Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events (Review)

Background Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-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 Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked.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 Unpublished data on mortality and serious adverse events were obtained from the sponsors.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

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

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

Reference values for body composition and associations with blood pressure in Kenyan adults aged ≥50 years old

Objectives: To develop age and sex-specific centile reference curves for fat free mass (FFM) and fat mass (FM) adjusted for height in an adult Kenyan population and to investigate the association between FM, FFM and blood pressure (BP). Methods: Measures of body composition from bioimpedance analyses and BP were collected in 1,995 participants aged ≥50y in Nakuru County, Kenya. Reference curves were produced using the LMS method. Multivariable linear regression models were used to test the cross-sectional association between body composition indexes and BP. Results: The age and sex-specific reference curves for body composition (FMI and FFMI) confirm that FFMI is lower in both men and women with increasing age. FMI declines with age in women while among men the decline starts after 70 years. FFM was higher in men (47.4 ± 7.2 kg) than in women (38.8 ± 5.5 kg), while FM was lower in men (17.3 ± 8.1 kg) than in women (24.4 ± 10.2 kg). FMI, FFMI and BMI were all positively associated with systolic and diastolic BP, and after adjusting for body weight, FFMI remained positively associated with systolic BP and the FMI remained positively associated with diastolic BP. There was no evidence to suggest that FMI and FFMI were superior to measurement of BMI alone. Conclusion: These body composition reference curves provide normative data on body composition for older adults in Kenya. Further research should consider the prospective associations with health, including frailty-related outcomes

Long-term safety and efficacy of fluticasone/formoterol combination therapy in asthma.

BACKGROUND The long-term safety of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol; flutiform(®)) was assessed. METHOD In an open-label study, mild to moderate-severe asthmatics (≥12 years; N=472) were treated twice daily with fluticasone/formoterol 100/10 μg (n=224) or 250/10 μg (n=248) for 6 months (n=256) or 12 months (n=216). The primary and secondary objectives were the long-term safety and efficacy of fluticasone/formoterol, respectively. RESULTS In total, 413 (87.5%) patients completed the study (of which 175 participated for 12 months). Adverse events (AEs) were reported by 174 patients (36.9%): 67 (29.9%) in the 100/10 μg group and 107 (43.1%) in the 250/10 μg group. The most common AEs (>2%) were nasopharyngitis, dyspnea, pharyngitis, and headache; the majority were mild to moderate. Only 18 (3.8%) patients reported AEs considered study drug-related. Five patients per group experienced 12 serious AEs; none was study medication-related. Asthma exacerbations were reported by 53 patients (11.2%): 46 mild to moderate and nine severe. Clinical laboratory tests and vital signs showed no abnormal trends or clinically important or dose-response-related changes. The efficacy analyses showed statistically significant improvements at every time point throughout the study period at both doses. CONCLUSION Fluticasone/formoterol had a good safety and efficacy profile over the 6- and 12-month study periods

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

The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years. Nearly all focus to date has been on intervention reporting in randomised trials. Yet clinicians are encouraged to use systematic reviews, whenever available, rather than single trials to inform their practice. This article explores the problem and implications of incomplete intervention details during the planning, conduct, and reporting of systematic reviews and makes recommendations for review authors, peer reviewers, and journal editors

An integrative review of systematic reviews related to the management of breathlessness in respiratory illnesses

Background: breathlessness is a debilitating and distressing symptom in a wide variety of diseases and still a difficult symptom to manage. An integrative review of systematic reviews of non-pharmacological and pharmacological interventions for breathlessness in non-malignant disease was undertaken to identify the current state of clinical understanding of the management of breathlessness and highlight promising interventions that merit further investigation.Methods: systematic reviews were identified via electronic databases between July 2007 and September 2009. Reviews were included within the study if they reported research on adult participants using either a measure of breathlessness or some other measure of respiratory symptoms.Results: in total 219 systematic reviews were identified and 153 included within the final review, of these 59 addressed non-pharmacological interventions and 94 addressed pharmacological interventions. The reviews covered in excess of 2000 trials. The majority of systematic reviews were conducted on interventions for asthma and COPD, and mainly focussed upon a small number of pharmacological interventions such as corticosteroids and bronchodilators, including beta-agonists. In contrast, other conditions involving breathlessness have received little or no attention and studies continue to focus upon pharmacological approaches. Moreover, although there are a number of non-pharmacological studies that have shown some promise, particularly for COPD, their conclusions are limited by a lack of good quality evidence from RCTs, small sample sizes and limited replication.Conclusions: more research should focus in the future on the management of breathlessness in respiratory diseases other than asthma and COPD. In addition, pharmacological treatments do not completely manage breathlessness and have an added burden of side effects. It is therefore important to focus more research on promising non-pharmacological intervention