Providing Answers to Healthcare by Observational Studies (PATHOS) Do all ICS/LABAs provide equal exacerbation protection & safety benefits to COPD patients?

Combination Inhalers Seretide Symbicort Fluticasone/Salmeterol Budesonide/Formoterol Combination Inhalers Seretide Symbicort

Goals for treatment of stable COPD Reduce symptom Relieve symptoms (Improve lung function) Improve exercise tolerance Improve health status Reduce risk Prevent and treat exacerbations Prevent disease progression Reduce mortality Exacerbation FEV1 decline Mortality GOLD updated 2014.

PATHOS Study Design Retrospective, observational, population-based study Medical records data from primary health care centres was collected and linked to data from national mandatory Swedish registries Patients were followed from January 1999 to December 2009, or end of treatment with fixed ICS/LABA combination therapy, emigration or death Title: PATHOS Study Design Notes: PATHOS is an observational, retrospective, population-based, cohort study that examined the medical records of 21,361 COPD patients in Sweden over an 11 year period. Medical records data from primary health care centers was linked to national, mandatory Swedish healthcare registries, including hospital, drug, and cause of death register data for 1999-2009. Seventy- six centres were included covering approximately 8% of Swedish primary care centres with a catchment area comprising 8% of the Swedish population. Patients were followed from 1 January 1999 to the end of the study on 31 December 2009, or end of treatment with the fixed ICS/LABA combination, emigration or death. Additional Notes: The Swedish primary care system is organized into primary healthcare centres (compulsory first point of contact). Each centre isresponsible for a defined population (a patient list or a defined catchment area). For specialist consultation, patients are referred to secondary care. No formal stratification of primary healthcare centres was performed, but effort was made to ensure that the sample was representative of the Swedish population reflecting the COPD healthcare provisionthrough a mixture of rural and urban areas, public and private providers and centre size. Reference: Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 Disclaimer: Fluticasone/Salmeterol combination 250/50 mcg twice daily is the only approved dosage for the treatment of COPD in Korea.

Full Population Register Merge Linked independent of AZ by Swedish National Board of Health and Welfare Hospital Discharge Register Hospital out-patient care Medical records data Cause of Death Register Socio economic register Prescription Register Uppsala University 21, 361 COPD patients were tracked through social security number from primary care centre Followed until death or emigration Department of Public Health and Caring Sciences Title: Full Population Register Notes: Data were extracted from medical records [e.g. date of birth, gender, diagnoses according to International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) codes, number of primary healthcare centre contacts, lung function assessments and collections of drug prescriptions] using an established software system (Pygargus Customized eXtraction Program, CXP; Pygargus AB, Stockholm, Sweden) [19, 20]. The personal identification number used to identify patients with respect to all contacts with healthcare professionals was replaced by a study identificationnumber prior to further data processing. Data were also extracted retrospectively from mandatory Swedish national registries. Data regarding morbidity and mortality were collected from the National Patient Register, inpatient (admission and discharge dates, and main and secondary diagnoses) and outpatient hospital care (number of contacts and diagnoses according to ICD-10-CM codes), and the Cause of Death register [date and cause(s) of death]. Data regarding drug prescriptions from hospital and primary care were collected from the Swedish Prescribed Drug Register. General population data, such as number and gender distribution per each year of birth, were generated by Statistics Sweden (SCB, Stockholm, Sweden). The linkage of data obtained from the national registers and primarycare centres was performed by the Swedish National Board of Health and Welfare. The linked database was managed by the Department of Public Health and Caring Sciences, Uppsala University,Sweden. Reference: Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 Adapted from Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 And Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Patient Flow Linked data from 76 centres throughout Sweden ~8% of the Swedish population Patients who met the COPD criteria in the time period n = 21,361 Patients with a record of fixed ICS/LABA therapy (Index date) n = 9,893 Pair-wise (1:1) matching of propensity scores was performed Title: Patient Flow Notes: A total of 21 361 patients who met the inclusion criteria of a recorded COPD diagnosis were identified within the study period. Of these patients, 9893 (53% female, mean age 67 years) had a record of fixed ICS/LABA combination therapy following COPD diagnosis and were eligible for matching: 7155 patients treated with budesonide/ formoterol and 2738 patients with fluticasone/ salmeterol at the index date, that is, the start of ICS/LABA treatment. The scores for estimated probability of treatment between the budesonide/f ormoterol and fluticasone/salmeterol populations showed overlapping distributions, indicating well-balanced cohorts prior to propensity score matching; however, there were some between-group differences (Table 1). Pairwise matching (1 : 1) resulted in two cohorts of 2734 patients each, with similar characteristics. All but four patients with fluticasone/salmeterol prescriptions at the index date could be matched into pairs with equivalent budesonide/formoterol patients. Reference: Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 BUD/FOR (7155 [72%]) matched cohort n = 2,734 FLU/SAL (2738 [28%]*) matched cohort n = 2,734 * All but 4 patients in FLU/SAL group at index date could be matched within the larger BUD/FOR cohort Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Propensity Score Matching Propensity score matching was used to assess each COPD patient’s disease severity on an individual basis before matching using up to 31 variables* A baseline period of 2 years pre-index was used for all variables Variables included in the propensity scoring: Age, gender, time since COPD diagnosis Medication (rate based): antibiotics, SABA, oral/inhaled steroids, anticholinergics, cardiovascular medications Hospitalisations (rate based) for exacerbations, any cardiovascular reason, pneumonia and asthma Co-morbidities: asthma diagnosis, diabetes, cancer, heart failure, hypertension, diagnosis of stroke FEV1 as % of predicted (if available) Title: Propensity Score Matching Notes: Propensity score matching was used to compensate for concerns related to nonrandom assignment of patients to treatments to reduce potential confounding caused by unbalanced covariates. A five to one digit matching was performed without replacement and a nonhierarchal order of variables. Statistical analyses were performed using the matched data. Patients treated with either budesonide/formoterol or fluticasone/ salmeterol were matched, and the propensity score calculated based on the following criteria 2 years preceding and/or at the index date: age; gender; available lung function measurements; number of outpatient visits for acute COPD; number of prescriptions for antibiotics, oral steroids, tiotropium, ipratropium, ICSs, SABAs, LABAs, angiotensin receptor blockers, b-blockers, statins, calcium antagonists and thiazides; diagnosis of diabetes, asthma, cancer, rheumatoid arthritis, heart failure, hypertension and stroke; and number of previous hospitalizations. The sum of outpatient visits, yearly rate of oral steroid and antibiotic prescriptions, and yearly rate of hospitalizations for acute COPD before the index date. was also included in the propensity score matching. A number of different sensitivity analyses were performed. The effect of propensity score matching was tested by adding the matching variables, both cumulative and one variable at a time, and by calculating the crude rates (without matching). A sensitivity analysis of the Poisson regression was conducted using only events that occurred up to 1 month after the first switch of fixed combination, and by adding the calendar year as a covariate. Reference: Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 * It was not possible to match for weight, height, BMI (measurements available for only a minority). Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Larsson K et al., Journal of Internal Medicine, 2013, 273; 584–594

AECOPD among pairwise (1 : 1) propensity score-matched populations of COPD patients treated with Symbicort vs. Seretide Larsson K et al., Journal of Internal Medicine, 2013, 273; 584–594

with BUD/FORM (n=2734) or FLU/SAL (n=2734) AECOPD among pairwise (1 : 1) propensity score-matched populations of COPD patients treated with Symbicort vs. Seretide Events per 100 patient/years for exacerbations in propensity matched COPD patients treated with BUD/FORM (n=2734) or FLU/SAL (n=2734) Rate ratio (95% CI) ** 0.74 (0.69, 0.79) NNT = 3.4 ** 0.74 (0.68, 0.81) ** 0.70 (0.66, 0.75) ** 0.71 (0.65, 0.78) NNT = 16 Title: COPD Exacerbations Notes: Following matching, the postindex exacerbation rates were 0.80 and 1.09 per patient-year in the budesonide/formoterol and fluticasone/salmeterol treatment groups, respectively, corresponding to a 26.6% lower exacerbation rate [rate ratio 0.74, 95% confidence interval (CI) 0.69–0.79; P < 0.0001] in the budesonide/formoterol group. This corresponded to a number needed to treat with budesonide/formoterol versus fluticasone/salmeterol to prevent one exacerbation per patient-year equal to 3.4. In budesonide/formoterol-treated patients, the yearly rate of COPD-related hospitalizations was 0.15 compared with 0.21 in patients treated with fluticasone/salmeterol (P < 0.0001), corresponding to a difference of 29.1% between the two groups (rate ratio 0.71, 95% CI 0.65–0.78; P < 0.0001). Thus, the number needed to treat to prevent one COPD-related hospitalization per patient-year was 16.0 with budesonide/formoterol versus fluticasone/salmeterol. In total, 27.0% fewer days were spent in hospital due to exacerbations of COPD in the group treated with budesonide/formoterol (0.63 days year1) compared with the fluticasone/salmeterol-treated group (0.95 days year1; rate ratio 0.66, 95% CI 0.62–0.71; P < 0.0001). In addition, there were 21.0% fewer emergency visits in the budesonide/formoterol treatment group (0.027 events per patient-year) compared with those treated with fluticasone/salmeterol (0.034 events/patient-year; rate ratio 0.79, 95% CI 0.71– 0.89; P = 0.0003). Budesonide/formoterol-treated patients had 26.0% fewer courses of oral steroids (0.63 vs. 0.85 events per year; rate ratio 0.74, 95% CI 0.68–0.81; P < 0.0001) and 29.0% fewer antibiotic courses (0.38 vs. 0.54 events per year; rate ratio 0.70, 95% CI 0.66–0.75; P < 0.0001) than patients treated with fluticasone/salmeterol. Reference: Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067 * 0.79 (0.71, 0.89) Adjusted yearly rates of healthcare utilisation events were compared using Poisson regression analysis. **P<0.0001; *P=0.0003 for difference. CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol Larsson K et al., Journal of Internal Medicine, 2013, 273; 584–594

Number of exacerbations per patient per year Larsson K et al., Journal of Internal Medicine, 2013, 273; 584–594

Symbicort vs. Seretide for the Pneumonia Risk

Table 1| Baseline characteristics in two years before first prescription for inhaled corticosteroid/long acting β2 agonist after diagnosis of COPD according to fixed combination treatment. Unmatched and pairwise (1:1) propensity matched populations are shown. Figures are means (SD) unless specified otherwise

Pneumonia events by type for pairwise (1:1) propensity score matched populations Janson C et al., BMJ 2013;346:f3306

Event rate per 100 patient-years Pneumonia and Pneumonia-Related Events Pneumonia events in propensity matched COPD patients, per 100 patient/years BUD/FOR (n = 2734) or FLU/SAL (n = 2734) Rate ratio (95% CI) Increase risk for FLU/SAL NNH 1.73 (1.57 to1.90) 73% P < .001 23 1.74 (1.56 to1.94) 74% P < .001 34 1.56 (1.39 to 1.75) 56% P < 0.001 1.75 (1.53 to 2.00) 75% P < 0.001 Title: Pneumonia and Pneumonia-Related Events Notes: The difference observed between budesonide/formoterol and fluticasone/salmeterol with regard to pneumonia diagnosis was independent of where the diagnosis was recorded, in primary care or at hospital (67% of all diagnoses). Reference: Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 Event rate per 100 patient-years Adjusted yearly pneumonia event rates compared using Poisson regression analysis. P<0.001 for all. CI, confidence intervals; BUD/FOR, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol Disclaimer: Fluticasone/Salmeterol combination 250/50 mcg twice daily is the only approved dosage for the treatment of COPD in Korea. Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Cumulative Pneumonia Rate vs Time Fluticasone/Salmeterol group Any pneumonia Hospitalised pneumonia Budesonide/Formoterol group Any pneumonia Hospitalised pneumonia 110 100 All pneumonias RR 1.73 (1.57to 1.90) P < .001 NNH 23 90 80 70 Cumulative pneumonia rate per 100 patients 60 Hospitalised pneumonias RR 1.74 (1.56 to 1.94) P < .001 NNH 34 50 40 Title: Cumulative Pneumonia Rate vs Time Post-Index Notes: Events related to pneumonia In the matched groups, 2115 patients (39%) had at least one diagnosis of pneumonia recorded during the study period, resulting in a total event burden of 2746 recorded pneumonia events during 19 170 patient years of follow-up. There were significantly more pneumonia events in patients treated with fluticasone/salmeterol than with budesonide/formoterol. The pneumonia rate was 73% higher with fluticasone/salmeterol than with budesonide/formoterol (rate ratio 1.73, 95% confidence interval 1.57 to 1.90; P<0.001), with event rates of 11.0 (10.4 to 11.8) and 6.4 (6.0 to 6.9) per 100 patient years, respectively. The difference remained when investigators included the beclometasone diproprionate equivalent dose as a covariate in the Poisson regression. The corresponding number needed to treat (NNT) to avoid one pneumonia event per year was 23 (95% confidence interval 18 to 37). Similarly, admission to hospital related to pneumonia was 74% higher in the fluticasone/salmeterol treatment group than the budesonide/formoterol group (rate ratio 1.74, 1.56 to 1.94; P<0.001; NNT=34, 24 to 59), with a corresponding 82% increase in days in hospital (53 v 29 days per 100 patient years,respectively; P<0.001). Reference: Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 30 20 10 1 2 3 4 5 6 7 8 9 Years Adjusted yearly pneumonia event rates compared using Poisson regression analysis. Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306 Disclaimer: Fluticasone/Salmeterol combination 250/50 mcg twice daily is the only approved dosage for the treatment of COPD in Korea.

Time to All-Cause & Pneumonia-Related Death FLU/SAL BUD/FOR All-cause death Pneumonia-related death 5 25 Pneumonia deaths over full study period FLU/SAL=97 (3.5 %) BUD/FOR=52 (1.9%) D 1.6% over <11 yrs 4 20 P = 0.59 No difference in All-Cause Mortality 3 Fraction of patients (%) 15 HR 1.76 [95%CI: 1.22, 2.53]; P = 0.003 2 10 Title: Time to All-Cause & Pneumonia-Related Death Notes: All cause mortality did not differ between the two treatments (hazard ratio 1.08, 0.93 to 1.14; P=0.59). During follow-up, 149 matched patients (52 patients in the budesonide/formoterol cohort and 97 patients in the fluticasone/salmeterol cohort) died with pneumonia listed as one cause of death. This corresponded to a 76% increase in risk of mortality related to pneumonia with fluticasone/salmeterol versus budesonide/formoterol (hazard ratio 1.76, 95% confidence interval 1.22 to 2.53; P=0.003). 1 5 Pneumonia-related deaths 1 2 3 4 5 1 2 3 4 5 6 7 8 9 Time after index date, years Time after index date, years BUD/FOR, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Summary ICS/LABA is effective in the prevention of acute exacerbation of COPD. COPD patients treated with BUD/FORM Turbuhaler may experience fewer moderate to severe exacerbations than patients treated with FLU/SAL Diskus COPD patients treated with FLU/SAL Diskus are significantly more likely to experience pneumonia and pneumonia related hospitalizations than patients treated with BUD/FORM Turbuhaler