INHALED AND NASAL CORTICOSTEROID USE AND THE RISK OF FRACTURE. Online data supplement.

Transcription

1 INHALED AND NASAL CORTICOSTEROID USE AND THE RISK OF FRACTURE. Online data supplement. Samy Suissa, PhD, Marc Baltzan, MD, MSc, Richard Kremer, MD, Pierre Ernst, MD, MSc 26

2 METHODS Source of data We used the health databases of the Régie de l'assurance maladie du Québec (RAMQ), the agency responsible for administering the universal health insurance program of the province of Québec, Canada, for all its seven million residents. The databases contain information on demographics, all medical services rendered, along with the diagnostic code of the service (ICD-9 code), and, for people aged 65 years or older, all out-patient prescription medications dispensed. Information obtained from the Quebec prescription claims databases has been previously validated. E1 Values in key fields such as drug, quantity, date dispensed and duration, were missing or out of range in less than 0.5% of records. These databases have been used previously to study the risks of glaucoma and cataracts associated with inhaled and oral corticosteroids. E2-E4 Study design A population-based cohort design with a nested case-control analysis was used. The source population consisted of all subjects who, between January 1, 1988 and December 31, 2001, were 65 years of age or older and were dispensed at least one of the following respiratory medications during this period: any form of ß-agonist, theophylline, ipratropium bromide, sodium cromoglycate, nedocromil, ketotifen, leukotriene antagonist, or inhaled corticosteroids. A cohort was formed from this source population by identifying all subjects with three or more prescriptions for these medications in any one-year period and on at least two different dates. Cohort entry was taken as the date of the third prescription. 27

3 Case definition A case was defined as the first fracture of the hip or upper extremities that required medical attention reported in the RAMQ databases (ICD9 codes 820, 812, 813) during cohort follow-up. These codes were found to have a degree of accuracy in these databases ranging from 92.7% for upper extremities to 99.2% for hip fracture. E5 Subjects with such a fracture furing the first four years of follow-up, as well as subjects with a vertebral fracture (ICD9 code 805) prior to cohort entry were excluded. The date of the case defining fracture was called the index date. Only cases occurring after four years of follow-up were considered, to ensure sufficient time to assess exposure information. Controls For each case, up to twenty age-matched controls were selected at random from all subjects who entered the cohort on the same year as the case and who were born within six months of the birth date of the case. Controls also had to be at risk on the date of their corresponding case event. This date was taken as the index date for the controls. Corticosteroid exposure All prescriptions of corticosteroid medications dispensed during the entire period prior to the index date were obtained for all cases and controls and classified according to their formulation, dose, quantity, duration, and date of dispensing. These include, in 28

4 inhaled and nasal forms, beclomethasone, budesonide, triamcinolone, fluticasone and flunisolide, and, in oral form, hydrocortisone, cortisone, prednisone, prednisolone, triamcinolone, methylprednisolone, betamethasone and dexamethasone. To combine the different corticosteroids, dose equivalencies were established. For oral corticosteroids, the dose equivalencies were taken directly from Goodman and Gilman. E6 Equivalent doses are therefore prednisone 5 mg, prednisolone 5 mg, hydrocortisone 20 mg, cortisone 25 mg, triamcinolone 4 mg, methylprednisolone 4mg, betamethasone 0.75 mg and dexamethasone 0.75 mg. The estimation of equivalencies for inhaled and nasal corticosteroids is more problematic since it may differ substantially for clinical efficacy and systemic activity E7 Given that the doses used in practice are chosen according to clinical efficacy, equivalences were chosen on the basis of relative topical potency and what experts consider to be comparable low doses according to the NAEP expert panel II report, figures 3-5b and 3-5c E8 and the Canadian asthma consensus statement, Table 8. E9 Accordingly, the equivalent doses for inhaled and nasal corticosteroids are beclomethasone 100µg, budesonide 80µg, triamcinolone 200µg, fluticasone 50µg and flunisolide 200µg. Information on the use of spacer devices, that can affect clinical potency, was not available. Covariates Covariates included age, gender and the severity of respiratory disease, as well as other conditions associated with the risk of fracture. E10 We quantified the severity of respiratory disease, independently of inhaled corticosteroid use, by counting the number of dispensed prescriptions of ß-agonists, ipratropium bromide and theophylline. 29

5 We assessed the concurrent use of oral corticosteroids use as the cumulative prednisone equivalent dose dispensed during the 4-year period prior to the index date. In addition to diuretics, NSAIDs, estrogens, and thyroid hormones, we adjusted for other drugs that might be associated with the risk for fractures. E11-E16 Central nervous system acting drugs included benzodiazepines, anti-depressants, major tranquillizers, anticonvulsants and drugs for parkinsonism, while cardiovascular drugs included cardiotropes, anti-hypertensives (except diuretics) and vasodilators. Rheumatic drugs included gold salts, methotrexate, azathioprine, hydroxychloroquine and chloroquine. We did not adjust for the dispensing of drugs used to treat osteoporosis (calcium, vitamin-d and biphosphonates) to avoid masking an adverse effect of corticosteroids on fractures. For adjustment purposes, exposure to these drugs was considered at any time during the 4-year period prior to the index date, except for the central nervous acting drugs, for which a 90-day period was used. Statistical analysis All analyses were based on techniques for matched data and performed separately for inhaled and nasal formulations. The primary analysis was based on the corticosteroid exposure during the four-year period prior to the index date. Crude and adjusted rate ratios of fracture for inhaled and nasal corticosteroid use were estimated by conditional logistic regression, with non-use during the 4-year period as the reference. Subjects were considered as current users if the last prescription was dispensed within 90 days of the index date. The cumulative dose during the 4-year span was computed by summing the dose equivalents of all prescriptions of the inhaled 30

6 and nasal formulations. The mean daily dose was taken as the cumulative dose divided by the time from the date of the first prescription to the index date. To assess longer term effects, all analyses were repeated for the subset of subjects who had 8 years or more of cohort follow-up and considered the 8-year exposure window prior to the index date. 31

7 Age and calendar time were inherently accounted for by the matching. Further adjustment factors included gender and the severity of respiratory disease, as well as all other covariates measuring conditions associated with the risk of fracture. We assessed effect-modification from the use of oral corticosteroids during the year prior to the index date, since only recent oral corticosteroid use appears to affect fracture risk. E17 As this interaction was not found to be significant, users and non-users of oral corticosteroids were combined in the analyses, after adjustment for the cumulative dose of oral corticosteroids. The number of cases and controls was determined so as to provide over 95% power to detect a rate ratio of 1.2 or higher for high-dose inhaled corticosteroid use. 32

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