For ease of use, pharmacotherapy in asthma guidelines is arranged in treatment steps. Increasing treatment in patients who require additional treatment medication involves selecting an option from among the treatments on the same or a higher step. Treatments are stratified on the basis of randomised trials comparing their efficacy in patients qualifying for that treatment step with due regard to their therapeutic index, that is, weighing up benefit and safety. The results of this post hoc analysis of five large clinical studies provides clinically useful information on the relative efficacy and benefits of BUD/FORM maintenance and reliever therapy compared with high-dose ICS or fixed-dose ICS/LABA combinations plus SABA when introduced in patients previously prescribed treatments at Steps 2, 3 or 4 in the GINA report.
Satisfactory control, defined as Controlled or Partly Controlled asthma in the GINA report, was achieved in at least as many, or, for some comparisons and treatment steps, in a higher proportion of patients treated with BUD/FORM maintenance and reliever therapy compared with other fixed-dose maintenance regimens + SABA. For most comparisons, this was achieved with a lower mean dose of ICS and was associated with a lower risk of exacerbations (future risk). From the primary analyses of each of these trials, it is clear that lower exacerbation rates also resulted in significantly lower requirements for short courses of oral corticosteroids [3
The superiority of BUD/FORM maintenance and reliever therapy over higher maintenance dose ICS alone with SABA as reliever in achieving satisfactory control (defined as Controlled or Partly Controlled by GINA) for patients previously prescribed Step 2 treatment is an important observation. This analysis suggests that using BUD/FORM both as maintenance and reliever for patients not controlled at this treatment step offers significant benefit. Secondly, BUD/FORM maintenance and reliever therapy at Steps 3 and 4 is also superior to fixed-dose ICS/LABA given at the same maintenance dose of ICS in achieving reductions in exacerbations, although it is only in patients at Step 4 that a statistically significant advantage is seen in current clinical control. Finally, BUD/FORM maintenance and reliever therapy achieves only similar levels of current clinical control to a higher maintenance dose of ICS/LABA but retains its advantage in reducing exacerbations (only statistically significant in patients on Step 4), making it an attractive option in patients on this step for reducing exposures to inhaled and systemic corticosteroids.
These results are supported by the changes in FEV1 and as-needed use of reliever medication. Improvements in FEV1 were significantly greater with BUD/FORM maintenance and reliever therapy for all comparisons other than at Step 2 when compared with same maintenance dose ICS/LABA + SABA and with a higher maintenance dose of ICS/LABA + SABA. The reduction in reliever use was significant in the comparison with a higher maintenance dose ICS + SABA in Steps 2-4 and Steps 3 and 4 when compared with same maintenance dose ICS/LABA + SABA.
A further finding of the analysis is the relationship between treatment step and other indicators of asthma severity. A recent American Thoracic Society/European Respiratory Society Task Force Report on asthma severity and control states that the level of treatment required to achieve and/or maintain control is the most consistent indicator of severity [11
]. In our analysis, patients on higher treatment steps at entry were older (less than 10 years' mean difference between Steps 2 and 4), possibly indicating increasing treatment requirements associated with lifelong asthma, and there was a trend towards lower FEV1
and higher symptom scores during run-in. Consistent with this, the proportion of patients with GINA-defined Controlled asthma and Controlled or Partly Controlled asthma at study end decreased with increasing GINA treatment step at entry, irrespective of study treatment. These results are also consistent with those of the Gaining Optimal Asthma Control (GOAL) study in which the proportion of patients achieving target levels of control decreased with increasing severity of asthma categorised according to prior treatment. This was in spite of escalation of ICS or fixed-dose ICS/LABA to maximum recommended levels for a prolonged period [12
The limitations of this study include that it is a post hoc
analysis; patients were not randomised according to GINA treatment step in each study. The assessment of GINA-defined asthma control was also post hoc
and based upon data derived from patient diary cards; however, the method that was employed and its usefulness have been discussed in a previous report [9
]. A further limitation is that, although in all the studies asthma symptoms and reliever use during run-in confirmed that patients were uncontrolled at entry, in three of the five studies some medications had been withdrawn during this phase, resulting in worse control than at recruitment. While this will have served to emphasise the benefits of subsequent treatments, it would not have favoured any of the treatments. In only one study was the control state known prior to run-in, and in this study the five-item Asthma Control Questionnaire score was higher than 2.1, confirming that the majority of those recruited were uncontrolled [7
]. Furthermore, the numbers of patients on Step 2 treatment and the relatively low exacerbation rates in this subgroup weakens the confidence of the estimate. Finally, because of the relatively short duration of the studies (6-12 months), we have not attempted to study other aspects of future risk such as lung function decline or the adverse effects of treatment. However, a recent combined analysis of these five and one additional study comparing BUD/FORM maintenance and reliever therapy with fixed-dose alternatives confirmed that the former was associated with fewer asthma-related serious adverse events and discontinuations during the studies and with no increased risk of deaths or cardiac-related serious adverse events [13