Jpn J Ophthalmol (2014) 58:68–74 DOI 10.1007/s10384-013-0284-2

CLINICAL INVESTIGATION

Persistence with topical glaucoma therapy among newly diagnosed Japanese patients Kenji Kashiwagi • Toshie Furuya

Received: 21 May 2013 / Accepted: 25 September 2013 / Published online: 25 October 2013 Ó Japanese Ophthalmological Society 2013

Abstract Purpose To investigate persistence with glaucoma medication use and factors associated with it among newly diagnosed Japanese patients. Patients and methods The subjects of this study were Japanese patients entered in the Japan Health Insurance Society database who were newly diagnosed as having glaucoma and who had been prescribed antiglaucoma medication. Newly diagnosed was defined as having no history of glaucoma diagnosis, antiglaucoma medication use, or glaucoma surgery, including laser treatment, during at least 6 months prior to enrollment. Discontinuation of glaucoma medication was defined as no record of an antiglaucoma medication prescription or monthly claims for medical expenses for 6 months or longer. Patients who met the following criteria were eliminated from the analysis: those who changed insurance systems, those without records in the Japan Health Insurance Society database, or those whose glaucoma diagnosis was retracted. Results A total of 2799 patients (age 47.3 ± 13.9 years) were defined as patients with newly diagnosed glaucoma. They comprised 1494 male (46.9 ± 13.6 years) and 1305 female (47.8 ± 14.1 years) patients. Soon after starting to take the antiglaucoma medication, many patients discontinued it. The persistence rates at 3 months, 6 months, 12 months, and 3 years after the initiation of medication were 73.2, 68.1, 60.9, and 52.5 %, respectively. Younger Electronic supplementary material The online version of this article (doi:10.1007/s10384-013-0284-2) contains supplementary material, which is available to authorized users. K. Kashiwagi (&)  T. Furuya Department of Ophthalmology, University of Yamanashi Faculty of Medicine, Chuo, Yamanashi 409-3898, Japan e-mail: [email protected]

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age, the number of medications, and the hospital size were significantly associated with the patients’ persistence with medication use. Conclusions One-quarter of the newly diagnosed glaucoma patients discontinued glaucoma medication within the first 3 months of being prescribed it, and some factors were significantly associated with persistence with medication use. Keywords Persistence  Glaucoma  Prostaglandin  Beta blocker  Carbonic anhydrase inhibitor

Introduction Glaucoma is a life-long disease, and a majority of glaucoma patients receive topical medication to maintain their visual function. In recent years, new antiglaucoma ophthalmic solutions have been introduced, and we now have many more tools to control glaucoma than ever before. Clinically important points in glaucoma medical therapy include maintaining good adherence and persistence [1]. However, many previous studies have shown poor adherence to and persistence with topical medication regimens among patients with glaucoma [2–5]. Nordstrom et al. [5] reported that nearly half of the studied glaucoma patients discontinued all topical ocular hypotensive therapy within 6 months. Quek et al. [6] performed a hospital-based study in which the persistence rate was lower in Singapore than that reported in Western countries. However, the number of studies focusing on persistence in Asian countries is limited in terms of how many glaucoma patients discontinue their glaucoma therapy and what risk factors are involved [7]. In the present study, we used the database of the Japan Health Insurance Society, one of the major health insurance

Persistence with glaucoma therapy

69

newly diagnosed with glaucoma and were beginning treatment with antiglaucoma topical medication were included in this study. The definitions of newly diagnosed glaucoma, persistence, and disenrollment are described in Table 1. Briefly, patients defined as having newly diagnosed glaucoma were those who had belonged to a Japan Health Insurance Society union for more than 6 months prior to enrollment, had no history of any type of glaucoma (see details in Supplemental Table S1), had been prescribed antiglaucoma ophthalmic solutions (see details in Supplemental Table S2), and had no laser and/or surgical treatments recorded in the JMDC database. Patients defined under discontinuation of glaucoma medication were those who had no further prescription claims for any antiglaucoma ophthalmic solutions or who had not visited the clinic for 6 months or more since the final visit to the medical institution. The duration from the initiation of medication to the date of the final prescription or the final visit to the medical institution was used to define the persistence period. Patients who met the following criteria were eliminated from the analysis: patients who changed insurance systems, those who had no records in the Japan Health Insurance Society database, and those whose glaucoma diagnosis was retracted. We did not define changes from the initially prescribed topical medication as discontinuation.

society unions in Japan, to investigate persistence among newly diagnosed glaucoma patients with topical antiglaucoma medication use and the factors associated with this persistence.

Patients and methods This study was performed in accordance with the Helsinki treaty and was approved by the ethics review board of the University of Yamanashi. Because the data used in this study do not contain any personal information, the ethics review board agreed to allow this study to be done without requiring that written informed consent be obtained from all of the patients. Database and investigated parameters In this study, we used the claims database of the Japan Medical Data Center (JMDC) that was established in 2003 for the purpose of accumulating receipts to aid in epidemiologic and health service research using receipt information [8]. The JMDC database employs an anonymous linkage system by using an encryption code and combines individual medical claim information from different health insurance societies by a computer-aided post-entry standardization method. This database covers more than 1 million employees and their dependents who belong to the Japan Health Insurance Society. The data include the patients’ encrypted personal identifier; their age and sex; their International Classification of Diseases 10th revision (ICD-10) diagnosis codes; the names of the dispensed drugs; and the size of the medical institutions. The encrypted personal identifiers can be used to link claims data from different hospitals, clinics, and pharmacies.

Main outcomes Persistence with topical glaucoma medication among newly diagnosed Japanese patients and the factors associated with this persistence were the main outcomes of this study. Investigated parameters The parameters for investigation were sex, age, the use of antiglaucoma ophthalmic solution, the number of antiglaucoma ophthalmic solutions prescribed, and the type of medical institution. All of the parameters at entry into the

Patients Among the patients who have belonged to the Japan Health Insurance Society unions since 2005, those who were Table 1 Definitions of discontinuing medication and disenrollment from the study

O, any records or medical claim; q, start of glaucoma medication; œ, end of persistency with medication use; , end of enrollment in the study

-6

-5

-

-1

q

1

2

3



N

N?1

Any records in the database

s

s



s

s

s

s

s



s

s

Medical claims of glaucoma treatment Glaucoma medication

s

s



s

s

s

s

s



s

u

u

u

u

Definition Discontinuing

Disenrollment Any records in the database Medical claims of glaucoma treatment Glaucoma medication

œ

s

s



s

s

s

s

s



s

s

s



s

s

s

s

s



s

u

u

u

u



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study were subject to analysis. We analyzed the number of antiglaucoma ophthalmic solutions used on a per-patient basis because the prescription claims did not provide individual eye data. The medical institutions were subdivided into 6 groups according to the number of hospital beds, namely, fewer than 19, 20 to 99, 100 to 199, 200 to 299, 300 to 499, and more than 500. Subgroup analysis We compared persistence with glaucoma topical medication among 3 antiglaucoma ophthalmic solutions, namely prostaglandin analogs (PGs), carbonic anhydrase inhibitors (CAIs), and beta blockers (BBs), because these are the 3 major types of antiglaucoma ophthalmic solutions. Patients with primary open angle glaucoma (POAG) were extracted from the group of glaucoma patients and were subject to the same analysis that was used for all glaucoma patients. Statistical analysis The data were analyzed using the JMP 8.0 software package (SAS Institute, Cary, NC, USA), and the values are presented as the means ± standard deviations. The Kaplan–Meier method was employed to investigate persistence with glaucoma topical medication use. Associations between persistence with glaucoma topical medication use and the investigated parameters were analyzed using the Cox proportional hazards model. The differences in persistence with glaucoma topical medication use between male and female patients and among antiglaucoma ophthalmic solutions were compared using the log-rank test. The difference in the number of antiglaucoma ophthalmic solutions used by the POAG group and that used by all patients was compared using the Wilcoxon signed rank test. The ages of the included and excluded patients were compared using the Mann–Whitney test. The sizes of the medical institutions and the patients’ sex were compared using contingency table analysis and the Fisher exact test, respectively. Probability values lower than 0.05 were considered significant.

K. Kashiwagi, T. Furuya

criteria. The reasons for elimination were changes in the patients’ health insurance systems (105 patients) or no records showing membership to a health insurance society. Ultimately, 2483 patients (47.2 ± 14.3 years; 54.2 % male patients) were included in the analysis. The mean number of antiglaucoma ophthalmic solutions used per patient was 1.08 ± 0.29. Among the patients, 94.1 % were medicated with a single antiglaucoma ophthalmic solution: 46.4 % with PGs, 44.5 % with BBs, and 3.2 % with CAIs. Table 2 provides detailed information on the enrolled patients depending on the type of medical institution. Persistence with glaucoma medication use As Fig. 1 shows, persistence with glaucoma medication use rapidly decreased very soon after the initiation of glaucoma medication. Persistence rates at 3 months, 6 months, 12 months, and 3 years after initiation were 73.2 % (95 % confidential interval [CI] 71.5–74.9 %), 68.1 % (95 % CI 66.2–70.0 %), 60.9 % (95 % CI 58.7–62.9 %), and 52.5 % (95 % CI 49.7–55.2 %), respectively.

Table 2 Comparison of backgrounds of enrolled patients among the types of medical institution Medical institutions (No. of hospital beds)

No. of patients

Age

No. of POAG

0–19

1906

47.1 ± 13.4

630

20–99

66

46.3 ± 12.0

19

100–199 200–299

58 36

50.0 ± 14.9 49.1 ± 17.3

15 10

300–499

153

46.7 ± 16.5

45

500–

264

46.9 ± 14.9

75

SD standard deviation, POAG primary open angle glaucoma

Results Patients The number of patients in the JMDC database was 1,181,102. Of these, 2799 (47.3 ± 13.9 years) met the entry criteria. They comprised 1494 male (46.9 ± 13.6 years) and 1305 female (47.8 ± 14.1 years) patients. Three hundred sixteen patients met the exclusion

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Fig. 1 Persistence with topical glaucoma medication use

Persistence with glaucoma therapy

71

Table 3 Factors associated with persistence with topical medication use Factor

Hazard ratio

95 % CI

Age

0.997/year

0.999–1.000

No. of ophthalmic solutions

0.745/bottle

0.645–0.856 \0.001

Sex Hospital size

0.931/female 1.10/full category

1.076–1.139

P value 0.04

0.07 0.008

CI confidence interval

Factors associated with persistence with topical medication use Table 3 shows the associations of sex, age, number of antiglaucoma ophthalmic solutions, and medical institution size with persistence for topical medication use. Older age and the number of antiglaucoma ophthalmic solutions significantly improved persistence with glaucoma medication use, while the medical institution size significantly worsened it. Female patients showed a tendency for better persistency with topical medication use than did male patients (P = 0.07).

Fig. 2 Comparison of persistence among antiglaucoma ophthalmic solutions. *P \ 0.001, log-rank test. PG indicates prostaglandins, BB beta blockers, and CAI carboxyl anhydrase inhibitors

Types of antiglaucoma ophthalmic solutions and persistence with topical medication use Detailed information on patients treated with 1 of the 3 major antiglaucoma ophthalmic solutions is provided in Table 4. Figure 2 compares the persistence with topical medication use among the 3 antiglaucoma ophthalmic solutions. PGs showed significantly better patient persistence with use than BBs(P \ 0.001, log-rank test)and CAIs(P \ 0.001, log-rank test)after adjustment for age, sex, and medical institution size. The odds ratios of PGs compared with BBs and CAIs were 0.680 and 0.679, respectively. In contrast, no significant difference was found between BBs and CAIs in patient persistence with topical medication use. Persistence with topical medication use among patients with POAG Seven hundred ninety-four patients (49.5 ± 11.9 years) had newly diagnosed POAG and comprised 443 male Table 4 Comparison of backgrounds of antiglaucoma topical ophthalmic solutions PG prostaglandins, BB beta blockers, CAI carbonic anhydrase inhibitors

Antiglaucoma ophthalmic solution

Fig. 3 Comparison of persistence with medication use between POAG patients and patients with other types of glaucoma. The POAG patients showed a significantly higher persistence rate than did the patients with other types of glaucoma. P = 0.01, log-rank test

patients (49.0 ± 11.1 years)and 351 female patients (50.1 ± 13.0 years). Their rates of persistent glaucoma medication use at 3 months, 6 months, 12 months, and 3 years were 80.7 % (95 % CI 77.6–83.3 %), 74.4 % (95 % CI 71.0–77.6 %), 66.6 % (95 % CI 62.6–70.3 %), and 51.9 % (95 % CI 45.2–58.5 %), respectively (Fig. 3). Patients with POAG showed significantly better persistence when compared with patients with other types of glaucoma (P = 0.01, log-rank test).

All cases

Male patients

PG

1151 (48.1 ± 13.2)

673 (49.1 ± 13.2)

478 (46.6 ± 15.1)

BB

1105 (46.4 ± 15.5)

51 (45.9 ± 14.3)

595 (46.8 ± 16.6)

80 (47.0 ± 14.7)

51 (48.0 ± 15.0)

29 (45.2 ± 14.2)

CAI

Female patients

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72

Discussion The current study shows that approximately 40 % of Japanese patients with newly diagnosed glaucoma discontinue their medication within 1 year of being first prescribed topical glaucoma medication. In particular, the persistence rate was significantly reduced within the first 3 months, which is consistent with the findings of previous reports [5, 9]. However, the persistence rate in the current study is better than those found in previous reports. Reardon summarized 14 reports focusing on the persistence with glaucoma medication use. On average, only 31 % of patients were still taking their glaucoma medication at the end of the 12 months since starting the therapy [10]. Nordstrom et al. [5] reported that nearly half of the glaucoma patients in their study discontinued all topical ocular hypotensive therapy within 6 months. One possible explanation for these differences in persistence rates is the differences in the health insurance systems of Japan and of other countries. The Japanese government introduced universal coverage of pensions and healthcare in 1961. All Japanese citizens are required to participate in a health insurance system. This health insurance covers at least 70 % of medical expenses, which allows patients to access medical institutions and keeps patients’ motivation for taking glaucoma medication high. Differences in socioeconomic circumstances may be another reason for the differences among the studies’ results. Differences in income are relatively small among the Japanese population. We should also consider the differences in study protocols among the reports. The current study revealed several factors associated with the persistent use of topical glaucoma medication. Younger age, fewer bottles of antiglaucoma ophthalmic solutions, and being treated at a larger hospital may be risk factors for reducing persistence with topical glaucoma medication use. Previous studies have reported that an older age improved persistence with topical glaucoma medication use [5, 6]. Glaucoma is frequently an asymptomatic disease for many glaucoma patients, especially at the early stage. Visual function disturbances become more pronounced with age, which makes it difficult to maintain the motivation to use glaucoma medication, especially among young glaucoma patients whose glaucomatous damage is usually milder than that of elderly patients and who are much busier with work or caring for children when compared with their elderly counterparts. Many studies reported that adherence to glaucoma medication use deteriorated according to the amount of antiglaucoma ophthalmic solution prescribed [11]. Interestingly, the current study showed that the number of bottles of antiglaucoma ophthalmic solutions exerted a

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positive effect on persistence with use. Although our study was entirely based on health insurance claims data without validation from medical record reviews, it is possible to assume that the patients who were prescribed more bottles of antiglaucoma ophthalmic solutions could have much more severe glaucoma. Patients with more severe glaucoma notice glaucoma-related symptoms much more frequently, and they may adhere more carefully to their medication use out of fear of developing blindness in the future. This association could exert a positive effect on the persistent glaucoma medication use. Generally, patients seen at larger hospitals tend to have more severe glaucoma than those cared for at smaller medical institutions, which assumes that hospital size exerts a positive effect on persistence. However, the current study showed that hospital size negatively affected topical glaucoma medication use. We analyzed the hospital size that patients initially visited. Patients who were referred to larger hospitals from smaller ones were registered as having initially received care at the smaller hospital. In Japan, patients can freely choose which hospitals to visit. Many patients tend to visit larger hospitals. Therefore, in the current study, there may be no substantial difference in glaucoma severity among patients based on the size of the hospital where the patient received services. More ophthalmologists tend to be working in larger hospitals than in smaller hospitals, and in larger hospitals, it is easier for patients to change their primary ophthalmologist. These circumstances could negatively affect patient-ophthalmologist communication, which has been reported to be an important factor in improving adherence [12, 13]. Conditions regarding the hospital’s accessibility, including costs and the duration of transportation and waiting times, are usually worse in bigger hospitals than in smaller hospitals. Hospital accessibility has been reported to be involved in adherence [14]. Altogether, in the current study, patients who received care at larger hospitals showed worse persistence with topical glaucoma medication use. The current study revealed that patients are significantly more likely to persist with using PGs than with using BBs or CAIs, if they are used alone. These findings are consistent with those of previous studies [5, 9, 15, 16]. PGs have a better potential for reducing IOP with less frequent dosing when compared with other antiglaucoma drugs, and PGs impart no systemic side effects when compared with BBs. In this regard, use of fixed combination therapy, which has been reported to show better efficacy and safety [17], may be better for achieving longer persistency than use of 2 bottles of antiglaucoma ophthalmic solutions. Whether medical expense is related to persistence with medication use is a controversial issue. Some studies have reported a positive correlation [18, 19], whereas others

Persistence with glaucoma therapy

have not [5]. In the current study, medical expense was not included in the analysis. The Health Insurance program covers 70 % or more of all medical expenses, and other public and private systems may be able to cover patient’s additional expenses, if necessary. Therefore, the economic burden borne by the patients themselves may not be a very severe problem in Japan. Some studies have noted the importance of health literacy to patients’ persistent use of glaucoma medication [20, 21]. Further investigation to clarify the risk factors for poor persistence should be undertaken by analyzing prescription and chart data. Our results showed that patients with POAG had better persistence rates than did patients with other types of glaucoma. Differences in glaucoma severity, the possibility that patients with other types of glaucoma showed transitory IOP elevation, or other reasons may explain this difference. The current study has some limitations. The patients in this study were employees and their dependents. There is another major health insurance system in Japan called the National Health Insurance, which primarily serves retired people and employers. People who are served by the Health Insurance Society are younger and have higher incomes than those who are served by the National Health Insurance system. Therefore, sample bias could not be completely eliminated. Unfortunately, the same type of analysis could not be performed among patients belonging to the National Health Insurance system as the one conducted in the current study because a unified database of the patients belonging to the National Health Insurance system is unavailable. Our study was based entirely on health insurance claims data without validation through medical record review. Therefore, the claims’ accuracy in presenting the correct diagnoses and the timing of drug exposure information must be considered with caution. The current study shows that approximately 40 % of newly diagnosed patients discontinued topical glaucoma medication within 1 year. For those patients who are new to therapy, the ophthalmologist and medical staff’s active engagement with the patient is especially important during the first year of treatment. To maximize persistence, ophthalmologists should pay attention to risk factors and employ adequate interventions, such as choosing the most appropriate topical medication and maintaining good patient-doctor communication. Acknowledgments We appreciate the kind cooperation of Ms. Makiko Furuya, Ms. Chie Ito, and Ms. Rie Nishikino in providing and analyzing the data. This study was performed with the help of the JMDC. Conflicts of interest

K. Kashiwagi, None; T. Furuya, None.

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Persistence with topical glaucoma therapy among newly diagnosed Japanese patients.

To investigate persistence with glaucoma medication use and factors associated with it among newly diagnosed Japanese patients...
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