Formoterol as reliever medication in asthma: a post-hoc analysis of the subgroup of the RELIEF study in East Asia

Current guidelines from the Global INitiative for Asthma (GINA) recommend an inhaled short-acting β₂-agonist (SABA), such as salbutamol, terbutaline, fenoterol, levalbuterol, reproterol or pirbuterol, for the relief of symptomatic bronchoconstriction [1]. Formoterol is a long-acting β₂-agonist (LABA) with a rapid onset of action and is recommended by GINA as an effective reliever medication in patients on regular controller therapy with inhaled corticosteroids (ICS) [1]. As-needed formoterol has previously been assessed [2, 3] and has been shown to effectively relieve asthma symptoms; a systematic review showed that formoterol used as reliever therapy reduced the number of exacerbations requiring oral corticosteroid treatment [4].

To determine the comparative efficacy and safety of formoterol and salbutamol as reliever therapy in patients with asthma, the global RELIEF study (REal LIfe EFfectiveness of Oxis® Turbuhaler® as-needed in asthmatic patients) was conducted [5]. In this 6-month, international, randomised, parallel-group study more than 18,000 adults and children with asthma from 24 countries used either formoterol or salbutamol as reliever therapy. The study was designed to mimic real-world clinical practice and therefore was open-label (i.e. no blinding), had minimal entry criteria and no run-in period; patient adherence to treatment was not monitored, as treatment was provided as-needed. The study included a large group of patients of varying age and asthma severity and who were receiving various maintenance medications. Overall, the safety profile of formoterol was similar to that of salbutamol (i.e. no significant differences in adverse events [AEs], serious AEs [SAEs] and discontinuations due to AEs [DAEs]), but patients treated with formoterol experienced a longer time to first exacerbation and required less as-needed and maintenance medication.

The availability of budesonide/formoterol as a maintenance and reliever therapy (Symbicort® SMART™) in countries in the Asia-Pacific region, including China, Japan, the Philippines and Thailand, means that formoterol in combination with ICS is now being used by these patients as a reliever therapy. Therefore, it is important to understand the safety of formoterol in such patients. Since limited real-world data exist regarding the comparative safety and efficacy of formoterol and salbutamol reliever medication in patients in East-Asia, a post-hoc analysis was performed to examine safety and efficacy outcomes among patients in the RELIEF study recruited from East-Asian countries.

The real-world global RELIEF study compared formoterol and salbutamol as reliever medication in a diverse group of patients with varying degrees of asthma severity and using a variety of maintenance treatments [5]. The RELIEF study found that formoterol was at least as safe as salbutamol when used as reliever medication, and that finding was reproduced during this post-hoc analysis of the East Asian patient subgroup. While the overall findings for both analyses are similar, key differences were noted between the full patient population and this subgroup. In the full study, significantly fewer asthma-related AEs and non-asthma-related AEs such as headaches, tremor and allergic rhinitis were reported for formoterol compared with salbutamol; however, there were also a significantly greater number of total DAEs (caused by non-serious AEs), asthma-related DAEs and non-asthma-related DAEs (including tremor, headache and tachycardia) reported for formoterol compared with salbutamol. By contrast, the East Asian subgroup analysis found no significant differences in risk of any AE (including SAEs and DAEs) between formoterol and salbutamol reliever treatments. There was a significant reduction in the risk of any exacerbation (14 %) and severe exacerbations (18 %) with use of formoterol compared with salbutamol. Formoterol treatment significantly increased the time to first exacerbation and reduced the need for additional reliever medication compared with salbutamol (−20 %).

The primary results of the global RELIEF study showed that the proportion of patients with an AE was similar between treatment groups (42 % of patients in both formoterol and salbutamol groups experienced at least one AE) as was the proportion of patients experiencing SAEs (3.1 % and 3.3 %, respectively). The most commonly reported AEs included aggravated asthma (12–13 % of each patient group) and nasopharyngitis (5 %). The time to first exacerbation was longer with formoterol (HR 0.86) and 16 % less as-needed medication was used in the formoterol group in the final treatment period [5]. In this subgroup of patients in East Asia, the results for SAEs (3.8 % and 4.7 %, respectively), time to first exacerbation (HR 0.86) and as-needed medication use (reliever use for formoterol was 18 % lower than salbutamol in the final treatment period) all favoured formoterol to a similar, if not the same, extent as in the main study population. Interestingly, only 21 % of patients recruited from East-Asian countries reported an AE compared with 42 % of the global RELIEF study population. It is possible that this result reflects cultural differences in study populations with regard to reporting events.

It should also be noted that the East Asian patient subgroup had high baseline levels of xanthine/oral β₂-agonist use (almost half of all patients); this information, in conjunction with the low AE rate reported in this subanalysis, suggests the relative safety of the addition of formoterol to concomitant xanthine/oral β₂-agonist and maintenance therapy. This cannot be confirmed, however, as the analysis was not designed to investigate this point, and the potential influence of cultural differences (as stated above) should also be considered.

The results of the global RELIEF study and this subgroup analysis of patients in East Asia are consistent with those described in the literature, in which more favourable efficacy outcomes with formoterol and similar safety profiles have been reported (compared with salbutamol) and no significant differences observed in subgroups from Asia [4, 6, 7]. A Cochrane review of formoterol treatment in chronic asthma found that compared with regular salbutamol or terbutaline, there was no significant increase in fatal or non-fatal SAEs with formoterol [6]. Another Cochrane review compared formoterol and SABAs when used as reliever medication in adults and children with asthma [4]. This review grouped all SABAs and found a significant effect in favour of formoterol versus any SABA for an exacerbation that was treated with oral corticosteroids. While there were fewer SAEs in patients who received formoterol, this did not reach statistical significance versus SABAs [4].

Recent data have shown that corticosteroid insensitivity may be reversed by formoterol treatment. The actions of formoterol and salbutamol were compared in an in vitro study using peripheral blood mononuclear cells from patients with severe asthma or COPD [8]. Formoterol was found to reverse corticosteroid insensitivity in both cell types, while salbutamol was found to be effective only in cells from patients with severe asthma. Although these data are preliminary, this may be of interest when considering the suitability of formoterol treatment for patients with severe asthma or asthma-COPD overlap syndrome.

The uniformity of results between the global RELIEF population and the East Asia subgroup is consistent with a sub-analysis of the COSMOS study, where the efficacy and safety of budesonide/formoterol maintenance and reliever therapy was compared with salmeterol/fluticasone propionate plus as-needed salbutamol [7]. Outcomes observed in patients enrolled across East-Asian countries (specifically China, Korea, Taiwan and Thailand) were consistent with those in the overall study population [5].

Strengths of the RELIEF study included minimal entry criteria (with respect to age, comorbidities and concomitant medications) as well as the absence of a run-in period and lung function or compliance monitoring. These features were deliberately chosen to maximise patient recruitment and ensure that the patient population and procedures reflected everyday clinical practice. This study also comprised a large patient population and was of a sufficient duration to detect treatment effects. The open-label nature of the study means that the data can be generalised to the real-world population of patients being treated in everyday clinical practice.

Limitations of the study design include the fact that the primary inclusion criterion for this subgroup analysis was based on residence and patients were not recruited based on ethnic origin. However, a very small proportion of patients in this analysis were not of Oriental descent, and it is unlikely that the results were skewed by the inclusion of 48 patients who were of Caucasian or other descent. As with any post-hoc analysis, the analysis is limited to the data that were originally collected. Such data could contain factors that are not apparent and could influence the results (e.g. patient characteristics or genetic factors that were not assessed).

The study investigators were permitted to adjust maintenance treatment as required according to clinical need, and any increase in asthma medication was defined as an exacerbation. Given the open-label nature of the study design there was consequently the potential for bias, as investigators had the option to increase asthma medication and consequently increase the apparent exacerbation rate.

The lack of information on patient adherence to treatment is another limitation of this study. Since treatment was provided as required, it would be difficult to distinguish between non-adherent patients (e.g. patients experiencing symptoms, but not using their medication or with few symptoms but over-using their medication) and adherent patients (e.g. those with fewer symptoms who have a reduced need for as-needed treatment or vice versa). Therefore, adherence monitoring was not attempted. However, as stated previously, the advantages of an open-label study (wide applicability to real-world practice) were thought to outweigh these potential limitations.

It is now widely acknowledged that when used alone, LABAs are associated with risks of increased exacerbations and increased mortality in patients with asthma compared with ICS/LABA [9, 10]. However, the addition of a LABA to an ICS is beneficial and the risk of death, intubation or hospital admissions for exacerbations is not increased with combination LABA and ICS therapy versus ICS alone [11]. All guidelines stress that LABAs should not be used without concomitant ICS treatment [9–11]. In the time since the main RELIEF study was conducted, the treatment landscape has changed and LABA-only regimens are not recommended in patients with asthma. Hence further studies using only formoterol or salbutamol will not be conducted. However, similar post-hoc analyses may help to elucidate whether or not differences exist between other regional or ethnic subgroups and broad, mixed populations.

This post-hoc analysis of the global RELIEF study demonstrates that among patients with asthma in East Asia, as-needed formoterol and salbutamol had similar safety profiles but formoterol reduced the risk of exacerbations, increased the time to first exacerbation and reduced the need for reliever medication compared with salbutamol.