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Background: Positive bronchodilator responsiveness (BDR) (change in forced expiratory volume in 1 second [ΔFEV 1 ] ≥ +200 mL and ≥ +12%) after inhalation of a short-acting beta-2 agonist has been an inclusion criterion in licensing trials of anti-interleukin 5/anti-interleukin 5 receptor alpha (anti-IL-5/anti-IL-5Rα) biologics in severe asthma. However, in clinical practice, patients with severe uncontrolled asthma frequently show a negative BDR., Objective: To investigate whether the response to anti-IL5/anti-IL5Rα therapies differs between patients with positive and negative BDR at baseline., Methods: Retrospective multicenter analysis of treatment outcomes in patients with severe asthma receiving anti-IL-5/anti-IL-5Rα stratified for baseline BDR., Results: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL-5/anti-IL-5Rα treatment, FEV 1 improved significantly in both groups compared with baseline (P < .0001), with no significant difference between patients with positive and negative BDR (ΔFEV 1  +493 mL vs +306 mL; P = .06). Forced vital capacity (FVC) increased (ΔFVC: +85 mL vs +650 mL; P < .01) and residual volume (RV) decreased (ΔRV +113 mL vs -307 mL; P < .01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; P = .7), reduction of exacerbation rate (Δexacerbations 0 vs -2; P = .07), continuous oral corticosteroids (OCS) use (Δpatients on OCS -35% vs -39%; P = .99) and improvement of Asthma Control Test (ACT) score (ΔACT 6 vs 5; P = .7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive versus negative BDR with response parameters., Conclusions: Both groups improved following treatment with similar responses concerning reduction of OCS therapy, exacerbations, and improvement of symptom control. Pulmonary function also improved in both groups during anti-IL-5/anti-IL-5Rα treatment, with differences in response patterns noted., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to describe the real-world treatment of German incident COPD patients, compare that treatment with clinical guidelines, and provide insight into disease development after incident diagnosis. In addition, the economic burden of the disease by assessing COPD-related healthcare costs was described., Patients and Methods: Based on a German claims dataset, continuously insured individuals (04/2014-03/2019) aged 40 years or older with at least two incident pulmonologist's diagnoses or one inpatient diagnosis of COPD (ICD-10-GM code J44.-; no respective diagnosis in a 12-month baseline period) were selected. Treatment patterns after incident diagnosis considering inhaled maintenance therapies identified by ATC codes (outpatient prescriptions) were analyzed. Prescription patterns were compared with recommendations of German COPD treatment guidelines. Severe exacerbations were assessed as hospitalizations with main diagnosis ICD-10-GM code J44.1. COPD-associated costs from the perspective of the health insurance fund AOK PLUS were calculated per patient-year (PY)., Results: The sample comprised 17,464 incident COPD patients with a mean age of 71.5 years. 58.9% were male and the mean Charlson-Comorbidity-Index was 5.3. During follow-up (median: 2.0 years), 57.1% of the patients received at least one prescription of an inhaled maintenance therapy, whereas 42.9% did not. Among treated patients, 35.2% started their treatment with LABA/LAMA, 25.3% with LAMA monotherapy, 16.2% with LABA/ICS, and 7.8% with LABA/LAMA/ICS therapy. Within four weeks after initial diagnosis, ICS-containing therapies were prescribed in 14.1% of patients. Of all patients with a prescribed triple therapy, 68.9% had no corresponding exacerbation history documented. On average, 0.16 severe exacerbations and 0.19 COPD-related hospitalizations were observed per PY during available follow-up. Direct COPD-related costs were 3,693 €/PY, with COPD-related hospitalizations being responsible for about 79.2% of these costs., Conclusion: Long-acting bronchodilators are the mainstay of pharmacological treatment of incident COPD patients in Germany, in line with guideline recommendations. Yet, a considerable proportion of incident COPD patients did not receive any inhaled maintenance therapy., Competing Interests: Professor Roland Buhl reports personal fees from AstraZeneca, Berlin-Chemie, Chiesi, Cipla, Sanofi, teva, and grants from Boehringer Ingelheim, GSK, Novartis, and Roche outside the submitted work. Professor Thomas Wilke reports grants from GSK and Cytel during the conduct of the study and grants from Pfizer, Janssen, and Apontis outside the submitted work. Nils Picker and Dr Olaf Schmidt have no conflicts of interest to disclose. Dr Marlene Hechtner and Dr Anke Kondla are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. Professor Claus F Vogelmeier reports personal fees from Aerogen, Insmed, Menarini, and Nuvaira; and grants from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, and Novartis outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Buhl et al.)

Older patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of adverse events (AEs) due to decreased protective organ function and increased comorbidities. TONADO® 1 + 2 were replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials comparing the efficacy and safety of tiotropium/olodaterol (5/5 µg) versus the monocomponents via the Respimat® inhaler in patients with moderate-to-very-severe COPD. In this prespecified safety analysis, patients were grouped by age. Of 3100 patients, 1585 (51.1%) were aged <65 years, 1198 (38.7%) 65-<75 years, 309 (10.0%) 75-<85 years, and eight (0.3%) ≥85 years. At baseline, 23.4% had a pre-existing cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diagnosed diabetes. Overall, there was no increase in major adverse cardiac events, other AEs, or serious AEs with tiotropium/olodaterol versus the monocomponents in any age group, supporting the safety of tiotropium/olodaterol in older patients with COPD.

Introduction: The efficacy of tiotropium/olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β 2 -agonists (LABAs) or inhaled corticosteroids (ICS) ("maintenance naïve") at study entry., Methods: TONADO ®  1/2 (52 weeks) and OTEMTO ®  1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) < 80% predicted (lower limit FEV 1  ≥ 30% in OTEMTO 1/2 only). We examined the effect of tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg on trough FEV 1 response, St. George's Respiratory Questionnaire (SGRQ) total score and Transition Dyspnoea Index (TDI) focal score at 12 weeks in four pooled studies., Results: The pooled analysis included 1078 maintenance-naïve patients. There were significant improvements with tiotropium/olodaterol versus tiotropium in trough FEV 1 [0.056 L; 95% confidence interval (CI) 0.033, 0.079; P < 0.0001], SGRQ score (- 1.780; 95% CI - 3.126 to - 0.434; P = 0.0096) and TDI score (0.409; 95% CI 0.077, 0.741; P = 0.0158) at week 12. For patients receiving tiotropium/olodaterol, the odds of achieving a minimal clinically important difference from baseline in any of the analysed outcomes (FEV 1 ≥ 0.1 L, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) were higher versus tiotropium., Conclusions: In patients who were maintenance naïve at baseline, treatment initiation with tiotropium/olodaterol resulted in greater improvements in lung function, health status and dyspnoea severity compared with tiotropium alone, without compromising patient safety. These results support the use of dual bronchodilation with tiotropium/olodaterol as first-line maintenance treatment in patients with COPD., Trial Registration: ClinicalTrials.gov: TONADO ® 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011) and OTEMTO ® 1 and 2 (NCT01964352 and NCT02006732, registered 14 October 2013).

Introduction: Previous studies demonstrated that tiotropium/olodaterol reduced rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this should be examined in a wider population., Methods: This post hoc analysis pooled data from TONADO ® 1 + 2 and DYNAGITO ® , three 52-week, parallel-group, randomised, double-blind, phase III trials investigating patients with moderate-to-very severe COPD, with and without previous exacerbations, who received tiotropium/olodaterol 5/5 µg or tiotropium 5 µg. Subgroup analyses were conducted on patients stratified by exacerbation history, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 disease severity and baseline inhaled corticosteroid (ICS) use., Results: In 9942 patients, tiotropium/olodaterol was associated with lower rates of moderate/severe exacerbations (0.68 vs. 0.77 per patient-year; rate ratio (RR) vs. tiotropium 0.89, 95% confidence interval (CI) 0.84, 0.95; P = 0.0003) and exacerbations requiring hospitalisation (0.11 vs. 0.13 per patient-year; RR 0.86, 95% CI 0.75, 0.99; P = 0.0380) versus tiotropium. Lower rates of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium were evident in patients with 0-1 moderate exacerbation in the previous year (0.54 vs. 0.60 per patient-year; RR 0.90, 95% CI 0.82, 0.98; P = 0.0187) and at least two moderate or at least one severe exacerbation(s) in the previous year (0.97 vs. 1.09 per patient-year; RR 0.89, 95% CI 0.82, 0.97; P = 0.0096). In patients with GOLD 2 and GOLD 3 COPD, moderate/severe exacerbation rates were lower with tiotropium/olodaterol versus tiotropium; GOLD 4 patients showed negligible difference between treatments. When evaluating patients by baseline ICS use, there was a significantly lower rate of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium in patients receiving ICS., Conclusions: Tiotropium/olodaterol decreased the rate of moderate/severe exacerbations and exacerbations leading to hospitalisation versus tiotropium. Results from this large, pooled, post hoc analysis support the use of dual bronchodilation with tiotropium/olodaterol in a broad range of patients, reflective of patients with COPD in clinical practice., Trial Registration: TONADO ®  1 (ClinicalTrials.gov: NCT01431274); TONADO ®  2 (ClinicalTrials.gov: NCT01431287); DYNAGITO ® (ClinicalTrials.gov: NCT02296138). People with chronic obstructive pulmonary disease (COPD) may have times when their symptoms worsen, known as exacerbations. This may mean that they need to take additional medications, such as antibiotics or oral steroids. Studies have shown that a combination of two types of inhaled medicine-tiotropium and olodaterol-can help to reduce exacerbations in some people. To see if this is also the case across a larger and more diverse range of people, we combined the results from three studies (TONADO ®  1 + 2 and DYNAGITO ® ) that looked at people who were taking tiotropium and olodaterol together and people who were taking tiotropium alone. We showed that, across a wide range of people, treatment with tiotropium/olodaterol was generally better at reducing exacerbations than tiotropium. Tiotropium/olodaterol also decreased the number of exacerbations that led to hospitalisation compared with tiotropium. Overall, our results support the use of combined tiotropium/olodaterol in people at different stages of COPD.

Introduction: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β 2 -agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted., Methods: TONADO ® 1&2 and OTEMTO ® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV 1 ), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI)., Results: Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV 1 , - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV 1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV 1  ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046)., Conclusion: In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone., Trial Registration: TONADO ® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO ® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO ® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO ® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

Tiotropium Respimat is an efficacious add-on to maintenance treatment in patients with symptomatic asthma. Currently, the Global Initiative for Asthma (GINA) strategy recommends tiotropium for patients at Steps 4-5. To assess the clinical benefits of tiotropium Respimat across asthma severities, GINA Steps 2-5, a post hoc analysis of five double-blind trials (12-48-weeks; patients aged 18-75 years) investigated the effect of tiotropium Respimat, 5 μg or 2.5 μg, versus placebo, on peak forced expiratory volume in 1 s (FEV 1 ) within 3 h post-dose (FEV 1(0-3h) ) response, and Asthma Control Questionnaire-7 (ACQ-7) responder rate. GINA step grouping was based on patients' background treatment regimen. Baseline characteristics of patients (N = 2926) were balanced between treatments. Tiotropium Respimat showed consistent improvements in lung function across GINA steps; placebo-corrected peak FEV 1(0-3h) improvements after tiotropium Respimat 5 μg and 2.5 μg were: Step 2 (Week 8), 135 mL (95% confidence interval: 84, 187) and 155 mL (103, 206); Step 3 (Week 24), 187 mL (139, 235) and 235 mL (187, 283); Step 4 (Week 24), 111 mL (63, 159) and 181 mL (35, 326); Step 5 (Week 24; 5 μg only), 164 mL (5, 323). Asthma control improved with tiotropium Respimat versus placebo, showing statistical significance (nominal P value) with tiotropium Respimat 5 μg at Step 4 (odds ratio 1.36 [1.03, 1.78]). Safety profiles were similar between treatments. In conclusion, tiotropium Respimat add-on therapy improves lung function, and may improve asthma control, in adults across disease severities., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Severe asthma affects less than 5% of asthmatics, but is associated with high costs and increased mortality. The aim of this study was to assess age- and sex-dependent differences in this patient group., Methods: Retrospective analysis of 1317 children and adults with severe asthma who are included in the German Asthma Net registry., Results: There were more adults than children in the registry and patients' mean age was 52. Apart from children <18 years, there were more women (57%) than men. The age of first diagnosis ranged from 0 to 76 years. 38% of patients had a positive bronchial reversibility after short acting bronchodilators. Quality of life, FEV1 and MEF 25 decreased with older age whereas treatment with oral steroids and monoclonal antibodies increased. An anti-eosinophil treatment was most frequently used in patients aged around 57 years, while an anti-IgE treatment was used in all age-groups including children. There were sex-dependent differences with lower values in men for FEV1, FVC, MEF 25 and DLCO. Yet, women were more frequently unable to work than men due to the disease., Conclusion: In patients with severe asthma, clinical characteristics, but also treatments differed between age groups and between the sexes, reflecting different phenotypes of the disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Patients with chronic obstructive pulmonary disease (COPD) show signs of reduced physical activity from the early stages of the disease, impacting morbidity and mortality. Data suggest treatment with tiotropium, a long-acting muscarinic antagonist, and olodaterol, a long-acting ß 2 -agonist (LABA), as monotherapies and in combination, increases exercise capacity. This study assessed the effects of fixed-dose tiotropium/olodaterol (delivered via Respimat ® ) on physical function in Global Initiative for Chronic Obstructive Lung Disease A-D patients requiring long-acting dual bronchodilation treatment in a real-world setting., Methods: This open-label, single arm, noninterventional study measured changes in physical function in COPD patients treated with tiotropium/olodaterol 5/5 μg for approximately 6 weeks (between Visit 1 [baseline] and Visit 2). Primary end point was therapeutic success, defined as a minimum 10-point increase in Physical Functioning Questionnaire (PF-10) score. Secondary end points included change in PF-10 from Visit 1 to Visit 2, the patient's general condition (measured by Physician's Global Evaluation score) at Visit 1 and Visit 2, and patient satisfaction with treatment delivered via the Respimat ® device (assessed by Patient Satisfaction Questionnaire) at study end., Results: Therapeutic success was observed in 51.5% of 1578 patients (95% confidence interval [CI] 49.0, 54.0) after approximately 6 weeks of treatment with tiotropium/olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 11.6 points (95% CI 10.7, 12.6). Patient general condition improved as indicated by a general improvement in scores between visits. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment (82.5%), inhalation (87.5%), and handling of Respimat ® (85.2%). One percent of patients reported an investigator-defined drug-related adverse events (AE)., Conclusion: Tiotropium/olodaterol treatment improved physical functioning in COPD patients. An associated increase in patient general condition was observed. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment, inhaling, and handling of the Respimat ® device. No unexpected drug-related AE occurred., Competing Interests: RB received grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche. He also received personal fees from AstraZeneca, Chiesi, Cipla and Teva, outside the submitted work. SP was an investigator in the submitted work. AK and VB are employees of Boehringer Ingelheim. MH was an employee of Boehringer Ingelheim at the time of the submitted work and is now an employee of CSL Behring GmbH. The authors report no other conflicts of interest in this work.

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 β 2 -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., Competing Interests: Disclosure ADD has received research, consulting, and lecturing fees from Almirall, Altana, AstraZeneca, Boehringer Ingelheim (Canada), Forest Laboratories, GlaxoSmithKline, KOS Pharmaceuticals, Merck Canada, Methapharm, Novartis Canada/USA, Ono Pharmaceutical, Pfizer Canada, Schering-Plow, Sepracor, and Skyepharma. MC has participated as a speaker and/or advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Lallemand, Menarini Group, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon, and is or has been a consultant to ABC Farmaceutici, Chiesi Farmaceutici, Lallemand, Novartis, Recipharm, Teva, Verona Pharma, and Zambon. His institution has received grants on his behalf from Almirall, Boehringer Ingelheim, Novartis, Verona Pharma, and Zambon. NAH has participated in scientific advisory boards and consulted for AstraZeneca, Genentech, GlaxoSmithKline, Mylan, Novartis, Roche, Sunovion, and Sanofi. His institution has received grants on his behalf from AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Mylan, and Sunovion. RB reports personal fees from Astra-Zeneca, Chiesi, GlaxoSmithKline, and Takeda, and grants and personal fees from Boehringer Ingelheim, Novartis, and Roche. MRMY has received research funding, consulting fees, and speaker honoraria from Almirall, AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmith-Kline, Novartis, Merck, Ono Pharmaceuticals, and Pfizer. The authors report no other conflicts of interest in this work.

Background: No observational studies have evaluated the "real-world" effectiveness of dual bronchodilation comprising a long-acting β 2 -agonist plus a long-acting muscarinic antagonist vs that of triple therapy (long-acting β 2 -agonist plus long-acting muscarinic antagonist plus inhaled corticosteroid) in COPD., Materials and Methods: DACCORD is a non-interventional, observational clinical study that recruited patients following COPD maintenance therapy initiation or change in maintenance therapy between or within therapeutic class. Given the non-interventional nature of the study, the decision to initiate or change medication had to be made by the patients' physicians prior to inclusion in DACCORD. We used a matched-pairs analysis to compare disease progression in two patient groups: those receiving dual bronchodilation vs those receiving triple therapy (each group n=1,046)., Results: In two subgroups of patients matched according to a broad range of demographic and disease characteristics, over 1 year, fewer patients receiving dual bronchodilation exacerbated than those receiving triple therapy (15.5% vs 26.6%; P <0.001), with a greater improvement from baseline in COPD Assessment Test total score at 1 year (mean±SD -2.9±5.8 vs -1.4±5.5; P <0.001). When analyzed according to prior therapy, the highest rate of exacerbations was in patients on triple therapy prior to the study who remained on triple therapy. Those changing from mono-bronchodilator to dual bronchodilation had the greatest COPD Assessment Test total score improvement., Conclusion: In this "real-life" cohort of patients with COPD, most of whom had not exacerbated in the 6 months prior to entry, triple therapy did not seem to improve outcomes compared with dual bronchodilation in terms of either exacerbations or health status. Our analyses clearly demonstrate the potential impact of prior medication on study results, something that should be taken into account when interpreting the results even of controlled clinical trials., Competing Interests: Disclosure Dr Buhl reports personal fees from AstraZeneca, Chiesi, Teva, and Cipla, grants and personal fees from Boehringer Ingelheim, Novartis, and Roche, and grants from GlaxoSmithKline, all of which are outside the submitted work. Dr Criée reports personal fees from Chiesi, Boehringer Ingelheim, Novartis, Menarini, and Takeda, all of which are outside the submitted work. Dr Kardos reports personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, and Takeda, all of which are outside the submitted work. Dr Vogelmeier reports personal fees from Almirall, Cipla, Berlin Chemie/Menarini, CSL Behring, and Teva, grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma, Novartis, and Takeda, and grants from the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Bayer Schering Pharma AG, MSD, and Pfizer, all of which are outside the submitted work. Dr Kostikas is employed by, and is a stockholder in Novartis, the sponsor of the study. Outside the submitted work, he reports personal fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, ELPEN, Novartis, and Takeda. Dr Lossi is employed by Novartis, the sponsor of the study. Dr Worth reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Klosterfrau, Menarini, Novartis, and Takeda, all of which are outside the submitted work. The authors report no other conflicts of interest in this work.

Introduction: The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO ® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies., Methods: These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat ® ) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies., Results: Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment., Conclusion: Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment., Competing Interests: Disclosure RB reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Roche, and Teva, as well as grants to Mainz University from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, outside the submitted work. ED’s clinical department has received financial support from Boehringer Ingelheim and Novartis to perform clinical studies; he has participated in advisory boards for Boehringer Ingelheim, Chiesi, Cipla, Novartis, and AstraZeneca, for which a fee was given (not related to this work); he has received travel grants from Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca to attend international congresses and has received speaker’s fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Novartis. UB, IMK, and MT are employees of Boehringer Ingelheim International. CLF has received financial support from Boehringer Ingelheim to perform clinical studies. The authors report no other conflicts of interest in this work.

Background and Purpose: While the efficacy and safety of combined tiotropium and olodaterol in patients with COPD was established in a large clinical trial program, it is important to assess whether clinical data can be applied to geographic patient groups, particularly for East Asian patients who may have a different phenotypic profile to the global trial population. This study aimed to compare the lung function and safety profiles of tiotropium/olodaterol and monocomponents in East Asian and global populations from the TONADO ® trials., Materials and Methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase III TONADO studies, patients received tiotropium/olodaterol, tiotropium, or olodaterol. We assessed the forced expiratory volume in 1 second (FEV 1 ) area under the curve from 0 to 3 hours (AUC 0-3 ) response and trough FEV 1 response at 24 weeks for the approved doses, tiotropium/olodaterol 5/5 μg, tiotropium 5 μg, and olodaterol 5 μg. Treatment-emergent adverse events were recorded throughout treatment and ≤21 days after study medication., Results: In the East Asian population, 1,152 patients were randomized (5,163 overall). After 24 weeks, FEV 1 AUC 0-3 and trough FEV 1 responses were greater ( P <0.0001) with tiotropium/olodaterol 5/5 μg in both populations versus tiotropium or olodaterol. The East Asian population showed slightly greater trough FEV 1 treatment differences between tiotropium/olodaterol 5/5 μg and tiotropium compared to the overall population. Generally, no increase in adverse events was seen with tiotropium/olodaterol 5/5 μg compared to tiotropium and olodaterol in either population., Conclusion: The efficacy and safety profile of tiotropium/olodaterol 5/5 μg has been demonstrated for both East Asian and global populations., Competing Interests: Disclosure RB reports grants from Boehringer Ingelheim, Novartis, and Roche, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Roche, GlaxoSmithKline, and Takeda. MI reports personal fees from Nippon Boehringer Ingelheim, AstraZeneca, Novartis Pharma KK, and Kyorin. OJ and UB are employees of Boehringer Ingelheim Pharma GmbH & Co. YZ is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. The authors report no other conflicts of interest in this work.

Chronic obstructive pulmonary disease is associated with significant morbidity and mortality. Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status. Our aim was to investigate the effects of tiotropium + olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy. Two pairs of replicate, phase III studies of 12 (OTEMTO 1 + 2) and 52 weeks' (TONADO 1 + 2) duration were evaluated, in which patients received either tiotropium + olodaterol 2.5/5 or 5/5 μg, tiotropium 2.5 or 5 μg, olodaterol 5 μg or placebo, all delivered once daily via Respimat inhaler. Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George's Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks. Outcomes from the pooled study data are reported. Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively. Significantly larger improvements in St George's Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George's Respiratory Questionnaire and transition dyspnoea index) with tiotropium + olodaterol compared to either monotherapy or to placebo. Tiotropium + olodaterol 5/5 µg significantly reduced night-time rescue medication usage., Chronic Obstructive Pulmonary Disease: COMBINED INHALER PROVES EFFECTIVE: Results from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease. Alleviating the symptoms of chronic obstructive pulmonary disease (COPD), particularly sleep disturbance, is crucial to enhancing patients' quality of life. Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan, together with other scientists across the USA and Germany, analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat, a combination of two bronchodilators-tiotropium, and olodaterol, which tackle airway obstruction and breathlessness, improving long-term lung function. They found that the new drug combination triggered significant improvements in patients' quality of life and levels of breathlessness. Use of night-time rescue medication in patients on STIOLTO Respimat was considerably reduced. A greater number of patients responded positively to the combined inhaler than to monotherapy.

Background: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β 2 -agonists and long-acting muscarinic antagonists, given potential cardiovascular effects., Methods: Two 52-week Phase III trials (TONADO ® ) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities., Results: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups., Conclusions: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity., Trial Registry: ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Increasing age is associated with poor prognosis in patients with COPD., Objective: This analysis from the replicate Phase III OTEMTO ® and TONADO ® studies examined the efficacy and safety of tiotropium, a long-acting anticholinergic, combined with olodaterol, a long-acting β 2 -agonist, compared to monotherapies and placebo in patients with COPD aged 40 years to <65 years, 65 years to <75 years, 75 years to <85 years, and ≥85 years., Methods: In these double-blind, parallel-group, active-controlled, multicenter, randomized studies, patients received tiotropium + olodaterol 2.5/5 μg or 5/5 μg, tiotropium 5 μg or 2.5 μg (TONADO only), olodaterol 5 μg (TONADO only), or placebo (OTEMTO only). This analysis used the approved doses of tiotropium + olodaterol 5/5 μg, tiotropium 5 μg, and olodaterol 5 μg. Primary end points at 12 weeks (OTEMTO) or 24 weeks (TONADO) included St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 second (FEV 1 ) area under the curve from 0 hour to 3 hours (AUC 0-3 ) response, and trough FEV 1 response., Results: A total of 1,621 patients were randomized (40 years to <65 years, n=749; 65 years to <75 years, n=674; 75 years to <85 years, n=186; ≥85 years, n=12) in OTEMTO and 5,162 patients (40 years to <65 years, n=2,654; 65 years to <75 years, n=1,967; 75 to <85 years, n=528; ≥85 years, n=13) in TONADO. FEV 1 AUC 0-3 and trough FEV 1 responses improved with tiotropium + olodaterol 5/5 μg at 12 weeks and 24 weeks compared to monotherapies or placebo for all age groups. SGRQ scores generally improved with tiotropium + olodaterol 5/5 μg after 12 weeks in OTEMTO and improved after 24 weeks in all age groups in TONADO. In all age groups receiving tiotropium + olodaterol 5/5 μg compared to monotherapies or placebo, transition dyspnea index scores generally improved, while rescue medication usage improved., Conclusion: No differences were noted in relative responses to treatment or safety when using tiotropium + olodaterol 5/5 μg compared to monotherapies or placebo across all age groups., Competing Interests: GTF has received consulting and advisory board fees from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Novartis, Forest, Sunovion, and Verona, consulting fees from Receptos, speaker fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Pearl Therapeutics, Forest, and Sunovion, and is in receipt of research grants from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Sunovion, Novartis, Theravance, Sanofi, Forest, and GlaxoSmithKline. JPK discloses no conflicts of interest. ECB, LG, and FV are employees of Boehringer Ingelheim. RB reports grants from Boehringer Ingelheim, GlaxoSmithKline, Roche, and the German Research Foundation. RB also reports consulting, Speaker Bureau, and advisory committee fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, Roche, and Takeda. The authors report no other conflicts of interest in this work.

Introduction: Randomized interventional trials generally recruit highly selected patients. In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations. DACCORD (Die ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland [Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany]) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD)., Methods: Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years, and were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and participation in a randomized clinical trial. Exacerbation data were collected every 3 months. COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period., Results: In the 6 months prior to baseline, 26.5% of the 3,974 patients experienced ≥1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384). Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk. There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations. COPD Assessment Test mean change from baseline was -1.9, with 48.9% of patients reporting a clinically relevant improvement. Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year., Conclusion: DACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully.

Background: Maintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD). We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting β2-agonist olodaterol on physical functioning in a real-world clinical setting., Methods: In this open-label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B-D patients with COPD aged ≥40 years were treated for 4-6 weeks with either tiotropium 5 μg + olodaterol 5 μg (both via Respimat(®) inhaler) or tiotropium 18 μg (HandiHaler(®)) + olodaterol 5 μg (Respimat(®)) once daily. Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10). The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF-10 between baseline (visit 1) and weeks 4-6 (visit 2). Secondary end points included absolute PF-10 scores, Physicians' Global Evaluation, satisfaction with Respimat(®) and adverse events., Results: A total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 μg + olodaterol 5 μg and 560 (30.1%) with tiotropium 18 μg + olodaterol 5 μg. At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point. Therapeutic success rates were significantly higher for maintenance-naïve patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naïve GOLD B (59.8%) and C (63.0%) patients. Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2. Patients' general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat(®) inhaler. Adverse events were reported by 7.5% of patients; the most common were respiratory in nature., Conclusion: Tiotropium + olodaterol improved physical functioning within 4-6 weeks in patients with moderate-to-very severe COPD. GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit.

Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids (ICS)., Objective: The objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat (5 μg or 2.5 μg), compared with placebo Respimat, as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma., Methods: A phase III, double-blind, placebo-controlled trial was conducted (NCT01316380). Adults with symptomatic asthma receiving low- to medium-dose ICS (200-400 μg budesonide or equivalent dose) and a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% and ≤90% of predicted normal were randomized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg, or placebo Respimat, as add-on therapy to ICS. The primary endpoint was peak FEV1(0-3h) response., Results: In total, 464 patients were randomized (61% female; mean age 43 years; mean baseline FEV1 78% of predicted normal). After 12 weeks, both tiotropium Respimat doses were superior to placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both P < .001). Both doses of tiotropium Respimat were also superior to placebo with regard to the secondary endpoints of adjusted mean trough FEV1 and FEV1 area under the curve(0-3h) responses, and the other endpoints of morning and evening peak expiratory flow. Adverse events were comparable across the treatment groups., Conclusions: Once-daily tiotropium Respimat add-on therapy to low- to medium-dose ICS in adults with symptomatic asthma is an efficacious bronchodilator, and its safety and tolerability are comparable with those of placebo Respimat., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate-very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity., Methods: 5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat(®) inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids., Results: Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3-4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0-3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline., Conclusions: Tiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0-3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease., Funding: Boehringer Ingelheim., Trial Registration: ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.

Background: QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD., Methods: This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety., Results: Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%)., Conclusions: QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD., Trial Registration Number: NCT01120717., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD., (Copyright ©ERS 2015.)

Introduction: Once-daily tiotropium Respimat(®) 5 μg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting β2-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., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A variety of large randomized controlled trials (RCT's) evaluating pharmacotherapy in chronic obstructive pulmonary disease (COPD) patients does exist. One of the drugs that has been tested is the new long-acting anticholinergic glycopyrronium bromide., Methods: As the generalizability of results from RCT's is questionable we designed a longitudinal, prospective non-interventional study (DACCORD) of two years duration plus two years extension with at least 6000 participants in approximately 500 primary and secondary care practices in Germany (within the new established COPD National Prospective Registry), to assess patient reported outcomes (PRO's), lung function, adherence and drug safety. To circumvent the hurdle of inappropriate COPD diagnosis in a non-interventional trial, patients have to fulfill the inclusion criteria of the COPD disease management program (DMP) of the German statutory health insurances. Patient management should follow the German national COPD guidelines, which are based on Global Initiative for Chronic Obstructive Lung Disease 2007 (GOLD) report. Labels of prescribed drugs should also be taken into account. Patients received treatment as part of their standard care: at the discretion of the investigator patients were included in one of two arms. A: standard care with glycopyrronium containing regimen, and arm B: standard care without glycopyrronium., Discussion: For 2016 we expect important results regarding longitudinal development of PRO's including exacerbations, lung function, adherence and side effects. We also investigate applicability of the new GOLD staging system in usual care. Data on diagnostic and treatment modalities in current German primary and secondary care, as well as pharmaco-economic data will be generated., Trial Registration: 1. German Register for non-interventional studies: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb . 2. EMA EnCePP http://www.encepp.eu/ .

Background: In patients with COPD, exacerbations are associated with poor quality of life and may shorten survival. Prevention of exacerbations is, therefore, a key objective in COPD management. Indacaterol, a once-daily ultra-long-acting β2-agonist, has been shown to reduce exacerbations in various studies. This pooled analysis evaluated the effect of indacaterol on exacerbations versus placebo., Methods: Six-month data were pooled from three randomized, double-blind, and placebo-controlled studies: indacaterol 300 μg versus placebo (1 year); indacaterol 150 μg and 300 μg versus placebo (6 months); and indacaterol 150 μg versus placebo (6 months). All treatments were administered once daily. Data from other treatment groups were excluded. All three studies enrolled patients aged ≥40 years with moderate-to-severe COPD and smoking history ≥20 pack-years. Time to exacerbation and exacerbation rate were analyzed., Results: Overall, the pooled data set included 2716 patients (indacaterol 150 μg [n = 746], indacaterol 300 μg [n = 819], placebo [n = 1151]). Both indacaterol doses 150 and 300 μg significantly reduced the COPD exacerbation rates compared with placebo (Rate ratios, RR [95% Confidence Interval, CI]: 0.69 [0.55-0.87], 0.71 [95% CI: 0.57-0.88] respectively; both p = 0.002). Over 6 months, indacaterol 150 and 300 μg also significantly prolonged the time to first moderate-to-severe exacerbation versus placebo (Hazard ratios, HR [95% CI]: 0.74: [0.59-0.93], p = 0.009; 0.73 [0.59-0.90], p = 0.004, respectively). At months 3 and 6, clinically relevant improvements in lung function versus placebo were observed with indacaterol 150 μg (Least squares mean treatment differences: Month 3 = 170 mL; Month 6 = 160 mL) and 300 μg (170 mL at both time-points; all p < 0.001)., Conclusions: In this pooled analysis, both indacaterol doses, 150 and 300 μg, were associated with significant reductions in exacerbations and significant improvements in bronchodilation versus placebo. The results suggest once-daily indacaterol is an effective treatment option for providing sustained bronchodilation and preventing exacerbations in patients with COPD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: To further assess the safety profile of the fixed-dose combination of indacaterol and glycopyrronium (QVA149) and its monocomponents; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and glycopyrronium safety databases., Methods: Data from 11,404 patients with chronic obstructive pulmonary disease (COPD) were pooled from 14 clinical studies of QVA149, indacaterol and glycopyrronium of ≥3 month's duration with at least two of the treatment groups: QVA149 110/50 μg, glycopyrronium 50 μg, indacaterol 150 μg, placebo or tiotropium 18 μg. Overall hazard ratio (HR) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction, inhaled corticosteroid use, cardiovascular risk factors, sex, age and body mass index for death, serious cases of cardio- and cerebrovascular (CCV) events, major adverse cardiovascular events (MACEs), pneumonia, COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation (AF/F)., Results: The HR for QVA149 versus placebo showed no significant increase in the overall risk for death (HR [95% confidence interval]: 0.93 [0.34-2.54]); CCV events (0.60 [0.29-1.24]); MACE (1.04 [0.45-2.42]); pneumonia (1.10 [0.54-2.25]); COPD exacerbations (0.60 [0.40-0.91]); and AF/F (1.03 [0.49-2.18]). Similar results were observed for indacaterol, glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups., Conclusions: There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149, and it had a comparable safety profile as its monocomponents and tiotropium versus placebo., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms., Methods: A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = 'less dyspnoea'; scores ≥2 = 'more dyspnoea'). Outcomes were assessed after 26 weeks., Results: The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose ('trough') forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated., Conclusions: In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting β₂ agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform(®)). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort(®) Turbohaler(®))., Methods: A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7- (± 3) day screening, 2-4-week run-in, and 12-week treatment periods. Patients aged ≥ 12 years with moderate to severe persistent asthma for ≥ 6 months before screening and forced expiratory volume in one second (FEV₁) 50-80% predicted and ≥ 15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 μg twice daily (n = 140) or budesonide/formoterol 400/12 μg twice daily (n = 139)., Results: Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV₁ from baseline to Week 12. The LS mean treatment difference was -0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non-inferiority limit of -0.2 L (95% CI: -0.130, 0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV₁ from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol., Conclusions: This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV₁ from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints.

Background: Studies with inhaled corticosteroids (ICS) in smoking asthmatics have mostly shown poorer treatment responses than in non-smoking asthmatics., Methods: EuroSMART, an open, randomised, 6-month study, compared budesonide/formoterol (Symbicort (®) Turbuhaler(®))(h) maintenance and reliever therapy (Symbicort SMART(®)) at two maintenance doses of budesonide/formoterol (160/4.5 μg), 1 × 2 and 2 × 2, in patients with asthma who were symptomatic despite treatment with ICS ± long-acting β(2)-agonists. The 8424 randomised patients included 886 smokers (11%; aged <40 years or with a smoking history <10 pack-years if older), who were compared with a propensity-matched group of non-smokers. At baseline, smokers had lower post-bronchodilator peak expiratory flow, lower peak flow reversibility and used more reliever medication per day. Severe asthma exacerbations were counted and changes in five-item Asthma Control Questionnaire (ACQ-5) scores from baseline calculated., Results: There were 48 and 47 exacerbations in smokers and non-smokers, respectively. Mean time to first severe exacerbation was not statistically different between the two groups. The mean change in ACQ-5 score was significantly greater in non-smokers. Considering the two treatment options there was a statistically significant prolonged time to first severe exacerbation with 2 × 2 versus 1 × 2 in the smokers, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 × 2 with similar or greater changes than in smokers treated with 1 × 2., Conclusion: Asthmatic patients with a limited smoking history benefit from treatment with budesonide/formoterol maintenance and reliever therapy with dosing 2 × 2 being superior to 1 × 2., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Recommended treatment for moderate to severe asthma is the combination of an inhaled corticosteroid and a long-acting beta2-agonist. The present study was designed to evaluate the efficacy of a newly developed fixed combination of ciclesonide and formoterol in comparison to the marketed fixed combination of fluticasone and salmeterol in patients with moderate asthma. This was a phase II, multi-centre, randomized, parallel-group, double-blind, double-dummy study. After a 2-week run-in period, 160 patients with moderate asthma were randomized to a 6-week treatment with ciclesonide/formoterol 320/9 μg bid (CIC/F) or fluticasone propionate/salmeterol 250/50 μg bid (FP/S), both delivered as powder formulations. The primary outcome FEV1 increased during treatment by 0.356 L in the CIC/F group and by 0.288 L in the FP/S group (p < 0.0001). The increases were statistically significant and clinically relevant. The between-treatment analysis demonstrated non-inferiority of CIC/F to FP/S treatment (p < 0.0001). A significant improvement from baseline in lung function, symptom score and rescue medication use was observed in both groups at all time points. No differences were observed between treatments in the frequency of adverse events and overnight urinary cortisol/creatinine ratio. The studied fixed combination of ciclesonide/formoterol is not inferior to the marketed fixed combination of fluticasone/salmeterol in terms of efficacy and tolerability., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Bronchodilators are central in the symptomatic management of chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) and long-acting β(2)-agonists (LABAs) are the main classes of long-acting bronchodilators. To date, tiotropium is the only once-daily LAMA available for the treatment of COPD. Glycopyrronium is a novel LAMA, currently in development for COPD. Phase II studies have shown that glycopyrronium 50 μg once daily provides clinically significant 24-hour bronchodilation with a rapid onset of action, which is faster than that of tiotropium, and a favorable safety and tolerability profile. The Phase III GLycopyrronium bromide in COPD airWays (GLOW) program has now confirmed the long-term efficacy and tolerability of glycopyrronium 50 μg once daily. The three studies included in this program have further shown that the effect of glycopyrronium versus placebo is similar to that of tiotropium in reducing dyspnea and the risk of exacerbations, as well as improving lung function, exercise tolerance, and health status in patients with COPD. The safety profile of glycopyrronium is also similar to that of tiotropium in terms of overall incidence of adverse events and muscarinic side effects. Glycopyrronium could be an alternative choice to tiotropium, and like tiotropium, has the potential to be used as a monotherapy or combination therapy. Phase II studies have shown that a fixed-dose combination of glycopyrronium and the 24-hour LABA indacaterol, produces rapid and sustained bronchodilation compared with indacaterol monotherapy in patients with COPD. Phase III studies are currently ongoing to assess the long-term efficacy and safety of this combination.

Background: Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART® Turbuhaler®) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4., Methods: This is a post hoc analysis of the results of five large clinical trials (>12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined., Results: At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) (plus short-acting β2-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps., Conclusions: BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.

Background: This randomised, double-blind, placebo controlled, four-period crossover study assessed the efficacy and safety of once-daily QVA149, a dual bronchodilator consisting of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), in patients with moderate to severe chronic obstructive pulmonary disease (COPD)., Methods: Patients (N=154) were randomly assigned to receive QVA149 (indacaterol/NVA237) 300/50 μg, indacaterol 300 μg, indacaterol 600 μg, or placebo, once daily for 7 days with a 7-day washout period between each treatment. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) (mean of 23 h 15 min and 23 h 45 min post-dose values) on day 7. Other endpoints included trough FEV1 on day 1, individual time point FEV1 and monitoring and recording of all adverse events., Results: A total of 135 (87.7%) patients completed the study (all randomly assigned patients: mean age 61.7 years, 61.4% male, post-bronchodilator FEV1 52.2% predicted, FEV1/forced vital capacity 47.6%). The estimated treatment difference (95% CI) for trough FEV1 on day 7 between QVA149 and placebo was 226 ml (192 to 260; p<0.001). The estimated treatment difference between QVA149 and indacaterol 300 and 600 μg was 123 ml (89 to 157; p<0.001) and 117 ml (83 to 150; p<0.001), respectively. The improvements in mean trough FEV1 exceeded the predefined minimal clinically important differences of 100–140 ml for QVA149 versus placebo and indacaterol. Similar results were observed on day 1. All treatments were well tolerated., Conclusions: QVA149 demonstrated rapid and sustained bronchodilation with significant improvements compared with indacaterol monotherapy and placebo in patients with COPD., Clinical Trial Registration: NCT00570778.

Background: Indacaterol is a long-acting inhaled beta(2)-agonist (LABA) for the treatment of chronic obstructive pulmonary disease (COPD). In previous studies, indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action. This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year., Methods: Patients with moderate to severe COPD were randomised to receive once-daily indacaterol 300 microg (n=437) or 600 microg (n=428), twice-daily formoterol 12 microg (n=435) or placebo (n=432) for 52 weeks in a double-blind double-dummy parallel group study. The primary efficacy variable was forced expiratory volume in 1 s (FEV(1)) measured 24 h postdose after 12 weeks (indacaterol vs placebo). Other outcomes included dyspnoea (transition dyspnoea index, TDI), use of as-needed salbutamol, symptom-based measures recorded on diary cards, exacerbations, health status (St George's Respiratory Questionnaire), BODE index (body mass index, obstruction, dyspnoea, exercise), safety and tolerability., Results: Indacaterol increased 24 h postdose FEV(1) after 12 weeks by 170 ml (both doses) versus placebo and by 100 ml versus formoterol (all p<0.001). These significant differences were maintained at 52 weeks. Symptomatic outcomes were improved compared with placebo with all active treatments, and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol. Indacaterol was well tolerated and had a good overall safety profile, including minimal impact on QTc interval and systemic beta(2)-mediated events., Conclusions: Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD., Trial Registration Number: NCT 00393458.

Background: Inhaled corticosteroids are the mainstay of therapy in asthma, but local and systemic side effects and adherence remain a concern. Ciclesonide is an inhaled corticosteroid with on-site lung activation that provides potent anti-inflammatory activity and has been shown to have a good safety profile, even at high doses., Objective: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide versus twice-daily fluticasone propionate at comparable daily doses in patients with asthma., Methods: In this multicenter, randomized, double-blind, double-dummy, parallel group study, 529 patients were randomized to ciclesonide 160 microg once daily or fluticasone propionate 88 microg twice daily for 12 weeks. The primary endpoint was change in lung function., Results: Both ciclesonide and fluticasone propionate significantly improved forced expiratory volume in 1s, forced vital capacity, and morning peak expiratory flow compared with baseline (p<0.0001 for all variables). Both medications reduced asthma symptoms and rescue medication use within the first 24 h. At the tested dose, both medications were equally safe and well tolerated., Conclusion: Ciclesonide 160 microg once daily was as effective as fluticasone propionate 88 microg twice daily in improving lung function and asthma symptoms, and in reducing rescue medication use in patients with asthma.

Bronchodilators form the foundation of the pharmacotherapy of patients with chronic obstructive pulmonary disease (COPD). Scores of information from numerous large-scale clinical trials, mechanistic differences between classes of bronchodilators, and anti-inflammatory/bronchodilator fixed combinations make the decision what compound primarily to prefer in COPD treatment a challenge. In this review of large, double-blind, clinical trials with anticholinergic drugs, long- and short-acting beta(2)-agonists, xanthines and different application forms and combination of these compounds will be examined for clinical efficacy. The following practical objectives were accepted to define effective disease management: improvement of lung function, physical parameters such as 6-min walking distance, reduction of exacerbation rate and severity, improvement of quality of life and dyspnea score. Based on this review, inhalation therapy with a long-acting bronchodilator such as tiotropium, formoterol or salmeterol is proposed for early treatment algorithm. The combination of an anticholinergic compound and a long-acting bronchodilator may have an additive effect on bronchodilatation. The addition of inhaled corticosteroids is only recommended in stages III and IV. Besides, pharmacotherapy of COPD should always be flanked by smoking prevention programs, and supportive therapy, if indicated in severe disease stages.

Objectives: To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma., Methods: In this prospective, randomised, open-label, parallel-group, multicentre trial conducted in Germany, patients with asthma received budesonide/formoterol 160 microg/4.5 microg in a single inhaler (Symbicort Turbuhaler with two inhalations twice daily for a 4-week run-in period. Patients were then randomised to either adjustable maintenance dosing (one inhalation twice daily, stepping up to four inhalations twice daily for 1 week if asthma worsened; n=1679) or fixed dosing (two inhalations twice daily; n=1618) for 12 weeks. The primary efficacy variable was the change in health-related quality of life (HR-QOL), measured using the Asthma Quality of Life Questionnaire (standardised) during the randomised treatment period. Resource utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs (year 2001 values)., Results: Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the randomised treatment period. However, overall, patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group (mean: 2.63 vs 3.82 inhalations; p<0.001). Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing (mean: 221 euro vs 292 euro; p<0.001). This pattern was maintained when patients were stratified into those with peak expiratory flow (PEF) of 60% to <80% predicted normal and those with PEF of>/=80% predicted normal and when total costs were considered., Conclusion: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ⩾60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes. [ABSTRACT FROM AUTHOR]

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory. [ABSTRACT FROM AUTHOR]

An abstract of the article "Characteristics of Patients With and Without COPD Exacerbations During the Tiotropium + Olodaterol TONADO Studies" by Roger Abrahams and colleagues is presented.