Exploratory data: COPD and blood eosinophils David Price: 9.23-9.35am
Blood Eosinophilia in COPD The reliability and utility of blood eosinophils as a marker of disease burden, healthcare resource utilisation and response to treatment in COPD Lead Investigator: David Price Working Group: o Alvar Augusti, Spain o Antonio Anzueto, USA o Ian Pavord, UK o Claus Vogelmeier, Germany o Nicolas Roche, France o Dirkje Postma, The Netherlands o Emillio Pizzichini, Brazil o Todor Popov, Bulgaria o Daryl Freeman, UK o Dermot Ryan, UK o Rupert Jones, UK o Alberto Papi, Italy
Background A recent observational study conducted by Research in Real Life Ltd suggests that asthma patients with blood eosinophil counts >400/µL tend to suffer from more exacerbations and have worse asthma control, despite being on more therapy. o The higher the eosinophil count, the less likely patients were to achieve asthma control. Eosinophilic airway inflammation is usually considered a feature of asthma, but it has been demonstrated in large and small airway tissue samples and in 20% 40% of induced sputum samples from patients with stable COPD. Raised eosinophil counts have also been shown to be associated with a good response to corticosteroids in COPD. 3
Phase 1 Research Question This exploratory analysis was undertaken to explore the extent of the available blood eosinophil data in UK COPD patients and to inform the next phase of the study that will level assess the potential utility of blood eosinophils as a predictor of future risk in COPD. Exploratory analysis research question: What is the relationship between categorical blood eosinophil counts ( 400/µL vs. >400 /µl) and future exacerbations (0, 1, 2 3, 4) o All all patients with COPD o A subset of patients with spirometry-confirmed COPD (i.e. with FEV1/FVC ratio<0.7) o Subset of patients with co-morbid asthma 4
Study design A retrospective database analysis of COPD patients consisting of: (i) a one-year baseline period, (ii) a one-year outcome period and (iii) an index date, defined as the date of the last valid eosinophil count. Patients were categorised by blood eosinophil count as: 400/µL OR >400/µL Date of last valid eosinophil count (at least one year prior to last data extraction) COPD patients Patients with blood eosinophil count 400 /µl Patients with blood eosinophil count >400 /µl One BASELINE YEAR year for confounder definition and patient characterisation One OUTCOME YEAR for outcome evaluation 5
Data source: The Optimum Patient Care Research Database The OPCRD comprises data extracted through the Optimum Patient Care (OPC) Clinical Service Evaluation. The clinical evaluation involves a combined review of (anonymised) electronic medical records (EMRs) and patients responses to disease-specific questionnaires and characterises patients in terms of their demographics, disease control and exacerbation history. The review process produces patient-level reports that makes guidelinebased recommendations for possible management changes to optimise control at the lowest possible therapeutic dose and reduce risk of future exacerbations. OPCRD contains anonymised, research-quality data for approximately 300,000 patients with asthma (and 100,000 patients with chronic obstructive pulmonary disease [COPD]) collected from more than 300 practices across the UK that subscribe to the OPC Clinical Service Evaluation h"p://www.op)mumpa)entcare.org/html_docs/adept.html 6
Patient selection criteria Inclusion Criteria o A COPD diagnostic code ever recorded; o At least one valid recorded blood-eosinophil count; o Aged 40+ years old at the last valid eosinophil count date; o Two year of continuous data (one year baseline period and one year outcome period) Exclusion Criteria o Any chronic respiratory disease other than COPD or asthma o Eosinophil counts >5000/µl o Unknown smoking status 7
Consort: Patients with COPD diagnosis at any time No other chronic respiratory disease diagnosis (inc. COPD) Eosinophil readings ever Numeric eosinophil counts (/µl) Data analysis period defined as 1 year prior to and 1 year after index date Aged >=40 at time of the last valid eosinophil count Known smoking status and eosinophil counts <=5000/µl OPCRD DB n 910,823 COPD patients n = 51,031 No other chronic resp. disease n = 50,716 Patients with eosinophil readings n = 43,436 Patients with valid eosinophil counts n = 42,291 Enough data in the study period n = 37,571 Aged 40+ n = 37,224 Final dataset n = 37,112 Patients with no COPD diagnosis. n = 859,792 Patients diagnosed with other chronic resp. diseases n = 315 No eosinophil readings. n = 7,280 No numeric value (n=1,000) or invalid unit of measure (n=145) Total n = 1,145 Time period not long enough n = 4,720 Aged <40. n = 347 Unknown smoking status (n=104) or eosinophil counts>5000/µl (n=9) Total 8 n = 112
Outcome: Exacerbation definition An exacerbation is defined as an occurrence 1 of: o COPD-related unscheduled hospital admission / A&E attendance 2 ; o An acute course of oral steroids prescribed with evidence of a respiratory review 3 ; o Antibiotics prescribed with evidence of a respiratory review 3. 1 Two exacerbations occurring within 2 weeks of each other, these events will be considered to be the result of the same exacerbation and will only be counted once. 2 COPD-related Hospitalisations consist of a) a definite COPD hospitalisation read code OR b) a generic hospitalisation read code recorded on the same day as a Lower Respiratory Consultation* excluding lower respiratory codes recorded for a lung function test 3 Evidence of a Respiratory Review - consists of the following: a) Any Lower Respiratory Consultation* AND b) Any additional respiratory examinations, referrals, chest x-rays, or events. * Lower Respiratory Consultations - consist of the following: a) Lower Respiratory read codes (including Asthma, COPD and LRTI read codes); b) Asthma/COPD review codes excl. any monitoring letter codes; c) Lung function and/or asthma monitoring. 9
Statistical Methods: exploratory analysis Data preparation: o Summary statistics (n, % of non-missing, mean, median, range, inter-quartile range, distribution by category ) o Investigation of outliers and missing data o Transformation and categorisation of skewed data Evaluation of potential confounders: o Significant baseline differences (T Test,Mann Whitney U Test, Chi squared Test, p<0.10) o Predictors (multivariate analyses, p 0.05) o Confounders collinearity (Spearman s correlation coefficient, ρ>0.3) Outcome analysis (modelling stage) o Unadjusted/adjusted cohort comparisons of exacerbation rates (Poisson regression model, p 0.05) 10
Baseline analysis One year prior to and including the date of the last valid eosinophil count (assists in confounder definition)
Eosinophil distribution count TOTAL BY EOSINOPHIL COUNTS 400/ΜL >400/ΜL Sample Size (n) 37,112 33,473 3,639 % Non-missing 100 100 100 Mean (SD) 244.51 (203.04) 197.23 (106.33) 679.36 (326.8) Median (IQR) 200 (100,300) 200 (100,300) 600 (500,700) Range: Minimum 0.00.00 500.00 Maximum 4700.00 400.00 4700.00 p-value* <0.001 90.2% 9.8% *Chi square 12
Demographics TOTAL POPULATION 400/µL N = 33,473 Eosinophil count P- >400/µL N = 3,639 value* Sex n (%) male 16,615 (49.6) 2,217 (60.9) <0.001 Age (years) median [IQR] 71 (63,78) 71 (63,79) 0.001 BMI (kg/m 2 ) COPD diagnosis based on FVC ratio n(%) GOLD status based on FEV 1 Predicted Percent n(%) Smoking Status n(%) % of non-missing 97.1% 96.5% Median (IQR) 26.51 (23,30.5) 26.44 (23.1,30.1) % of non-missing 58.1% 58.5% Yes (FVC ratio<0.7) 14,515 (74.6) 1,603 (75.3) % of non-missing 81% 82% GOLD 4 (very severe): <30 n (%) 1,422 (5.3) 152 (5.2) GOLD 3 (severe): 30-49 n (%) 6,477 (24.2) 688 (23.7) GOLD 2 (moderate): 50-79 n (%) 13,903 (52) 1,541 (53.1) GOLD 1 (mild): >=80 n (%) 4,921 (18.4) 523 (18) Non-smokers 5,460 (14.7) 4,832 (14.4) Current smokers 12,448 (33.5) 11,371 (34) Ex-smokers 19,204 (51.7) 17,270 (51.6) 0.329 0.502 0.768 <0.001 Co-morbid Asthma n(%) 14,081 (42.1) 1,754 (48.2) <0.001 Co-morbid rhinitis n(%) Allergic 2,467 (7.4) 341 (9.4) Non-allergic 1,895 (5.7) 230 (6.3) <0.001 Co-morbid Eczema n(%) 7,019 (21) 838 (23) 0.004 * Mann-Whitney/Chi square 13
Baseline clinical characteristics TOTAL POPULATION Eosinophil count 400/µL >400/µL N = 33,473 N = 3,639 0 n (%) 18,077 (54) 1,823 (50.1) Severe exacerbations 1 n (%) 8,278 (24.7) 913 (25.1) n(%) 2-3 n (%) 5448 (16.3) 688 (18.9) 4+ n (%) 1,670 (5) 215 (5.9) ICS + LABA n (%) 8,923 (26.7) 1,066 (29.3) NONE n (%) 7,602 (22.7) 685 (18.8) ICS + LABA + LAMA n (%) 4,874 (14.6) 549 (15.1) SAMA +/- SABA n (%) 4,812 (14.4) 492 (13.5) ICS n (%) 3,828 (11.4) 423 (11.6) LAMA n (%) 1,394 (4.2) 131 (3.6) LABA n (%) 593 (1.8) 82 (2.3) ICS + LAMA n (%) 455 (1.4) 49 (1.3) Treatment therapy ICS + LABA + LTRA n (%) 383 (1.1) 72 (2) n(%) ICS + LABA + LAMA + LTRA n (%) 242 (0.7) 41 (1.1) LABA + LAMA n (%) 193 (0.6) 22 (0.6) OTHER n (%) 56 (0.2) 10 (0.3) LTRA n (%) 50 (0.1) 10 (0.3) ICS + LTRA n (%) 39 (0.1) 2 (0.1) LAMA + LTRA n (%) 17 (0.1) 1 (0) ICS + LAMA + LTRA n (%) 9 (0) 3 (0.1) LABA + LTRA n (%) 3 (0) 1 (0) 0 14,693 (43.9) 1,431 (39.3) ICS daily dose 1-400 5,963 (17.8) 676 (18.6) (mcg, FP-equivalent) 401-800 4,551 (13.6) 534 (14.7) n(%) >800 8,266 (24.7) 998 (27.4) 14 * Mann-Whitney/Chi square P- value* <0.001 <0.001 <0.001
Outcome analysis One year after the date of the last valid eosinophil count for outcome evaluation 15
Severe exacerbations: total population TOTAL 400 /µl >400 /µl N (%) 37,112 (100) 33,473 (90.2) 3,639 (9.8) Rate Ratio unadjusted (95% CI) 1.00 1.13 (1.07,1.94) p*=0.001 The incidence rate of outcome COPD exacerbations is estimated to be 13% higher in the group of patients with raised eosinophil counts (p<0.001). *Chi square 16
Exacerbations: spirometry-defined COPD TOTAL 400 /µl >400 /µl N (%) 16,118 (100) 14,515 (90.1) 1,603 (9.9) Rate Ratio unadjusted (95% CI) 1.00 1.15 (1.07,1.25) p*=0.001 The incidence rate of outcome COPD exacerbations is estimated to be 15% higher in the group of patients with raised eosinophil counts (p<0.001). *Chi square 17
Exacerbations: comorbid asthma Comorbid Asthma Diagnosis NO Comorbid Asthma Diagnosis TOTAL 400 /µl >400 /µl N (%) 15,835 (100) 14,081 (88.9) 1,754 (11.1) Rate Ratio unadjusted (95% CI) 1.00 1.11(1.04,1.19) TOTAL 400 /µl >400 /µl N (%) 21,277 (100) 19,392 (91.1) 1,885 (8.9 Rate Ratio unadjusted (95% CI) 1.00 1.09(1.01,1. p*=0.006 p*=0.107 The incidence rate of outcome COPD exacerbations is estimated to be 11% higher in the group of patients with raised eosinophil counts (p=0.002). *Chi square The incidence rate of outcome COPD exacerbations is estimated to be 9% higher in the group of patients with raised eosinophil counts (p=0.023). 18
Exacerbations: summary by subgroup 400/µl eosinophil count = 1.00 Total Population Patients with FVC Ratio<0.7 Patients with co-morbid asthma Patients with no co-morbid asthma Lower in patients with higher eosinophil counts Higher in patients with higher eosinophil counts 1.13 (1.07,1.94) 1.15 (1.07,1.25) 1.11 (1.04,1.19) 1.09 (1.01,1.19) Higher exacerbations rates in patients with higher eosinophil counts 0.7 0.85 1 1.10 1.15 1.20 Rate ratios (95% CI) 19