Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

Objectives Increasingly, there is emphasis on identifying and initiating treatment of osteoarthritis (OA) in the early phases of the disease. This study aimed to identify the perceived barriers and facilitators to managing clients with early knee OA and the contextual factors affecting implementation of care by physical therapists (PTs). Design Qualitative study using in-depth semistructured interviews with 33 PTs. The interviews were audio-recorded, transcribed verbatim and analysed inductively using thematic analysis. Setting Canada. Participants A purposive sample of PTs who managed clients with knee symptoms and/or diagnosed knee OA in community/outpatient settings in three provinces in Canada (Ontario, Alberta, British Columbia). Results Factors that affected physical therapy management of early knee OA were identified at four levels: the community, healthcare system, healthcare provider and client level. Some healthcare provider factors acted primarily as enablers of management, such as PTs’ confidence in their ability to manage perceived early knee OA, PTs’ beliefs about consequences of OA and the PT scope of practice. However, the study illuminated a range of modifiable factors that can act as barriers to management. These factors included access to services in the community and healthcare system; healthcare provider factors such as time, access to evidence and physician’s role in referrals and messaging; and client factors related to client characteristics (eg, general health, socioeconomic status), engagement in management and beliefs about OA. Conclusion These findings provide us with a basis to begin to address specific barriers and to optimise care for early knee OA.

https://pharmrev.aspetjournals.org/content/pharmrev/72/1/218.full.pdf

Pharmacology and Therapeutics of Bronchodilators Revisited.

Background: Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class. Objectives: To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA). Search methods: We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers' websites. The most recent searches were conducted on 6 April 2018. Selection criteria: We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups. Data collection and analysis: We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta-analyses. Main results: We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good. The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations. There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively). There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies. The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events. None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population. Authors' conclusions: The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia. Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines.

/pdf/dual-combination-therapy-versus-long-acting-bronchodilators-3keluntvvd.pdf

Dual combination therapy versus long‐acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta‐analysis

Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

https://www.dovepress.com/getfile.php?fileID=46912

Triple therapy (ICS/LABA/LAMA) in COPD: time for a reappraisal

In this guideline update, we highlight important and new findings related to pharmacological therapy of chronic obstructive pulmonary disease (COPD) that should change clinical practice and improve...

Canadian Thoracic Society Clinical Practice Guideline on pharmacotherapy in patients with COPD – 2019 update of evidence

Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study.

Background The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old. Objective To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma. Methods This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β 2 -agonist. Children symptomatic during a 7–28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks. Results Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide ( P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments. Conclusion Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone. Trial Registration ClinicalTrials.gov Identifier: NCT02091986.

Kristina Sandin

Papers

Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study.

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6–<12 years)