further, 28.0% patients treated with UMEC/VIL and 29.2% patients treated with FSC were predicted to die after 10 years. Incremental cost effectiveness analysis showed that UMEC/VIL was dominant to FSC. Sensitivity analyses confirmed that the results were robust.ConclusionUMEC/VIL is a cost-effective treatment option compared with FSC among patients with moderate-to-very severe COPD.

Therapeutic Success in Swiss COPD Patients Receiving Dual Bronchodilation Therapy as COPD Maintenance Treatment.

Health-related quality of life (HRQoL) in patients with moderate to severe chronic obstructive pulmonary disease (COPD) is often reduced by high symptom burden and frequent exacerbations. So far, data on therapeutic success in Swiss COPD patients receiving dual bronchodilation therapy as COPD maintenance treatment are limited. Data from a recently published, non-interventional study on clinical benefit after the start of combined tiotropium–olodaterol treatment were analyzed focusing on Swiss patients compared to the overall cohort including patients from various European countries. Demographic data on the changes in Clinical COPD Questionnaire (CCQ) for the assessment of HRQoL in correlation to symptoms and the number of exacerbations, as well as physician’s global assessment (PGE), were evaluated 6 weeks after treatment start. In Switzerland (n = 61), significantly more patients had comorbidities and exacerbations but showed less symptoms compared to the overall cohort (n = 4639). HRQoL improved in both cohorts, with a negative correlation to symptom burden and number of exacerbations in the overall cohort. PGE scores improved after 6 weeks with a better general condition at baseline in Swiss patients (PGE score 4/5: 68.9% [Swiss cohort] vs. 49.0% [overall cohort]. Despite significant differences regarding the presence of symptoms and exacerbations, therapeutic success was similar in both patient groups. Highly symptomatic patients benefited mostly from tiotropium–olodaterol treatment.

Beyond Dual Bronchodilation - Triple Therapy, When and Why.

Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.

The role of long-acting muscarinic antagonist/long-acting β agonist fixed-dose combination treatment for chronic obstructive pulmonary disease in China: a narrative review.

ObjectiveTo provide an overview of the existing international and Chinese evidence regarding dual bronchodilator inhalation therapy and to make recommendations for the further improvement of chronic obstructive pulmonary disease (COPD) management in clinical practice in China.BackgroundCOPD is a progressive lung disease that is characterized by persistent airflow limitation and is a major contributor to the disease burden in China. Symptoms in Chinese patients are relatively more severe. Currently, many Chinese COPD patients are undertreated. Dual bronchodilator therapy consisting of a long-acting muscarinic antagonist (LAMA) and a long-acting β agonist (LABA) is considered a good choice for COPD patients due to the increased bronchodilation without an increase in adverse events; these combinations can fill in the gap in currently available COPD treatments and provide new pharmacotherapy options for Chinese patients. LAMA/LABA fixed-dose combinations (FDCs) have become more important in clinical practice and guidelines in China regarding their therapeutic effects and safety.MethodsClinical trials on LAMA/LABA in COPD were retrieved in ClinicalTrials.gov, while important COPD guidelines published in English or Chinese were found in PubMed and Wanfang Database.ConclusionsWe recommend the adoption of a clinical pathway in China that includes an assessment and management algorithm that considers the clinical characteristics in China and classifies the phenotypic characteristics of COPD according to a suitable system. Based on the current information, we can conclude that LAMA/LABA FDCs are a suitable and economically viable choice to reduce symptoms and improve the quality of life (QoL) of patients.

Triple therapy in a single inhaler for chronic obstructive pulmonary disease: clinical studies and case report (real practice)

Algorithms for de-escalation of basic therapy, including the abolition of inhaled corticosteroids (ICS), in patients with chronic obstructive pulmonary disease (COPD), as well as the development of clear criteria for prescribing triple therapy in clinical practice remain the subject of numerous studies and discussions. The given case report of managing a patient with a long experience of smoking and severe COPD demonstrated an unsuccessful experience of de-escalation of therapy with the abolition of ICS due to concerns about the fact of pneumonia. The dual bronchodilator therapy prescribed in accordance with modern recommendations was insufficiently effective in preventing exacerbations, and the stabilization of the patient’s condition was observed after the appointment of a fixed triple combination of drugs in a single inhaler (VI/UMEC/FF), which contains vilanterol (VI), umeclidinium bromide (UMEC) and ICS fluticasone furoate (FF). An additional contribution to ensuring clinical success was made by such factors as strict compliance with medical prescriptions by the patient, smoking cessation and compliance with recommendations for maintaining physical activity, compliance with a strict self-isolation regime during the pandemic, which reduced the risks of respiratory viral infections. Additional clinical predictors of the effectiveness of ICS in COPD were the bronchitis type, the persistence of symptoms and the recurrence of exacerbations of the disease after discontinuation of the drug, the level of blood eosinophilia. When deciding whether to prescribe or cancel triple therapy, it is recommended to take into account the data on the effect of ICS on improving the functional parameters and clinical course of the disease with a decrease in symptoms, on reducing the risk of exacerbations, on increasing patient survival and a positive prognosis during COPD.

Pharmacotherapeutic strategy for COPD patients: focus on dual bronchodilators

For two decades, the GOLD Initiative has consistently identified the use of bronchodilators as a priority in the pharmacotherapeutic strategy for COPD. The authors of international and national clinical guidelines consider fixed combinations of long-acting beta2-agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) as “first-line” drugs in most patients with COPD. Numerous clinical studies have shown that fixed LABAs/LAMAs combinations provide optimal bronchodilation and play a paramount role in preventing exacerbations of COPD. Outperforming placebo and active controls, LABAs, LAMAs, inhaled glucocorticosteroids (ICS)/LABAs combination bronchodilators may differ in their therapeutic potential. The available evidence base currently does not allow to make an unambiguous choice in favor of one or another fixed LABAs/ LAMAs combination. With the appearance of “triple” combinations (ICS/LABAs/LAMAs) on the pharmaceutical market, the issue of their comparison with “dual” bronchodilators has become particularly acute. Currently available data suggest that the use of “triple” therapy is not considered as a starting treatment option for COPD and is appropriate only in a subgroup of patients with a higher baseline risk of exacerbations: in the presence of a history of exacerbations ≥ 1, which required prescription of systemic antibiotics and/or glucocorticosteroids, or necessitated hospitalization during the previous year. Thus, ICS-containing therapy is justified only in cases of recurrent exacerbations of moderate COPD or single episodes of severe exacerbations, despite the continued administration of LABAs/LAMAs, as well as in certain categories of patients whose inflammatory profile suggests a “response” to ICS.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial

BackgroundIn patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids.MethodsThe double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10−30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21–24, and rescue medication use (puffs/day) over Weeks 1–24. Analyses were conducted across the full range of reversibility (−850–896 mL); however, results are presented for the range −100–400 mL because there were few participants with values outside this range.ResultsThe mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range.ConclusionsFP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

EFFECTIVENESS OF COPD MAINTENANCE THERAPY WITH LAMA/LABA VS LAMA/LABA/ICS IN A UNITED STATES CLAIMS DATABASE

TOPIC: Obstructive Lung Diseases TYPE: Original Investigations PURPOSE: This retrospective cohort study compared time to a) first hospitalization for community-acquired pneumonia and b) first COPD exacerbation in patients initiating maintenance therapy with the long-acting dual bronchodilator therapy tiotropium/olodaterol (T/O) vs triple therapy (TT) with long-acting muscarinic antagonist (LAMA)/long-acting beta agonist (LABA)/inhaled corticosteroids (ICS). METHODS: Administrative data from the US HealthCore Integrated Research Database (Jan 2013–Mar 2019) were used to compare patients for up to 1 year. Eligible patients were aged ≥40 years, diagnosed with COPD (not asthma), and had ≥1 inhaler prescription of fixed-dose T/O, or fixed or free TT (first prescription=index date). Propensity scores were calculated. Within the area of overlap, fine stratification and reweighting were used to balance measured covariates between the cohorts. Residual imbalances (standardized difference >0.10 [10%]) in the reweighted pseudo-population were adjusted for in the outcome models. A sensitivity analysis excluded patients with an exacerbation ≤30 days pre-index to minimize confounding e.g. due to higher TT prescription in frequent exacerbators. Further sensitivity analyses excluded patients with any prior use of maintenance therapy, and substituted the propensity score fine stratification/reweighting method with a 1:1 greedy match (propensity score caliper: 0.05). In all analyses, a Cox proportional hazard regression model was used to assess outcomes (as-treated analysis). RESULTS: The study population had 2,864 T/O and 24,326 TT users (after reweighting: 2,785 T/O and 15,465 TT users; mean age, 65.6 years; female, 47.1% [T/O] vs 49.7% [TT]). There were no differences in baseline characteristics, except for calendar year and season of cohort entry. No difference in prior exacerbations (any) was observed (std diff: <0.1); however, a higher proportion of TT users had severe exacerbations ≤1 year pre-index (32.7% vs 17.3%) and any exacerbations ≤30 days pre-index (25.8% vs 10.8%) vs T/O users. For T/O vs TT, adjusted hazard ratio (aHR) for exacerbation was 0.85 (95% CI: 0.76–0.96) (adjusted for calendar year, season of cohort entry). Excluding exacerbators ≤30 days pre-index balanced the cohorts (std diff: <0.1) in terms of prior exacerbations (any, moderate or severe). In this population, the aHR for exacerbation was 1.04 (95% CI: 0.91–1.19) (adjusted for calendar year, LABA/ICS use, season of cohort entry). Results were similar when applying 1:1 matching (aHR 1.02; 95% CI 0.84–1.24) and when restricting to treatment-naïve patients (no LABA, LAMA, ICS use prior to T/O or TT) (aHR 1.08; 95% CI 0.81–1.44). T/O users had a numerically lower risk of pneumonia than TT users (aHR 0.83; 95% CI 0.64–1.07). CONCLUSIONS: This study showed no benefit of TT vs T/O in reducing exacerbation risk in patients with no recent exacerbations, including treatment-naïve patients. In line with previous data, T/O was associated with a numerically lower risk of pneumonia vs TT. CLINICAL IMPLICATIONS: In an infrequently exacerbating population, prescribing T/O in place of TT appears not to increase exacerbation risk and could reduce pneumonia risk. DISCLOSURES: Employee relationship with Boehringer Ingelheim Please note: $20001 - $100000 by Alberto de la Hoz, source=Web Response, value=Salary Consultant relationship with HealthCore, Inc Please note: 2010-2018 Added 05/04/2021 by Daina Esposito, source=Web Response, value=Consulting fee Employee relationship with Moderna Please note: Since Feb 2021 Added 05/04/2021 by Daina Esposito, source=Web Response, value=Salary Owner/Founder relationship with Ciconia Inc Please note: 2018-2021 Added 05/04/2021 by Daina Esposito, source=Web Response, value=Ownership interest Employee relationship with Anthem Inc (HealthCore Inc) Please note: April 2019-present Added 05/04/2021 by Xintong He, source=Web Response, value=Salary Employee relationship with Boehringer-Ingelheim Please note: 2016- Added 05/03/2021 by Jukka Montonen, source=Web Response, value=Salary Advisory Committee Member relationship with GlaxoSmithKline Please note: Last 24 months Added 04/29/2021 by Jennifer Quint, source=Web Response, value=Honoraria Advisory Committee Member relationship with Boehringer Ingelheim Please note: Last 24 months Added 04/29/2021 by Jennifer Quint, source=Web Response, value=Honoraria Advisory Committee Member relationship with AstraZeneca Please note: Last 24 months Added 04/29/2021 by Jennifer Quint, source=Web Response, value=Honoraria Advisory Committee Member relationship with Bayer Please note: Last 24 months Added 04/29/2021 by Jennifer Quint, source=Web Response, value=Honoraria

Triple Inhaler versus Dual Bronchodilator Therapy in COPD: Real-World Effectiveness on Mortality

Randomized trials of triple therapy including an inhaled corticosteroid (ICS) for chronic obstructive pulmonary disease (COPD) reported remarkable benefits on mortality compared with dual bronchodilators, likely resulting from ICS withdrawal at randomization. We compared triple therapy with dual bronchodilator combinations on major COPD outcomes in a real-world clinical practice setting. We identified a cohort of COPD patients, age 50 or older, treated during 2002-2018, from the United Kingdom’s Clinical Practice Research Datalink. Patients initiating treatment with a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA) and an ICS on the same day, were compared with patients initiating a LAMA and LABA, weighted by fine stratification of propensity scores. Subjects were followed-up one year for all-cause mortality, severe exacerbation and pneumonia. The cohort included 117,729 new-users of LAMA-LABA-ICS and 26,666 of LAMA-LABA. The adjusted hazard ratio (HR) of all-cause mortality with LAMA-LABA-ICS compared with LAMA-LABA was 1.17 (95% CI: 1.04-1.31) while for severe exacerbation and pneumonia it was 1.19 (1.08-1.32) and 1.29 (1.16-1.45) respectively. However, mortality was not elevated with triple therapy among patients with asthma diagnosis (HR 0.99; 95% CI: 0.74-1.34), with two or more prior exacerbations (HR 0.88; 95% CI: 0.70-1.11), and with FEV1 percent predicted >30%. In a real-world setting of COPD treatment, triple therapy initiation was not more effective than dual bronchodilators at preventing all-cause mortality and severe COPD exacerbations. Triple therapy may be unsafe among patients without prior exacerbations, in whom ICS are not recommended, with no asthma diagnosis and with very severe airflow obstruction. Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1977789 .

Budesonide/Glycopyrrolate/Formoterol Fumarate Co-suspension Metered Dose Inhaler: A Triple Therapy for the Treatment of Chronic Obstructive Pulmonary Disease.

To review current evidence on the use of a fixed-dose combination (FDC) of budesonide/glycopyrrolate/formoterol fumarate (BGFF) triple therapy delivered via metered dose inhaler (MDI) in patients with chronic obstructive pulmonary disease (COPD) and offer clinical practice insights. We used PubMed to conduct the literature search from 1946 through June 30, 2021, using budesonide, glycopyrrolate or glycopyrronium, and formoterol. We included clinical trials in patients with COPD along with pharmacokinetic or pharmacodynamic studies. In all, 19 citations were included. BGFF MDI reduces the risk of exacerbations regardless of exacerbation history compared with dual bronchodilators or inhaled corticosteroid/long-acting β-agonist. Rescue inhaler use decreased, and patient-reported outcomes of symptoms and well-being improved with triple therapy. Mortality was decreased with the higher-dose BGFF MDI in comparison to dual bronchodilator therapy. Dysphonia and candidiasis were more common with BGFF MDI compared with dual bronchodilators, as was pneumonia. BGFF MDI is the second FDC triple therapy approved for COPD treatment. BGFF MDI improves important patient outcomes in COPD, including exacerbation risk. The unique co-suspension technology allows delivery of 3 active ingredients in 1 inhaler, a potential benefit to overcome adherence and technique-related barriers. These benefits must be gently weighed against the increased risk of pneumonia. The findings from phase 3 trials support the efficacy and safety of triple therapy in COPD. Future studies are needed to confirm potential mortality benefit and the role of triple therapy in patients without an exacerbation history.

Dual versus single long-acting bronchodilator use could raise acute coronary syndrome risk by over 50%: A population-based nested case-control study.

BackgroundCoronary heart disease occurs more frequently among patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD. While some research suggests that long‐acting bronchodilators might confer an additional risk of acute coronary syndrome (ACS), information from real‐world clinical practice about the cardiovascular impact of using two versus one long‐acting bronchodilator for COPD is limited. We undertook a population‐based nested case–control study to estimate the risk of ACS in users of both a long‐acting muscarinic antagonist (LAMA) and a long‐acting beta2‐agonist (LABA) relative to users of a LAMA.MethodsThe study was based on the primary care PREDICT Cardiovascular Disease Cohort and linked data from regional laboratories and the New Zealand Ministry of Health's national data collections. The underlying cohort (n = 29,993) comprised patients aged 45–84 years, who initiated treatment with a LAMA and/or LABA for COPD between 1 February 2006 and 11 October 2016. 1490 ACS cases were matched to 13,550 controls by date of birth, sex, date of cohort entry (first long‐acting bronchodilator dispensing), and COPD severity.ResultsRelative to current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a significantly higher risk of ACS (adjusted OR = 1.72; [95% CI: 1.28–2.31]).ConclusionDual long‐acting bronchodilator therapy, rather than LAMA mono‐therapy, could increase the risk of ACS by more than 50%. This has important implications for decisions about the potential benefit/harm ratio of COPD treatment intensification, given the modest benefits of dual therapy.

Swiss Experience in Therapy With Dual Bronchodilation in Chronic Obstructive Pulmonary Disease in Relation to Self-Reported Physical Functionality.

BackgroundMedical therapy in chronic obstructive pulmonary disease (COPD) usually includes inhaled dual bronchodilation leading not only to an improvement in symptoms but also to an increase in physical performance. However, it remains unknown whether responder rates to dual bronchodilation differ between the Swiss subgroup in comparison to participants of other European countries.MethodsThe non-interventional OTIVACTO trial investigated changes in self-reported physical functioning in COPD patients treated with tiotropium/olodaterol 5/5 µg fixed dose combination for 6 weeks. The cut-off between responder and non-responder was defined as a minimum increase of 10 points using the 10-question physical functioning questionnaire (PF-10) score. We searched for patterns of the responder patient group and compared the results of the whole dataset with the subgroup of Swiss participants.ResultsCompared to the total cohort (n = 7,608), the Swiss participants (n = 94) were predominantly > 65 years of age and had significantly more comorbidities. There were no significant differences according to COPD stage, smoking status, exacerbation rate in the last 12 months and modified Medical Research Council questionnaire (mMRC) score between the total cohort and the Swiss collective. There were no significant differences between the Swiss subgroup and the total cohort with regard to response to the medication in the PF-10 score. In the intragroup comparison, patients with high mMRC score showed significantly higher values in the PF-10 in both groups. The number of exacerbations had no influence on the PF-10 score in the Swiss subgroup but in the total cohort.ConclusionIn terms of age and number of comorbidities, significant differences were found between the overall patient population and the Swiss participants, having no influence on the success of the medication. The patients suffering from increased dyspnea benefited most from tiotropium/olodaterol treatment (Clinical Trials Registry NCT02720757).

Aclidinium bromide/formoterol fumarate as a treatment for COPD: an update

ABSTRACT Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium/formoterol has been demonstrated consistently in patients with moderate-to-severe COPD versus placebo and monocomponents, with a comparable safety profile. Areas covered: This review examines recent research findings that expand our understanding of the impact of aclidinium/formoterol on the burden of COPD. Reviewed outcomes include improvements in lung function, respiratory symptoms, health-related quality of life, exercise tolerance, exacerbation rates, and clinically important deteriorations. In addition, the reported cardiovascular safety of aclidinium and current LAMA/LABA treatment recommendations are discussed. Expert opinion: Aclidinium/formoterol reduces disease burden in patients with COPD, including those that are treatment-naïve, without a significant increase in safety risk compared with monotherapies. Furthermore, evidence supports an improvement in lung function over a 24-hour period with aclidinium/formoterol treatment versus monotherapy and placebo, which may offer an advantage over some once-daily LAMA/LABA combinations. In summary, the recent evidence discussed in this review adds weight to the use of LAMA/LABA combinations as an initial therapy for certain patients newly diagnosed with COPD.