Pressure modification or humidification for improving usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is the repetitive closure of the upper airway during sleep. This results in disturbed sleep and excessive daytime sleepiness. It is a risk factor for long-term cardiovascular morbidity. Continuous positive airway pressure (CPAP) machines can be applied during sleep. They deliver air pressure by a nasal or oronasal mask to prevent the airway from closing, reducing sleep disturbance and improving sleep quality. Some people find them difficult to tolerate because of high pressure levels and other symptoms such as a dry mouth. Switching to machines that vary the level of air pressure required to reduce sleep disturbance could increase comfort and promote more regular use. Humidification devices humidify the air that is delivered to the upper airway through the CPAP circuit. Humidification may reduce dryness of the throat and mouth and thus improve CPAP tolerability. This updated Cochrane Review looks at modifying the delivery of positive pressure and humidification on machine usage and other clinical outcomes in OSA. OBJECTIVES: To determine the effects of positive pressure modification or humidification on increasing CPAP machine usage in adults with OSA. SEARCH METHODS: We searched Cochrane Airways Specialised Register and clinical trials registries on 15 October 2018. SELECTION CRITERIA: Randomised parallel group or cross-over trials in adults with OSA. We included studies that compared automatically adjusting CPAP (auto-CPAP), bilevel positive airway pressure (bi-PAP), CPAP with expiratory pressure relief (CPAPexp), heated humidification plus fixed CPAP, automatically adjusting CPAP with expiratory pressure relief, Bi-PAP with expiratory pressure relief, auto bi-PAP and CPAPexp with wakefulness detection with fixed pressure setting. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We assessed the certainty of evidence using GRADE for the outcomes of machine usage, symptoms (measured by the Epworth Sleepiness Scale (ESS)), Apnoea Hypopnoea Index (AHI), quality of life measured by Functional Outcomes of Sleep Questionnaire (FOSQ), blood pressure, withdrawals and adverse events (e.g. nasal blockage or mask intolerance). The main comparison of interest in the review is auto-CPAP versus fixed CPAP. MAIN RESULTS: We included 64 studies (3922 participants, 75% male). The main comparison of auto-CPAP with fixed CPAP is based on 36 studies with 2135 participants from Europe, USA, Hong Kong and Australia. The majority of studies recruited participants who were recently diagnosed with OSA and had not used CPAP previously. They had excessive sleepiness (ESS: 13), severe sleep disturbance (AHI ranged from 22 to 59), and average body mass index (BMI) of 35 kg/m2. Interventions were delivered at home and the duration of most studies was 12 weeks or less. We judged that studies at high or unclear risk of bias likely influenced the effect of auto-CPAP on machine usage, symptoms, quality of life and tolerability, but not for other outcomes. Primary outcome Compared with average usage of about five hours per night with fixed CPAP, people probably use auto-CPAP for 13 minutes longer per night at about six weeks (mean difference (MD) 0.21 hours/night, 95% confidence interval (CI) 0.11 to 0.31; 31 studies, 1452 participants; moderate-certainty evidence). We do not have enough data to determine whether auto-CPAP increases the number of people who use machines for more than four hours per night compared with fixed CPAP (odds ratio (OR) 1.16, 95% CI 0.75 to 1.81; 2 studies, 346 participants; low-certainty evidence). Secondary outcomes Auto-CPAP probably reduces daytime sleepiness compared with fixed CPAP at about six weeks by a small amount (MD -0.44 ESS units, 95% CI -0.72 to -0.16; 25 studies, 1285 participants; moderate-certainty evidence). AHI is slightly higher with auto-CPAP than with fixed CPAP (MD 0.48 events per hour, 95% CI 0.16 to 0.80; 26 studies, 1256 participants; high-certainty evidence), although it fell with both machine types from baseline values in the studies. Ten per cent of people in auto-CPAP and 11% in the fixed CPAP arms withdrew from the studies (OR 0.90, 95% CI 0.64 to 1.27; moderate-certainty evidence). Auto-CPAP and fixed CPAP may have similar effects on quality of life, as measured by the FOSQ but more evidence is needed to be confident in this result (MD 0.12, 95% CI -0.21 to 0.46; 3 studies, 352 participants; low-certainty evidence). Two studies (353 participants) provided data on clinic-measured blood pressure. Auto-CPAP may be slightly less effective at reducing diastolic blood pressure compared to fixed CPAP (MD 2.92 mmHg, 95% CI 1.06 to 4.77 mmHg; low-certainty evidence). The two modalities of CPAP probably do not differ in their effects on systolic blood pressure (MD 1.87 mmHg, 95% CI -1.08 to 4.82; moderate-certainty evidence). Nine studies (574 participants) provided information on adverse events such as nasal blockage, dry mouth, tolerance of treatment pressure and mask leak. They used different scales to capture these outcomes and due to variation in the direction and size of effect between the studies, the comparative effects on tolerability outcomes are uncertain (very low-certainty evidence).  The evidence base for other interventions is smaller, and does not provide sufficient information to determine whether there are important differences between pressure modification strategies and fixed CPAP on machine usage outcomes, symptoms and quality of life. As with the evidence for the auto-CPAP, adverse events are measured disparately. AUTHORS' CONCLUSIONS: In adults with moderate to severe sleep apnoea starting positive airway pressure therapy, auto-CPAP probably increases machine usage by about 13 minutes per night. The effects on daytime sleepiness scores with auto-CPAP are not clinically meaningful. AHI values are slightly lower with fixed CPAP. Use of validated quality of life instruments in the studies to date has been limited, although where they have been used the effect sizes have not exceeded proposed clinically important differences. The adoption of a standardised approach to measuring tolerability would help decision-makers to balance benefits with harms from the different treatment options available. The evidence available for other pressure modification strategies does not provide a reliable basis on which to draw firm conclusions. Future studies should look at the effects of pressure modification devices and humidification in people who have already used CPAP but are unable to persist with treatment.

School-based self-management interventions for asthma in children and adolescents: a mixed methods systematic review.

BACKGROUND: Asthma is a common respiratory condition in children that is characterised by symptoms including wheeze, shortness of breath, chest tightness, and cough. Children with asthma may be able to manage their condition more effectively by improving inhaler technique, and by recognising and responding to symptoms. Schools offer a potentially supportive environment for delivering interventions aimed at improving self-management skills among children. The educational ethos aligns with skill and knowledge acquisition and makes it easier to reach children with asthma who do not regularly engage with primary care. Given the multi-faceted nature of self-management interventions, there is a need to understand the combination of intervention features that are associated with successful delivery of asthma self-management programmes. OBJECTIVES: This review has two primary objectives.• To identify the intervention features that are aligned with successful intervention implementation.• To assess effectiveness of school-based interventions provided to improve asthma self-management among children.We addressed the first objective by performing qualitative comparative analysis (QCA), a synthesis method described in depth later, of process evaluation studies to identify the combination of intervention components and processes that are aligned with successful intervention implementation.We pursued the second objective by undertaking meta-analyses of outcomes reported by outcome evaluation studies. We explored the link between how well an intervention is implemented and its effectiveness by using separate models, as well as by undertaking additional subgroup analyses. SEARCH METHODS: We searched the Cochrane Airways Trials Register for randomised studies. To identify eligible process evaluation studies, we searched MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the Cochrane Database of Systematic Reviews (CDSR), Web of Knowledge, the Database of Promoting Health Effectiveness Reviews (DoPHER), the Database of Abstracts of Reviews of Effects (DARE), the International Biography of Social Science (IBSS), Bibliomap, Health Technology Assessment (HTA), Applied Social Sciences Index and Abstracts (ASSIA), and Sociological Abstracts (SocAbs). We conducted the latest search on 28 August 2017. SELECTION CRITERIA: Participants were school-aged children with asthma who received the intervention in school. Interventions were eligible if their purpose was to help children improve management of their asthma by increasing knowledge, enhancing skills, or changing behaviour. Studies relevant to our first objective could be based on an experimental or quasi-experimental design and could use qualitative or quantitative methods of data collection. For the second objective we included randomised controlled trials (RCTs) where children were allocated individually or in clusters (e.g. classrooms or schools) to self-management interventions or no intervention control. DATA COLLECTION AND ANALYSIS: We used qualitative comparative analysis (QCA) to identify intervention features that lead to successful implementation of asthma self-management interventions. We measured implementation success by reviewing reports of attrition, intervention dosage, and treatment adherence, irrespective of effects of the interventions.To measure the effects of interventions, we combined data from eligible studies for our primary outcomes: admission to hospital, emergency department (ED) visits, absence from school, and days of restricted activity due to asthma symptoms. Secondary outcomes included unplanned visits to healthcare providers, daytime and night-time symptoms, use of reliever therapies, and health-related quality of life as measured by the Asthma Quality of Life Questionnaire (AQLQ). MAIN RESULTS: We included 55 studies in the review. Thirty-three studies in 14,174 children provided information for the QCA, and 33 RCTs in 12,623 children measured the effects of interventions. Eleven studies contributed to both the QCA and the analysis of effectiveness. Most studies were conducted in North America in socially disadvantaged populations. High school students were better represented among studies contributing to the QCA than in studies contributing to effectiveness evaluations, which more commonly included younger elementary and junior high school students. The interventions all attempted to improve knowledge of asthma, its triggers, and stressed the importance of regular practitioner review, although there was variation in how they were delivered.QCA results highlighted the importance of an intervention being theory driven, along with the importance of factors such as parent involvement, child satisfaction, and running the intervention outside the child's own time as drivers of successful implementation.Compared with no intervention, school-based self-management interventions probably reduce mean hospitalisations by an average of about 0.16 admissions per child over 12 months (SMD -0.19, 95% CI -0.35 to -0.04; 1873 participants; 6 studies, moderate certainty evidence). They may reduce the number of children who visit EDs from 7.5% to 5.4% over 12 months (OR 0.70, 95% CI 0.53 to 0.92; 3883 participants; 13 studies, low certainty evidence), and probably reduce unplanned visits to hospitals or primary care from 26% to 21% at 6 to 9 months (OR 0.74, 95% CI 0.60 to 0.90; 3490 participants; 5 studies, moderate certainty evidence). Self-management interventions probably reduce the number of days of restricted activity by just under half a day over a two-week period (MD 0.38 days 95% CI -0.41 to -0.18; 1852 participants; 3 studies, moderate certainty evidence). Effects of interventions on school absence are uncertain due to the variation between the results of the studies (MD 0.4 fewer school days missed per year with self-management (-1.25 to 0.45; 4609 participants; 10 studies, low certainty evidence). Evidence is insufficient to show whether the requirement for reliever medications is affected by these interventions (OR 0.52, 95% CI 0.15 to 1.81; 437 participants; 2 studies; very low-certainty evidence). Self-management interventions probably improve children's asthma-related quality of life by a small amount (MD 0.36 units higher on the Paediatric AQLQ(95% CI 0.06 to 0.64; 2587 participants; 7 studies, moderate certainty evidence). AUTHORS' CONCLUSIONS: School-based asthma self-management interventions probably reduce hospital admission and may slightly reduce ED attendance, although their impact on school attendance could not be measured reliably. They may also reduce the number of days where children experience asthma symptoms, and probably lead to small improvements in asthma-related quality of life. Many of the studies tested the intervention in younger children from socially disadvantaged populations. Interventions that had a theoretical framework, engaged parents and were run outside of children's free time were associated with successful implementation.

Influenza vaccination for healthcare workers who care for people aged 60 or older living in long-term care institutions.

BACKGROUND: A systematic review found that 3% of working adults who had received influenza vaccine and 5% of those who were unvaccinated had laboratory-proven influenza per season; in healthcare workers (HCWs) these percentages were 5% and 8% respectively. Healthcare workers may transmit influenza to patients. OBJECTIVES: To identify all randomised controlled trials (RCTs) and non-RCTs assessing the effects of vaccinating healthcare workers on the incidence of laboratory-proven influenza, pneumonia, death from pneumonia and admission to hospital for respiratory illness in those aged 60 years or older resident in long-term care institutions (LTCIs). SEARCH METHODS: We searched CENTRAL (2015, Issue 9), MEDLINE (1966 to October week 3, 2015), EMBASE (1974 to October 2015) and Web of Science (2006 to October 2015), but Biological Abstracts only from 1969 to March 2013 and Science Citation Index-Expanded from 1974 to March 2013 due to lack of institutional access in 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of healthcare workers caring for individuals aged 60 years or older in LTCIs and the incidence of laboratory-proven influenza and its complications (lower respiratory tract infection, or hospitalisation or death due to lower respiratory tract infection) in individuals aged 60 years or older in LTCIs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. Effects on dichotomous outcomes were measured as risk differences (RDs) with 95% confidence intervals (CIs). We assessed the quality of evidence with GRADE. MAIN RESULTS: We identified four cluster-RCTs and one cohort study (n = 12,742) of influenza vaccination for HCWs caring for individuals ≥ 60 years in LTCIs. Four cluster RCTs (5896 residents) provided outcome data that addressed the objectives of our review. The studies were comparable in their study populations, intervention and outcome measures. The studies did not report adverse events. The principal sources of bias in the studies related to attrition, lack of blinding, contamination in the control groups and low rates of vaccination coverage in the intervention arms, leading us to downgrade the quality of evidence for all outcomes due to serious risk of bias.Offering influenza vaccination to HCWs based in long term care homes may have little or no effect on the number of residents who develop laboratory-proven influenza compared with those living in care homes where no vaccination is offered (RD 0 (95% CI -0.03 to 0.03), two studies with samples taken from 752 participants; low quality evidence). HCW vaccination probably leads to a reduction in lower respiratory tract infection in residents from 6% to 4% (RD -0.02 (95% CI -0.04 to 0.01), one study of 3400 people; moderate quality evidence). HCW vaccination programmes may have little or no effect on the number of residents admitted to hospital for respiratory illness (RD 0 (95% CI -0.02 to 0.02, one study of 1059 people; low quality evidence). We decided not to combine data on deaths from lower respiratory tract infection (two studies of 4459 people) or all cause deaths (four studies of 8468 people). The direction and size of difference in risk varied between the studies. We are uncertain as to the effect of vaccination on these outcomes due to the very low quality of evidence. Adjusted analyses, which took into account the cluster design, did not differ substantively from the pooled analysis with unadjusted data. AUTHORS' CONCLUSIONS: Our review findings have not identified conclusive evidence of benefit of HCW vaccination programmes on specific outcomes of laboratory-proven influenza, its complications (lower respiratory tract infection, hospitalisation or death due to lower respiratory tract illness), or all cause mortality in people over the age of 60 who live in care institutions. This review did not find information on co-interventions with healthcare worker vaccination: hand-washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, antivirals and asking healthcare workers with influenza or influenza-like illness (ILI) not to work. This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in LTCIs. High quality RCTs are required to avoid the risks of bias in methodology and conduct identified by this review and to test further these interventions in combination.

Educational, supportive and behavioural interventions to improve usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea.

BACKGROUND: Although effective in the treatment of obstructive sleep apnoea (OSA), continuous positive airway pressure (CPAP) is not universally accepted by users. Educational, supportive and behavioural interventions may help people with OSA recognise the need for regular and continued use of CPAP. OBJECTIVES: To assess the effectiveness of strategies that are educational, supportive or behavioural in encouraging people who have been prescribed CPAP to use their machines. SEARCH METHODS: Searches were conducted on the Cochrane Airways Group Specialised Register of trials. Searches are current to 17 January 2013. SELECTION CRITERIA: We included randomised parallel controlled trials that assessed an intervention designed to inform participants about CPAP or OSA, to support them in using CPAP or to modify their behaviour in increasing their use of CPAP machines. Studies of any duration were considered. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies to determine their suitability for inclusion in the review. Data were extracted independently and were entered into Review Manager software for analysis. MAIN RESULTS: Thirty studies (2047 participants) were included. We categorised studies by intervention type: supportive interventions during follow-up, educational interventions and behavioural therapy. Across all three intervention classes, most studies incorporated elements of more than one intervention. For the purposes of this systematic review, we categorised them by the prevailing type of intervention, which we expected would have the greatest impact on the study outcome.Baseline Epworth Sleepiness Scale (ESS) scores indicated that most participants experienced daytime sleepiness, and CPAP was indicated on the basis of sleep disturbance indices. A vast majority of recruited participants had not used CPAP previously. Most of the studies were at an unclear risk of bias overall, although because of the nature of the intervention, blinding of both study personnel and participants was not feasible, and this affected a number of key outcomes. Adverse events were not reported in these studies.Low- to moderate-quality evidence showed that all three types of interventions led to increased machine usage in CPAP-naive participants with moderate to severe OSA syndrome. Compared with usual care, supportive ongoing interventions increased machine usage by about 50 minutes per night (0.82 hours, 95% confidence interval (CI) 0.36 to 1.27, N = 803, 13 studies; low-quality evidence), increased the number of participants who used their machines for longer than four hours per night from 59 to 75 per 100 (odds ratio (OR) 2.06, 95% CI 1.22 to 3.47, N = 268, four studies; low-quality evidence) and reduced the likelihood of study withdrawal (OR 0.65, 95% CI 0.44 to 0.97, N = 903, 12 studies; moderate-quality evidence). With the exception of study withdrawal, considerable variation was evident between the results of individual studies across these outcomes. Evidence of an effect on symptoms and quality of life was statistically imprecise (ESS score -0.60 points, 95% CI -1.81 to 0.62, N = 501, eight studies; very low-quality evidence; Functional Outcomes of Sleep Questionnaire 0.98 units, 95% CI -0.84 to 2.79, N = 70, two studies; low-quality evidence, respectively).Educational interventions increased machine usage by about 35 minutes per night (0.60 hours, 95% CI 0.27 to 0.93, N = 508, seven studies; moderate-quality evidence), increased the number of participants who used their machines for longer than four hours per night from 57 to 70 per 100 (OR 1.80, 95% CI 1.09 to 2.95, N = 285, three studies; low-quality evidence) and reduced the likelihood of withdrawal from the study (OR 0.67, 95% CI 0.45 to 0.98, N = 683, eight studies; low-quality evidence). Participants experienced a small improvement in symptoms, the size of which may not be clinically significant (ESS score -1.17 points, 95% CI -2.07 to -0.26, N = 336, five studies).Behavioural therapy led to substantial improvement in average machine usage of 1.44 hours per night (95% CI 0.43 to 2.45, N = 584, six studies; low-quality evidence) and increased the number of participants who used their machines for longer than four hours per night from 28 to 47 per 100 (OR 2.23, 95% CI 1.45 to 3.45, N = 358, three studies; low-quality evidence) but with high levels of statistical heterogeneity. The estimated lower rate of withdrawal with behavioural interventions was imprecise and did not reach statistical significance (OR 0.85, 95% CI 0.57 to 1.25, N = 609, five studies, very low-quality evidence). AUTHORS' CONCLUSIONS: In CPAP-naive people with severe sleep apnoea, low-quality evidence indicates that supportive interventions that encourage people to continue to use their CPAP machines increase usage compared with usual care. Moderate-quality evidence shows that a short-term educational intervention results in a modest increase in CPAP usage. Low-quality evidence indicates that behavioural therapy leads to a large increase in CPAP machine usage. The impact of improved CPAP usage on daytime sleepiness, quality of life and long-term cardiovascular risks remains unclear. For outcomes reflecting machine usage, we downgraded for risk of bias and inconsistency. An additional limitation for daytime sleepiness and quality of life measures was imprecision. Trials in people who have struggled to persist with treatment are needed, as currently little evidence is available for this population. Optimal timing and duration and long-term effectiveness of interventions remain uncertain. The relationship between improved machine usage and effect on symptoms and quality of life requires further assessment. Studies addressing the choice of interventions that best match individual patient needs and therefore result in the most successful and cost-effective therapy are needed.

Study found increasing use of core outcome sets in Cochrane systematic reviews and identified facilitators and barriers.

OBJECTIVES: In 2019, only 7% of Cochrane systematic reviews (SRs) cited a core outcome set (COS) in relation to choosing outcomes, even though a relevant COS existed but was not mentioned (or cited) for a further 29% of SRs. Our objectives for the current work were to (1) examine the extent to which authors are currently considering COS to inform outcome choice in Cochrane protocols and completed SRs, and (2) understand author facilitators and barriers to using COS. STUDY DESIGN AND SETTING: We examined all completed Cochrane SRs published in the last 3 months of 2022 and all Cochrane protocols published in 2022 for the extent to which they: (a) cited a COS, (b) searched for COS, (c) used outcomes from existing COS, and (d) reported outcome inconsistency among included studies and/or noted the need for COS. One investigator extracted information; a second extractor verified all information, discussing discrepancies to achieve consensus. We then conducted an online survey of authors of the included SRs to assess awareness of COS and identify facilitators and barriers to using COS to inform outcome choice. RESULTS: Objective 1: We included 294 SRs of interventions (84 completed SRs and 210 published SR protocols), of which 13% cited specific COS and 5% did not cite but mentioned searching for COS. A median of 83% of core outcomes from cited COS (interquartile range [IQR] 57%-100%) were included in the corresponding SR. We identified a relevant COS for 39% of SRs that did not cite a COS. A median of 50% of core outcomes from noncited COS (IQR 35%-72%) were included in the corresponding SR. Objective 2: Authors of 236 (80%) of the 294 eligible SRs completed our survey. Seventy-seven percent of authors noted being aware of COS before the survey. Fifty-five percent of authors who did not cite COS but were aware of them reported searching for a COS. The most reported facilitators of using COS were author awareness of the existence of COS (59%), author positive perceptions of COS (52%), and recommendation in the Cochrane Handbook regarding COS use (48%). The most reported barriers related to matching of the scope of the COS and the SR: the COS target population was too narrow/broad relative to the SR population (29%) or the COS target intervention was too narrow/broad relative to the SR intervention (21%). Most authors (87%) mentioned that they would consider incorporating missing core outcomes in the SR/update. CONCLUSION: Since 2019, there is increasing consideration and awareness of COS when choosing outcomes for Cochrane SRs of interventions, but uptake remains low and can be improved further. Use of COS in SRs is important to improve outcome standardization, reduce research waste, and improve evidence syntheses of the relevant effects of interventions across health research.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

A survey of experts to identify methods to detect problematic studies: Stage 1 of the INSPECT-SR Project.

Background: Randomised controlled trials (RCTs) inform healthcare decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INSPECT-SR project is developing a tool to identify problematic RCTs in systematic reviews of healthcare-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion. Methods: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorised these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list. Results: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool. Conclusions: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool.

PRISMA for Abstracts: reporting systematic reviews in journal and conference abstracts.

Elaine Beller and colleagues from the PRISMA for Abstracts group provide a reporting guidelines for reporting abstracts of systematic reviews in journals and at conferences.

Influenza vaccination for healthcare workers who care for people aged 60 or older living in long-term care institutions.

BACKGROUND: Healthcare workers' influenza rates are unknown but may be similar to those of the general public. Healthcare workers may transmit influenza to patients. OBJECTIVES: To identify all randomised controlled trials (RCTs) and non-RCTs assessing the effects of vaccinating healthcare workers on the incidence of laboratory-proven influenza, pneumonia, death from pneumonia and admission to hospital for respiratory illness in those aged 60 years or older resident in long-term care institutions (LTCIs). SEARCH METHODS: We searched CENTRAL 2013, Issue 2, MEDLINE (1966 to March week 3, 2013), EMBASE (1974 to March 2013), Biological Abstracts (1969 to March 2013), Science Citation Index-Expanded (1974 to March 2013) and Web of Science (2006 to March 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of healthcare workers caring for individuals aged 60 years or older in LTCIs and the incidence of laboratory-proven influenza and its complications (lower respiratory tract infection, or hospitalisation or death due to lower respiratory tract infection) in individuals aged 60 years or older in LTCIs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. MAIN RESULTS: We identified four cluster-RCTs (C-RCTs) (n = 7558) and one cohort study (n = 12,742) of influenza vaccination for HCWs caring for individuals ≥ 60 years in LTCFs. Three RCTs (5896 participants) provided outcome data that met our criteria. These three studies were comparable in study populations, intervention and outcome measures. The studies did not report adverse events. The principal sources of bias in the studies related to attrition and blinding. The pooled risk difference (RD) from the three cluster-RCTs for laboratory-proven influenza was 0 (95% confidence interval (CI) -0.03 to 0.03) and for hospitalisation was RD 0 (95% CI -0.02 to 0.02). The estimated risk of death due to lower respiratory tract infection was also imprecise (RD -0.02, 95% CI -0.06 to 0.02) in individuals aged 60 years or older in LTCIs. Adjusted analyses which took into account the cluster design did not differ substantively from the pooled analysis with unadjusted data. AUTHORS' CONCLUSIONS: The results for specific outcomes: laboratory-proven influenza or its complications (lower respiratory tract infection, or hospitalisation or death due to lower respiratory tract illness) did not identify a benefit of healthcare worker vaccination on these key outcomes. This review did not find information on co-interventions with healthcare worker vaccination: hand-washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, antivirals and asking healthcare workers with influenza or influenza-like-illness (ILI) not to work. This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in LTCIs. High-quality RCTs are required to avoid the risks of bias in methodology and conduct identified by this review and to test further these interventions in combination.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events.

BACKGROUND: An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in previous Cochrane reviews. OBJECTIVES: We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol. SEARCH METHODS: We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked manufacturers' websites of clinical trial registers for unpublished trial data and also checked Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was January 2012. SELECTION CRITERIA: We included controlled, parallel-design clinical trials on patients of any age and with any severity of asthma if they randomised patients to treatment with regular formoterol versus regular salmeterol (without randomised inhaled corticosteroids), and were of at least 12 weeks' duration. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review and extracted outcome data. We sought unpublished data on mortality and serious adverse events from the sponsors and authors. MAIN RESULTS: The review included four studies (involving 1116 adults and 156 children). All studies were open label and recruited patients who were already taking inhaled corticosteroids for their asthma, and all studies contributed data on serious adverse events. All studies compared formoterol 12 µg versus salmeterol 50 µg twice daily. The adult studies were all comparing Foradil Aerolizer with Serevent Diskus, and the children's study compared Oxis Turbohaler to Serevent Accuhaler. There was only one death in an adult (which was unrelated to asthma) and none in children, and there were no significant differences in non-fatal serious adverse events comparing formoterol to salmeterol in adults (Peto odds ratio (OR) 0.77; 95% confidence interval (CI) 0.46 to 1.28), or children (Peto OR 0.95; 95% CI 0.06 to 15.33). Over a six-month period, in studies involving adults that contributed to this analysis, the percentages with serious adverse events were 5.1% for formoterol and 6.4% for salmeterol; and over a three-month period the percentages of children with serious adverse events were 1.3% for formoterol and 1.3% for salmeterol. AUTHORS' CONCLUSIONS: We identified four studies comparing regular formoterol to regular salmeterol (without randomised inhaled corticosteroids, but all participants were on regular background inhaled corticosteroids). The events were infrequent and consequently too few patients have been studied to allow any firm conclusions to be drawn about the relative safety of formoterol and salmeterol. Asthma-related serious adverse events were rare and there were no reported asthma-related deaths.

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease.

BACKGROUND: Both inhaled steroids (ICS) and long-acting beta(2)-agonists (LABA) are used in the management of chronic obstructive pulmonary disease (COPD). This updated review compared compound LABA plus ICS therapy (LABA/ICS) with the LABA component drug given alone. OBJECTIVES: To assess the efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search was November 2011. SELECTION CRITERIA: We included randomised, double-blind controlled trials. We included trials comparing compound ICS and LABA preparations with their component LABA preparations in people with COPD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, while secondary outcomes were health-related quality of life (measured by validated scales), lung function, withdrawals due to lack of efficacy, withdrawals due to adverse events and side-effects. Dichotomous data were analysed as random-effects model odds ratios or rate ratios with 95% confidence intervals (CIs), and continuous data as mean differences and 95% CIs. We rated the quality of evidence for exacerbations, mortality and pneumonia according to recommendations made by the GRADE working group. MAIN RESULTS: Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality.Primary outcomes There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I(2) = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate.There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses or types of inhaled corticosteroid.Secondary outcomes ICS/LABA was more effective than LABA alone in improving health-related quality of life measured by the St George's Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF), rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and forced expiratory volume in one second (FEV(1)) (70 mL higher with FPS, 50 mL higher with BDF). Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as the results were very inconsistent. AUTHORS' CONCLUSIONS: Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV(1) improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations.More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.

Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children.

BACKGROUND: Long-acting beta-agonists are a common second line treatment in people with asthma inadequately controlled with inhaled corticosteroids. Single device inhalers combine a long-acting beta-agonist with an inhaled steroid delivering both drugs as a maintenance treatment regimen. This updated review compares two fixed-dose options, fluticasone/salmeterol FP/SALand budesonide/formoterol, since this comparison represents a common therapeutic choice. OBJECTIVES: To assess the relative effects of fluticasone/salmeterol and budesonide/formoterol in people with asthma. SEARCH METHODS: We searched the Cochrane Airways Group register of trials with prespecified terms. We performed additional hand searching of manufacturers' web sites and online trial registries. Search results are current to June 2011. SELECTION CRITERIA: We included randomised studies comparing fixed dose fluticasone/salmeterol and budesonide/formoterol in adults or children with a diagnosis of asthma. Treatment in the studies had to last for a minimum of 12 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion in the review. We combined continuous data outcomes with a mean difference (MD), and dichotomous data outcomes with an odds ratio (OR). We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. MAIN RESULTS: Five studies met the review entry criteria (5537 adults). Study populations entered the studies having previously been treated with inhaled steroids and had moderate or mild airway obstruction (mean FEV(1) predicted between 65% and 84% at baseline). Most of the studies assessed treatment over a period of six months. The studies were at a low risk of selection and performance/detection bias, although we could not determine whether missing data had an impact on the results. Availablility of outcome data was satisfactory.Primary outcomesThe odds ratio for exacerbations requiring oral steroids was lower with fluticasone/salmeterol but did not reach statistical significance (OR 0.89, 95% confidence interval (CI) 0.74 to 1.07, four studies, N = 4949). With an assumed risk with budesonide/formoterol of 106/1000 participants requiring oral steroids, treatment with fluticasone/salmeterol would lead to between 25 fewer and seven more people per 1000 experiencing a course of oral steroids. Although the odds of hospital admission was higher with fluticasone/salmeterol, this did not reach statistical significance (OR 1.29, 95% CI 0.68 to 2.47, four studies, 4879 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between two fewer and 10 more people per 1000 would be hospitalised on fluticasone/salmeterol. The odds of a serious adverse event related to asthma was higher with fluticasone/salmeterol but did not differ significantly between treatments (OR 1.47, 95% CI 0.75 to 2.86, three studies, 4054 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between two fewer and 13 more people per 1000 would experience a serious adverse event on fluticasone/salmeterol.Secondary outcomesLung function outcomes, symptoms, rescue medication, composite of exacerbations leading to either emergency department visit or hospital admission, withdrawals and adverse events did not differ statistically between treatments. Assessment of quality of life was limited to two studies, both of which gave results that did not reach statistical significance. One study reported one death out of 1000 participants on fluticasone/salmeterol and no deaths in a similar number of participants treated with budesonide/formoterol. No deaths were reported in the other studies. AUTHORS' CONCLUSIONS: Statistical imprecision in the effect estimates for exacerbations and serious adverse events do not enable us to conclude that either therapy is superior. The uncertainty around the effect estimates justify further trials to provide more definitive conclusions; the overall quality of evidence based on GRADE recommendations for the three primary outcomes and withdrawals due to serious adverse events was moderate. We rated the quality of evidence for mortality to be low. Results for lung function outcomes showed that the drugs were sufficiently similar that further research is unlikely to change the effects. No trials were identified in the under-12s and research in this population is a high priority. Evaluation of quality of life is a priority for future research.

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma.

BACKGROUND: Asthma patients who continue to experience symptoms despite being on regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta(2)-agonists (LABA) or anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS. OBJECTIVES: We compared the efficacy and safety profile of adding either daily LABA or LTRA in adults and children with asthma who remain symptomatic on ICS. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register (up to and including March 2010). We consulted reference lists of all included studies and contacted authors and pharmaceutical manufacturers for other published or unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS and where a fixed dose of a long-acting beta(2)-agonist or leukotriene agent was added for a minimum of 28 days. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design, where necessary. MAIN RESULTS: We included 17 RCTs (7032 participants), of which 16 recruited adults and adolescents (6850) and one recruited children aged 6 to 17 years (182). Participants demonstrated substantial reversibility to short-acting beta-agonist at baseline. The studies were at a low risk of bias. The risk of exacerbations requiring systemic corticosteroids was lower with the combination of LABA and ICS compared with LTRA and ICS, from 11% to 9% (RR 0.83, 95% CI 0.71 to 0.97; six studies, 5571 adults). The number needed to treat (NNT) with LABA compared to LTRA to prevent one exacerbation over 48 weeks was 38 (95% CI 22 to 244). The choice of LTRA did not significantly affect the results. The effect appeared stronger in the trials using a single device to administer ICS and LABA compared to those using two devices. In the absence of data from the paediatric trial and the clinical homogeneity of studies, we could not perform subgroup analyses. The addition to ICS of LABA compared to LTRA was associated with a statistically greater improvement from baseline in several of the secondary outcomes, including lung function, functional status measures and quality of life. Serious adverse events were more common with LABA than LTRA, although the estimate was imprecise (RR 1.35, 95% CI 1.00 to 1.82), and the NNT to harm for one additional patient to suffer a serious adverse event on LABA over 48 weeks was 78 (95% CI 33 to infinity). The risk of withdrawal for any reason in adults was significantly lower with LABA and ICS compared to LTRA and ICS (RR 0.84, 95% CI 0.74 to 0.96). AUTHORS' CONCLUSIONS: In adults with asthma that is inadequately controlled on low doses of inhaled steroids and showing significant reversibility with beta(2)-agonists, LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest. There is some evidence of increased risk of SAEs with LABA. The findings support the use of a single inhaler for the delivery of LABA and inhaled corticosteroids. We are unable to draw conclusions about which treatment is better as add-on therapy for children.

Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults.

BACKGROUND: Gastroesophageal reflux disease (GORD) is said to be the causative factor in up to 41% of adults with chronic cough. Treatment for GORD includes conservative measures (diet manipulation), pharmaceutical therapy (motility or prokinetic agents, H(2)-antagonist and proton pump inhibitors (PPI)) and fundoplication. OBJECTIVES: To evaluate the efficacy of GORD treatment on chronic cough in children and adults with GORD and prolonged cough that is not related to an underlying respiratory disease, i.e. non-specific chronic cough. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, review articles and reference lists of relevant articles. The date of last search was 8 April 2010. SELECTION CRITERIA: All randomised controlled trials (RCTs) on GORD treatment for cough in children and adults without primary lung disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information. MAIN RESULTS: We included 19 studies (six paediatric, 13 adults). None of the paediatric studies could be combined for meta-analysis. A single RCT in infants found that PPI (compared to placebo) was not efficacious for cough outcomes (favouring placebo OR 1.61; 95% CI 0.57 to 4.55) but those on PPI had significantly increased adverse events (OR 5.56; 95% CI 1.18 to 26.25) (number needed to treat for harm in four weeks was 11 (95% CI 3 to 232)). In adults, analysis of H(2) antagonist, motility agents and conservative treatment for GORD was not possible (lack of data) and there were no controlled studies of fundoplication. We analysed nine adult studies comparing PPI (two to three months) to placebo for various outcomes in the meta-analysis. Using intention-to-treat, pooled data from studies resulted in no significant difference between treatment and placebo in total resolution of cough (OR 0.46; 95% CI 0.19 to 1.15). Pooled data revealed no overall significant improvement in cough outcomes (end of trial or change in cough scores). We only found significant differences in sensitivity analyses. We found a significant improvement in change of cough scores at end of intervention (two to three months) in those receiving PPI (standardised mean difference -0.41; 95% CI -0.75 to -0.07) using generic inverse variance analysis on cross-over trials. Two studies reported improvement in cough after five days to two weeks of treatment. AUTHORS' CONCLUSIONS: PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux.

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

BACKGROUND: An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. OBJECTIVES: We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment. SEARCH STRATEGY: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. SELECTION CRITERIA: Controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included 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 authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. MAIN RESULTS: Eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I(2) = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I(2) = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions.No studies were found in children. AUTHORS' CONCLUSIONS: The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children.Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.