Inhaled Corticosteroid vs. Add-On Long-Acting Beta-Agonist for Step-Up Therapy in Asthma

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1 Online Data Supplement Inhaled Corticosteroid vs. Add-On Long-Acting Beta-Agonist for Step-Up Therapy in Asthma Elliot Israel, Nicolas Roche, Richard J. Martin, Gene Colice, Paul M. Dorinsky, Dirkje S. Postma, Theresa W. Guilbert, Willem M. C. van Aalderen, Jonathan Grigg, Elizabeth V. Hillyer, Anne Burden, Julie von Ziegenweidt, Victoria Thomas, David B. Price

2 Supplementary Methods We drew on two UK primary care databases, the General Practice Research Database (GPRD) and the Optimum Patient Care Research Database (OPCRD) to study asthma-related outcomes for patients treated with ICS monotherapy who were prescribed a step up in asthma therapy. The GPRD (now part of the Clinical Practice Research Datalink) (E1) contained de-identified medical record data, including 3.6 million active records, from approximately 450 subscribing primary care practices throughout the UK (E2, E3). The OPCRD is an anonymized clinical research database containing medical record data and results of patient questionnaires from the OPC clinical advisory service, including approximately 350,000 patients with asthma or chronic obstructive pulmonary disease (COPD) at 300 primary care practices across the UK at the time of this study (E4, E5) Approval was given for use of the GPRD data by the GPRD Independent Scientific Advisory Committee. The OPCRD has been approved by Trent Multi Centre Research Ethics Committee for clinical research use, and the study protocol was approved by ADEPT (Anonymised Data Ethics Protocols and Transparency Committee), OPC s independent scientific advisory committee. The study was conducted to standards suggested for observational studies, including an independent advisory group, use of an a priori analysis plan, commitment to publish, and use of well-maintained and monitored study databases (E6). For the inhaled corticosteroid (ICS) step-up cohorts, the index date was defined as the date of the latest recorded increase in ICS dose with at least 1 year follow-up in the database. E2

3 Study Oversight Data acquisition and analysis were funded by an unrestricted grant from Teva Pharmaceuticals. Access to data from the Optimum Patient Care Research Database was co-funded by Research in Real Life Ltd (RiRL). Teva played no role in the conduct of the study, final interpretation of the results, or decision to submit the manuscript for publication. Data were collected and analyzed by the authors in the research team at RiRL, and the first draft of the manuscript was written by one of the authors. All authors provided input on the study design, selection of outcome measures, interpretation of the data, writing and revision of the paper, and decision to submit the paper for publication. Statistical Analysis We elected to conduct matched cohort analyses because characterization of patients at baseline indicated statistically and clinically significant differences between cohorts. Unmatched patients in the ICS step-up cohort had markers of less severe asthma (for example, fewer recorded exacerbations and lower prescribed ICS doses); patients in the combination ICS/LABA cohort were more likely to be male. Matching was conducted before the analysis of outcomes; therefore, the matching was blinded to outcomes in the outcome year. If more than one match was identified for a given patient, bespoke software was used to randomly select unique matched pairs. For matching purposes, doses of budesonide and large-particle beclomethasone (Clenil Modulite, Chiesi) were halved, and fluticasone doses of 250 μg and 500 μg were treated as equivalent to small-particle beclomethasone (Qvar) 200 μg and 400 μg, respectively. Index date E3

4 ICS doses are reported as halved budesonide doses and actual small-particle beclomethasone and fluticasone doses. E4

5 Labeled Doses Used in These Analyses: UK Labeling Medication Labeled dose Ex-valve dose Ex-actuator (μg/puff) (μg) dose (μg) Salbutamol (albuterol) Small-particle beclomethasone (Qvar) Fluticasone (Flixotide) Potential Confounders Examined We assessed numerous potential confounding variables, including differences between treatment cohorts at baseline that we considered possibly important (P<0.10) and baseline variables predictive (P<0.05) of each effectiveness outcome in multivariate analyses. Variables meeting these criteria were examined for collinearity and clinical importance to select those used as potential confounders in the regression modeling of outcomes. Spearman correlation coefficients were calculated between all potential confounders to determine strengths of linear relationships between variables. The correlation coefficients were considered, in conjunction with clinical interpretation, to identify pairings of variables that could present collinearity issues at the modelling stage. Scatter plots and error bars were used if necessary to further investigate E5

6 relationships. This final group of non-collinear potential confounders was entered into the relevant model which was step-wise reduced. Potential confounders examined at (or closest to) the relevant index date: Age Sex Height Weight Lung function, in terms of peak flow readings Smoking status Potential confounders examined regardless of when they occurred relative to the index date: Date of first asthma, other respiratory and allergy-related diagnosis (where known) Other respiratory or other confounding diagnoses, including: rhinitis, smoking history, COPD, gastroesophageal reflux disease and cardiac disease. Comorbidities were also expressed using the Charlson comorbidity index (CCI). Potential confounders examined in the year before the index date: All asthma, allergy, and other respiratory treatments Where ICS have been prescribed, the total dose prescribed as actual dose for smallparticle beclomethasone (Qvar) and fluticasone and half of prescribed dose of budesonide and large-particle beclomethasone (Clenil) for equivalence with smallparticle beclomethasone Number of GP consultations for asthma or other respiratory illness SABA dose E6

7 Proxy composite measure for asthma control Number of hospital outpatient department (OPD) attendances where asthma was recorded as the reason for referral Number of asthma or possibly respiratory-related hospitalizations (a non-specific hospitalization code and an asthma / respiratory code within a 1-week window) Number of prescriptions for any antibiotic where the reason for the prescription was either a lower or upper respiratory tract infection Other medications that might interfere with asthma control, e.g., beta blockers, nonsteroidal anti-inflammatory drugs, and acetaminophen E7

8 References E1 The Clinical Practice Research Datalink. NHS National Institute for Health Research (NIHR) and the Medicines and Healthcare products Regulatory Agency (MHRA). Available at: Accessed November 20, E2 Jick SS, Kaye JA, Vasilakis-Scaramozza C, Garcia Rodriguez LA, Ruigomez A, Meier CR, Schlienger RG, Black C, Jick H. Validity of the General Practice Research Database. Pharmacotherapy 2003;23: E3 Hollowell J. The General Practice Research Database: quality of morbidity data. Popul Trends 1997: E4 Optimum Patient Care Research Database. Available at: Accessed November 20, E5 Jones RC, Price D, Ryan D, Sims EJ, von Ziegenweidt J, Mascarenhas L, Burden A, Halpin DM, Winter R, Hill S, Kearney M, Holton K, Moger A, Freeman D, Chisholm A, Bateman ED. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med 2014;2: E6 Roche N, Reddel H, Martin R, Brusselle G, Papi A, Thomas M, Postma D, Thomas V, Rand C, Chisholm A, Price D. Quality standards for real-world research. Focus on observational database studies of comparative effectiveness. Ann Am Thorac Soc 2014;11 Suppl 2:S99- S104. E8

9 Figure legends Figure E1. Patient selection in the datasets for small-particle ICS and ICS/LABA combination cohorts Definition of abbreviations: BDP = beclomethasone dipropionate; BAI = breath-actuated inhaler; COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; FDC = fixed-dose combination; ICS = inhaled corticosteroid; COPD = chronic obstructive pulmonary disease; LABA = long-acting β-agonist; OCS = oral corticosteroid; pmdi = pressurized metered-dose inhaler; Rx = therapy; Script = prescription. Figure E2. Patient cohort two-way matching for small-particle ICS and ICS/LABA combination cohorts. Definition of abbreviations: BDP = denotes beclomethasone dipropionate; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; SABA = short-acting β-agonist. Figure E3. Patient selection in the datasets for standard size-particle ICS (see Figure E1 for patient selection for the ICS/LABA combination cohort) and two-way matching for standard size-particle ICS vs. ICS/LABA combination cohorts. Definition of abbreviations: ICS = inhaled corticosteroid; COPD = chronic obstructive pulmonary disease; LABA = long-acting β-agonist; OCS = oral corticosteroid; SABA = short-acting β-agonist. E9

10 Table E1. Additional baseline demographic and clinical characteristics of the patients in ICS step-up and ICS/LABA combination inhaler cohorts Small-particle ICS step-up vs. ICS/LABA comb inhaler Standard size-particle ICS step-up vs. ICS/LABA comb inhaler Characteristic ICS/LABA ICS/LABA ICS step-up ICS step-up combination combination (N = 3036) (N = 809) (N = 3036) (N = 809) Body mass index, kg/m 2, mean (SD) 27.6 (6.2) 27.6 (6.3) 25.9 (9.1) 27.7 (6.2)*** 1 prescription prior 12 mo, n (%) Nonsteroidal anti-inflammatory drug 678 (22.3) 701 (23.1) 194 (24.0) 190 (23.5) Beta blocker 91 (3.0) 91 (3.0) 19 (2.3) 28 (3.5) Acetaminophen 662 (21.8) 654 (21.5) 166 (20.5) 189 (23.4) Database code for asthma, n (%) 2912 (95.9) 2898 (95.5) 791 (97.8) 789 (97.5) Spacer device used, n (%) 418 (13.8) 394 (13.0) 167 (20.6) 122 (15.1) Acute respiratory events, n (%) (66.1) 2027 (66.8) 508 (62.8) 510 (63.0) (21.2) 648 (21.3) 173 (21.4) 180 (22.2) (8.3) 229 (7.5) 85 (10.5) 74 (9.1) (4.3) 132 (4.3) 43 (5.3) 45 (5.6) Asthma prescriptions, median (IQR) 5 (3 9) 5 (3 8)** 6 (3 9) 5 (3 9) E10

11 1 LTRA prescription prior 12 months, n (%) 51 (1.7) 61 (2.0) 23 (2.8) 26 (3.2) All primary care consultations, median (IQR) 7 (4 11) 7 (4 11) 8 (5 14) 7 (4 12)* Oropharyngeal candidiasis, n (%) 111 (3.7) 87 (2.9) 40 (4.9) 30 (3.7) Definition of abbreviations: ICS = inhaled corticosteroid; IQR = interquartile range; LABA = long-acting β-agonist. *P 0.05, **P<0.01, ***P<0.001, conditional logistic regression for two-way comparison between cohorts. Recorded data were available for body mass index for 2781 (91.6%) and 2778 (91.5%) patients in small-particle ICS step-up and ICS/LABA combination cohorts, respectively, and for 771 (95.3%) and 742 (91.7%) in standard size-particle ICS and ICS/LABA combination cohorts, respectively. E11

12 Table E2. Sensitivity analysis: baseline exacerbations and acute respiratory events in non-smoking matched patients in ICS step-up and ICS/LABA combination inhaler cohorts Characteristic Severe exacerbations, n (%) Small-particle ICS step-up vs. ICS/LABA comb inhaler ICS/LABA ICS step-up combination (N = 2040) (N = 2040) Standard size-particle ICS step-up vs. ICS/LABA comb inhaler ICS/LABA ICS step-up combination (N = 571) (N = 571) (76.0) 1554 (76.2) 415 (72.7) 418 (73.2) (16.2) 347 (17.0) 95 (16.6) 98 (17.2) (5.1) 93 (4.6) 40 (7.0) 36 (6.3) 3 56 (2.7) 46 (2.3) 21 (3.7) 19 (3.3) Acute respiratory events, n (%) (68.2) 1406 (68.9) 367 (64.3) 368 (64.4) (19.8) 413 (20.2) 116 (20.3) 117 (20.5) (7.5) 137 (6.7) 60 (10.5) 54 (9.5) 3 92 (4.5) 84 (4.1) 28 (4.9) 32 (5.6) No significant differences between cohorts (conditional logistic regression). E12

13 Table E3. Sensitivity analysis: outcome year exacerbations and acute respiratory events in non-smoking matched patients in ICS step-up and ICS/LABA combination inhaler cohorts Outcome Severe exacerbations, n (%) ICS Step-Up Small-particle ICS step-up (N = 2040) ICS/LABA Combination ICS/LABA combination (N = 2040) Adjusted Rate Ratio for ICS Step-Up (95% CI) (84.4) 1733 (85.0) 1.05 ( )* (11.2) 225 (11.0) 2 45 (2.2) 48 (2.4) 3 44 (2.2) 34 (1.7) Acute respiratory events, n (%) (77.4) 1573 (77.1) 1.05 ( ) (15.7) 337 (16.5) 2 83 (4.1) 81 (4.0) 3 58 (2.8) 49 (2.4) Severe exacerbations, n (%) Standard Size-Part. ICS step-up (N = 571) ICS/LABA combination (N = 571) (80.9) 476 (83.4) 1.21 ( ) 1 69 (12.1) 63 (11.0) 2 25 (4.4) 18 (3.2) 3 15 (2.6) 14 (2.5) Acute respiratory events, n (%) (72.7) 435 (76.2) 1.21 ( ) 1 99 (17.3) 92 (16.1) E13

14 2 34 (6.0) 22 (3.9) 3 23 (4.0) 22 (3.9) Definition of abbreviations: ICS = inhaled corticosteroid; LABA = long-acting β-agonist. *Adjusted for numbers of primary care consultations and acute courses of oral steroids. Adjusted for numbers of antibiotic prescriptions for lower respiratory tract infection and acute courses of oral steroids. Adjusted for Charlson comorbidity index score and number of baseline severe exacerbations. Adjusted for number of non-asthma consultations for lower respiratory tract infection and baseline acute respiratory events. E14

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