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

1. Does Greater Long-Term IOP Variability Increase Probability of Primary Open Angle Glaucoma in the Ocular Hypertension Treatment Study (OHTS)? • M.O. Gordon, J.A. Beiser, J. Miller, M. Kass, F. Gao • The Ocular Hypertension Treatment Study Group (OHTS) • May 3, 2011 • ARVO • Ft. Lauderdale, FL • National Eye Institute, National Center for Minority Health and Health Disparities, NIH grants EY09307, EY09341, Unrestricted Grant from Research to Prevent Blindness, Merck Research Laboratories and Pfizer, Inc.

2. Sources of Support • NIH grants • National Eye Institute • National Center for Minority Health and Health Disparities, EY09307, EY09341 • Unrestricted Grants • Research to Prevent Blindness • Merck Research Laboratories • Pfizer, Inc.

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

4. Patient found eligible for OHTS • Eligible untreated IOPs on 2 visits • 2 sets of normal & reliable HVFs per VFRC • Optic discs judged normal by ODRC Randomization Medication Topical treatment to lower IOP 20% and IOP < 24 mm Hg n=817 Observation No topical treatment to lower IOP n=819 Adjust therapy if target not met Monitoring Humphrey 30-2 q6 months Stereoscopic disc photos annually

5. Analysis Dataset • Baseline data: Age, CCT, PSD, VCD • F/up of >4 visits (< 3 unstable results) • Eye to develop POAG or random eye • Censored data after: Initiation of topical hypotensive medication Eye surgery POAG

6. IOP Variables POAG eye or random eye • Mean f/up IOP: Baseline & 6 mo. follow-up in Obs. group • Standard deviation of f/up IOP • Maximum f/up IOP • Range of f/up IOP (maximum – minimum)

7. Definition of POAG • 3 consecutive reliable, abnormal visual fields and/or 2 consecutive stereo-optic disc photographs showing progression per Reading Center • Masked Endpoint Committee (DH, EH, RP) adjudicated if change could be attributable to POAG. • Optic disc progression also had to be “clinically significant” (JND not adequate)

8. Result: Analysis Dataset • Median 16 visits • 84% (687 of 819) Observation pts. (no CCT, censored< 4 visits, < 4 visits) • 12% (84 of 687) pts developed POAG in 1 or both eyes

9. Description of F/up IOP VariablesN=687 Obs. pts. Mean + SD • Mean IOP 24.0 + 3.1 • SD IOP 2.5 + 1.0 • Max IOP 28.4 + 3.9 • Range IOP 8.5 + 3.5

10. Correlation of IOP Variables

11. Analysis Plan • Cox proportional hazards model for each measure of IOP variability • Univariate Cox proportional hazards model • Multivariable Cox proportional hazards models: Age, CCT, mean IOP, VCD, PSD + Var • C statistic for predictive accuracy • Calibration chi-square for model fit

12. Quartiles Mean IOP (baseline & f/up)Obs. Group Cox Proportional Hazards *First quartile used as the reference level. +Multi-variable model includes baseline age, CCT, PSD, VCD and mean IOP.

13. Quartiles IOP SDObs. group Cox Proportional Hazards *First quartile used as the reference level. +Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP SD.

14. Quartiles IOP MaxObs. group Cox Proportional Hazards • *First quartile was used as the reference level • +Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP Max.

15. Quartiles IOP RangeObs. group Cox Proportional Hazards • *First quartile was used as the reference level • +Multi-variable model includes baseline age, CCT, PSD, VCD , mean follow up IOP, and IOP range.

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

17. > 26.0 22% 24% 29% 36% > 23.9 to <26.0 6% 19% 6% 15% >21.9 to <23.9 2% 8% 8% 4% < 21.9 3% 4% 5% <1.9 >1.9 to <2.4 >2.4 to <3.0 > 3.0 Standard Deviation of f/up IOP Percent POAG (n=84/687) by Quartile of Mean IOP and SD IOP Interaction of mean IOP * SD IOP is not statistically significant Mean f/up IOP (mm Hg) 0%

18. Conclusions • Higher long-term IOP variability (SD) is an independent risk factor for the development of POAG in the Obs. Group in the OHTS • SD IOP does not improve predictive accuracy of model with age, mean f/up IOP, CCT, VCD and PSD • SD IOP difficult to measure, uncertain value in clinical practice

19. Bascom Palmer Eye Institute Baylor Eye Clinic Charles R. Drew University Devers Eye Institute Emory University Eye Center Eye Associates of Washington, DC Eye Consultants of Atlanta Eye Doctors of Washington Eye Physicians and Surgeons of Atlanta Glaucoma Care Center Great Lakes Ophthalmology Henry Ford Hospitals Johns Hopkins University Jules Stein Eye Institute, UCLA Kellogg Eye Center Kresge Eye Institute Krieger Eye Institute Maryland Center for Eye Care Mayo Clinic/Foundation New York Eye & Ear Infirmary Ohio State University Salus University Scheie Eye Institute University of California, Davis University of California, San Diego University of California, San Francisco University of Louisville University Suburban Health Center Washington Eye Physicians & Surgeons Washington University, St. Louis OHTS Clinical Centers

20. OHTS Resource Centers Study Chairman’s Office & Coordinating Center Washington University St. Louis, MO Optic Disc Reading Center Bascom Palmer Eye Institute University of Miami Miami, FL Visual Field Reading Center University of California, Davis Sacramento, CA

21. Thank-you! Questions?