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.