PMID- 36472162
OWN - NLM
STAT- MEDLINE
DCOM- 20221207
LR  - 20231207
IS  - 1469-493X (Electronic)
IS  - 1361-6137 (Linking)
VI  - 12
IP  - 12
DP  - 2022 Dec 6
TI  - Effectiveness and tolerability of dual and triple combination inhaler therapies 
      compared with each other and varying doses of inhaled corticosteroids in 
      adolescents and adults with asthma: a systematic review and network 
      meta-analysis.
PG  - CD013799
LID - 10.1002/14651858.CD013799.pub2 [doi]
LID - CD013799
AB  - BACKGROUND: Current guidelines recommend a higher-dose inhaled corticosteroids 
      (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not 
      controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination 
      therapy. OBJECTIVES: To assess the effectiveness and safety of dual (ICS/LABA) 
      and triple therapies (ICS/LABA/LAMA) compared with each other and with varying 
      doses of ICS in adolescents and adults with uncontrolled asthma. SEARCH METHODS: 
      We searched multiple databases for pre-registered randomised controlled trials 
      (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022. 
      SELECTION CRITERIA: We searched studies, including adolescents and adults with 
      uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, 
      comparing dual and triple therapies. We excluded cluster- and cross-over RCTs. 
      DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network 
      meta-analysis according to the previously published protocol. We used Cochrane's 
      Screen4ME workflow to assess search results and Grading of Recommendations 
      Assessment, Development and Evaluation (GRADE) to assess the certainty of 
      evidence. The primary outcome was steroid-requiring asthma exacerbations and 
      asthma-related hospitalisations (moderate to severe and severe exacerbations). 
      MAIN RESULTS: We included 17,161 patients with uncontrolled asthma from 17 
      studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean 
      forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The 
      quality of included studies was generally good except for some outcomes in a few 
      studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple 
      therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 
      [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) 
      (high-certainty evidence), but not asthma-related hospitalisations, compared to 
      MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma 
      exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], 
      [moderate certainty]). Subgroup analyses suggest the reduction in 
      steroid-requiring exacerbations associated with triple therapies may be only for 
      those with a history of asthma exacerbations in the previous year but not for 
      those without. High-dose triple therapy, but not MD triple, results in a 
      reduction in all-cause adverse events (AEs) and likely reduces dropouts due to 
      AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high 
      certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). 
      Triple therapy results in little to no difference in all-cause or asthma-related 
      serious adverse events (SAEs) compared to dual therapy (high certainty). The 
      evidence suggests triple therapy results in little or no clinically important 
      difference in symptoms or quality of life compared to dual therapy considering 
      the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely 
      to result in any significant benefit or harm compared to MD-ICS/LABA. AUTHORS' 
      CONCLUSIONS: Medium-dose and HD triple therapies reduce steroid-requiring asthma 
      exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA 
      especially in those with a history of asthma exacerbations in the previous year. 
      High-dose triple therapy is likely superior to MD triple therapy in reducing 
      steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in 
      clinically meaningful improvement in symptoms or quality of life compared to dual 
      therapy considering the MCIDs. High-dose triple therapy, but not MD triple, 
      results in a reduction in all-cause AEs and likely reduces dropouts due to AEs 
      compared to MD-ICS/LABA. Triple therapy results in little to no difference in 
      all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is 
      unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, 
      although long-term safety of higher rather than MD- ICS remains to be 
      demonstrated given the median duration of included studies was six months. The 
      above findings may assist deciding on a treatment option when asthma is not 
      controlled with MD-ICS/LABA.
CI  - Copyright (c) 2022 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 - Maduke, Tinashe
AU  - Maduke T
AD  - Division of Pulmonary and Critical Care Medicine, University of Missouri, 
      Columbia, MO, USA.
FAU - Patel, Tarang
AU  - Patel 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/NCT00424008
SI  - ClinicalTrials.gov/NCT01686633
SI  - ClinicalTrials.gov/NCT01099722
SI  - ClinicalTrials.gov/NCT00646594
SI  - ClinicalTrials.gov/NCT03158311
SI  - ClinicalTrials.gov/NCT00772538
SI  - ClinicalTrials.gov/NCT00776984
SI  - ClinicalTrials.gov/NCT02571777
SI  - ClinicalTrials.gov/NCT02924688
SI  - ClinicalTrials.gov/NCT02175771
SI  - ClinicalTrials.gov/NCT00394368
SI  - ClinicalTrials.gov/NCT00651768
SI  - ClinicalTrials.gov/NCT01475721
SI  - ClinicalTrials.gov/NCT02554786
SI  - ClinicalTrials.gov/NCT02676076
SI  - ClinicalTrials.gov/NCT02676089
SI  - ClinicalTrials.gov/NCT00381485
SI  - ClinicalTrials.gov/NCT01147848
SI  - ClinicalTrials.gov/NCT01202084
SI  - ClinicalTrials.gov/NCT00901368
SI  - ClinicalTrials.gov/NCT00350207
SI  - ClinicalTrials.gov/NCT02301975
SI  - ClinicalTrials.gov/NCT01018186
SI  - ClinicalTrials.gov/NCT01257230
SI  - ClinicalTrials.gov/NCT01277523
SI  - ClinicalTrials.gov/NCT03358147
SI  - ClinicalTrials.gov/NCT00379288
SI  - ClinicalTrials.gov/NCT01570478
SI  - ClinicalTrials.gov/NCT02892344
SI  - ClinicalTrials.gov/NCT03376932
SI  - ClinicalTrials.gov/NCT01244984
SI  - ClinicalTrials.gov/NCT01340209
SI  - ClinicalTrials.gov/NCT01316380
SI  - ClinicalTrials.gov/NCT00565266
SI  - ClinicalTrials.gov/NCT02139644
SI  - ClinicalTrials.gov/NCT03063086
SI  - ClinicalTrials.gov/NCT01290874
SI  - ClinicalTrials.gov/NCT01471340
SI  - ClinicalTrials.gov/NCT03387241
SI  - ClinicalTrials.gov/NCT04191434
SI  - ClinicalTrials.gov/NCT04191447
SI  - ClinicalTrials.gov/NCT04609878
SI  - ClinicalTrials.gov/NCT04609904
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PT  - Systematic Review
DEP - 20221206
PL  - England
TA  - Cochrane Database Syst Rev
JT  - The Cochrane database of systematic reviews
JID - 100909747
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Adrenal Cortex Hormones)
RN  - 0 (Muscarinic Antagonists)
SB  - IM
UOF - doi: 10.1002/14651858.CD013799
MH  - Adult
MH  - Male
MH  - Adolescent
MH  - Humans
MH  - Middle Aged
MH  - *Adrenergic beta-2 Receptor Agonists/therapeutic use
MH  - Network Meta-Analysis
MH  - Drug Therapy, Combination
MH  - Adrenal Cortex Hormones/therapeutic use
MH  - *Asthma/drug therapy
MH  - Muscarinic Antagonists
MH  - Nebulizers and Vaporizers
MH  - Administration, Inhalation
PMC - PMC9723963
COIS- Y. Oba: has provided consultation and received honoraria from Genentech unrelated 
      to the current review. T Patel: none known. S Anwer: none known. T Maduke: none 
      known. S Dias: none known.
EDAT- 2022/12/07 06:00
MHDA- 2022/12/10 06:00
PMCR- 2023/12/06
CRDT- 2022/12/06 04:42
PHST- 2022/12/06 04:42 [entrez]
PHST- 2022/12/07 06:00 [pubmed]
PHST- 2022/12/10 06:00 [medline]
PHST- 2023/12/06 00:00 [pmc-release]
AID - CD013799.pub2 [pii]
AID - 10.1002/14651858.CD013799.pub2 [doi]
PST - epublish
SO  - Cochrane Database Syst Rev. 2022 Dec 6;12(12):CD013799. doi: 
      10.1002/14651858.CD013799.pub2.