© 2004 American Thoracic Society doi: 10.1164/rccm.2408006
Can Guideline-defined Asthma Control Be Achieved?The Gaining Optimal Asthma Control StudyDepartment of Respiratory Medicine London Chest Hospital London, United Kingdom There have been relatively few large long-term studies in asthma, so the data within the GOAL study reported in this issue of the Journal (pp. 836–844) are likely to lead to new insights (1). Rather than the traditional design comparing two treatments using a primary outcome, usually lung function and secondary measures of symptoms and exacerbations, this trial used an innovative endpoint of asthma control. Three groups were recruited: an inhaled steroid-naive group (although how long they had been inhaled steroid–free was not defined) and groups on low and moderate doses of inhaled steroids. Subjects were treated with either fluticasone or fluticasone/salmeterol. If totally controlled, they stayed on their treatment; if not, they increased the dose until either control was achieved or the highest dose of fluticasone or fluticasone/salmeterol was reached. The primary outcome was the difference in the proportion of subjects well controlled on fluticasone/salmeterol compared with fluticasone during Phase 1. "Well controlled" asthma is defined in the paper; it differs from "total control" only in that mild symptoms and occasional ß2 agonist usage was allowed. The stepping up of treatment after 3 months approximates routine clinical practice and is a strength of the study. That well controlled asthma was the primary outcome variable is not optimally apparent as the abstract focuses more on total control (a rather Orwellian term). The results of the three strata are often amalgamated in the paper, as in the phrase "total control was achieved across all strata, 31% versus 19%." However, the three strata should be considered as three separate trials of similar design. The Stratum 1 results reinforce the recommendation in guidelines that inhaled corticosteroids are the initial treatment option (2, 3). Well controlled status was achieved in 40% of patients without dose escalation and in 58% using fluticasone 500 mcg/day. Control was achieved more rapidly, with a lower dose of inhaled corticosteroids when salmeterol was added; however, differences were small. It will be a matter of debate whether these differences justify the additional cost. The largest difference occurred in Stratum 3, where few patients were controlled with fluticasone, reinforcing guideline recommendations on the addition of a long-acting inhaled ß2 agonist. The dose escalation of inhaled steroids necessary to move from well to total control is not reported, but the results suggest that significant increases in steroid dose was required in patients treated with a long acting ß2 agonist. Whether this increase to prevent occasional symptoms or bronchodilator use is justified or desirable will depend on health care professionals' and patients' views, and will be a matter of debate. The study also demonstrates that some patients do respond to an increased dose of inhaled steroids, indicating that no single dose of inhaled steroid can be defined at which a long-acting ß2 agonist must be added. A weakness in the study is the paucity of data on adrenocortical function. It is apparent that falls in adrenocortical function occurred particularly at the highest doses of both treatments. These results also indicate the need for new treatments for more severe patients. In Stratum 3, only 60% were well controlled on combination therapy. In such patients there is currently no properly controlled clinical trial to determine what the next best treatment option should be (3). There is a gradual increase in the percentage of patients who achieved total and well controlled status during the year-long trial. The difference between the percentage of patients achieving total control in the fluticasone and fluticasone/salmeterol groups is constant after about 2 months, suggesting the improvement relates to the prolonged use of inhaled corticosteroids. This is consistent with studies investigating the time course of action of inhaled corticosteroids on bronchial hyperresponsiveness and exacerbation control, which show gradual improvement over time (4). The implications are that disease control improves slowly and that stepping down should occur after 3–6 months; this consistent with guidelines and the limited amount of controlled clinical trial data (2, 3, 5). The study will probably lead to the demise of the GINA severity classification, which depends on a combination of lung function and symptoms (2). This classification is too complex to be of clinical use. In addition, it is only applicable to patients when they are first seen and is akin to defining the severity of diabetes mellitus by the blood glucose and pH on first presentation with ketoacidosis. The GINA guidelines will probably move toward a classification based on treatment requirement to achieve control as used by other guidelines (3). The difference between the level of control achieved within this trial and that achieved in clinical practice is emphasized. The study cannot indicate what percentage of patients with asthma in practice can be controlled. Trial participants are a selected group who are more likely to be compliant. Furthermore, patients with other significant diseases were excluded. Smokers of more than 10 pack-years also were not included in the study. The study only included patients over the age of 12. Long-acting ß2 agonists seem to be relatively less efficacious in children than adults, and a similar study in children is needed (6, 7). Problems in practice come from those with asthma plus concomitant diseases and poor compliance. The high compliance achieved in the study may be irreproducible in practice. Lord Kelvin said "if you cannot measure it, you cannot improve it." Until inhalers are developed for research or clinical practice that allow compliance to be accurately measured, we will never know the scale of the problem and how we might improve it. To bridge the gap between what can be achieved in a trial and what occurs in practice will require research in patients with concomitant disease including current smokers, precise measurement of compliance, and the development of simple techniques to improve compliance. The strategy of increasing treatment until control is achieved is at variance with two other strategies. Targeting inflammation has shown superior outcomes to traditional management in preventing exacerbations (8, 9). Employing the combination of budesonide and formoterol, with patients increasing treatment in response to symptoms, has also decreased exacerbations (10). Therefore, because three strategies have been compared with the traditional guideline approach and been shown to offer advantages, a comparison between the options is now needed. At present, choice between the options will depend on clinician preference, patient wishes, local facilities, and resources. FOOTNOTES Conflict of Interest Statement: N.C.B. has acted on Advisory Boards for GlaxoSmithKline (GSK), AstraZeneca (AZ), Pfizer, Altana, and ICOS and has lectured for GSK, AZ, Boehringer Ingelheim, and Pfizer and has research funding which has gone into departmental funds from GSK ($200,000) and ICOS ($20,000). REFERENCES
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