Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease

In this analysis, the daily number of inhalations of SABA needed for relief of symptoms was a predictor for future exacerbations in patients with COPD and a history of exacerbations in a study of combination BUD/FORM as maintenance therapy. SABA use predicted both short- and long-term risk of exacerbations. High SABA use in a single day was a predictor of the short-term probability of exacerbation in the following 21 days, whereas the average daily SABA use over 1 week of stable maintenance treatment was a strong predictor of an exacerbation in the following 10 months. This was true for patients taking BUD/FORM and FORM alone; however, patients treated with BUD/FORM had a lower short- and long-term risk of exacerbation compared with FORM monotherapy.

Although a relationship between as-needed SABA use and exacerbations in patients with COPD has long been suspected by clinicians, to our knowledge this is the first systematic investigation demonstrating this relationship. Indeed, although an increasing number of studies testing the efficacy of long-acting bronchodilators have used this index as an objective measure of the impact of treatment and a surrogate marker for breakthrough symptoms [18‐21], none have specifically analyzed the data in relation to the predictive capacity of as-needed SABA use in this context. In this analysis of data from a randomized, controlled study, we showed that as-needed SABA use in COPD patients can predict exacerbation risk over the short (≤21 days) and long (≤10 months) term, if patients are taking appropriate doses of long-acting β₂-agonist either alone or in combination with an inhaled corticosteroid. Our data suggest that for COPD, as in asthma [22], reliever use may be implemented as an important parameter for disease stability and future exacerbation risk. If our results are confirmed in other studies, it may be useful for clinicians to monitor patterns of reliever medication use so that they can identify patients at risk for an exacerbation, take steps to prevent the occurrence of a COPD exacerbation and ensure that when these events do occur, they are more rapidly identified and effectively treated. Similarly, patients may be educated to recognize increasing reliever use as a warning sign for an exacerbation and to take steps early to prevent further deterioration.

While we consider these findings to be robust for this group of patients with moderate-to-very-severe COPD and a history of exacerbations, further studies in patients with milder disease are needed before the predictive capacity of the use of SABA as a reliever can be generalized to all symptomatic patients with COPD. Ideally, for implementation in clinical trials, the findings should be confirmed in other large datasets in which similar instructions have been given to participants, with records of SABA use kept in a comparable way throughout the study. In addition, further studies would enable assessment of the degree of individual variability and clarify the ideal reliever use cut-points in predicting COPD exacerbations. We wished to validate our findings in a larger study population receiving similar BUD/FORM and FORM doses and recording reliever use, using data from five randomized controlled trials of BUD/FORM [17, 23‐26], including the use of BUD/FORM in combination with a long-acting muscarinic antagonist [17]. However, methodological differences between the studies, specifically a mix of methodology (paper versus electronic diaries, different study duration and devices), meant that this analysis could not be undertaken in a suitably rigorous manner.

The reliever use categories in the present analysis were defined empirically to broadly reflect use in clinical practice based on the authors’ clinical expertise, and future analyses should validate reliever use categories to identify specific thresholds that may predict future exacerbations. However, even in the absence of further validation, measures of SABA reliever use could be incorporated into risk prediction tools for exacerbations to initiate early treatment and potentially mitigate an upcoming exacerbation. We have previously developed a risk prediction tool (SCOPEX) based on a range of demographic and baseline parameters from a pooled database of BUD/FORM COPD studies; data from this tool showed that higher mean daily reliever use was a dominant predictor of a COPD exacerbation in the next 6 months [27]. In agreement with the current analysis, the risk prediction tool showed that FORM was associated with a higher exacerbation risk than BUD/FORM.

As with the original study [16], it is unclear whether discontinuation of inhaled corticosteroids in those patients who received FORM alone contributed to worse exacerbation outcomes compared with those receiving BUD/FORM. Long-acting β₂-agonist monotherapy is not recommended in patients with severe-to-very-severe COPD, limiting the interpretability of our data in the FORM only group. We note, however, a trend to undertake studies assessing bronchodilators alone even in severe/Group D patients, so the issue of a non-inhaled corticosteroid approach to Group D – especially those who do not exacerbate frequently – is still being discussed. In addition, we cannot verify whether the number of daily inhalations or occasions of SABA use as reliever medication was exactly as patients recorded in their electronic diaries. However, reliever use was recorded twice daily and entries were permitted only in specific time windows (morning and evening), which prevented retrospective recordings. It is well known that paper diaries may permit retrospective and fictitious entries, and even electronic diaries may suffer from recall errors [28, 29]. Optimally, electronic inhaler adherence monitoring should be used to confirm these records, but the data we analyzed were taken from a study in which this was not undertaken.