PMID- 33945639 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20230320 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 5 IP - 5 DP - 2021 May 4 TI - Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma. PG - CD013518 LID - 10.1002/14651858.CD013518.pub2 [doi] LID - CD013518 AB - BACKGROUND: Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta(2)-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta(2)-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma. OBJECTIVES: To evaluate the efficacy and safety of single combined (fast-onset beta(2)-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control. MAIN RESULTS: We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 mug and formoterol 6 mug in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers. FABA / ICS as required versus FABA as required Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS, were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 mug beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence). FABA/ICS as required versus regular ICS plus FABA as required There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 mug/day, 95% CI -207.94 to -101.09). AUTHORS' CONCLUSIONS: We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events. Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks. CI - Copyright (c) 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Crossingham, Iain AU - Crossingham I AD - East Lancashire Hospitals NHS Trust, Blackburn, UK. FAU - Turner, Sally AU - Turner S AD - East Lancashire Hospitals NHS Trust, Blackburn, UK. FAU - Ramakrishnan, Sanjay AU - Ramakrishnan S AD - Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. AD - NIHR Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK. AD - School of Medical and Health Sciences, Edith Cowan University, Perth, Australia. FAU - Fries, Anastasia AU - Fries A AD - Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - Gowell, Matthew AU - Gowell M AD - New College, University of Oxford Medical School, Oxford, UK. FAU - Yasmin, Farhat AU - Yasmin F AD - Pharmacy, Kettering General Hospital, Kettering, UK. FAU - Richardson, Rebekah AU - Richardson R AD - East Lancashire Hospitals NHS Trust, Blackburn, UK. FAU - Webb, Philip AU - Webb P AD - East Lancashire Hospitals NHS Trust, Blackburn, UK. FAU - O'Boyle, Emily AU - O'Boyle E AD - New College, University of Oxford Medical School, Oxford, UK. FAU - Hinks, Timothy Sc AU - Hinks TS AD - Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. AD - NIHR Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20210504 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Adrenal Cortex Hormones) RN - 0 (Adrenergic beta-2 Receptor Agonists) RN - 0 (Anti-Asthmatic Agents) RN - 0 (Drug Combinations) RN - 51333-22-3 (Budesonide) RN - 9PHQ9Y1OLM (Prednisolone) RN - KGZ1SLC28Z (Beclomethasone) RN - N8ONU3L3PG (Terbutaline) RN - W34SHF8J2K (Formoterol Fumarate) SB - IM UOF - doi: 10.1002/14651858.CD013518 MH - Adolescent MH - Adrenal Cortex Hormones/*administration & dosage MH - Adrenergic beta-2 Receptor Agonists/*administration & dosage MH - Adult MH - Anti-Asthmatic Agents/*administration & dosage MH - Asthma/*drug therapy MH - Beclomethasone/administration & dosage MH - Budesonide/*administration & dosage MH - Child MH - Disease Progression MH - Drug Combinations MH - Formoterol Fumarate/*administration & dosage MH - Hospitalization/statistics & numerical data MH - Humans MH - Nebulizers and Vaporizers MH - Prednisolone/administration & dosage MH - Quality of Life MH - Randomized Controlled Trials as Topic MH - Terbutaline/administration & dosage PMC - PMC8096360 COIS- 1. I Crossingham works in a clinically-relevant speciality. He has been involved in recruitment for a GlaxoSmithKline-sponsored trial of inhaled nemiralisib for COPD, but did not directly receive funding for this. 2. S Turner reports money for travel from Novartis in 2019 for an educational event. 3. S Ramakrishnan is undertaking a PhD supported by an unrestricted research grant from AstraZeneca. He has attended educational events sponsored by AstraZeneca (2019). He also works in a clinically relevant specialty. 4. A Fries works in a clinically relevant speciality (respiratory medicine). 5. M Gowell: none known. 6. F Yasmin: none known. 7. R Richardson: none known. 8. P Webb works in a clinically relevant speciality (respiratory medicine). 9. E O'Boyle: none known. 10. TSC Hinks has received research funding from the Wellcome Trust (4 February 2015 to 31 July 2018, 3 December 2018 ‒ ongoing), NIHR (1 May 2019 ‒ ongoing), and the Beit Guardians (3 December 2018 ‒ ongoing). He has received speaker fees from AstraZeneca in June 2019, Boehringer Ingelheim (March 2019) and his research team have received funding from Sanofi (September 2019 ‒ ongoing). EDAT- 2021/05/05 06:00 MHDA- 2021/06/22 06:00 PMCR- 2022/05/04 CRDT- 2021/05/04 17:35 PHST- 2021/05/04 17:35 [entrez] PHST- 2021/05/05 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2022/05/04 00:00 [pmc-release] AID - CD013518.pub2 [pii] AID - 10.1002/14651858.CD013518.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2021 May 4;5(5):CD013518. doi: 10.1002/14651858.CD013518.pub2.