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View PowerPoint Presentation - Vision Research Coordinating Center

The Ocular HypertensionTreatment Study (OHTS)Supported by the National Eye Institute,National Center on Minority Health and HealthDisparities, Research to Prevent Blindness, andMerck Research Laboratories


Ocular Hypertension Elevated IOP in the absence of clinicallydetectable optic nerve or visual fieldchanges A common finding What to do?–Treat all?–Treat no one?–Treat some? Then who?June, 2002


Why did we do this study?Don’t we know that treatmentprevents open angle glaucoma?June, 2002


Does Treatment ofOcular Hypertension prevent POAG?InvestigatorProtectiveInvestigatorProtectiveGrahamnoBecker & MortonyesNorskovnoShin et al.yesLevenenoKitazawayesDavid et al.noEpstein et al.yesChisholmnoKass et al.yesSchulzer et al.noHeijl et al.Kamal et al.nonoLimitations of previous studies:Varying endpointsLimited treatment regimensSmall sample sizeJune, 2002


Ocular Hypertension Treatment Study (OHTS)Primary GoalsJune, 2002 Evaluate the safety and efficacy oftopical ocular hypotensive medicationin delaying or preventing thedevelopment of POAG in individualswith elevated IOP Identify baseline demographic andclinical factors that predict whichparticipants will develop POAG


The OHTS Entry Criteria Age 40 - 80Normal visual fields– Humphrey 30-2Normal optic discsUntreated IOP:– 24 to 32 mmHg in qualifying eye– 21 to 32 mmHg in fellow eyeJune, 2002


Patient found eligible for OHTS• Eligible untreated IOPs on 2 visits• 2 sets of normal & reliable HVFs per VFRC• Optic discs judged normal by ODRCRandomizationMedicationTopical treatment to lower IOP 20%and IOP < 24 mm HgAdjust therapy iftarget not metObservationNo topical treatment to lower IOPMonitoringHumphrey 30-2 q6 monthsStereoscopic disc photos annuallyReproducible Abnormality3 consecutive visual fields and/or 2 consecutive sets of optic disc photographsas determined by masked readers at ODRC or VFRCJune, 2002POAGVisual field and/or optic disc changes attributed toPOAG by masked Endpoint Committee


Baseline Characteristics by Randomization GroupGender & AgeMedicationn=817Observationn=819Male 43.9% 42.2%Female 56.1% 57.8%Ages40 to 50 35.6% 35.0%> 50 to 60 33.0% 31.6%> 60 to 70 24.7% 25.6%> 70 to 80 6.6% 7.7%June, 2002


Baseline Characteristics by Randomization GroupSelf-designated RaceMedicationn=817Observationn=819Native American 0.1% 0.4%Asian 0.5% 1.2%African American 25.0% 25.0%Hispanic 2.9% 4.3%Caucasian 70.6% 68.4%Other 1.0% 0.7%June, 2002


Baseline Characteristics by Randomization GroupOphthalmic MeasurementsMedicationn=817(mean ± S.D.)Observationn=819(mean ± S.D.)IOP (mm Hg) 24.9 ± 2.6 24.9 ± 2.7Cup:Disc Ratio (Horizontal) 0.36 ± 0.19 0.36 ± 0.18Cup:Disc Ratio (Vertical) 0.39 ± 0.20 0.39 ± 0.19Central Corneal Thickness(microns)*Refraction (sphericalequivalent in Diopters)570.5 ± 38.9 574.5 ± 37.7-0.67 ± 2.31 -0.60 ± 2.35June, 2002* Overall n=1398 for central corneal thickness, n=699 (86%) perrandomization group. Measurements were conducted after 1999,about 2 years after the last participant was randomized.


Baseline Characteristics by Randomization GroupVisual Field IndicesMedicationn=817(mean ± S.D.)Observationn=819(mean ± S.D.)Mean Deviation (dB) +0.27 ± 1.07 +0.21 ± 1.03Pattern Standard Deviation(dB)Corrected Pattern StandardDeviation (dB)1.92 ± 0.21 1.90 ± 0.211.12 ± 0.34 1.12 ± 0.36June, 2002


Baseline Characteristics by Randomization GroupPossible Risk FactorsMedicationn=817Observationn=819Prior use of Ocular Hypotensive Medication 35.0% 39.3%First Degree Family History of Glaucoma 34.0% 35.6%Myopia > 1 diopter Spherical Equivalent 34.4% 33.7%Oral Beta Adrenergic Antagonist 5.4% 4.6%Oral Calcium Channel Blocker 12.8% 14.0%June, 2002


Baseline Characteristics by Randomization GroupMedical HistoryMedicationn=817Observationn=819Migraine 10.4% 11.7%Diabetes 11.5% 12.1%Hypertension 37.5% 38.1%Low Blood Pressure 4.8% 4.0%Cardiovascular Disease 5.8% 6.5%Stroke 0.9% 1.6%June, 2002


IOP (mm Hg)Box Plot of IOP by Randomization GroupMedian IOP is joined by a line. Box: 25% and 75% Whiskers: 10% and 90%3432MedicationObservation3028262422201816June, 2002140 6 12 18 24 30 36 42 48 54 60 66 72Months


IOP By RaceMedicationObservationAfricanAmericanOtherAfricanAmericanOthern=203n=614n=205n=614IOP at baseline 25.1 ± 2.9 24.9 ± 2.6 25.1 ± 2.8 24.9 ± 2.7IOP averaged overscheduled followupvisitsPercent reductionfrom baseline19.3 ± 2.3 19.3 ± 2.1 23.9 ± 3.2 23.9 ± 2.8-22.9 ± 10% -22.4 ± 10% -4.7 ± 13% -3.8 ± 11%June, 2002


Percent of Medication Patients on Different MedicationsPatients may be on more than one medicationEpinephrine/Dipivefrin100.00%90.00%80.00%Parasympathetic agentAlpha-2 adrenergic agonistTopical CAIProstaglandin AnalogBeta-adrenergic antagonist70.00%60.00%50.00%40.00%30.00%20.00%10.00%June, 20020.00%0122436Months48607284


Progress and Outcome of Study ParticipantsMedication Observation Alln % n % n %Randomized 817 100 819 100 1636 100Died 26 3.2 29 3.5 55 3.4Inactive 89 10.9 84 10.2 173 10.6Non-adherence torandomizationReproducible VF or Optic Discabnormality due to any cause40 4.9 42 5.1 82 5.081 9.9 137 16.7 218 13.3Endpoints attributed to POAG 36 4.4 89 10.9 125 7.6Log rank p


Proportion POAGPrimary POAG Endpoints*Log Rank P-value


Proportion POAG1 st Visual Field POAG Endpoint*Log Rank P-value=0.002, Hazard Ratio=0.45, 95% CI (0.26, 0.76)0.15MedicationObservation0.100.05June, 20020.006 12 18 24 30 36 42 48 54 60 66 72 78 84Months*through 8 Nov 2001


Proportion POAG1 st Optic Disc POAG Endpoint*Log Rank P-value


First POAG Endpoint per ParticipantMedicationObservationN % N %Visual Field 15 41.7 29 32.6Optic Disc 18 50.0 51 57.3Concurrent VisualField and Optic Disc3 8.3 9 10.1Total 36 100 89 100June, 2002


All cause reproducible abnormalitiesin visual fields and/or optic discswere significantly reduced inmedication group.Hazard ratio 0.58, 95% CI (0.44-0.76)P=0.00008June, 2002


Treatment perhaps less protectivein African AmericansAfrican Americans 12.7% POAGendpoints inobservation group 6.9% POAGendpoints inmedication group Hazard Ratio 0.54Others 10.2% POAGendpoints inobservation group 3.6% POAGendpoints inmedication group Hazard Ratio 0.34June, 2002 P value forinteraction 0.26


No Significant Safety DifferenceBetween Randomization Groups Mortality Hospitalizations New Medical Conditions Worsening of Pre-existingConditions SF – 36/any subscale Patient Reported Ocularand Systemic SymptomsJune, 2002


Percent Reporting Changes inIris, Lids or LashesProstaglandin analog > 6 monthsn = 380Observation groupn = 63117%8%P


No difference betweenrandomization groups in seriousAEs for 9 of 11 organ systems.June, 2002


Borderline Safety DifferencesBetween Randomization Groups Cataract surgery Serious psychiatric adverse events Serious genitourinary adverse eventsJune, 2002


Summary Treatment produced about a 20% reductionin IOP. Treatment reduced incidence of POAG in OHTparticipants by more than 50% at 5 years from9.5% in the Observation Group to 4.4 % in theMedication Group. Little evidence of safety concerns.June, 2002


Significant Baseline Predictive Factorsfrom Univariate Proportional Hazards ModelsAge DecadeHazard Ratio (95% CI)1.43 (1.19, 1.71)African American origin1.59 (1.09, 2.32)Male gender1.87 (1.31, 2.67)Diabetes Mellitus0.40 (0.18, 0.92)Heart Disease2.11 (1.23, 3.62)IOP per mm Hg1.11 (1.04, 1.18)CCT per 40 microns decrease1.88 (1.55, 2.29)PSD per 0.2 dB increaseHorizontal C/D Ratio per 0.1 increase1.36 (1.16, 1.60)1.25 (1.14, 1.38)June, 2002Vertical C/D Ratioper 0.1 increase0 1 2 3 4 51.32 (1.19, 1.46)


Non Significant Baseline Predictive Factorsfrom Univariate Proportional Hazards ModelsFamily History GlaucomaHazard Ratio (95% CI)1.10 (0.7, 1.59)Oral Beta Adrenergic AntagonistsOral Calcium Channel Blocker0.70 (0.26, 1.89)1.35 (0.83, 2.19)Migraine1.01 (0.58, 1.76)High Blood Pressure1.31 (0.92, 1.87)Low Blood Pressure1.49 (0.73. 3.05)Stroke1.42 (0.35, 5.75)CPSD per 0.3 dB1.16 (0.99, 1.35)Mean Deviation0.86 (0.73, 1.02)June, 2002Myopia0 1 2 3 4 5(0.91 (0.62, 1.32)


Significant Baseline Predictive Factorsfrom Multivariate Proportional Hazard ModelsAge (decade)Diabetes MellitusIOP (per mmHg)CCT (per 40 µM decrease)Hazard Ratio (95% CI)1.22 (1.01, 1.49)0.37 (0.15, 0.90)1.10 (1.04, 1.17)1.71 (1.40, 2.09)PSD (per 0.2 dB increase)1.27 (1.06, 1.52)Horizontal C/D Ratio (per 0.1increase)Vertical C/D Ratio (per 0.1increase)1.27 (1.14, 1.40)1.32 (1.19, 1.47)June, 20020.0 1.0 2.0 3.0 4.0 5.0


African Americans have a higherprevalence and incidence of POAG. OHTS data suggests that this racialeffect may be due to thinner centralcorneas and larger cup/disc ratios.June, 2002


POAG Endpoints by Central Corneal Thicknessand Baseline IOP (mmHg) in Observation Group*Baseline IOP (mmHg)>25.75>23.75 to < 25.7536% 13% 6%< 23.7512% 10% 7%17% 9% 2%< 555 >555 to < 588 >588Central Corneal Thickness (microns)June, 2002* through 8 Nov 2001


POAG Endpoints by Central Corneal Thicknessand Baseline Vertical C/D Ratio in Observation Group*Vertical C/D Ratio>0.5022% 16% 8%>0.30 to 555 to < 588 >588Central Corneal Thickness (microns)June, 2002* through 8 Nov 2001


60-year-old WF IOP 24 / 24 C/D ratio 0.1 vertical Corneal thickness 600 μ Risk of POAG ~ 1% / 5 yearsJune, 2002


60-year-old WF IOP 24 / 24 C/D ratio 0.3 Corneal thickness 540 μ Risk of POAG ~ 7% / 5 yearsJune, 2002


60-year-old WF IOP 28 / 28 C/D ratio 0.1 Corneal thickness 600 μ Risk of POAG ~ 2% / 5 yearsJune, 2002


60-year-old WF IOP 24 / 24 C/D ratio 0.5 Corneal thickness 490 μ Risk of POAG ~ 20% / 5 yearsJune, 2002


72-year-old BM IOP 25 / 25 C/D ratio 0.6 Corneal thickness 510 μ Risk of POAG ~ 35% / 5 yearsJune, 2002


StrengthsJune, 20021. Large sample size2. Careful follow-up3. Masked assessment of endpoints4. Attribution of endpoints to cause by maskedcommittee5. Inclusion of all commercially available drugs6. Careful quality control and feedback totechnicians and photographers7. True-incidence cases


Weaknesses1. Convenience sample rather than populationbased2. Relatively small number of POAG endpoints3. Healthy volunteers4. Limited IOP range5. Limited to patients with reliable visual fields6. “Squeaky clean” participants at baseline7. High thresholds for endpointsJune, 20028. Some risk factors under-represented


Summary Not every patient with OHT should be treated Offer treatment to OHT patient at moderate tohigh risk taking into consideration: Age Medical status Life expectancy Likely treatment benefit Consider measuring corneal thickness in allpatients with OHT or glaucoma.June, 2002


Possible Misinterpretations of OHTS1. Treat all patients with elevated IOP.2. Risk of POAG is low in this population.3. Glaucoma medications are harmless.4. Risk factors for developing POAG are clearlydelineated; influence of race, gender,hypertension, heart disease, family history, bloodpressure, and diabetes are all clear.5. 20% lowering of IOP is the correct target for OHT.6. Drug X is proven to prevent glaucoma in OHT.June, 2002


OHTS Resource CentersStudy Chairman’s Office&Coordinating CenterWashington UniversitySt. Louis, MOOptic Disc Reading CenterBascom Palmer Eye InstituteUniversity of MiamiMiami, FLVisual Field Reading CenterUniversity of California, DavisSacramento, CAJune, 2002


OHTS Clinical CentersBascom Palmer Eye InstituteEye Consultants of AtlantaEye Physicians and SurgeonsCullen Eye InstituteDevers Eye InstituteEmory Eye InstituteHenry Ford HospitalsJohns Hopkins UniversityKrieger Eye InstituteHoward UniversityUniversity of MarylandUniversity of California, LosAngelesCharles Drew UniversityKellogg Eye CenterKresge Eye InstituteJune, 2002Great Lakes Eye InstituteUniversity of LouisvilleMayo ClinicNew York Eye & Ear InfirmaryOhio State UniversityOphthalmic Surgeons & ConsultantsPennsylvania College of OptometryMCP/Hahnemann UniversityScheie Eye InstituteUniversity of California, DavisUniversity of California, San DiegoUniversity of California, SanFranciscoUniversity Suburban Health CenterUniversity of OphthalmicConsultantsWashington Eye Physicians &SurgeonsEye Associates of Washington, DCWashington University, St. Louis

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