This investigation is based on the Hallym DR Study, an ongoing cohort study conducted at Hallym University Medical Center (HUMC). To explore the large database of hospital-collected clinical information on patients with DR, we used the common integrated CDW system of HUMC, which is an electronic data repository of patients’ information.9 A detailed description of the CDW system was also introduced in previous studies, with some modification.10,11 The common CDW system of HUMC collects and stores extensive electronic medical data including medical records, laboratory results, physical measurements, diagnostic and therapeutic history, and medication history over a period of 10 years.11
We accessed the CDW system and investigated the medical data of patients who were diagnosed with DR and treated with PRP between January 2009 and December 2015. This study was approved by the institutional review board of HUMC, and all protocols were in accordance with the tenets of the Declaration of Helsinki. The need for informed consent was waived by the Institutional Review Boards of Hallym University Sacred Heart Hospital because of the retrospective nature of the study and the de-identification of data by the CDW system before we accessed the database.
Study population
We first identified patients diagnosed with DR, Korean Standard Classification of Diseases (KCD) code H34.8, corresponding to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 362.01 for DR during the study period. Next, to ensure the inclusion of patients who newly underwent PRP during the follow-up period, we verified the presence of a previous history of PRP by reviewing the visit data for all eligible patients, beginning from the earliest period for which medical records were provided by the CDW system (January 2009 for HUMC).
DR patients who have completed more than 4 sessions of PRP in at least one eye from 2009 to 2015 and who met these criteria were included: 1) followed up for at least 3 years after completing PRP; and 2) able to confirm the clinical information (underlying systemic comorbidities, physical measurements, and laboratory findings of blood tests and urine tests). Exclusion criteria were: 1) a history of other retinal disease, neovascular age-related macular degeneration, retinal vein occlusion, posterior uveitis, or ischemic optic neuropathy; 2) a history of intraocular surgery other than uncomplicated cataract surgery; 3) media opacity rendering fundus reading difficult for diagnosis (significant cataract, asteroid hyalosis, or vitreous opacity); 4) a history of laser before PRP; and 5) advanced DR with complications requiring immediate surgical treatment,12,13 such as vitreous hemorrhage or tractional retinal detachment at the first ophthalmologic visit.
Outcome measurements, systemic variables
The data of the study subjects were investigated with regard to the systemic conditions at the time of receiving PRP. When two or more test results were available, values obtained at the date closest to the date of initiating PRP treatment were selected. Systemic diseases diagnosed before PRP treatment were defined as underlying comorbidities. Not all laboratory test results were obtainable for all the patients, and only those tests whose results were available for more than 80% of the study participants were included in the analyses.
Demographic characteristics included the patients’ sex and age at initial PRP. Systemic comorbidities were investigated using the KCD code system. We also investigated the presence of underlying disease that may affect retinal vasculature, including hypertension, ischemic heart disease (IHD), cerebrovascular disease, and chronic kidney disease. Physical measurements included height, weight, systolic blood pressure, diastolic blood pressure, and the body mass index (BMI). The laboratory protocol for DR included differential cell counts [platelet count, hemoglobin, hematocrit, etc.]; blood coagulation-related tests [activated partial thromboplastin time, and prothrombin time; lipid profile [total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides]; liver enzyme test, including alanine transaminase (ALT) and aspartate aminotransferase (AST) levels; and kidney function test, including blood urea nitrogen (BUN) and creatinine measurement.
Anthropometric measurements such as height and body weight were assessed. BMI was calculated as weight (kg) divided by height (m) squared. The BMI was categorized into 4 groups: BMI less than 20 kg/m2 (Thin), BMI 20~25 (Normal), BMI of 25–30 kg/m2 (Overweight), and more than 30 kg/m2 (Obese).10,14 systolic blood pressure, diastolic blood pressure were measured in the right arm after a 5-minute stabilization period using a standard mercury sphygmomanometer (Baumanometer; Baum, NY, USA). Further, the level of smoking was categorized as ‘‘have never smoked,’’ ‘‘previously smoked but no longer smoking,’’ or ‘‘currently smoking.’’
Outcome measurements, ophthalmic variables
All patients underwent comprehensive ocular examinations, including best-corrected visual acuity (BCVA, Snellen chart), intraocular pressure, detailed slit-lamp biomicroscopy and dilated fundus examination after dilatation of the pupils, fundus photography, optical coherence tomography (OCT) imaging, and fluorescein angiography. IOP was measured using a non-contact tonometer (CT-80 or CT-1P; Topcon Inc., Tokyo, Japan), and fundus photographs were taken using a 45° digital fundus camera (CR6-45NW; Canon Inc., Utsunomiya, Japan or TRC-NW8, Topcon Inc., Tokyo, Japan). OCT imaging was performed using the swept-source mode of a high-definition OCT system (DRI OCT Triton, Topcon, Tokyo, Japan). An ultra-wide-field scanning laser ophthalmoscope (Optos Optomap Panoramic 200MA; Optos PLC, Dunfermline, Scotland) allows wide-angle retinal imaging. During follow-up periods, we checked occurrence of NVG, types and number of intravitreal injection, occurrence of vitreous hemorrhage, tractional retinal detachment, and implementation of pars plana vitrectomy. The presence of any type of glaucoma, POAG, normal-tension glaucoma NTG, NVG, and others was also investigated.
Evaluation and management of diabetic retinopathy
The stage of DR was determined by comparison with standard photographs from the ETDRS.15 If PDR or progression of severe NPDR was suspected in the fundus photography, fluorescein angiography was conducted. Indications of PRP were defined as PDR, very severe NPDR15, or aggravation of severe NPDR. Intravitreal injections of anti-vascular endothelial growth factor were given in cases of diabetic macular edema with central macular thickness of above 300 µm or vitreous hemorrhage.
Panretinal photocoagulation
Two experienced retinal specialists (S.K, I.W.P) performed PRP according to the ETDRS and DRS. According to DRS protocol using a standard argon-type laser PRP, the recommended settings include burns that range approximately 400 μm in size, pulse durations of 100 milliseconds, and 200 mW of power.
Laser burns (1200 to 1600) are evenly beamed or scattered on the retina away from the macula, almost to the equator. Burns were spaced at a one-burn spacing pattern. PRP was performed across 4 treatment sessions, 1 session performed per week.7
Definition of DR progression
In this study, DR worsening was assessed in patients with prior PRP using the previously described composite end point of time to new proliferative event.16-18 This composite end point takes into account clinical outcomes associated with DR worsening as defined by progression to PDR, any occurrence of newly diagnosed iris or retinal neovascularization, treatment with PRP or vitrectomy for DR-related reasons, or new cases of PDR identified by ophthalmoscopy.16-18 The clinical experiences of patients who underwent on-study PRP were assessed by determining the incidence and timing of first on-study occurrences of vitrectomy, retinal neovascularization, or iris neovascularization. Progressive DR changes were confirmed and agreed on by the same two experienced specialists (S.K, I.W.P), each of whom was masked to the subject’s identity and to all other test results.
Progression group and non-progression group
The patients were subdivided into progression group and non-progression group according to progression of DR: the progression group that consisted of eyes exhibiting DR progression (progression to PDR or newly developed NVI or NVE or NVG, or implementation of vitrectomy), and the ‘non-progression’ group that consisted of eyes exhibiting stationary DR.
Statistical analysis
The baseline demographics and clinical variables were summarized by means and standard deviations or frequencies and percentages, as appropriate. The clinical characteristics of the progression group versus non-progression group were compared using unpaired t-tests or Mann-Whitney U tests for continuous values and the Chi-square test for categorical variables. Univariate and multivariate logistic regression analyses employing a forward conditional method were performed to determine the associations of various factors with progression of DR; hazard ratios (HRs) and 95% confidence intervals (CI) were reported. To avoid multicollinearity, variables correlated significantly with each other were not analyzed simultaneously. Instead, the variable with the highest significance among correlated variables was chosen. If significances were similar between correlated variables, multiple analyses were conducted separately using each variable. Kaplan–Meier survival analysis was used to compare the inter-group cumulative probability of maintenance of the DR without progression, as stratified by the significant variables derived from multivariate logistic regression. All statistical analyses were performed using SPSS version 21.0 (SPSS, Chicago, IL, USA). All P-values were two-sided and considered significant when P <0.05.