To date, we found no other studies that identified the risk factors associates with GS in patients with glaucoma in Japan or other countries. Our study did and revealed a significant influence of 11variables on GS extracted from the claims database. Of these, 7 were significant more likely to increase GS, and 4 were significant more likely to decrease GS. The immune-related comorbidities and concomitant drugs use were the most likely to be GS. Although there was no difference in the treatment pattern of prescribed glaucoma eye drops between the GS cohort and the non-GS cohort, the rate of the comorbidities and the rate of concomitant drugs use were similar trend to the above identified variables. Therefore, careful management of glaucoma patients with these variables may be important factor for reducing glaucoma surgery burden.
In Japan, TLO is also often preferred as GS, and TRAB may target relatively sever glaucoma patients. Since this study used DPC data collected form patients who were admitted to the nationwide acute care hospitals, we assumed that patients with relatively sever glaucoma were included and considered appropriate to select only TRAB as GS. On the other hand, since TLO such as microhook TLO is often additionally used during CS, it is difficult to be an indicator for estimating exacerbation risk of glaucoma.
Among the 17 disease as the possible risk factors for glaucoma23–26 (see Variable in the Method section), allergies were identified as the risk factors of comorbidities leading to GS. Our finding might be explained by the previous studies: the toll-like receptor 4 (TLR4), a transmembrane receptor that mediates immune responses to exogenous, is associated with the risk of NTG.30 The microglia are related to the immunocompetent cells of the central nervous system, and microglial activation has been reported in glaucoma,31 which might contribute to a higher prevalence of immune-related comorbidities such as allergies.
Among systemic oral drugs for the 17 disease, cancer, depression, ischemic heart disease or peptic ulcer were identified as the risk factors of concomitant drugs leading to GS. According to the previous studies, the downregulation of cell cycle progression by checkpoint inhibitors has recently been targeting for cancer therapy,32, 33 can cause cell death beyond cancer cells, and therefore may induce neurodegenerative disorders such as glaucoma.34 However, one of the risk factors for glaucoma is increased oxidative stress, and drugs targeting oxidative stress in cancer could reduce the oxidative stress-induced apoptosis of retinal ganglion cells in glaucoma.35, 36 Therefore, we have not been able to identify reports from previous studies of whether cancer drugs is associated with GS. Other studies report that depression is strongly linked with glaucoma37 and results in elevated oxidative stress.38 Likewise, ischemic heart disease is linked with glaucoma probably affect vasculature dysfunction.39 Furthermore, many factors contribute to peptic ulcer including glaucoma40 is another likely reason that may contribute to the positive association. In contrast, hypertension and its drug were identified as the risk factors leading to non-GS. Our finding might to be in line with the previous studies that hypertension improve ocular blood flow,41 however, hypertension oral administration is a risk of glaucoma progression.42 Stratified analysis based in CS showed that none of the 17 disease were identified as the risk factors leading to CS combined with GS.
In addition, patients with POAG was also identified as the significant more likely to be GS. The rate for glaucoma type in subjects 40 years of age and older was estimated at 5.0% for all glaucoma, 0.3% for POAG, and 3.6% for NTG.5 In contrast, this study showed that the rates of POAG, OAG and NTG at the index admission were 36.6%, 35.0% and 6.2%, respectively, in the GS cohort, and 32.0%, 36.0% and 7.6%, respectively, in the non-GS cohort. The ratios of NTG seem to be fewer than expected. One possible explanation could be that the rate of progress of glaucomatous optic neuropathy among patients with NTG is generally slower than that among those with other types of glaucoma, therefore, patients with NTG have less need to go to DPC hospitals.
Furthermore, this study identified longer LOS as the factors associate with GS. Japanese hospitals generally provide rehabilitation and nursing care in addition to acute medical care, which may contribute to the longer LOS.
Patients in both cohorts, the high rate of comorbidities and concomitant drugs use were similar trend to the above identified variables. In the GS cohort, allergy and cancer drugs were most significantly higher than the non-GS cohort. Diabetes was the most common comorbidities in both, the GS (14.6%) and non-GS cohort (13.6%), and significantly higher in the GS cohorts, but not identified as the risk factors leadings to GS. On the other hand, the rate of the diabetes drug use was low in both, the GS (4.9%) and non-GS cohort (3.6%). Patients with glaucoma who had diabetes may be able to handle with drug treatment without surgical treatment.
The treatment patterns of prescribed glaucoma eye drops at the index admission was similar between the two cohorts; PG was most commonly prescribed, AA and CAI were second and third, respectively. Our result is in line with the data from a published report indicating that the most commonly used first-line monotherapy was a PG,43–46 while CAI/BB was the most commonly used fixed combination as first- and second-line treatment.47, 48 Although BB is also recommended as a first-line monotherapy in the guideline for glaucoma, the prescription rate of BB was low in this study. This is probably because the patients had comorbidities of asthmas, chronic obstructive pulmonary disease or heart failure may not prescribed BB according to the respective drug information. Or elderly patients may have difficult using BB. On the other hand, BB was considered to be common in the GS cohorts because of bradycardia, but not so in our results. The ROCKI as well as the EP2 receptor agonist become available in Japan recently and has been reported to show an additional IOP-lowering in combination with other glaucoma ophthalmic solutions.49–52 Thus, the prescription trend for glaucoma eye drops may change in the future.
This study had several limitations. First, we included only DPC hospitals with glaucoma beds, so the results may not be generalizable; however, DPC database contains detailed medical data on numerous patients residing throughout the Japan in a broad array of geographic regions. Moreover, the variables included in the final predictive model are available in other Japanese administrative claims databases. Second, limitations common to studies using administrative claims data apply to this study.53–56 These limitations include lack of certain information in the database and errors or omissions in claims coding. Third, claims data lack clinical information (such as IOP, visual field, etc.) to access disease severity. Therefore, it was not possible to evaluate whether the severity level of documented comorbid conditions was comparable between our study cohorts and whether different stages of glaucoma were associated with specific comorbidity profiles. Fourth, our data did not exclude laser trabeculoplasty (LT). Although, LT reported to be an alternative to topical glaucoma drug treatment and the same IOP-lowering effect as eye drops as monotherapy,57 it may have influenced the results of our analysis. Fifth, unmeasured confounders may limit the findings. Finally, the present analyses were built according to the assumption that all 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.