Abstract Objective: To summarize the principal findings pertaining to most effective long-term pharmacologic treatment of childhood asthma. Methods: Systematic reviews of randomized clinical trials (SRCTs) on pharmacologic chronic treatment in children (1-18 years) with persistent asthma were retrieved through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR (up to January2014). Results: One hundred eighty-three SRCTs were searched from databases. Among those, 39 SRCTs were included: two were related to step 1, 24 to step 2, nine to steps 3 and 4, and four to step 5 (according with NAEPP and GINA guidelines). The methodological quality of these SRCTs was determined by using the AMSTAR tool. Results: For step 1: addition of ipatropium bromide to short-acting beta2-agonists does not show any benefit. For step 2: in preschoolers, inhaled corticosteroids (ICSs) reduce severe exacerbations and improve other clinical and lung function parameters. In children, ICSs are superior to leukotriene receptor antagonist (LTRA), cromones, or xantines in reducing severe exacerbations, improving lung function and other clinical outcomes. Fluticasone propionate (FP) is better than beclomethasone dipropionate (BDP) or budesonide only for lung function; but similar to hydrofluoroalkane-BDP or to ciclosenide. Compared to low ICSs doses, moderate doses result in only better lung function, but this is not true for FP. For steps 3 and 4: adding LTRA to ICS confers a small benefit; adding LABA improves lung function but does not reduce exacerbations more than double or higher ICS doses. For step 5: adding omalizumab decreases exacerbations. Conclusions: SRCTs are useful for guiding decisions in chronic childhood asthma treatment.
BACKGROUND: For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken together with ICS in a single (combination) inhaler. Improved symptom control can be assessed in the individual; however, the long-term risk of hospital admission or death requires evidence from randomised controlled trials. Clinical trials record these safety outcomes as non-fatal and fatal serious adverse events (SAEs), respectively.
OBJECTIVES: To assess the risk of serious adverse events in adults with asthma treated with regular maintenance formoterol or salmeterol compared with placebo, or when randomly assigned in combination with regular ICS, compared with the same dose of ICS.
METHODS: We included Cochrane reviews on the safety of regular formoterol and salmeterol from a June 2013 search of the Cochrane Database of Systematic Reviews. We carried out a search for additional trials in September 2013 and incorporated the new data. All reviews were independently assessed for inclusion and for quality (using the AMSTAR tool). We extracted from each review data from trials recruiting adults (participants older than 12 or 18 years of age).
We combined the results from reviews on formoterol and salmeterol to assess the safety of twice-daily regular LABA as a class effect, both as monotherapy versus placebo and as combination therapy versus the same dose of ICS.
We did not combine the results of direct and indirect comparisons of formoterol and salmeterol, or carry out a network meta-analysis, because of concerns over transitivity assumptions that posed a threat to the validity of indirect comparisons.
MAIN RESULTS: We identified six high-quality, up-to-date Cochrane reviews. Of these, four reviews (89 trials with 61,366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from trials in which adults were randomly assigned to formoterol versus salmeterol. These included three trials with 1116 participants given monotherapy (all prescribed background ICS) and 10 trials with 8498 adults receiving combination therapy. An additional search for trials in September 2013 identified five new included studies contributing data from 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, as well as from 447 adults for whom formoterol monotherapy was compared with placebo.
No trials reported separate results in adolescents. Overall, risks of bias for the primary outcomes were assessed as low.
None of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy vs placebo or as combination therapy versus ICS) in adults with asthma. Pooled mortality results from direct comparisons were as follows: formoterol monotherapy (odds ratio (OR) 4.49, 95% confidence interval (CI) 0.24 to 84.80, 13 trials, N = 4824), salmeterol monotherapy (OR 1.33, 95% CI 0.85 to 2.08, 10 trials, N = 29,128), formoterol combination (OR 3.56, 95% CI 0.79 to 16.03, 25 trials, N = 11,271) and salmeterol combination (OR 0.90, 95% CI 0.31 to 2.6, 35 trials, N = 13,447). In each case, we did not detect heterogeneity, and the quality of evidence was rated as moderate. Absolute differences in mortality were very small, translating into an increase of 7 per 10,000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10,000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more).
Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore we could not use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy.
Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality.
Direct evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (OR 1.14, 95% 1.01 to 1.28, I2 = 0%,13 trials, N = 30,196) but were not significantly increased in any of the other reviews: formoterol monotherapy (OR 1.26, 95% CI 0.78 to 2.04, I2 = 15%, 17 trials, N = 5758), formoterol combination (OR 0.99, 95% CI 0.77 to 1.27, I2 = 0%, 25 trials, N = 11,271) and salmeterol combination (OR 1.15, 95% CI 0.91 to 1.44, I2 = 0%, 35 trials, N = 13,447). This represents an absolute increase on any monotherapy of 43 per 10,000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10,000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy.
Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy).
AUTHORS' CONCLUSIONS: Available evidence from the reviews of randomised trials cannot definitively rule out an increased risk of fatal serious adverse events when regular formoterol or salmeterol was added to an inhaled corticosteroid (as background or as randomly assigned treatment) in adults or adolescents with asthma.
An increase in non-fatal serious adverse events of any cause was found with salmeterol monotherapy, and the same increase cannot be ruled out when formoterol or salmeterol was used in combination with an inhaled corticosteroid, although possible increases are small in absolute terms.
However, if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give formoterol or salmeterol in the form of a combination inhaler (as recommended by the US Food and Drug Administration (FDA)). This prevents the substitution of LABA for an inhaled corticosteroid if symptom control is improved on LABA.
The results of three large ongoing trials in adults and adolescents are awaited; these will provide more information on the safety of combination therapy under less supervised conditions and will report separate results for the adolescents included.
Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
INTRODUCTION: About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS: We found 54 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding anti-IgE treatment; beta(2) agonists (adding long-acting inhaled beta(2) agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta(2) agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).
BACKGROUND: Allergic rhinitis represents a global health problem affecting 10% to 20% of the population. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines have been widely used to treat the approximately 500 million affected patients globally., OBJECTIVE: To develop explicit, unambiguous, and transparent clinical recommendations systematically for treatment of allergic rhinitis on the basis of current best evidence., METHODS: The authors updated ARIA clinical recommendations in collaboration with Global Allergy and Asthma European Network following the approach suggested by the Grading of Recommendations Assessment, Development and Evaluation working group., RESULTS: This article presents recommendations about the prevention of allergic diseases, the use of oral and topical medications, allergen specific immunotherapy, and complementary treatments in patients with allergic rhinitis as well as patients with both allergic rhinitis and asthma. The guideline panel developed evidence profiles for each recommendation and considered health benefits and harms, burden, patient preferences, and resource use, when appropriate, to formulate recommendations for patients, clinicians, and other health care professionals., CONCLUSION: These are the most recent and currently the most systematically and transparently developed recommendations about the treatment of allergic rhinitis in adults and children. Patients, clinicians, and policy makers are encouraged to use these recommendations in their daily practice and to support their decisions. Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Abstract Objective: To summarize the principal findings pertaining to most effective long-term pharmacologic treatment of childhood asthma. Methods: Systematic reviews of randomized clinical trials (SRCTs) on pharmacologic chronic treatment in children (1-18 years) with persistent asthma were retrieved through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR (up to January2014). Results: One hundred eighty-three SRCTs were searched from databases. Among those, 39 SRCTs were included: two were related to step 1, 24 to step 2, nine to steps 3 and 4, and four to step 5 (according with NAEPP and GINA guidelines). The methodological quality of these SRCTs was determined by using the AMSTAR tool. Results: For step 1: addition of ipatropium bromide to short-acting beta2-agonists does not show any benefit. For step 2: in preschoolers, inhaled corticosteroids (ICSs) reduce severe exacerbations and improve other clinical and lung function parameters. In children, ICSs are superior to leukotriene receptor antagonist (LTRA), cromones, or xantines in reducing severe exacerbations, improving lung function and other clinical outcomes. Fluticasone propionate (FP) is better than beclomethasone dipropionate (BDP) or budesonide only for lung function; but similar to hydrofluoroalkane-BDP or to ciclosenide. Compared to low ICSs doses, moderate doses result in only better lung function, but this is not true for FP. For steps 3 and 4: adding LTRA to ICS confers a small benefit; adding LABA improves lung function but does not reduce exacerbations more than double or higher ICS doses. For step 5: adding omalizumab decreases exacerbations. Conclusions: SRCTs are useful for guiding decisions in chronic childhood asthma treatment.
