Predictive Factors for Glaucomatous Visual Field Progression in the Advanced Glaucoma Intervention Study Kouros Nouri-Mahdavi, MD,1 Douglas Hoffman, BA,1 Anne L. Coleman, MD, PhD,1 Gang Liu, MS,2 Gang Li, PhD,2 Douglas Gaasterland, MD,3 Joseph Caprioli, MD1 Purpose: To investigate the risk factors associated with visual field (VF) progression in the Advanced Glaucoma Intervention Study (AGIS) with pointwise linear regression (PLR) analysis of serial VFs. Design: Prospective, multicenter, randomized clinical trial. Participants: Five hundred nine eyes of 401 patients from the AGIS with a baseline VF score of Յ16, Ն7VF examinations, and Ն3 years of follow-up were selected. Main Outcome Measure: Visual field progression. Methods: This is a cohort study of patients enrolled in a prospective randomized clinical trial (AGIS). Worsening of a test location on PLR analysis was defined as a change of threshold sensitivity of Ն1.00 decibels a year, with PՅ0.01. Visual field progression was defined as worsening of at least 2 test locations within a Glaucoma Hemifield Test cluster with PLR analysis. Multivariate logistic regression was used to determine risk factors associated with VF worsening. Intraocular pressure (IOP) fluctuation was defined as standard deviation of the IOP at all visits after the initial surgery. Results: The mean (Ϯ standard deviation) follow-up time and baseline AGIS score were 7.4 (Ϯ1.7) years and 7.7 (Ϯ4.4), respectively. Visual field progression was detected with PLR analysis in 151 eyes (30%). Older age at the initial intervention (P ϭ 0.0012; odds ratio [OR], 1.30; 95% confidence interval [CI], 1.11–1.50), larger IOP fluctuation (P ϭ 0.0013; OR, 1.31; 95% CI, 1.12–1.54), increasing number of glaucoma interventions (P ϭ 0.01; OR, 1.74; 95% CI, 1.14–2.64), and longer follow-up (P ϭ 0.02; OR, 1.19; 95% CI, 1.03–1.38) were associated with increased odds of VF progression. When regression analyses were repeated in eyes with and without a history of cataract extraction, IOP fluctuation was the only variable to be consistently associated with VF progression. Conclusion: Both increasing age and greater IOP fluctuation increase the odds of VF progression by 30% (for each 5-year increment in age and 1-mmHg increase in IOP fluctuation). The higher risk conferred by IOP fluctuation was consistently observed in eyes with and without a history of cataract extraction. Ophthalmology 2004;111:1627–1635 © 2004 by the American Academy of Ophthalmology. Over the last 2 decades a number of studies have addressed the issue of risk factors associated with or predictive for glaucoma progression.1–21 A better understanding of clini- Originally received: January 7, 2004. Accepted: February 9, 2004. Manuscript no. 240023. cal risk factors for worsening of glaucoma may help us 1 Glaucoma Division, Jules Stein Eye Institute, University of California develop new strategies to improve glaucoma care. A major Los Angeles, Los Angeles, California. obstacle has been the lack of a uniformly accepted and 2 Department of Biostatistics, UCLA School of Public Health, Los Ange- efficient approach to detect glaucoma progression. Evalua- les, California. tion of visual field (VF) series remains the clinical method 3 University Ophthalmology Consultants of Washington, Washington, DC. most frequently used to assess the course of glaucoma and Presented at: American Academy of Ophthalmology Annual Meeting, the efficacy of its treatment. November, 2003; Anaheim, California. The Advanced Glaucoma Intervention Study (AGIS) Supported by an unrestricted grant from Research to Prevent Blindness, used a single method for longitudinal evaluation of VFs. New York, New York, and the National Institutes of Health, Bethesda, Due to the lack of a gold standard and only fair concordance Maryland (grant no.: R01 EY12738). among various analytic methods, this could cause important The authors do not have any commercial or proprietary interest in any of associations to be missed or spurious ones to be detected. the products or companies cited in the article. Likewise, they have no We compared the results of an independent approach, point- financial interest in and have not received payment as a consultant, re- viewer, or evaluator from any of the companies mentioned. wise linear regression (PLR) analysis, with the AGIS 22 Correspondence to Joseph Caprioli, MD, Glaucoma Division, Jules Stein method in a subgroup of patients from that study. The 2 Eye Institute, 100 Stein Plaza, Los Angeles, CA 90095. E-mail: methods were concordant in two thirds of study eyes. [email protected]. The primary objective of this report is to identify the risk © 2004 by the American Academy of Ophthalmology ISSN 0161-6420/04/$–see front matter 1627 Published by Elsevier Inc. doi:10.1016/j.ophtha.2004.02.017 Ophthalmology Volume 111, Number 9, September 2004 factors associated with progression of VF damage in the omitting the last threshold in a series and (2) after deleting the AGIS with PLR analysis to evaluate sequential VFs for threshold before last for the same series. This approach has been clinically and statistically significant change. shown, in simulation experiments, to be more specific than using all the data points for a single regression analysis, and it maintains a sensitivity comparable to other stringent algorithms used for the same purpose, such as two of two5 or three of four.4,6,7 Regression Materials and Methods slopes were considered statistically and clinically significant if Ն1.00 decibels (dB)/year or ՅϪ1.0 dB/year in the presence of The AGIS design and methods are described in detail elsewhere PՅ0.01. and are summarized here.2,23 Thirty-five- to 80-year-old phakic For evaluation of VF series, we used the most rigorous and patients with open-angle glaucoma no longer controlled by max- clinically relevant set of criteria explored in the aforementioned imally tolerated medical treatment were recruited. Eligible eyes investigation, the 2-point Glaucoma Hemifield Test change crite- had a best-corrected visual acuity (VA) score of at least 56 letters rion. According to this, a VF series is considered to be changing if (Early Treatment Diabetic Retinopathy Study) and met specified 2 test locations belonging to the same Glaucoma Hemifield Test criteria for combinations of consistently elevated intraocular pres- cluster demonstrate change in the same direction. This set of sure (IOP), glaucomatous VF defect, and optic disc rim deteriora- criteria was found to be the most conservative among different tion.2 Between 1988 and 1992, investigators at 12 participating PLR approaches. It yielded the smallest number of progressing VF AGIS clinical centers enrolled 789 eyes of 591 patients. Eyes were series, minimized the number of improving VF series, and dem- randomly assigned to 1 of 2 surgical intervention sequences: argon onstrated the highest agreement with AGIS criteria. laser trabeculoplasty (ALT)–trabeculectomy–trabeculectomy Visual field progression according to AGIS criteria was defined (ATT) or trabeculectomy–ALT–trabeculectomy (TAT). Data in as the first occurrence in an eye, at 3 consecutive 6-month visits, this report are based on a database closure of March 31, 2001. The of worsening in the VF defect score of Ն4 from the baseline value. institutional review boards at each of the participating centers Changes in the AGIS VF defect score were measured from prein- approved the AGIS protocol, and all patients gave informed con- tervention reference values. sent. Visual field outcomes from PLR were classified as progressing Visual field tests were conducted with a Humphrey Visual or nonprogressing. Improving and stable eyes were categorized as Field Analyzer I (Carl Zeiss Ophthalmic Systems, Inc., Dublin, nonprogressing. Associations between VF progression and various CA) set for the central 24-2 threshold test, size III white stimulus, preoperative and postoperative potential risk factors were evalu- and full threshold strategy, with the foveal threshold test turned on. ated with multivariate logistic regression.25 The 24-2 program of the Humphrey Visual Field Analyzer records It has been shown that both eyes of the same patient are at least data from 55 locations in the VF, all of which, except the locations partially correlated with respect to progression of the VF.8 We above and below the blind spot and the foveal threshold, are used used a generalized linear mixed model to account for the intereye for calculating the AGIS VF score.3 Scoring is based on the correlation. The generalized linear mixed model is a commonly number, pattern, and depth of depression of threshold sensitivities used random-effects model that permits the data to exhibit corre- as found in the Humphrey total deviation plot. Points are awarded lation and nonconstant variability and allows the response to come for the presence of a nasal defect (a cluster of Ն3 depressed from several distributions such as binomial, Poisson, and ␥. locations in the nasal field), nasal step (Ն1 depressed locations in Preoperative and postoperative factors that were associated the nasal field, in the absence of depression in any of the 3 with VF progression in univariate analyses (␹2 test, unpaired t test, locations on the opposite side of the horizontal midline), and or Wilcoxon rank sum test, depending on the type of data) at a P hemifield defect (cluster of Ն3 depressed sites in a hemifield). The value of Յ0.20 were included in the final model. In addition, we translation of an array of VF thresholds into a single number included all the variables that might potentially predict or con- simplifies the comparison of test results and the determination of found detection of VF progression from a clinical point of view progression or stability. Visual field defect scores ranged from 0 (Table 1). Mean IOP was calculated by averaging all the available (no defect) to 20 (advanced glaucoma).