1-——
`
`The Ocular Hypertension Treatment Study ;'tT='r'E"‘ii}vt%s rxéfi
`
`A Randomized Trial Determines That Topical Ocular Hypotensive
`Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma
`
`Michael A. Kass, MD; Dale K. Heuer, MD; Eve J. Higginbotham, MD; Chris A. Johnson, PhD; john L. Keltner, MD;
`]. Philip Miller, AB; Richard K. Parrish H, MD; M. Roy Wilson, MD; Mae 0. Gordon, PhD;
`for the Ocular Hypertension Treatment Study Group
`
`Background: Primary open—angle glaucoma (POAG) is one
`of the leading causes of blindness in the United States and
`worldwide. Three to 6 million people in the United States
`are at increased risk for developing POAG because ofelevated
`intraocular pressure (IOP), or ocular hypertension. There
`is no consensus on the efficacy of medical treatment in de-
`laying or preventing the onset of POAG in individuals with
`elevated IOP. Therefore, we designed a randomized clini-
`cal trial, the Ocular Hypertension Treatment Study.
`
`Obioclivo: To determine the safety and efficacy of topi-
`cal ocular hypotensive medication in delaying or pre-
`venting the onset of POAG.
`
`Methods: A total of 1636 participants with no evidence
`of glaucomatous damage, aged 40 to 80 years, and with an
`IOP between 24 mm Hg and 32 mm Hg in one eye and be-
`tween 21 mm Hg and 32 mm Hg in the other eye were ran-
`domized to either observation or treatment with commer-
`
`cially available topical ocular hypotensive medication. The
`goal in the medication group was to reduce the IOP by 20%
`or more and to reach an IOP of 24 mm Hg or less.
`
`or reproducible optic disc deterioration attributed to POAG.
`Abnormalities were determined by masked certified read-
`ers at the reading centers, and attribution to POAG was
`decided by the masked Endpoint Committee.
`
`ROIIIIII: During the course of the study, the mean:SD
`reduction in IOP in the medication group was
`22.5%:t:9.9%. The IOP declined by 4.0%: 11.6% in the
`observation group. At 60 months, the cumulative prob-
`ability of developing POAG was 4.4% in the medication
`group and 9.5% in the observation group (hazard ratio,
`0.40; 95% confidence interval, 0.27-0.59; P<.0O01). There
`was little evidence of increased systemic or ocular risk
`associated with ocular hypotensive medication.
`
`Conclusions: Topical ocular hypotensive medication was
`effective in delaying or preventing the onset of POAG in
`individuals with elevated IOP. Although this does not im-
`ply that all patients with borderline or elevated IOP should
`receive medication, clinicians should consider initiat-
`ing treatment for individuals with ocular hypertension
`who are at moderate or high risk for developing POAG.
`
`Main Ounomo Moosuros: The primary outcome was
`the development of reproducible visual field abnormality
`
`Arch Ophthalmol. 2002;120:701-713
`
`
`
`URVEYS snow that glaucoma
`is among the leading causes
`of blindness in the United
`States and worldwide.” It is
`estimated that more than 2.5
`
`million people in the United States have
`glaucoma and that more than 130000
`people are legally blind from the dis-
`ease.‘ Population surveys indicate that less
`than 50% of those with glaucomatous vi-
`sual field loss have received an appropri-
`ate diagnosis or treatrnent.”
`Glaucoma is the leading cause of
`blindness in individuals of West African
`
`origin?-9'” In the Baltimore Eye Survey} the
`age-adjusted prevalence rates of primary
`open—angle glaucoma (POAG) were 4 to 5
`times higher in African Americans than in
`white individuals. The prevalence ranged
`
`from 1.2% in African Americans between the
`
`ages of 40 and 49 years to 1 1.3% in those 80
`years and older." Furthermore, the Barba-
`dos Eye Study7‘” found a high prevalence
`and incidence ofglaucoma among black in-
`dividuals in an Afro-Caribbean population.
`
`See also pages 714
`and 829
`
`It is estimated that 3 to 6 millionpeople
`in the United States, including 4% to 7% of
`those older than 40 years, have elevated in-
`traocular pressure (IOP) without detectable
`glaucomatous damage on standard clinical
`tests.” These individuals are at increased risk
`
`Author affiliations are listed
`at the end of this article. A
`complete list of the participants
`in this study appears on page
`709. A list offinancial
`disclosures appears on
`page 712.
`
`for developing POAG and are sometimes re-
`ferred to as ocular hypertensives or glaucoma
`suspects.‘3"5 Kerrigan-Baumrind et all“ re-
`
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`PARTICIPANTS AND METHODS
`
`The design and methods of the OHTS were described pre-
`viously,”’35 can be found on the World Wide Web at
`www.vrcc.wustl.edu, and are briefly summarized as follows.
`
`PARTICIPANTS
`
`Eligibility criteria included age between 40 and 80 years, a
`qualifying IOP between 24 mm Hg and 32 mm Hg in one
`eye and between 21 mm Hg and 32 mm Hg in the other eye,
`gonioscopically open angles, 2 normal and reliable visual field
`tests per eye as determined by the Visual Field Reading Cen-
`ter, and normal optic discs seen at clinical examination and
`on stereoscopic photographs as determined by the Optic Disc
`Reading Center. Exclusion criteria included a visual acuity
`worse than 20/40 in either eye, previous intraocular sur-
`gery (other than uncomplicated cataract extraction with pos-
`terior chamber lens implantation), and diabetic retinopa-
`thy or other diseases capable of causing visual field loss or
`optic disc deterioration. Both eyes of each participant had
`to meet eye-specific eligibility criteria. Participants signed a
`statement of informed consent approved by the institu-
`tional review board of each participating clinic.
`
`STUDY DESIGN
`
`This study was conducted at 22 clinical centers; eligible in-
`dividuals were randomized in equal proportion to either the
`medication group or observation group. Randomization as-
`signments were released by the Coordinating Center dur-
`ing the participant’s baseline visit. The randomization unit
`was the individual, and randomization was performed us-
`ing a permuted block design stratified by clinic and race. Nei-
`ther the participant nor the clinician was masked to the ran-
`domization assignment during follow-up.
`Participants randomized to medication began treat-
`ment to achieve a target IOP of 24 mm Hg or less and a
`minimum 20% reduction in IOP from the average of the
`qualifying IOP and IOP at the baseline randomization visit,
`except that an IOP of less than 18 mm Hg was not re-
`quired. Topical medication was changed and/or added un-
`til both of these goals were met or the participant was re-
`ceiving maximum-tolerated topical medical therapy.
`Medications were added and changed in one-eyed thera-
`peutic trials. Drugs were distributed to clinics from the
`study’s central pharmacy, which included all topical ocu-
`lar hypotensive medications commercially available in the
`
`United States. As new medications became commercially
`available, they were added to the study formulary.
`Follow-up visits were scheduled every 6 months from
`the date of randomization. Each semiannual examination
`included an ocular and medical history, refraction, best-
`corrected visual acuity, full-threshold Humphrey white-
`on-white 30-2 visual field tests, slitlamp examination, IOP
`measurement, and direct ophthalmoscopy. Additional evalu-
`ations at annual visits included a dilated fundus examina-
`
`tion and stereoscopic optic disc photographs.
`Information on adverse effects was collected using di-
`verse sources of information. Prior to each examination, the
`participants completed the Glaucoma Symptom Scale,” a
`checklist of 13 ocular symptoms and 15 systemic symp-
`toms. They rated the “bothersomeness” of symptoms on
`a scale of 1 to 4: from 1, “not at all," to 4, “a lot.” At annual
`visits, participants completed the Medical Outcomes Study
`Short Form (SF-36),” a survey of 36 questions designed to
`measure health-related quality oflife. At each visit, clinic staff
`recorded medical and ocular history and completed an
`adverse-event form when a new health problem was diag-
`nosed, an existing medical condition worsened, an inpa-
`tient hospitalization had occurred, or surgery had been re-
`quired. Clinic staff recorded the organ system affected and
`determined the severity of the condition. Clinicians judged
`whether the event was related to the study medication. Se-
`rious adverse events were defined as death, cancer or other
`life-threatening conditions, inpatient hospitalization, pro-
`longation of hospitalization, or outpatient hospitalization for
`an incapacitating condition. Clinic personnel obtained hos-
`pital discharge summaries and death certificates. In Janu-
`ary 1997, the OHTS protocol for reporting adverse events
`was made more rigorous because of large clinic-to-clinic varia-
`tion in the completion of the adverse-event forms. There-
`fore, data from the adverse-event forms are reported from
`January 1997 to the present.
`
`PRIMARY OUTCOME AND MONITORING
`
`The primary outcome was the development of POAG in one
`or both eyes. This was defined as reproducible visual field
`abnormality or reproducible clinically significant optic disc
`deterioration attributed to POAG by the masked End-
`point Committee.
`Development of visual field abnormality was deter-
`mined by masked certified readers at the Visual Field
`Reading Center. A technically acceptable visual field was
`considered abnormal ifP< .05 for the corrected pattern stan-
`dard deviation or if the glaucoma hemifield test result was
`
`ported that a substantialpercentage of the optic nerve fi-
`bers are lost before glaucomatous visual field defects can
`be detected with routine perimetry.
`The study of Kerrigan-Baumrind and colleagues, to-
`gether with the high prevalence of glaucoma and the po-
`tentially serious consequences of this disease, could sug-
`gest the need for early detection and treatment. However,
`there is no consensus on the efficacy of medical treat-
`ment in delaying or preventing the onset of POAG among
`individuals with elevated IOP.”‘3‘ Furthermore, it is un-
`clear whether the benefits of treatment outweigh the po-
`tential risks of long-term ocular hypotensive medica-
`tion use. Therefore, the Ocular Hypertension Treatment
`
`Study (OHTS) was designed to evaluate the safety and
`efficacy of topical ocular hypotensive medication in de-
`laying or preventing the onset of POAG in individuals
`with elevated IOP.
`
`me
`RECRUITMENT AND BASELINE
`CHARACTERISTICS OF PARTICIPANTS
`
`Recruitment was extended from 24 months to 30 months
`
`to achieve an enrollment of 400 African American partici-
`pants. Between February 28, 1994, and October 31, 1996,
`
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`outside normal limits according to StatPac 2 statistical soft-
`ware (StatPac Inc, Minneapolis, Minn). Because most ab-
`normal visual fields were found to be normal when re-
`tested,“ the protocol was changed (effectivejune 1, 1997)
`so that an endpoint required 3 consecutive abnormal re-
`sults on visual field tests with the same type, location, and
`index of abnormality. If a visual field test was judged to be
`abnormal, the test was repeated at the next visit approxi-
`mately 6 months later. If the second visual field test was
`judged to be abnormal, a third visual field test was per-
`formed 1 day to 8 weeks later. If 3 consecutive visual field
`tests met the criteria for abnormality, the Visual Field Read-
`ing Center initiated the endpoint review process. Addi-
`tional details about the process of reviewing visual fields
`were provided in a previously published article?“
`Optic disc deterioration was determined by masked
`certified readers at the Optic Disc Reading Center. Optic
`disc deterioration was defined as a generalized or local-
`ized thinning of the neuroretinal rim compared with base-
`line stereoscopic optic disc photographs in side-by-side com-
`parisons. The readers were masked as to which set of
`photographs was taken at baseline and which set was taken
`at a follow-up visit. If 1 or both readers in the Optic Disc
`Reading Center detected a difference between the baseline
`and follow-up photographs, the photographs were re-
`viewed in a masked fashion by a senior reader. If the se-
`nior reader agreed that deterioration had occurred, the Op-
`tic Disc Reading Center requested that the affected eye be
`rephotographed to confirm the change. If readers masked
`to the result of the first comparison confirmed the dete-
`rioration in the second set of photographs, the Optic Disc
`Reading Center initiated the endpoint review process. The
`classification of progression in a quality control sample of
`86 eyes (50 normal eyes and 36 with progression) showed
`test-retest agreement at K =0.70 (95% confidence interval
`[CI] , 0.55-0.85). Additional details about the process of re-
`viewing optic disc photographs were provided in a previ-
`ously published article.”
`The purpose of the endpoint review process was to dis-
`tinguish glaucomatous optic nerve and visual field changes
`from changes due to other causes. The members of the End-
`point Committee were masked to the randomization as-
`signments of the study participants. Each member of the
`Committee independently reviewed the participant’s ocu-
`lar and medical history, visual fields, and stereoscopic op-
`tic disc photographs of both eyes from baseline to the date
`of review. The Endpoint Committee determined whether
`visual field changes were due to POAG and whether optic
`disc deterioration was clinically significant and resulted from
`
`POAG. (Examples of clinically significant optic disc dete-
`rioration appear on the World Wide Web at www.vrc-
`c.wustl.edu.) Barely detectable changes in optic discs were
`not considered POAG endpoints in the OHTS. Partici-
`pants classified as developing POAG continued to receive
`follow-up with regularly scheduled visits and tests. Obser-
`vation participants who reached a POAG endpoint were pre-
`scribed medication. Medication participants who reached
`a POAG endpoint received increased glaucoma therapy, in-
`cluding argon laser trabeculoplasty and trabeculectomy, at
`the discretion of the treating clinician.
`The Data and Safety Monitoring Committee met twice
`yearly to review the conduct of the trial, including the safety
`and efficacy of medication. The Committee approved all
`protocol changes.
`
`STATISTICAL ANALYSIS
`
`The target sample size of 1500 participants (750 partici-
`pants per group) was selected to provide 90% power to de-
`tect a 40% reduction in the 5-year incidence of POAG (15%
`incidence in the observation group and 9% incidence in the
`medication group) with a 2-sided error at or = .05. The sample
`size allowed for a 15% loss to follow-up and a 10% cross-
`over between randomization groups. Because of the impor-
`tance of glaucoma in the African American community, we
`set a goal of enrolling 400 African Americans among the 1500
`participants. Recruitment was expected to take 24 months.
`All comparisons of randomization groups were made
`on an intention-to-treat basis. For the purposes of the pri-
`mary analysis, the number of days to the onset of POAG
`was determined by the date of the first abnormal finding
`that was subsequently confirmed and attributed to POAG.
`The primary hypothesis was tested using the Mantel-
`1-Iaenszel log-rank test to compare the cumulative prob-
`ability of developing POAG in each randomization group.
`Cox proportional hazards models were used to estimate haz-
`ard ratios for POAG, adjusting for the influence of base-
`line factors. Analyses were performed with SAS statistical
`software, version 8.1 (SAS Institute Inc, Cary, NC). P val-
`ues were 2-tailed. To adjust for multiple interim tests of
`the primary hypothesis, we calculated symmetric O’Brien-
`Fleming sequential log-rank boundaries using the oc-spend-
`ing function of Lan and DeMets.39v"°
`The Data and Safety Monitoring Committee ap-
`proved the termination of the trial when the last random-
`ized participant reached 5 years of follow-up, as specified
`in the original protocol. This article includes data through
`November 8, 2001.
`
`3328 individuals were considered for study enrollment, and
`1636 individuals with documented informed consent were
`
`randomized as follows: 817 were assigned to receive topi-
`cal ocular hypotensive medication, and 819 were as-
`signed to observation. A total of 1692 people were not eli-
`gible for randomization for a variety of reasons including
`an IOP outside the specified range, abnormal or unreli-
`able visual field test results, poor visual acuity, optic disc
`abnormalities, the inability to obtain clear photographs, and
`refusal to participate. A flowchart shows the progress of
`participants during the study (Figure I).
`No statistically significant differences in demo-
`graphic or clinical factors were found between the 2 ran-
`
`domized groups at baseline (for all comparisons, P>.05)
`(Tabla I ). Additional details on the randomized partici-
`pants were provided in a previously published article.”
`
`FOLLOW-UP
`
`The median duration of follow-up was 72 months for Af-
`rican American participants and 78 months for other par-
`ticipants. Of the expected follow-up visits, 90% were com-
`pleted during the study, and the visit completion rate did
`not differ by randomization group. The visit comple-
`tion rate was 86.6% for African Americans and 9 1 .4%
`
`for other participants (P<.O01). Technically acceptable
`
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`Documented as Screened
`(n =3328)
`
`Not Randomized
`(n = 1692)
`
`Randomized
`(n =1636)
`
`Observation Group
`(n= 819)
`Medication Initiated
`(n =42)
`
`Lost to Follow-up
`(inactive)
`in =84)
`
`Completed Trial
`(n=706)
`
`Medication Group
`(n=817)
`Medication Withdrawn
`(n=40)
`
`Lost to Follow-up
`(inactive)
`(fl =39)
`
`Completed Trial
`(n=702)
`
`Figure 1. Flowchart of participant progress in the Ocular Hypertension
`Treatment Study (OHTS). The “not randomized” group includes individuals
`who were ineligible. refused. or were eligible but not randomized.
`
`visual field test results and stereoscopic optic disc pho-
`tographs were obtained at 99% and 96%, respectively, of
`the specified completed follow-up visits and did not dif-
`fer by randomization group. The numbers of partici-
`pants completing each follow-up visit are shown at the
`bottom of Figure 2.
`
`ADHERENCE TO RANDOMIZATION
`
`Forty participants in the medication group (4.9%) were
`withdrawn from medication or chose to stop medica-
`tion for 6 months or more during the study. Fifteen of
`these individuals eventually resumed treatment. Forty-
`two participants in the observation group (5.1%) re-
`ceived topical ocular hypotensive medication for 6 months
`or more during the study. In most cases, treatment was
`initiated by the OHTS clinician because of concern about
`the participant’s high IOP. Three of these individuals even-
`tually stopped treatment.
`
`IOP REDUCTION AND MEDICATION
`
`in this group. At 60 months, 44.5% (65 of 146) of African
`American participants in the medication group were pre-
`scribed multiple medications, compared with 38.3% (194
`of 507) of the other medication participants.
`
`PRIMARY OPEN-ANGLE GLAUCOMA
`
`Table 3 reports the progress and outcome of random-
`ized participants, unadjusted for follow-up time. In the
`medication group, 36 of the 817 randomized participants
`developed POAG compared with 89 of 819 randomized par-
`ticipants in the observation group. The first POAG end-
`point for each participant is reported in Tulslo 4. At 60
`months, the cumulative probability of developing POAG
`was 4.4% in the medication group and 9.5% in the obser-
`vation group. During the course of the entire study, the cu-
`mulative probability of developing POAG was signifi-
`cantly lower in the medication group compared with the
`observation group (hazard ratio, 0.40; 95% CI, 0.27-0.59;
`Mantel—Haenszel log-rank test; P< .0001) (Figure 4). The
`estimate of the effect of treatment was not substantially
`altered after adjusting for baseline age, visual field pattern
`standard deviation, vertical cup-disc ratio, IOP, and corneal
`thickness, which was measured after randomization (haz-
`ard ratio, 0.34; 95% CI, 0.23-0.5 1). A treatment benefit was
`observed for reproducible visual field abnormality attributed
`to POAG (hazard ratio, 0.45; 95% CI, 0.27-0.76; P=.0O2)
`and for reproducible optic disc deterioration attributed to
`POAG (hazard ratio, 0.36; 95% CI, 0.23-0.56; P<.0001).
`There was a trend for treatment to be less protective
`among self-identified African American participants (haz-
`ard ratio, 0.54; 95% CI, 0.28-1.03) compared with the other
`participants in the trial (hazard ratio, 0.34; 95% CI, 0.21-
`0.56), although this difference was not statistically sig-
`nificant (P=.26). Primary open-angle glaucoma devel-
`oped in 14 (6.9%) of 203 African American participants
`in the medication group and 26 (12.7%) of 205 African
`Americans in the observation group, compared with 22
`(3.6%) of 614 other medication participants and 63 (10.2%)
`of 614 other observation participants.
`A total of 218 participants (137 participants in the
`observation group and 81 participants in the medica-
`tion group) developed reproducible visual field abnor-
`mality or reproducible optic disc deterioration due to
`POAG or a Variety of other causes including trauma,
`stroke, branch retinal vein occlusion, macular degenera-
`tion, and testing artifact. The cumulative probability of
`developing a reproducible abnormality from any cause
`was statistically significantly lower in the medication
`group than in the observation group (hazard ratio, 0.58;
`95% CI, 0.44-0.76; P=.00008).
`
`The baseline and follow-up IOP for the medication group
`and observation group are reported by race in Table 2.
`The distribution of IOP at baseline and follow-up for the
`medication and observation groups is shown in Figure 2.
`The IOP goal was met in both eyes at 87% (7515 of 8621)
`To ascertain the safety of treatment, the medication and
`and in one eye at 7% (613 of 8621) of the scheduled fol-
`low-up visits completed by medication participants.
`observation groups were compared for participant self-
`Figure 3 shows the percentage of participants who were
`report of symptoms (Glaucoma Symptom Scale and SF-
`36) and for medical and ocular history (new conditions,
`prescribed each class of topical ocular hypotensive medi-
`worsening of existing conditions, hospitalization, prolon-
`cation at each follow-up visit. At 60 months, 2 or more
`topical medications were prescribed for 39.7% (259 of 653)
`gation of hospitalization, or death) as collected by clinic
`of the medication participants, and 3 or more medica-
`staff during the course of the study. The following P val-
`ues are unadjusted for multiple comparisons between
`tions were prescribed for 9.3% (61 of 653) of participants
`
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`Observation
`(n = 819)
`
`346 (42.2)
`473 (57.3)
`
`237 (35.0)
`259 (31.6)
`210 (25.6)
`63 (7.7)
`
`3 (0.4)
`10 (1.2)
`205 (25.0)
`35 (4.3)
`560 (68.4)
`6 (0.7)
`24.9 (2.7)
`0.36 (0.13)
`0.39 (0.19)
`+0.21 (1.03)
`1.90 (0.21)
`1.12 (0.36)
`574.5 (37.7)
`39.3
`35.6
`33.7
`4.6
`14.0
`11.7
`12.1
`38.1
`4.0
`6.5
`1.6
`
`Overall
`(11 . 1636)
`
`705 (43.1)
`931 (56.9)
`
`573 (35.3)
`529 (32.3)
`412 (25.6)
`117 (7.2)
`
`4 (0.2)
`14 (0.9)
`403 (25.0)
`59 (3.6)
`1137 (69.5)
`14 (0.9)
`24.9 (2.7)
`0.36 (0.13)
`0.39 (0.19)
`+0.24 (1.05)
`1.91 (0.21)
`1.12 (0.35)
`572.5 (33.4)
`37.2
`34.3
`34.1
`5.0
`13.4
`11 .1
`11 .3
`37.8
`4.4
`6.1
`1 .2
`
`Medication
`(n = 811)
`
`359 (43.9)
`453 (56.1)
`
`291 (35.6)
`270 (33.0)
`202 (24.7)
`54 (3.6)
`
`1 (0.1)
`4 (0.5)
`203 (25.0)
`24 (2.9)
`577 (70.6)
`3 (1.0)
`24.9 (2.6)
`0.36 (0.19)
`0.39 (0.20)
`+0.27 (1.07)
`1.92 (0.21)
`1.12 (0.34)
`570.5 (38.9)
`35.0
`34.0
`34.4
`5.4
`12.3
`10.4
`11 .5
`37.5
`4.3
`5.3
`0.9
`
`Table 1. Baseline characteristics by Randomization Group
`
`characteristic
`
`Sex, No. We)
`
`MF
`
`Age, No. ("/5), y
`40 to 550
`>50 to $60
`>60 to $70
`>70 to 80
`Race, No. (%)
`Native American
`Asian
`African American
`Hispanic
`While
`other
`lntraocular pressure, mean (SD), mm Hg
`Horizontal cup-disc ratio, mean (SD)
`Vertical cup-disc ratio, mean (SD)
`Visual field mean deviation, mean (SD), dB
`Visual field pattern standard deviation, mean (SD), dB
`Visual field corrected pattern standard deviation, mean (SD), dB
`Central corneal thickness, mean (SD), um*
`Previous use of ocular hypotensive medication, %
`First—degree iamily history of glaucoma, %
`Myopia 21-diopter spherical equivalent, %
`Oral )3~adrenergic antagonist, “/3
`Oral calcium channel blocker, "/6
`History of migraine, "/6
`History of diabetes. °/o
`History of hypertension, %
`History of low blood pressure, %
`History of cardiovascular disease, %
`History of stroke, °/0
`
`*For central corneal thickness, n = 699 for medication, n = 699 for observation, and n = 1398 overall. Measurements were conducted after 1999, about 2 years
`after randomization of the last participant.
`
`groups. In the self-administered surveys, there was no evi-
`dence that the medication group had increased ocular or
`systemic symptoms compared with the observation group
`(Figure 5). In the medical and ocular histories collected
`by clinic staff, a higher percentage of participants in the
`medication group, compared with the observation group,
`reported ocular symptoms (57% vs 47%; P< .001) or symp-
`toms affecting the skin, hair, or nails (23% vs 18%; P<.001).
`The most common symptoms affecting the eyes were dry-
`ness, tearing, and itching. Changes in iris color, darken-
`ing of the eyelids, and growth of eyelashes occurred H1 17%
`(65 of 380) of the medication participants who were pre-
`scribed a prostaglandin analogue for 6 months or longer,
`compared with 7.6% (48 of 631) of the participants in the
`observation group (P<.001). There was no difference be-
`tween randomization groups in total hospitalizations
`(P: .56), worsening of preexisting conditions (P: .28), or
`mortality rates (P: .70). There was no difference between
`groups in visual acuity throughout the study (P> .05 at all
`follow-up periods). There was a slight excess of cataract
`surgery in the medication group: 6.4% (52 of 806) of par-
`ticipants compared with 4.3% (35 of 813) of participants
`in the observation group (P=.06).
`Clinic staff recorded serious psychiatric adverse
`events in 1.5% (12 of 800) of the medication partici-
`
`pants compared with 0.5% (4 of 802) of the observation
`participants (P: .05). Clinicians judged none of the 12
`serious psychiatric adverse events in the medication group
`to be “probably” or “definitely” related to the study medi-
`cation. Clinic staff recorded serious genitourinary ad-
`verse events in 5.5% (44 of 800) of the medication par-
`ticipants compared with 3.4% (27 of 802) of the
`observation participants (P: .04). Clinicians judged none
`of the 44 serious genitourinary adverse events in the medi-
`cation group to be “probably” or “definitely” related to
`the study medication. These differences were not statis-
`tically significant when corrected for multiple compari-
`sons. No differences between randomization groups were
`found in the rates of serious adverse events for the 11
`
`other organ systems inventoried, including ocular events
`or those related to the skin, hair, or nails (P>.O5).
`
`2%-
`
`The OHTS has shown that topical ocular hypotensive
`medication is effective in reducing the incidence of glau-
`comatous visual field loss and/or optic nerve deteriora-
`tion in individuals with elevated IOP between 24 mm Hg
`and 32 mm Hg. The mean1.~SD baseline IOP of all par-
`ticipants was 24.9:2.7 mm Hg with no difference be-
`
`
`WWW.ARCl-lOPHTHAI_MOL.COM
`(REPRINTED) ARCH OPHTHALMOU VOL 120, JUNE 2002
`705
`
`©2002 American Medical Associatimi. All rights rrzservml.
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`

`Randomization Assignment
`--- Observation
`— Medication
`
`0
`(Baseline)
`OBS MED
`819
`817
`
`6
`
`12
`
`18
`
`24
`
`OBS MED
`783
`767
`
`OBS MED
`772
`771
`
`OBS MED
`772
`750
`
`OBS MED
`754 747
`
`OBS MED
`734
`73
`0
`
`36
`Follow-up, mo
`OBS MED
`715
`714
`
`42
`
`48
`
`54
`
`60
`
`66
`
`72
`
`OBS MED
`693
`704
`
`088 MED
`663
`685
`
`OBS MED
`649
`662
`
`UBS MED
`627
`653
`
`OBS MED
`566
`613
`
`088 MED
`497
`514
`
`Figure 2. Distribution of intraocular pressure (IOP) at baseline and follow-up for the medication (MED) and observation (OBS) groups. The median IOP in each
`randomization group is joined by a line. The top and bottom of the boxes include the 75th and 25th percentiles. respectively. and the marks above and below
`include the 90th and 10th percentiles. Each participant's right and left eye was averaged to calculate a mean. The numbers of participants completing each
`follow-up visit are shown at the bottom.
`
`Table 2. lntraooular Pressure at Baseline and Follow-up in the Medication Group and Observation Group Reported by Race*
`
`Medication Group
`
`observation Group
`
`-4.7 1 12.8
`
`IOP at baseline
`IOP averaged across scheduled follow-up visits
`Reduction from baseline, "/2
`
`Atrican American
`(I1 = 203)
`25.1 1 2.9
`19.3 1 2.3
`-22.9 1 9.9
`
`other
`(it = 614)
`24.9 1 2.6
`19.3 1 2.1
`-22.4 1 9.9
`
`All
`(I1 = 317)
`24.9 1 2.6
`19.3 1 2.2
`-22.5 1 9.9
`
`Alrican American
`(n = 205)
`25.1 1 2.8
`23.9 1 3.2
`
`other
`(it = 614)
`24.9 1 2.7
`23.9 1 2.8
`-3.8 1 11.1
`
`All
`(it = 819)
`24.9 1 2.7
`23.9 1 2.9
`-4.0 1 11.6
`
`*|ntraocular pressure measurements (in millimeters of mercury) are excluded after the date participants developed primary open-angle glaucoma. Data are
`presented as mean 1 SD. l0P indicates intraocular pressure; sample size, number of randomized participants.
`
`tween randomization groups. Individuals were random-
`ized either to observation or to receive topical ocular
`hypotensive medication. The goal of treatment was to re-
`duce the IOP by 20°/o or more and to reach an IOP of 24
`mm Hg or less. In the medication group, the mean1SD
`reduction in IOP during the follow-up period was 22.5%
`1 9.9%. The IOP declined by 4.0% 1 11.6% in the obser-
`vation group. Randomization groups had similar base-
`line demographic and clinical characteristics as well as
`similar rates of visit completion and outcome ascertain-
`ment throughout follow-up. The rate of adherence to ran-
`domization assignment was high and did not differ by
`group.
`To our knowledge, the OHTS is the largest random-
`ized trial to date of the safety and efficacy of ocular hy-
`potensive medication in delaying or preventing the on-
`set of POAG in individuals with ocular hypertension. At
`60 months, the cumulative probability of developing
`
`WWW.ARCHOPHTI-IALMOLCOM
`(REPRINTED) ARCH OPHTHAI.MOL/ VOL 120, JUNE 2002
`706
`
`POAG was 4.4% in the medication group and 9.5% in
`the observation group. It is difficult to compare the in-
`cidence of POAG in this study with that in many previ-
`ous publications because the incidence rate reflects both
`study-specific eligibility criteria and endpoint criteria. The
`OHTS used strict entry criteria and included generally
`healthy volunteers. In addition, stringent endpoint cri-
`teria included only reproducible visual field abnormal-
`ity and optic disc deterioration attributable to POAG. The
`OHTS used quality control criteria for certifying and moni-
`toring visual field technicians and photographers.
`Criteria for POAG were made more stringent dur-
`ing the course of the study. The number of consecutive
`abnormal visual field test results required to confirm an
`abnormality was increased from 2 to 3. In addition, the
`criterion for optic disc deterioration was increased from
`a “barely detectable difference” to a “clinically signifi-
`cant change” in the optic disc neuroretinal rim.
`
`©2002 American Medical A.ssociat.i<m. All rights reserved.
`Downloaded From: http://jamanetwork.eom/pdfaccess.ashx?url=/data/journals/ophth/6800/ on 02/26/2017
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`

`— B-Adrenerglc Antagonist
`-— Topical Carbonic Anydrase Inhibitors
`-—- Parasympathomimetic Agents
`
`— Prostaglandln Analogue
`0:2-Adrenergic Agonists
`- Epinephrine/Dlpivefrln
`
`8o
`
`09O
`
`U)O
`
`-5o
`
`59::as
`.9.2‘C{Un.
`:S:3
`
`38
`
`23u. Follow-up, mo
`125 (7.6)
`
`Figure 3. Percentage of medication participants prescribed each class of
`medication at each follow-up visit. Percentages sum to greater than 100%
`because more than 1 class of medication may be prescribed. Combination
`drugs are counted twice.
`
`Table 3. Progress and Outcome of