Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis.

BACKGROUND: Pharmacological therapy for chronic obstructive pulmonary disease (COPD) is aimed at relieving symptoms, improving quality of life and preventing or treating exacerbations.Treatment tends to begin with one inhaler, and additional therapies are introduced as necessary. For persistent or worsening symptoms, long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers. Several Cochrane reviews have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments. However for patients and clinicians, it is important to understand the merits of these treatments relative to each other, and whether a particular class of inhaled therapies is more beneficial than the others. OBJECTIVES: To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease cannot be controlled by short-acting therapies alone. The review will not look at combination therapies usually considered later in the course of the disease.As part of this network meta-analysis, we will address the following issues.1. How does long-term efficacy compare between different pharmacological treatments for COPD?2. Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta-analysis? If so, what are the implications for future research? SEARCH METHODS: We identified randomised controlled trials (RCTs) in existing Cochrane reviews by searching the Cochrane Database of Systematic Reviews (CDSR). In addition, we ran a comprehensive citation search on the Cochrane Airways Group Register of trials (CAGR) and checked manufacturer websites and reference lists of other reviews. The most recent searches were conducted in September 2013. SELECTION CRITERIA: We included parallel-group RCTs of at least 6 months' duration recruiting people with COPD. Studies were included if they compared any of the following treatments versus any other: long-acting beta2-agonists (LABAs; formoterol, indacaterol, salmeterol); long-acting muscarinic antagonists (LAMAs; aclidinium, glycopyrronium, tiotropium); inhaled corticosteroids (ICSs; budesonide, fluticasone, mometasone); combination long-acting beta2-agonist (LABA) and inhaled corticosteroid (LABA/ICS) (formoterol/budesonide, formoterol/mometasone, salmeterol/fluticasone); and placebo. DATA COLLECTION AND ANALYSIS: We conducted a network meta-analysis using Markov chain Monte Carlo methods for two efficacy outcomes: St George's Respiratory Questionnaire (SGRQ) total score and trough forced expiratory volume in one second (FEV1). We modelled the relative effectiveness of any two treatments as a function of each treatment relative to the reference treatment (placebo). We assumed that treatment effects were similar within treatment classes (LAMA, LABA, ICS, LABA/ICS). We present estimates of class effects, variability between treatments within each class and individual treatment effects compared with every other.To justify the analyses, we assessed the trials for clinical and methodological transitivity across comparisons. We tested the robustness of our analyses by performing sensitivity analyses for lack of blinding and by considering six- and 12-month data separately. MAIN RESULTS: We identified 71 RCTs randomly assigning 73,062 people with COPD to 184 treatment arms of interest. Trials were similar with regards to methodology, inclusion and exclusion criteria and key baseline characteristics. Participants were more often male, aged in their mid sixties, with FEV1 predicted normal between 40% and 50% and with substantial smoking histories (40+ pack-years). The risk of bias was generally low, although missing information made it hard to judge risk of selection bias and selective outcome reporting. Fixed effects were used for SGRQ analyses, and random effects for Trough FEV1 analyses, based on model fit statistics and deviance information criteria (DIC). SGRQ SGRQ data were available in 42 studies (n = 54,613). At six months, 39 pairwise comparisons were made between 18 treatments in 25 studies (n = 27,024). Combination LABA/ICS was the highest ranked intervention, with a mean improvement over placebo of -3.89 units at six months (95% credible interval (CrI) -4.70 to -2.97) and -3.60 at 12 months (95% CrI -4.63 to -2.34). LAMAs and LABAs were ranked second and third at six months, with mean differences of -2.63 (95% CrI -3.53 to -1.97) and -2.29 (95% CrI -3.18 to -1.53), respectively. Inhaled corticosteroids were ranked fourth (MD -2.00, 95% CrI -3.06 to -0.87). Class differences between LABA, LAMA and ICS were less prominent at 12 months. Indacaterol and aclidinium were ranked somewhat higher than other members of their classes, and formoterol 12 mcg, budesonide 400 mcg and formoterol/mometasone combination were ranked lower within their classes. There was considerable overlap in credible intervals and rankings for both classes and individual treatments. Trough FEV1 Trough FEV1 data were available in 46 studies (n = 47,409). At six months, 41 pairwise comparisons were made between 20 treatments in 31 studies (n = 29,271). As for SGRQ, combination LABA/ICS was the highest ranked class, with a mean improvement over placebo of 133.3 mL at six months (95% CrI 100.6 to 164.0) and slightly less at 12 months (mean difference (MD) 100, 95% CrI 55.5 to 140.1). LAMAs (MD 103.5, 95% CrI 81.8 to 124.9) and LABAs (MD 99.4, 95% CrI 72.0 to 127.8) showed roughly equivalent results at six months, and ICSs were the fourth ranked class (MD 65.4, 95% CrI 33.1 to 96.9). As with SGRQ, initial differences between classes were not so prominent at 12 months. Indacaterol and salmeterol/fluticasone were ranked slightly better than others in their class, and formoterol 12, aclidinium, budesonide and formoterol/budesonide combination were ranked lower within their classes. All credible intervals for individual rankings were wide. AUTHORS' CONCLUSIONS: This network meta-analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators. Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and at 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1 that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been established by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines

Long-acting bronchodilators improve Health Related Quality of Life in patients with COPD

Summary Background Long-acting bronchodilators are first-line treatment for chronic obstructive pulmonary disease (COPD), and their efficacy on lung function and clinical parameters is recognized. Objective To explore the available evidence about the effects of long acting bronchodilators on Health Related Quality of Life (HRQoL) and Health Status (HS) in clinical research. Methods Randomized controlled trials published till December 2012 evaluating HRQoL/HS in COPD by means of validated questionnaires were analysed. Results Fifty-one trials on Long acting β 2 agonist (LABA) and Long acting Anticholinergic (LAMA) met the inclusion criteria. A total of 37,225 moderate-severe COPD patients testing 6 drugs, 12 different devices and 22 different dosages, with a study duration ranging from 4 weeks to 4 years were studied. A statistical significant HRQoL/HS improvement was reached in 93% of the studies. Nevertheless, the Minimal Important Difference (MID) was reached in 70,6% of the studies considering the difference between baseline and end of the study, and in 50% when comparing active treatment and placebo. Conclusions The data coming from the review support the efficacy of long acting bronchodilators in improving HRQoL/HS of COPD patients. Further research evaluating HRQoL/HS as primary outcome and according to guidelines on Patient Reported Outcomes is needed

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients