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Higher short-acting beta-agonist use is associated with greater COPD burden

Open ArchivePublished:October 16, 2019DOI:https://doi.org/10.1016/j.rmed.2019.10.007

      Highlights

      • The mean age for the 2,196 patients with COPD in the study was 60 years.
      • Highest (vs. lowest) burden CAT scores were associated with 1.1 higher SABA use.
      • Highest (vs. lowest) burden CAT scores were associated with 10% lower adherence.

      Abstract

      Introduction

      The COPD Assessment Test (CAT) is a self-administered questionnaire that measures symptomatic burden. CAT is used as part of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines refined ABCD tool and is usually performed during office visit assessment. Electronic medication monitors (EMMs) capture utilization of short-acting beta-agonists (SABA) that may indicate disease worsening in real-time. The primary objective was to assess the relationship of CAT with SABA utilization.

      Methods

      From 8/2017-1/2019, COPD patients ≥40 years of age were enrolled in a digital health platform consisting of EMMs and a mobile application to track time and date of SABA use. Patients with a completed CAT and ≥81 days of continuous EMM data were included in analyses. Using one-way ANOVA, SABA use and maintenance medication adherence were compared by CAT score categories: <10 (low burden), 10–20 (medium), 21–30 (high), and 31–40 (very high). Associations were additionally estimated in patients who used ≥1 puff/week of their rescue and maintenance medication.

      Results

      The population included 2196 COPD patients (mean age: 60 years). CAT scores from low to high burden were associated with greater SABA use, from 0.8 to 1.9 puffs/day (+1.1 [95% CI: 0.6, 1.6 puffs/day], P < 0.001), and lower adherence, from 69% to 59%, (−10% [95% CI: −1, −19%], P = 0.04). Sensitivity analyses yielded similar results.

      Conclusions

      This study found a significant association between greater SABA use and lower adherence with higher burden CAT scores. This finding may suggest that passive collection of inhaled medications could serve as a surrogate for CAT.

      Keywords

      1. Introduction

      Timely assessment of increasing symptom burden is needed to prevent exacerbations due to chronic obstructive pulmonary disease (COPD). However, assessments of disease status commonly occur in physicians’ offices or hospital settings after the patient experiences a worsening of symptoms. Monitoring patient reported outcomes and risk factors before significant symptom deterioration may allow for therapeutic intervention to reduce exacerbations risk.
      Currently, guidelines from the Global Initiative for Chronic Obstructive Lung Disease 2019 (GOLD) include the use of spirometry and self-report questionnaires to assess disease severity and impairment [
      • Global Initiative for Chronic Obstructive Lung
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: 2019 Report.
      ]. ABCD classification in GOLD 2019 is derived from the patients’ symptom burden and history of exacerbations to inform on therapeutic decisions. Self-report questionnaires such as the COPD Assessment Test (CAT) [
      • Jones P.W.
      • Harding G.
      • Berry P.
      • Wiklund I.
      • Chen W.-H.
      • Kline Leidy N.
      Development and first validation of the COPD assessment test.
      ] assess symptom burden. Increasing CAT scores reflect higher disease impairment.
      Real-time monitoring of short-acting beta-agonists (SABA) and maintenance medication can help close the time gap in response to disease change, providing an opportunity to detect disease worsening and allow for earlier intervention to prevent exacerbations. In asthma, self-reported SABA use is a predictor of exacerbation risk [
      • Cajigal S.
      • Wells K.E.
      • Peterson E.L.
      • Ahmedani B.K.
      • Yang J.J.
      • Kumar R.
      • Burchard E.G.
      • Williams L.K.
      Predictive properties of the asthma control test and its component questions for severe asthma exacerbations.
      ] and is a component of the Asthma Control Test (ACT) [
      • Schatz M.
      • Sorkness C.A.
      • Li J.T.
      • Marcus P.
      • Murray J.J.
      • Nathan R.A.
      • Kosinski M.
      • Pendergraft T.B.
      • Jhingran P.
      Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists.
      ,
      • Nathan R.A.
      • Sorkness C.A.
      • Kosinski M.
      • Schatz M.
      • Li J.T.
      • Marcus P.
      • Murray J.J.
      • Pendergraft T.B.
      Development of the asthma control test.
      ] but is not a component of CAT. In COPD randomized clinical trials, quantifying SABA inhalations is a common secondary outcome [
      • Dransfield M.T.
      • Bourbeau J.
      • Jones P.W.
      • Hanania N.A.
      • Mahler D.A.
      • Vestbo J.
      • Wachtel A.
      • Martinez F.J.
      • Barnhart F.
      • Sanford L.
      • Lettis S.
      • Crim C.
      • Calverley P.M.A.
      Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials.
      ,
      • Agustí A.
      • de Teresa L.
      • De Backer W.
      • Zvarich M.T.
      • Locantore N.
      • Barnes N.
      • Bourbeau J.
      • Crim C.
      A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD.
      ,
      • Martinez F.J.
      • Boscia J.
      • Feldman G.
      • Scott-Wilson C.
      • Kilbride S.
      • Fabbri L.
      • Crim C.
      • Calverley P.M.A.
      Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial.
      ]. Objective monitoring of inhalers, now with the use of electronic medication monitors (EMMs), creates an opportunity to close the gap in response to symptom change. EMMs provide passive documentation of SABA use, and may provide a rapid, informative, daily measure of disease burden. In this report, we estimated the association between SABA use and CAT scores to assess whether EMM-collected SABA utilization can predict COPD burden. Additionally, we assessed the relationship between adherence to maintenance medications and CAT scores.

      2. Methods

      Patients ≥40 years of age with a self-reported diagnosis of COPD enrolled from 8/2017 to 1/2019 in a digital health platform (Propeller Health, Madison, WI) that included EMMs and a dedicated mobile application (“app”). Patients enrolled to the platform online or in person through their healthcare system or print and digital media campaigns after giving their name, self-reported disease status (asthma or COPD), mailing address and email address. Patients attached an EMM to each of their SABA and/or maintenance medication inhalers. EMMs recorded the time and date of every inhaler actuation and synchronized these data to patients’ smartphone app or data hub via Bluetooth.
      At the time of enrollment, patients self-reported their age and assessed their clinical status with the CAT. EMMs passively and objectively recorded time and date of SABA and maintenance inhaler use. Maintenance medications studied included long-acting muscarinic antagonist (LAMA), long-acting β2-agonists (LABA), LABA/LAMA, LABA/inhaled corticosteroids (ICS) and LABA/LAMA/ICS. Patients with a baseline CAT and ≥81 days of continuous EMM data for SABA, maintenance medication or both were included. The first three weeks constituted a training period – a time when the patients tend to have higher than usual inhaler use due to intervention effect and/or novelty of the sensor – and were excluded in analyses. A sensitivity analysis was completed in patients who used ≥1 puff/week of their rescue and maintenance medication.
      SABA use was quantified as the number puffs per day. Maintenance medication adherence (%) was calculated as the mean daily number of maintenance medication puffs taken divided by the number prescribed, capped at 100%. Using one-way ANOVA, daily SABA use and adherence was compared between CAT score categorizations: <10 (low burden), 10–20 (medium), 21–30 (high), and 31–40 (very high).

      3. Results

      The cohort of 2196 COPD patients included 649 with rescue and maintenance medication, 203 with maintenance only and 1344 with rescue only. The mean (standard deviation [SD]) age was 60 (SD: 8) years. CAT scores from low to very high burden categories were associated with increasing SABA from 0.8 to 1.9 puffs/day on average (+1.1 [95% CI: 0.6, 1.6 puffs/day], P < 0.001), in patients using rescue medication (n = 1993). In patients using SABA at least once a week (n = 452), the sensitivity analysis demonstrated a similar pattern, with increasing SABA from 2.5 to 4.6 puffs/day on average (+2.1 [95% CI: 0.6, 3.7 puffs/day], P = 0.007) correlating with low to very high burden COPD (Fig. 1).
      Fig. 1
      Fig. 1Mean daily rescue use by CAT score category.
      In the 203 patients monitoring their inhaled maintenance medications, lower CAT scores were associated with higher maintenance medication adherence (Fig. 2). Mean daily adherence for patients with low vs. very high burden CAT scores was 69% and 59%, (−10% [95% CI: −1, −19%], P = 0.04). In patients monitoring both maintenance and rescue medications – compared to those only using maintenance medications – the fall-off in adherence was blunted for patients in the higher two CAT categories, with a mean daily adherence at 66% and 61% for high and very high burden COPD (Fig. 3). Sensitivity analyses in patients using their inhaled maintenance medication at least once weekly yielded similar results, but with higher adherence for every CAT category. In this group, mean daily adherence in low and very high burden COPD classifications was 85% and 76%, respectively (−9% [95% CI: −1, −17%], P = 0.03).
      Fig. 2
      Fig. 2Mean daily maintenance medication adherence by CAT score category.
      Fig. 3
      Fig. 3Mean daily maintenance medication adherence by CAT score category and monitoring of maintenance only vs. both maintenance and rescue medications.

      4. Discussion

      Determining the COPD patients at risk of an exacerbation is a goal for clinicians and researchers. Earlier risk detection allows for greater opportunity to prevent exacerbations. The SCOPEX (score to predict short-term risk of COPD exacerbations) study sought to establish predictive markers for COPD exacerbations [
      • Make B.J.
      • Eriksson G.
      • Calverley P.M.
      • Jenkins C.R.
      • Postma D.S.
      • Peterson S.
      • Östlund O.
      • Anzueto A.
      A score to predict short-term risk of COPD exacerbations (SCOPEX).
      ]. Both the intensity of therapy with rescue and maintenance medications were found to be 2 of the 5 key predictive criteria for COPD exacerbation risk.
      The present analysis demonstrates an important relationship between CAT and SABA use and an inverse relationship between CAT and maintenance medication adherence. This relation holds for both occasional and more frequent users of SABA. The association of higher CAT scores and increasing SABA use suggests the potential value of SABA data as a surrogate for CAT. SABA use is passively collected and may provide real-time assessment of symptomatic burden, while CAT is typically self-administered in clinical settings. The ACT [
      • Schatz M.
      • Sorkness C.A.
      • Li J.T.
      • Marcus P.
      • Murray J.J.
      • Nathan R.A.
      • Kosinski M.
      • Pendergraft T.B.
      • Jhingran P.
      Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists.
      ,
      • Nathan R.A.
      • Sorkness C.A.
      • Kosinski M.
      • Schatz M.
      • Li J.T.
      • Marcus P.
      • Murray J.J.
      • Pendergraft T.B.
      Development of the asthma control test.
      ] and the Asthma Control Questionnaire [
      • Juniper E.F.
      • Bousquet J.
      • Abetz L.
      • Bateman E.D.
      Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire.
      ,
      • Juniper E.F.
      • O′byrne P.M.
      • Guyatt G.
      • Ferrie P.
      • King D.
      Development and validation of a questionnaire to measure asthma control.
      ] both include assessment of SABA use as strong predictors of asthma worsening. CAT does not include SABA use, but the present data indicate that SABA use may be an appropriate alternative to assess burden. The advantages include the ability to continuously detect day-to-day changes in symptoms, allowing for earlier intervention.
      Patients with lower mean CAT scores had higher levels of maintenance medication adherence. The data highlight that patients who monitor both rescue and maintenance medications have a blunting of the decline in adherence with higher CAT. This may reflect greater engagement by patients monitoring both medications and/or recognition of symptoms requiring treatment.
      This study is limited in that patients may not monitor all of their prescribed inhaled medications. Although the use of EMMs provides a more accurate report of actual use of inhaled medications compared to self-report, it does not assure that patients are correctly using their medications [
      • Anderson W.C.
      • Gondalia R.
      • Hoch H.E.
      • Kaye L.
      • Szefler S.J.
      • Stempel D.A.
      Screening for inhalation technique errors with electronic medication monitors.
      ]. Additionally, we depended on self-report of COPD and were not able to confirm the diagnosis with spirometry.

      5. Conclusions

      This study found an association between CAT with SABA use and maintenance medication adherence. Data from EMMs can give the provider the opportunity to detect symptomatic burden via high SABA use and maintenance medication non-adherence in real-time – outside of providers’ offices. This information can help identify patients to have a discussion with their provider to address barriers to adherence and possible therapy alterations to reduce exacerbation risk [

      B.G. Bender, Promoting adherence and effective self-management in patients with asthma, Pediatr. Allergy Princ. Pract. (1AD) 354-359.e2. doi:10.1016/B978-0-323-29875-9.00038-0.

      ].

      Declaration of competing interest

      Rahul Gondalia, Benjamin Theye, and David Stempel receive compensation from their employer, Propeller Health, an affiliate of ResMed. Bruce Bender does not have a declaration of interest.

      Acknowledgements

      This research – the study design; collection, analysis and interpretation of data; and writing and critically reviewing the manuscript – was supported by Propeller Health. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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      1. B.G. Bender, Promoting adherence and effective self-management in patients with asthma, Pediatr. Allergy Princ. Pract. (1AD) 354-359.e2. doi:10.1016/B978-0-323-29875-9.00038-0.