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A Holy Grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids.

ABSTRACT: There is unequivocal evidence that the combination of an inhaled corticosteroid (ICS) -- i.e. glucocorticoid -- and an inhaled long-acting beta(2)-adrenoceptor agonist (LABA) is superior to each component administered as a monotherapy alone in the clinical management of asthma. Moreover, Calverley and colleagues (Lancet 2003, 361: 449-456; N Engl J Med 2007, 356: 775-789) reporting for the 'TRial of Inhaled STeroids ANd long-acting beta(2)-agonists (TRISTAN)' and 'TOwards a Revolution in COPD Health (TORCH)' international study groups also demonstrated the superior efficacy of LABA/ICS combination therapies over ICS alone in the clinical management of chronic obstructive pulmonary disease. This finding has been independently confirmed indicating that the therapeutic benefit of LABA/ICS combination therapies is not restricted to asthma and may be extended to other chronic inflammatory diseases of the airways. Despite the unquestionable benefit of LABA/ICS combination therapies, there is a vast gap in our understanding of how these two drugs given together deliver superior clinical efficacy. In this article, we review the history of LABA/ICS combination therapies and critically evaluate how these two classes of drugs might interact at the biochemical level to suppress pro-inflammatory responses. Understanding the molecular basis of this fundamental clinical observation is a Holy Grail of current respiratory diseases research as it could permit the rational exploitation of this effect with the development of new 'optimized' LABA/ICS combination therapies.

SUBMITTER: Giembycz MA

PROVIDER: S-EPMC2275445 | biostudies-other | 2008 Mar

REPOSITORIES: biostudies-other

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Project description:BackgroundThe Risk of Bias (RoB) tool is used to assess internal validity of randomized controlled trials (RCTs). Our objectives were to: 1) evaluate inter-rater agreement of the RoB tool; 2) determine the time to access supplemental study information; 3) compare the RoB tool with the Jadad scale and Schulz allocation concealment (AC); and 4) examine the relationship between RoB and effect estimates.MethodsWe conducted a systematic review of long-acting beta agonists (LABA) combined with inhaled corticosteroids (ICS) for adults with persistent asthma. Two reviewers independently assessed 107 trials using RoB, Jadad, and AC. One reviewer searched for study protocols. We assessed inter-rater agreement using weighted Kappa (?) and the correlation between tools using Kendall's Tau (?). Mean differences in effect sizes for RCTs with different RoB were calculated using inverse variance method and random effects model.ResultsTrials had good Jadad scores (median 4, IQR 3-4); however, 85% had unclear AC and 87% high RoB. The factor that most influenced RoB was the potential inappropriate influence of study sponsors (95% industry funded). Agreement on RoB domains was fair (??=?0.40) to almost perfect (??=?0.86), and moderate for overall RoB (??=?0.41). Median time to complete RoB assessments was 21 minutes (IQR 14-27) and 12 minutes (IQR 9-16) to search for protocols. Protocols were identified for 5/42 studies (12%); in 3 cases the assessment of selective outcome reporting changed. There was low correlation between overall RoB vs. Jadad (??=?0.04, p?=?0.3) and AC (??=?-0.02, p?=?0.7). Analyses comparing effect estimates and risk showed no important patterns.ConclusionsInter-rater agreement on RoB assessments was better than previously reported suggesting that review-specific guidelines are important. The correlation between RoB and Jadad was low suggesting measurement of different constructs (risk of bias vs. quality of reporting). The extensive involvement of the pharmaceutical industry in this LABA/ICS research should raise concerns about potential overestimates of treatment effects.

Project description:There are several new treatment options for patients whose asthma remains uncontrolled on free-dose and fixed-dose combinations of inhaled corticosteroids plus long-acting ?2-agonists (ICS+LABA). In order to evaluate the likely impact of these treatments, we assessed the effect of uncontrolled asthma on healthcare and patient burden within the UK among adult patients treated with ICS+LABA. Data obtained from 2010-2011 UK National Health and Wellness Surveys identified 701 patients treated with ICS+LABA. Patients with not well-controlled asthma (Asthma Control Test™ score <20) were compared with well-controlled asthma (score???20) patients on multiple measures. Cost burden was calculated using healthcare resource utilisation models and work productivity and impairment questionnaire. Overall, 452 and 249 patients reported not well-controlled and well-controlled asthma, respectively. A greater proportion of not well-controlled patients visited the accident & emergency department (21 vs. 14%, P?=?0.016), were hospitalised (13 vs. 8%, P?=?0.022) and had lower mental and physical health-related quality of life (P?<?0.001) and impaired work productivity and activity scores: presenteeism (23 vs. 11%, P?<?0.001), work impairment (29 vs. 17%, P?<?0.001) and activity impairment (46 vs. 24%, P?<?0.001). Calculated direct and indirect yearly costs/person doubled among not well-controlled compared to well-controlled asthma patients (£6592 vs. £3220). Total cost to society was estimated at £6172 million/year (direct costs, £1307 million; indirect costs, £4865 million). In conclusion, not well-controlled asthma is common among UK adults treated with ICS+LABA, resulting in impairments across a number of important health outcomes and represents a significant unmet need and resource burden.AsthmaDRUG COMBO LEAVES MANY WITH UNCONTROLLED DISEASE: Many people who take inhaled steroids combined with long-acting ?2-agonist drugs still have poorly controlled asthma. A team led by Ian Pavord from the University of Oxford, UK, identified 701 people from the 2010-2011 UK National Health and Wellness Surveys who were taking this drug combination for their asthma. The researchers found that nearly two-thirds of these individuals had poorly controlled asthma associated with more visits to the emergency room, worse quality of life (both mentally and physically), impaired productivity and other health problems. The calculated direct and indirect costs per person with poorly controlled asthma were about double that for someone whose asthma was under control. The authors conclude that better treatment and management is needed to reduce costs and address the unmet medical need for people with persistent uncontrolled asthma.

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A Holy Grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids.

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