Inhaled corticosteroids/formoterol as a reliever in mild asthma

The primary goal of management is to achieve optimal asthma control,1 which consists of two domains. These are optimizing current (day-to-day) control, defined as the no daytime or night-time symptoms, no limitation of activity, minimal rescue bronchodilator use and no airway narrowing, and minimizing future risk defined by long-term decline in lung function, severe asthma exacerbations and unwanted effects from medications. These two domains are not independent. The more poorly controlled day-to-day asthma is, the greater the risk of a severe asthma exacerbation.2 A major paradox of asthma management is that despite the availability of very effective and safe medications to treat asthma, many (perhaps most) asthma patients remain poorly controlled.3 The most important reason for this is poor adherence to maintenance treatment.4 Short-acting β2-agonists (SABA) are rapid-onset bronchodilators, providing symptom relief, but have no anti-inflammatory properties. By contrast, inhaled corticosteroids (ICS) effectively reduce eosinophilic airway inflammation, improve asthma control and reduce asthma exacerbation risk, even in patients with mild asthma. These two classes of drugs remain the most commonly prescribed treatments for asthma. Until recently, how and when they should be used for the treatment of mild asthma (traditionally considered step 1 or 2 in asthma treatment guidelines) remained unclear. Fast and effective symptom relief is a priority for patients. In mild asthma, when symptoms are not present, patients can find adhering to daily preventative medication with ICS difficult. In contrast, because symptom treatment with SABA is so effective, it may appear logical for patients to use SABA intermittently as their only treatment. The use of an ICS (budesonide) with a rapid-onset long-acting β2-agonist (LABA) (formoterol) as both a maintenance and reliever therapy has been extensively studied in patients with moderate to severe asthma. This approach demonstrated a reduction in severe exacerbation risk compared with fixed-dose ICS alone, or in combination with a LABA, but with SABA as reliever.5 The rationale was that, when used as a reliever, the fast-acting bronchodilator formoterol improves symptoms, but at the same time the underlying inflammation is treated with ICS. This approach was initially studied in patients with milder asthma, using an ICS (beclomethasone) with a SABA (salbutamol) delivered from a single inhaler as a reliever.6 This study demonstrated that as-needed ICS/SABA improved peak flow rates and reduced exacerbations, compared with as-needed SABA alone, but was not different to maintenance ICS or maintenance ICS/SABA. Subsequent studies used a combination inhaler containing budesonide and formoterol (BUD/FORM), as needed in mild asthma. The first two reported (SYGMA trials) were double-blind randomized studies in more than 8000 patients, eligible if they needed maintenance low-dose ICS treatment. SYGMA 1 study compared BUD/FORM used as needed, to terbutaline as needed, and to budesonide twice daily (bd) plus terbutaline as needed7; SYGMA 2 compared BUD/FORM as needed to bd budesonide with terbutaline as needed.8 In SYGMA 1, BUD/FORM as needed was superior to terbutaline as needed, but inferior to maintenance budesonide, at increasing the number of well-controlled asthma weeks. BUD/FORM as needed also resulted in a 64% lower rate of severe exacerbations compared to terbutaline as needed, and was equivalent to maintenance budesonide, but with an 83% lower median daily ICS dose. However, the Asthma Control Questionnaire (ACQ)-5 score was higher and the forced expiratory volume in 1 s (FEV1) was lower in the BUD/FORM group compared to maintenance budesonide, albeit the differences were small and did not meet minimally clinical important differences. In SYGMA 2, treatment with BUD/FORM as needed was non-inferior to the maintenance budesonide group for reducing severe asthma exacerbations, but with a 75% lower median daily ICS dose in the BUD/FORM group, with ACQ-5 and FEV1 changes similar to SYGMA 1. The third and fourth studies were pragmatic, randomized, open label, parallel group studies. The first reported was Novel START, which compared albuterol as needed, budesonide plus albuterol as needed or BUD/FORM as needed.9 Patients were eligible if they used SABA as their only asthma therapy. The annualized asthma exacerbation rate was 51% lower in the BUD/FORM group compared to the albuterol alone group, with no significant difference compared to the maintenance budesonide group. Interestingly, in contrast to the SYGMA studies, the number of severe exacerbations was also 66% lower in the BUD/FORM group compared with both other treatment arms. However, maintenance budesonide demonstrated the greatest improvements in ACQ-5 scores. The Practical study had two treatment arms; BUD/FORM as needed or maintenance budesonide with terbutaline as needed.10 The study again demonstrated a 31% reduction in severe exacerbations, with an increase in the time to first exacerbation. Potential criticisms of these studies are that the treatment arms did not contain an asthma action plan for management of symptom deterioration prior to an exacerbation. The use of asthma action plans may reduce exacerbation risk, although the evidence for this is weak. Also, only one study (Novel START) included an inflammatory biomarker, exhaled nitric oxide (FENO), to help allay the concern that intermittent doses of ICS would allow progressive airway inflammation to develop, when compared to maintenance ICS. Both of the ICS-containing arms of the study significantly reduced FENO, despite the substantially lower average daily ICS dose with BUD/FORM as needed treatment, when compared to the SABA treatment arm. Finally, all of these studies have recruited adolescents and adult patients. There are no available data on children younger than 12 years. These studies have been very consistent in demonstrating that, for patients with mild asthma, the use of a reliever medication that contains a rapid-onset bronchodilator and an ICS in the same inhaler is superior to SABA for all asthma outcomes, and most importantly reduces the risk of severe asthma exacerbations. These results support the conclusion that SABA alone should not be used as a reliever, even in patients with mild asthma. When compared to maintenance ICS, as-needed BUD/FORM is less effective in providing day-to-day asthma control, albeit the differences are small, but is equally effective in reducing asthma exacerbation risk. Thus, for patients with mild asthma, who are not adherent to maintenance ICS, taking BUD/FORM as needed is effective, and is superior to treating these patients with SABA alone. These studies have resulted in a major change in the Global Initiative for Asthma (GINA) recommendations concerning the treatment of adolescents and adults with mild asthma.1 This is to recommend that ICS/formoterol is the preferred option as a reliever for all patients, and that it is considered a treatment option for patients for whom maintenance ICS is considered the best treatment, but who are not adherent. While these recommendations do not resolve the important challenge of poor adherence to maintenance ICS in mild asthma, they do allow for a reduction in the asthma outcome that is of most concern to patients and their healthcare providers, severe asthma exacerbations and all of their consequences, in patients who previously relied on as-needed SABA as their only asthma treatment. P.M.O. has received honoraria and speakers fees from Astra Zeneca, GSK, Chiesi and Meranari, and grants-in-aid from Medimmune, AstraZeneca, GSK, Novartis and Merck.

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