Current Control and Future Risk of Asthma Exacerbations: Maintenance and Reliever Strategies Revisited

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PHYSICIAN PERSPECTIVE - Viewpoint based on the following article: J Allergy Clin Immunol 2010;125(3):600-8.

May 2012

Guest Editor: 

Malcolm Sears, MB, ChB, FRACP, FRCPC, FAAAAI
Professor of Medicine
Division of Respirology
St. Joseph’s Healthcare
Endowed Chair in Respiratory Epidemiology McMaster University
Hamilton, Ontario


In contrast to diabetes and hypertension, where achieving targets for glycemic control or blood pressure is widely acknowledged as an important strategy to reduce the risk of future complications,  the same concept has only recently received attention in asthma management. The Gaining Optimal Asthma ControL (GOAL) study showed for the first time that guideline-defined levels of asthma control lead to long-term benefits including, most notably, a reduction in acute exacerbations. However, many patients involved in the GOAL study had relatively mild asthma, with levels of mean forced expiratory volume in 1 second (FEV1)  of 75% or greater on study entry; about one-third of them were also naive to inhaled corticosteroids (ICS). In order to explore whether or not current asthma control affects future risk in patients with more severe disease, investigators pooled results from 5 separate studies in which a combination inhaler containing an ICS and a rapid-acting long-acting bronchodilator (LABA) was used for both maintenance and reliever therapy. Outcomes were compared to those achieved by other maintenance/reliever regimens in patients with moderate to severe asthma. This analysis showed that while combination therapy used for both maintenance and relief achieved similar levels of asthma control, it reduced the risk of future instability and exacerbations more effectively than comparator regimens. Evidence supports the concept that patients with more frequent exacerbations have significantly greater annual declines in lung function than those who do not. Consequently, a reduction in the frequency of exacerbations may help reduce progressive declines in lung function, an important consideration in patients with more severe disease.

GOAL Study

GOAL (Gaining Optimal Asthma ControL) investigators under lead author Eric Bateman, University of Cape Town, South Africa,1 sought to determine whether guideline-defined asthma control could be achieved. Some 3421 patients with uncontrolled asthma were randomized to 1 of 2 controller therapies: fluticasone or the combination of salmeterol/fluticasone. In phase I,
treatment was stepped up until either total control had been achieved or patients had reached a maximum dose of 500 µg b.i.d. of corticosteroids. In phase II, patients continued on a stable dose until the end of the year-long study. Whether patients had previously been corticosteroid-free or had been taking low or moderate doses of corticosteroids on study enrolment, total asthma control was achieved across a proportion of all strata. Significantly more patients in each stratum achieved either total or well-controlled asthma with the combination product than with inhaled corticosteroids (ICS) monotherapy. The majority of patients who achieved control in the first dose-escalation phase of the study were also controlled at the end of phase II when dosing was constant.

GOAL was the first study to demonstrate that guideline-defined control can be both achieved and maintained in the majority of patients with uncontrolled asthma across a range of severities and that those who achieve control have very low exacerbation rates. Even patients who did not attain total control as stringently defined by study investigators, had a reduction in exacerbation rates and improvement in health status over the year-long study.

In revisiting the GOAL data a few years later2,  Bateman and colleagues examined the association between the level of asthma control achieved during the step-up phase of the study (phase I) and the stability of that control during the maintenance phase (phase II). Again, across all 3 strata of corticosteroid use (or non-use), patients whose asthma was totally controlled in phase I remained totally controlled for most of the time in phase II; once total control had been achieved in phase I, patients maintained that level of control for at least 3 months. The data also indicated that the achievement of a higher level of control at the end of phase I was predictive of an increased likelihood of being controlled during phase II.

Indeed, patients who were totally controlled at the end of phase I were 30 times more likely to be totally controlled during phase II than patients who were not well controlled at the end of phase I (OR 30.5, P<0.001). Totally controlled patients were almost 7 times more likely to be totally controlled during phase II than patients who were only well controlled at the end of phase I (OR 6.63, P<0.001).

Findings from this post-hoc analysis again demonstrate that once asthma control is achieved for 8 weeks, future risk of instability—measured by the weeks during which patients are uncontrolled—is greatly reduced. Conversely, GOAL patients who were not well controlled and who were experiencing variable asthma control were most likely to require unscheduled health care visits. Stability of control is therefore central to a reduction in future exacerbation risk and stability is best achieved with unwavering compliance to prescribed medications.

Poor Asthma Control

Poor asthma control is associated with an increased risk of future exacerbations and potential for hospitalization or emergency room visits. Moreover, unstable control has been shown to significantly impair quality of life and has both psychosocial and economic consequences as well. Patients with poor asthma control also experience an accelerated loss of lung function through a process often referred to as remodelling. In a study by Bai et al.,3 investigators assessed the effect of severe exacerbations—defined in the study by hospitalizations for worsening asthma or as a significant and reversible reduction in forced expiratory volume 1 second (FEV1)—on progression of airway obstruction in 93 non-smoking individuals with moderate-to-severe disease. Median follow-up was 11 years. Patients with frequent exacerbations had a significantly greater annual decline in FEV1 and more severe airway obstruction after 11 years of follow-up than patients with fewer exacerbations. Individuals with more or less than the median number of exacerbations had a decline in FEV1 of 31.5 mL·yr-1 and 6.5 mL·yr-1, respectively. In the same study, one severe exacerbation predicted an excess decline of 30 mL·yr-1.

Findings from a Retrospective Analysis

Whether effective therapy can prevent decline in lung function has been explored with mixed results, but it is a logical hypothesis that a reduction in the number of exacerbations should help preserve lung function. Using a database of 5 studies in which budesonide/formoterol maintenance and reliever therapy was compared with 3 other maintenance regimens, Bateman4 and multicentre colleagues investigated the relationship between baseline Asthma Control Questionnaire (ACQ-5) results and Global Initiative for Asthma (GINA)-defined clinical control (Table 1) and future risk of instability and exacerbations.

Table 1.

The comparator regimens in this database included higher-dose ICS therapy; the same dose ICS with long-acting beta agonist (LABA) therapy; and higher-dose ICS with LABA. A short-acting beta agonist (SABA) was used as a reliever medication in all 3 comparator regimens. Studies were either 6 or 12 months in duration. Time to first severe exacerbation was the primary end point for each of the studies included in this retrospective analysis. For the analysis, a severe asthma exacerbation was defined as deterioration in control resulting in hospitalization or emergency room treatment and/or oral steroid use.

Overall GINA-defined asthma control was determined by several criteria and in 3 studies, the ACQ-5 was self-assessed at clinic visits. On study entry, mean FEV1 was approximately 72% in all treatment arms; the mean ICS dose was approximately 700 µg/day and about one-third to one-half of patients were also on some form of LABA therapy as well. Mean symptom-free days ranged from about 10 to 17% and the median duration of asthma was about 11 years.

Analyses demonstrated that the percentage of patients achieving a week of controlled or controlled/partly controlled asthma as defined by GINA criteria increased throughout the study periods, irrespective of treatment used, although most of the improvement occurred during the first 3 to 6 months. Within-study comparisons showed that the percent controlled or partly controlled was similar with budesonide/formoterol maintenance and reliever therapy to the other 3 comparator regimens at 56% vs. 45% for the higher-dose ICS regimen; 56% vs. 53% for the same dose ICS + LABA regimen; and 54% vs. 54% for the higher-dose ICS + LABA regimen.

The authors also found that the better the level of current control, the higher the probability of remaining at the same level of control and the lower the risk of having an exacerbation in future weeks. Most importantly, fewer patients on the budesonide/formoterol maintenance and reliever regimen experienced exacerbations requiring medical intervention each week compared to all 3 comparator arms (Figure 1).

Figure 1.

Perhaps as importantly, there were fewer hospital admissions at 9 per 100 patients/year in the budesonide/formoterol maintenance and reliever arm than in the maximal-dose salmeterol plus fluticasone arm at 13 per 100 patients/year (P=0.046), as well as fewer exacerbations at 25 per 100 patients/year compared with 31 per 100 patients/year, respectively (P=0.039). The average ICS dose was also significantly lower in the budesonide/formoterol maintenance and reliever therapy arm at 1238 µg/day vs. 2000 µg/day in the maximal-dose ICS arm (P<0.0001).


Upon closer review of these findings from this pooled analysis, a number of issues arise. Firstly, for patients with this degree of disease severity, it is important to recognize that it is very difficult to achieve total asthma control. This is true both in clinical trials and in clinical practice and the fact that all 4 regimens achieved comparable levels of control is noteworthy, suggesting that when used as prescribed, most asthma regimens are effective. But it is important to note that while achieving comparable levels of asthma control, the lower proportion of patients experiencing exacerbations in the budesonide/formoterol maintenance and reliever arm suggests that patients are getting additional benefit from the steroid component of the combination strategy when they begin to flare, and that this additional anti-inflammatory boost may abort the impending exacerbation in some patients. In contrast, the reliever medication used in the other 3 comparator arms consisted of a SABA alone, so patients in the other arms were only getting additional bronchodilation at the time of the flare, not additional anti-inflammatory therapy.

Higher-dose ICS plus LABA combination was more effective than lower-dose ICS plus LABA but low-dose ICS with LABA was still better than high-dose ICS alone. The fact that all patients improved with time regardless of the regimen also reflects what we know about achieving good asthma control. When patients enter into a study, they are told what they have to do, and generally are more compliant with their therapy, as they are being followed up and encouraged to persevere. In other words, most patients get better if they use their treatment as prescribed. This is again true in clinical practice where if patients are compliant, they can anticipate becoming  and staying well.

From a compliance perspective, probably the most important aspect of asthma management is to convince patients, at least those with moderate to severe asthma, not to abandon their medication when they start feeling better and not only use their inhaler when they think they need it. Similarly, parents need to be educated about the real as opposed to feared adverse effects from long-term use of the low-dose ICS therapy used for children and that children with moderate to severe asthma need to use their treatment on a regular basis. For first-time patients, we always ask an asthma educator to demonstrate to patients or the parents and their child correct inhaler technique, and ensure they have achieved this. Physicians also need to keep in mind that compliance is critical to the current and future control of asthma and that patients need to be encouraged to be compliant at every visit. 


There is clear evidence from previous studies and the pooled analyses reported by Bateman and colleagues that achieving and maintaining good asthma control reduces the risk of future exacerbations and declines in lung function. Evidence supports the use of a combination of ICS with a rapidly-acting and long-acting bronchodilator for both maintenance and symptom relief, with fewer exacerbations compared with other regimens as the major differentiating benefit. However, regardless of how effective a particular inhaler regimen is, it will only be maximally effective if used as prescribed by educated patients. Physicians, therefore, have a key role in helping patients understand the benefits of adherence to therapy, enabling them to achieve sustained control for increased protection against future exacerbations and reduction of the risk of a progressive decline in lung function.  



Bateman et al. Am J Respir Crit Care Med 2004;170:836-44.

Bateman et al. Allergy 2008;63:932-38.

Bai et al. Eur Respir J 2007;30:452-56.

Bateman et al. J Allergy Clin Immunol 2010;125:600-8.


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