1040-5488/15/9209-e227/0 VOL. 92, NO. 9, PP. e227Ye232 OPTOMETRY AND VISION SCIENCE Copyright * 2015 American Academy of Optometry
ORIGINAL ARTICLE
Association between Glaucoma Medication Usage and Dry Eye in Taiwan Hsin-Yi Chen*, Cheng-Li Lin†, Yi-Yu Tsai‡, and Chia-Hung Kao*
ABSTRACT Purpose. To evaluate the relationship between glaucoma medication usage and dry eye using a Taiwan nationally representative sample. Methods. We identified patients with glaucoma diagnoses (ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] codes 365) from Taiwan claims data. The study group included 2065 glaucoma patients with newly diagnosed dry eye (ICD-9-CM code 375.15) identified during 2000 and 2011. The control subjects were 8260 glaucoma patients without dry eye who were frequency matched for age, sex, and the year of the index date. The following variables were considered: sex (male/female) and age (12 to 34 years, 35 to 49 years, 50 to 64 years, and Q65 years). Six available glaucoma drugs in Taiwan were analyzed, namely, prostaglandin analog, A-blocker, carbonic anhydrase inhibitor, >-agonists, pilocarpine, and combination drugs. Univariate and multivariate unconditional logistic regressions were used to estimate the effects of glaucoma treatment and comorbidities on the risk of dry eye as indicated by odds ratios (ORs) with 95% confidence intervals (CIs). Further analysis was performed to assess the dose-response effect on the risk of dry eye according to the cumulative number of different types of glaucoma medications used. Results. Among the 2065 dry eye case patients, 63.3% were female and 48.9% were aged 65 years and older. After adjusting for potential confounding factors, an increased risk of dry eye was observed for all glaucoma medications (prostaglandin analog: adjusted OR, 1.48; 95% CI, 1.30 to 1.69; A-blocker: adjusted OR, 1.57; 95% CI, 1.35 to 1.83; carbonic anhydrase inhibitor: adjusted OR, 1.38; 95% CI, 1.20 to 1.59; pilocarpine: adjusted OR, 1.19; 95% CI, 1.07 to 1.32; combination drugs: adjusted OR, 1.32; 95% CI, 1.09 to 1.58) with the exception of >-agonists. The adjusted OR of having dry eye increased with the number of glaucoma medications used. Similar trends were observed for both female and male subjects. Conclusions. An increased number of glaucoma medications used may increase dry eye risk, particularly in subjects who use more than two types of glaucoma medications and in female subjects. Clinicians should be cautious when prescribing medications for glaucoma patients. (Optom Vis Sci 2015;92:e227Ye232) Key Words: glaucoma medication, dry eye, Taiwan health insurance database
T
here is strong evidence suggesting that glaucoma medications may contribute to ocular surface disease (OSD) and the development of dry eye.1Y4 Using the Ocular Surface Disease Index score, it has been shown that up to 60% of glaucoma patients have OSD, which can impact quality of life and compliance.3,5,6 It has been noted that multiple daily exposures
*MD † MSc ‡ MD, PhD Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan (H-YC, Y-YT); School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (H-YC, Y-YT, C-HK); and Management Office for Health Data (C-LL) and Department of Nuclear Medicine and PET Center (C-HK), China Medical University Hospital, Taichung, Taiwan.
of the ocular surface to active compounds and preservatives can worsen the burden of OSD in glaucoma patients.3,7 The severity of OSD symptoms is positively correlated with the number of intraocular pressure (IOP)Ylowering medications used.3 There are various commercially available glaucoma medications from which a clinician must choose.7 In addition to the clinical effectiveness of IOP reduction, ocular surface changes that may affect patient compliance should also be considered.7 Several factors are considered to influence the prevalence of OSD, such as age, sex, and race.8 The greater prevalence of dry eye in women compared with men suggests that sex hormones may play a role in this condition.9 Furthermore, some comorbid conditions related to glaucoma should also be considered. To better understand the relationship
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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e228 Glaucoma Medication Use and Dry EyeVChen et al.
between glaucoma medication usage and dry eye in Taiwan, we conducted this study using a nationally representative sample. To the best of our knowledge, this is one of the few studies that address this important issue using a large claims database in a Chinese population.
excluded if they had dry eye before the index date or were younger than 12 years old. Finally, a total of 2065 case patients with dry eye and 8260 control subjects without dry eye were included in this study.
Variables of Interest METHODS Data Source In 1995, Taiwan launched a one single-payer National Health Insurance (NHI) program. This program replaced previous separate workplace health insurance funds and provided insurance coverage for about 99% of Taiwan’s population. The National Health Research Institute created the National Health Insurance Research Database (NHIRD) for medical research using administrative and health claims data generated by the NHI program. The data used for this study were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000), a subset of the NHIRD. Briefly, the LHID2000 was constructed by randomly selecting 1,000,000 enrollees from the Registry for Beneficiaries of the NHI program in 2000. There were no significant differences in the sex or age distributions or in the average insurable income between random samples selected from the LHID2000 and the enrollees recorded in the original NHIRD (http://w3.nhri.org.tw/nhird/date_01.html). These deidentified secondary data included all registry and claims data, ranging from demographic data to detailed orders from ambulatory and inpatient care. Diseases were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Medications were classified by the NHI drug code and the Anatomic Therapeutic Chemical (ATC) code, which is an internationally accepted classification system for drugs coordinated by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012).
Sampled Subjects We identified patients with glaucoma diagnoses (ICD-9-CM codes 365) from claims data. Subjects taking prescription glaucoma medications, including a prostaglandin analog (PGA) (ATC codes S01EE04, S01EE01, S01EE03, and S01EE02), a topical A-blocker (ATC codes C07AB05, S01ED02, S01ED52, C07AA06, C07AA06, S01ED01, C07BA06, S01ED51, C07DA06, C07AA15, S01ED05, S01ED55, and S01ED03), a topical carbonic anhydrase inhibitor (CAI) (ATC codes S01EC04 and S01EC03), >-agonists (ATC code S01EA05), pilocarpine (ATC code S01EB01), and combination drugs (ATC codes S01EE04, S01EE01, S01EE01, S01EC04, S01EC03, and S01EA05), were analyzed. Patients aged 12 years and older with newly diagnosed dry eye (ICD-9-CM code 375.15) between 2000 and 2011 were selected for the case group. The date of the first diagnosis of dry eye was used as the index date. The control group was randomly selected from the group of glaucoma patients without dry eye. For each patient in the case group, 4 control subjects were randomly selected and frequency matched by sex, age (every 5-year span), and index date year. Patients in both groups were
The following variables were considered in this study: sex (male/female) and age (12 to 34 years, 35 to 49 years, 50 to 64 years, and Q65 years). Six commercially available glaucoma drugs in Taiwan were analyzed, namely, a PGA, a topical A-blocker, a topical CAI, >-agonists, pilocarpine, and combination drugs. The baseline comorbidities, including diabetes mellitus (ICD-9-CM 250), hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD9-CM 272), and coronary artery disease (ICD-9-CM 410-414), were considered covariates.
Statistical Analysis We used the W2 and t tests to analyze differences in the demographic data, the type of glaucoma medication, and comorbidities between the dry eye case and control groups. Univariate and multivariate unconditional logistic regressions were used to estimate the effects of glaucoma treatment and comorbidities on the risk of dry eye as indicated by odds ratios (ORs) with 95% confidence intervals (CIs). The multivariate analysis was performed to adjust for possible confounders (including hypertension, hyperlipidemia, and coronary artery disease). Further analysis was performed to assess the dose-response effect on the risk of dry eye according to the cumulative number of different types of glaucoma medications used. This study used the SAS statistical package, version 9.3 (SAS Institute Inc, Cary, NC), with p = 0.05 set as the level of significance. We performed two-tailed tests for all analyses.
RESULTS The demographic status, glaucoma medications, and comorbidities between the dry eye case and control groups are compared in Table 1. No significant differences in the distributions of sex and age were found between the case and control groups. Among the 2065 dry eye case patients, 63.3% were female and 48.9% were aged 65 years and older. The mean (TSD) age of the study and control groups was 62.0 (T15.2) and 61.9 (T15.3) years, respectively. Compared with the control subjects, the dry eye case group exhibited higher incidences of glaucoma medication usage, hypertension, hyperlipidemia, and coronary artery disease (all with p G 0.01). Table 2 shows the crude and adjusted ORs for the model fitted to examine the association between glaucoma treatment and dry eye development. After adjusting for potential confounding factors, an increased risk of dry eye was observed for all glaucoma medications (PGA: adjusted OR, 1.48; 95% CI, 1.30 to 1.69; A-blocker: adjusted OR, 1.57; 95% CI, 1.35 to 1.83; CAI: adjusted OR, 1.38; 95% CI, 1.20 to 1.59; pilocarpine: adjusted OR, 1.19; 95% CI, 1.07 to 1.32; combination drugs: adjusted OR, 1.32; 95% CI, 1.09 to 1.58) with the exception of >-agonists. In the multivariate model, hyperlipidemia (adjusted OR, 1.17; 95% CI, 1.05 to 1.31) and coronary artery disease (adjusted OR,
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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Glaucoma Medication Use and Dry EyeVChen et al. TABLE 1.
Sociodemographic comparison between dry eye case patients and control subjects Case patients Control subjects (n = 2065) (n = 8260) Sex, n (%) Female Male Age group, n (%) 12Y34 y 35Y49 y 50Y64 y Q65 y Age, mean (SD), y* Glaucoma medication, n (%) PGA A-Blocker CAI >-Agonist Pilocarpine Combination drugs Comorbidity, n (%) Diabetes mellitus Hypertension Hyperlipidemia Coronary artery disease
p 0.99
1307 (63.3) 758 (36.7)
5228 (63.3) 3032 (36.7)
139 (6.73) 267 (12.9) 649 (31.4) 1010 (48.9) 62.0 (15.2)
556 (6.73) 1068 (12.9) 2596 (31.4) 4040 (48.9) 61.9 (15.3)
0.80
488 (23.6) 1818 (88.0) 384 (18.6) 440 (21.3) 706 (34.2) 197 (9.54)
1242 (15.0) 6948 (84.1) 963 (11.7) 1527 (18.5) 2364 (28.6) 479 (5.80)
G0.001 G0.001 G0.001 0.004 G0.001 G0.001
467 (22.6) 1238 (60.0) 885 (42.9) 725 (35.1)
1889 (22.9) 4626 (56.0) 3114 (37.7) 2426 (29.4)
0.81 0.001 G0.001 G0.001
0.99
The W2 test was used. *t test.
1.23; 95% CI, 1.10 to 1.38) were significantly associated with an increased dry eye risk. Regarding the number of glaucoma medications used, the adjusted OR of having dry eye increased with the TABLE 2.
Odds ratio and 95% CI of dry eye associated with glaucoma medication and comorbidities Crude Variable Glaucoma medication PG A-Blocker CAI >-Agonist Pilocarpine Combination drugs Comorbidity Diabetes mellitus Hypertension Hyperlipidemia Coronary artery disease
e229
number of glaucoma medications used (Fig. 1). Similar trends were observed for both female and male subjects. Among subjects aged less than 49 years, patients using more than two types of glaucoma medications had a significantly higher risk for dry eye than patients using only one type of glaucoma medication (adjusted OR, 1.42; 95% CI, 1.08 to 1.87 for two types of glaucoma medications; adjusted OR, 1.92; 95% CI, 1.29 to 2.86 for three types of glaucoma medications; adjusted OR, 2.86; 95% CI, 1.86 to 4.41 for four types of glaucoma medications) (Table 3). A similar trend was noted for subjects aged between 50 and 64 years. Among the subjects aged 65 years and older, patients using more than three types of glaucoma medications had a significantly higher risk for dry eye than those using only one type of glaucoma medication (adjusted OR, 1.56; 95% CI, 1.25 to 1.95 for three types of glaucoma medications; adjusted OR, 2.58; 95% CI, 2.06 to 3.24 for four types of glaucoma medication). Female patients aged less than 64 years using more than three types of glaucoma medications had a higher risk for dry eye compared with those using only one type of glaucoma medication. Among the subjects aged 65 years and older, female patients using more than two types of glaucoma medications had a significantly higher risk for dry eye than those using only one type of glaucoma medication. Male patients in all age groups using more than four types of glaucoma medications had a higher risk of dry eye than those using only one type of glaucoma medication. In particular, male patients aged between 50 and 64 years using three types of glaucoma medications had a significantly higher risk for dry eye.
DISCUSSION It is well known that the long-term use of topical medications for chronic ophthalmic conditions, such as glaucoma, may adversely affect the ocular surface.10 Furthermore, the mechanisms of ocular surface damage and the role of active compounds and
Adjusted*
OR
(95% CI)
OR
(95% CI)
1.75 1.39 1.73 1.19 1.30 1.71
(1.55, 1.97)† (1.20Y1.61)† (1.52Y1.97)† (1.06Y1.35)‡ (1.17Y1.44)† (1.44Y2.04)†
1.48 1.57 1.38 1.13 1.19 1.32
(1.30Y1.69)‡ (1.35Y1.83)† (1.20Y1.59)† (0.99Y1.29) (1.07Y1.32)‡ (1.09Y1.59)‡
0.99 1.18 1.24 1.30
(0.88Y1.11) V V (1.07Y1.30)‡ 0.99 (0.89Y1.11) (1.12Y1.37)† 1.17 (1.05Y1.31)‡ (1.18Y1.44)† 1.23 (1.10Y1.38)†
Additionally adjusted for hypertension, hyperlipidemia, and coronary artery disease. *Covariables that were significantly associated with risk of dry eye in the univariable unconditional logistic regression model were further analyzed using the multivariable unconditional logistic regression model. †p G 0.001. ‡p G 0.01.
FIGURE 1. Association between glaucoma medication usage and dry eye according to sex, OR, and 95% CI.
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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e230 Glaucoma Medication Use and Dry EyeVChen et al. TABLE 3.
Age and sex effect on the association between glaucoma medication and dry eye, OR, and 95% CI
No. glaucoma medication used Age e49 y 1 2 3 4+ p for trend Age 50Y64 y 1 2 3 4+ p for trend Age Q65 y 1 2 3 4+ p for trend
All (N = 10,325)
Women (n = 6535)
Men (n = 3790)
Adjusted* OR (95% CI)
Adjusted* OR (95% CI)
Adjusted* OR (95% CI)
1.00 (Reference) 1.42 (1.08Y1.87)† 1.92 (1.29Y2.86)‡ 2.86 (1.86Y4.41)§ G0.001
1.00 (Reference) 1.41 (0.98Y2.03) 2.07 (1.21Y3.53)‡ 3.37 (1.92Y5.92)§ G0.001
1.00 (Reference) 1.45 (0.95Y2.23) 1.76 (0.96Y3.22) 2.34 (1.19Y4.59)†
1.00 (Reference) 1.31 (1.07Y1.61)† 1.72 (1.29Y2.28)‡ 2.66 (1.95Y3.63)§ G0.001
1.00 (Reference) 1.27 (1.00Y1.63) 1.66 (1.18Y2.33)‡ 2.73 (1.83Y4.06)§ G0.001
1.00 (Reference) 1.40 (0.96Y2.04) 1.86 (1.11Y3.10)† 2.62 (1.59Y4.31)§ G0.001
1.00 (Reference) 1.18 (1.00Y1.39) 1.56 (1.25Y1.95)§ 2.58 (2.06Y3.24)§ G0.001
1.00 1.29 1.69 2.76
1.00 (Reference) 1.01 (0.77Y1.33) 1.39 (0.96Y2.01) 2.34 (1.63Y3.34)§ G0.001
(Reference) (1.05Y1.59)† (1.28Y2.23)§ (2.06Y3.70)§ G0.001
*Additionally adjusted for hypertension, hyperlipidemia, and coronary artery disease. †p G 0.05. ‡p G 0.01. §p G 0.001.
preservatives involved in ophthalmic solutions have been widely investigated.10 Benzalkonium chloride (BAK), benzododecinium bromide, and purite are commonly used preservatives in glaucoma medications.10 Benzalkonium chloride and benzododecinium bromide have been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia, apoptosis, disruption of the corneal epithelium barrier, and damage to corneal nerves.11,12 Purite is used in brimonidine topical drops.13 Clinical studies have shown that purite causes the least amount of damage to corneal epithelial cells.14 Additionally, the number of inflammatory cells in the conjunctiva was significantly lower with brimonidine-purite.15 Here, we report that an increased risk of dry eye was observed in glaucoma patients who used all glaucoma medications except for >-agonists. We believe that this important result may remind clinicians that >-agonists (brimonidine) impose a lower dry eye risk compared with other glaucoma medications. For any glaucoma patient with potential dry eye risk, >-agonists may be considered a good treatment option. In addition, among all the glaucoma medications studied, A-blockers have demonstrated the highest adjusted OR (1.57; 95% CI, 1.35 to 1.83). Studies have shown that A-blockers induce more damage to the ocular surface, suggesting the role of dosing and the active substances in addition to preservatives in ocular surface damage induction.7,16 Prostaglandin analog was found to have the second highest adjusted OR (1.48; 95% CI, 1.30 to 1.69) in our study. Prostaglandin analogs have been reported to produce inflammatory damage to the ocular surface in glaucoma patients as a result of allergies combined with toxicity.17 In one study comparing the ocular surface tolerability of three types of PGAs, it was reported that there was no significant difference in objective
clinical measures of ocular surface tolerability after 3 months of treatment with bimatoprost (with 0.02% BAK), travoprost (with sofZia), and latanoprost (with 0.02% BAK).18 Based on the limitations of the claims database, we could not directly compare the dry eye risk of the three types of PGAs in this study. Longitudinal long-term studies are needed to further evaluate the ocular surface tolerability of these prostaglandin analogs. One interesting finding is that hyperlipidemia and coronary artery disease were significantly associated with an increase in dry eye risk, although the associated reasons are unclear. It is possible that underlying medical conditions treated with complicated medications may lead to dry eye.19 Further studies should be conducted to examine this issue. Another meaningful finding is that a higher percentage of dry eye was noted in female subjects (63.3%), and 48.9% of the dry eye cases occurred in those aged 65 years and older. Compared with the control subjects, the dry eye case group exhibited higher percentages of glaucoma medication usage, hypertension, hyperlipidemia, and coronary artery disease. Furthermore, the adjusted OR of having dry eye increased with the number of glaucoma medications used for female and male subjects. Similar findings were proposed by Fechtner et al.,3 who reported that OSD is prevalent among medically treated patients with glaucoma and that the severity of OSD symptoms is positively correlated with the number of IOP-lowering medications used based on the Ocular Surface Disease Index. Our findings are in agreement with the general notion that increases in the number of glaucoma medications used increase the risk of dry eye. We also analyzed the age and sex effects on dry eye risk. We noted an increased adjusted OR with an increase in the number
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Glaucoma Medication Use and Dry EyeVChen et al.
of glaucoma medications used, regardless of age. However, female patients using more than three types of glaucoma medications had a higher risk for dry eye compared with female patients who used one type of glaucoma medication among subjects less than 64 years old. Among subjects 65 years and older, female patients using more than two types of glaucoma medications had a significantly higher risk for dry eye compared with female patients who used only one type of glaucoma medication. In all age groups, male patients using more than four types of glaucoma medications had a higher risk for dry eye compared with those who used only one type of glaucoma medication. In particular, male patients between 50 and 64 years old who used three or four types of glaucoma medications had a significantly higher risk for dry eye. The greater prevalence of dry eye in female subjects compared with male subjects suggests that sex hormones may play a role.9,20 It is hypothesized that hormonal changes alter the homeostasis of the ocular surface and contribute to dry eye.20 It has also been reported that dry eye risk increases with age in both sexes, whereas its incidence is higher among female subjects.21 Menopause in aging female subjects may also contribute to dry eye as a consequence of an overall hormonal imbalance.21 Reduced estrogen levels were thought to be responsible for agerelated dry eye onset, but more recent studies have reconsidered the role of androgens in the protection of the ocular surface.21 We believe that our results may be a good basis for future evaluations of the influence of hormones on the risk of dry eye in female subjects. This study yielded some important findings; however, some limitations should be mentioned. First, we defined glaucoma and dry eye entirely by relying on claims data (ICD-9 coding from clinicians), which may be less accurate than individually determined diagnoses by professional ophthalmologists using standardized procedures.22 Second, there was selection bias in this study. Because the NHI database only included patients who sought treatment, those who did not seek help may have been recruited in the control cohort.22 Third, most of the residents of Taiwan are of Chinese ethnicity; thus, the current results may not directly apply to other racial/ethnic groups. Fourth, preservative-free glaucoma medications are not included in the current health insurance system; therefore, information on the use of preservative-free glaucoma medications is not available in the current database. It is unfortunate that we could not compare the risk for dry eye between glaucoma medications with and without preservatives.23 However, we believe our study has some strengths. First, the strength of the database was high because of good sample randomization.22 Second, the large sample size of Taiwan’s NHI database allows for statistically powerful assessment of the relative risk for diseases with potential risk factors. This fact is meaningful from a public health standpoint. Third, we think that the findings of our analysis are significant. Because glaucoma medications are not inexpensive, in Taiwan, most glaucoma patients seek treatment from ophthalmologists; therefore, the claims database for glaucoma medication usage used in this study appears to be reliable. In conclusion, this Taiwan populationYbased, case-control study reveals that an increased number of glaucoma medications used may increase dry eye risk, particularly in subjects who use more than two types of glaucoma medications and in female subjects.
e231
Clinicians should be cautious when prescribing medications for patients with glaucoma.
ACKNOWLEDGMENTS The authors have no commercial or proprietary interest in any of the materials discussed in this article. Received December 28, 2014; accepted April 28, 2015.
REFERENCES 1. Anwar Z, Wellik SR, Galor A. Glaucoma therapy and ocular surface disease: current literature and recommendations. Curr Opin Ophthalmol 2013;24:136Y43. 2. Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res 2011;36:391Y8. 3. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010;29:618Y21. 4. Garcia-Feijoo J, Sampaolesi JR. A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol 2012;6:441Y6. 5. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350Y5. 6. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol 2012;153:1Y9. 7. Aydin Kurna S, Acikgoz S, Altun A, Ozbay N, Sengor T, Olcaysu OO. The effects of topical antiglaucoma drugs as monotherapy on the ocular surface: a prospective study. J Ophthalmol 2014;2014:460483. 8. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol 2001;45(Suppl. 2):S199Y202. 9. Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and the dry eye. Clin Exp Optom 2014;97:324Y36. 10. Martone G, Frezzotti P, Tosi GM, Traversi C, Mittica V, Malandrini A, Pichierri P, Balestrazzi A, Motolese PA, Motolese I, Motolese E. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147:725Y35.e1. 11. Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol 2008;86:716Y26. 12. Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008;25:743Y51. 13. Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma 2002;11:119Y26. 14. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001;18:205Y15. 15. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea 2004;23:490Y6. 16. Lee S, Kim MK, Choi HJ, Wee WR, Kim DM. Comparative crosssectional analysis of the effects of topical antiglaucoma drugs on the ocular surface. Adv Ther 2013;30:420Y9.
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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e232 Glaucoma Medication Use and Dry EyeVChen et al. 17. Baudouin C, Liang H, Hamard P, Riancho L, Creuzot-Garcher C, Warnet JM, Brignole-Baudouin F. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both T-helper 1 and T-helper 2 pathways. Ophthalmology 2008;115:109Y15. 18. Whitson JT, Trattler WB, Matossian C, Williams J, Hollander DA. Ocular surface tolerability of prostaglandin analogs in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther 2010;26:287Y92. 19. Wong J, Lan W, Ong LM, Tong L. Non-hormonal systemic medications and dry eye. Ocul Surf 2011;9:212Y26. 20. Rocha EM, Mantelli F, Nominato LF, Bonini S. Hormones and dry eye syndrome: an update on what we do and don’t know. Curr Opin Ophthalmol 2013;24:348Y55. 21. Versura P, Giannaccare G, Campos EC. Sex-steroid imbalance in females and dry eye. Curr Eye Res 2015;40:162Y75.
22. Chen HY, Chang YC, Lin CC, Sung FC, Chen WC. Obstructive sleep apnea patients having surgery are less associated with glaucoma. J Ophthalmol 2014;2014:838912. 23. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol 2014;8:903Y13.
Hsin-Yi Chen Department of Ophthalmology China Medical University Hospital No. 118, 5F-1, Yu-Der Rd Taichung 404 Taiwan e-mail: [email protected]
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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ORIGINAL ARTICLE
Association between Glaucoma Medication Usage and Dry Eye in Taiwan Hsin-Yi Chen*, Cheng-Li Lin†, Yi-Yu Tsai‡, and Chia-Hung Kao*
ABSTRACT Purpose. To evaluate the relationship between glaucoma medication usage and dry eye using a Taiwan nationally representative sample. Methods. We identified patients with glaucoma diagnoses (ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] codes 365) from Taiwan claims data. The study group included 2065 glaucoma patients with newly diagnosed dry eye (ICD-9-CM code 375.15) identified during 2000 and 2011. The control subjects were 8260 glaucoma patients without dry eye who were frequency matched for age, sex, and the year of the index date. The following variables were considered: sex (male/female) and age (12 to 34 years, 35 to 49 years, 50 to 64 years, and Q65 years). Six available glaucoma drugs in Taiwan were analyzed, namely, prostaglandin analog, A-blocker, carbonic anhydrase inhibitor, >-agonists, pilocarpine, and combination drugs. Univariate and multivariate unconditional logistic regressions were used to estimate the effects of glaucoma treatment and comorbidities on the risk of dry eye as indicated by odds ratios (ORs) with 95% confidence intervals (CIs). Further analysis was performed to assess the dose-response effect on the risk of dry eye according to the cumulative number of different types of glaucoma medications used. Results. Among the 2065 dry eye case patients, 63.3% were female and 48.9% were aged 65 years and older. After adjusting for potential confounding factors, an increased risk of dry eye was observed for all glaucoma medications (prostaglandin analog: adjusted OR, 1.48; 95% CI, 1.30 to 1.69; A-blocker: adjusted OR, 1.57; 95% CI, 1.35 to 1.83; carbonic anhydrase inhibitor: adjusted OR, 1.38; 95% CI, 1.20 to 1.59; pilocarpine: adjusted OR, 1.19; 95% CI, 1.07 to 1.32; combination drugs: adjusted OR, 1.32; 95% CI, 1.09 to 1.58) with the exception of >-agonists. The adjusted OR of having dry eye increased with the number of glaucoma medications used. Similar trends were observed for both female and male subjects. Conclusions. An increased number of glaucoma medications used may increase dry eye risk, particularly in subjects who use more than two types of glaucoma medications and in female subjects. Clinicians should be cautious when prescribing medications for glaucoma patients. (Optom Vis Sci 2015;92:e227Ye232) Key Words: glaucoma medication, dry eye, Taiwan health insurance database
T
here is strong evidence suggesting that glaucoma medications may contribute to ocular surface disease (OSD) and the development of dry eye.1Y4 Using the Ocular Surface Disease Index score, it has been shown that up to 60% of glaucoma patients have OSD, which can impact quality of life and compliance.3,5,6 It has been noted that multiple daily exposures
*MD † MSc ‡ MD, PhD Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan (H-YC, Y-YT); School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (H-YC, Y-YT, C-HK); and Management Office for Health Data (C-LL) and Department of Nuclear Medicine and PET Center (C-HK), China Medical University Hospital, Taichung, Taiwan.
of the ocular surface to active compounds and preservatives can worsen the burden of OSD in glaucoma patients.3,7 The severity of OSD symptoms is positively correlated with the number of intraocular pressure (IOP)Ylowering medications used.3 There are various commercially available glaucoma medications from which a clinician must choose.7 In addition to the clinical effectiveness of IOP reduction, ocular surface changes that may affect patient compliance should also be considered.7 Several factors are considered to influence the prevalence of OSD, such as age, sex, and race.8 The greater prevalence of dry eye in women compared with men suggests that sex hormones may play a role in this condition.9 Furthermore, some comorbid conditions related to glaucoma should also be considered. To better understand the relationship
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e228 Glaucoma Medication Use and Dry EyeVChen et al.
between glaucoma medication usage and dry eye in Taiwan, we conducted this study using a nationally representative sample. To the best of our knowledge, this is one of the few studies that address this important issue using a large claims database in a Chinese population.
excluded if they had dry eye before the index date or were younger than 12 years old. Finally, a total of 2065 case patients with dry eye and 8260 control subjects without dry eye were included in this study.
Variables of Interest METHODS Data Source In 1995, Taiwan launched a one single-payer National Health Insurance (NHI) program. This program replaced previous separate workplace health insurance funds and provided insurance coverage for about 99% of Taiwan’s population. The National Health Research Institute created the National Health Insurance Research Database (NHIRD) for medical research using administrative and health claims data generated by the NHI program. The data used for this study were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000), a subset of the NHIRD. Briefly, the LHID2000 was constructed by randomly selecting 1,000,000 enrollees from the Registry for Beneficiaries of the NHI program in 2000. There were no significant differences in the sex or age distributions or in the average insurable income between random samples selected from the LHID2000 and the enrollees recorded in the original NHIRD (http://w3.nhri.org.tw/nhird/date_01.html). These deidentified secondary data included all registry and claims data, ranging from demographic data to detailed orders from ambulatory and inpatient care. Diseases were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Medications were classified by the NHI drug code and the Anatomic Therapeutic Chemical (ATC) code, which is an internationally accepted classification system for drugs coordinated by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012).
Sampled Subjects We identified patients with glaucoma diagnoses (ICD-9-CM codes 365) from claims data. Subjects taking prescription glaucoma medications, including a prostaglandin analog (PGA) (ATC codes S01EE04, S01EE01, S01EE03, and S01EE02), a topical A-blocker (ATC codes C07AB05, S01ED02, S01ED52, C07AA06, C07AA06, S01ED01, C07BA06, S01ED51, C07DA06, C07AA15, S01ED05, S01ED55, and S01ED03), a topical carbonic anhydrase inhibitor (CAI) (ATC codes S01EC04 and S01EC03), >-agonists (ATC code S01EA05), pilocarpine (ATC code S01EB01), and combination drugs (ATC codes S01EE04, S01EE01, S01EE01, S01EC04, S01EC03, and S01EA05), were analyzed. Patients aged 12 years and older with newly diagnosed dry eye (ICD-9-CM code 375.15) between 2000 and 2011 were selected for the case group. The date of the first diagnosis of dry eye was used as the index date. The control group was randomly selected from the group of glaucoma patients without dry eye. For each patient in the case group, 4 control subjects were randomly selected and frequency matched by sex, age (every 5-year span), and index date year. Patients in both groups were
The following variables were considered in this study: sex (male/female) and age (12 to 34 years, 35 to 49 years, 50 to 64 years, and Q65 years). Six commercially available glaucoma drugs in Taiwan were analyzed, namely, a PGA, a topical A-blocker, a topical CAI, >-agonists, pilocarpine, and combination drugs. The baseline comorbidities, including diabetes mellitus (ICD-9-CM 250), hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD9-CM 272), and coronary artery disease (ICD-9-CM 410-414), were considered covariates.
Statistical Analysis We used the W2 and t tests to analyze differences in the demographic data, the type of glaucoma medication, and comorbidities between the dry eye case and control groups. Univariate and multivariate unconditional logistic regressions were used to estimate the effects of glaucoma treatment and comorbidities on the risk of dry eye as indicated by odds ratios (ORs) with 95% confidence intervals (CIs). The multivariate analysis was performed to adjust for possible confounders (including hypertension, hyperlipidemia, and coronary artery disease). Further analysis was performed to assess the dose-response effect on the risk of dry eye according to the cumulative number of different types of glaucoma medications used. This study used the SAS statistical package, version 9.3 (SAS Institute Inc, Cary, NC), with p = 0.05 set as the level of significance. We performed two-tailed tests for all analyses.
RESULTS The demographic status, glaucoma medications, and comorbidities between the dry eye case and control groups are compared in Table 1. No significant differences in the distributions of sex and age were found between the case and control groups. Among the 2065 dry eye case patients, 63.3% were female and 48.9% were aged 65 years and older. The mean (TSD) age of the study and control groups was 62.0 (T15.2) and 61.9 (T15.3) years, respectively. Compared with the control subjects, the dry eye case group exhibited higher incidences of glaucoma medication usage, hypertension, hyperlipidemia, and coronary artery disease (all with p G 0.01). Table 2 shows the crude and adjusted ORs for the model fitted to examine the association between glaucoma treatment and dry eye development. After adjusting for potential confounding factors, an increased risk of dry eye was observed for all glaucoma medications (PGA: adjusted OR, 1.48; 95% CI, 1.30 to 1.69; A-blocker: adjusted OR, 1.57; 95% CI, 1.35 to 1.83; CAI: adjusted OR, 1.38; 95% CI, 1.20 to 1.59; pilocarpine: adjusted OR, 1.19; 95% CI, 1.07 to 1.32; combination drugs: adjusted OR, 1.32; 95% CI, 1.09 to 1.58) with the exception of >-agonists. In the multivariate model, hyperlipidemia (adjusted OR, 1.17; 95% CI, 1.05 to 1.31) and coronary artery disease (adjusted OR,
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Glaucoma Medication Use and Dry EyeVChen et al. TABLE 1.
Sociodemographic comparison between dry eye case patients and control subjects Case patients Control subjects (n = 2065) (n = 8260) Sex, n (%) Female Male Age group, n (%) 12Y34 y 35Y49 y 50Y64 y Q65 y Age, mean (SD), y* Glaucoma medication, n (%) PGA A-Blocker CAI >-Agonist Pilocarpine Combination drugs Comorbidity, n (%) Diabetes mellitus Hypertension Hyperlipidemia Coronary artery disease
p 0.99
1307 (63.3) 758 (36.7)
5228 (63.3) 3032 (36.7)
139 (6.73) 267 (12.9) 649 (31.4) 1010 (48.9) 62.0 (15.2)
556 (6.73) 1068 (12.9) 2596 (31.4) 4040 (48.9) 61.9 (15.3)
0.80
488 (23.6) 1818 (88.0) 384 (18.6) 440 (21.3) 706 (34.2) 197 (9.54)
1242 (15.0) 6948 (84.1) 963 (11.7) 1527 (18.5) 2364 (28.6) 479 (5.80)
G0.001 G0.001 G0.001 0.004 G0.001 G0.001
467 (22.6) 1238 (60.0) 885 (42.9) 725 (35.1)
1889 (22.9) 4626 (56.0) 3114 (37.7) 2426 (29.4)
0.81 0.001 G0.001 G0.001
0.99
The W2 test was used. *t test.
1.23; 95% CI, 1.10 to 1.38) were significantly associated with an increased dry eye risk. Regarding the number of glaucoma medications used, the adjusted OR of having dry eye increased with the TABLE 2.
Odds ratio and 95% CI of dry eye associated with glaucoma medication and comorbidities Crude Variable Glaucoma medication PG A-Blocker CAI >-Agonist Pilocarpine Combination drugs Comorbidity Diabetes mellitus Hypertension Hyperlipidemia Coronary artery disease
e229
number of glaucoma medications used (Fig. 1). Similar trends were observed for both female and male subjects. Among subjects aged less than 49 years, patients using more than two types of glaucoma medications had a significantly higher risk for dry eye than patients using only one type of glaucoma medication (adjusted OR, 1.42; 95% CI, 1.08 to 1.87 for two types of glaucoma medications; adjusted OR, 1.92; 95% CI, 1.29 to 2.86 for three types of glaucoma medications; adjusted OR, 2.86; 95% CI, 1.86 to 4.41 for four types of glaucoma medications) (Table 3). A similar trend was noted for subjects aged between 50 and 64 years. Among the subjects aged 65 years and older, patients using more than three types of glaucoma medications had a significantly higher risk for dry eye than those using only one type of glaucoma medication (adjusted OR, 1.56; 95% CI, 1.25 to 1.95 for three types of glaucoma medications; adjusted OR, 2.58; 95% CI, 2.06 to 3.24 for four types of glaucoma medication). Female patients aged less than 64 years using more than three types of glaucoma medications had a higher risk for dry eye compared with those using only one type of glaucoma medication. Among the subjects aged 65 years and older, female patients using more than two types of glaucoma medications had a significantly higher risk for dry eye than those using only one type of glaucoma medication. Male patients in all age groups using more than four types of glaucoma medications had a higher risk of dry eye than those using only one type of glaucoma medication. In particular, male patients aged between 50 and 64 years using three types of glaucoma medications had a significantly higher risk for dry eye.
DISCUSSION It is well known that the long-term use of topical medications for chronic ophthalmic conditions, such as glaucoma, may adversely affect the ocular surface.10 Furthermore, the mechanisms of ocular surface damage and the role of active compounds and
Adjusted*
OR
(95% CI)
OR
(95% CI)
1.75 1.39 1.73 1.19 1.30 1.71
(1.55, 1.97)† (1.20Y1.61)† (1.52Y1.97)† (1.06Y1.35)‡ (1.17Y1.44)† (1.44Y2.04)†
1.48 1.57 1.38 1.13 1.19 1.32
(1.30Y1.69)‡ (1.35Y1.83)† (1.20Y1.59)† (0.99Y1.29) (1.07Y1.32)‡ (1.09Y1.59)‡
0.99 1.18 1.24 1.30
(0.88Y1.11) V V (1.07Y1.30)‡ 0.99 (0.89Y1.11) (1.12Y1.37)† 1.17 (1.05Y1.31)‡ (1.18Y1.44)† 1.23 (1.10Y1.38)†
Additionally adjusted for hypertension, hyperlipidemia, and coronary artery disease. *Covariables that were significantly associated with risk of dry eye in the univariable unconditional logistic regression model were further analyzed using the multivariable unconditional logistic regression model. †p G 0.001. ‡p G 0.01.
FIGURE 1. Association between glaucoma medication usage and dry eye according to sex, OR, and 95% CI.
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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e230 Glaucoma Medication Use and Dry EyeVChen et al. TABLE 3.
Age and sex effect on the association between glaucoma medication and dry eye, OR, and 95% CI
No. glaucoma medication used Age e49 y 1 2 3 4+ p for trend Age 50Y64 y 1 2 3 4+ p for trend Age Q65 y 1 2 3 4+ p for trend
All (N = 10,325)
Women (n = 6535)
Men (n = 3790)
Adjusted* OR (95% CI)
Adjusted* OR (95% CI)
Adjusted* OR (95% CI)
1.00 (Reference) 1.42 (1.08Y1.87)† 1.92 (1.29Y2.86)‡ 2.86 (1.86Y4.41)§ G0.001
1.00 (Reference) 1.41 (0.98Y2.03) 2.07 (1.21Y3.53)‡ 3.37 (1.92Y5.92)§ G0.001
1.00 (Reference) 1.45 (0.95Y2.23) 1.76 (0.96Y3.22) 2.34 (1.19Y4.59)†
1.00 (Reference) 1.31 (1.07Y1.61)† 1.72 (1.29Y2.28)‡ 2.66 (1.95Y3.63)§ G0.001
1.00 (Reference) 1.27 (1.00Y1.63) 1.66 (1.18Y2.33)‡ 2.73 (1.83Y4.06)§ G0.001
1.00 (Reference) 1.40 (0.96Y2.04) 1.86 (1.11Y3.10)† 2.62 (1.59Y4.31)§ G0.001
1.00 (Reference) 1.18 (1.00Y1.39) 1.56 (1.25Y1.95)§ 2.58 (2.06Y3.24)§ G0.001
1.00 1.29 1.69 2.76
1.00 (Reference) 1.01 (0.77Y1.33) 1.39 (0.96Y2.01) 2.34 (1.63Y3.34)§ G0.001
(Reference) (1.05Y1.59)† (1.28Y2.23)§ (2.06Y3.70)§ G0.001
*Additionally adjusted for hypertension, hyperlipidemia, and coronary artery disease. †p G 0.05. ‡p G 0.01. §p G 0.001.
preservatives involved in ophthalmic solutions have been widely investigated.10 Benzalkonium chloride (BAK), benzododecinium bromide, and purite are commonly used preservatives in glaucoma medications.10 Benzalkonium chloride and benzododecinium bromide have been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia, apoptosis, disruption of the corneal epithelium barrier, and damage to corneal nerves.11,12 Purite is used in brimonidine topical drops.13 Clinical studies have shown that purite causes the least amount of damage to corneal epithelial cells.14 Additionally, the number of inflammatory cells in the conjunctiva was significantly lower with brimonidine-purite.15 Here, we report that an increased risk of dry eye was observed in glaucoma patients who used all glaucoma medications except for >-agonists. We believe that this important result may remind clinicians that >-agonists (brimonidine) impose a lower dry eye risk compared with other glaucoma medications. For any glaucoma patient with potential dry eye risk, >-agonists may be considered a good treatment option. In addition, among all the glaucoma medications studied, A-blockers have demonstrated the highest adjusted OR (1.57; 95% CI, 1.35 to 1.83). Studies have shown that A-blockers induce more damage to the ocular surface, suggesting the role of dosing and the active substances in addition to preservatives in ocular surface damage induction.7,16 Prostaglandin analog was found to have the second highest adjusted OR (1.48; 95% CI, 1.30 to 1.69) in our study. Prostaglandin analogs have been reported to produce inflammatory damage to the ocular surface in glaucoma patients as a result of allergies combined with toxicity.17 In one study comparing the ocular surface tolerability of three types of PGAs, it was reported that there was no significant difference in objective
clinical measures of ocular surface tolerability after 3 months of treatment with bimatoprost (with 0.02% BAK), travoprost (with sofZia), and latanoprost (with 0.02% BAK).18 Based on the limitations of the claims database, we could not directly compare the dry eye risk of the three types of PGAs in this study. Longitudinal long-term studies are needed to further evaluate the ocular surface tolerability of these prostaglandin analogs. One interesting finding is that hyperlipidemia and coronary artery disease were significantly associated with an increase in dry eye risk, although the associated reasons are unclear. It is possible that underlying medical conditions treated with complicated medications may lead to dry eye.19 Further studies should be conducted to examine this issue. Another meaningful finding is that a higher percentage of dry eye was noted in female subjects (63.3%), and 48.9% of the dry eye cases occurred in those aged 65 years and older. Compared with the control subjects, the dry eye case group exhibited higher percentages of glaucoma medication usage, hypertension, hyperlipidemia, and coronary artery disease. Furthermore, the adjusted OR of having dry eye increased with the number of glaucoma medications used for female and male subjects. Similar findings were proposed by Fechtner et al.,3 who reported that OSD is prevalent among medically treated patients with glaucoma and that the severity of OSD symptoms is positively correlated with the number of IOP-lowering medications used based on the Ocular Surface Disease Index. Our findings are in agreement with the general notion that increases in the number of glaucoma medications used increase the risk of dry eye. We also analyzed the age and sex effects on dry eye risk. We noted an increased adjusted OR with an increase in the number
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Glaucoma Medication Use and Dry EyeVChen et al.
of glaucoma medications used, regardless of age. However, female patients using more than three types of glaucoma medications had a higher risk for dry eye compared with female patients who used one type of glaucoma medication among subjects less than 64 years old. Among subjects 65 years and older, female patients using more than two types of glaucoma medications had a significantly higher risk for dry eye compared with female patients who used only one type of glaucoma medication. In all age groups, male patients using more than four types of glaucoma medications had a higher risk for dry eye compared with those who used only one type of glaucoma medication. In particular, male patients between 50 and 64 years old who used three or four types of glaucoma medications had a significantly higher risk for dry eye. The greater prevalence of dry eye in female subjects compared with male subjects suggests that sex hormones may play a role.9,20 It is hypothesized that hormonal changes alter the homeostasis of the ocular surface and contribute to dry eye.20 It has also been reported that dry eye risk increases with age in both sexes, whereas its incidence is higher among female subjects.21 Menopause in aging female subjects may also contribute to dry eye as a consequence of an overall hormonal imbalance.21 Reduced estrogen levels were thought to be responsible for agerelated dry eye onset, but more recent studies have reconsidered the role of androgens in the protection of the ocular surface.21 We believe that our results may be a good basis for future evaluations of the influence of hormones on the risk of dry eye in female subjects. This study yielded some important findings; however, some limitations should be mentioned. First, we defined glaucoma and dry eye entirely by relying on claims data (ICD-9 coding from clinicians), which may be less accurate than individually determined diagnoses by professional ophthalmologists using standardized procedures.22 Second, there was selection bias in this study. Because the NHI database only included patients who sought treatment, those who did not seek help may have been recruited in the control cohort.22 Third, most of the residents of Taiwan are of Chinese ethnicity; thus, the current results may not directly apply to other racial/ethnic groups. Fourth, preservative-free glaucoma medications are not included in the current health insurance system; therefore, information on the use of preservative-free glaucoma medications is not available in the current database. It is unfortunate that we could not compare the risk for dry eye between glaucoma medications with and without preservatives.23 However, we believe our study has some strengths. First, the strength of the database was high because of good sample randomization.22 Second, the large sample size of Taiwan’s NHI database allows for statistically powerful assessment of the relative risk for diseases with potential risk factors. This fact is meaningful from a public health standpoint. Third, we think that the findings of our analysis are significant. Because glaucoma medications are not inexpensive, in Taiwan, most glaucoma patients seek treatment from ophthalmologists; therefore, the claims database for glaucoma medication usage used in this study appears to be reliable. In conclusion, this Taiwan populationYbased, case-control study reveals that an increased number of glaucoma medications used may increase dry eye risk, particularly in subjects who use more than two types of glaucoma medications and in female subjects.
e231
Clinicians should be cautious when prescribing medications for patients with glaucoma.
ACKNOWLEDGMENTS The authors have no commercial or proprietary interest in any of the materials discussed in this article. Received December 28, 2014; accepted April 28, 2015.
REFERENCES 1. Anwar Z, Wellik SR, Galor A. Glaucoma therapy and ocular surface disease: current literature and recommendations. Curr Opin Ophthalmol 2013;24:136Y43. 2. Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res 2011;36:391Y8. 3. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010;29:618Y21. 4. Garcia-Feijoo J, Sampaolesi JR. A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol 2012;6:441Y6. 5. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350Y5. 6. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol 2012;153:1Y9. 7. Aydin Kurna S, Acikgoz S, Altun A, Ozbay N, Sengor T, Olcaysu OO. The effects of topical antiglaucoma drugs as monotherapy on the ocular surface: a prospective study. J Ophthalmol 2014;2014:460483. 8. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol 2001;45(Suppl. 2):S199Y202. 9. Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and the dry eye. Clin Exp Optom 2014;97:324Y36. 10. Martone G, Frezzotti P, Tosi GM, Traversi C, Mittica V, Malandrini A, Pichierri P, Balestrazzi A, Motolese PA, Motolese I, Motolese E. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147:725Y35.e1. 11. Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol 2008;86:716Y26. 12. Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008;25:743Y51. 13. Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma 2002;11:119Y26. 14. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001;18:205Y15. 15. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea 2004;23:490Y6. 16. Lee S, Kim MK, Choi HJ, Wee WR, Kim DM. Comparative crosssectional analysis of the effects of topical antiglaucoma drugs on the ocular surface. Adv Ther 2013;30:420Y9.
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e232 Glaucoma Medication Use and Dry EyeVChen et al. 17. Baudouin C, Liang H, Hamard P, Riancho L, Creuzot-Garcher C, Warnet JM, Brignole-Baudouin F. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both T-helper 1 and T-helper 2 pathways. Ophthalmology 2008;115:109Y15. 18. Whitson JT, Trattler WB, Matossian C, Williams J, Hollander DA. Ocular surface tolerability of prostaglandin analogs in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther 2010;26:287Y92. 19. Wong J, Lan W, Ong LM, Tong L. Non-hormonal systemic medications and dry eye. Ocul Surf 2011;9:212Y26. 20. Rocha EM, Mantelli F, Nominato LF, Bonini S. Hormones and dry eye syndrome: an update on what we do and don’t know. Curr Opin Ophthalmol 2013;24:348Y55. 21. Versura P, Giannaccare G, Campos EC. Sex-steroid imbalance in females and dry eye. Curr Eye Res 2015;40:162Y75.
22. Chen HY, Chang YC, Lin CC, Sung FC, Chen WC. Obstructive sleep apnea patients having surgery are less associated with glaucoma. J Ophthalmol 2014;2014:838912. 23. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol 2014;8:903Y13.
Hsin-Yi Chen Department of Ophthalmology China Medical University Hospital No. 118, 5F-1, Yu-Der Rd Taichung 404 Taiwan e-mail: [email protected]
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