Risk of glaucoma in elderly patients treated with inhaled corticosteroids for chronic airflow obstruction

Pulmonary Pharmacology & Therapeutics 23 (2010) 65–70

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Risk of glaucoma in elderly patients treated with inhaled corticosteroids for chronic airflow obstruction Anne V. Gonzalez a, Gisele Li b, Samy Suissa c, d, Pierre Ernst c, d, e, * a

Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University Health Centre, Canada Department of Ophthalmology, Maisonneuve-Rosemont Hospital, University of Montreal, Canada c Center for Clinical Epidemiology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada d Departments of Medicine and Epidemiology and Biostatistics, McGill University, Montreal, Canada e Division of Pulmonary Diseases, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 July 2009 Received in revised form 14 October 2009 Accepted 26 October 2009

Background: Topical and systemic corticosteroids are well known to raise intra-ocular pressure while the effect of inhaled corticosteroids (ICS) on the risk of glaucoma remains uncertain. We sought to determine the risk of new onset ocular hypertension or glaucoma requiring treatment, associated with the use of ICS in elderly patients treated for airways disease. Methods: We carried out a nested case–control study using the databases from the Que´bec provincial health insurance plan. A cohort of patients receiving respiratory medications was formed among all subjects 66 years of age and older. Cases were subjects in whom treatment for glaucoma was initiated between January 1, 1988 and December 31, 2003 after a first ever visit to an ophthalmologist within the preceding 90 days. Age-matched controls were selected among individuals who also visited an ophthalmologist for the first time within 90 days of the case’s treatment date and did not receive a treatment for glaucoma. Results: A total of 2291 cases were identified. For comparison, a total of 13,445 age-matched controls were selected. The mean age was (75  4.2 years). The adjusted rate ratio for glaucoma was 1.05 (95% CI 0.91–1.20) with ICS use in the preceding 30 days. There was no dose-related effect of ICS on the risk of glaucoma or raised intra-ocular pressure requiring treatment. Continuous use of high-dose ICS for 3 of more months was not associated with an increased risk of glaucoma. Conclusion: In a large cohort of elderly patients treated for airways disease, we found that current use and continuous use of high-dose ICS did not result in an increased risk of glaucoma or raised intra-ocular pressure requiring treatment. Ó 2009 Elsevier Ltd. All rights reserved.

Keywords: Glaucoma Chronic Obstructive Pulmonary Disease Inhaled Corticosteroids

1. Introduction Glaucoma is the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is a progressive optic neuropathy, characterized by the degeneration of retinal ganglion cells [1]. It is estimated that more than 66 million individuals worldwide are affected by glaucoma [2], and the burden of disease is expected to increase as the population ages [3]. Raised intraocular pressure is a well-established risk factor for glaucoma. While the pathophysiology of glaucoma remains incompletely understood, the loss of retinal ganglion cells is related to the level of

* Correspondence to: Pierre Ernst MD, Division of Pulmonary Diseases, SMBD – Jewish General Hospital, 3755 Coˆte Ste. Catherine G-203, Montreal, Quebec H3T 1E2, Canada. E-mail address: [email protected] (P. Ernst). 1094-5539/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2009.10.014

intra-ocular pressure [1,4]. Recent trials suggest that lowering intra-ocular pressure can prevent or delay the onset of open-angle glaucoma, and delay disease progression [4–6]. The ocular or systemic administration of corticosteroids can cause an elevation of intra-ocular pressure [7,8]. This is thought to result from an increase in resistance to aqueous humor outflow, mediated by glucocorticoid receptors present on trabecular meshwork cells [9,10]. In contrast, whether inhaled corticosteroids (ICS) raise intra-ocular pressure and increase the risk of developing primary open-angle glaucoma is less clear. Case reports have suggested an association between the use of inhaled or intranasal corticosteroids and the development of ocular hypertension or open-angle glaucoma [11,12]. The study by Garbe and colleagues raised concerns by reporting an increased risk of glaucoma or raised intra-ocular pressure among subjects who had been dispensed high doses of ICS regularly in the preceding 3 months or more [13]. There was no apparent effect of ICS at lower doses, and

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no effect of intranasal steroids on the risk of glaucoma or ocular hypertension. Certain limitations of the study by Garbe and co-workers have been raised [14]. The case definition for the study was based on either the diagnosis or the treatment of ocular hypertension or glaucoma. As a result, approximately half of the cases did not receive treatment for their condition, raising questions about its clinical significance. The reliability of the diagnosis recorded by physicians when not followed by treatment can also be questioned. Furthermore, the study by Garbe pertained to a period when inhaled fluticasone, the most systemically potent [15] and currently the most prescribed ICS in Canada was not widely used. The role of ICS in the treatment of asthma is well established, and ICS have become first-line therapy for patients with persistent disease [16]. In contrast, the place of ICS in the treatment of patients with COPD is less clear [17,18]. Yet despite controversial evidence as to their efficacy, ICS are prescribed to as many as 50 percent of patients with COPD [19,20]. Both COPD and glaucoma are diseases whose prevalence is increasing, as the population ages. Clarifying whether ICS treatment contributes to the risk of developing glaucoma is therefore essential to weigh the risks and benefits of such therapy in individual patients. In a large cohort of elderly patients treated for airways disease, we sought to determine whether the use of ICS is associated with an increased risk of glaucoma or raised intra-ocular pressure requiring therapy. 2. Methods 2.1. Source of data We used the databases from the Que´bec provincial health insurance plan. The Re´gie de l’Assurance Maladie du Que´bec (RAMQ) administers the universal health insurance program for the seven and a half million residents of the Canadian province. The databases contain information on demographics, all medical services rendered with ICD-9 diagnostic codes and, for individuals aged 65 years and older, all outpatient prescription medications dispensed. The accuracy and comprehensiveness of the prescription claims database of Que´bec has been verified previously [21]. 2.2. 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 66 years of age or more, and were dispensed at least one of the following respiratory medications: any form of ß-agonist, theophylline, ipratropium bromide, sodium cromoglycate, nedocromil, ketotifen, leukotriene antagonists or inhaled corticosteroids. A cohort of patients with airways disease (asthma and COPD) was formed from this source population by identifying all subjects with three or more prescriptions for these respiratory medications in any one-year period, and on at least two different dates. Cohort entry was taken as the date of the third prescription. Subjects were followed until they underwent a first medical or surgical intervention for glaucoma, death, or until December 31, 2003. Individuals with any diagnosis of angle-closure glaucoma or secondary glaucoma documented in the database (including glaucoma associated with congenital anomalies, disorders of the lens and other ocular disorders) were excluded from the cohort. The ICD-9 codes corresponding to these exclusion diagnoses are as follows: 365.13, 365.2, 365.4, 365.5, 365.6, 365.8 and 364.5. In addition, individuals with any diagnosis of glaucoma documented prior to cohort entry (ICD-9 codes 365.0, 365.1, 365.3 and 365.9), or who

received any prior medical or surgical treatment for glaucoma, were excluded. 2.3. Case definition Cases were subjects 66 years and older, who received a first prescription for a medication designated for glaucoma, or underwent glaucoma surgery, anytime between January 1, 1988 and December 31, 2003, and visited the ophthalmologist for the first time in the 90 days preceding the date of treatment. Of note, medications and surgical procedures used in the treatment of ocular hypertension or glaucoma are specific to these conditions. The duration of clinical information preceding the first glaucoma treatment received was at least one year, because cases were 66 years of age and older, and the drug treatment data is available from the age of 65 years onwards. The date of the first visit to the ophthalmologist in the 90-day period up to and including the date of treatment was taken as the index date. 2.4. Selection of controls Controls matched within 1 year of age were selected at random among subjects who had never received a medical or surgical treatment for glaucoma up to and including the date of treatment of their matched case, and who visited an ophthalmologist for the first time after cohort entry within the 90 days preceding this treatment date. We selected controls from among patients visiting an ophthalmologist, rather than from the whole population, as suggested by Garbe et al. [22]. In their database study of inhaled and nasal corticosteroids and the risk of raised intra-ocular pressure, they demonstrated that random selection of population controls may lead to selection bias. The date of visit to the ophthalmologist by the control, which could be anywhere within 0–90 days of the matched case visit to the ophthalmologist, was taken as the index date for the control. 2.5. Inhaled corticosteroid exposure All forms of prescribed inhaled corticosteroids were examined during the 12-month period preceding the index date. These included inhaled beclomethasone, budesonide, triamcinolone, fluticasone, and flunisolide. The doses of inhaled corticosteroids were converted to equivalent doses of fluticasone, based on comparative dosages proposed in the NAEP expert panel report II [23], and the Canadian asthma consensus statement [24]. Accordingly, the equivalent doses for inhaled corticosteroids are beclomethasone 100 mcg, beclomethasone HFA 50 mcg, budesonide 80 mcg, triamcinolone 200 mcg, fluticasone 50 mcg and flunisolide 200 mcg. All prescriptions of inhaled corticosteroids were then categorized according to defined daily dose [25] as high (fluticasone 1000 mcg per day or more), moderate (fluticasone 500–999 mcg per day), and low (less than 500 mcg per day). Current exposure was defined based on the most recent prescription within 30 days of the index date. To determine the risk associated with continuous or near-continuous use of high-dose ICS, we examined prescriptions of high-dose ICS dispensed in the 3, 6, and 12 months preceding the index date. Based on the number of doses per canister, and the usual defined daily dose of the particular ICS inhaler, a duration of exposure to high-dose ICS in months was calculated. An exposure duration of at least two thirds of the preceding period (2/3 months, 4/6 months and 8/12 months) was considered continuous. A cumulative dose of ICS in the year preceding the index date was also calculated, by adding the amount of ICS per dispensed canister during this period (number of doses per canister multiplied by quantity of ICS in mg for each dose). This

A.V. Gonzalez et al. / Pulmonary Pharmacology & Therapeutics 23 (2010) 65–70

cumulative exposure was divided into low, medium and high doses. A high cumulative dose corresponded to a daily fluticasone dose of 1000 mg or more, while a low cumulative dose was equivalent to a daily fluticasone dose of less than 500 mg. 2.6. Covariates Potential risk factors for glaucoma were identified and adjusted for in the analysis. Covariates included age (matched for in the design), gender, prescription of corticosteroids other than inhaled, cardiovascular disease and diabetes. Corticosteroid prescriptions were classified according to route (oral, ophthalmic, nasal or topical) and tabulated. A cumulative dose of oral corticosteroids dispensed in the year prior to the index date was calculated. The prescriptions of oral corticosteroids were converted to prednisone, using the following equivalent doses: hydrocortisone (cortisol) 20 mg, cortisone 25 mg, prednisone 5 mg, prednisolone 5 mg, methylprednisolone 4 mg, triamcinolone 4 mg, betamethasone 0.75 mg, dexamethasone 0.75 mg [26]. We also adjusted for co-morbid conditions included in the index created by Van Korff [27]. Co-morbidity was measured using prescriptions for various classes of medications associated with the treatment of disorders of interest, dispensed in the year prior to the index date. We quantified the severity of airway disease, independently of corticosteroid use, by the number of prescriptions of other respiratory medications, the number of antibiotic prescriptions dispensed, and the number of hospitalizations with a primary diagnosis of COPD, in the year prior to the index date. 2.7. Statistical analysis All analyses were based on techniques for matched data. Crude and adjusted rate ratios for developing ocular hypertension or glaucoma requiring treatment were estimated using conditional logistic regression. Use of inhaled corticosteroids was examined in the period of 30 days preceding the index date. The risk associated with regular (continuous) use of high-dose ICS in the 3, 6 and 12 months preceding the index date was also examined. Age and calendar time were accounted for by the matching. Gender, potential risk factors for glaucoma (including the cumulative dose of oral corticosteroids received in the year preceding the index date), and severity of respiratory disease were adjusted for in the analysis. The rate ratio for developing ocular hypertension or glaucoma requiring treatment was also examined in subjects who had not been treated with oral corticosteroids during the preceding year. All analyses were conducted using SAS version 9.1. 3. Results The cohort consisted of 196,964 individuals aged 66 years and older, with airways disease as defined by three prescriptions for respiratory medications on at least two separate dates, in any one-year period. We excluded 2506 individuals with the diagnosis of secondary or narrow angle glaucoma, 16,247 individuals treated for glaucoma before cohort entry, 11,511 subjects with visits to an ophthalmologist prior to the 90-day period preceding treatment for glaucoma, as well as 1051 subjects without a documented visit to an ophthalmologist in the 90 days prior to treatment, leaving a cohort of 165,685 subjects treated for respiratory disease. Of these, 2291 underwent glaucoma treatment and visited an ophthalmologist for the first time in the 90 days preceding the treatment date: these individuals constituted the cases. Up to 4 age-matched controls were selected for each case, for a total of 13,445 control subjects.

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Characteristics of cases and controls are shown in Table 1. The mean age of case and control subjects was 75 years (SD 4.2 years). Women constituted just over 50% of cases and controls, and the mean duration of follow-up was 4 years in both groups. Drug treatment received in the prior year is similar for cases and controls except that cases had received more prescriptions for ophthalmic corticosteroids. Overall the risk for developing glaucoma or raised intra-ocular pressure requiring treatment was not increased in current users of ICS (Table 2). The adjusted rate ratio associated with dispensing of an ICS within the prior 30 days was 1.05 (95%CI 0.92–1.20). No dose response relation between the current ICS dose and the rate ratio of ocular hypertension or glaucoma requiring treatment was detected. Fluticasone represented 23.1% of the prescriptions of ICS dispensed within the prior 30 days. The estimate of risk for fluticasone was not different than the risk associated with other ICS. A mild protective effect of past ICS use was detected; for ICS use in the preceding 61–365 days, the rate ratio was 0.88 (95% CI 0.78–0.99). We examined the risk associated with regular use of high-dose ICS (Table 3). Patients dispensed prescriptions covering at least two thirds of the preceding period were considered to have had continuous exposure. Continuous use of high-dose ICS in the preceding 3 months, 6 months or 12 months were associated with adjusted rate ratios of 1.01 (95% CI 0.70–1.44), 0.92 (95% CI 0.61– 1.38), and 0.84 (95% CI 0.52–1.33), respectively. The risk of glaucoma or raised intra-ocular pressure requiring treatment was examined in patients who had received a cumulative ICS dose of 365 mg or more (corresponding to an average daily dose of at least 1000 mcg of fluticasone). The adjusted rate ratio was 1.17 with a 95% confidence interval of 0.90–1.52. All analyses were adjusted for the cumulative dose of oral corticosteroids dispensed in the year prior to the index date. We repeated the analysis for subjects who had not used oral corticosteroids in the prior year (Table 4). The results were very similar, again showing no excess risk with exposure to ICS in the prior 30 days. No risk could be demonstrated even at current ICS doses

Table 1 Comparison of cases and controls.

Number Age in years (mean  SD) Follow-up in years (mean  SD) Gender (% women) The year prior to the index datea Antibiotics (no. prescriptions) Respiratory drugs (no. prescriptions) Hospitalizations for COPD or asthma in the prior year Corticosteroids injection (no. prescriptions) Corticosteroids oral (no. prescriptions) Corticosteroids oral (cumulative dose in mg) Corticosteroids nasal (no. prescriptions) Corticosteroids ophthalmic (no. prescriptions) Corticosteroids dermatoid (no. prescriptions) Narcotics (%) Anti-depression drugs (%) Diabetes drugs(%) Cardiac drugs (%) Central nervous system drugs (%) Osteoporosis drugs(%) NSAIDs (%) Rheumatoids(%) Miscellaneous drugs(%)

Cases

Controls

2291 75.0  4.2 4.0  3.0 53.9

13,445 75.0  4.2 4.0  3.1 52.1

0.9  1.4 14.4  19.1 0.1  0.4

0.9  1.4 14.9  19.8 0.1  0.6

0.05  0.49 0.8  3.0 261.7  974.2 0.3  1.3 0.32  0.76 2.0  4.4 3.6 11.1 12.6 60.8 4.3 6.7 36.6 1.1 10.8

0.05  0.41 0.8  2.8 277.0  851.9 0.3  1.4 0.15  0.65 2.1  4.4 3.4 12.7 12.7 60.9 4.4 7.1 37.5 1.0 12.2

a Mean number of prescriptions or events in the year prior to the index date, or proportion of subjects with a given co-morbidity based on prescriptions dispensed in the year prior the index date.

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Table 2 Crude and adjusted rate ratios of glaucoma for current use of inhaled corticosteroids. Proportion of subjects

No use of ICS

Cases N ¼ 2,291

Controls N ¼ 13,445

53.3

51.7

Crude rate ratio

1.00

Adjusteda Rate ratio

95% CI

1.00

Reference

Current use (30 days)

21.1

19.5

1.02

1.05

0.91–1.20

Fluticasone Other ICS

4.9 16.2

4.5 15.0

0.98 1.03

1.04 1.05

0.81–1.33 0.91–1.21

Past use (31–365 days)

25.7

28.8

0.86

0.88

0.78–0.99

Current use High ‡1000 mg Medium 500–999 mg Low <500 mg

2.5 13.3 5.2

2.5 12.5 4.6

0.89 1.02 1.06

0.96 1.05 1.08

0.70–1.32 0.89–1.22 0.87–1.35

a

Rate ratios are adjusted for all the factors in Table 1.

equivalent to fluticasone 1000 mg per day or more (adjusted RR 1.25 with 95% confidence interval of 0.81–1.95). 4. Discussion In a large cohort of elderly patients with airway disease, we found that current use of ICS did not result in an increased risk of glaucoma or raised intra-ocular pressure requiring treatment. There was no dose response seen, so that no apparent risk was observed event at high doses equivalent to fluticasone 1000 mg per day or more. Furthermore, continuous use of high-dose ICS in the months preceding the index date was not associated with an increased risk of glaucoma. Oral corticosteroids are an established risk factor for the development of raised intra-ocular pressure, and the analyses were adjusted for the cumulative dose of oral corticosteroids dispensed over the year preceding the index date. Because it may still be difficult to disentangle the effects of inhaled and oral corticosteroids, we examined the risk of glaucoma or increased intra-ocular pressure requiring treatment in subjects not dispensed oral corticosteroids in the past year, and again found no effect of ICS. Inhaled corticosteroids exhibit certain dose-related systemic adverse effects including adrenal suppression, reduction in bone density and skin bruising [15]. The reported ocular side effects of ICS use consist of cataracts and glaucoma. The association between ICS use and cataracts has been well established [28,29]. Cumming et al. reported a convincing dose-related increase in the risk of

posterior subcapsular cataracts with ICS use [30]. In contrast, the relationship of ICS use to the development of primary open-angle glaucoma is less clear. Case reports by Opatowsky and Dreyer initially raised concerns about a possible association between ICS use and ocular hypertension or glaucoma [11,12]. A large case–control study by Garbe et al. [13] found that, overall, current use of inhaled and nasal glucocorticoids was not associated with an increased risk of ocular hypertension or open-angle glaucoma. However, subjects who had been dispensed high doses of ICS regularly in the preceding 3 or more months were at increased risk, with an adjusted OR of 1.44 (95% CI, 1.01–2.06). This study was criticized, however, for including cases not requiring treatment, and therefore of uncertain clinical significance as well as not completely accounting for the effect of oral corticosteroids. We designed a case–control study nested in a large cohort of elderly patients with airways disease. The choice of an elderly cohort was dictated by the limitations of the medication database, but examination of such an elderly population is quite relevant as the risk of developing glaucoma increases sharply with age [3]. The case definition was restricted to patients having received medical or surgical treatment for glaucoma, avoiding the uncertainties related to the diagnosis recorded by physicians strictly for billing purposes. Central to the validity of this case definition is the fact that medications and surgical procedures used in the treatment of ocular hypertension or glaucoma are specific to these conditions. We were able to examine the effect of exposure to fluticasone, the

Table 3 Crude and adjusted rate ratios of glaucoma for various exposures (dose and duration) to inhaled corticosteroids. Proportion of subjects

Continuous exposure to high dose ICS Preceding 3 months Continuous use Non-continuous use Preceding 6 months Continuous use Non-continuous use Preceding 12 months Continuous use Non-continuous use Cumulative dose High ‡365 mg Medium 182.5–365 mg Low <182.5 mg a

Cases N ¼ 2291

Controls N ¼ 13,445

1.9 0.6

1.8 0.7

1.4 1.1

Crude rate ratio

Adjusteda Rate ratio

95% CI

0.94 0.78

1.01 0.84

0.70–1.44 0.46–1.53

1.5 1.0

0.87 0.93

0.92 1.02

0.61–1.38 0.64–1.62

1.1 1.5

1.2 1.3

0.80 0.98

0.84 1.07

0.52–1.33 0.71–1.61

4.2 8.6 34.1

3.5 9.0 35.8

1.11 0.92 0.91

1.17 0.94 0.93

0.90–1.52 0.78–1.14 0.83–1.04

Rate ratios are adjusted for all the factors in Table 1.

A.V. Gonzalez et al. / Pulmonary Pharmacology & Therapeutics 23 (2010) 65–70

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Table 4 Crude and adjusted rate ratios of glaucoma for current use of inhaled corticosteroids in patients who have not been dispensed oral corticosteroids in the past year. Proportion of subjects

Crude Rate Ratio

Adjusteda Rate Ratio

95% CI

Cases N ¼ 1839

Controls N ¼ 10,473

No use of ICS

60.9

59.8

1.00

1.00

Reference

Current use (30 days)

16.3

14.9

1.03

1.07

0.91–1.26

Fluticasone Other ICS

3.6 12.6

3.1 11.8

1.15 1.00

1.21 1.04

0.87–1.68 0.88–1.24

Past use (31–365 days)

22.9

25.3

0.90

0.93

0.81–1.07

a

Rate ratios are adjusted for all the factors in Table 1.

most potent ICS on the market, which was dispensed to almost a quarter of patients receiving an ICS in the 30 days before the index date. We chose to examine ICS prescriptions dispensed in the 30-day period preceding the index date to ensure true current ICS exposure. Focusing on current exposure was particularly important for our drug of interest, since ocular hypertension associated with steroids may develop rapidly [31], and intra-ocular pressure has been reported to decrease within approximately one month of discontinuation of intranasal steroids [32]. Controls were selected from among patients who visited an ophthalmologist, rather than from the general population. As previously reported by Garbe et al. [22], the random selection of population controls may lead to selection bias if two conditions are met. First, if the target disease has a prolonged asymptomatic clinical course and its detection depends on a specific examination, which is the case for open-angle glaucoma. Second, if exposed patients have a higher likelihood of having the disease detected than unexposed subjects, which may occur because of general concern regarding the potential adverse effects of inhaled corticosteroids on the eyes. Some limitations are inherent to pharmacoepidemiology studies. No information was available on glaucoma risk factors such as race or family history, making adjustment for these covariates impossible. The analyses were adjusted for diabetes and cardiovascular disease as potential risk factors for glaucoma, despite conflicting epidemiologic evidence [33]. We selected patients with first-ever visits to the ophthalmologist to limit the potential for ICS dose reduction or withdrawal in response to a raised intra-ocular pressure measurement, prior to the initiation of glaucoma therapy. However, visits to an optometrist are not recorded as part of the provincial database; intra-ocular pressure measurement is part of the routine optometrist examination, and an elevated reading could conceivably result in a recommendation to modify ICS treatment. Indeed, the ‘‘protective’’ effect associated with past use of ICS may be the result of such study limitations: individuals without risk factors for glaucoma, such as family history, may be more likely to receive ICS, or a prior visit to an optometrist may have resulted in withdrawal or dose reduction of ICS. Our results are consistent with the findings of a prospective study by Samiy and colleagues, who reported no significant rise in intra-ocular pressure in patients without glaucoma, within 12 weeks of starting ICS for various pulmonary conditions [34]. However, approximately 90% of patients enrolled in this 1995 study received only a low dose of beclomethasone dipropionate for a range of pulmonary conditions. Importantly, our study does not address the question of whether individuals who develop ocular hypertension or glaucoma while receiving inhaled corticosteroids should see their treatment diminished or withdrawn. A retrospective chart review of 12 patients suggested that discontinuation of nasal steroids might lower intra-ocular pressure in patients with

glaucoma [32]. We also cannot exclude that a subgroup of elderly individuals with chronic airflow obstruction may be at particularly high risk of developing ocular hypertension following ICS exposure. A large cross-sectional study suggested an association between ever use of ICS and ocular hypertension or glaucoma in subjects with a glaucoma family history [35]; no association was found in patients without such a family history. High myopes [36], diabetics [37] and patients with connective tissue diseases, especially rheumatoid arthritis [38] have a higher risk of developing steroidinduced glaucoma. Individuals with risk factors for glaucoma and steroid-induced glaucoma in particular, may warrant closer monitoring if prescribed ICS. The results of the present study suggest that monitoring of intra-ocular pressure beyond what is currently recommended for primary prevention and screening is unnecessary in elderly patients receiving ICS for airways disease, in the absence of established risk factors for glaucoma. Nevertheless, achieving the lowest possible maintenance dose should remain an important goal of ICS therapy.

Appendix Medication and surgical treatment codes used for case definition. Medical treatment of glaucoma Medication Topical b-blockers Betaxolol Levobunolonol

Topical a-adrenergic agonists Apraclonidine Brimonidine

Cholinergic agonists Pilocarpine

DIN

Medication

DIN

2235971 1908448 2241575 2197456 2031159 2241715 2237991 2241574 2197464 2031167 2241716

Timolol

755826 893773 2083353 2240248 2241731 2166712 755834 893781 2083345 2240249 2241732 2166720 451207 2171880 2171899

Pilocarpine/Timolol

1905082 1905090 655 663

2076306 2246284 2243026 2236876 575240 841 868 884

Carbachol

(continued on next page)

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Appendix (continued ) Medical treatment of glaucoma Medication Carbonic anhydrase inhibitors Acetazolamide

DIN

Brinzolamide Dorzolamide Dorzolamide/Timolol Methazolamide

2238073 545015 2238873 2216205 2240113 2245882

Prostaglandin analogues Latanoprost Travoprost Bimatoprost

2231493 2244896 2245860

Surgical treatment of glaucoma Procedure Trabeculectomy Aqueous shunt  scleral patch graft

Code 7237 7800

Medication

DIN

* DIN Drug Identification Number.

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