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Clinical Trial Retrospective |

Ocular Hypertension Treatment Study FREE

Eve J. Higginbotham, MD
[+] Author Affiliations

Author Affiliations: Department of Surgery, Morehouse School of Medicine and the Department of Ophthalmology, Emory School of Medicine, Atlanta, Georgia.


Section Editor: Simmons Lessell, MD

More Author Information
Arch Ophthalmol. 2009;127(2):213-215. doi:10.1001/archophthalmol.2008.599.
Text Size: A A A
Published online

For decades before the initiation of the Ocular Hypertension Treatment Study (OHTS),1no consensus existed among ophthalmologists regarding the treatment of patients with ocular hypertension. Some studies26affirmed the protective benefits of treatment, and other studies712did not support the use of preventive medical therapy. Therefore, it was unclear if early treatment was beneficial. Most of these studies did not enroll a diverse patient population,212others used a single medication as an intervention,2,3,5,6,10and all differed in their definitions of glaucoma. Moreover, questions were raised by health outcomes experts outside the field of ophthalmology regarding whether treatment of glaucoma in general was beneficial.13Thus, a well-designed clinical trial was needed to assist clinicians in determining whether treatment is protective and, if so, which patients would benefit most from treatment.

What were the primary objectives and study design of the OHTS? The 2 primary study objectives were (1) to determine the safety and efficacy of topical ocular medication in delaying or preventing the development of primary open-angle glaucoma in individuals with ocular hypertension and (2) to determine the factors that predict which patients with ocular hypertension will develop primary open-angle glaucoma. Eligible patients were between the ages of 40 and 80 years and had an intraocular pressure (IOP) between 24 and 32 mm Hg in one eye and 21 and 32 mm Hg in the other eye. Given the high prevalence of glaucoma among African Americans, 25% of the participants enrolled were self-reported African Americans. Participants were randomized to topical medication or observation. The goal in the medication group was a 20% reduction of IOP and an IOP of less than 24 mm Hg. Clinicians could choose any commercially available topical medication to try to reduce IOP. All patients were followed up with perimetric tests and stereoscopic optic disc photography. The primary end point of glaucoma was defined as either a reproducible visual field abnormality or a reproducible, clinically significant change in the optic nerve. Change was judged independently by masked readers at the Visual Field Reading Center (University of California at Davis or Sacramento, California) and the Optic Disc Reading Center (Bascom Palmer Eye Center, University of Miami, Florida). An end point committee, which consisted of masked clinicians, independently judged whether the changes were caused by primary open-angle glaucoma.1

The importance of the characterization of the end points cannot be overemphasized, considering the imprecision of diagnosing glaucoma in clinical practice. Initially, the investigators agreed on a requirement of 2 consecutive perimetric tests to confirm a functional defect; however, analysis of this definition revealed that 85.9% of abnormalities initially detected were not confirmed on the next test.14Therefore, 3 consecutive perimetric tests were required for an end point for the remainder of the study. A subsequent review of those end points based on 2 fields vs 3 fields confirmed the wisdom of this change in protocol.15When considering the precision of characterizing the optic disc, the Optic Disc Reading Center reported exceptional reproducibility when horizontal cup-disc ratios were determined during a 3-year period.16These same investigators later demonstrated a high level of consistency in their ability to detect deterioration in the optic disc appearance over time.17Both functional and structural measures proved to be important, considering that 41 of 168 eyes reached an end point based on both visual field abnormality and optic disc deterioration, 40 of 168 eyes on visual field abnormality alone, and 87 of 168 eyes on optic disc deterioration alone.18

What was the primary outcome of the study? Patients treated with medication were less likely to develop glaucoma during a period of 60 months compared with those who were simply observed: 4.4% of the medication group patients developed primary open-angle glaucoma vs 9.5% of the observation group patients.1Among self-reported African Americans, 8.4% of the medication participants converted to glaucoma vs 16.1% in the observation group. Compared with all other ethnic groups taken together, the conversion rate for African Americans was 200% greater in the medication group and 58% greater in the observation group.19The benefits of medical therapy and the difference in disease progression in different ethnic groups in a diverse cohort were not previously documented in a randomized trial. The design of the study and the quality of the measures chosen for the end points provide a level of certainty that the results are valid and translatable to clinical practice.

The goal of reducing IOP was achieved among the treated eyes, with a mean (SD) reduction of 22.5% (9.9%) vs 4.0% (11.6%) in the observation group.1No difference was found in the response to therapy among self-reported African Americans compared with others20; however, a difference in the measured IOP response to topical therapy was noted among those with thinner corneas vs thicker corneas.21Moreover, not surprisingly, among those individuals who started taking a β-blocker, 45% of the untreated contralateral eyes demonstrated a reduction in IOP of 3 mm Hg or more.22When considering the question of safety, a greater proportion of individuals in the medication group reported symptoms such as dryness, tearing, and itching compared with those in the observation group.1Little difference was noted between the medication group and the observation group in overall adverse events and serious adverse events. Among those participants randomized to medication, there was a slightly higher rate of cataract surgery in the medication group, but no apparent overall impact was seen on either lens opacification or visual function.23Severe psychiatric and genitourinary adverse events were slightly more common in the medication group.1

The analysis of baseline demographic and clinical data provided the most effective vehicle for the OHTS to ultimately influence clinical practice. Gordon and coworkers24identified several key baseline factors predictive of primary open-angle glaucoma: older age, higher IOP, larger vertical cup-disc ratio, a higher pattern standard deviation on visual field testing, and thinner corneal measurement. After an analysis of the baseline factors among the self-reported African Americans in the study, ethnicity proved to not be a significant risk factor when adjustments were made for key parameters, such as larger cup-disc ratio and thinner corneal measurement.19The presence of a disc hemorrhage was associated with an increased risk of developing glaucoma, with a 3.7-fold increased risk in a multivariate analysis.25Among a subset of patients who were followed up with confocal laser ophthalmoscopy, a number of baseline indices were significantly associated with the development of glaucoma.26As a further testimony to the validity and relevance of the OHTS to other populations, a prediction model was developed based on the observation group of the OHTS and then subsequently tested on the placebo group of the European Glaucoma Prevention Study.27This additional analysis confirmed the same predictors for developing primary open-angle glaucoma as did the original model reported by the OHTS.

The authors of the OHTS appropriately concluded that not everyone with ocular hypertension should be treated; treatment should be considered for patients at moderate to high risk for developing primary open-angle glaucoma. A clinician must consider a patient's risk of developing primary open-angle glaucoma, as well as the patient's health, life expectancy, and personal preferences. A cost-utility analysis of the OHTS data supports the early treatment of those individuals with an IOP of 24 mm Hg or higher and a 2% or greater annual risk of developing glaucoma and reaffirms that the treatment of all patients with ocular hypertensives is not cost-effective.28These observations are the most significant products of this multicenter randomized clinical trial.

The OHTS has yielded a wealth of useful clinical information, which will guide the management of individuals with ocular hypertension for decades to come. Not only did this study provide a definitive basis for managing patients with ocular hypertension but also the profession has benefited by lessons learned in the study related to optic disc assessment, analysis of perimetric test findings, and corneal thickness measurements. Until clinicians have the benefit of specific genetic profiles for patients to guide their clinical decisions, they can be guided by measurable biological risk factors (ie, thin central corneal measurement, large cup-disc ratio, increasing age, abnormal visual function, and higher IOP) to determine which patients should be considered for early treatment.

ARTICLE INFORMATION

Correspondence: Eve J. Higginbotham, MD, Department of Ophthalmology and Visual Science, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310 (ejhigginbotham@msm.edu).

Submitted for Publication: December 21, 2007; final revision received January 8, 2008; accepted January 9, 2008.

Financial Disclosure: None reported.

Kass  MAHeuer  DKHigginbotham  EJ  et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120 (6) 701- 713
PubMed Link to Article
Becker  BMorton  WR Topical epinephrine in glaucoma suspects. Am J Ophthalmol 1966;62 (2) 272- 277
PubMed
Shin  DHKolker  AEKass  MAKaback  MBBecker  B Long-term epinephrine therapy of ocular hypertension. Arch Ophthalmol 1976;94 (12) 2059- 2060
PubMed Link to Article
Kitazawa  Y Prophylactic therapy of ocular hypertension: a prospective study. Trans Ophthalmol Soc N Z 1981;3330- 32
PubMed
Epstein  DLKrug  JH  JrHertzmark  ERemis  LLEdelstein  DJ A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology 1989;96 (10) 1460- 1467
PubMed Link to Article
Kass  MAGordon  MOHoff  MR  et al.  Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals: a randomized, double-masked long-term clinical trial. Arch Ophthalmol 1989;107 (11) 1590- 1598
PubMed Link to Article
Schulzer  MDrance  SMDouglas  GR A comparison of treated and untreated glaucoma suspects. Ophthalmology 1991;98 (3) 301- 307
PubMed Link to Article
Graham  PA The definition of pre-glaucoma: a prospective study. Trans Ophthalmol Soc U K 1969;88153- 165
PubMed
Norskov  K Routine tonometry in ophthalmic practice, II: five-year follow-up. Acta Ophthalmol (Copenh) 1970;48 (5) 873- 895
PubMed Link to Article
Leven  RZ Uniocular miotic therapy. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1975;79 (2) OP376- OP380
PubMed
David  RLivingston  DGLuntz  MH Ocular hypertension: a long-term follow-up of treated and untreated patients. Br J Ophthalmol 1977;61 (11) 668- 674
PubMed Link to Article
Chisholm  IAStead  STan  LMelenchuk  JW Prognostic indicators in ocular hypertension. Can J Ophthalmol 1980;15 (1) 4- 8
PubMed
Eddy  DMBillings  J The Quality of Medical Evidence and Medical Practice.  Washington, DC National Leadership Commission on Heath Care1987;
Keltner  JLJohnson  CRQuigg  JMCello  KEKass  MAGordon  MOOcular Hypertension Treatment Study Group, Conformation of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2000;118 (9) 1187- 1194
PubMed Link to Article
Keltner  JLJohnson  CALevine  RA  et al.  Normal visual field test results following glaucomatous visual field end points in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2005;123 (9) 1201- 1206
PubMed Link to Article
Feuer  WJParrish  RK  IISchiffman  JC  et al.  The Ocular Hypertension Treatment Study: reproducibility of cup/disk ratio measurements over time at an optic disc reading center. Am J Ophthalmol 2002;133 (1) 19- 28
PubMed Link to Article
Parrish  RK IISchiffman  JCFeuer  WJ  et al.  Test-retest reproducibility of optic disk deterioration detected from stereophotographs by masked graders. Am J Ophthalmol 2005;140 (4) 762- 764
PubMed Link to Article
Keltner  JLJohnson  CAAnderson  DR  et al.  The association between glaucomatous visual fields and optic nerve head features in the Ocular Hypertension Treatment Study. Ophthalmology 2006;113(9)1603- 1612
Link to Article
Higginbotham  EJGordon  MOBeiser  JA  et al. Ocular Hypertension Treatment Study Group, The Ocular Hypertension Treatment Study: topical medication delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol 2004;122 (6) 813- 820
PubMed Link to Article
Mansberger  SLHughes  BAGordon  MO  et al. Ocular Hypertension Treatment Study Group, Comparison of initial intraocular pressure response with topical β-adrenergic antagonists and prostaglandin analogues in African American and white individuals in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2007;125 (4) 454- 459
PubMed Link to Article
Brandt  JDBeiser  JAGordon  MOKass  MAOcular Hypertension Treatment Study (OHTS) Group, Central corneal thickness and measured IOP response to topical ocular hypertensive medication in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2004;138 (5) 717- 722
PubMed Link to Article
Piltz  JGross  RShin  D  et al.  Contralateral effect of topical β-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2000;130 (4) 441- 453
PubMed Link to Article
Herman  DCGordon  MOBeiser  JA  et al. Ocular Hypertension Treatment Study (OHTS) Group, Topical ocular hypotensive medication and lens opacification: evidence from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;142 (5) 800- 810
PubMed Link to Article
Gordon  MOBeiser  JABrandt  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
PubMed Link to Article
Budenz  DLAnderson  DRFeuer  WJ  et al. Ocular Hypertension Treatment Study Group, Detection and prognostic significance of optic disc hemorrhages during the Ocular Hypertension Treatment Study. Ophthalmology 2006;113 (12) 2137- 2143
PubMed Link to Article
Zangwill  LMWeinreb  RNBeiser  J  et al.  Baseline topographic optic disc measurements are associated with the development of primary open-angle glaucoma: the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study. Arch Ophthalmol 2005;123 (9) 1188- 1197
PubMed Link to Article
Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group,Gordon  MOTorri  VMiglior  S  et al.  Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology 2007;114 (1) 10- 19
Link to Article
Kymes  SMKass  MAAnderson  DRMiller  JPGordon  MOOcular Hypertension Treatment Study Group (OHTS), Management of ocular hypertension: a cost effectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141 (6) 997- 1008
PubMed Link to Article

Figures

Tables

References

Kass  MAHeuer  DKHigginbotham  EJ  et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120 (6) 701- 713
PubMed Link to Article
Becker  BMorton  WR Topical epinephrine in glaucoma suspects. Am J Ophthalmol 1966;62 (2) 272- 277
PubMed
Shin  DHKolker  AEKass  MAKaback  MBBecker  B Long-term epinephrine therapy of ocular hypertension. Arch Ophthalmol 1976;94 (12) 2059- 2060
PubMed Link to Article
Kitazawa  Y Prophylactic therapy of ocular hypertension: a prospective study. Trans Ophthalmol Soc N Z 1981;3330- 32
PubMed
Epstein  DLKrug  JH  JrHertzmark  ERemis  LLEdelstein  DJ A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology 1989;96 (10) 1460- 1467
PubMed Link to Article
Kass  MAGordon  MOHoff  MR  et al.  Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals: a randomized, double-masked long-term clinical trial. Arch Ophthalmol 1989;107 (11) 1590- 1598
PubMed Link to Article
Schulzer  MDrance  SMDouglas  GR A comparison of treated and untreated glaucoma suspects. Ophthalmology 1991;98 (3) 301- 307
PubMed Link to Article
Graham  PA The definition of pre-glaucoma: a prospective study. Trans Ophthalmol Soc U K 1969;88153- 165
PubMed
Norskov  K Routine tonometry in ophthalmic practice, II: five-year follow-up. Acta Ophthalmol (Copenh) 1970;48 (5) 873- 895
PubMed Link to Article
Leven  RZ Uniocular miotic therapy. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1975;79 (2) OP376- OP380
PubMed
David  RLivingston  DGLuntz  MH Ocular hypertension: a long-term follow-up of treated and untreated patients. Br J Ophthalmol 1977;61 (11) 668- 674
PubMed Link to Article
Chisholm  IAStead  STan  LMelenchuk  JW Prognostic indicators in ocular hypertension. Can J Ophthalmol 1980;15 (1) 4- 8
PubMed
Eddy  DMBillings  J The Quality of Medical Evidence and Medical Practice.  Washington, DC National Leadership Commission on Heath Care1987;
Keltner  JLJohnson  CRQuigg  JMCello  KEKass  MAGordon  MOOcular Hypertension Treatment Study Group, Conformation of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2000;118 (9) 1187- 1194
PubMed Link to Article
Keltner  JLJohnson  CALevine  RA  et al.  Normal visual field test results following glaucomatous visual field end points in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2005;123 (9) 1201- 1206
PubMed Link to Article
Feuer  WJParrish  RK  IISchiffman  JC  et al.  The Ocular Hypertension Treatment Study: reproducibility of cup/disk ratio measurements over time at an optic disc reading center. Am J Ophthalmol 2002;133 (1) 19- 28
PubMed Link to Article
Parrish  RK IISchiffman  JCFeuer  WJ  et al.  Test-retest reproducibility of optic disk deterioration detected from stereophotographs by masked graders. Am J Ophthalmol 2005;140 (4) 762- 764
PubMed Link to Article
Keltner  JLJohnson  CAAnderson  DR  et al.  The association between glaucomatous visual fields and optic nerve head features in the Ocular Hypertension Treatment Study. Ophthalmology 2006;113(9)1603- 1612
Link to Article
Higginbotham  EJGordon  MOBeiser  JA  et al. Ocular Hypertension Treatment Study Group, The Ocular Hypertension Treatment Study: topical medication delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol 2004;122 (6) 813- 820
PubMed Link to Article
Mansberger  SLHughes  BAGordon  MO  et al. Ocular Hypertension Treatment Study Group, Comparison of initial intraocular pressure response with topical β-adrenergic antagonists and prostaglandin analogues in African American and white individuals in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2007;125 (4) 454- 459
PubMed Link to Article
Brandt  JDBeiser  JAGordon  MOKass  MAOcular Hypertension Treatment Study (OHTS) Group, Central corneal thickness and measured IOP response to topical ocular hypertensive medication in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2004;138 (5) 717- 722
PubMed Link to Article
Piltz  JGross  RShin  D  et al.  Contralateral effect of topical β-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2000;130 (4) 441- 453
PubMed Link to Article
Herman  DCGordon  MOBeiser  JA  et al. Ocular Hypertension Treatment Study (OHTS) Group, Topical ocular hypotensive medication and lens opacification: evidence from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;142 (5) 800- 810
PubMed Link to Article
Gordon  MOBeiser  JABrandt  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
PubMed Link to Article
Budenz  DLAnderson  DRFeuer  WJ  et al. Ocular Hypertension Treatment Study Group, Detection and prognostic significance of optic disc hemorrhages during the Ocular Hypertension Treatment Study. Ophthalmology 2006;113 (12) 2137- 2143
PubMed Link to Article
Zangwill  LMWeinreb  RNBeiser  J  et al.  Baseline topographic optic disc measurements are associated with the development of primary open-angle glaucoma: the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study. Arch Ophthalmol 2005;123 (9) 1188- 1197
PubMed Link to Article
Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group,Gordon  MOTorri  VMiglior  S  et al.  Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology 2007;114 (1) 10- 19
Link to Article
Kymes  SMKass  MAAnderson  DRMiller  JPGordon  MOOcular Hypertension Treatment Study Group (OHTS), Management of ocular hypertension: a cost effectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141 (6) 997- 1008
PubMed Link to Article

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