The global burden of symptoms in patients with chronic obstructive pulmonary disease (COPD) is high [
]. Under-recognition and under-treatment of COPD can have a significant impact on day-to-day activities and quality of life for patients, resulting in avoidable disease burden, activity impairment [
], and hospitalization risk [
It remains unclear which endpoints most sensitively reflect the day-to-day variation in symptoms in patients with COPD. Ideally, outcomes in COPD trials should reflect the real-world behavior of patients as well as the potential of treatment to influence both current disease state and future risk [
]. The forced expiratory volume in 1 s (FEV
) is a reproducible and responsive measurement that reflects aspects of the pathophysiology characterizing COPD. However, FEV
impairment is only weakly related to overall patient well-being [
], and other endpoints are needed that are easier to obtain in routine clinical practice and that reflect the day-to-day impact of COPD on the patient, in order to guide treatment decisions [
]. New symptom-based questionnaires address this need, but they may neglect the important information patients report during routine office visits or in surveys accompanied by objective measures of symptom impact [
]. An example of this type of information is the frequency with which patients use reliever medication to control symptoms experienced in the real world.
In asthma trials, the use of short-acting β
-agonists (SABA) as reliever medication to decrease symptoms has been accepted as a measure of day-to-day asthma control [
]. This outcome is included in widely used asthma control questionnaires as a surrogate measure of symptom frequency and a reflection of treatment efficacy [
]. Until relatively recently, SABAs were prescribed to COPD patients as background maintenance therapy 1–4 times per day and, traditionally, their frequency of use has not been considered to reflect the variability of symptoms and patients’ responses. With the widespread use of long-acting inhaled bronchodilators as first-line maintenance medication in COPD [
], SABAs are now seen as reliever medication in COPD [
]. Thus, by analogy with asthma, reliever use in COPD may be a sensitive marker of symptom variability [
] and of the extent to which an intervention improves symptom control. Conversely, since increased reliever use is an indicator of sub-optimal control in asthma, it could have a similar significance in COPD, reflecting worsening symptom control or an impending exacerbation. Evidence already exists to show that, compared with as-needed SABA use, regular SABA use is not associated with additional benefit across a range of clinical and functional outcomes in COPD [
We hypothesized that more SABA taken as reliever medication would predict increased short- and long-term risk of exacerbations in patients with COPD, and tested our hypothesis retrospectively by analyzing reliever use collected by electronic diary recording in patients who participated in a clinical trial of budesonide/formoterol (BUD/FORM) or formoterol (FORM) [
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 [
], 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 β
-agonist either alone or in combination with an inhaled corticosteroid. Our data suggest that for COPD, as in asthma [
], 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 [
], including the use of BUD/FORM in combination with a long-acting muscarinic antagonist [
]. 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 [
]. 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 [
], 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 β
-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 [
]. 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.
CRJ is an advisory board member for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Limited, and Novartis, and a consultant for AstraZeneca, Chiesi, GlaxoSmithKline, and Pieris. Educational presentations have been developed for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Novartis, with honoraria paid to CRJ or her institution. Lectures have been presented on behalf of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hunter Immunology, and Novartis. Support for travel to meetings has been provided by AstraZeneca and Boehringer Ingelheim.
The University of Groningen has received honoraria for DSP advising on the conduct and analysis of clinical trial data from AstraZeneca, Nycomed, and Teva, as well as for lectures at meetings supported by AstraZeneca, Chiesi, GlaxoSmithKline, Nycomed, and Teva. The University of Groningen has received money for research by unrestricted educational grants from AstraZeneca and Chiesi. AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Nycomed have provided support for travel to meetings.
ARA is a consultant and speaker for AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Dey Pharma, GlaxoSmithKline, and Pfizer, and has received honoraria from these companies. Educational presentations have been developed for AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Dey Pharma, GSK, and Pfizer. The University of Texas Health Science Center at San Antonio has received money for research to perform clinical trials. Support for travel to meetings has also been provided by AstraZeneca.
BJM is an advisory board member for Aerocrine, AstraZeneca, Forest, Boehringer Ingelheim, CSL Bering, Forest, Novartis, and Theravance and a consultant for Astellas, Forest, and Chiesi. Clinical trial data have been reviewed for Spiration, with grants received and controlled by National Jewish Health from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Forest, MedImmune, Nabi, National Institutes of Health, Pfizer, and Sunovian. Lectures have been presented on behalf of Boehringer Ingelheim and GlaxoSmithKline. Educational presentations and programs have been developed (Carden Jennings, Cleveland Clinic, Consensus Medical, Foundation for Improving Patient Outcomes, Hybrid Communications, Integrity, Intellisphere, Medscape, National Jewish Health, Projects in Knowledge, SPIRE, Synapse, and WebMD). Royalties have been received from Up-To-Date. BJM has been a speaker for educational programs at Abbott, the American Academy of Family Practice, the American College of Chest Physicians, and the American Thoracic Society. Support for travel to meetings has also been provided by AstraZeneca.
GSE is an ex-employee of AstraZeneca. He is a consultant for Novartis, ALK, and MVIC and has been a consultant for Almirall.
SP is an ex-employee of AstraZeneca and own stocks within the company.
PMC is a board member for Boehringer Ingelheim, the Department of Health Respiratory Programme Board, GlaxoSmithKline, and Nycomed. He has been a consultant for Novartis and provided expert testimony for Forest. PMC has received honoraria for advising on the conduct and analysis of clinical trial data from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Nycomed. He has also spoken at meetings supported by these companies. Support for travel to meetings has been provided by AstraZeneca.
This study and the analysis performed for this manuscript were funded by AstraZeneca.
CRJ, DSP, ARA, BJM, SP, GSE, and PMC all contributed to data-interpretation, and conceiving, writing, and revising the manuscript. SP was responsible for statistical analyses. CRJ, the corresponding author, had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors approved the final draft of the manuscript.