GSK Medicine: salmeterol, Salmeterol+Fluticasone proprionate, fluticasone propionate, beclomethasone

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1 GSK Medicine: salmeterol, Salmeterol+Fluticasone proprionate, fluticasone propionate, beclomethasone Study No.: WWE111984/WEUSRTP2640/EPI40528 Title: The Asthma Death Case Control Study (ADCCS): Association between Recent Medication Use and Asthma Mortality Rationale: Two clinical trials reported evidence of an increased risk of asthma-related death in patients treated with salmeterol, a long-acting beta2-agonist (LABA) [Castle, 1993; Nelson, 2006]; however, observational studies conducted to date have not reported this association. The largest observational study conducted to date is the British Asthma Death Case-Control Study (ADCCS), which consisted of 532 asthma deaths (cases) and 532 controls with hospital admissions for asthma (controls) [Anderson, 2005]. Based on mentions in the primary care record, this original ADCCS study investigated use of LABA in the 0 to 3 months, >3 to 12 months or >1 to 5 years prior to index date (date of death for cases; date of asthma admission for controls). However, comparisons between cases and controls in the period immediately leading up to the index date may have been differentially biased, as medication information in the primary care notes was not as complete in the cases relative to the controls. Objectives: After adjusting for previously identified sources of bias in the 2005 Anderson study, this study was conducted using ADCCS data to investigate the association between asthma death and recent mention of LABA in the primary care record including potential effect modification by inhaled corticosteroids (ICS). The primary objective of the current study was to examine: current use of LABA ( 2 months of index date) and the risk of asthma death including effect modification by the concurrent use of ICS (within one month either side of LABA). Secondary objectives were to examine 1) Recent use of LABA (>2 to 6 months prior to index date) and the risk of asthma death including effect modification by the concurrent use of ICS, 2) Use of other medications and the risk of asthma death (oral corticosteroids, inhaled corticosteroids, inhaled short-acting beta2-agonists and antibiotics), and 3) Effect modification by age and by deprivation rank. Indication: asthma Study Investigators/Centers: H. Ross Anderson, St. George s, University of London. Research Methods: Data Source: The original ADCSS study extracted data from anonymized photocopies of primary care records covering the 5 years prior to the index date. Primary care records could include the general practitioner s notes, computer printouts, referral letters, hospital discharge, and outpatient letters. Data for the original analysis were extracted in a blinded fashion to patient case-control status from the paper records with details described previously [Anderson, 2005]. As a continuation of the ADCCS, more detailed information was extracted on asthma medications and antibiotics mentioned in the 7 months leading up to the index event. In addition, information on COPD and other chronic lung diseases was re-extracted in an attempt to improve data quality. The new information required for this study was extracted twice in a blinded fashion and resulting data was entered into the preexisting ADCCS study database. 1

2 Study Design: Case-control study. This was a retrospective case-control study of asthma patients in Britain. The ADCCS consisted of 532 asthma deaths (cases) between 1994 and 1998 and 532 hospital admissions with a primary discharge diagnosis of asthma (controls). The index date was the date of death for cases and the date of hospital admission for the controls. Cases and controls were matched on hospital, index date and age. Study Population: Asthma patients in this study were younger than 65 years of age living within specific areas of England, the populated central belt of Scotland, and all of Wales. Study areas in England included East Anglia, North Essex, West Midlands, Northampton and Kettering, Cumbria and districts north of the Tyne. Asthma deaths (cases) were identified between for England and Wales, and in Scotland between 1996 and All patients were considered to have severe asthma as controls experienced an asthma-related hospitalization and cases died due to asthma. Study Exposures, Outcomes: Exposure: Exposures were defined as prescribed asthma medications according to the primary care record. The primary exposure of interest was long-acting beta2-agonists (LABA) prescription in the 0-2 months or >2 to 6 months prior to index date, with and without concurrent inhaled corticosteroids (ICS) prescription. Outcome: asthma-related death per death certificate Data Analysis Methods: The analysis was based on 532 cases and 532 controls analyzed in STATA 9 and10 using conditional logistic regression with case-control status as the dependent variable. Cases and controls were matched 1:1 on hospital, date of index event within 6 months, and age within 5 years. In terms of matching by hospital, the control was selected from the same or next nearest hospital to its case. If the case died in the community, the hospital to which the patient would have been admitted was chosen. For each medication class of interest, conditional logistic regression models were fitted to examine the effect of adjustment for important confounders. Unadjusted and adjusted model estimates were presented. The primary analysis adjusted for all confounders including age of asthma onset, mention of ever being obese, sex, number of previous hospital admissions for asthma in the past year and the >1 to 5 years prior, mention of COPD in the past 5 years, mention of other chronic lung disease in the past 5 years, mention of prescription for other asthma medication classes, index of deprivation rank, and country. Deprivation scores and their ranks were based on government indices calculated by each country and were not directly comparable. Variables in the model that were not dichotomous were entered as continuous variables, after assessing linearity using fractional polynomials. Interactions were examined in the model to identify potential effect modification. Effect modification of the association between LABA and risk of asthma death by concurrent ICS was evaluated. Effect modification was also examined with respect to age (< 45 years and 45 to 64 years) and deprivation (England less deprived, England more deprived, Scotland less deprived, Scotland more deprived, Wales less deprived and Wales more deprived), having categorised deprivation rank within country according to being above or below the country-specific median rank. The associations between medication class and asthma death and interaction terms in the model were assessed at the 5% significance level using the likelihood ratio test. 2

3 Limitations: This study utilized paper records from the general practice notes, including 5 years prior to the index date (death among cases or asthma hospitalization among controls). The analysis was based on mentions of patient demographics, asthma history, and asthma medication in the paper record. Mentions of medication and/or references to prescriptions in the paper record may not correspond to actual use of medications. In addition, information in the records may not have been as detailed or complete for some patients relative to others. There was the potential for residual confounding by severity despite matching cases and controls and having a control group that had been hospitalized for asthma Cases were significantly different with respect to earlier age of asthma onset and a higher proportion with mention of COPD and other chronic lung diseases in the last 5 years. While these factors were adjusted for in the analysis, cases and controls could be different in other ways that could not be accounted for in the analysis. Asthma management and treatment guidelines have changed since this study period ( ), which was before the approval of treatment alternatives including ICS/LABA combination therapy in a single device; therefore, the use of ICS and LABA in a single device could not be evaluated. The modifying effect of ICS use with LABA used in two devices could not be fully evaluated due to low power, as 92% of patients with mention of LABA in the past 6 months also had a mention of ICS concurrently (within one month in the patient record). Despite these limitations, these data provide important information on the safety of LABA including salmeterol. 3

4 Study Results: Median age was 53 years (interquartile range 40 to 59) for both cases and controls, who were also similar with respect to their proportion of males and females. The case series included 262 community deaths and 270 deaths in hospital with 140 dying on the day of admission. Compared to controls, cases had a significantly earlier age of asthma onset (p=0.013), higher proportions with mention of COPD (p=0.010) and other chronic lung disease (p=0.046) in the last 5 years, and a higher proportion of obesity (p=0.037) (Table1 ). Primary Objective: There was no evidence of an overall association between asthma death and mention of LABA in the primary care record in the 0-2 months prior to index date (odds ratio = 0.89 (0.61 to 1.30)) (Table 2). The odds ratios for LABA with and without a concurrent mention of inhaled corticosteroids were 0.92 (0.62 to 1.37) and 0.75 (0.32 to 1.77), respectively. Most controls with mention of LABA within the past 6 months also had a concurrent mention of ICS (92%), limiting the statistical power to detect any potential modifying effects of ICS. Secondary Objectives: There was no evidence of an overall association between asthma death and mention of LABA in the primary care record in the >2-6 months prior to index date (odds ratio = 1.08 (0.76 to 1.53)); although odds ratios differed significantly when comparing the under 45 year age group (0.63 (0.34 to 1.15) and the year age group (1.35 (0.90 to 2.03)). The odds ratios for LABA with and without a concurrent mention of inhaled corticosteroids were 1.05 (0.73 to 1.51) and 1.39 (0.53 to 3.65), respectively. Regarding medications in the two month period prior to the index date, mention of oral corticosteroids, injected corticosteroids or antibiotics were each significantly associated with a lower risk of asthma death. There was no evidence of an association of asthma death with either methylzanthines or inhaled corticosteroids. Atimuscarinics were associated with a statistically significant greater risk of asthma death, which was persistent in magnitude but was not statistically significant after full adjustment. In the period >2-6 months prior to the index date, there was no evidence of an association between asthma death and mention of corticosteroids (oral, inhaled, or injected), methylzanthines, antimuscarinics or antibiotics. During this period, short-acting beta2-agonists (SABA) were associated with a statistically significant increased risk of asthma death that persisted in magnitude but was not statistically significant after full adjustment. The odds ratios for SABA differed significantly across the 6 categories (i.e. England less deprived, England more deprived, Scotland less deprived, Scotland more deprived, Wales less deprived, Wales more deprived) formed by country and deprivation rank (OR=2.72 (1.48 to 5.00); OR=1.56 (0.97 to 2.52); OR=1.04 (0.28 to 3.83); OR=0.87 (0.39 to 1.93); OR=0.48 (0.14 to 1.64); OR=0.72 (0.33 to 1.55)) respectively. This pattern of results by SABA and region was unexpected and difficult to interpret. Table 1: Demographics/Baseline Characteristics Characteristic Cases (n = 532) Controls (n = 532) % % Median age (yrs) (interquartile range) 53 (40-59) 53 (40-59) Country England

5 Scotland Wales Females Median age at onset (yrs) 30 (10-47) 33 (13-49) COPD mentioned in the last 5 years Other chronic lung disease in the last 5 years # Obesity mentioned ever Death Information (Cases Only) Community death 49.2 NA Hospital death relative to admission Death on day of admission 29.7 NA 1-7 days after admission 12.2 NA 8-14 days after admission 3.0 NA days after admission 3.2 NA days after admission 1.3 NA >52 days after admission 1.3 NA Hospital admissions for asthma In the last year >1 to 5 years Median No. of hospital admissions for asthma in 2 (1-3) 2 (1-3) the last year (interquartile range) Median No. of hospital admissions for asthma in the last >1 to 5 years (interquartile range) 2 (1-5) 2 (1-5) # Other chronic lung diseases include bronchiectasis, aspergillosis, pulmonary TB and pulmonary fibrosis Information on age of onset missing for 39 cases and 30 controls. Includes 18 patients with missing information on length of stay. Figures take account of length of index admission etc. through censoring 5

6 Table 2: Primary and Secondary Outcome(s): Risk of asthma-related death associated with asthma medication use in time periods prior to index date Drug class Unadjusted Model Adjusted Model OR (95% CI) OR (95% CI) Mention in prior 0-2 months (n=1032) Short acting 2-agonists All to to 1.93 Long acting 2-agonists All to to 1.30 Salmeterol to to 1.20 Antimuscarinics All 1.34* 1.01 to to 1.95 Corticosteroids All to *** 0.36 to 0.73 Inhaled to to 1.22 Oral to ** 0.49 to 0.88 Injected 0.41* 0.18 to * 0.14 to 0.81 Methylzanthines All to to 1.73 Antibiotics All to * 0.50 to 0.92 Drug class Unadjusted Model Adjusted Model OR (95% CI) OR (95% CI) Mention in the >2 months to 6 months prior (n=1052) Short acting 2-agonists All 1.35* 1.05 to to 1.99 Long acting 2-agonists All to to 1.53 Salmeterol to to 1.45 Antimuscarinics All to to 1.55 Corticosteroids All to to 1.43 Inhaled to to 1.20 Oral to to 1.33 Injected to to 2.58 Methylzanthines All to to 1.38 Antibiotics All to to 1.26 Adjusted for matching and sex only Adjusted for matching, sex, age of asthma onset, mention of obesity ever, number of hospital admissions for asthma in the past year and >1 to 5 years prior, mention of COPD in the past 5 years, mention of other chronic lung disease in the past 5 years, mention / prescription of other asthma drug classes (as appropriate), and deprivation rank within country (Sources of deprivation data: National Statistics, Ordinance Survey, Office of the Deputy Priminister, Welsh Assembly Government, The Scottish Government). * p<0.05, ** p<0.01, *** p<0.001 Conclusion: In this British population-based case-control study, there was no evidence of an overall association between asthma death and recent prescriptions of LABA either in the 0-2 months prior or the >2-6 months prior to the index date after adjusting for measured confounders. In the 6-month period prior to the index date, most controls with LABA mentioned in their primary care record also had a mention of concurrent ICS (92%), limiting the statistical power to detect any modifying effects of ICS when used with LABA. In the 0-2 month period prior to the index date, mention of oral corticosteroids, injected corticosteroids and antibiotics were each significantly associated with a lower risk of asthma death, which may reflect appropriate asthma treatment and/or health care utilization. 6