Publications by authors named "Toby J Lasserson"

33 Publications

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

Cochrane Database Syst Rev 2019 12 2;12:CD003531. Epub 2019 Dec 2.

Royal Papworth Hospital, Respiratory Support and Sleep Centre, Papworth Everard, Cambridge, UK, CB23 3RE.

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/m. 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.
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http://dx.doi.org/10.1002/14651858.CD003531.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888022PMC
December 2019

A cross-sectional audit showed that most Cochrane intervention reviews searched trial registers.

J Clin Epidemiol 2019 09 28;113:86-91. Epub 2019 May 28.

Cochrane Breast Cancer Group, Systematic Reviews and Health Technology Assessments, NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia. Electronic address:

Objective: The objective of this study was to assess current Cochrane Review practice in identifying and incorporating information from clinical trial registers.

Study Design And Setting: A cross-sectional study was conducted to assess a sample of new or updated intervention reviews from all Cochrane Review Groups up to February 1, 2017. Two assessors independently extracted data from each review using a pretested audit questionnaire. Data were analyzed relating to the frequency of reporting (1) the register source and search strategy; (2) the results of trial register searches; and (3) the use of trial register information in the review.

Results: Over 90% (236/260) of Cochrane Reviews reported searching a trial register (e.g., ClinicalTrials.gov or the WHO International Clinical Trials Registry Platform). In reviews that reported trial register searches, 39% (92/236) indicated the number of trial records retrieved and 56.8% (134/236) used information from the trial register records in the review. Trial record information was incorporated into the results (39.6%; 53/134), risk of bias assessments (53.7%; 72/134), and discussion (24.6%, 33/134) and conclusion sections (25.4%, 34/134).

Conclusion: Most audited reviews used trial register information. Guidance may be needed to better incorporate information from these valuable resources in Cochrane Reviews to assist future research decisions made by funders and prospective study investigators.
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http://dx.doi.org/10.1016/j.jclinepi.2019.05.020DOI Listing
September 2019

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

Cochrane Database Syst Rev 2019 01 28;1:CD011651. Epub 2019 Jan 28.

Centre for Child Health, Blizard Institute, Queen Mary University of London, London, UK, E1 2AT.

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.
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http://dx.doi.org/10.1002/14651858.CD011651.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353176PMC
January 2019

Enhancing the usability of systematic reviews by improving the consideration and description of interventions.

BMJ 2017 07 20;358:j2998. Epub 2017 Jul 20.

Centre for Research in Evidence-Based Practice, Faculty of Health Sciences and Medicine, Bond University, Queensland, Australia.

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http://dx.doi.org/10.1136/bmj.j2998DOI Listing
July 2017

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

Cochrane Database Syst Rev 2016 Jun 2(6):CD005187. Epub 2016 Jun 2.

Department of Family Medicine, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, AB, Canada, T2N 4N1.

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.
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http://dx.doi.org/10.1002/14651858.CD005187.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504984PMC
June 2016

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

Cochrane Database Syst Rev 2014 Jan 8(1):CD007736. Epub 2014 Jan 8.

Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridge, UK, CB23 3RE.

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.
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http://dx.doi.org/10.1002/14651858.CD007736.pub2DOI Listing
January 2014

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

Cochrane Database Syst Rev 2013 Jul 22(7):CD005187. Epub 2013 Jul 22.

Department of Family Medicine, Faculty ofMedicine, University of Calgary, Calgary, Canada.

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.
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http://dx.doi.org/10.1002/14651858.CD005187.pub4DOI Listing
July 2013

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

Cochrane Database Syst Rev 2012 Sep 12(9):CD006829. Epub 2012 Sep 12.

Pulmonary Section, Hospital E Peron, G. Baigorria, Argentina.

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.
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http://dx.doi.org/10.1002/14651858.CD006829.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170910PMC
September 2012

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

Cochrane Database Syst Rev 2012 Mar 14(3):CD007695. Epub 2012 Mar 14.

Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

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.
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http://dx.doi.org/10.1002/14651858.CD007695.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015850PMC
March 2012

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

Cochrane Database Syst Rev 2011 Dec 7(12):CD004106. Epub 2011 Dec 7.

Cochrane Editorial Unit, The Cochrane Collaboration, 13 Cavendish Square, London, UK, W1G 0AN.

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.
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December 2011

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

Cochrane Database Syst Rev 2011 May 11(5):CD003137. Epub 2011 May 11.

Research Centre, CHU Sainte-Justine and the Department of Pediatrics, University of Montreal, Room number 7939, 3175 Cote Sainte-Catherine, Montreal, Québec, Canada, H3T 1C5.

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.
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May 2011

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

Cochrane Database Syst Rev 2011 Jan 19(1):CD004823. Epub 2011 Jan 19.

Royal Children's Hospital, Brisbane and Menzies School of Health Research, CDU, Darwin, Queensland Children's Respiratory Centre and Queensland Children's Medical Research Institute, Herston Road, Herston, Brisbane, Queensland, Australia, 4029.

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.
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http://dx.doi.org/10.1002/14651858.CD004823.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885040PMC
January 2011

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

Sao Paulo Med J 2010 ;128(5):310-1

Centro Cochrane do Brasil, São Paulo, Brasil.

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, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 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.
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http://dx.doi.org/10.1590/s1516-31802010000500014DOI Listing
August 2011

Influenza vaccination for healthcare workers who work with the elderly: systematic review.

Vaccine 2010 Dec 18;29(2):344-56. Epub 2010 Nov 18.

Department of Family Medicine, University of Calgary Medical Clinics North Hill, University of Calgary, 1707-1632 14 Avenue NW, Calgary, Canada T2M1M1.

Aim: To identify studies of influenza vaccination of HCWs and influenza in elderly residents in long-term care facilities.

Scope: We searched seven electronic databases for randomised controlled trials (RCTs) and non-RCTs. Two reviewers independently extracted data and assessed trial quality.

Conclusions: The key outcomes are serologically proven influenza, pneumonia, and deaths from pneumonia, and pooled data from three C-RCTs showed no effect. Pooled data from three C-RCTs showed lower resident all-cause mortality, but as influenza constituted less than 10% of all deaths even in epidemic years we question the appropriateness of this outcome measure. Pooled data from three C-RCTs showed vaccination of HCWs reduced ILI and data from one C-RCT that HCW vaccination reduced GP consultations for ILI, but as influenza constitutes less than 25% of ILI and we did not show that HCW influenza vaccination reduced serologically proven influenza we question whether this effect is due to confounding.
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http://dx.doi.org/10.1016/j.vaccine.2010.09.085DOI Listing
December 2010

Herbal interventions for chronic asthma in adults and children: a systematic review and meta-analysis.

Prim Care Respir J 2010 Dec;19(4):307-14

Peninsula College of Medicine & Dentistry, Primary Care Research Group, Institute of Health Services Research, Exeter, Devon, UK.

Aims: To assess the efficacy of herb and plant extracts in the management of asthma.

Method: Systematic review and meta-analysis. Multiple database searches identified randomised placebo controlled trials of herbal interventions reporting at least one primary outcome measure. Where possible data were combined for meta-analysis. Primary outcome measures were lung function, exacerbations and reduction in corticosteroid use. Secondary outcome measures were symptoms and symptom scores, use of reliever medications, changes in rates of consultation and adverse effects.

Results: Twenty-six studies reporting on 20 herbal preparations were included. Two of six studies reporting change in FEV1 were positive. Little data was available on frequency of exacerbations. For primary outcomes single studies of Boswellia, Mai-Men-Dong-Tang, Pycnogenol, Jia-Wei-Si-Jun-Zi-Tang and Tylophora indica showed potential to improve lung function, and a study of 1.8-Cineol (eucalyptol) showed reduced daily oral steroid dosage.

Conclusions: Improvements in symptoms were not strongly supported by objective changes. Most trials were of small sample size, short duration, and poor methodology. Further adequately powered trials are needed to assess these compounds. Such trials should conform to CONSORT guidance, report standardised spirometry, and use validated symptom and severity scores. No recommendations for herbal treatment of asthma can be made from the current evidence.
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http://dx.doi.org/10.4104/pcrj.2010.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602454PMC
December 2010

Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children.

Cochrane Database Syst Rev 2010 May 12(5):CD005535. Epub 2010 May 12.

Research Centre, CHU Sainte-Justine and the Department of Pediatrics, University of Montreal, 3175 Cote Sainte-Catherine, Montreal, Québec, Canada, H3T 1C5.

Background: Long-acting inhaled ss(2)-adrenergic agonists (LABAs) are recommended as 'add-on' medication to inhaled corticosteroids (ICS) in the maintenance therapy of asthmatic adults and children aged two years and above.

Objectives: To quantify in asthmatic patients the safety and efficacy of the addition of LABAs to ICS in patients insufficiently controlled on ICS alone.

Search Strategy: We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers until May 2008.

Selection Criteria: We included RCTs if they compared the addition of inhaled LABAs versus placebo to the same dose of ICS in children aged two years and above and in adults.

Data Collection And Analysis: Two review authors independently assessed studies for methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the relative risk (RR) of asthma exacerbations requiring rescue oral corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), rescue beta2-agonist use, symptoms, withdrawals and adverse events.

Main Results: Seventy-seven studies met the entry criteria and randomised 21,248 participants (4625 children and 16,623 adults). Participants were generally symptomatic at baseline with moderate airway obstruction despite their current ICS regimen. Formoterol or salmeterol were most frequently added to low-dose ICS (200 to 400 microg/day of beclomethasone (BDP) or equivalent) in 49% of the studies. The addition of a daily LABA to ICS reduced the risk of exacerbations requiring oral steroids by 23% from 15% to 11% (RR 0.77, 95% CI 0.68 to 0.87, 28 studies, 6808 participants). The number needed to treat with the addition of LABA to prevent one use of rescue oral corticosteroids is 41 (29, 72), although the event rates in the ICS groups varied between 0% and 38%. Studies recruiting adults dominated the analysis (6203 adult participants versus 605 children). The subgroup estimate for paediatric studies was not statistically significant (RR 0.89, 95% CI 0.58 to 1.39) and includes the possibility of the superiority of ICS alone in children.Higher than usual dose of LABA was associated with significantly less benefit. The difference in the relative risk of serious adverse events with LABA was not statistically significant from that of ICS alone (RR 1.06, 95% CI 0.87 to 1.30). The addition of LABA led to a significantly greater improvement in FEV(1) (0.11 litres, 95% 0.09 to 0.13) and in the proportion of symptom-free days (11.88%, 95% CI 8.25 to 15.50) compared to ICS monotherapy. It was also associated with a reduction in the use of rescue short-acting ss(2)-agonists (-0.58 puffs/day, 95% CI -0.80 to -0.35), fewer withdrawals due to poor asthma control (RR 0.50, 95% CI 0.41 to 0.61), and fewer withdrawals due to any reason (RR 0.80, 95% CI 0.75 to 0.87). There was no statistically significant group difference in the risk of overall adverse effects (RR 1.00, 95% 0.97 to 1.04), withdrawals due to adverse health events (RR 1.04, 95% CI 0.86 to 1.26) or any of the specific adverse health events.

Authors' Conclusions: In adults who are symptomatic on low to high doses of ICS monotherapy, the addition of a LABA at licensed doses reduces the rate of exacerbations requiring oral steroids, improves lung function and symptoms and modestly decreases use of rescue short-acting ss(2)-agonists. In children, the effects of this treatment option are much more uncertain. The absence of group difference in serious adverse health events and withdrawal rates in both groups provides some indirect evidence of the safety of LABAs at usual doses as add-on therapy to ICS in adults, although the width of the confidence interval precludes total reassurance.
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http://dx.doi.org/10.1002/14651858.CD005535.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169792PMC
May 2010

Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma.

Cochrane Database Syst Rev 2010 Apr 14(4):CD005533. Epub 2010 Apr 14.

Research Centre, CHU Sainte-Justine and the Department of Pediatrics, University of Montreal, 3175 Cote Sainte-Catherine, Montreal, Québec, Canada, H3T 1C5.

Background: In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled ss2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids.

Objectives: To determine the effect of the combination of long-acting ss(2) agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the risk of asthma exacerbations, pulmonary function and on other measures of asthma control, and to look for characteristics associated with greater benefit for either treatment option.

Search Strategy: We identified randomised controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs, clinical trial registries and correspondence with manufacturers until May 2008.

Selection Criteria: RCTs that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children and adults with asthma.

Data Collection And Analysis: Two authors independently assessed methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the number of patients experiencing one or more asthma exacerbations requiring oral corticosteroids.

Main Results: This review included 48 studies (15,155 participants including 1155 children and 14,000 adults). Participants were inadequately controlled on their current ICS regimen, experiencing ongoing symptoms and with generally moderate (FEV1 60% to 79% of predicted) airway obstruction. The studies tested the combination of salmeterol or formoterol with a median dose of 400 mcg/day of beclomethasone or equivalent (BDP-eq) compared to a median of 1000 mcg/day of BDP-eq, usually for 24 weeks or less. There was a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73 (median study duration: 12 weeks). The study results were dominated by adult studies; trial data from three paediatric studies showed a trend towards increased risk of rescue oral steroids (RR 1.24, 95% CI 0.58 to 2.66) and hospital admission (RR 2.21, 95% CI 0.74 to 6.64) associated with combination therapy. Overall, there was no statistically significant difference in the risk ratios for either hospital admission (RR 1.02, 95% CI 0.67 to 1.56) or serious adverse events (RR 1.12, 95% CI 0.91 to 1.37). The combination of LABA and ICS resulted in significantly greater but modest improvement from baseline in lung function, symptoms and rescue medication use than with higher ICS dose. Despite no significant group difference in the risk of overall adverse events (RR 0.99, 95% CI 0.95 to 1.03), there was an increase in the risk of tremor (RR 1.84, 95% CI 1.20 to 2.82) and a lower risk of oral thrush (RR 0.58, 95% CI 0.40 to 0.86)) in the LABA and ICS compared to the higher ICS group. There was no significant difference in hoarseness or headache between the treatment groups. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS (RR 0.65, 95% CI 0.51 to 0.83).

Authors' Conclusions: In adolescents and adults with sub-optimal control on low dose ICS monotherapy, the combination of LABA and ICS is modestly more effective in reducing the risk of exacerbations requiring oral corticosteroids than a higher dose of ICS. Combination therapy also led to modestly greater improvement in lung function, symptoms and use of rescue ss(2) agonists and to fewer withdrawals due to poor asthma control than with a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor and less oral candidiasis with combination therapy, the two options appear relatively safe in adults although adverse effects associated with long-term ICS treatment were seldom monitored. In children, combination therapy did not lead to a significant reduction, but rather a trend towards an increased risk, of oral steroid-treated exacerbations and hospital admissions. These trends raised concern about the safety of combination therapy in view of modest improvement in children under the age of 12 years.
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http://dx.doi.org/10.1002/14651858.CD005533.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169793PMC
April 2010

Influenza vaccination for healthcare workers who work with the elderly.

Cochrane Database Syst Rev 2010 Feb 17(2):CD005187. Epub 2010 Feb 17.

Department of Medicine, University of Calgary, UCMC, #1707-1632 14th Avenue, Calgary, Alberta, Canada, T2M 1N7.

Background: Healthcare workers' (HCWs) influenza rates are unknown, but may be similar to the general public and they may transmit influenza to patients.

Objectives: To identify studies of vaccinating HCWs and the incidence of influenza, its complications and influenza-like illness (ILI) in individuals >/= 60 in long-term care facilities (LTCFs).

Search Strategy: We searched CENTRAL (The Cochrane Library 2009, issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2009), EMBASE (1974 to 2009) and Biological Abstracts and Science Citation Index-Expanded.

Selection Criteria: Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of HCWs caring for individuals >/= 60 in LTCFs and the incidence of laboratory-proven influenza, its complications or ILI.

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 (n = 12742) of influenza vaccination for HCWs caring for individuals >/= 60 in LTCFs. Pooled data from three C-RCTs showed no effect on specific outcomes: laboratory-proven influenza, pneumonia or deaths from pneumonia. For non-specific outcomes pooled data from three C-RCTs showed HCW vaccination reduced ILI; data from one C-RCT that HCW vaccination reduced GP consultations for ILI; and pooled data from three C-RCTs showed reduced all-cause mortality in individuals >/= 60.

Authors' Conclusions: No effect was shown for specific outcomes: laboratory-proven influenza, pneumonia and death from pneumonia. An effect was shown for the non-specific outcomes of ILI, GP consultations for ILI and all-cause mortality in individuals >/= 60. These non-specific outcomes are difficult to interpret because ILI includes many pathogens, and winter influenza contributes < 10% to all-cause mortality in individuals >/= 60. The key interest is preventing laboratory-proven influenza in individuals >/= 60, pneumonia and deaths from pneumonia, and we cannot draw such conclusions.The identified studies are at high risk of bias.Some HCWs remain unvaccinated because they do not perceive risk, doubt vaccine efficacy and are concerned about side effects. This review did not find information on co-interventions with HCW vaccination: hand washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, anti-virals, and asking HCWs with ILI not to work. We conclude there is no evidence that vaccinating HCWs prevents influenza in elderly residents in LTCFs. High quality RCTs are required to avoid risks of bias in methodology and conduct, and to test these interventions in combination.
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February 2010

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

Cochrane Database Syst Rev 2010 Jan 20(1):CD007694. Epub 2010 Jan 20.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

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.
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http://dx.doi.org/10.1002/14651858.CD007694.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015852PMC
January 2010

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

Cochrane Database Syst Rev 2009 Oct 7(4):CD007695. Epub 2009 Oct 7.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

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 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 January 2009.

Selection Criteria: Controlled parallel design clinical trials on patients of any age and severity of asthma were included 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. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors.

Main Results: Four studies were included in the review (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 mug versus salmeterol 50 mug 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 OR 0.77; 95% 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 percentage with serious adverse events were 5.1% for formoterol and 6.4% for salmeterol; and over a 3 month period the percentage of children with serious adverse events were 1.3% for formoterol, and 1.3% for salmeterol.

Authors' Conclusions: Four studies have been identified comparing regular formoterol to regular salmeterol (without randomised inhaled corticosteroids, but all subjects 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.
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October 2009

Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children.

Cochrane Database Syst Rev 2009 Oct 7(4):CD005307. Epub 2009 Oct 7.

Division of Children's Services, Cork University Hospital, Cork, Ireland.

Background: Consensus statements recommend the addition of long-acting inhaled ss2-agonists (LABA) only in asthmatic patients who are inadequately controlled on inhaled corticosteroids (ICS). It is not uncommon for some patients to be commenced on ICS and LABA together as initial therapy.

Objectives: To compare the efficacy of combining inhaled corticosteroids with long-acting ss2-agonists (ICS+LABA) with inhaled corticosteroids alone (ICS alone) in steroid-naive children and adults with persistent asthma. We assessed two protocols: (1) LABA + ICS versus a similar dose of ICS (comparison 1) and (2) LABA + ICS versus a higher dose of ICS (comparison 2).

Search Strategy: We identified randomised controlled trials through electronic database searches (May 2008).

Selection Criteria: Randomised trials comparing ICS + LABA with ICS alone in children and adults with asthma who had no inhaled corticosteroids in the preceding 28 days prior to enrolment.

Data Collection And Analysis: Each author assessed studies independently for risk of bias and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was rate of patients with one or more asthma exacerbations requiring rescue systemic corticosteroids. Results are expressed as relative risks (RR) for dichotomous data and as mean differences (MD) or standardised mean differences (SMD) for continuous data.

Main Results: Twenty-eight study comparisons drawn from 27 trials (22 adult; five paediatric) met the review entry criteria (8050 participants). Baseline data from the studies indicated that trial populations had moderate or mild airway obstruction (FEV1>/=65% predicted), and that they were symptomatic prior to randomisation. In comparison 1, the combination of ICS and LABA was not associated with a significantly lower risk of patients with exacerbations requiring oral corticosteroids (RR 1.04; 95% confidence interval (CI) 0.73 to 1.47) or requiring hospital admissions (RR 0.38; 95% CI 0.09 to 1.65) compared to a similar dose of ICS alone. The combination of LABA and ICS led to a significantly greater improvement from baseline in FEV1 (0.12 L/sec; 95% CI 0.07 to 0.17), in symptoms (SMD -0.26; 95% CI -0.37 to -0.14) and in rescue ss2-agonist use (-0.41 puffs/day; 95% CI -0.73 to -0.09) compared with a similar dose of ICS alone. There was no significant group difference in the risk of serious adverse events (RR 1.15; 95% CI 0.64 to 2.09), any adverse events (RR 1.02; 95% CI 0.96 to 1.09), study withdrawals (RR 0.95; 95% CI 0.82 to 1.11), or withdrawals due to poor asthma control (RR 0.94; 95% CI 0.63 to 1.41).In comparison 2, the combination of LABA and ICS was associated with a higher risk of patients requiring oral corticosteroids (RR 1.24; 95% CI 1 to 1.53) and study withdrawal (RR 1.31; 95% CI 1.07 to 1.59) than a higher dose of ICS alone. For every 100 patients treated over 43 weeks, nine patients using a higher dose ICS compared to 11 (95% CI 9 to 14) on LABA and ICS suffered one or more exacerbations requiring rescue oral corticosteroids. There was a high level of statistical heterogeneity for FEV1 and morning peak flow. There was no statistically significant group difference in the risk of serious adverse events. Due to insufficient data we could not aggregate results for hospital admission, symptoms and other outcomes.

Authors' Conclusions: In steroid-naive patients with mild to moderate airway obstruction, the combination of ICS and LABA does not significantly reduce the risk of patients with exacerbations requiring rescue oral corticosteroids over that achieved with a similar dose of ICS alone. However, it significantly improves lung function, reduces symptoms and marginally decreases rescue ss2-agonist use. Initiation of a higher dose of ICS is more effective at reducing the risk of exacerbations requiring rescue systemic corticosteroids, and of withdrawals, than combination therapy. Although children appeared to respond similarly to adults, no firm conclusions can be drawn regarding combination therapy in steroid-naive children, given the small number of children contributing data.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170786PMC
October 2009

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

Cochrane Database Syst Rev 2009 Oct 7(4):CD003531. Epub 2009 Oct 7.

Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridge, UK, CB3 8RE.

Background: Continuous Positive Airways Pressure (CPAP) is considered to be the cornerstone of therapy for obstructive sleep apnoea (OSA). However, compliance with this treatment is frequently poor, which may lead to ongoing symptoms of sleep disruption, daytime sleepiness and poor waking cognitive function. Mechanical interventions which involve changing the way that positive pressure is delivered, and the addition of humidification, might improve compliance.

Objectives: To determine the efficacy of pressure level modifications and additional humidification in increasing CPAP machine usage.

Search Strategy: We searched the Cochrane Airways Group Specialised Register (September 2008).

Selection Criteria: Randomised controlled trials (RCTs) assessing interventions to improve compliance with CPAP usage. Control groups received fixed pressure CPAP.

Data Collection And Analysis: Two authors assessed articles for inclusion in the review and extracted data. We made attempts to obtain additional unpublished data from the trialists.

Main Results: Forty-five studies met the inclusion criteria (1874 participants). Auto-CPAP (30 studies, 1136 participants): a statistically significant difference in machine usage of 0.21 hours/night (0.08 to 0.35) was observed in favour of auto-CPAP from cross-over studies. This difference is of questionable clinical significance. Pooled effect estimates from parallel group trials detected a similar sized difference for average nightly machine usage, but this was not statistically significant. Evidence from parallel group studies did not identify a statistically significant difference between pressure modes in Epworth Sleepiness Scores, but there was an overall reduction of 0.64 units with cross-over studies (-0.12 to -1.16) in favour of auto-CPAP. Parallel group studies did not identify a significant difference. More participants preferred auto-CPAP to fixed CPAP where this was measured. Bi-level PAP (six studies, 285 participants): no significant differences were observed in machine usage. One small study found no difference in preference. C-Flex (six studies, 318 participants): no significant difference was observed in machine usage. Humidification (three studies, 135 participants): there were conflicting findings between the studies. Two parallel group trials found no significant difference in machine usage, whereas a cross-over study found a significant difference.

Authors' Conclusions: Improvement in average machine use of auto-CPAP was superior in studies with a cross-over design; the point estimate in parallel group trials was similar, but did not reach statistical significance. It is uncertain how use of machines in study settings relates to 'real world' use. Where preference was measured participants preferred auto-CPAP to fixed pressure CPAP. Further studies are required to assess the evidence for Bi-PAP, C-Flex(TM) and humidification. The studies assembled were characterised by high machine usage in the control groups, and low withdrawal rates. Future studies need to consider the effects of treatment in participants with more mild disease, and those who struggle to accept therapy despite persistent symptoms.
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October 2009

Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children.

Cochrane Database Syst Rev 2009 Jul 8(3):CD007949. Epub 2009 Jul 8.

Division of Children's Services, Cork University Hospital, Cork, Ireland.

Background: Long-acting ss(2)- agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed in asthmatic children.

Objectives: To compare the safety and benefit of adding LABA to ICS with the same or an increased dose of ICS in children with persistent asthma.

Search Strategy: We searched the Cochrane Airways Group Asthma Trials Register (May 2008).

Selection Criteria: We included randomised controlled trials testing the combination of LABA and ICS versus the same or an increased dose of ICS for minimum of at least 28 days in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included pulmonary function, symptoms, adverse events, and withdrawals.

Data Collection And Analysis: Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible.

Main Results: A total of 25 trials representing 31 control-intervention comparisons were included in the review randomising 5572 children. Most of the participants were inadequately controlled on current ICS dose. We assessed the addition of LABA to the same dose of ICS and to an increased dose of ICS:(1) The addition of LABA to ICS was compared to same dose ICS, namely 400 mcg/day of beclomethasone or less in 16 of the 24 studies. The mean age of participants was 10 years and males accounted for 64% of the study populations. The mean FEV(1) at baseline was 80% of predicted or above in 10 studies; FEV(1) 61% to 79% of predicted in eight studies; and unreported in the remaining study. Participants were inadequately controlled before randomisation in all but seven studies. Compared to ICS alone, the addition of LABA to ICS was not associated with a significant reduction in exacerbations requiring oral steroids (seven studies, RR 0.92 95% CI 0.60 to 1.40). Compared to ICS alone, there was a significantly greater improvement in FEV1 with the addition of LABA (nine studies; 0.08 Litres, 95% CI 0.06 to 0.11) but no statistically significant group differences in symptom-free days, hospital admission, quality of life, use of reliever medication, and adverse events. Withdrawals occurred significantly less frequently with the addition of LABA.(2) A total of seven studies assessed the addition of LABA to ICS therapy compared with an increased dose of ICS randomising 1021 children. The mean age of participants was 8 years with 67% of males. The baseline mean FEV(1) was 80% of predicted or above in 2 of the 3 studies reporting this characteristic. All trials enrolled participants who were inadequately controlled on a baseline dose equivalent to 400 mcg/day of beclomethasone or less. There was no group significant difference in the risk of an exacerbation requiring oral steroids with the combination of LABA and ICS compared to a double dose of ICS (two studies, RR 1.5 95% CI 0.65 to 3.48). The increased risk of hospital admission with combination therapy was also not statistically significant (RR 2.21 95% CI 0.74 to 6.64). Compared to double dose ICS, use of LABA was associated with a significantly greater improvement in morning PEF (four studies; MD 7.55 L/min 95% CI: 3.57 to 11.53) and evening PEF L/min (three studies, MD 5.5 L/min; 95% CI 1.21 to 9.79), but there were insufficient data to aggregate data on FEV(1), symptoms, rescue reliever use, and quality of life. There was no statistically significant difference in the overall risk of all cause withdrawals (five studies; RR 0.71; 95% CI 0.42 to 1.20. There was no group difference in the risk of overall adverse effects detected. Short term growth was significantly greater in children treated with combination therapy compared to double dose ICS (two studies: MD 1.2 cm/year; 95% CI 0.72 to 1.7).

Authors' Conclusions: In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but was superior for improving lung function compared to the same dose of ICS. Similarly, compared to a double dose ICS, the combination of LABA and ICS did not significantly increase the risk of exacerbations requiring oral steroids, but was associated with a significantly greater improvement in PEF and growth. The possibility of an increased risk of rescue oral steroids and hospital admission with LABA therapy needs to be further examined.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167878PMC
July 2009

Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events.

Cochrane Database Syst Rev 2009 Jul 8(3):CD006922. Epub 2009 Jul 8.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

Background: Epidemiological evidence has suggested a link between beta(2)-agonists and increased asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe.

Objectives: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone.

Search Strategy: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to salmeterol were also checked. The date of the most recent search was October 2008.

Selection Criteria: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular salmeterol and inhaled corticosteroids (in separate or combined inhalers), and were of at least 12 weeks duration.

Data Collection And Analysis: Two authors independently selected trials for inclusion in the review. Outcome data were independently extracted by two authors. Unpublished data on mortality and serious adverse events were obtained from the sponsors, and from FDA submissions.

Main Results: The review included 30 studies (10,873 participants) in adults and adolescents, and three studies (1,173 participants) in children. The overall risk of bias was low and data on serious adverse events were obtained from all studies.Six deaths occurred in 5,710 adults on regular salmeterol with inhaled corticosteroids, and five deaths in 5,163 adults on regular inhaled corticosteroids at the same dose. The difference was not statistically significant (Peto OR 1.05; 95% CI 0.32 to 3.47) and the absolute difference between groups in risk of death of any cause was 0.00005 (95% CI -0.002 to 0.002). No deaths were reported in 1,173 children, and no deaths were reported to be asthma-related.Non-fatal serious adverse events of any cause were reported in 134 adults on regular salmeterol with inhaled corticosteroids, compared to 103 adults on regular inhaled corticosteroids; again this was not a significant increase (Peto OR 1.17; 95% CI 0.90 to 1.52). The absolute difference in the risk of non-fatal serious adverse events was 0.003 (95% CI -0.002 to 0.009).There were three of 586 children with serious adverse events on regular salmeterol with inhaled corticosteroids, compared to four out of 587 on regular inhaled corticosteroids: there was no significant difference between treatments (Peto OR 0.75; 95% CI 0.17 to 3.31).Asthma-related serious adverse events were reported in 23 and 21 adults in each group respectively, a non-significant difference (Peto OR 0.95; 95% CI 0.52 to 1.73), and only one event was reported in children.

Authors' Conclusions: No significant differences have been found in fatal or non-fatal serious adverse events in trials in which regular salmeterol has been randomly allocated with inhaled corticosteroids, in comparison to inhaled corticosteroids at the same dose. Although 10,873 adults and 1,173 children have been included in trials, the number of patients suffering adverse events is too small, and the results are too imprecise to confidently rule out a relative increase in all-cause mortality or non-fatal adverse events. It is therefore not possible to determine whether the increase in all-cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular inhaled corticosteroids. The absolute difference between groups in the risk of serious adverse events was small. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.
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July 2009

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

Cochrane Database Syst Rev 2009 Apr 15(2):CD007736. Epub 2009 Apr 15.

Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridge, UK, CB3 8RE.

Background: Although effective in the treatment of obstructive sleep apnoea (OSA), continuous positive airway pressure (CPAP) does not meet with universal acceptance by users. Educational, supportive and behavioural interventions may help people with obstructive sleep apnoea recognise the need for regular and continued use of continuous positive airway pressure.

Objectives: To critically assess strategies that are educational, or supportive, or behavioural in encouraging people who have been prescribed or offered CPAP to use their machines.

Search Strategy: Searches were conducted on the Cochrane Airways Group Sleep Apnoea trials register. Searches are current to September 2008.

Selection Criteria: Randomised parallel group studies which assessed an intervention aimed to inform participants about CPAP or OSA, or 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 authors assessed studies to determine their suitability for inclusion in the review. Data were extracted independently and entered in to Review Manager software.

Main Results: Seventeen studies met the review entry criteria (1070 participants). Support/encouragement offered on an ongoing basis led to increased average machine usage (0.59 hours/night (95% CI 0.26 to 0.92), although there was a significant degree of variation between the results of the studies. The effects of these interventions on the likelihood of study withdrawal, symptoms and quality of life were not statistically significant.Short-course educational intervention was not more successful in improving average machine usage than usual care.Cognitive behavioural therapy led to a significant improvement in average machine usage in two studies (2.92 hours/night (95% CI 1.93 to 3.92)), and a number needed to treat of 3 (95% CI 2 to 6) for one additional patient to achieve machine usage of six or more hours per night. Overall, In the control groups 85 people out of 100 had failed to comply with CPAP over 4 to 12 weeks, compared to 46 (95% CI 68 to 25) out of 100 for the cognitive behaviour groups.

Authors' Conclusions: There is some evidence that a supportive intervention which encourages people to continue to use their CPAP machines leads to greater levels of CPAP machine usage than control, although the variation across the studies introduces some uncertainty over how consistent this effect is. We could not find evidence that a short-term educational intervention led to improvements in usage. Cognitive behavioural therapy led to the largest increases in average machine usage, partly because more participants were prepared to try out the treatment. Studies generally recruited CPAP naive patients whose sleep apnoea was severe. Trials in patients who have struggled to persist with treatment are required, as there is currently little evidence in this population. This could make a valuable contribution to our understanding of the complex relationship between initial motivation, ongoing perception of benefit and long-term health benefits.
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April 2009

Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children.

Cochrane Database Syst Rev 2009 Apr 15(2):CD007313. Epub 2009 Apr 15.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

Background: Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy).

Objectives: The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler.

Search Strategy: We last searched the Cochrane Airways Group trials register in September 2008.

Selection Criteria: Randomised controlled trials in adults and children with chronic asthma.

Data Collection And Analysis: Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.

Main Results: Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run-in for these studies involved withdrawal of long-acting beta(2)-agonists, and patients were recruited who were symptomatic during run-in.One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm].There was no significant difference found in fatal or non-fatal serious adverse events for any of the comparisons.

Authors' Conclusions: Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long-acting beta(2)-agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.
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http://dx.doi.org/10.1002/14651858.CD007313.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053857PMC
April 2009

Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events.

Cochrane Database Syst Rev 2009 Apr 15(2):CD006924. Epub 2009 Apr 15.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

Background: Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe when used alone or in conjunction with inhaled corticosteroids.

Objectives: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone.

Search Strategy: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was October 2008.

Selection Criteria: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and inhaled corticosteroids, and were of at least 12 weeks duration.

Data Collection And Analysis: Two authors independently selected trials for inclusion in the review. Outcome data were independently extracted by two authors. Unpublished data on mortality and serious adverse events were obtained from the sponsors.

Main Results: The review included 14 studies on adults and adolescents (8,028 participants) and seven studies on children and adolescents (2,788 participants). Data on all cause fatal and non-fatal serious adverse events were found for all studies, and the overall risk of bias was low.Four deaths occurred on regular formoterol with inhaled corticosteroids, and none on regular inhaled corticosteroids alone. All the deaths were in adults, and one was reported to be asthma-related. The difference was not statistically significant.Non-fatal serious adverse events of any cause were very similar in adults [Peto Odds Ratio 0.99 (95% CI 0.74 to 1.33)], and an increase in events in children on regular formoterol was not statistically significant [Peto Odds Ratio 1.62 (95% CI 0.80 to 3.28)].Asthma related serious adverse events on formoterol were lower in adults [Peto Odds Ratio 0.53 (95% CI 0.28 to 1.00)] and although they were higher in children [Peto Odds Ratio 1.49 (95% CI 0.48 to 4.61)], this was not statistically significant.

Authors' Conclusions: It is not possible, from the data in this review, to reassure people with asthma that inhaled corticosteroids with regular formoterol carries no risk of increasing mortality in comparison to inhaled corticosteroids alone as all four deaths occurred among 6,594 people using inhaled corticosteroids with formoterol. On the other hand, we have found no conclusive evidence of harm and there was only one asthma related death registered during over 3,000 patient year observation on formoterol. In adults, the decrease in asthma-related serious adverse events on regular formoterol with inhaled corticosteroids was not accompanied by a decrease in all cause serious adverse events. In children the number of events was too small, and consequently the results too imprecise, to determine whether the increase in all cause non-fatal serious adverse events found in the previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids. Clinical decisions and information for patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty and concern associated with its potential harmful effects.
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April 2009

Interventions for educating children who are at risk of asthma-related emergency department attendance.

Cochrane Database Syst Rev 2009 Apr 15(2):CD001290. Epub 2009 Apr 15.

Royal Children's Hospital , Herston Road, Herston , Queensland , Australia, 4029.

Background: Asthma is the most common chronic childhood illness and is a leading cause for paediatric admission to hospital. Asthma management for children results in substantial costs. There is evidence to suggest that hospital admissions could be reduced with effective education for parents and children about asthma and its management.

Objectives: To conduct a systematic review of the literature and update the previous review as to whether asthma education leads to improved health outcomes in children who have attended the emergency room for asthma.

Search Strategy: We searched the Cochrane Airways Group Trials Register, including the MEDLINE, EMBASE and CINAHL databases, and reference lists of trials and review articles (last search May 2008).

Selection Criteria: We included randomised controlled trials of asthma education for children who had attended the emergency department for asthma, with or without hospitalisation, within the previous 12 months.

Data Collection And Analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We pooled dichotomous data with a fixed-effect risk ratio. We used a random-effects risk ratio for sensitivity analysis of heterogenous data.

Main Results: A total of 38 studies involving 7843 children were included. Following educational intervention delivered to children, their parents or both, there was a significantly reduced risk of subsequent emergency department visits (RR 0.73, 95% CI 0.65 to 0.81, N = 3008) and hospital admissions (RR 0.79, 95% CI 0.69 to 0.92, N = 4019) compared with control. There were also fewer unscheduled doctor visits (RR 0.68, 95% CI 0.57 to 0.81, N = 1009). Very few data were available for other outcomes (FEV1, PEF, rescue medication use, quality of life or symptoms) and there was no statistically significant difference between education and control.

Authors' Conclusions: Asthma education aimed at children and their carers who present to the emergency department for acute exacerbations can result in lower risk of future emergency department presentation and hospital admission. There remains uncertainty as to the long-term effect of education on other markers of asthma morbidity such as quality of life, symptoms and lung function. It remains unclear as to what type, duration and intensity of educational packages are the most effective in reducing acute care utilisation.
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http://dx.doi.org/10.1002/14651858.CD001290.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079713PMC
April 2009

Combination formoterol and inhaled steroid versus beta2-agonist as relief medication for chronic asthma in adults and children.

Cochrane Database Syst Rev 2009 Jan 21(1):CD007085. Epub 2009 Jan 21.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

Background: Formoterol has a fast onset of action and can therefore be used to relieve symptoms of asthma. A combination inhaler can deliver formoterol with different doses of inhaled corticosteroid; when used as a reliever both drugs will be delivered more frequently when asthma symptoms increase. This has the potential to treat both bronchoconstriction and inflammation in the early stages of exacerbations.

Objectives: To assess the efficacy and safety of combined inhalers containing both formoterol and an inhaled corticosteroid when used for reliever therapy in adults and children with chronic asthma.

Search Strategy: We last searched the Cochrane Airways Group trials register in April 2008.

Selection Criteria: Randomised trials in adults and children with chronic asthma, where a combination inhaler containing formoterol and inhaled corticosteroid is compared with fast-acting beta2-agonist alone for the relief of asthma symptoms. This should be the only planned difference between the trial arms.

Data Collection And Analysis: Two review authors independently extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.

Main Results: Three trials involving 5905 participants were included. In patients with mild asthma who do not need maintenance treatment, no clinically important advantages of budesonide/formoterol as reliever were found in comparison to formoterol as reliever.Two studies enrolled patients with more severe asthma who were not controlled on high doses of inhaled corticosteroids (around 700 mcg/day in adults), and had suffered a clinically important asthma exacerbation in the past year. Hospitalisations related to asthma in the two studies comparing budesonide/formoterol for maintenance and relief with the same dose of budesonide/formoterol for maintenance with terbutaline for relief yielded an odds ratio of 0.68 (95% CI 0.40 to 1.16), which was not a statistically significant reduction. One adult study found a reduction in exacerbations requiring oral corticosteroids compared to terbutaline, odds ratio 0.56 (95% CI 0.42 to 0.74) and the study in children found less serious adverse events with budesonide/formoterol used for maintenance and relief. There was no significant difference in annual growth in children using budesonide/formoterol reliever in comparison to terbutaline.

Authors' Conclusions: In mild asthma it is not yet known whether patients who use a budesonide/formoterol inhaler for relief of asthma symptoms derive any clinically important benefits. In more severe asthma, one study that enrolled patients who were not controlled on quite high doses of inhaled corticosteroids, and had suffered an exacerbation in the previous year, demonstrated a reduction in the risk of exacerbations that require oral corticosteroids with budesonide/formoterol for maintenance and relief in comparison with budesonide/formoterol for maintenance and terbutaline or formoterol for relief. The incidence of serious adverse events in children was also less using budesonide/formoterol for maintenance and relief in one study, which similarly enrolled children who were not controlled on medium to high doses of inhaled corticosteroids, and compared to terbutaline relief with an explorative maintenance dose of budesonide/formoterol that is not approved for treatment.
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http://dx.doi.org/10.1002/14651858.CD007085.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023854PMC
January 2009

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

Cochrane Database Syst Rev 2008 Oct 8(4):CD006923. Epub 2008 Oct 8.

Community Health Sciences, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.

Background: Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe.

Objectives: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists.

Search Strategy: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was July 2008.

Selection Criteria: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and were of at least 12 weeks duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.

Data Collection And Analysis: Two authors independently selected trials for inclusion in the review. Outcome data were extracted by one author and checked by the second author. Unpublished data on mortality and serious adverse events were sought.

Main Results: The review includes 22 studies (8,032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Odds Ratio 1.57 [95% CI: 1.05 to 2.37]). One extra serious adverse event occurred over 16 weeks for every 179 people treated with regular formoterol [95% CI: 75 to 2022]. The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicates that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline.

Authors' Conclusions: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age-groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all adverse events or limited to those events that are thought by the investigator to be drug-related.
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http://dx.doi.org/10.1002/14651858.CD006923.pub2DOI Listing
October 2008
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