Blood Eosinophil Counts, Withdrawal of Inhaled Corticosteroids and Risk of COPD Exacerbations and Mortality in the Clinical Practice Research Datalink (CPRD)

Abstract

Although recently introduced in the pharmacological treatment algorithm of chronic obstructive pulmonary disease (COPD), there is a need for more data supporting the use of blood eosinophil counts as a biomarker to guide inhaled corticosteroids (ICS) therapy. The aim of this study was to evaluate the risk of moderate and/or severe exacerbations and all-cause mortality in a large primary care population after withdrawal of ICS compared to continued users stratified by elevated blood eosinophil counts. In this population based cohort study, we used data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom. We included subjects' aged 40 years or more who had a diagnosis of COPD. We excluded subjects with a history of asthma, pulmonary fibrosis, cardiac arrhythmia and bronchiectasis, COPD exacerbations occurring within 6 weeks prior to index date, or with a myocardial infarction within 3 months prior to index date. Continuous users were subjects who received their most recent ICS prescription within 3 months before the start of an interval. ICS withdrawals were those who discontinued ICS for more than 3 months. We evaluated the risk of moderate and/or severe exacerbations and all-cause mortality among subjects with various blood eosinophil thresholds who withdrew from ICS compared to continuous ICS users with elevated blood eosinophil levels using Cox regression analysis adjusted for potential confounders. We identified 48,157 subjects diagnosed with COPD between 1 January 2005 to 31 January 2014. Withdrawal of ICS was not associated with an increased risk of moderate-to-severe exacerbations among subjects with absolute blood eosinophil counts !0.34 Â 10 9 cells/L [adjusted hazard ratio (adj. HR) 0.72; 95% confidence interval (CI) 0.63-0.81] or relative counts ! 4.0% (adj. HR 0.72; 95% CI: 0.66-0.78). Similarly, withdrawal of ICS was not associated with an increased risk of severe exacerbations among subjects with absolute blood eosinophil !0.34 Â 10 9 cells/L (adj. HR 0.82; 95% CI: 0.61-1.10) or relative blood eosinophil counts !4.0% (adj. HR 0.80; 95% CI: 0.61-1.04). No increased risk of all-cause mortality was observed among subjects who withdrew from ICS irrespective of elevated absolute or relative blood eosinophil counts. In a real-world primary care population, we did not observe an increased risk of moderate and/or severe COPD exacerbations or all-cause mortality among subjects with eosinophilia who withdrew their use of ICS.

Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis

“…Hx atopy, allergic rhinitis. Blood eos > 5% IgE > 100FEV1% predicted 55.5 ± 18Mean 31.9% patients AECOPD in 12 months prior to study enrolment.Recorded 6-monthly patient reviews59%43%Not statedSuissa 2018 [36]24,732 patients≥55 years.COPD new users of LAMA or LABA+ICS from 1.1.02.Blood eosinophil count before cohort entryInitiated on LAMA & LABA+ICS at same time.Asthma NOT excludedNot knownRecord drawn from READ code.Mean 33.6% patients had ≥1 AECOPD in 12 months prior to study enrolment0%0%Prior to study entry.Oshagbemi 2018 [37]32,693 patients≥40 year.New diagnosis COPD from 1.1.05Asthma.Any previous AECOPD.ICS use in past yearNot knownRecord drawn from READ code14%0%Single eosinophil measure at point closest to index date (start of follow-up)Oshagbemi 2019 [38]48,157 patients≥40 year.New diagnosis COPD from 1.1.05Asthma.AECOPD in 6 months prior to index dateNot knownRecord drawn from READ code18%28%Single eosinophil measure at point closest to index date (start of follow-up)Suissa 2019 [39]3954 patients≥55 years.new use LAMA or LABA+ICS from 1.1.02.Blood eosinophil count before cohort entryAsthmaFEV1% predicted53.9% (LABA + LAMA)52.7% (LABA + ICS)Record drawn from READ code.Mean 41% of patients had ≥1 AECOPD in 12 months prior to study enrolment77% (LABA+LAMA)49.1% (LABA + ICS)37% (LABA+LAMA)52.8% (LABA+ICS)Baseline…”

“…In three of the observational studies [35, 36, 39] the proportion of patients reported to have experienced ≥1 exacerbation in the past 12 months was between 32 & 41%. The remaining two observational studies excluded patients who had experienced an exacerbation either in the 6 months prior to the index date [38] or at any point in the past [37]. COPD patients with the greatest degree of airflow impairment may experience the largest number of exacerbations.…”

“…All of the RCTs recruited patients with either severe to very severe airflow limitation [27, 32] or moderate to severe airflow limitation. In 3 of the 5 observational studies the disease severity of the patients was unknown [36–38]. Participants in the remaining 2 observational studies had a mean FEV1% predicted of > 50% [35, 39].…”

Inhaled corticosteroid withdrawal may improve outcomes in elderly patients with COPD exacerbation: a nationwide database study

“…Patients with ⩾300 blood eosinophils•µL −1 had a higher risk of exacerbation after ICS withdrawal [11,27]. However, a recent database study that evaluated the association between eosinophil counts and COPD exacerbation or all-cause mortality reported that ICS withdrawal did not increase the risk, even in patients with eosinophilia [28]. Because our study only included patients who were discharged before March 2016, it is unlikely that recent studies referring to the role of blood eosinophil counts induced confounding by indication.…”

Initial inhaler choice in COPD: real-world evidence

“…A contradictory study, also based on the CPRD, was published in COPD this year, which showed that withdrawal of ICS in 48 157 participants with COPD resulted in a lower risk of moderate or severe exacerbations regardless of peripheral blood eosinophil count [12]. People with a diagnosis of asthma were excluded; however, it was not specified that the blood eosinophil measurement was taken prior to enrolment, the definition of an exacerbation was based purely on coding and the data were not linked to HES.…”