Long-acting Bronchodilator Therapy Research Articles

Inhaled Corticosteroids in Subjects with Chronic Obstructive Pulmonary Disease: An Old, Unfinished History.

Chronic obstructive pulmonary disease (COPD) is one of the major causes of disability and death. Maintenance use of inhaled bronchodilator(s) is the cornerstone of COPD pharmacological therapy, but inhaled corticosteroids (ICSs) are also commonly used. This narrative paper reviews the role of ICSs as maintenance treatment in combination with bronchodilators, usually in a single inhaler, in stable COPD subjects. The guidelines strongly recommend the addition of an ICS in COPD subjects with a history of concomitant asthma or as a step-up on the top of dual bronchodilators in the presence of hospitalization for exacerbation or at least two moderate exacerbations per year plus high blood eosinophil counts (≥300/mcl). This indication would only involve some COPD subjects. In contrast, in real life, triple inhaled therapy is largely used in COPD, independently of symptoms and in the presence of exacerbations. We will discuss the results of recent randomized controlled trials that found reduced all-cause mortality with triple inhaled therapy compared with dual inhaled long-acting bronchodilator therapy. ICS use is frequently associated with common local adverse events, such as dysphonia, oral candidiasis, and increased risk of pneumonia. Other side effects, such as systemic toxicity and unfavorable changes in the lung microbiome, are suspected mainly at higher doses of ICS in elderly COPD subjects with comorbidities, even if not fully demonstrated. We conclude that, contrary to real life, the use of ICS should be carefully evaluated in stable COPD patients.

Clinical Implications of Peak Inspiratory Flow in COPD: Post Hoc Analyses of the TRONARTO Study.

In patients with COPD, inhalation ability should be assessed when considering inhaler choice. To evaluate whether the soft mist inhaler (SMI) is suitable for COPD patients irrespective of inhalation ability, the TRONARTO study investigated the efficacy of dual long-acting bronchodilator therapy delivered via the Respimat® SMI on lung function in patients with COPD stratified by inhalation ability. Tiotropium/olodaterol delivered via the SMI was effective both in patients with peak inspiratory flow (PIF) <60L/min and PIF ≥60L/min, measured against medium-low resistance. This congress compilation summarizes post hoc analyses from the TRONARTO study presented at the annual American Thoracic Society 2022 and European Respiratory Society 2022 meetings. These analyses evaluated PIF in over 200 patients, with PIF measurements taken daily at home for 4weeks, and in the clinic at baseline, Weeks 2 and 4. Overall, 57.9% of patients had a PIF range (difference between lowest and highest PIF measurements) <20 L/min (12.4% of patients had PIF range <10 L/min). At-home PIF range decreased over the study period, suggesting that inhaler training/repeated PIF measurements may help to make patients' inspiratory effort more consistent. Some patient characteristics correlated with lower PIF (female gender, shorter stature, more severe disease, worse airflow obstruction) and lower PIF range (more severe disease). PIF measurements differed between medium-low and high-resistance settings, highlighting the importance of measuring PIF at the resistance of a patient's inhaler. PIF correlated poorly with spirometry measurements. As indicated in COPD management guidelines, choice of inhaler is essential to optimize pharmacologic therapies for COPD. Poor inspiratory ability should be viewed as a treatable trait that can help to inform inhaler choice. Inhaler training and consideration of PIF (if patients use a dry powder inhaler) can reduce patient-to-inhaler mismatch, with potential consequences for health status and exacerbation risk.

COPD - An Underestimated Disease

COPD - An Underestimated Disease Abstract: Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition with a complex clinical picture. The diagnosis is not easy to make because COPD can develop insidiously and remain unnoticed for a long time. Therefore, general practitioners play a central role in the early detection of the disease. Suspected COPD can be confirmed by special examinations in collaboration with pulmonologists. The new GOLD guideline defines three COPD risk groups (A-B-E) which should guide the personalized treatment concept. A short- or long-acting bronchodilator (SAMA/SABA or LAMA/LABA) is recommended for group A, and a dual long-acting bronchodilator therapy (LABA+LAMA) is recommended for group B and E. In case of blood eosinophilia (≥300 cells/µl) and/or recent hospitalization for COPD exacerbation, triple therapy (LABA+LAMA+ICS) is recommended. General practitioners are important in implementing non-pharmacological measures (smoking cessation, regular exercise, vaccinations, patient selfmanagement education). However, this also underlines the high demands of the implementation of the GOLD guideline in daily practice.

New Perspectives on Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide; many recent advances have been made in many aspects of the disease. The aim of this article is to illustrate and discuss some of these advances in the management of different types of patients. Large-scale trials have confirmed that long-acting bronchodilator therapy, particularly using the combination of LABA/LAMA, remains the mainstay of COPD treatment, with special attention being paid to careful selection of inhaler devices. The initial choice of pharmacological therapy is based on the GOLD ABCD grouping of patients. It is very important to stress that there is a need to implement a management cycle because COPD is a chronic disease with varying clinical course and a high number of potential comorbidities that may affect morbidity and mortality. Therefore, regular reevaluation of the patient is mandatory. This allows identification of characteristics aimed at maximizing the benefits for a specific patient or a subset of patients. Within this context, the role of the blood eosinophil count as a marker of inhaled corticosteroids response to prevent future exacerbations in patients who, despite appropriate bronchodilator therapy, still suffer from them has been proven to be a useful simple biomarker in medication selection. These advances support the concept of precision medicine, with the goal that patients get the right medicine at the right time for the right reason. Finally, recent studies have shown that early life events may be of critical relevance for the development of COPD. With this as a background, concepts to identify individuals at risk and early identification of cases have become an important objective of current research with the hope of maximizing the effects of therapy and the possibility of impacting disease progression.

Effect of timing of bronchodilator therapy initiation on exacerbations in patients with chronic obstructive pulmonary disease: a retrospective cohort study

BackgroundThe benefit of prompt vs delayed treatment initiation with inhaled long-acting bronchodilators in reducing exacerbations in chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to investigate if long-acting bronchodilator therapy initiation within 30 days of COPD diagnosis reduces exacerbation risk in patients with COPD.MethodsThis was a retrospective cohort study of patients with COPD based on claims and electronic medical records data extracted from the Real World Data database. The index date (day 0) was the date of the first confirmed inpatient or outpatient COPD diagnosis between January 1, 2005, and December 31, 2018. Patients with COPD without an asthma diagnosis and aged ≥ 40 years at the index date were included. Patients who initiated inhaled long-acting bronchodilator therapy within the first 30 days (day 0 to day 29) were categorized into the “prompt therapy” group and the rest into the “delayed therapy” group. Time from day 30 post-diagnosis to the first exacerbation and annual exacerbation rate (AER) were evaluated for the overall population and those stratified by COPD phenotype, including chronic bronchitis (CB) and emphysema.ResultsCompared with the delayed therapy group (n = 1516), time to first exacerbation was prolonged (hazard ratio 0.78; 95% confidence interval [CI] [0.70, 0.87]) and annual rates of moderate or severe exacerbations were lower (rate ratio 0.74; 95% CI [0.65, 0.84]) in the prompt therapy group (n = 1466). Similarly, time to first exacerbation was prolonged and AERs were lower in the prompt therapy group in the subgroups of patients with CB or emphysema.ConclusionsThis is the first study to demonstrate a prolonged time to first exacerbation upon initiation of long-acting bronchodilators within 30 days of COPD diagnosis. A beneficial effect was also observed in patients with CB and emphysema. Our data support advising patients to initiate long-acting bronchodilators soon after COPD diagnosis.

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

313Long-acting bronchodilators and risk of acute coronary syndrome

Abstract Background There is concern that long-acting bronchodilators (long-acting muscarinic antagonists [LAMAs]) and long-acting beta2-agonists [LABAs]) may further increase the already elevated risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD). Guidelines recommend stepwise escalation from one to two long-acting bronchodilators in patients with uncontrolled symptoms, but information about the impact of this treatment intensification on acute coronary syndrome (ACS) risk is limited. Methods We undertook a nested case-control study using national administrative data to estimate the risk of ACS in users of dual LAMA and LABA therapy, and users of LABA monotherapy, relative to users of LAMA monotherapy. The underlying study cohort comprised patients aged &amp;gt;45 years who initiated long-acting bronchodilator therapy for COPD between 2006 and 2013 (n = 83,417). Cases were patients diagnosed with fatal or non-fatal ACS after cohort entry (n = 5,399). Up to 10 controls per case, matched by age, sex, date of cohort entry, and COPD severity, were randomly selected from the study cohort using risk set sampling. Odd ratios and 95% confidence intervals were estimated using conditional logistic regression. Results Relative to current use of LAMA monotherapy, the adjusted odds ratios for current use of dual LAMA and LABA therapy, and of LABA monotherapy, were 1.28 (95% CI 1.13–1.44) and 1.0 (95% CI 0.91–1.10), respectively. Conclusions Use of two long-acting bronchodilators rather than LAMA monotherapy, is associated with a higher risk of ACS, while the risks associated with LAMA and LABA monotherapy are comparable. Key messages The clinical benefit of adding a second long-acting bronchodilator to LAMA or LABA monotherapy is modest and, at the same time, is associated with an increased risk of ACS in a patient group already at high risk.

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.

A Real-World Analysis of Treatment Patterns and Clinical Characteristics Among Patients with COPD Who Initiated Multiple-Inhaler Triple Therapy in New Zealand.

PurposeReal-world data on maintenance treatment and prescription patterns provide insights into healthcare management among patients with chronic obstructive pulmonary disease (COPD), which benefits our understanding of current COPD treatment patterns in New Zealand.MethodsWe retrospectively analyzed real-world data from the HealthStat general practice database to evaluate treatment patterns among patients with COPD in New Zealand who initiated multiple-inhaler triple therapy (MITT): inhaled corticosteroid (ICS) + long-acting muscarinic antagonist + long-acting β2-agonist (LABA). Our main objective described treatment patterns (class, duration, modification, persistence, and adherence) and characteristics of patients with COPD initiating MITT between 1 May 2016 and 30 April 2017, with 12-months’ follow-up. We also assessed the number of patients receiving MITT between 2015 and 2017, among a larger patient population receiving long-acting bronchodilator and ICS-containing therapies.ResultsOf 6249 eligible patients, 421 (mean age 67.3 years; mean number exacerbations at baseline 1.8) initiated MITT: 59.1% received combination ICS/LABA therapy prior to MITT initiation, and median treatment duration prior to MITT initiation was 350 days. Overall, 33.5% of patients remained on index treatment for 12 months. Of the remaining patients who modified treatment (on average at 144.4 days), those who had a direct switch (24.9%) or retreatment (13.5%) remained on MITT, 19.7% of patients stepped down to mono/dual therapy, and 8.3% discontinued treatment. Mean (standard deviation) persistence to any MITT over 12 months was 47.3 (50.0), and 53.4% of patients were considered adherent to MITT. Total proportions of patients receiving long-acting bronchodilator therapy and MITT increased between 2015 and 2017.ConclusionMost patients with COPD in New Zealand who initiated MITT had characteristics appropriate for triple therapy prescription, suggesting prescription behavior among general practitioners was largely consistent with treatment guidelines. Our findings may help optimize treatment decisions, with a focus on improving long-term triple therapy persistence and adherence.

Clinical Characterization of Nursing Facility Residents With Chronic Obstructive Pulmonary Disease.

To describe clinical characteristics, medication use, and low peak inspiratory flow rate (PIFR) (< 60 L/min) prevalence in nursing facility residents with chronic obstructive pulmonary disease (COPD). Residents 60 years of age and older with a COPD diagnosis and≥ 6 months' nursing facility residence, were enrolled between December 2017 and February 2019 from 26 geographically varied United States nursing facilities. Data, extracted from residents' charts, included demographic/clinical characteristics, COPD-related medications, exacerbations and hospitalizations within the past 6 months, and functional status from the most recent Minimum Data Set. At enrollment, residents completed the modified Medical Research Council (mMRC) Dyspnea Scale and COPD Assessment Test (CAT™). Spirometry and PIFR were also assessed. Residents' (N = 179) mean age was 78.0 ± 10.6 years, 63.7% were female, and 57.0% had low PIFR. Most prevalent comorbidities were hypertension (79.9%), depression (49.2%), and heart failure (41.9%). The average forced expiratory volume in 1 second (FEV11) % predicted was 45.9% ± 20.9%. On the CAT, 78.2% scored≥ 10 and on the mMRC Dyspnea Scale, 74.1% scored≥ 2, indicating most residents had high COPD symptom burden. Only 49.2% were receiving a scheduled long-acting bronchodilator (LABD). Among those with low PIFR prescribed a LABD, > 80% used dry powder inhalers for medication delivery. This study highlights underutilization of scheduled LABD therapy in nursing facility residents with COPD. Low PIFR was prevalent in residents while the majority used suboptimal medication delivery devices. The findings highlight opportunities for improving management and outcomes for nursing facility residents with COPD.

The effect of long-acting dual bronchodilator therapy on exercise tolerance, dynamic hyperinflation, and dead space during constant work rate exercise in COPD.

We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (VD/VT) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, n = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous (Tc) measurement was used for VD/VT estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV1) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV1 by 0.18 ± 0.21 L relative to placebo (PL; P < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; P = 0.013; confidence interval: 20–90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL (P ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; P = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; P = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, P = 0.865). Isotime VD/VT did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; P = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering VD/VT.NEW & NOTEWORTHY This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (VD/VT) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess VD/VT (transcutaneous carbon dioxide, Tc) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement.

Is the use of two versus one long-acting bronchodilator by patients with COPD associated with a higher risk of acute coronary syndrome in real-world clinical practice?

BackgroundCardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2 agonists (LABAs)) may further...

Triple Therapy versus Dual or Monotherapy with Long-Acting Bronchodilators for Chronic Obstructive Pulmonary Disease. A Systematic Review and Meta-analysis.

Rationale: There is uncertainty on the use of using triple therapy (inhaled corticosteroids/long-acting β-agonist/long-acting muscarinic antagonist) inhaler therapy for patients with chronic obstructive pulmonary disease (COPD), who complain of dyspnea and/or exercise intolerance.Objectives: We conducted a systematic review and meta-analyses to estimate the safety and efficacy of using triple therapy compared with long-acting β-agonist/long-acting muscarinic antagonist dual therapy or monotherapy with a single long-acting bronchodilator in patients with stable COPD who complained of dyspnea and/or exercise intolerance.Methods: A search of MEDLINE, Embase, and the Cochrane Library databases was conducted for randomized controlled trials pertaining to the clinical question. A systematic approach was used to screen, abstract, and critically appraise the studies. The grading of recommendations assessment, development, and evaluation method was applied to rate the certainty/quality of the evidence.Results: Eleven studies were eligible for inclusion (n = 14,145 patients). Pairwise random-effects meta-analysis revealed an increase in risk of pneumonia (relative risk, 1.47; 95% confidence interval [95% CI], 1.20-1.80; P < 0.001) and decreased risk of acute exacerbations of COPD (AECOPDs) (relative risk, 0.75; 95% CI, 0.68-0.82; P < 0.001) with triple therapy compared with treatment with dual and monotherapy long-acting bronchodilator therapy. No significant difference in dyspnea scores (standardized mean difference, 0.09; 95% CI, -0.02 to 0.19; P = 0.09) or risk of hospitalization (rate ratio, 0.78; 95% CI, 0.58-1.06; P = 0.11) was noted. When subgroup analysis based on inhaler class was performed, no significant difference was noted between the groups in any of the critical outcomes studied. For patients with a history of one or more AECOPDs in the past year, triple therapy resulted in 230 fewer AECOPDs and 16 more cases of pneumonia per 1,000 patients.Conclusions: In patients with COPD who complain of dyspnea and/or exercise intolerance, triple therapy is not superior to maintenance long-acting bronchodilator therapy, except in patients with a history of one or more exacerbations in the past year, in whom the benefits of reduction in AECOPD outweigh the increased risk of pneumonia.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial

IntroductionMost guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. MethodsThis was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 μg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. ResultsA total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0–6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. ConclusionAmong patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Dual- Versus Mono-Bronchodilator Therapy in Moderate to Severe COPD: A Meta-analysis.

Chronic obstructive pulmonary disease (COPD) guidelines recommend both long-acting and dual bronchodilator therapy. It is unclear if there are differences in efficacy and safety. This meta-analysis evaluates the efficacy of dual therapy with long-acting β-agonist (LABA) + long acting muscarinic antagonist (LAMA) compared with monotherapy with LAMA for COPD. We searched PubMed, CINAHL, and Web of Science databases from inception through March 2020 to identify English-language, prospective randomized controlled trials (RCTs) that compared dual therapy with monotherapy in adult patients with COPD. Risk of bias was assessed using the Jadad score. Overall analysis was performed using Review Manager 5.3. Treatment effect was determined with the random-effects model using the Mantel-Haenszel method and was reported as mean difference (MD) with 95% CI. A total of 18 RCTs were included (n = 6086; median Jadad score 5/5) that compared LAMA + LABA with LAMA. There was a greater improvement in forced expiratory volume at 1 s (FEV1) with dual therapy compared with LAMA: MD = 0.08; 95% CI = [0.05, 0.11]. There was no difference in St George Respiratory Questionnaire (SGRQ) scores between groups: OR = -0.85; 95% CI = [-1.83, 0.13]. There were no differences in overall adverse events (OR = 1.00; 95% CI = 0.92, 1.09), serious adverse events (OR = 1.01; 95% CI = 0.86, 1.18), or cardiovascular events (OR = 0.88; 95% CI = 0.58, 1.34). Dual therapy improves FEV1 and is as safe as LAMA. Dual therapy does not improve SGRQ scores more than LAMA.

PRS69 TREATMENT OF COPD PATIENTS IN GERMANY AND THE NEED FOR THERAPY ESCALATION: A CLAIMS DATA ANALYSIS

Known guidelines recommend a treatment escalation procedure in case a patient is diagnosed with COPD. The study aimed (1) to assess epidemiology of patients receiving/not receiving long-acting COPD therapy and (2) to assess percentage of patients in need of therapy optimization. This retrospective analysis utilized claims data (AOK PLUS; 2015-2016). Included were patients (i) with ≥1 inpatient and/or ≥2 confirmed outpatient COPD diagnoses [ICD-10 J44%] in 2015-2016; (ii) no asthma diagnosis [ICD-10 J45%]; (iii) aged ≥40 years; (iv) with enrolment in a COPD-disease management program (DMP). Based on the second half of the year 2016, patients were assigned to the following subgroups: (A) therapy-naïve starting or in need of a long-acting bronchodilator therapy (LABA/LAMA); (B) therapy-naïve not in need of LABA/LAMA therapy; (C) receiving LABA/LAMA, but in need of therapy optimization; (D) stable on LABA/LAMA. Therapy optimization need was defined as either >2 prescriptions of antibiotics or oral corticosteroids, or ≥1 inpatient or ≥2 outpatient exacerbation diagnoses (ICD-10 J44.1 and/or documented within DMP), or another DMP documentation indicating additional treatment needs. We identified 22,839 COPD patients (mean/median age 72.1/73; 37.8% female); 9.7% could not be assigned to one of the subgroups due to COPD treatment in 2015 but no treatment in the observational period. Patient numbers were as follows: therapy-naïve patients:10.5% of patients with 5.2% in need of LABA-therapy initiation (A) and 5.3% not in need (B); patients receiving LABA/LAMA 79.8% of patients with 16.3% in need of therapy optimization (C) and 63.5% being stable on current therapy (D). In group C, 100% had a documentation of at least one exacerbation in the observational period, 39.7% had at least one inpatient exacerbation. About 16% of currently treated and additional 5.2% of currently untreated patients are in need of a therapy optimization.

Triple therapy versus single and dual long-acting bronchodilator therapy inCOPD: a systematic review and meta-analysis.

We performed a meta-analysis to compare the impact of triple combination therapy with inhaled corticosteroids (ICS), long-acting β2-agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) versus LABA/LAMA combination therapy or single long-acting bronchodilator therapy in chronic obstructive pulmonary disease. The ICS/LABA/LAMA combination reduced the risk of exacerbation (relative risk 0.70, 95% CI 0.53-0.94) and improved trough forced expiratory volume in 1 s (mean difference in mL +37.94, 95% CI 18.83-53.89) versus LABA/LAMA combination therapy. The protective effect of triple combination therapy versus LABA/LAMA combination therapy against risk of exacerbation was greater in patients with blood eosinophil counts ≥300 cells·µL-1 (relative risk 0.57, 95% CI 0.48-0.68). While ∼38 patients had to be treated for 1 year with ICS/LABA/LAMA combination therapy to prevent one exacerbation compared to LABA/LAMA combination therapy, the number needed to treat (NNT) was ∼21 when compared to single long-acting bronchodilator therapy. The person-based NNT per year of ICS/LABA/LAMA combination therapy versus LABA/LAMA combination therapy was significantly (p<0.05) lower in patients with eosinophil counts ≥300 cells·µL-1 (NNT value: 8.58) than in those with counts <300 cells·µL-1 (NNT value: 46.28). The risk of pneumonia did not differ between ICS/LABA/LAMA combination therapy and its comparators. The number needed to harm was ∼195. This meta-analysis suggests that patients on single long-acting bronchodilator therapy or LABA/LAMA combination therapy, who still have exacerbations and have blood eosinophil counts ≥300 cells·µL-1, could benefit from ICS/LABA/LAMA combination therapy.

Evaluation of Bronchodilator Use During Chronic Obstructive Pulmonary Disease Exacerbation Inpatient Admissions.

Background: It is unknown whether the timing of initiation of a long-acting bronchodilator (LABD) during a chronic obstructive pulmonary disease (COPD) exacerbation or the method of short-acting bronchodilator (SABD) delivery may aid in improving patient outcomes. Objective: The goal of this study was to determine the impact of bronchodilator management in the hospital setting on clinical outcomes in patients with COPD exacerbation. Methods: This retrospective, single-center study evaluated patients admitted to the non-intensive care unit setting with a COPD exacerbation as defined by the International Classification of Diseases, Ninth Revision codes. The primary outcome was difference in 30-day readmission rates for early LABD therapy (<24 hours from hospital admission) versus late/no LABD therapy (>24 hours from hospital admission or not during hospitalization). Secondary objectives included length of stay (LOS) for this group, and 30-day readmission rates and LOS for the SABD via inhaler versus nebulizer groups. Results: Two hundred twenty patients were included. There was no difference in 30-day readmission rate (15.2% vs 18.2%, P = .6) and LOS (median 4 [interquartile range, IQR 3-6]) days for both groups, P = .34) between early versus late/no LABD therapy initiation, respectively. No difference was observed in 30-day readmission rate (16.7% vs 16.6%) and LOS (median 2.5 [IQR 1.1-3.9] days vs median 4 [IQR 2-6] days) between inhaler and nebulizer SABD therapy groups. Conclusions: No difference was observed in 30-day readmission rates or LOS when utilizing early LABD compared with late/no LABD therapy or comparing inhaler and nebulizer SABD delivery methods during COPD exacerbation.

Real-world outcomes in patients with chronic obstructive pulmonary disease initiating long-acting mono bronchodilator therapy.

Background:Randomized clinical trials have shown long-acting mono bronchodilator therapy to be efficacious in improving lung function and dyspnea, while reducing exacerbations; however, less is known regarding the effectiveness in routine clinical practice. This study examined treatment patterns, rescue medication use, healthcare resource utilization and costs, and exacerbations in patients with chronic obstructive pulmonary disease (COPD) who initiated long-acting mono bronchodilator therapy in real-world settings.Methods:This retrospective study used US claims data from adult patients with COPD initiating long-acting mono bronchodilator therapy between 1 January 2008 and 31 January 2015. Patients were required to have continuous health plan enrollment 12 months prior to (baseline period) and 12 months following therapy initiation (follow-up period). Outcomes, including treatment patterns, rescue medication use, exacerbations, and healthcare utilization and costs, were measured until the earliest of treatment augmentation or discontinuation, death, health plan disenrollment, or the end of the study period. Results were analyzed descriptively for all measures. Baseline and follow-up measures of all-cause and COPD-related healthcare costs and exacerbations [per patient per month (PPPM)] were compared using paired t tests.Results:Among 27,394 patients with a mean follow up of 6.3 months, 18.2% augmented, 74.2% discontinued, and 7.6% continued long-acting mono bronchodilator therapy. Rescue medication use was prevalent during the follow-up period, with an average of 1.0 short-acting β agonist (SABA) fills/month and 0.8 short-acting muscarinic antagonist (SAMA) fills/month, among patients with at least one fill for the medication of interest. PPPM mean number of exacerbations was more than triple (0.17 versus 0.05, p < 0.001) and PPPM exacerbation-related costs were more than double over the follow-up period compared with baseline ($1070 versus $485). COPD-related costs accounted for 50% of all-cause costs during the follow-up period and were significantly higher compared with baseline ($1206 versus $592, p < 0.001).Conclusions:Patients initiating long-acting mono bronchodilator therapy had high rates of medication discontinuation or augmentation. Patients used more rescue medications and experienced significantly more COPD exacerbations with higher healthcare costs compared with baseline. Further research is warranted to determine whether more aggressive initial therapy would result in symptom improvement.

The Role of Tiotropium+Olodaterol Dual Bronchodilator Therapy in the Management of Chronic Obstructive Pulmonary Disease.

Bronchodilator therapy is central to the management of chronic obstructive pulmonary disease and are recommended as the preferred treatment by the Global Obstructive Lung Disease Initiative (GOLD). Long acting anti-muscarinics (LAMA) and long acting β2 agonists (LABA) are both more effective than regular short-acting drugs but many patients remain symptomatic despite monotherapy with these drugs. Combination therapy with LAMA and LABA increases the therapeutic benefit while minimizing dose-dependent side effects of long-acting bronchodilator therapy. The TOviTO programme has investigated the benefits of treatment with a combination of tiotropium and olodaterol administered via a single inhaler. Tiotropium+olodaterol 5/5 µg significantly improved forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours, trough FEV1 health status and breathlessness versus the mono-components and placebo. Tiotropium+olodaterol 5/5 µg also increased endurance time and reduced dynamic hyperinflation during constant work rate cycle ergometry. On the basis of these and other studies the 2017 GOLD report recommends escalating to dual bronchodilator therapy in patients in groups B and C if they remain symptomatic or continue to have exacerbations and as initial therapy for patients in group D.