We performed a retrospective review of the medical records of all patients who were evaluated by a single glaucoma specialist (KRS) in the glaucoma clinic at Asan Medical Center (Seoul, Korea) from March 2008 to March 2015. Participants who met the inclusion criteria were consecutively enrolled. At the initial test, each participant received a comprehensive ophthalmological examination, including a review of their medical history, measurement of their best-corrected visual acuity, slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, central corneal thickness (CCT) measurement (DGH-550 instrument; DGH Technology, Exton, PA, USA), dilated fundoscopic examination using a 90- or 78-diopter lens, stereoscopic optic disc photography, RNFL photography, a VF test, and spectral domain optical coherence tomography (SD-OCT). To be included in the study, participants had to meet the following criteria at their initial assessment: best-corrected visual acuity of 20 / 40 or better, the presence of a normal anterior chamber and an open-angle on slit-lamp and gonioscopic examinations, glaucomatous optic disc damage (the presence of focal thinning of the neuroretinal rim or notching and RNFL defects), and a glaucomatous VF defect. These findings were confirmed and agreed upon by two glaucoma specialists (KRS and JYL). Glaucomatous VF defects were defined as those with a cluster of three points with probabilities of less than 5% on the pattern deviation map in at least one hemifield, including at least one point with a probability of less than 1%; a cluster of two points with a probability of less than 1% and a glaucoma hemifield test result outside normal limits; or a pattern standard deviation outside 95% of the normal limits. We excluded participants with any other ophthalmic or neurological condition that could result in a VF defect or who had a history of diabetes mellitus. Eyes that had undergone intraocular or refractive surgeries were also excluded. If both eyes of the same patient were found to be eligible, one eye was randomly selected for analysis.

All of the participants with glaucoma in our present study were newly diagnosed cases and received follow-ups at 6-month intervals with stereoscopic optic disc photography, RNFL photography, VF testing, and SD-OCT scanning. All tests were performed at the same visit or within a 2-week period. To be included in the analyses, all participants were followed for at least 3 years. All patients underwent medical therapy during the follow-up periods. If the participant required intraocular surgery or laser therapy during the follow-up period, only data obtained before such operations were included. The institutional review board of the Asan Medical Center approved this study, and the study design followed the principles of the Declaration of Helsinki.

VF tests were performed using a Humphrey field analyzer (Swedish Interactive Threshold Algorithm 24-2; Carl Zeiss Meditec, Dublin, CA, USA). Only reliable VF test results (false-positive errors <15%, false-negative errors <15%, and fixation loss <20%) were included in the analysis. The VF test was repeated within 2 weeks of the baseline measurement for confirmation. Patients were expected to return approximately 1 month after the baseline exam to assess their response to the medication and to undergo a third VF test at that time. Thus, three total VF tests were performed within the first 6 weeks. The initial VF test data were excluded from the analysis to obviate any learning effect. Therefore, the second and third VF results, which were performed within 1 month, were incorporated into the analysis as baseline exams. For inclusion in the study cohort, at least five reliable VF tests (except for the initial VF) that were performed on separate visits were required. The VF progression was determined using commercial software (Humphrey Field Analyzer Guided Progression Analysis, Carl Zeiss Meditec) and was defined as a significant deterioration from the baseline pattern deviation at three or more test points that were evaluated on three consecutive examinations, or as a significantly negative slope (p < 0.05) in a linear regression analysis using the VF mean deviation (MD) data [11].

The progression of the optic disc and the presence of any RNFL defects were determined through an evaluation of an entire series of stereoscopic optic disc and red-free RNFL photographs. Serial stereoscopic photographs were displayed on a liquid crystal display monitor. Two glaucoma experts (KRS and JYL) independently assessed all photographs to estimate the glaucoma progression. The most recent photograph was compared to the baseline photograph for each patient. The experts were not aware of each other's assessments and were also blind to all clinical, OCT, and VF information. Both evaluators reviewed all photographs for each eye before making an assessment and were asked to determine the glaucomatous optic disc or RNFL progression, as revealed by an increase in the extent of neuroretinal rim thinning, enhancement of disc excavation, and/or any widening or deepening or new appearance of an RNFL defect. Each grader classified each glaucomatous eye as either stable or progressing. If the RNFL photographs were difficult to evaluate due to the presence of diffuse atrophy or an invisible RNFL resulting from a lightly pigmented fundus, the progression was determined by an optic disc assessment. If the opinions of the two graders differed, that eye was excluded from the subsequent analysis.

SD-OCT images were obtained using a Cirrus HD-OCT system (Carl Zeiss Meditec). The image acquisition procedure has been described in detail elsewhere [12,13,14]. Our Cirrus HD-OCT system is regularly calibrated by a technician employed by the manufacturer. Circumpapillary RNFL (cRNFL) thicknesses were measured using the optic disc cube mode. Pupil dilatation was performed when necessary. All accepted images exhibited a centered optic disc or fovea, were well-focused with even and adequate illumination, exhibited no eye motion within the measurement circle, and had a signal strength of at least 7.

The eyes of the study participants were divided into the following two groups, according to the conventional cutoff value (21 mmHg) for the baseline IOP: the conventional high-tension glaucoma (cHTG) group (>21 mmHg) and the conventional NTG (cNTG) group (≤21 mmHg). The same participants were classified into another two groups, according to the median value of the baseline IOP among our participants: the median HTG (mHTG) group (>15 mmHg) and the median NTG (mNTG) group (≤15 mmHg). Baseline and follow-up data were compared between each NTG and HTG group using an independent t-test or chi-square test. Glaucomatous progression was defined based on two criteria: either serial optic disc/RNFL photographs or VF exams. We fitted univariate and multivariate Cox proportional hazard models to detect any associations between potential risk factors, including the category of refractive error, baseline untreated IOP and mean follow-up IOP, IOP fluctuation (SD of follow-up IOP measurements), CCT, baseline average cRNFL thickness, baseline VF MD, and glaucoma progression time based on two different criteria. Both univariate and multivariate analyses were performed separately for each group. Variables with a p-value less than or equal to 0.20 in the univariate analyses were included as candidate variables for the multivariate regression analysis. A backwards elimination process was used to develop the final multivariate model. Data are presented as adjusted hazard ratios (HRs) with 95% confidence intervals. The Schoenfeld residuals test was used to verify the proportional-hazards assumption; no violations were detected during this analysis. All statistical analyses were performed using the SPSS ver. 15.0 (SPSS Inc., Chicago, IL, USA).