Assessment of Cumulative Incidence and Severity of Primary Open-Angle Glaucoma Among Participants in the Ocular Hypertension Treatment Study After 20 Years of Follow-up | Glaucoma | JAMA Ophthalmology | JAMA Network
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Figure 1.  Participant Flowchart for Ocular Hypertension Treatment Study (OHTS) Phases 1, 2, and 3
Participant Flowchart for Ocular Hypertension Treatment Study (OHTS) Phases 1, 2, and 3

POAG indicates primary open-angle glaucoma.

aData collection period.

bAssessment of visual function required an OHTS examination or ocular and medical history after January 1, 2013, or within 2 years of death.

cThe cumulative number of deaths from February 1994 to April 2019 was 515, which includes 225 participants with OHTS 1 and OHTS 2 visits or medical history within 2 years of death, 19 participants who died after completing an OHTS 3 visit, and 9 participants who died but provided medical history after January 2013.

Figure 2.  Kaplan-Meier Curves of Cumulative Incidence of Primary Open-Angle Glaucoma (POAG) at 5, 10, 15, and 20 Years
Kaplan-Meier Curves of Cumulative Incidence of Primary Open-Angle Glaucoma (POAG) at 5, 10, 15, and 20 Years

A, Cumulative incidence of POAG by treatment group. B, Cumulative incidence of POAG by race. C, Cumulative incidence of POAG by risk tertile. The whiskers indicate 95% CIs.

Table 1.  Participants in the Original Cohort Who Developed POAG Diagnosed by Optic Disc Deterioration or VF Abnormality
Participants in the Original Cohort Who Developed POAG Diagnosed by Optic Disc Deterioration or VF Abnormality
Table 2.  Cumulative Incidence of Primary Open-Angle Glaucoma Adjusted for Exposure Timea
Cumulative Incidence of Primary Open-Angle Glaucoma Adjusted for Exposure Timea
Table 3.  Visual Function Assessed After 20 Years or Within 2 Years of Death
Visual Function Assessed After 20 Years or Within 2 Years of Death
1.
Kass  MA, Heuer  DK, Higginbotham  EJ,  et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma.   Arch Ophthalmol. 2002;120(6):701-713. doi:10.1001/archopht.120.6.701 PubMedGoogle ScholarCrossref
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Gordon  MO, Beiser  JA, Brandt  JD,  et al.  The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma.   Arch Ophthalmol. 2002;120(6):714-720. doi:10.1001/archopht.120.6.714 PubMedGoogle ScholarCrossref
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Gordon  MO, Torri  V, Miglior  S,  et al; Ocular Hypertension Treatment Study Group; European Glaucoma Prevention Study Group.  Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension.   Ophthalmology. 2007;114(1):10-19. doi:10.1016/j.ophtha.2006.08.031 PubMedGoogle Scholar
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Medeiros  FA, Weinreb  RN, Sample  PA,  et al.  Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma.   Arch Ophthalmol. 2005;123(10):1351-1360. doi:10.1001/archopht.123.10.1351 PubMedGoogle ScholarCrossref
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Kass  MA, Gordon  MO, Gao  F,  et al; Ocular Hypertension Treatment Study Group.  Delaying treatment of ocular hypertension: the ocular hypertension treatment study.   Arch Ophthalmol. 2010;128(3):276-287. doi:10.1001/archophthalmol.2010.20 PubMedGoogle Scholar
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Gordon  MO, Kass  MA.  The Ocular Hypertension Treatment Study: design and baseline description of the participants.   Arch Ophthalmol. 1999;117(5):573-583. doi:10.1001/archopht.117.5.573 PubMedGoogle ScholarCrossref
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Gordon  MO, Higginbotham  EJ, Heuer  DK,  et al; Ocular Hypertension Treatment Study.  Assessment of the impact of an endpoint committee in the Ocular Hypertension Treatment Study.   Am J Ophthalmol. 2019;199:193-199. doi:10.1016/j.ajo.2018.11.006 PubMedGoogle ScholarCrossref
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Bengtsson  B, Heijl  A.  Inter-subject variability and normal limits of the SITA standard, SITA fast, and the Humphrey full threshold computerized perimetry strategies, SITA STATPAC.   Acta Ophthalmol Scand. 1999;77(2):125-129. doi:10.1034/j.1600-0420.1999.770201.x PubMedGoogle ScholarCrossref
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Sharma  AK, Goldberg  I, Graham  SL, Mohsin  M.  Comparison of the Humphrey Swedish interactive thresholding algorithm (SITA) and full threshold strategies.   J Glaucoma. 2000;9(1):20-27. doi:10.1097/00061198-200002000-00005 PubMedGoogle ScholarCrossref
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Sun J. The Statistical Analysis of Interval-Censored Failure Time Data. Springer; 2006.
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Hodapp  E, Parrish  RK  II, Anderson  DR.  Clinical Decisions in Glaucoma. 1st ed. Mosby; 1993.
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Lundberg  L, Wettrell  K, Linner  E.  Ocular hypertension. a prospective twenty-year follow-up study.   Acta Ophthalmol (Copenh). 1987;65(6):705-708. doi:10.1111/j.1755-3768.1987.tb07067.x PubMedGoogle ScholarCrossref
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Hovding  G, Aasved  H.  Prognostic factors in the development of manifest open angle glaucoma. a long-term follow-up study of hypertensive and normotensive eyes.   Acta Ophthalmol (Copenh). 1986;64(6):601-608. doi:10.1111/j.1755-3768.1986.tb00675.x PubMedGoogle ScholarCrossref
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Oskarsdottir  SE, Heijl  A, Midlov  P, Bengtsson  B.  Lifetime risk of visual impairment resulting from glaucoma in patients initially followed up for elevated intraocular pressure.   Ophthalmol Glaucoma. 2020;3(1):60-65. doi:10.1016/j.ogla.2019.09.002 PubMedGoogle ScholarCrossref
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Gordon  MO, Gao  F, Beiser  JA, Miller  JP, Kass  MA.  The 10-year incidence of glaucoma among patients with treated and untreated ocular hypertension.   Arch Ophthalmol. 2011;129(12):1630-1631. doi:10.1001/archophthalmol.2011.337 PubMedGoogle ScholarCrossref
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    Original Investigation
    April 15, 2021

    Assessment of Cumulative Incidence and Severity of Primary Open-Angle Glaucoma Among Participants in the Ocular Hypertension Treatment Study After 20 Years of Follow-up

    Author Affiliations
    • 1Washington University School of Medicine in St Louis, St Louis, Missouri
    • 2David Geffen School of Medicine, Los Angeles, California
    • 3Office of Inclusion and Diversity, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 4Bascom Palmer Eye Institute, Miami, Florida
    • 5Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
    • 6Davis Eye Center, University of California, Davis, Davis
    • 7University of Louisville, Louisville, Kentucky
    • 8University of Iowa, Iowa City
    • 9University of California, Davis, Davis
    • 10Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 11Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St Louis, St Louis, Missouri
    JAMA Ophthalmol. 2021;139(5):558-566. doi:10.1001/jamaophthalmol.2021.0341
    Key Points

    Question  Do 20-year follow-up data from the Ocular Hypertension Treatment Study inform the management of patients with ocular hypertension?

    Findings  In this cohort study of 1636 participants with ocular hypertension who participated in the Ocular Hypertension Treatment Study, the 20-year cumulative incidence of primary open-angle glaucoma was 46% in 1 or both eyes, and the cumulative incidence of visual field loss was 25% after adjusting for exposure time.

    Meaning  This study’s findings, together with a predictive model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension.

    Abstract

    Importance  Ocular hypertension is an important risk factor for the development of primary open-angle glaucoma (POAG). Data from long-term follow-up can be used to inform the management of patients with ocular hypertension.

    Objective  To determine the cumulative incidence and severity of POAG after 20 years of follow-up among participants in the Ocular Hypertension Treatment Study.

    Design, Setting, and Participants  Participants in the Ocular Hypertension Treatment Study were followed up from February 1994 to December 2008 in 22 clinics. Data were collected after 20 years of follow-up (from January 2016 to April 2019) or within 2 years of death. Analyses were performed from July 2019 to December 2020.

    Interventions  From February 28, 1994, to June 2, 2002 (phase 1), participants were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). From June 3, 2002, to December 30, 2008 (phase 2), both randomization groups received medication. Beginning in 2009, treatment was no longer determined by study protocol. From January 7, 2016, to April 15, 2019 (phase 3), participants received ophthalmic examinations and visual function assessments.

    Main Outcomes and Measures  Twenty-year cumulative incidence and severity of POAG in 1 or both eyes after adjustment for exposure time.

    Results  A total of 1636 individuals (mean [SD] age, 55.4 [9.6] years; 931 women [56.9%]; 1138 White participants [69.6%]; 407 Black/African American participants [24.9%]) were randomized in phase 1 of the clinical trial. Of those, 483 participants (29.5%) developed POAG in 1 or both eyes (unadjusted incidence). After adjusting for exposure time, the 20-year cumulative incidence of POAG in 1 or both eyes was 45.6% (95% CI, 42.3%-48.8%) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The 20-year cumulative incidence of POAG was 55.2% (95% CI, 47.9%-61.5%) among Black/African American participants and 42.7% (95% CI, 38.9%-46.3%) among participants of other races. The 20-year cumulative incidence for visual field loss was 25.2% (95% CI, 22.5%-27.8%). Using a 5-factor baseline model, the cumulative incidence of POAG among participants in the low-, medium-, and high-risk tertiles was 31.7% (95% CI, 26.4%-36.6%), 47.6% (95% CI, 41.6%-53.0%), and 59.8% (95% CI, 53.1%-65.5%), respectively.

    Conclusions and Relevance  In this study, only one-fourth of participants in the Ocular Hypertension Treatment Study developed visual field loss in either eye over long-term follow-up. This information, together with a prediction model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension.

    Trial Registration  ClinicalTrials.gov Identifier: NCT00000125.

    Introduction

    Ocular hypertension (OHT), a common condition, is a leading risk factor for the development of primary open-angle glaucoma (POAG). The Ocular Hypertension Treatment Study (OHTS) was designed to address the debate regarding the management of patients with OHT. The OHTS was completed in 3 phases (OHTS 1, OHTS 2, and OHTS 3). The OHTS 1 was a randomized clinical trial conducted from February 28, 1994, to June 2, 2002, with the aim of answering 2 questions: (1) Does early treatment reduce the incidence of POAG in patients with OHT? (2) Do baseline demographic and clinical factors predict which patients with OHT are at low, medium, or high risk of developing POAG? Between February 1994 and October 1996, 1636 participants with OHT were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). Treatment with medication was associated with a reduction in the 5-year cumulative incidence of POAG from 9.5% in the observation group to 4.4% in the medication group (hazard ratio [HR], 0.40; 95% CI, 0.27-0.59).1 A baseline prediction model that included participant age, intraocular pressure (IOP), central corneal thickness, vertical cup-disc ratio (VCDR), and visual field pattern SD (PSD) accurately predicted which participants would have a low, medium, or high risk of developing POAG.2 This prediction model was confirmed in the European Glaucoma Prevention Study and the Diagnostic Innovations in Glaucoma Study.3,4

    The OHTS 2 (conducted from June 3, 2002, to December 30, 2008) was designed to determine whether delaying treatment with medication was detrimental to participants in the observation group (ie, whether delaying treatment initiated a process of glaucomatous deterioration that was difficult to reverse). Both of the original randomization groups received medication during the OHTS 2. The incidence of POAG in the OHTS 2 was found to be generally equal in the 2 randomization groups (HR, 1.06; 95% CI, 0.74-1.50), indicating that delaying treatment in the observation group during the OHTS 1 did not initiate a process of irreversible deterioration in most participants.5 Treatment was no longer determined by study protocol beginning in 2009.

    This article reports data from the OHTS 3 (conducted from January 7, 2016, to April 15, 2019) regarding the incidence and severity of POAG after 20 years of follow-up or over the lifetime of participants (ie, within 2 years of death). This information may be useful to clinicians and patients in determining the frequency of examinations and tests and the potential benefits of preventive treatment.

    Methods

    Protocols for the core battery of tests and measures and the determination of POAG end points remained the same in the OHTS 1, OHTS 2, and OHTS 3. The schedule of tests and measures used during each study phase is summarized in eTable 1 in Supplement 1. The OHTS 1 and OHTS 2 study protocols are described in detail elsewhere5,6 and are summarized in eMethods 1 in Supplement 1; the OHTS 3 study protocol is described in detail in eMethods 2 in Supplement 1. In the OHTS 1, 1636 participants with OHT were enrolled in 22 clinics. Participants signed separate informed consent forms for the OHTS 1, OHTS 2, and OHTS 3; these forms were approved by the local institutional review board of each participating clinic.

    Quiz Ref IDA POAG end point required 2 steps: (1) confirmation of optic disc deterioration and/or visual field abnormality that was identified by masked readers at reading centers through repeat testing, and (2) determination that this deterioration and/or abnormality was associated with POAG based on the assessment of a masked end point committee.7 In the OHTS 1 and the OHTS 2, participants who developed POAG continued to participate in the study, but treatment was not determined by study protocol. Visual field testing results and photographs obtained from outside sources underwent the same review process. In the OHTS 3, optical coherence tomographic (OCT) measurements of the retinal nerve fiber layer and macula were performed but were not used to determine an end point to ensure that the end point determination was consistent across the OHTS 1, OHTS 2, and OHTS 3.

    Data collection for the 20-year follow-up of participants in the OHTS 3 was performed from January 7, 2016, to April 15, 2019. The Battelle Memorial Institute Tracing Department assisted with retrieval of participant vital status and contact information using multiple proprietary databases. We assumed participants were alive unless death was confirmed by obituary or by registration in the National Death Index or the Social Security Death Index. Assessment of visual function over the participants’ lifetimes or after 20 years required (1) OHTS examination, interim clinical data, or medical records within 2 years of death or (2) data after January 2013 that included OHTS 3 examination or medical records released by participants or their legally authorized representatives. Quality-of-life surveys were completed at OHTS 3 visits or by telephone, and survey findings will be reported in a future article.

    Clinical status was assessed by visual field mean deviation (MD), visual field PSD, foveal sensitivity (using the Humphrey Field Analyzer; Carl Zeiss Meditech), Early Treatment Diabetic Retinopathy Study and Snellen visual acuity measures, Pelli-Robson contrast sensitivity testing, VCDR from optic disc images, and OCT assessment of peripapillary retinal nerve fiber layer. To accommodate the change from the Humphrey full-threshold test algorithm to the Swedish interactive threshold algorithm, 1.2 dB was added to the full-threshold test points to make them comparable with the Swedish interactive threshold algorithm standard test points.8,9

    Statistical Analysis

    Statistical methods are detailed in eMethods 3 in Supplement 1. In brief, the conversion rate to POAG was calculated using 2 methods: (1) percentage of the original cohort of 1636 participants without adjustment for exposure time and (2) incidence of POAG with adjustment for person-years of exposure time. The 20-year cumulative incidences of POAG at 5, 10, 15, and 20 years were estimated using Kaplan-Meier product limit methods and were reported by baseline risk tertile (low, medium, or high), randomization group (medication or observation), and participant race (Black/African American or other race, including American Indian or Alaska Native, Asian or Pacific Islander, and Hispanic). Kaplan-Meier product limit methods with interval censoring time were used to estimate the 20-year incidence of POAG.10 Statistical analysis was performed using SAS software, version 9.4 (SAS Institute Inc) and the R survfit package, version 2.11-4 (R Foundation for Statistical Computing). The significance threshold was P < .05. Data were analyzed from July 2019 to December 2020.

    Results
    Follow-up

    A total of 1636 participants (mean [SD] age, 55.4 [9.6] years; 931 women [56.9%]; 1138 White participants [69.6%]; 407 Black/African American participants [24.9%]) were enrolled in the original OHTS 1 cohort. A total of 515 participants (31.5%) died over the course of the OHTS. An assessment of clinical status after January 1, 2013, or within 2 years of death was available for 971 of 1636 participants from the original cohort (59.4%), representing 718 of 1121 surviving participants (64.0%) and 253 of 515 deceased participants (49.1%) (Figure 1). The median duration of follow-up was 20.2 years (range, 0-24.5 years). Sources of data for assessing the clinical status of the 971 participants included in phase 3 (59.4% of the original cohort) included an OHTS 3 examination (661 participants [40.4%]), interim clinical data or medical records (85 participants [5.2%]), and an OHTS 1 or OHTS 2 examination within 2 years of death (225 participants [13.8%]) (eTable 2 in Supplement 1). The mean (SD) age of participants in the OHTS 3 was 73.8 (8.4) years; 427 participants (44.0%) were male, and 220 participants (22.7%) were Black/African American. Clinically meaningful differences between participants who did and did not receive ophthalmic examinations and visual function assessments were not detected, with the exception of age at enrollment and race (eTable 3 in Supplement 1).

    The mean (SD) of right and left eyes for eye-specific measures were as follows: for IOP, 18.4 (4.5) mm Hg; for VCDR, 0.52 (0.20); for visual field MD, −2.53 (4.64) dB; for visual field PSD, 2.73 (1.96) dB; for foveal sensitivity, 30.8 (10.2) dB; and for mean logMAR visual acuity, 0.09 (0.17; Snellen equivalent, 20/25). Change in clinical status from baseline to 20 years or within 2 years of death did not differ between participants who were originally randomized to the observation or medication groups (eTable 4 in Supplement 1).

    20-Year Cumulative Incidence

    Among the original cohort of 1636 participants in the OHTS 1, 483 participants (29.5%) developed POAG in 1 or both eyes without adjustment for exposure time; 199 participants (12.2%) developed optic disc deterioration in 1 or both eyes without visual field loss (based on study criteria), and 284 participants (17.4%) developed visual field loss in 1 or both eyes with or without optic disc deterioration (Table 1).

    Quiz Ref IDThe 20-year cumulative incidence of POAG in 1 or both eyes, adjusted per 21 864 person-years of exposure, was 45.6% (95% CI, 42.3%-48.8%; annual incidence, 2.2% based on Kaplan-Meier estimation) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The incidence of POAG was higher in the observation group during the OHTS 1, but this difference remained relatively constant thereafter (Figure 2A and Table 2). The 20-year cumulative incidence among Black/African American participants was higher (55.2% [95% CI, 47.9%-61.5%]) compared with participants of other races (42.7% [95% CI, 38.9%-46.3%]); P < .001) (Table 2; Figure 2B). The 20-year incidence of visual field POAG was 25.2% (95% CI, 22.5%-27.8%).

    Quiz Ref IDA baseline prediction model was used to categorize participants into low-, medium-, and high-risk tertiles (Table 2; Figure 2C). The 20-year cumulative incidences of POAG, adjusted for exposure time, were 31.7% (95% CI, 26.4%-36.6%) for participants in the low-risk tertile, 47.6% (95% CI, 41.6%-53.0%) for participants in the medium-risk tertile, and 59.8% (95% CI, 53.1%-65.5%) for participants in the high-risk tertile (Table 2). These 20-year cumulative incidences represented significant differences between low-risk vs medium-risk tertiles (P < .001), low-risk vs high-risk tertiles (P < .001), and medium-risk vs high-risk tertiles (P < .001). Cumulative incidences of POAG among the risk tertiles were different at 5, 10, 15, and 20 years.

    During the entire study, 11 of 1636 participants (0.7%) developed clinical evidence of pseudoexfoliation in 1 or both eyes (an exclusion criterion at baseline); of those, 5 participants (45.5%) developed pseudoexfoliation glaucoma. Although 89 of 1636 participants (5.4%) had laser iridotomy, the treating clinicians and end point committee diagnosed only 3 of 89 participants (3.4%) with angle-closure glaucoma and 3 of 89 participants (3.4%) with combined-mechanism glaucoma. The other 83 of 89 participants (93.3%) had laser iridotomy for narrow angles only. One of 1636 participants (0.1%) developed pigmentary glaucoma. Data from these 12 participants were censored at the time of diagnosis and were not included in the cumulative incidence of POAG or in other analyses of POAG.

    Severity

    Clinical measures after 20 years of follow-up or within 2 years of death for the eye with the better and worse visual field MD grouped by 5 categories of POAG status are shown in Table 3. Reliable visual field data were available for 933 of 1636 participants (57.0%). Among the 565 participants who did not develop POAG, the mean (SD) visual field MD was −0.6 (2.7) dB in the better eye and −2.2 (4.4) dB in the worse eye (Table 3). Among the 62 participants who developed bilateral POAG optic disc deterioration without detectable POAG visual field loss (based on study criteria), the mean (SD) visual field MD was −1.5 (4.1) dB in the better eye and −2.9 (5.0) dB in the worse eye. Among the 91 participants who developed unilateral POAG visual field loss and POAG disc deterioration in the same eye, the mean (SD) visual field MD was −2.6 (4.8) dB in the better eye and −7.4 (7.2) dB in the worse eye. Among the 63 participants who developed both bilateral POAG visual field loss and bilateral POAG disc deterioration, the mean (SD) visual field MD was −6.8 (5.8) dB in the better eye and −12.6 (9.0) dB in the worse eye. Distribution of visual field loss severity using a modified Hodapp-Parrish-Anderson scale is shown in eTable 5 in Supplement 1.11 Other measures of clinical status by better and worse eye by visual field MD are shown in Table 3.

    Visual Impairment and Glaucoma Therapy

    At 20 years of follow-up or within 2 years of death, best-corrected visual acuity that was worse than 20/40 and associated with any factor occurred in 85 of 775 participants (11.0%); of those, 67 participants (8.6%) had visual acuity worse than 20/40 in 1 eye, and 18 participants (2.3%) had visual acuity worse than 20/40 in both eyes. Visual acuity worse than 20/200 in 1 eye was noted in 9 of 775 participants (1.2%). Visual field MD that was worse than or equal to −22 dB and associated with any factor occurred in 31 of 957 participants (3.2%); 24 participants (2.5%) and 7 participants (0.7%) had MD that was worse than or equal to −22 dB in 1 eye and both eyes, respectively.

    After 20 years of follow-up or within 2 years of death, 696 of 967 participants (72.0%) were receiving ocular hypotensive medication, as documented by an OHTS visit, medical history, or telephone survey. Among those, 397 of 488 participants (81.4%) were originally randomized to the medication group, and 317 of 479 participants (66.2%; P = .001) were originally randomized to the observation group. Medication receipt was higher among Black/African American participants (169 of 219 participants [77.2%]) than among participants of other races (527 of 748 participants [70.5%]; P = .05). Medication receipt was also higher among participants who developed POAG (304 of 372 participants [81.7%]) compared with those who did not develop POAG (392 of 595 participants [65.9%]; P < .001).

    Glaucoma surgery was not specified in the OHTS protocol. However, 296 of 1636 participants (18.1%) underwent 1 or more of the following surgical procedures for the treatment of glaucoma during the OHTS: laser trabeculoplasty (157 participants [9.6%]), laser iridotomy (89 participants [5.4%]), filtering surgery (55 participants [3.4%]), combined cataract and filtering surgery (55 participants [3.4%]), and tube shunt surgery (16 participants [1.0%]). The incidence of glaucoma surgery among participants originally randomized to the medication group was 146 of 817 participants (17.9%) vs 150 of 819 participants (18.3%; χ2 P = .81) originally randomized to the observation group. The incidence of glaucoma surgery among Black/African American participants was slightly higher (86 of 407 participants [21.1%]) compared with participants of other races (210 of 1229 participants [17.1%]; P = .07).

    Discussion

    The OHTS 3 was a cohort study designed to determine the incidence and severity of POAG after 20 years of follow-up or within 2 years of death among a cohort of participants with OHT with a median age of 55 years at baseline. Of the 1636 participants enrolled, 483 participants (29.5%) developed POAG in 1 or both eyes over a median follow-up of 20.2 years (range, 0-24.5 years). The cumulative incidence of POAG at 20 years, adjusted for exposure time, was 45.6%. The Kaplan-Meier estimator was used to censor participants at the time of death because they were no longer at risk of developing POAG (if they had not developed POAG before death), which explains much of the difference between the unadjusted incidence of 29.5% and the adjusted incidence of 45.6%. Over the course of the OHTS, 515 participants died. It is concerning that the number of participants who died and the number who developed POAG were approximately the same during the OHTS. The incidence of POAG appeared to be generally linear over 20 years, with a possible modest increase in the rate of conversion after 15 years. We cannot determine whether this increase was a true change associated with increasing age or whether it was associated with missing data from loss to follow-up and death.

    One should be cautious in generalizing the incidence of POAG reported in the OHTS cohort to patients seen in standard clinical settings. Several factors have implications for the generalizability of the results. The OHTS participants had a higher risk of developing POAG because the mean baseline IOP of participants in the OHTS was 24.9 mm Hg, and the OHTS intentionally recruited a higher percentage of Black/African American participants (25.0%) than is representative of the general population.1 Participants in the OHTS may have a lower risk of developing POAG because volunteers in any study may be more likely to return for follow-up visits and adhere to medication. In addition, the OHTS used strict criteria for conversion to POAG. If other diagnostic criteria, such as OCT results, had been included or if less stringent reproducibility criteria had been used, a higher incidence of POAG would have been observed.

    Black/African American participants had a higher 20-year cumulative incidence of POAG than participants of other races (55.2% vs 42.7%). This discrepancy occurred despite similar baseline and follow-up IOP and a higher percentage of Black/African American participants in the OHTS 3 reporting receipt of treatment. Higher incidences of POAG among Black/African American participants were also observed in the OHTS 1 and OHTS 2.1,5 One might conclude that Black/African American individuals should receive more aggressive treatment than others; however, when patients are stratified by baseline risk, Black/African American individuals and others in the same risk category have similar outcomes.5 Therefore, the decision about treatment may be better determined based on a predictive model and patient age, health status, life expectancy, and preference rather than race.

    Few studies of patients with OHT have reported 20-year outcomes. Lundberg et al12 found that 11 of 33 patients with OHT (33.3%) developed POAG over 20 years. Hovding and Aasved13 reported that 20 of 80 patients with OHT (25.0%) and no pseudoexfoliation developed POAG after 20 years. Oskarsdottir et al14 followed up 77 high-risk patients with OHT until death. After a mean follow-up of 17.6 years, 7 patients (9.1%) developed bilateral visual impairment, and 2 patients (2.6%) developed bilateral blindness associated with glaucoma. The unadjusted rates of conversion to POAG reported in these studies are similar to those reported in the OHTS 3.

    In total, 199 participants developed optic disc POAG deterioration in 1 or both eyes without visual field abnormality based on study criteria. As a group, these participants had few differences from participants who did not develop POAG when comparing the last assessed visual field MD (<1 dB difference) or visual field PSD, visual acuity, contrast sensitivity, or foveal sensitivity. Greater functional differences might have been detected with more rigorous psychophysical, performance, or electrophysiologic tests that were not performed in the OHTS.

    A baseline prediction model that included age, IOP, central corneal thickness, VCDR, and visual field PSD differentiated participants with low, medium, or high risk of developing POAG at 20 years (31.7%, 47.6%, and 59.8%, respectively). This model has been useful to clinicians and patients in determining the frequency of examinations and the potential benefits of preventive treatment. The baseline prediction model included VCDR from optic disc photographs, which has been replaced in most practices by OCT measurements of the optic disc, peripapillary nerve fiber layer, and macula. Visual field testing and evaluation have also evolved over 20 years. Future prediction models will be more accurate as they incorporate genetic, environmental, and clinical factors using artificial intelligence and deep learning algorithms.

    A major challenge in interpreting the results of this study is determining how the association of treatment with long-term incidence and severity of POAG should be evaluated. The OHTS 1 and OHTS 2 were performed as randomized clinical trials; however, treatment was continued or stopped thereafter at the discretion of clinicians and participants. In the OHTS 3, more than 70% of patients were receiving topical ocular hypotensive treatment, and some patients had undergone glaucoma surgery. Treatment in the OHTS 1 was associated with a greater than 50% reduction in the 5-year incidence of POAG.1 A similar 50% reduction in the incidence of POAG was projected in a 10-year model.15 The OHTS 3 did not provide data to extrapolate the 10-year model of treatment vs observation to 20 years, although it seems likely that long-term decreases in IOP would continue to be associated with reductions in the incidence of POAG.

    Strengths and Limitations

    This study has several strengths. These include a large sample, a diverse patient cohort, careful follow-up procedures, an onset date of glaucoma diagnosis within 6 months in the OHTS 1 and OHTS 2, use of standardized tests, and masked determination of end points by reading centers and an end point committee.

    Quiz Ref IDThis study also has limitations. These include a limited baseline IOP range of 21 to 32 mm Hg, collection of medical history and family history of glaucoma only by self-report, loss to follow-up over the 20-year study period, missing data on participants (particularly between the OHTS 2 and the OHTS 3), nonrandomized treatment after the OHTS 2, and lack of OCT measurements until the OHTS 3.

    Conclusions

    The cumulative 20-year incidence of POAG was 45.6%, with 25.2% of participants developing visual field loss in 1 or both eyes after adjustment for exposure time. These findings, combined with the use of a prediction model, may help to inform clinicians and patients about the prognosis of OHT and facilitate patient-specific management that takes into consideration age, health status, life expectancy, and personal preference.

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    Article Information

    Accepted for Publication: January 26, 2021.

    Published Online: April 15, 2021. doi:10.1001/jamaophthalmol.2021.0341

    Correction: This article was corrected on July 22, 2021, to fix labeling errors in Figure 2A.

    Corresponding Author: Mae O. Gordon, PhD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St Louis, 660 S Euclid, CB 8096, St Louis, MO 63122 (gordon.mae@wustl.edu).

    Author Contributions: Drs Gordon and Kass had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Kass, Heuer, Higginbotham, Parrish, Johnson, Miller, Brandt, Khanna, Quigley, Gordon.

    Acquisition, analysis, or interpretation of data: Heuer, Johnson, Keltner, Huecker, Wilson, Liu, Miller, Brandt, Khanna, Soltau, Gordon.

    Drafting of the manuscript: Kass, Parrish, Wilson, Liu, Khanna, Quigley, Gordon.

    Critical revision of the manuscript for important intellectual content: Kass, Heuer, Higginbotham, Johnson, Keltner, Huecker, Miller, Brandt, Khanna, Soltau, Gordon.

    Statistical analysis: Wilson, Liu, Miller, Gordon.

    Obtained funding: Kass, Brandt, Gordon.

    Administrative, technical, or material support: Kass, Heuer, Higginbotham, Johnson, Keltner, Huecker, Brandt, Khanna, Gordon.

    Supervision: Kass, Parrish, Soltau, Gordon.

    Other—Served on study Executive Committee: Brandt.

    Conflict of Interest Disclosures: Dr Kass reported receiving grants from Merck, the National Institutes of Health, Pfizer, and Research to Prevent Blindness during the conduct of the study and owning stock options in Smartlens outside the submitted work. Dr Heuer reported receiving personal fees from Washington University as a subcontractor for the National Eye Institute and the National Institutes of Health during the conduct of the study and receiving personal fees from Advanced Clinical (for serving as consultant to Google) and InnFocus outside the submitted work. Dr Higginbotham reported receiving grants from the National Eye Institute and being a subcontractor for Washington University during the conduct of the study. Ms Huecker reported receiving grants from the National Eye Institute during the conduct of the study and outside the submitted work. Mr Wilson reported receiving grants from the National Eye Institute during the conduct of the study. Dr Liu reported receiving grants from the National Institutes of Health during the conduct of the study and receiving consulting fees from Mesoblast outside the submitted work. Mr Miller reported receiving grants from the National Institutes of Health during the conduct of the study and receiving grants from the National Institutes of Health and the Patient-Centered Outcomes Research Institute and personal fees from General Dynamics (US Department of Defense) and the National Institutes of Health outside the submitted work. Dr Brandt reported receiving grants from the National Eye Institute during the conduct of the study and receiving consulting fees from Aerie Pharmaceuticals and Graybug Vision outside the submitted work. Dr Soltau reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Gordon reported receiving grants from the National Eye Institute during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was supported by grant UL1 TR002345 (Drs Liu and Gordon and Mr Miller) from the Institute of Clinical and Translational Sciences; grants U10 EY09341 (Dr Gordon), U10 EY09370 (Dr Kass), UG1 EY025180 (Dr Kass, chairman), UG1 EY025181 (Dr Gordon, clinical center), UG1 EY025182 (Dr Gordon, coordinating center), and UG1 EY025183 (Dr Kass, resource centers) from the National Eye Institute; grant P30 EY002687 (Dr Gordon, Ms Huecker, and Mr Wilson) from the National Institutes of Health; and an unrestricted grant from Research to Prevent Blindness.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: The Ocular Hypertension Study Group Investigators, Coordinators, and Executive Committee are listed in Supplement 2.

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