PMID- 37602534 OWN - NLM STAT- MEDLINE DCOM- 20230822 LR - 20240306 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 8 IP - 8 DP - 2023 Aug 21 TI - Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis. PG - CD013797 LID - 10.1002/14651858.CD013797.pub2 [doi] LID - CD013797 AB - BACKGROUND: Inhaled corticosteroids (ICS) are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA) or doubling the dose of ICS. OBJECTIVES: To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD)-ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov, and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022. SELECTION CRITERIA: We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD)-ICS, ICS/LAMA, or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe). MAIN RESULTS: We included 38,276 participants from 35 studies (median duration 24 weeks (range 12 to 78); mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 litres and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio (HR) 0.70, 95% credible interval (CrI) 0.59 to 0.82; moderate certainty; HR 0.59, 95% CrI 0.46 to 0.76; moderate certainty; and HR 0.56, 95% CrI 0.38 to 0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70 to 1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio (OR) 1.47, 95% CrI 1.23 to 1.76; high certainty; and OR 1.59, 95% CrI 1.31 to 1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22 to 2.13; moderate certainty and OR 1.55, 95% CrI 1.20 to 2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11 to 1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or qualify of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.77 to 0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26 to 0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity. AUTHORS' CONCLUSIONS: The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA, or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than medium-dose ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was six months. CI - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Oba, Yuji AU - Oba Y AD - Division of Pulmonary and Critical Care Medicine, University of Missouri, Columbia, MO, USA. FAU - Anwer, Sumayya AU - Anwer S AD - Centre for Reviews and Dissemination, University of York, York, UK. FAU - Patel, Tarang AU - Patel T AD - Division of Pulmonary and Critical Care Medicine, University of Missouri, Columbia, MO, USA. FAU - Maduke, Tinashe AU - Maduke T AD - Division of Pulmonary and Critical Care Medicine, University of Missouri, Columbia, MO, USA. FAU - Dias, Sofia AU - Dias S AD - Centre for Reviews and Dissemination, University of York, York, UK. LA - eng SI - ClinicalTrials.gov/NCT00565266 PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20230821 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Muscarinic Antagonists) RN - 0 (Adrenal Cortex Hormones) SB - IM UOF - doi: 10.1002/14651858.CD013797 MH - Male MH - Humans MH - Adolescent MH - Adult MH - Female MH - *Muscarinic Antagonists/adverse effects MH - Network Meta-Analysis MH - *Asthma/drug therapy MH - Adrenal Cortex Hormones MH - Combined Modality Therapy PMC - PMC10441001 COIS- Y. Oba has provided consultation and received honoraria from Genentech unrelated to the current review. This author, who is a Cochrane Editor, was not involved in the editorial process. T Patel: none known. S Anwer: none known. T Maduke: none known. S Dias: none known. EDAT- 2023/08/21 12:42 MHDA- 2023/08/22 06:43 PMCR- 2024/08/21 CRDT- 2023/08/21 07:31 PHST- 2024/08/21 00:00 [pmc-release] PHST- 2023/08/22 06:43 [medline] PHST- 2023/08/21 12:42 [pubmed] PHST- 2023/08/21 07:31 [entrez] AID - CD013797.pub2 [pii] AID - 10.1002/14651858.CD013797.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2023 Aug 21;8(8):CD013797. doi: 10.1002/14651858.CD013797.pub2.