Incidence of Glaucomatous Visual Field Loss Incidence of Glaucomatous Visual Field Loss Subsequent to Glaucomatous Optic Disc Subsequent to Glaucomatous Optic Disc

DeteriorationDeterioration

The Ocular Hypertension Treatment Study Group (OHTS)The Ocular Hypertension Treatment Study Group (OHTS)ARVO May 3, 2010ARVO May 3, 2010

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.

The OHTS Entry CriteriaThe OHTS Entry Criteria

• Age 40 - 80Age 40 - 80• Normal visual fieldsNormal visual fields

– Humphrey 30-2Humphrey 30-2• Normal optic discsNormal optic discs• Untreated IOP:Untreated IOP:

– 24 to 32 mmHg in qualifying eye24 to 32 mmHg in qualifying eye– 21 to 32 mmHg in fellow eye21 to 32 mmHg in fellow eye

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

ObservationObservationNo topical treatment to lower IOP

n=819

RandomizationRandomization

MonitoringMonitoringHumphrey 30-2 q6 months

Stereoscopic disc photos annually

Adjust Adjust therapy if therapy if

target not mettarget not met

OHTS set a high bar for POAG endpoints.OHTS set a high bar for POAG endpoints.

High specificity is important in a clinical trial High specificity is important in a clinical trial of treatment efficacy.of treatment efficacy.

Visual Field DefectVisual Field Defect

• Determined by masked readers Determined by masked readers Visual Field Reading Center, U-California DavisVisual Field Reading Center, U-California Davis

• Defects defined as:Defects defined as:• CPSD pCPSD p< .05 and/or < .05 and/or • GHT outside normal limits by Stat Pac 2GHT outside normal limits by Stat Pac 2• Defect in the Defect in the samesame location and on the location and on the

samesame index on 3 consecutive reliable index on 3 consecutive reliable visual fieldsvisual fields

Optic Disc DeteriorationOptic Disc Deterioration

• Determined by masked readersDetermined by masked readers• Optic Disc Reading Center, Bascom Palmer Optic Disc Reading Center, Bascom Palmer

Eye Institute, MiamiEye Institute, Miami

• Defined as: Defined as: • Generalized or localized thinning of neuroretinal Generalized or localized thinning of neuroretinal

rim compared with baseline photos rim compared with baseline photos • Detected on 2 consecutive sets of f/up photosDetected on 2 consecutive sets of f/up photos• Readers masked as to which set is baseline or Readers masked as to which set is baseline or

f/up f/up

POAG EndpointsPOAG Endpoints

• All cases of a confirmed visual field defect All cases of a confirmed visual field defect and/or optic disc deterioration referred to the and/or optic disc deterioration referred to the endpoint committee.endpoint committee.

• 3 masked clinicians reviewed clinical data and 3 masked clinicians reviewed clinical data and determined whether changes due to POAG determined whether changes due to POAG (endpoint) or some other condition.(endpoint) or some other condition.

• Optic disc deterioration had to be “clinically Optic disc deterioration had to be “clinically significant.”significant.”

What is the prognosis of patients with What is the prognosis of patients with glaucomatous optic disc deterioration?glaucomatous optic disc deterioration?

Is disc deterioration a predictor of Is disc deterioration a predictor of glaucomatous visual field loss?glaucomatous visual field loss?

Sample For Analysis In Sample For Analysis In This ReportThis Report

• Includes the first eye that developed a 1Includes the first eye that developed a 1°° POAG POAG endpoint in OHTS Phase 1 (1994-2002)endpoint in OHTS Phase 1 (1994-2002)

• Includes Includes 2° 2° POAG endpoints to the end of the study in POAG endpoints to the end of the study in the same eye (2009)the same eye (2009)

• Includes one eye selected randomly if the participant Includes one eye selected randomly if the participant

developed 1developed 1°° POAG in both eyes at the same visit. POAG in both eyes at the same visit.

• Excludes participants who developed both VF POAG Excludes participants who developed both VF POAG and optic disc POAG in the same eye at the same visit.and optic disc POAG in the same eye at the same visit.

Primary Primary 1° 1° POAG Endpoints POAG Endpoints in OHTS Phase 1in OHTS Phase 1

Participants who developed a1° POAG endpoint

in one eyeIn two eyes(one eye selected randomly for analysis)

134

10

Participants who developed VF POAG and optic disc POAG in the same eye are excluded (12)

1° POAG N of eyes/participants 144 eyes/144 pts.

11°° POAG Endpoints in Phase 1 POAG Endpoints in Phase 1

1° 1° optic disc endpointsoptic disc endpoints 58% 84 of 144 eyes58% 84 of 144 eyes1° 1° visual field endpointsvisual field endpoints 42% 60 of 144 eyes42% 60 of 144 eyes

Duration of f/up from 1° POAG to last f/up visit wasDuration of f/up from 1° POAG to last f/up visit was7.8 ± 2.9 yrs. (mean 7.8 ± 2.9 yrs. (mean ++ SD) SD)

All participants treated after All participants treated after 1° 1° POAG endpointPOAG endpoint(both treatment and observation groups)(both treatment and observation groups)

• 44% (63 of 144) 144% (63 of 144) 1° ° POAG eyes POAG eyes developed a 2developed a 2° POAG endpoint in the ° POAG endpoint in the same eye by study endsame eye by study end

84 eyes had a 1° optic disc POAG84 eyes had a 1° optic disc POAG

39% 33/84 eyes developed 2° VF 39% 33/84 eyes developed 2° VF POAG POAG Mean time 3.8 ± 2.9 yearsMean time 3.8 ± 2.9 years

6% 5/84 eyes developed confirmed 6% 5/84 eyes developed confirmed VF abnormalities not due to VF abnormalities not due to POAG POAG

60 eyes had 1° visual field POAG60 eyes had 1° visual field POAG

50%50% 30 of 60 developed 30 of 60 developed 2° optic disc POAG2° optic disc POAGMean time 2.6 ± 2.5 yearsMean time 2.6 ± 2.5 years

1.7%1.7% 1 of 60 developed confirmed 1 of 60 developed confirmed disc deterioration that was disc deterioration that was “not clinically significant”“not clinically significant”

Cumulative Proportion of Cumulative Proportion of 1° POAG Eyes 1° POAG Eyes Developing a 2°Developing a 2° POAG endpoint POAG endpointAt 96 mos. 45% (95% CI of 36% to 54%)At 96 mos. 45% (95% CI of 36% to 54%)

Months after Primary POAG endpoint

Prop

ortio

n de

velop

ing P

OAG

oth

er m

odali

ty

0.0

0.2

0.4

0.6

0.8

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cumulative Proportion of Cumulative Proportion of 1° POAG Eyes 1° POAG Eyes Developing a 2°Developing a 2° POAG Endpoint by Modality POAG Endpoint by Modality

At 96 mos. 39% (95% CI of 28% to 51%) of 1At 96 mos. 39% (95% CI of 28% to 51%) of 1o o Disc POAG eyes develop VF POAG Disc POAG eyes develop VF POAG At 96 mos. 52% (95% CI of 39% to 66%) of 1 At 96 mos. 52% (95% CI of 39% to 66%) of 1o o VF POAG eyes develop Disc POAG VF POAG eyes develop Disc POAG

Complementary log log at 96 months p=0.09Complementary log log at 96 months p=0.09

Months after Primary POAG

Pro

porti

on d

evel

opin

g P

OA

G o

ther

mod

ality

0.0

0.2

0.4

0.6

0.8

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Disc to VF VF to Disc

Cumulative Proportion of Cumulative Proportion of 1° POAG Eyes 1° POAG Eyes Developing a 2°Developing a 2° POAG Endpoint by Randomization Group POAG Endpoint by Randomization Group

At 96 mos. 46% (95% CI of 36% to 56%) for OBSAt 96 mos. 46% (95% CI of 36% to 56%) for OBSAt 96 mos. 40% (95% CI of 24% to 57%) for MEDAt 96 mos. 40% (95% CI of 24% to 57%) for MED

Complementary log log at 96 months p= 0.72Complementary log log at 96 months p= 0.72

Months after Primary POAG

Medication Observation

Prop

ortio

n de

velop

ing P

OAG

oth

er m

odali

ty

0.0

0.2

0.4

0.6

0.8

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Factors Associated with Eyes that Factors Associated with Eyes that Developed Developed 2° POAG Endpoint2° POAG Endpoint

Did 1° POAG Eye Develop 2° POAG

NoN=81

Mean ± SD

YesN=63

Mean ± SD

Univariate Logistic Regression P-value

Age 59.6±9.5 59.8±8.2 0.70

CCT (microns) 557±41 546±33 0.10

Baseline Vertical C/D 0.47±0.19 0.52±0.16 0.09

Baseline PSD dB 1.9±0.2 2.1±0.2 0.0001

Factors Associated with Eyes that Factors Associated with Eyes that Developed Developed 2° POAG Endpoint2° POAG Endpoint

Did 1° POAG Eye Develop 2° POAG

NoN=81

Mean ± SD

YesN=63

Mean ± SD

Univariate Logistic Regression P-value

Baseline IOP mmHg

26±3 26±3 0.52

F/up IOP before 1° POAG mmHg

24±4 26 ±5 0.04

F/up IOP after 1° POAG mmHg

17±3 20±4 0.0001

SummarySummary

• 39% of eyes with a 1° optic disc POAG endpoint developed reproducible glaucomatous visual field loss within a mean of 3.8 years despite treatment.

• 50% of eyes with a 1° visual field POAG endpoint developed glaucomatous optic disc deterioration within a mean of 2.6 years despite medical treatment.

• Glaucomatous optic disc deterioration has prognostic significance for glaucomatous visual field loss.

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