Development of MDS-Based Predication Model for COPD Severity in Nursing Home Residents.

BACKGROUND: Assessing chronic obstructive pulmonary disease (COPD) severity is challenging in nursing home (NH) residents due to incomplete symptom assessments and exacerbation history. OBJECTIVE: The objective of this study was to predict COPD severity in NH residents using the Minimum Data Set (MDS), a clinical assessment of functional capabilities and health needs. METHODS: A cohort analysis of prospectively collected longitudinal data was conducted. Residents from geographically varied Medicare-certified NHs with age ≥60 years, COPD diagnosis, and ≥6 months NH residence at enrollment were included. Residents with severe cognitive impairment were excluded. Demographic characteristics, medical history, and MDS variables were extracted from medical records. The care provider-completed COPD Assessment Test (CAT) and COPD exacerbation history were used to categorize residents by Global Initiative for Chronic Lung Disease (GOLD) A to D groups. Multivariate multinomial logit models mapped the MDS to GOLD A to D groups with stepwise selection of variables. RESULTS: Nursing home residents (N = 175) were 64% women and had a mean age of 77.9 years. Among residents, GOLD B was most common (A = 13.1%; B = 44.0%; C = 5.7%; D = 37.1%). Any long-acting bronchodilator (LABD) use and any dyspnea were significant predictors of GOLD A to D groups. The predicted MDS-GOLD group (A = 6.9%; B = 52.6%; C = 4.6%; D = 36.0%) showed good model fit (correctly predicted = 60.6%). Nursing home residents may underuse group-recommended LABD treatment (no LABD: B = 53.2%; C = 80.0%; D = 40.0%). CONCLUSION AND RELEVANCE: The MDS, completed routinely for US NH residents, could potentially be used to estimate COPD severity. Predicted COPD severity with additional validation could provide a map to evidence-based treatment guidelines and may help to individualize treatment pathways for NH residents.

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-naïve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials.

BACKGROUND: Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear. METHODS: Data from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety. RESULTS: GFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117-188) mL, 73 (45-100) mL, and 56 (29-84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P < 0.0001). GFF reduced the risk of CID by 17-43% in NMT (P ≤ 0.0157) and 18-52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies. CONCLUSIONS: NMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

Major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study.

BACKGROUND: While inhaled bronchodilators reduce symptoms and acute exacerbations of chronic obstructive pulmonary disease (COPD), their use is associated with increased cardiovascular events in some studies. This study investigates the risk of adverse events associated with the use of inhaled bronchodilators in COPD patients with multimorbidity. METHODS: A case-control study was conducted between January 2015 and December 2017, and patients with spirometry-confirmed diagnosis of COPD (N = 1565) using inhaled long-acting bronchodilators were enrolled. Medical records were reviewed and clinical data, including age, gender, smoking status, major comorbidities, lung function stage, history of exacerbations, bronchodilator regimens, and treatment duration were analyzed. Major adverse cardiovascular events occurring during long-acting bronchodilator use were recorded. RESULTS: The most common comorbidities were cardiovascular disease (CVD) (53.6%) and chronic kidney disease (CKD) (25.8%). We observed that CVD (odds ratio [OR], 5.77), CKD (OR, 2.02) and history of frequent exacerbations (OR, 2.37) were independent risk factors for cardiovascular events, regardless of the type of bronchodilators use. Moreover, COPD patients with both CKD and CVD had higher risk (6.32-fold) of adverse cardiovascular effects than those with neither comorbidity. Eighty-seven of 1565 (5.56%) COPD patients died during this study period. Of them, 21.8% (19/87) were cardiovascular-related and 73.6% (64/87) patients were respiratory-related mortality. Among COPD patients using long-acting bronchodilators, CKD was the only risk factor to predict cardiovascular events and cardiovascular-related mortality (OR, 4.87; 95% confidence interval [CI], 1.75-13.55]. CONCLUSIONS: COPD patients had higher risk of cardiovascular events were associated with their CVD and/or CKD comorbidities and history of frequent exacerbations, rather than associated with their use of inhaled bronchodilators.

Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies.

BACKGROUND: As lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history. METHODS: Four subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George's Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks. RESULTS: In all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment. CONCLUSIONS: These data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01964352 and NCT02006732 .

Eligibility of real-life patients with COPD for inclusion in trials of inhaled long-acting bronchodilator therapy.

BACKGROUND: Management guidelines of chronic obstructive pulmonary disease (COPD) are mainly based on results of randomised controlled trials (RCTs), but some authors have suggested limited representativeness of patients included in these trials. No previous studies have applied the full range of selection criteria to a broad COPD patient population in a real-life setting. METHODS: We identified all RCTs of inhaled long-acting bronchodilator therapy, during 1999-2013, at ClinicalTrials.gov and translated trial selection criteria into definitions compatible with electronic medical records. Eligibility was calculated for each RCT by applying these criteria to a uniquely representative, well-characterised population of patients with COPD from the Optimum Patient Care Research Database (OPCRD). RESULTS: Median eligibility of 36 893 patients with COPD for participation in 31 RCTs was 23 % (interquartile range 12-38). Two studies of olodaterol showed the highest eligibility of 55 and 58 %. Conversely, the lowest eligibility was observed in two studies that required a history of exacerbations in the past year (3.5 and 3.9 %). For the patient subgroup with modified Medical Research Council score ≥2, the overall median eligibility was 27 %. CONCLUSIONS: By applying an extensive range of RCT selection criteria to a large, representative COPD patient population, this study highlights that the interpretation of results from RCTs must take into account that RCT participants are variably, but generally more representative of patients in the community than previously believed.

Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation.

RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Treatment patterns in patients with stable COPD in China: analysis of a prospective, 52-week, nationwide, observational cohort study (REAL).

BACKGROUND: Underdiagnosis and undertreatment pose major barriers to optimal management of chronic obstructive pulmonary disease (COPD) in China. OBJECTIVE: The REAL trial was performed to generate reliable information on real-world COPD management, outcomes and risk factors among Chinese patients. Here, we present study outcomes related to COPD management. DESIGN: It is a 52-week, prospective, observational, multicentre study. METHODS: Outpatients (aged ⩾40 years) enrolled from 50 secondary and tertiary hospitals across six geographic regions of China were followed up for 12 months, with two onsite visits and by telephone every 3 months following baseline. RESULTS: Between June 2017 and January 2019, 5013 patients were enrolled and 4978 included in the analysis. Mean [standard deviation (SD)] age was 66.2 (8.9) years, the majority of patients were male (79.5%) and mean (SD) time since COPD diagnosis was 3.8 (6.2) years. The most common treatments at each study visit were inhaled corticosteroids/long-acting beta-agonists (ICSs/LABAs; 28.3-36.0%), long-acting muscarinic antagonists (LAMAs; 13.0-16.2%) and ICS/LABA + LAMA (17.5-18.7%), but up to 15.8% of patients at each visit received neither ICS nor long-acting bronchodilators. The use of ICS/LABA, LAMA and ICS/LABA + LAMA differed across regions and hospital tiers; up to fivefold, more patients received neither ICS nor long-acting bronchodilators in secondary (17.3-25.4%) versus tertiary hospitals (5.0-5.3%). Overall, rates of nonpharmacological management were low. Direct treatment costs increased with disease severity, but the proportion of direct treatment costs incurred due to maintenance treatment decreased with disease severity. CONCLUSION: ICS/LABA, LAMA and ICS/LABA + LAMA were the most frequently prescribed maintenance treatments for patients with stable COPD in China, although their use differed between region and hospital tier. There is a clear need for improved COPD management across China, particularly in secondary hospitals. REGISTRATION: The trial was registered on 20 March 2017 (ClinicalTrials.gov identifier: NCT03131362; https://clinicaltrials.gov/ct2/show/NCT03131362). PLAIN LANGUAGE SUMMARY: Treatment patterns in patients with COPD in ChinaBackground: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by progressive and irreversible airflow limitation. In China, many patients with this disease do not receive a diagnosis or appropriate treatment.Objective: This study aimed to generate reliable information on the treatment patterns among patients with COPD in China to help inform future management strategies.Study design and methods: Patients (aged ⩾40 years) were enrolled from 50 hospitals across 6 regions of China and physicians collected data over the course of 1 year during routine outpatient visits.Results: The majority of patients were receiving long-acting inhaled treatments, which are recommended to prevent worsening of the disease. Up to 16% of patients in this study, however, did not receive any of these recommended treatments. The proportion of patients who received long-acting inhaled treatments differed across regions and hospital tiers; there were about five times more patients in secondary hospitals (about 25%) who did not receive these treatments compared with those in tertiary hospitals (about 5%). Guidelines recommend that pharmacological treatment should be complemented by nondrug treatment, but this was only received by a minority of patients in this study. Patients with higher disease severity incurred greater direct treatment costs compared with those with milder disease. Maintenance treatment costs made up a smaller proportion of overall direct costs for patients with higher disease severity (60-76%) compared with patients with milder disease (81-94%).Conclusion: Long-acting inhaled treatments were the most frequently prescribed maintenance treatments among patients with COPD in China, but their use differed between region and hospital tier. There is a clear need to improve disease management across China, especially in secondary hospitals.

Duplicate Prescription Rates of Long-Acting Bronchodilator Inhalers.

Background: Long-acting bronchodilator inhalers are widely used with or without inhaled corticosteroids (ICs) by patients with lung diseases. In Israel alone, there are 21 inhalers containing long-acting ß2 agonists (LABAs) and/or long-acting muscarinic antagonists (LAMAs). Some patients are treated incorrectly with several inhalers of the same pharmacologic group. Methods: Electronic data of LABA and/or LAMA inhalers purchased during a period of 1 year were extracted in one district of Clalit Health Services in Israel. Patients who were treated with two or more inhalers from the same pharmacologic group were compared with patients without duplicate treatment. Inhaler purchases during the 12 months before and after the first duplicate purchase were compared with the purchases by patients without duplication of treatment. New diagnoses were compared to identify possible side effects. Results: Of the 13,528 patients who were treated with LABA and/or LAMA inhalers, 244 (1.8%) purchased at least two different inhalers from the same pharmacologic group. Inhaler purchases were 3.8 times higher in the duplication group during the 12 months before the first duplication. Inhaler purchase increased by 28% in the duplication group compared with a 4.5% increase in the nonduplication group (p < 0.001) during the following year. The risk for duplicated consumption was significantly higher in patients with a chronic obstructive pulmonary disease (COPD) diagnosis, males, and persons aged between 61 and 80 years. Conclusions: Nearly 2% of the patients treated with long-acting bronchodilators consumed different medications of the same pharmacologic group even when adherence was satisfactory. COPD patients are at higher risk for inhaler duplication. Clinical Trial Registration Number: 0151-20-COM1.

Adequacy of Therapy for People with Both COPD and Heart Failure in the UK: Historical Cohort Study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) often occur concomitantly, presenting diagnostic and therapeutic challenges for clinicians. We examined the characteristics of patients prescribed adequate versus inadequate therapy within 3 months after newly diagnosed comorbid COPD or HF. PATIENTS AND METHODS: Eligible patients in longitudinal UK electronic medical record databases had pre-existing HF and newly diagnosed COPD (2017 GOLD groups B/C/D) or pre-existing COPD and newly diagnosed HF. Adequate COPD therapy was defined as long-acting bronchodilator(s) with/without inhaled corticosteroid; adequate HF therapy was defined as beta-blocker plus angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker. RESULTS: Of 2439 patients with HF and newly diagnosed COPD (mean 75 years, 61% men), adequate COPD therapy was prescribed for 726 (30%) and inadequate for 1031 (42%); 682 (28%) remained untreated for COPD. Adequate (vs inadequate) COPD therapy was less likely for women (35%) than men (45%), smokers (36%) than ex-/non-smokers (45%), and non-obese (41%) than obese (47%); spirometry was recorded for 57% prescribed adequate versus 35% inadequate COPD therapy. Of 12,587 patients with COPD and newly diagnosed HF (mean 75 years, 60% men), adequate HF therapy was prescribed for 2251 (18%) and inadequate for 5332 (42%); 5004 (40%) remained untreated for HF. Adequate (vs inadequate) HF therapy was less likely for smokers (27%) than ex-/non-smokers (32%) and non-obese (30%) than obese (35%); spirometry was recorded for 65% prescribed adequate versus 39% inadequate HF therapy. CONCLUSION: Many patients with comorbid COPD/HF receive inadequate therapy after new diagnosis. Improved equity of access to integrated care is needed for all patient subgroups.

New developments in optimizing bronchodilator treatment of COPD: a focus on glycopyrrolate/formoterol combination formulated by co-suspension delivery technology.

COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes.

Health resource utilization for inpatients with COPD treated with nebulized arformoterol or nebulized formoterol.

OBJECTIVE: Arformoterol is the (R,R)-enantiomer of formoterol. Preclinical studies suggest that it is a stronger bronchodilator than the racemic (R,R/S,S)-formoterol; however, its potential clinical advantages have not been demonstrated. This study compared the length of stay (LOS), 30-day readmission rates, and doses of rescue medication administered in hospitalized patients with COPD who were treated with nebulized arformoterol or nebulized formoterol. METHODS: This retrospective analysis utilized data from Premier, Inc. (Charlotte, NC, USA), the largest nationwide hospital-based administrative database. COPD patients ≥40 years of age were included if they were hospitalized between January 2011 and July 2014, had no asthma diagnoses, and were treated with nebulized arformoterol or nebulized formoterol. LOS was measured from the day the patients initiated the study medication (index day). Rescue medications were defined as short-acting bronchodilators used from the index day onward. Multivariate statistical models included a random effect for hospital and controlled for patient demographics, hospital characteristics, admission characteristics, prior hospitalizations, comorbidities, pre-index service use, and pre-index medication use. RESULTS: A total of 7,876 patients received arformoterol, and 3,612 patients received nebulized formoterol. There was no significant difference in 30-day all-cause (arformoterol =11.9%, formoterol =12.1%, odds ratio [OR] =0.981, P=0.82) or COPD-related hospital readmission rates (arformoterol =8.0%, formoterol =8.0%, OR =1.002, P=0.98) after adjusting for covariates. The adjusted mean LOS was significantly shorter for arformoterol-treated vs formoterol-treated patients (4.6 vs 4.9 days, P=0.039), and arformoterol-treated patients used significantly fewer doses of rescue medications vs formoterol-treated patients (5.9 vs 6.6 doses, P=0.006). CONCLUSION: During inpatient stays, treating with arformoterol instead of nebulized formoterol may lead to shorter LOS and lower rescue medication use.

A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 µg on health-related quality of life in patients with COPD.

BACKGROUND: The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting ß2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population. METHODS: This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25 µg (via ELLIPTA(®) dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George's Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1-12 and trough forced expiratory volume in 1 second on day 84. Adverse events were also assessed. RESULTS: A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups. UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: -4.03 [95% confidence interval {CI}: -6.28, -1.79]; P<0.001). UMEC/VI 62.5/25 µg resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P<0.001). UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P<0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 µg and PBO groups, respectively). CONCLUSION: The results of this study demonstrate that treatment with UMEC/VI 62.5/25 µg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD.

Once-daily tiotropium Respimat(®) 5 µg is an efficacious 24-h bronchodilator in adults with symptomatic asthma.

INTRODUCTION: Once-daily tiotropium Respimat(®) 5 µg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting ß2-agonists in patients with symptomatic asthma. The objective of this study was to investigate whether the dosing regimen of tiotropium (once- versus twice-daily), delivered via the Respimat(®) SoftMist™ inhaler, affected 24-h bronchodilator efficacy and safety versus placebo Respimat(®) in patients with asthma who were symptomatic despite medium-dose ICS therapy. METHODS: A randomised, double-blind, placebo-controlled, crossover study with 4-week treatment periods of tiotropium 5 µg (once-daily, evening) and 2.5 µg (twice-daily, morning and evening). The primary efficacy end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC)(0-24h) at the end of each treatment period. Secondary end points included peak forced expiratory volume in 1 s measured within 24 h of the last evening inhalation (peak FEV1(0-24h)), trough FEV1 measured prior to evening dosing, morning and evening peak expiratory flow (PEFam and PEFpm) and pharmacokinetic assessments. RESULTS: 94 patients were randomised (mean age 44.3 years; mean asthma duration 21.3 years) and 89 (94.7%) completed the study. Significant and comparable bronchodilation was achieved over a 24-h period with both tiotropium dosing regimens. FEV1 AUC(0-24h) response (mean ± standard error) was significantly greater with both tiotropium dosing regimens (once-daily 5 µg: 158 ± 24 mL; twice-daily 2.5 µg; 149 ± 24 mL; both p < 0.01) when compared with placebo. Improvements in peak FEV1(0-24h), trough FEV1 and pre-dose PEFam/pm with both dosing regimens versus placebo were statistically significant (all p < 0.01), with no statistically significant differences between the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. CONCLUSIONS: Lung function improvements with tiotropium Respimat(®) add-on to medium-dose ICS were sustained and similar for once-daily 5 µg and twice-daily 2.5 µg, supporting tiotropium Respimat(®) 5 µg as a once-daily bronchodilator that provides efficacy over the whole 24-h dosing interval in patients with symptomatic asthma. ClinicalTrials.gov identifier: NCT01152450.

Tiotropium + olodaterol shows clinically meaningful improvements in quality of life.

BACKGROUND: Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD. METHODS: In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 µg, 2.5/5 µg, tiotropium 5 µg or placebo for 12 weeks, via the Respimat(®) inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response and trough FEV1 response. RESULTS: In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 µg improved SGRQ total score by 4.89 (95% confidence interval [CI] -6.90, -2.88) and 4.56 (95% CI -6.50, -2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI -4.47, -0.51; p < 0.05) and 1.72 (95% CI -3.63, 0.19) units versus tiotropium 5 µg. Tiotropium + olodaterol 2.5/5 µg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0-3 response compared to placebo and tiotropium 5 µg. Tiotropium + olodaterol 5/5 and 2.5/5 µg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 µg in OTEMTO 2. Adverse-event incidence was similar between treatment groups. CONCLUSION: Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 µg. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01964352 and NCT02006732.

A real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study.

AIM: INFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa. METHODS: Patients newly prescribed or switched to indacaterol or other long-acting ß2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study. RESULTS: Data were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81-1.26 points (all P<0.0001), 63%-84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%-80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability. CONCLUSION: In real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians.

Characteristics of patients with COPD newly prescribed a long-acting bronchodilator: a retrospective cohort study.

INTRODUCTION: This study aimed to characterize patients with chronic obstructive pulmonary disease (COPD) newly prescribed a long-acting bronchodilator (LABD), and to assess changes in medication over 24 months. METHODS: A cohort of patients with COPD aged ≥40 years newly prescribed an LABD between January 1, 2007 and December 31, 2009 were identified from the Truven Marketscan(®) Commercial Database (Truven Health Analytics, Ann Arbor, MI, USA) and followed for 24 months. Inclusion criteria included no prior prescription for an LABD or inhaled corticosteroids for 12 months prior to the LABD index date (baseline). Patient characteristics were examined. As LABDs were mainly long-acting muscarinic antagonists (LAMAs), additions, switches, discontinuation, adherence to (medication possession ratio), and persistence (proportion of days covered) with LAMA monotherapy were assessed for 24 months following the index date. Adherence and persistence with long-acting ß2-agonists (LABAs) were also assessed. RESULTS: A cohort of 3,268 patients aged 40-65 years was identified (mean age 55.8 years, 48% male). LAMA monotherapy was prescribed to 93% of patients who received an LABD. During the 24-month follow-up, 16% of these patients added COPD medication, 10% switched to an inhaled corticosteroid-containing medication, and 25% discontinued after one LAMA prescription at baseline. Over 12 and 24 months, adherence to LAMA was 40% and 33%, respectively, and adherence to LABA was 29% and 24%, respectively. Over the same time periods, persistence with LAMA monotherapy was 19% and 15%, respectively, and persistence with LABA was 9% and 7%, respectively. CONCLUSION: Adherence to newly initiated LAMA monotherapy was low, with one in four patients adding to or switching from LAMA and many patients discontinuing therapy. Adherence to LABA was also low. These results suggest that additional medication to a single LABD may be required in some patients with COPD to achieve optimal disease control.

The association between inhaled long-acting bronchodilators and less in-hospital care in newly-diagnosed COPD patients.

BACKGROUND: Although the efficacy of inhaled long-acting bronchodilators has been well documented in randomised controlled studies, whether similar effects are obtained in real-life clinical practice is not clear. In this study, we analysed the effect of inhaled long-acting bronchodilators in newly-diagnosed COPD patients. METHODS: The Korean Health Insurance Review and Assessment Service databases were used. Participants ≥40-years-old who had not been diagnosed with COPD between 2007 and 2008 but were diagnosed and prescribed COPD medication in 2009 were designated as newly-diagnosed COPD patients. Patients were divided into three groups based on the use of bronchodilators, an inhaled long-acting bronchodilator (LA-B), an inhaled short-acting bronchodilator (SA-B) and an oral medication (OM) group. RESULTS: A total of 77,480 newly-diagnosed COPD patients with a mean age of 68.5 years, among which 43,530 (56.2%) were men, were included in the study. ER visits and hospitalisation were associated with SA-B group, male gender, older age, Medicaid coverage, tertiary healthcare centre visits and higher comorbidities. Multivariate analysis showed that the SA-B group was associated with more ER visits, recurrent ER visits, hospitalisation and recurrent hospitalisation (adjusted ORs [95% confidence intervals] = 4.32 [3.93-4.75], 6.19 [5.24-7.30], 5.04 [2.95-3.39], and 8.49 [7.67-9.39], respectively) compared with the LA-B group. Medical utilisation cost was also higher in the SA-B group. CONCLUSION: Inhaled long-acting bronchodilator use was associated with lower rates of hospitalisation, fewer ER visits and lower medical costs in newly-diagnosed COPD patients in real-life clinical practice.

Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD.

STUDY OBJECTIVE: To examine the efficacy and safety of the once-daily, inhaled, long-acting muscarinic antagonist/ß2-agonist combination umeclidinium/vilanterol (UMEC/VI) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this 24-week, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov: NCT01313650) eligible patients were randomised 3:3:3:2 to treatment with UMEC/VI 62.5/25 mcg, UMEC 62.5 mcg, VI 25 mcg or placebo administered once daily via dry powder inhaler (N = 1532; intent-to-treat population). Primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic, and health-related quality-of-life endpoints were assessed, including 0-6 h weighted-mean FEV1, rescue salbutamol use, Transition Dyspnoea Index (TDI), Shortness Of Breath With Daily Activity (SOBDA) and St. George's Respiratory Questionnaire (SGRQ) scores. Safety evaluations included adverse events (AEs), vital signs, 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements. RESULTS: All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 (0.072-0.167 L, all p < 0.001); increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies (0.052-0.095 L, p ≤ 0.004). Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 (0.242 L, p < 0.001), rescue salbutamol use during Weeks 1-24 (-0.8 puffs/day, p = 0.001), TDI (1.2 units, p < 0.001), SOBDA (-0.17 units, p < 0.001) and SGRQ (-5.51 units, p < 0.001) scores. No clinically-significant changes in vital signs, electrocardiography, or laboratory parameters were observed. CONCLUSION: Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinically-significant improvements in lung function and symptoms in patients with COPD.

Optimizing management of chronic obstructive pulmonary disease in the upcoming decade.

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and mortality. Caring for patients with COPD, particularly those with advanced disease who experience frequent exacerbations, places a significant burden on health care budgets, and there is a global need to reduce the financial and personal burden of COPD. Evolving scientific evidence on the natural history and clinical course of COPD has fuelled a fundamental shift in our approach to the disease. The emergence of data highlighting the heterogeneity in rate of lung function decline has altered our perception of disease progression in COPD and our understanding of appropriate strategies for the management of stable disease. These data have demonstrated that early, effective, and prolonged bronchodilation has the potential to slow the rate of decline in lung function and to reduce the frequency of exacerbations that contribute to functional decline. The goals of therapy for COPD are no longer confined to controlling symptoms, reducing exacerbations, and maintaining quality of life, and slowing disease progression is now becoming an achievable aim. A challenge for the future will be to capitalize on these observations by improving the identification and diagnosis of patients with COPD early in the course of their disease, so that effective interventions can be introduced before the more advanced, disabling, and costly stages of the disease. Here we critically review emerging data that underpin the advances in our understanding of the clinical course and management of COPD, and evaluate both current and emerging pharmacologic options for effective maintenance treatment.

Nebulized formoterol: a review of clinical efficacy and safety in COPD.

A nebulized formulation of formoterol, Perforomist, 20 microg/2 ml, has been available since 2007 for the maintenance treatment of chronic obstructive pulmonary disease (COPD). We review the safety and efficacy data obtained during its development. In a dose-finding study, formoterol inhalation solution (FFIS) was similar to the formoterol originator, Foradil 12 microg DPI (FA) in patients with COPD. In a 12-week efficacy study, FFIS manifested a rapid onset of action and FEV(1) peak, AUC(0-12), and trough levels similar to FA. No loss of efficacy, tachyphylaxis, was observed over 12 weeks of regular administration. In placebo-controlled studies in COPD patients receiving maintenance tiotropium, the addition of FFIS significantly augmented bronchodilation over the 6-week treatment duration, signifying that nebulized formoterol can further improve lung function in patients who are receiving tiotropium without an observed increase in adverse reactions. The safety profile of FFIS during 12-week and 1-year studies revealed adverse events that were similar to those of placebo and FA. Cardiac rhythm studies, including frequent ECGs and Holter monitoring, did not indicate any increase in rate or rhythm disturbances greater than placebo or FA. We conclude that maintenance use of Perforomist is appropriate for patients with COPD who require or prefer a nebulizer for management of their disease.