Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta2-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta2-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments. OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid. SEARCH METHODS: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was  24 February 2021. SELECTION CRITERIA: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect. MAIN RESULTS: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.

Inhaled steroids with and without regular formoterol for asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019. SELECTION CRITERIA: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events. MAIN RESULTS: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.

Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between use of beta2-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta2-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA).  OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018. SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration. DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations. MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.

Methods for including information from multi-arm trials in pairwise meta-analysis.

Systematic reviewers conducting pairwise meta-analyses sometimes encounter multi-arm studies. To include these studies, and to avoid a unit-of-analysis error, often two or more arms are combined or the control arm is split. In this tutorial, we present 5 different approaches that can be used. Particularly, we present a novel approach (method 4) that to the best of our knowledge has not been presented before. We demonstrate their application on 3 selected data sets, discuss their scope of application and their advantages and limitations, and give recommendations.

Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Guidelines have provided positive recommendations for pulmonary rehabilitation after exacerbations of chronic obstructive pulmonary disease (COPD), but recent studies indicate that postexacerbation rehabilitation may not always be effective in patients with unstable COPD. OBJECTIVES: To assess effects of pulmonary rehabilitation after COPD exacerbations on hospital admissions (primary outcome) and other patient-important outcomes (mortality, health-related quality of life (HRQL) and exercise capacity). SEARCH METHODS: We identified studies through searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PEDro (Physiotherapy Evidence Database) and the Cochrane Airways Review Group Register of Trials. Searches were current as of 20 October 2015, and handsearches were run up to 5 April 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing pulmonary rehabilitation of any duration after exacerbation of COPD versus conventional care. Pulmonary rehabilitation programmes had to include at least physical exercise (endurance or strength exercise, or both). We did not apply a criterion for the minimum number of exercise sessions a rehabilitation programme had to offer to be included in the review. Control groups received conventional community care without rehabilitation. DATA COLLECTION AND ANALYSIS: We expected substantial heterogeneity across trials in terms of how extensive rehabilitation programmes were (i.e. in terms of number of completed exercise sessions; type, intensity and supervision of exercise training; and patient education), duration of follow-up (< 3 months vs ≥ 3 months) and risk of bias (generation of random sequence, concealment of random allocation and blinding); therefore, we performed subgroup analyses that were defined before we carried them out. We used standard methods expected by Cochrane in preparing this update, and we used GRADE for assessing the quality of evidence. MAIN RESULTS: For this update, we added 11 studies and included a total of 20 studies (1477 participants). Rehabilitation programmes showed great diversity in terms of exercise training (number of completed exercise sessions; type, intensity and supervision), patient education (from none to extensive self-management programmes) and how they were organised (within one setting, e.g. pulmonary rehabilitation, to across several settings, e.g. hospital, outpatient centre and home). In eight studies, participants completed extensive pulmonary rehabilitation, and in 12 studies, participants completed pulmonary rehabilitation ranging from not extensive to moderately extensive.Eight studies involving 810 participants contributed data on hospital readmissions. Moderate-quality evidence indicates that pulmonary rehabilitation reduced hospital readmissions (pooled odds ratio (OR) 0.44, 95% confidence interval (CI) 0.21 to 0.91), but results were heterogenous (I2 = 77%). Extensiveness of rehabilitation programmes and risk of bias may offer an explanation for the heterogeneity, but subgroup analyses were not statistically significant (P values for subgroup effects were between 0.07 and 0.11). Six studies including 670 participants contributed data on mortality. The quality of evidence was low, and the meta-analysis did not show a statistically significant effect of rehabilitation on mortality (pooled OR 0.68, 95% CI 0.28 to 1.67). Again, results were heterogenous (I2 = 59%). Subgroup analyses showed statistically significant differences in subgroup effects between trials with more and less extensive rehabilitation programmes and between trials at low and high risk for bias, indicating possible explanations for the heterogeneity. Hospital readmissions and mortality studies newly included in this update showed, on average, significantly smaller effects of rehabilitation than were seen in earlier studies.High-quality evidence suggests that pulmonary rehabilitation after an exacerbation improves health-related quality of life. The eight studies that used St George's Respiratory Questionnaire (SGRQ) reported a statistically significant effect on SGRQ total score, which was above the minimal important difference (MID) of four points (mean difference (MD) -7.80, 95% CI -12.12 to -3.47; I2 = 64%). Investigators also noted statistically significant and important effects (greater than MID) for the impact and activities domains of the SGRQ. Effects were not statistically significant for the SGRQ symptoms domain. Again, all of these analyses showed heterogeneity, but most studies showed positive effects of pulmonary rehabilitation, some studies showed large effects and others smaller but statistically significant effects. Trials at high risk of bias because of lack of concealment of random allocation showed statistically significantly larger effects on the SGRQ than trials at low risk of bias. High-quality evidence shows that six-minute walk distance (6MWD) improved, on average, by 62 meters (95% CI 38 to 86; I2 = 87%). Heterogeneity was driven particularly by differences between studies showing very large effects and studies showing smaller but statistically significant effects. For both health-related quality of life and exercise capacity, studies newly included in this update showed, on average, smaller effects of rehabilitation than were seen in earlier studies, but the overall results of this review have not changed to an important extent compared with results reported in the earlier version of this review.Five studies involving 278 participants explicitly recorded adverse events, four studies reported no adverse events during rehabilitation programmes and one study reported one serious event. AUTHORS' CONCLUSIONS: Overall, evidence of high quality shows moderate to large effects of rehabilitation on health-related quality of life and exercise capacity in patients with COPD after an exacerbation. Some recent studies showed no benefit of rehabilitation on hospital readmissions and mortality and introduced heterogeneity as compared with the last update of this review. Such heterogeneity of effects on hospital readmissions and mortality may be explained to some extent by the extensiveness of rehabilitation programmes and by the methodological quality of the included studies. Future researchers must investigate how the extent of rehabilitation programmes in terms of exercise sessions, self-management education and other components affects the outcomes, and how the organisation of such programmes within specific healthcare systems determines their effects after COPD exacerbations on hospital readmissions and mortality.

Vitamin D for the management of asthma.

BACKGROUND: Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking. OBJECTIVES: To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016. SELECTION CRITERIA: Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). MAIN RESULTS: We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above. AUTHORS' CONCLUSIONS: Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups.

Home telemonitoring and remote feedback between clinic visits for asthma.

BACKGROUND: Asthma is a chronic disease that causes reversible narrowing of the airways due to bronchoconstriction, inflammation and mucus production. Asthma continues to be associated with significant avoidable morbidity and mortality. Self management facilitated by a healthcare professional is important to keep symptoms controlled and to prevent exacerbations.Telephone and Internet technologies can now be used by patients to measure lung function and asthma symptoms at home. Patients can then share this information electronically with their healthcare provider, who can provide feedback between clinic visits. Technology can be used in this manner to improve health outcomes and prevent the need for emergency treatment for people with asthma and other long-term health conditions. OBJECTIVES: To assess the efficacy and safety of home telemonitoring with healthcare professional feedback between clinic visits, compared with usual care. SEARCH METHODS: We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to May 2016. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal and reference lists of other reviews, and we contacted trial authors to ask for additional information. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of adults or children with asthma in which any form of technology was used to measure and share asthma monitoring data with a healthcare provider between clinic visits, compared with other monitoring or usual care. We excluded trials in which technologies were used for monitoring with no input from a doctor or nurse. We included studies reported as full-text articles, those published as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the search and independently extracted risk of bias and numerical data, resolving disagreements by consensus.We analysed dichotomous data as odds ratios (ORs) while using study participants as the unit of analysis, and continuous data as mean differences (MDs) while using random-effects models. We rated evidence for all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach. MAIN RESULTS: We found 18 studies including 2268 participants: 12 in adults, 5 in children and one in individuals from both age groups. Studies generally recruited people with mild to moderate persistent asthma and followed them for between three and 12 months. People in the intervention group were given one of a variety of technologies to record and share their symptoms (text messaging, Web systems or phone calls), compared with a group of people who received usual care or a control intervention.Evidence from these studies did not show clearly whether asthma telemonitoring with feedback from a healthcare professional increases or decreases the odds of exacerbations that require a course of oral steroids (OR 0.93, 95% confidence Interval (CI) 0.60 to 1.44; 466 participants; four studies), a visit to the emergency department (OR 0.75, 95% CI 0.36 to 1.58; 1018 participants; eight studies) or a stay in hospital (OR 0.56, 95% CI 0.21 to 1.49; 1042 participants; 10 studies) compared with usual care. Our confidence was limited by imprecision in all three primary outcomes. Evidence quality ratings ranged from moderate to very low. None of the studies recorded serious or non-serious adverse events separately from asthma exacerbations.Evidence for measures of asthma control was imprecise and inconsistent, revealing possible benefit over usual care for quality of life (MD 0.23, 95% CI 0.01 to 0.45; 796 participants; six studies; I(2) = 54%), but the effect was small and study results varied. Telemonitoring interventions may provide additional benefit for two measures of lung function. AUTHORS' CONCLUSIONS: Current evidence does not support the widespread implementation of telemonitoring with healthcare provider feedback between asthma clinic visits. Studies have not yet proven that additional telemonitoring strategies lead to better symptom control or reduced need for oral steroids over usual asthma care, nor have they ruled out unintended harms. Investigators noted small benefits for quality of life, but these are subject to risk of bias, as the studies were unblinded. Similarly, some benefits for lung function are uncertain owing to possible attrition bias.Larger pragmatic studies in children and adults could better determine the real-world benefits of these interventions for preventing exacerbations and avoiding harms; it is difficult to generalise results from this review because benefits may be explained at least in part by the increased attention participants receive by taking part in clinical trials. Qualitative studies could inform future research by focusing on patient and provider preferences, or by identifying subgroups of patients who are more likely to attain benefit from closer monitoring, such as those who have frequent asthma attacks.

Remote versus face-to-face check-ups for asthma.

BACKGROUND: Asthma remains a significant cause of avoidable morbidity and mortality. Regular check-ups with a healthcare professional are essential to monitor symptoms and adjust medication.Health services worldwide are considering telephone and internet technologies as a way to manage the rising number of people with asthma and other long-term health conditions. This may serve to improve health and reduce the burden on emergency and inpatient services. Remote check-ups may represent an unobtrusive and efficient way of maintaining contact with patients, but it is uncertain whether conducting check-ups in this way is effective or whether it may have unexpected negative consequences. OBJECTIVES: To assess the safety and efficacy of conducting asthma check-ups remotely versus usual face-to-face consultations. SEARCH METHODS: We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to 24 November 2015. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal, reference lists of other reviews and contacted trial authors for additional information. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of adults or children with asthma that compared remote check-ups conducted using any form of technology versus standard face-to-face consultations. We excluded studies that used automated telehealth interventions that did not include personalised contact with a health professional. We included studies reported as full-text articles, as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the literature search results and independently extracted risk of bias and numerical data. We resolved any disagreements by consensus, and we contacted study authors for missing information.We analysed dichotomous data as odds ratios (ORs) using study participants as the unit of analysis, and continuous data as mean differences using the random-effects models. We rated all outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Six studies including a total of 2100 participants met the inclusion criteria: we pooled four studies including 792 people in the main efficacy analyses, and presented the results of a cluster implementation study (n = 1213) and an oral steroid tapering study (n = 95) separately. Baseline characteristics relating to asthma severity were variable, but studies generally recruited people with asthma taking regular medications and excluded those with COPD or severe asthma. One study compared the two types of check-up for oral steroid tapering in severe refractory asthma and we assessed it as a separate question. The studies could not be blinded and dropout was high in four of the six studies, which may have biased the results.We could not say whether more people who had a remote check-up needed oral corticosteroids for an asthma exacerbation than those who were seen face-to-face because the confidence intervals (CIs) were very wide (OR 1.74, 95% CI 0.41 to 7.44; 278 participants; one study; low quality evidence). In the face-to-face check-up groups, 21 participants out of 1000 had exacerbations that required oral steroids over three months, compared to 36 (95% CI nine to 139) out of 1000 for the remote check-up group. Exacerbations that needed treatment in the Emergency Department (ED), hospital admission or an unscheduled healthcare visit all happened too infrequently to detect whether remote check-ups are a safe alternative to face-to-face consultations. Serious adverse events were not reported separately from the exacerbation outcomes.There was no difference in asthma control measured by the Asthma Control Questionnaire (ACQ) or in quality of life measured on the Asthma Quality of Life Questionnaire (AQLQ) between remote and face-to-face check-ups. We could rule out significant harm of remote check-ups for these outcomes but we were less confident because these outcomes are more prone to bias from lack of blinding.The larger implementation study that compared two general practice populations demonstrated that offering telephone check-ups and proactively phoning participants increased the number of people with asthma who received a review. However, we do not know whether the additional participants who had a telephone check-up subsequently benefited in asthma outcomes. AUTHORS' CONCLUSIONS: Current randomised evidence does not demonstrate any important differences between face-to-face and remote asthma check-ups in terms of exacerbations, asthma control or quality of life. There is insufficient information to rule out differences in efficacy, or to say whether or not remote asthma check-ups are a safe alternative to being seen face-to-face.

Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear. OBJECTIVES: To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015. SELECTION CRITERIA: We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. MAIN RESULTS: This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies). AUTHORS' CONCLUSIONS: The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease.

BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Personal and healthcare costs associated with exacerbations indicate that any therapy that reduces the occurrence of exacerbations is useful. A marked difference among countries in terms of prescribing of mucolytics reflects variation in perceptions of their effectiveness. OBJECTIVES: Primary objective• To determine whether treatment with mucolytics reduces frequency of exacerbations and/or days of disability in patients with chronic bronchitis or chronic obstructive pulmonary disease. Secondary objectives• To assess whether mucolytics lead to improvement in lung function or quality of life.• To determine frequency of adverse effects associated with use of mucolytics. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 10 separate occasions, most recently in July 2014. SELECTION CRITERIA: We included randomised studies that compared oral mucolytic therapy versus placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. DATA COLLECTION AND ANALYSIS: This review analysed summary data only, most derived from published studies. For earlier versions, one review author extracted data, which were rechecked in subsequent updates. In later versions, review authors double-checked extracted data and then entered data into RevMan for analysis. MAIN RESULTS: We added four studies for the 2014 update. The review now includes 34 trials, recruiting a total of 9367 participants. Many studies did not clearly describe allocation concealment; hence selection bias may have inflated the results, which reduces our confidence in the findings.Results of 26 studies with 6233 participants show that the likelihood that a patient could be exacerbation-free during the study period was greater among mucolytic groups (Peto odds ratio (OR) 1.75, 95% confidence interval (CI) 1.57 to 1.94). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an additional beneficial outcome for an average of 10 months - to keep an additional participant free from exacerbations - was eight (NNTB 8, 95% CI 7 to 10). Use of mucolytics was associated with a reduction of 0.03 exacerbations per participant per month (mean difference (MD) -0.03, 95% CI -0.04 to -0.03; participants = 7164; studies = 28; I(2) = 85%) compared with placebo, that is, about 0.36 per year, or one exacerbation every three years. Very high heterogeneity was noted for this outcome, so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies.Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with placebo (95% CI -0.56 to -0.30; studies = 13; I(2) = 61%). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I(2) = 58%). Investigators reported improved quality of life with mucolytics (MD -2.64, 95% CI -5.21 to -0.08; participants = 2231; studies = 5; I(2) = 51%). Although this mean difference did not reach the minimal clinically important difference of -4 units, we cannot assess the population impact, as we do not have the data needed to carry out a responder analysis. Mucolytic treatment was not associated with any significant increase in the total number of adverse effects, including mortality (Peto OR 1.03, 95% CI 0.52 to 2.03; participants = 2931; studies = 8; I(2) = 0%), but the confidence interval is too wide to confirm that the treatment has no effect on mortality. AUTHORS' CONCLUSIONS: In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics may produce a small reduction in acute exacerbations and a small effect on overall quality of life. Our confidence in the results is reduced by the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies, possibly because the earlier smaller trials were at greater risk of selection or publication bias, thus benefits of treatment may not be as great as was suggested by previous evidence.

Effects of opioid, hypnotic and sedating medications on sleep-disordered breathing in adults with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is a common sleep disorder characterised by partial or complete upper airway occlusion during sleep, leading to intermittent cessation (apnoea) or reduction (hypopnoea) of airflow and dips in arterial oxygen saturation during sleep. Many patients with recognised and unrecognised OSA receive hypnotics, sedatives and opiates/opioids to treat conditions including pain, anxiety and difficulty sleeping. Concerns have been expressed that administration of these drugs to people with co-existing OSA may worsen OSA. OBJECTIVES: To investigate whether administration of sedative and hypnotic drugs exacerbates the severity of OSA (as measured by the apnoea-hypopnoea index (AHI) or the 4% oxygen desaturation index (ODI)) in people with known OSA. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR) of trials. The search was current as of March 2015. SELECTION CRITERIA: Randomised, placebo-controlled trials including adult participants with confirmed OSA, where participants were randomly assigned to use opiates or opioids, sedatives, hypnotics or placebo. We included participants already using continuous positive airway pressure (CPAP) or a mandibular advancement device. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by The Cochrane Collaboration. MAIN RESULTS: Fourteen studies examining the effects of 10 drugs and including a total of 293 participants contributed to this review. Trials were small, with only two trials, which used sodium oxybate, recruiting more than 40 participants, and all but three trials were of only one to three nights in duration. Most participants had mild to moderate OSA with a mean AHI of 11 to 25 events/h, and only two trials recruited patients with severe OSA. Two trials investigating the effects of ramelteon, a treatment option for insomnia, recruited adults over 60 years of age with OSA and concomitant insomnia.The drugs studied in this review included remifentanil (infusion) 0.75 mcg/kg/h, eszopiclone 3 mg, zolpidem 10 and 20 mg, brotizolam 0.25 mg, flurazepam 30 mg, nitrazepam 10 mg to 15 mg, temazepam 10 mg, triazolam 0.25 mg, ramelteon 8 mg and 16 mg and sodium oxybate 4.5 g and 9 g. We were unable to pool most of the data, with the exception of data for eszopiclone and ramelteon.None of the drugs in this review produced a significant increase in AHI or ODI. Two trials have shown a beneficial effect on OSA. One study showed that a single administration of eszopiclone 3 mg significantly decreased AHI compared with placebo (24 ± 4 vs 31 ± 5; P value < 0.05), and a second study of sodium oxybate 4.5 g showed a significant decrease in AHI compared with placebo (mean difference (MD) -7.41, 95% confidence interval (CI) -14.17 to -0.65; N = 48).Only four trials reported outcome data on ODI. No significant increase, in comparison with placebo, was shown with eszopiclone (21 (22 to 37) vs 28.0 (15 to 36); P value = NS), zolpidem (0.81 ± 0.29 vs 1.46 ± 0.53; P value = NS), flurazepam (18.6 ± 19 vs 19.6 ± 15.9; P value = NS) and temazepam (6.53 ± 9.4 vs 6.56 ± 8.3; P value = 0.98).A significant decrease in minimum nocturnal peripheral capillary oxygen saturation (SpO2) was observed with zolpidem 20 mg (76.8 vs 85.2; P value = 0.002), flurazepam 30 mg (81.7 vs 85.2; P value = 0.002), remifentanil infusion (MD -7.00, 95% CI -11.95 to -2.05) and triazolam 0.25 mg in both rapid eye movement (REM) and non-REM (NREM) sleep (MD -14.00, 95% CI -21.84 to -6.16; MD -10.20, 95% CI -16.08 to -4.32, respectively.One study investigated the effect of an opiate (remifentanil) on patients with moderate OSA. Remifentanil infusion did not significantly change AHI (MD 10.00, 95% CI -9.83 to 29.83); however it did significantly decrease the number of obstructive apnoeas (MD -9.00, 95% CI -17.40 to -0.60) and significantly increased the number of central apnoeas (MD 16.00, 95% CI -2.21 to 34.21). Similarly, although without significant effect on obstructive apnoeas, central apnoeas were increased in the sodium oxybate 9 g treatment group (MD 7.3 (18); P value = 0.005) in a cross-over trial.Drugs studied in this review were generally well tolerated, apart from adverse events reported in 19 study participants prescribed remifentanil (n = 1), eszopiclone (n = 6), sodium oxybate (n = 9) or ramelteon (n = 3). AUTHORS' CONCLUSIONS: The findings of this review show that currently no evidence suggests that the pharmacological compounds assessed have a deleterious effect on the severity of OSA as measured by change in AHI or ODI. Significant clinical and statistical decreases in minimum overnight SpO2 were observed with remifentanil, zolpidem 20 mg and triazolam 0.25 mg. Eszopiclone 3 mg and sodium oxybate 4.5 g showed a beneficial effect on the severity of OSA with a reduction in AHI and may merit further assessment as a potential therapeutic option for a subgroup of patients with OSA. Only one trial assessed the effect of an opioid (remifentanil); some studies included CPAP treatment, whilst in a significant number of participants, previous treatment with CPAP was not stated and thus a residual treatment effect of CPAP could not be excluded. Most studies were small and of short duration, with indiscernible methodological quality.Caution is therefore required when such agents are prescribed for patients with OSA, especially outside the severity of the OSA cohorts and the corresponding dose of compounds given in the particular studies. Larger, longer trials involving patients across a broader spectrum of OSA severity are needed to clarify these results.

Indacaterol, a once-daily beta2-agonist, versus twice-daily beta2-agonists or placebo for chronic obstructive pulmonary disease.

BACKGROUND: Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain. OBJECTIVES: To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014. SELECTION CRITERIA: We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD. DATA COLLECTION AND ANALYSIS: Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC). MAIN RESULTS: A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted.The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.63, 95% CI 1.46 to 1.84). Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. Data were insufficient for analysis of differences in exacerbation rates for both placebo and twice-daily beta2-agonist comparisons. AUTHORS' CONCLUSIONS: For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists. The comparative effect on quality of life remains uncertain, as important differences cannot be excluded.

The Cochrane Library and safety of systemic corticosteroids for acute respiratory conditions in children: an overview of reviews.

BACKGROUND: Acute respiratory conditions are a leading cause of childhood morbidity and mortality. Corticosteroids are effective and established treatments in some acute respiratory infections (e.g. croup) and asthma exacerbations; however, their role is controversial in other conditions owing to inconsistent effectiveness or safety concerns (e.g. bronchiolitis, acute wheeze). OBJECTIVES: To examine clinically relevant short-term safety outcomes related to acute single or recurrent systemic short-term (<2 weeks) corticosteroid use based on systematic reviews of acute respiratory conditions. METHODS: We searched the Cochrane Database of Systematic Reviews in February 2013 for systematic reviews comparing systemic corticosteroids with placebo for children (aged 0-18 years) with acute asthma, preschool wheezing, bronchiolitis, croup, pharyngitis/tonsillitis or pneumonia. We selected the following outcomes a priori: gastrointestinal (GI) bleeding and abdominal pain; behavioural effects (tremor or hyperactivity, jitteriness, irritability or emotional distress); hypertension; serious adverse events, including death, length of stay in hospital; and relapse leading to hospitalization. One reviewer extracted data and another reviewer independently verified data. Results were combined using Peto odds ratios and risk differences (RD) for dichotomous outcomes and mean differences for continuous outcomes. MAIN RESULTS: Seven reviews containing 44 relevant randomized controlled trials were included. Three reviews were on asthma and one each on bronchiolitis, croup, wheeze and pharyngitis/tonsillitis. Six trials (2114 patients) assessed GI bleeding and/or abdominal pain and showed no significant differences between corticosteroids and placebo (1.5% vs. 1.8%, respectively). Various behavioural effects and hypertension/blood pressure were measured in four trials each (838 and 1617 patients, respectively), with no significant differences reported. None of the trials reported deaths in any of the treatment groups. Based on 17 trials (2056 patients), there were significantly fewer admissions at day 1 with corticosteroids (risk differences = -0.11, 95% confidence interval -0.18 to -0.05; Peto odds ratios = 0.63, 95% confidence interval 0.52 to 0.78). Based on 16 trials (1502 patients) corticosteroids resulted in over 8 fewer hours in hospital compared with placebo (mean differences = -8.49 hours, 95% confidence interval -1.76 to -3.23). There were significantly fewer relapses leading to hospitalization (13 trials, 1099 patients) with corticosteroids (Peto odds ratios 0.42, 95% confidence interval 0.23 to 0.76). While differences favouring corticosteroids in hospital-related outcomes were restricted to asthma and/or croup, we did not find any increase in hospital admission at day 1, length of stay or re-hospitalization in the other acute respiratory conditions. AUTHORS' CONCLUSIONS: Practitioners may prescribe systemic corticosteroids in otherwise healthy children when indicated for the management of acute respiratory conditions (i.e. infections or asthma exacerbations) with minimal concern about short-term adverse effects.

Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies.

BACKGROUND: Although several systematic reviews investigated the safety of long-acting beta-agonists (LABAs) in asthma, they mainly addressed randomized clinical trials while evidence from non-randomized studies has been mostly neglected. We aim to assess the risk of serious adverse events in adults and children with asthma treated with LABAs and Inhaled Corticosteroids (ICs), compared to patients treated only with ICs, from published non-randomized studies. METHODS: The protocol registration number was CRD42012003387 (http://www.crd.york.ac.uk/Prospero). Literature search for articles published since 1990 was performed in MEDLINE and EMBASE. Two authors selected studies independently for inclusion and extracted the data. A third reviewer resolved discrepancies. To assess the risk of serious adverse events, meta-analyses were performed calculating odds ratio summary estimators using random effect models when heterogeneity was found, and fixed effect models otherwise. RESULTS: Of 4,415 candidate articles, 1,759 abstracts were reviewed and 220 articles were fully read. Finally, 19 studies met the inclusion criteria. Most of them were retrospective observational cohorts. Sample sizes varied from 50 to 514,216. The meta-analyses performed (69,939-624,303 participants according to the outcome considered) showed that odds ratio of the LABAs and ICs combined treatment when compared with ICs alone was: 0.88 (95% CI 0.69-1.12) for asthma-related hospitalization; 0.75 (95% CI 0.66-0.84) for asthma-related emergency visits; 1.02 (95% CI 0.94-1.10) for systemic corticosteroids; and 0.95 (95% CI 0.9-1.0) for the combined outcome. CONCLUSIONS: Evidence from observational studies shows that the combined treatment of LABAs and ICs is not associated with a higher risk of serious adverse events, compared to ICs alone. Major gaps identified were prospective design, paediatric population and inclusion of mortality as a primary outcome.

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.

Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews.

BACKGROUND: For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken together with ICS in a single (combination) inhaler. Improved symptom control can be assessed in the individual; however, the long-term risk of hospital admission or death requires evidence from randomised controlled trials. Clinical trials record these safety outcomes as non-fatal and fatal serious adverse events (SAEs), respectively. OBJECTIVES: To assess the risk of serious adverse events in adults with asthma treated with regular maintenance formoterol or salmeterol compared with placebo, or when randomly assigned in combination with regular ICS, compared with the same dose of ICS. METHODS: We included Cochrane reviews on the safety of regular formoterol and salmeterol from a June 2013 search of the Cochrane Database of Systematic Reviews. We carried out a search for additional trials in September 2013 and incorporated the new data. All reviews were independently assessed for inclusion and for quality (using the AMSTAR tool). We extracted from each review data from trials recruiting adults (participants older than 12 or 18 years of age).We combined the results from reviews on formoterol and salmeterol to assess the safety of twice-daily regular LABA as a class effect, both as monotherapy versus placebo and as combination therapy versus the same dose of ICS.We did not combine the results of direct and indirect comparisons of formoterol and salmeterol, or carry out a network meta-analysis, because of concerns over transitivity assumptions that posed a threat to the validity of indirect comparisons. MAIN RESULTS: We identified six high-quality, up-to-date Cochrane reviews. Of these, four reviews (89 trials with 61,366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from trials in which adults were randomly assigned to formoterol versus salmeterol. These included three trials with 1116 participants given monotherapy (all prescribed background ICS) and 10 trials with 8498 adults receiving combination therapy. An additional search for trials in September 2013 identified five new included studies contributing data from 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, as well as from 447 adults for whom formoterol monotherapy was compared with placebo.No trials reported separate results in adolescents. Overall, risks of bias for the primary outcomes were assessed as low. Death of any causeNone of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy vs placebo or as combination therapy versus ICS) in adults with asthma. Pooled mortality results from direct comparisons were as follows: formoterol monotherapy (odds ratio (OR) 4.49, 95% confidence interval (CI) 0.24 to 84.80, 13 trials, N = 4824), salmeterol monotherapy (OR 1.33, 95% CI 0.85 to 2.08, 10 trials, N = 29,128), formoterol combination (OR 3.56, 95% CI 0.79 to 16.03, 25 trials, N = 11,271) and salmeterol combination (OR 0.90, 95% CI 0.31 to 2.6, 35 trials, N = 13,447). In each case, we did not detect heterogeneity, and the quality of evidence was rated as moderate. Absolute differences in mortality were very small, translating into an increase of 7 per 10,000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10,000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more).Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore we could not use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy.Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality. Non-fatal serious adverse events of any causeDirect evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (OR 1.14, 95% 1.01 to 1.28, I(2) = 0%,13 trials, N = 30,196) but were not significantly increased in any of the other reviews: formoterol monotherapy (OR 1.26, 95% CI 0.78 to 2.04, I(2) = 15%, 17 trials, N = 5758), formoterol combination (OR 0.99, 95% CI 0.77 to 1.27, I(2) = 0%, 25 trials, N = 11,271) and salmeterol combination (OR 1.15, 95% CI 0.91 to 1.44, I(2) = 0%, 35 trials, N = 13,447). This represents an absolute increase on any monotherapy of 43 per 10,000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10,000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy.Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy). AUTHORS' CONCLUSIONS: Available evidence from the reviews of randomised trials cannot definitively rule out an increased risk of fatal serious adverse events when regular formoterol or salmeterol was added to an inhaled corticosteroid (as background or as randomly assigned treatment) in adults or adolescents with asthma.An increase in non-fatal serious adverse events of any cause was found with salmeterol monotherapy, and the same increase cannot be ruled out when formoterol or salmeterol was used in combination with an inhaled corticosteroid, although possible increases are small in absolute terms.However, if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give formoterol or salmeterol in the form of a combination inhaler (as recommended by the US Food and Drug Administration (FDA)). This prevents the substitution of LABA for an inhaled corticosteroid if symptom control is improved on LABA.The results of three large ongoing trials in adults and adolescents are awaited; these will provide more information on the safety of combination therapy under less supervised conditions and will report separate results for the adolescents included.

Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma.

BACKGROUND: In acute asthma inhaled beta(2)-agonists are often administered by nebuliser to relieve bronchospasm, but some have argued that metered-dose inhalers with a holding chamber (spacer) can be equally effective. Nebulisers require a power source and need regular maintenance, and are more expensive in the community setting. OBJECTIVES: To assess the effects of holding chambers (spacers) compared to nebulisers for the delivery of beta(2)-agonists for acute asthma. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies to identify additional trials. Date of last search: February 2013. SELECTION CRITERIA: Randomised trials in adults and children (from two years of age) with asthma, where spacer beta(2)-agonist delivery was compared with wet nebulisation. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria (one review author for the first version of the review), extracted the data and assessed risks of bias. Missing data were obtained from the authors or estimated. Results are reported with 95% confidence intervals (CIs). MAIN RESULTS: This review includes a total of 1897 children and 729 adults in 39 trials. Thirty-three trials were conducted in the emergency room and equivalent community settings, and six trials were on inpatients with acute asthma (207 children and 28 adults). The method of delivery of beta(2)-agonist did not show a significant difference in hospital admission rates. In adults, the risk ratio (RR) of admission for spacer versus nebuliser was 0.94 (95% CI 0.61 to 1.43). The risk ratio for children was 0.71 (95% CI 0.47 to 1.08, moderate quality evidence). In children, length of stay in the emergency department was significantly shorter when the spacer was used. The mean duration in the emergency department for children given nebulised treatment was 103 minutes, and for children given treatment via spacers 33 minutes less (95% CI -43 to -24 minutes, moderate quality evidence). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -5% baseline (95% CI -8% to -2%, moderate quality evidence), as was the risk of developing tremor (RR 0.64; 95% CI 0.44 to 0.95, moderate quality evidence). AUTHORS' CONCLUSIONS: Nebuliser delivery produced outcomes that were not significantly better than metered-dose inhalers delivered by spacer in adults or children, in trials where treatments were repeated and titrated to the response of the participant. Spacers may have some advantages compared to nebulisers for children with acute asthma.