Does Greater Long-Term IOP Variability Increase Does Greater Long-Term IOP Variability Increase Probability of Primary Open Angle Glaucoma Probability of Primary Open Angle Glaucoma

in the Ocular Hypertension Treatment Study (OHTS)?in the Ocular Hypertension Treatment Study (OHTS)?

M.O. Gordon, J.A. Beiser, J. Miller, M. Kass, F. Gao M.O. Gordon, J.A. Beiser, J. Miller, M. Kass, F. Gao The Ocular Hypertension Treatment Study Group (OHTS)The Ocular Hypertension Treatment Study Group (OHTS)

May 3, 2011May 3, 2011ARVOARVO

Ft. Lauderdale, FL Ft. Lauderdale, FL

National Eye Institute, National Center for Minority Health and Health Disparities, National Eye Institute, National Center for Minority Health and Health Disparities, NIH grants EY09307, EY09341, Unrestricted Grant from Research to Prevent NIH grants EY09307, EY09341, Unrestricted Grant from Research to Prevent

Blindness, Merck Research Laboratories and Pfizer, Inc.Blindness, Merck Research Laboratories and Pfizer, Inc.

Sources of SupportSources of Support

NIH grantsNIH grants• National Eye InstituteNational Eye Institute• National Center for Minority Health and National Center for Minority Health and

Health Disparities, EY09307, EY09341Health Disparities, EY09307, EY09341

Unrestricted Grants Unrestricted Grants • Research to Prevent BlindnessResearch to Prevent Blindness• Merck Research Laboratories Merck Research Laboratories • Pfizer, Inc.Pfizer, Inc.

Question?Question?

• Is greater long-term IOP variability an Is greater long-term IOP variability an independent factor for the risk of independent factor for the risk of primary open angle glaucoma primary open angle glaucoma (POAG) in the OHTS?(POAG) in the OHTS?

Patient found eligible for OHTSPatient found eligible for OHTS• Eligible untreated IOPs on 2 visits

• 2 sets of normal & reliable HVFs per VFRC• Optic discs judged normal by ODRC

Patient found eligible for OHTSPatient found eligible for OHTS• Eligible untreated IOPs on 2 visits

• 2 sets of normal & reliable HVFs per VFRC• Optic discs judged normal by ODRC

MedicationMedicationTopical treatment to lower IOP 20%

and IOP < 24 mm Hgn=817

MedicationMedicationTopical treatment to lower IOP 20%

and IOP < 24 mm Hgn=817

ObservationObservationNo topical treatment to lower IOP

n=819

ObservationObservationNo topical treatment to lower IOP

n=819

RandomizationRandomizationRandomizationRandomization

MonitoringMonitoringHumphrey 30-2 q6 months

Stereoscopic disc photos annually

MonitoringMonitoringHumphrey 30-2 q6 months

Stereoscopic disc photos annually

Adjust Adjust therapy if therapy if

target not mettarget not met

Analysis Dataset Analysis Dataset

• Baseline data: Baseline data: Age, CCT, PSD, VCDAge, CCT, PSD, VCD

• F/up of F/up of >>4 visits (4 visits (<< 3 unstable results) 3 unstable results)

• Eye to develop POAG or random eyeEye to develop POAG or random eye

• Censored data after:Censored data after:Initiation of topical hypotensive medication Initiation of topical hypotensive medication Eye surgery Eye surgery POAG POAG

IOP Variables IOP Variables POAG eye or random eyePOAG eye or random eye

• Mean f/up IOP: Mean f/up IOP: Baseline & 6 mo. follow-up in Obs. groupBaseline & 6 mo. follow-up in Obs. group

• Standard deviation of f/up IOPStandard deviation of f/up IOP

• Maximum f/up IOPMaximum f/up IOP

• Range of f/up IOP Range of f/up IOP (maximum – minimum)(maximum – minimum)

Definition of POAGDefinition of POAG• 3 consecutive reliable, abnormal visual fields 3 consecutive reliable, abnormal visual fields

and/or 2 consecutive stereo-optic disc and/or 2 consecutive stereo-optic disc photographs showing progression per Reading photographs showing progression per Reading CenterCenter

• Masked Endpoint Committee (DH, EH, RP) Masked Endpoint Committee (DH, EH, RP) adjudicated if change could be attributable to adjudicated if change could be attributable to POAG. POAG.

• Optic disc progression also had to be “clinically Optic disc progression also had to be “clinically significant” (JND not adequate)significant” (JND not adequate)

Result: Analysis DatasetResult: Analysis Dataset

• Median 16 visitsMedian 16 visits

• 84% (687 of 819) Observation pts. 84% (687 of 819) Observation pts. (no CCT, censored< 4 visits, < 4 visits)(no CCT, censored< 4 visits, < 4 visits)

• 12% (84 of 687) pts developed POAG 12% (84 of 687) pts developed POAG in 1 or both eyesin 1 or both eyes

Description of F/up IOP VariablesDescription of F/up IOP VariablesN=687 Obs. pts.N=687 Obs. pts.

Mean Mean ++ SD SD

• Mean IOP Mean IOP 24.0 24.0 ++ 3.1 3.1• SD IOPSD IOP 2.5 2.5 ++ 1.0 1.0• Max IOPMax IOP 28.4 28.4 ++ 3.9 3.9• Range IOPRange IOP 8.5 8.5 ++ 3.5 3.5

Correlation of IOP VariablesCorrelation of IOP Variables

Mean IOP

SD Max Range

Mean IOP ----- 0.08 0.69 0.06

SD IOP ----- 0.34 0.79

Max IOP ----- 0.34

Range IOP -----

Analysis Plan Analysis Plan

• Cox proportional hazards model for each Cox proportional hazards model for each measure of IOP variabilitymeasure of IOP variability

• Univariate Cox proportional hazards modelUnivariate Cox proportional hazards model

• Multivariable Cox proportional hazards Multivariable Cox proportional hazards models: Agmodels: Age, CCT, mean IOP, VCD, PSD + Vare, CCT, mean IOP, VCD, PSD + Var

• C statistic for predictive accuracyC statistic for predictive accuracy

• Calibration chi-square for model fitCalibration chi-square for model fit

Quartiles Mean IOP (baseline & f/up)Quartiles Mean IOP (baseline & f/up)Obs. Group Cox Proportional HazardsObs. Group Cox Proportional Hazards

Univariate Multivariable+

Mean IOP Quartiles HR 95% CI HR 95% CI

Q1: [15.5, 21.8)* Mean=20.4 1.0 N/A 1.0 N/A

Q2: [21.9, 23.8) Mean=22.9 2.1 0.7 - 6.1 2.0 0.7 - 5.9

Q3: [23.9,26.0) Mean=24.8 3.6 1.4 - 9.8 3.4 1.3 - 9.2

Q4: [26.0,35.0] Mean=28.1 11.3 4.5 -28.4 10.8 4.3 -27.1

P-Value <0.0001 <0.0001

C-statistic and Calibration χ2 0.81 and 4.48

*First quartile used as the reference level.+Multi-variable model includes baseline age, CCT, PSD, VCD and mean IOP.

Quartiles IOP SDQuartiles IOP SDObs. group Cox Proportional HazardsObs. group Cox Proportional Hazards

Univariate Multivariable

IOP Standard Deviation HR 95% CI HR 95% CI

Q1: [0.67, 1.88)* Mean=1.5 1.0 N/A 1.0 N/A

Q2: [1.89, 2.36) Mean=2.1 1.5 0.8 - 3.0 2.7 1.3 - 5.5

Q3: [2.37, 2.99) Mean=2.7 1.2 0.6 - 2.5 1.6 0.8 - 3.5

Q4: [3.0, 9.25] Mean=3.9 2.8 1.5 - 5.3 2.2 1.2 - 4.3

P-Value 0.0021 0.0376

C-statistic and Calibration χ2 0.82 and 8.57

*First quartile used as the reference level.+Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP SD.

Quartiles IOP MaxQuartiles IOP MaxObs. group Cox Proportional HazardsObs. group Cox Proportional Hazards

Univariate Multivariable

IOP Maximum HR 95% CI HR 95% CI

Q1: [19.0, 25.6)* Mean=24.3 1.0 N/A 1.0 N/A

Q2: [25.7, 27.6) Mean=26.7 1.6 0.6 - 4.1 0.8 0.3 - 2.8

Q3: [27.7, 30.2) Mean=28.9 3.8 1.6 - 8.7 0.8 0.2 - 3.0

Q4: [30.3, 51.0] Mean=33.9 6.4 2.9 - 14.3 0.9 0.2 - 3.6

P-Value <0.0001 0.96

C-statistic and Calibration χ2 0.81 and 4.53

*First quartile was used as the reference level+Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP Max.

Quartiles IOP RangeQuartiles IOP RangeObs. group Cox Proportional HazardsObs. group Cox Proportional Hazards

Univariate Multivariable

IOP Range HR 95% CI HR 95% CI

Q1: [2.0, 6.2)* Mean=4.8 1.0 N/A 1.0 N/A

Q2: [6.2, 8.3) Mean=7.3 0.96 0.5 – 1.8 2.0 1.0 – 3.8

Q3: [8.3, 10.2) Mean=9.2 0.8 0.4 – 1.5 1.2 0.6 – 2.3

Q4: [10.2, 27.3] Mean=13.0 1.3 0.7 – 2.2 1.1 0.6 – 2.1

P-Value 0.56 0.19

C-statistic and Calibration χ2 0.81 and 4.74

*First quartile was used as the reference level+Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP range.

SummarySummary(replicated w (replicated w >> 4,5,6 visits in Obs. group) 4,5,6 visits in Obs. group)

MultivariableP-Value C Statistic

Calibration Chi-Square

Mean IOP <0.0001 0.81 4.48

SD IOP 0.037 0.82 8.57

Max IOP 0.960 0.81 4.53

Range IOP 0.19 0.81 4.47

Percent POAG (n=84/687) Percent POAG (n=84/687) by Quartile of Mean IOP and SD IOP by Quartile of Mean IOP and SD IOP

Interaction of mean IOP * SD IOP is not statistically significantInteraction of mean IOP * SD IOP is not statistically significant

< 21.9

>21.9 to <23.9

> 23.9 to <26.0

> 26.0

<1.9 >1.9 to <2.4 >2.4 to <3.0 > 3.0

Standard Deviation of f/up IOP

3% 4% 5%

2% 8% 8% 4%

6% 19% 6% 15%

22% 24% 29% 36%

0%

Mean f/up IOP (mm Hg)

ConclusionsConclusions

• Higher long-term IOP variability (SD) is an Higher long-term IOP variability (SD) is an independent risk factor for the development of independent risk factor for the development of POAG in the Obs. Group in the OHTSPOAG in the Obs. Group in the OHTS

• SD IOP does not improve predictive accuracy of SD IOP does not improve predictive accuracy of model with age, mean f/up IOP, CCT, VCD and model with age, mean f/up IOP, CCT, VCD and PSD PSD

• SD IOP difficult to measure, uncertain value in SD IOP difficult to measure, uncertain value in clinical practiceclinical practice

OHTS Clinical CentersOHTS Clinical Centers

Bascom Palmer Eye InstituteBascom Palmer Eye Institute Baylor Eye ClinicBaylor Eye Clinic Charles R. Drew UniversityCharles R. Drew University Devers Eye InstituteDevers Eye Institute Emory University Eye CenterEmory University Eye Center Eye Associates of Washington, Eye Associates of Washington,

DCDC Eye Consultants of AtlantaEye Consultants of Atlanta Eye Doctors of WashingtonEye Doctors of Washington Eye Physicians and Surgeons Eye Physicians and Surgeons

of Atlantaof Atlanta Glaucoma Care CenterGlaucoma Care Center Great Lakes OphthalmologyGreat Lakes Ophthalmology Henry Ford HospitalsHenry Ford Hospitals Johns Hopkins UniversityJohns Hopkins University Jules Stein Eye Institute, UCLAJules Stein Eye Institute, UCLA Kellogg Eye CenterKellogg Eye Center Kresge Eye InstituteKresge Eye Institute

Krieger Eye InstituteKrieger Eye Institute Maryland Center for Eye CareMaryland Center for Eye Care Mayo Clinic/FoundationMayo Clinic/Foundation New York Eye & Ear InfirmaryNew York Eye & Ear Infirmary Ohio State UniversityOhio State University Salus UniversitySalus University Scheie Eye InstituteScheie Eye Institute University of California, DavisUniversity of California, Davis University of California, San DiegoUniversity of California, San Diego University of California, San University of California, San

FranciscoFrancisco University of LouisvilleUniversity of Louisville University Suburban Health CenterUniversity Suburban Health Center Washington Eye Physicians & Washington Eye Physicians &

SurgeonsSurgeons Washington University, St. LouisWashington University, St. Louis

OHTS Resource CentersOHTS Resource Centers

Study Chairman’s Office Study Chairman’s Office &&

Coordinating CenterCoordinating CenterWashington UniversityWashington University

St. Louis, MOSt. Louis, MO

Visual Field Reading CenterVisual Field Reading CenterUniversity of California, DavisUniversity of California, Davis

Sacramento, CASacramento, CA

Optic Disc Reading CenterOptic Disc Reading CenterBascom Palmer Eye InstituteBascom Palmer Eye Institute

University of MiamiUniversity of MiamiMiami, FLMiami, FL

QUESTIONS?QUESTIONS?

Thank-you!Thank-you!