Comparison of adherence between fixed and unfixed topical combination glaucoma therapies using Japanese healthcare/pharmacy claims database: a retrospective non-interventional cohort study

Glaucoma is the most common causative disease of blindness in Japan [1]. One of the critical risk factors for glaucoma is the intraocular pressure (IOP) [2‐5]. IOP-lowering eye drops and surgeries, such as selective laser trabeculoplasty (SLT) and minimally invasive glaucoma surgery (MIGS), have been developed and used for treatment. Consequently, glaucoma has become manageable, provided that it is diagnosed early and the treatment is implemented in a timely manner to prevent the development and delay the progression of the disease [6, 7]. Recently a randomized study, called the LiGHT study, compared the clinical effectiveness as well as cost-effectiveness between the eye drops and the SLT groups and demonstrated that SLT is cost effective, suggesting that SLT should be offered as a first-line treatment for open-angle glaucoma and ocular hypertension [8]. However, IOP-lowering eye drops still remain a first-line treatment option in many countries including Japan.

The treatment for glaucoma is generally started with a monotherapy, such as prostaglandin analogs (PG) or β-blockers (BB). If the first monotherapy is ineffective or intolerable, switching to another monotherapy is preferred. Whenever a monotherapy does not reach the target IOP or the target must be lowered as the disease progresses, a concomitant therapy with a medication that has a different mechanism of action should be considered. If such treatment regimens are successful, patients can avoid laser intervention and surgery. However, adherence to the therapy should be crucially improved for a successful glaucoma treatment [9], considering that nonadherence to glaucoma therapies has been a serious concern [10, 11].

Risk factors for nonadherence to glaucoma therapies include patients’ problems (financial concern, poor understanding of the disease, and frequent eye drop application), healthcare providers’ issues (insufficient instruction/explanation and assessment of each patient’s conditions), and the relationship between patients and physicians (lack of communication and trust) [12‐14]. A previous study reported that a fixed-combination therapy improved the long-term adherence of patients with glaucoma compared with the unfixed therapy [15]. According to a nationwide survey performed in 2011–2012 in Japan using a questionnaire, good adherence to IOP-lowering eye drops was observed in 72.4% of patients [16]. However, these risk factors and adherence rates were based on the data obtained from clinical studies under controlled conditions or an experimental setting. Therefore, patients’ adherence to the therapies should be investigated, and the risk factors in ordinary clinical settings should be determined using real-world data.

In several previous studies, adherence to glaucoma therapies was evaluated using pharmacy claims data [17‐22]. Unfortunately, to our knowledge, no such study has been conducted in Japan. Therefore, this study aimed to compare patients’ adherence between a fixed-combination therapy and an unfixed-combination therapy and to identify risk factors for nonadherence in Japanese patients with glaucoma by using a healthcare database.

In total, 57,899 patients were diagnosed with glaucoma and prescribed with any IOP-lowering drug in the database, of whom 309 patients were in the fixed-combination cohort and 329 patients were in the unfixed-combination cohort (Fig. 1). The two cohorts had similar baseline demographic and clinical characteristics (Table 1). The mean age was 56–57 years and clinical measurement values were within the normal ranges. Comorbidities reported in > 20% of patients were hypertension, hyperlipidemia, diabetes mellitus, and cancer. In both cohorts, over 80% of patients lived in East Japan (especially residents of Tokyo or large cities).

The eye drops claimed at the index date are summarized in Fig. 2. In the fixed-combination cohort, PG/BB (78.0%) and CAI/BB (22.0%) were used by drug class, and the most commonly used eye drop was latanoprost/timolol (39.8%) by generic name. In the unfixed-combination cohort, the top three most frequently administered drug combinations were PG + BB (39.5%), PG + α2-agonist (AA) (26.4%), and PG + CAI (14.3%) by drug class; the most common drugs were latanoprost and brimonidine (12.2%), followed by latanoprost and timolol (11.9%) by generic name.

Common patterns of switching eye drops during the post-index period are shown in Fig. 3. In the fixed-combination cohort, out of 241 patients prescribed with PG/BB, 165 (68.5%) continued the same drug class, and out of 68 patients prescribed with CAI/BB, 38 (55.9%) continued the same drug class. Other major switching patterns were the addition of AA or CAI. In the unfixed cohort, the same drug class combination therapies were continued by only less than 50% of patients, regardless of the kind of combination.

The mean PDC over the 12-month post-index period was 70.4% in all the patients, 79.1% in the fixed-combination cohort, and 62.2% in the unfixed-combination cohort; hence, the PDC in the fixed-combination cohort was significantly higher than that in the unfixed-combination cohort (P < 0.0001) (Table 2). High adherence (PDC ≥ 80%) was observed in 58.8% of all the patients, 69.6% in the fixed-combination cohort, and 48.6% in the unfixed-combination cohort; hence, it was significantly higher in the fixed-combination cohort than in the unfixed-combination cohort (P < 0.0001). As for the popular combination of latanoprost and timolol, the mean PDC was 82.9% in the fixed-combination cohort and 66.5% in the unfixed-combination cohort; hence, it was higher in the fixed-combination cohort (P = 0.0191) (Table 3), but it was not significant (NS). A proportion of patients with PDC ≥ 80% was 75.6% in the fixed-combination cohort and 53.8% in the unfixed-combination cohort, showing that it was higher in the fixed-combination cohort (P = 0.0095, NS). Furthermore, when compared between the PG/BB and CAI/BB of the same fixed-combination cohort, PG/BB had an approximately 10% higher mean PDC value (P = 0.0438, NS) and an approximately 15% higher proportion of patients with good adherence (P = 0.0131, NS) (Table 4).

Univariate analyses identified treatment (fixed-combination vs. unfixed-combination) and hemoglobin A1c (HbA1c) as potential risk factors for nonadherence (P < 0.1) (Table 5). Conversely, variables, such as age, sex, body mass index, smoking habit, hospital locations, and comorbidities, were not associated with nonadherence. In multivariate analyses, treatment (adjusted OR: 0.388 [95% CI: 0.259, 0.583], P < 0.0001) and HbA1c (adjusted OR: 1.606 per 1% [95% CI: 1.105, 2.333], P = 0.0130) were also considered as significant risk factors.

Kaplan–Meier curves of persistence are presented in Fig. 4a. According to nonoverlapping 95% CIs, more patients in the fixed-combination cohort than in the unfixed cohort continued their treatment after 2 months post-index, with a significant difference between the two cohorts (log-rank test, P < 0.0001). The persistence rates at 6 and 12 months post-index were approximately 67.6% (95% CI: 62.1, 72.5) and 47.6% (95% CI: 41.9, 53.0), respectively, in the fixed-combination cohort, and 48.0% (95% CI: 42.5, 53.3) and 24.9% (95% CI: 20.4, 29.7), respectively, in the unfixed-combination cohort.

Likewise, the persistence rate of the fixed-combination therapy with latanoprost and timolol was significantly higher than that of the unfixed-combination cohort (log-rank test, P = 0.0001) (Fig. 4b). Persistence rates at 6 and 12 months post-index were approximately 74.0% (95% CI: 65.3, 80.3) and 54.5% (95% CI: 45.3, 62.8), respectively, in the latanoprost/timolol fixed-combination cohort and 46.2% (95% CI: 30.2, 60.7) and 25.6% (95% CI: 13.3, 39.9), respectively, in the counterpart cohort.

Additionally, when compared between classes of the fixed-combination therapies, that is, PG/BB vs. CAI/BB, at 12 months post-index, the persistence rate of the PG/BB group was approximately 8% higher than that of the CAI/ BB group (49.4% [95% CI: 42.9, 55.5] vs. 41.2% [95% CI: 29.5, 52.5]). However, it remained to be not statistically significant (log-rank test, P = 0.1454) (Fig. 4c).

The present study found that patients with fixed-combination therapy adhered to their therapies better than those with unfixed-combination therapy after switching from at least 12 months of monotherapy to a combination therapy with two drugs. Our findings are clinically important because no comparative study of adherence and persistence between fixed and unfixed-combination therapies has been reported in Japanese patients with glaucoma by using real-world data.

Most of the patients were prescribed with a combination of PG and BB in accordance with the guideline recommendation [9]. Overall, good adherence (PDC ≥ 80%) was noted in 58.8% of patients, lower than the results (72.4%) of a nationwide survey using a questionnaire in Japan [16]. In the fixed-combination cohort, 47.6% of patients continued the two-drug combination drugs at 12 months post-index, and 69.6% showed good adherence during the 12 months. Patients receiving a fixed-combination also had a higher 12-month persistence rate. The persistence rate of latanoprost/timolol fixed-combination was as high as 54.5%. Otherwise, most patients continued treatment using the same drops or the same class of drops, or switched to add-on therapy with the third drug (AA or CAI), suggesting that a fixed-combination was preferred. Although not significant, the PG/BB type had a slightly higher persistence rate than the CAI/BB type. Meanwhile, in the unfixed-combination cohort, only approximately 50% of the patients had good adherence. Furthermore, only 24.9% stayed on the unfixed two-drug combination therapy at 12 months post-index. Of note, the persistence rate of unfixed latanoprost plus timolol was as low as 25.6%. Therefore, if eye drops had the same combination, the fixed-combination therapy would achieve high adherence and persistence.

The major reason for the high adherence of the fixed combination therapy may be because they are more convenient for patients. An interval of 5 min or more is required when two ophthalmic solutions are used in unfixed combination eye drops, whereas two types of eye drops can easily be administered using a single eye drop in fixed combination drugs. Moreover, the number of eye drops and applications in fixed combinations are very small. Furthermore, to reduce the physical and economic burden on patients, physicians should explain to patients that the use of the fixed-combination therapies is advantageous because it requires less frequent medication and decreased exposure to preservatives (decreased risk of developing ocular surface diseases) [30, 31] with similar efficacies [15, 32‐34], or possibly superior in daily practice [35], compared with unfixed-combination therapies. In an overseas clinical study, patients can better adhered with fixed-combination therapies than with unfixed-combination therapies [15]. Considering that good adherence to therapies is critical for controlling glaucoma progression [9, 36, 37], we believe that a fixed-combination therapy is an advantageous option for glaucoma treatment.

Given that the analyzed patients had received eye drop monotherapy for at least 1 year and continued to visit hospitals, they seemed to have been educated by doctors and have possibly understood the importance of continuing treatment with eye drops. However, many patients were nonadherent to the index therapy. In fact, an unfixed-combination therapy was consistently a risk factor for adherence. Furthermore, a high HbA1c level, but not diabetes mellitus, was another risk factor for nonadherence to the treatment. Considering the small sample size and numerous missing data, HbA1c is carefully concluded as a risk factor. However, diabetic patients with higher HbA1c levels are apt to be nonadherent to the therapy because a higher HbA1c level; i.e., poor glycemic control can be partly explained by poor adherence to antidiabetic medications and medical visits [38‐41]. Type 2 diabetes mellitus, as well as glaucoma, is a chronic disease in which patients may have few symptoms despite having complex medication. If patients have complications, they need to take more pills at different times as per medicine. These patients may pay minimal attention to eye drops, leading to glaucoma progression. Therefore, glaucoma should be treated with continuous intervention in patients with diabetes mellitus, especially patients with poor glycemic control.

Moreover, other common risk factors were previously identified [12‐14]. All of these risk factors need to be solved by education, communication with patients, and patient training in improving proficiency of self-administration of eye drops [42].

Specific reasons on why physicians prescribed unfixed combinations for certain patients would be interesting to identify. Such reasons may include a risk of adverse events caused by the concentration of the fixed-combination, preservative formulations, and dosage adjustment of eye drops. If so, developing a new fixed-combination therapy would be worthwhile.

This study, however, has limitations. First, this study assumes that patients took eye drops for the number of days that they were prescribed, because the claims database does not track whether the patient actually administrated the eye drops as prescribed. However, we set a 30-day grace period so that the PDC did not underestimate adherence. Second, the study did not consider baseline PDC in patients that had being continuing monotherapy for 12 months prior to the index date, although baseline may or may not differ between the groups. Third, we used the MinaCare database to gather healthcare information covering nearly 2 million individuals, of which 90% were aged 20–59 years who worked for a nationwide large company, of which, most individuals lived in Tokyo or large cities in East Japan, and their dependents in private corporate health insurance societies [24, 25]. Therefore, regional and income biases might have affected the results. Moreover, only few elderly patients were included in this study. However, this study is worth considering for treating glaucoma because young patients are more likely to have glaucoma progression during their long life-spans. Fourth, the patients between the two cohorts possessed an uncontrolled nature, which includes the numerous drug types used as monotherapy during the pre-index period and the severity of glaucoma. Although background information and baseline characteristics were limited, they were similar between the two cohorts. Finally, the present analyses were built according to the assumption that all of the claimed drugs were used by the patients. To address these limitations, we need to conduct further studies using the real-world data combined with clinical data.

The present results using the real-world data showed that city patients who received fixed-combination therapies exhibited better adherence to medications compared with those who received unfixed-combination therapies. A high HbA1c level was one risk factor for nonadherence. Therefore, a fixed-combination therapy would better serve as a glaucoma therapy, considering that adherence to the therapy is a key for effectively preventing glaucoma progression.