Normal-tension glaucoma (NTG) is a form of primary open-angle glaucoma (POAG) that develops even within the normal range of intraocular pressure (IOP). It is characterized by glaucomatous optic neuropathy and the corresponding visual field defects. While NTG occurs in approximately 30% to 40% of patients with POAG in Western populations [
1], it has been reported to be higher in East Asian populations. The Japanese Tajimi study [
2] showed that NTG comprised 92% of POAG patients in its study population, and the Korean Namil study [
3] reported a corresponding rate of 77%. Due to the high prevalence of NTG in East Asia, an effective acute management strategy is of utmost importance in this region.
Despite the high proportion of NTG among glaucoma cases in Korea, few studies have been conducted to date that accurately describe as to how NTG treatment proceeds in clinical practice. Kim et al. [
7] reported, based on a retrospective medical chart review, that the most frequently used glaucoma drugs in Korean NTG management are prostaglandin, carbonic anhydrase inhibitor/beta-blocker fixed combination, and brimonidine/beta-blocker fixed combination. However, no study investigating the opinion of Korean glaucoma specialists regarding NTG management has been published. Thus, we investigated the usual practice of Korean glaucoma subspecialists regarding NTG management and the extent to which the CNTGS and LoGTS have influenced their treatment of patients.
Results
Survey respondents
We sent emails to a total of 238 glaucoma subspecialists, and 134 of them completed the survey.
The survey response rate was 56.3% (134 / 238). Questions 3 and 4, which were the inverse of each other, showed 90.2% matching results.
Awareness of two clinical trials
Most of the respondents answered that they were familiar with the CTNGS and the LoGTS (88.1% and 77.6%, respectively; questions 1 and 2).
Initiation of NTG treatment
Questions 3 and 4 concerned the starting point of the treatment for mild-to-moderate NTG. A binary analysis of the responses (always/usually vs. sometimes/rarely/never) showed 9.0% vs. 91.0% for question 3 and 87.3% vs. 12.7% for question 4, meaning that 87% to 91% of the respondents tended to treat without waiting for further NTG deterioration.
Impact of LoGTS on NTG management
Of all the respondents, 47.4% answered that the LoGTS had influenced their clinical treatment (question 7). Questions 5 and 6 were related to the results of the LoGTS and the preferences of brimonidine or beta-blocker, respectively. To this end, the results of the binary analysis of the responses (always/usually vs. sometimes/rarely/never) were 19.8% vs. 80.2% and 16.7% vs. 83.3% for questions 5 and 6, respectively, which implies that 80% to 83% of the respondents did not particularly prefer brimonidine over beta-blockers or avoid beta-blockers.
First-choice topical drug for NTG
The respondents stated that prostaglandin analogues (75.8%), brimonidine (9.1%), beta-blocker (8.3%), and topical carbonic anhydrase inhibitor (6.1%) were their first-choice topical drugs for NTG treatment (question 8).
Discussion
In East Asian populations, the majority of patients (77-92%) diagnosed with POAG have IOP under 21 mmHg; thus, it would be particularly important to know the real-world practice for NTG management in these regions.
As we have endeavored to include as many KGS members as possible in the survey, we believe that the results may effectively represent the current NTG practice in Korea. Additionally, the response rate of our survey (56.3%) was higher than the previously reported mean response rate (35.0%) [
9] for web-based surveys; thus, our survey seems to have been successful in terms of the response rate.
The CNTGS suggested two implications: (1) NTG patients benefit from IOP lowering, and (2) some portion of NTG patients (59%) show disease stability without treatment over as many as 5 years of follow-up. Therefore, some ophthalmologists suggest that the mode of initial NTG treatment should be carefully selected. However, 87% to 91% of Korean glaucoma subspecialists do not delay the NTG treatment until they confirm a further progressive change. The progression rate,s and thus, times to progression have been known to vary considerably among high-tension glaucoma, NTG, and pseudoexfoliation glaucoma [
10]. The progression rate among cases of untreated NTG is also highly variable, with some cases showing progression within a few months [
11]. A Japanese study group recently reported that the probability of NTG patients progressing to unilateral blindness was 9.9% at 20 years [
12], which suggests that the NTG prognosis would be more severe than expected from the CNTGS. Additionally, individual factors that increase the risk of progression in NTG patients, such as optic disc hemorrhage [
4,
13], migraine [
4], female [
4], or IOP fluctuation [
14,
15], can affect the decision of Korean glaucoma subspecialists on whether to start treatment in the real-world clinical setting.
Symes and Mikelberg [
8] reported contemporary NTG-management patterns among North American (American and Canadian) glaucoma subspecialists, whose data was compared with our present findings on Korean glaucoma subspecialists (
Table 2) [
8]. As shown, the North American glaucoma subspecialist (98.5%) were more familiar with the CTNGS than the Koreans (88.1%,
p = 0.001). However, awareness of the LoGTS did not differ between the two groups. The Korean group (91.0% and 87.3%) showed a greater tendency to select immediate treatment than did the North American group (72.0% and 67.4%) (questions 3 and 4,
p < 0.001). The North American group (34.0%) tended to use brimonidine more often in patients with NTG than did the Korean group (19.8%) (question 5,
p = 0.005). Also, the North American group (34.1%) tended to avoid using topical beta-blockers more often than did the Korean group (16.7%) (question 6,
p < 0.001). For question 7, the responses of the two groups with regard to the impact of the LoGTS did not significantly differ (
p = 0.67). As for question 8, the first-choice drug for NTG was significantly different between the two groups (
p < 0.001): the North American group chose prostaglandin analogues (91.3%), followed by brimonidine (8.0%), and they did not select beta-blockers (0%), whereas the Korean group selected prostaglandin analogues (75.8%), brimonidine (9.1%), beta-blockers (8.3%), and topical carbonic anhydrase inhibitor (6.1%).
The Korean glaucoma subspecialists, as compared with the North American group, tended to start treatment earlier without waiting for further progression in mild-to-moderate NTG. According to previous studies, the proportion of NTG among glaucoma patients was 77% [
3] in Korea and 30% to 40% [
1] in Western countries. This difference in NTG incidence between East Asian and Western people may have influenced the NTG treatment pattern in Korea. In terms of the LoGTS, both groups were well-aware of the trial, but the Korean group, relative to the North American group, tended to use less brimonidine and more beta-blockers. Brimonidine has the effect of reducing IOP in glaucoma regardless of race, whether Asian [
16,
17] or Western [
18]; however, there have been no reports on ethnic differences in IOP drop. Due to the high drop-out rate (36.4%) in the brimonidine group, Korean glaucoma specialists seem to have relatively less confidence in LoGTS results [
6]. Another possible reason why Korean glaucoma specialists prefer brimonidine less than Western specialists is the seemingly higher frequency of occurrence of brimonidine allergy in Asians. Allergic reactions to brimonidine have been reported in 7.4% to 25.7% of the Western participants [
19,
20], and in 22.02% of Korean patients [
21]. Moreover, as it has been reported that brimonidine metabolism is slower and its concentration is higher in highly pigmented eyes compared with relatively non-pigmented eyes [
22,
23], there is a possibility that Koreans with dark brown irises might have increased susceptibility to allergies. These ethnic differences in NTG management should be investigated further by detailed surveying.
In our results, the overall response rate was 56.3%, and thus, this study cannot be considered to completely represent the views of Korean glaucoma subspecialists for NTG management. Nonetheless, our response rate was higher than the published mean response rate for emailed questionnaire surveys of physician specialists (35.0%) [
9] or those of North American glaucoma subspecialists (21%-23%). In addition, our survey was limited to two of the largest NTG clinical trials. Ideally, it would also have been interesting to ask the participants about other factors related to NTG management, such as nocturnal hypertension, diastolic blood pressure [
24], or neuroprotective agents (e.g.,
Gingko biloba [
25]). However, to maximize the questionnaire completion rate, it was necessary to keep it relatively short.
In conclusion, Korean glaucoma subspecialists tended to treat patients with mild-to-moderate NTG without waiting for disease progression. A minority of Korean glaucoma subspecialists have been influenced by the LoGTS results. Prostaglandin analogs are the most selected first-choice drug for the management of NTG.