Health Technology Assessment (May 2011)
A pragmatic single-blind randomised controlled trial and economic evaluation of the use of leukotriene receptor antagonists in primary care at steps 2 and 3 of the national asthma guidelines (ELEVATE study)
Abstract
Objectives: To evaluate, under real-life practice conditions in UK primary care, asthma control and cost-effectiveness of commencing therapy with leukotriene antagonists compared with inhaled corticosteroids (ICSs) as initial controller therapy and compared with long-acting β2-agonist as add-on therapy for patients with uncontrolled asthma already receiving ICS. Comparisons were made in terms of short-term efficacy (2 months) and longer-term effectiveness (2 years). Design: The study comprised two randomised controlled trials, powered for equivalence. Incremental cost-effectiveness approaches were used to study health-economic outcomes utilising NHS and societal costs. Setting: Study visits coincided with routine patient follow-up in the patients’ own primary care practices by their normal health-care providers to obtain a ‘real-life’ setting. Participants: Enrolled patients were aged 12–80 years, with asthma uncontrolled by (1) short-acting β2-agonist or (2) ICS. Active smokers and patients with small impairment of lung function/other morbidities were included in the trial. Interventions: Leukotriene antagonists were compared with ICS, as initial controller therapy, and with long-acting β2-agonist, as add-on therapy to ICS. Main outcome measures: The primary study outcome was the Mini Asthma Quality of Life Questionnaire (MiniAQLQ). An analysis of covariance was used, with treatment as a fixed effect, and baseline value as covariate, to analyse MiniAQLQ scores at 2 months (the primary time point), examining efficacy, and 2 years, as a measure of effectiveness, using an intention-to-treat approach. Results: In total, 687 patients were randomised and 650 participants (95%) had evaluable data for the primary study outcome. Comparing leukotriene antagonists with ICSs as initial controller therapy: at 2 months, the MiniAQLQ scores met the equivalence criterion, with adjusted difference (95% CI) between leukotriene antagonist and ICS of –0.02 (–0.24 to 0.20). At 2 years, however, the 95% CIs excluded the threshold for equivalence of 0.3, favouring ICS [–0.11 (–0.35 to 0.13)]. No significant between-group differences were found in Asthma Control Questionnaire (ACQ) score at either 2 months [adjusted difference 0.01 (–0.20 to 0.22)] or 2 years [0.13 (–0.07 to 0.33)]. Comparing leukotriene antagonist with long-acting β2-agonist as add-on therapy to ICS: at 2 months, the MiniAQLQ scores met the equivalence criterion [adjusted difference –0.10 (–0.29 to 0.10)], while at 2 years, the 95% CIs for MiniAQLQ score were marginally over the equivalence threshold, favouring long-acting β2-agonist as add-on therapy [adjusted difference –0.11 (–0.32 to 0.11)]. There were no significant between-group differences in ACQ score [adjusted difference at 2 months 0.12 (–0.06 to 0.30), and at 2 years 0.04 (–0.15 to 0.22)]. Daily ICS dose did not differ between the two treatment groups. Analysis of cost-effectiveness revealed that participants receiving leukotriene antagonist had significantly higher NHS and societal costs at both 2 months and 2 years but the outcomes were not statistically significantly different. For patients receiving add-on therapy to ICS, no significant differences between leukotriene antagonist and long-acting β2-agonist in NHS or societal cost were found at 2 months, but, after 2 years, participants receiving leukotriene antagonist had higher societal costs of borderline statistical significance. Conclusions: The evidence suggests that leukotriene antagonists are unlikely to be a cost-effective alternative to ICSs, at 2005 prices, as initial asthma controller therapy at step 2. Leukotriene antagonists were clinically equivalent to ICS as initial controller therapy and to long-acting β2-agonists as add-on to ICS in terms of QOL at 2 months; equivalence was not proven at 2 years. Future research should establish, in primary care, whether leukotriene antagonists will be more or less beneficial than ICSs alone or as an add-on to ICSs in treating patients with asthma who are also active smokers; determine why the ACQ correlates more poorly with economic outcomes of asthma than the Mini AQLQ and the European Quality of life-5 Dimensions questionnaire; and understand further the reasons why patients were switched from study medication when there was no real clinical indication to do so. Trial registration: Current Controlled Trials ISRCTN99132811. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 21. See the HTA programme website for further project information.
Keywords
