Purpose
To investigate the risk of glaucoma development after being prescribed topiramate.
Design
A retrospective, population-based cohort study using an administrative database.
Methods
The study group comprised 1956 patients who received their first prescription of topiramate between 2001 and 2007. The comparison cohort consisted of 15 648 randomly matched patients who never took topiramate. Each sampled patient was traced for a 1-year period from his or her index date to identify patients who subsequently received a diagnosis of glaucoma.
Results
Glaucoma was diagnosed in 0.36%, 0.05%, and 0.66% of the study cohort during the first month, second to third month, and fourth to twelfth month following the index date, respectively. For the comparison cohort, glaucoma was diagnosed in 0.04%, 0.11%, and 0.46% of subjects during the first month, second to third month, and fourth to twelfth month following the index date, respectively. After adjusting for potential confounding factors, patients prescribed topiramate were found to have a 7.41-fold (95% confidence interval [CI] = 2.45-22.46) greater risk of subsequently being diagnosed with glaucoma than the comparison cohort during the first month after the index date. However, this association became statistically nonsignificant during the second-to-third-month and fourth-to-twelfth-month periods following the index date between the 2 cohorts (adjusted hazard ratio, 0.56, 95% CI = 0.07-4.29; and 1.35, 95% CI = 0.74-2.47, respectively).
Conclusions
Topiramate use in Taiwan was associated with a significantly increased risk of being diagnosed with glaucoma within the first month after receiving a prescription for the drug.
Topiramate is a monosaccharide with sulfamate functionality that is mainly used as an anticonvulsant in the treatment of epilepsy. It is not structurally similar to other categories of anti-epilepsy agents and has been shown to be effective in migraine prophylaxis, smoking cessation, and the management of alcohol dependence, depression, and neuropathic pain. A case of uveal effusion with associated secondary acute angle-closure glaucoma was first reported in 2001. This rare adverse drug reaction was subsequently reported by other reports and permanent visual loss might ensue in some cases. In most such cases, glaucoma developed within days after topiramate use and symptoms subsided after stopping the drug.
One previous study investigated whether the use of topiramate was associated with an increased risk of glaucoma. In that case-control study by Etminan and associates, which utilized the British Columbia Linked Health Database of Canada, it was found that there was a slight increase in the risk of glaucoma among current users of topiramate (risk ratio = 1.23 [95% confidence interval (CI), 1.09-1.40]). This risk was greater among new users of topiramate (risk ratio = 1.54 [95% CI, 1.09-2.17]).
Etminan and associates’ study was performed in a population mainly consisting of white subjects, and data on the incidence and relative risk of topiramate-induced glaucoma are lacking in people of other ethnicities. Given the higher prevalence of narrow or occludable angles or angle closure in the Chinese population, it is of clinical significance to investigate the relative risk and incidence of this adverse drug reaction in a Chinese population and compare the results with those obtained from people of white ethnicity.
While a case-control study usually cannot provide information regarding the incidence of a disease- or drug-related complication, this study used a retrospective cohort study design and population-based dataset from Taiwan, which allowed us to calculate incidence rates (absolute risk) as well as relative risk of glaucoma during the first year following prescription with topiramate.
Methods
Database
We used a retrospective cohort study design to examine the association of topiramate and glaucoma development during the first year following prescription with topiramate. We retrieved the data for analysis from the Longitudinal Health Insurance Database 2000. This database is derived from Taiwan’s Bureau of National Health Insurance records and is maintained by the Taiwan National Health Research Institute. The Longitudinal Health Insurance Database 2000 includes the registration files and original claims data for the reimbursement of 1 000 000 beneficiaries under the National Health Insurance program. These 1 000 000 beneficiaries were randomly selected from the year 2000 Registry of Beneficiaries (n = 23.72 million) of the National Health Insurance. The completeness and accuracy of the claims data of the National Health Insurance research database are appropriately monitored. Hundreds of studies based on these data have been published in peer-reviewed journals. In addition, there was 1 study demonstrating validation of the diagnosis coding in Taiwan’s National Health Insurance database.
The Longitudinal Health Insurance Database 2000 consists of de-identified secondary data released to the public for research purposes and was therefore exempted from full review following consultation with the Taipei Medical University’s Institutional Review Board. The study adhered to the Declaration of Helsinki and all laws in Taiwan.
Study Sample
This retrospective cohort study features a case cohort and a comparison cohort. In selecting the case cohort, we first identified 2462 patients who received their first prescription of topiramate between January 1, 2001 and December 31, 2007. In Taiwan, no topiramate prescriptions are ever shorter than a 7-day course. We assigned the date of receipt of their first prescription of topiramate as the index date. We then excluded patients less than 18 years old (n = 374) in order to address only the adult population. In addition, we excluded patients who had received a diagnosis of any type of glaucoma (International Classification of Diseases, 9th edition, Clinical Modification [ICD-9-CM] code 365.xx) (n = 132) prior to index date. The resulting study cohort included 1956 patients.
The comparison cohort was likewise extracted from the remaining beneficiaries of the Longitudinal Health Insurance Database 2000. We randomly selected 15 648 beneficiaries (8 for every patient in the study cohort) matched with the study cohort in terms of sex, age (<30, 30-39, 40-49, 50-59, 60-69, and >69), geographic region, urbanization level (5 levels, with 1 referring to the most urbanized and 5 referring to the least), and the year of index date using the SAS program’s Survey Select procedure (SAS System for Windows, version 8.2; SAS, Cary, North Carolina, USA). We chose 8 comparison subjects per study subject on account of the very low prevalence of glaucoma. This large sample size allowed us to detect the real difference in the incidence of glaucoma between study cohort and comparison cohort. We assigned their first use of medical care occurring in the year of index as their index date. The reason for including geographic region and urbanization level of the patient’s residence as matching criteria was to help control for error variables, namely unmeasured neighborhood socioeconomic characteristics between the study cohort and comparison cohort. We ensured that patients selected for the comparison cohort had never been prescribed topiramate since the initiation of the National Health Insurance program in 1995. We also assured that none of the patients selected for the comparison cohort had received a diagnosis of glaucoma prior to their index date.
As a result, 17 604 subjects were included in this study. Each subject in this study was individually traced for 1-, 3-, and 12-month periods from their index date to distinguish patients who subsequently received a diagnosis of glaucoma (ICD-9-CM code 365). In order to increase the validity of the glaucoma diagnoses sourced from the dataset, this study included only glaucoma patients who had received treatment with topical antiglaucoma medication.
Statistical Analysis
We used the SAS statistical package (SAS System for Windows, version 8.2) to perform the statistical analyses conducted in this study. The 1-, 3-, and 12-month glaucoma-free survival rates were subsequently estimated by the Kaplan-Meier method, with the log-rank test also being used to examine differences in glaucoma-free survival rates between cohorts. Furthermore, we used stratified Cox proportional hazards regressions (stratified on sex, age group, urbanization level, and the year of index date) to compare the 1-, 3-, and 12-month glaucoma-free survival rates between the 2 cohorts, after adjusting for monthly income, geographic region (northern, central, eastern, and southern Taiwan) and selected comorbidities (hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, renal disease, and hypothyroidism). A 2-sided P value of <.05 was considered statistically significant for this study.
Results
The distribution of demographic characteristics and comorbidities between the study cohort and comparison cohort is presented in Table 1 . Of the total of 17 604 subjects, the mean age was 44.1 years (standard deviation = 17.0 years) and 58.2% were female. After matching for sex, age group, geographic region, and urbanization level, subjects who were prescribed topiramate had a higher prevalence of comorbidities of diabetes ( P = .004) and renal disease ( P < .001) than comparison subjects. No significant difference in the prevalence of hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, or hypothyroidism was detected between the study cohort and comparison cohort.
| Variables | Patients Receiving Topiramate (N = 1956) | Comparison Patients (N = 15 648) | P Value | ||
|---|---|---|---|---|---|
| N | % | N | % | ||
| Sex | >.999 | ||||
| Male | 818 | 41.8 | 6541 | 41.8 | |
| Female | 1138 | 58.2 | 9107 | 58.2 | |
| Age (y) | >.999 | ||||
| 18-29 | 447 | 22.8 | 3568 | 22.8 | |
| 30-39 | 400 | 20.5 | 3207 | 20.5 | |
| 40-49 | 446 | 22.8 | 3568 | 22.8 | |
| 50-59 | 305 | 15.6 | 2441 | 15.6 | |
| 60-69 | 152 | 7.8 | 1221 | 7.8 | |
| ≥70 | 206 | 10.5 | 1643 | 10.5 | |
| Urbanization level | >.999 | ||||
| 1 (most urbanized) | 596 | 30.5 | 4773 | 30.5 | |
| 2 | 560 | 28.6 | 4475 | 28.6 | |
| 3 | 301 | 15.4 | 2410 | 15.4 | |
| 4 | 306 | 15.6 | 2441 | 15.6 | |
| 5 (least urbanized) | 193 | 9.9 | 1549 | 9.9 | |
| Monthly income | .936 | ||||
| NT$1-15 840 | 946 | 48.4 | 7577 | 48.4 | |
| NT$15 841-25 000 | 646 | 33.0 | 5235 | 33.5 | |
| ≥NT$25 001 | 364 | 18.6 | 2836 | 18.1 | |
| Geographic region | >.999 | ||||
| Northern | 926 | 47.3 | 7402 | 47.3 | |
| Central | 614 | 31.4 | 4913 | 31.4 | |
| Southern | 357 | 18.3 | 2864 | 18.3 | |
| Eastern | 59 | 3.0 | 469 | 3.0 | |
| Diabetes | 179 | 9.2 | 1143 | 7.3 | .004 |
| Hypertension | 370 | 18.9 | 2951 | 18.9 | .951 |
| Coronary heart disease | 113 | 2.8 | 791 | 5.1 | .173 |
| Obesity | 17 | 0.9 | 49 | 0.9 | .760 |
| Hyperlipidemia | 230 | 11.8 | 1927 | 12.3 | .480 |
| Renal disease | 61 | 3.1 | 212 | 1.4 | <.001 |
| Hypothyroidism | 22 | 1.1 | 180 | 1.2 | .920 |
Table 2 presents the incidence of glaucoma during the 1-, 3-, and 12-month follow-up periods after the index date of the sampled subjects. Compared with comparison subjects, subjects prescribed topiramate had significantly higher glaucoma rates within the 1-month (0.36% vs 0.04%, P < .001), 3-month (0.41% vs 0.15%, P = .009), and 12-month (1.07% vs 0.61%, P = .016) periods after the index date. The log-rank test suggests that subjects who were prescribed topiramate had consistently and significantly lower 1-, 3-, and 12-month glaucoma-free survival rates compared with comparison subjects.
| Development of Glaucoma | Total | Patients Receiving Topiramate (N = 1956) | Comparison Patients (N = 15 648) | |||
|---|---|---|---|---|---|---|
| N | % | N | % | N | % | |
| Panel A: 1-month follow-up period | ||||||
| Yes | 13 | 0.07 | 7 | 0.36 | 6 | 0.04 |
| No | 17 591 | 99.93 | 1949 | 99.64 | 15 642 | 99.96 |
| Crude HR (95% CI) | – | 9.36 b (3.14-27.89) | 1.00 | |||
| Adjusted HR (95% CI) a | – | 7.41 b (2.45-22.46) | 1.00 | |||
| Panel B: 3-month follow-up period | ||||||
| Yes | 31 | 0.18 | 8 | 0.41 | 23 | 0.15 |
| No | 17 573 | 99.82 | 1948 | 99.59 | 15 625 | 99.85 |
| Crude HR (95% CI) | – | 2.79 c (1.25-6.25) | 1.00 | |||
| Adjusted HR (95% CI) a | – | 2.88 c (1.27-6.53) | 1.00 | |||
| Panel C: 12-month follow-up period | ||||||
| Yes | 116 | 0.66 | 21 | 1.07 | 95 | 0.61 |
| No | 17 488 | 99.34 | 1935 | 98.93 | 15 553 | 99.39 |
| Crude HR (95% CI) | – | 1.78 c (1.11-2.86) | 1.00 | |||
| Adjusted HR (95% CI) a | – | 1.71 c (1.06-2.77) | 1.00 | |||
a Adjustments are made for patient’s monthly income, diabetes, hypertension, coronary heart disease, obesity, hyperlipidemia, renal disease, and hypothyroidism.
Table 2 also shows the crude and adjusted hazard ratio (HR) of glaucoma between the cohorts. Stratified Cox proportional hazards regressions (stratified on sex, age group, geographic region, urbanization level, and the year of index date) show that the hazard ratios for glaucoma for subjects who were prescribed topiramate were 7.41 times as high within the 1-month period (95% CI = 2.45-22.46, P < .001), 2.88 times as high within the 3-month period (95% CI = 1.27-6.53, P < .05), and 1.71 times as high within the 1-month period (95% CI = 1.06-2.77, P < .05) as comparison subjects after adjusting for patient monthly income, diabetes, hypertension, coronary heart disease, obesity, hyperlipidemia, renal disease, and hypothyroidism.
We further analyzed the crude and adjusted HR of glaucoma during the 3-month period by excluding those patients who had glaucoma during the 1-month period. That is, we calculated and compared the incidence of new of glaucoma cases during the second to third months after the index date in the case and comparison cohorts (not including the cases of glaucoma occurring during the first month following the index date). Table 3 shows that there was no significant difference in the risk of glaucoma during the second-to-third-month follow-up period between subjects who were prescribed topiramate and comparison subjects (adjusted HR = 0.56 [95% CI, 0.07-4.29]). Similarly, no increased risk of glaucoma was observed during the fourth-to-twelfth-month follow-up period between subjects who were prescribed topiramate and comparison subjects (adjusted HR = 1.35 [95% CI, 0.74-2.47]).
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