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Review
. 2014 May 13:348:g3009.
doi: 10.1136/bmj.g3009.

Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis

Rik J B Loymans  1 , Armin Gemperli  2 , Judith Cohen  3 , Sidney M Rubinstein  4 , Peter J Sterk  5 , Helen K Reddel  6 , Peter Jüni  7 , Gerben ter Riet  3
Affiliations
Review

Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis

Rik J B Loymans et al. BMJ. .

Abstract

Objective: To determine the comparative effectiveness and safety of current maintenance strategies in preventing exacerbations of asthma.

Design: Systematic review and network meta-analysis using Bayesian statistics.

Data sources: Cochrane systematic reviews on chronic asthma, complemented by an updated search when appropriate. ELIGIBILITY CRITERIA TRIALS OF Adults with asthma randomised to maintenance treatments of at least 24 weeks duration and that reported on asthma exacerbations in full text. Low dose inhaled corticosteroid treatment was the comparator strategy. The primary effectiveness outcome was the rate of severe exacerbations. The secondary outcome was the composite of moderate or severe exacerbations. The rate of withdrawal was analysed as a safety outcome.

Results: 64 trials with 59,622 patient years of follow-up comparing 15 strategies and placebo were included. For prevention of severe exacerbations, combined inhaled corticosteroids and long acting β agonists as maintenance and reliever treatment and combined inhaled corticosteroids and long acting β agonists in a fixed daily dose performed equally well and were ranked first for effectiveness. The rate ratios compared with low dose inhaled corticosteroids were 0.44 (95% credible interval 0.29 to 0.66) and 0.51 (0.35 to 0.77), respectively. Other combined strategies were not superior to inhaled corticosteroids and all single drug treatments were inferior to single low dose inhaled corticosteroids. Safety was best for conventional best (guideline based) practice and combined maintenance and reliever therapy.

Conclusions: Strategies with combined inhaled corticosteroids and long acting β agonists are most effective and safe in preventing severe exacerbations of asthma, although some heterogeneity was observed in this network meta-analysis of full text reports.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; HKR has participated on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Novartis, is participating on a joint data monitoring committee for AstraZeneca, GlaxoSmithKline, Merck, and Novartis, has provided consultancy services for AstraZeneca, GlaxoSmithKline, and Mundipharma, has provided continuing medical education presentations at symposiums funded by AstraZeneca, Boehringer Ingelheim, Getz, GlaxoSmithKline, and Merck, and has received unconditional research funding from AstraZeneca and GlaxoSmithKline. PJ is an unpaid member of steering groups or executive committees of trials funded by Abbott Vascular, Biosensors, Medtronic, and St Jude Medical. CTU Bern, which is part of the University of Bern, has a staff policy of not accepting individual honorariums or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by Abbott Vascular, Ablynx, Amgen, AstraZeneca, Biosensors, Biotronic, Boehrhinger Ingelheim, Eisai, Eli Lilly, Exelixis, Geron, Gilead Sciences, Nestlé, Novartis, Novo Nordisc, Padma, Roche, Schering-Plough, St Jude Medical, and Swiss Cardio Technologies; there are no non-financial interests that may be relevant to the submitted work.

Figures

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Fig 1 Flow chart of study selection
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Fig 2 Overview of treatment strategies, with lines representing direct (head to head) comparisons; surface areas of circles proportional to number of patients identified in strategy. Numbers in lines are number of direct comparisons. COMBI=combined inhaled corticosteroid (ICS) and long acting β agonist (LABA) in single inhaler; COMBI MAR=COMBI as maintenance and reliever treatment; COMBI FIX=COMBI in fixed daily dose; COMBI AMD=COMBI in adjustable maintenance dose; H=high dose; LABA=long acting β agonists, regular use; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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Fig 3 Forest plot showing asthma exacerbation rate ratios and median ranks with corresponding 95% credible intervals for each strategy compared with low dose inhaled corticosteroids (ICS). COMBI=combined ICS and long acting β agonist (LABA) in single inhaler; COMBI MAR=COMBI as maintenance and reliever treatment; COMBI FIX=COMBI in fixed daily dose; COMBI AMD=COMBI in adjustable maintenance dose; H=high dose; LABA=long acting β agonists, regular use; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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Fig 4 Rankograms showing probability (percentage) of each strategy having each specific rank (1-16) for effectiveness in the prevention of severe and composite of moderate or severe asthma exacerbations. Strategies ordered by rank from top left to bottom right. In severe exacerbations, combined inhaled corticosteroids (ICS) and long acting β agonists (LABA) in single inhaler as maintenance and reliever treatment (COMBI MAR), and in fixed daily dose (COMBI FIX) have highest probabilities to be ranked first and placebo the highest probability to be ranked last. COMBI AMD=combined ICS and LABA in adjustable maintenance dose; H=high dose; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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Fig 5 Difference in estimated treatment effects for severe asthma exacerbations between direct comparison (based on classic meta-analysis) and indirect estimate from multi-treatment comparison (without respective direct comparison). Difference on log-relative risk scale for rates; variance constructed by adding up variances of both estimates. Best practice is an open label comparator in which practitioners are encouraged to treat patients according to current treatment guidelines. COMBI=combined ICS and long acting β agonist (LABA) in single inhaler; COMBI MAR=COMBI as maintenance and reliever treatment; COMBI FIX=COMBI in fixed daily dose; COMBI AMD=COMBI in adjustable maintenance dose; H=high dose; LABA=long acting β agonists, regular use; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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Fig 6 Difference in estimated treatment effect for composite of moderate or severe asthma exacerbations between direct comparison (based on classic meta-analysis) and indirect estimate from multi-treatment comparison (without respective direct comparison). Difference on log-relative risk scale for rates; variance constructed by adding up variances of both estimates. Best practice is an open label comparator in which practitioners are encouraged to treat patients according to current treatment guidelines. COMBI=combined ICS and long acting β agonist (LABA) in single inhaler; COMBI MAR=COMBI as maintenance and reliever treatment; COMBI FIX=COMBI in fixed daily dose; COMBI AMD=COMBI in adjustable maintenance dose; H=high dose; LABA=long acting β agonists, regular use; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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Fig 7 Forest plot showing withdrawals as a result of adverse events and total number of withdrawals compared with low dose inhaled corticosteroids (ICS). Best practice is an open label comparator in which practitioners are encouraged to treat patients according to current treatment guidelines. COMBI=combined ICS and long acting β agonist (LABA) in single inhaler; COMBI MAR=COMBI as maintenance and reliever treatment; COMBI FIX=COMBI in fixed daily dose; COMBI AMD=COMBI in adjustable maintenance dose; H=high dose; LABA=long acting β agonists, regular use; LTRA=leukotriene receptor antagonist; SABA=short acting β agonists, regular use
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