Transcript Lessons from the Ocular Hypertension Treatment Study (OHTS)

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.
Sources of Support
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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.
Question?
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Is greater long-term IOP variability an
independent factor for the risk of
primary open angle glaucoma
(POAG) in the OHTS?
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
Observation
Topical treatment to lower IOP 20%
and IOP < 24 mm Hg
n=817
Adjust
therapy if
target not met
No topical treatment to lower IOP
n=819
Monitoring
Humphrey 30-2 q6 months
Stereoscopic disc photos annually
Analysis Dataset
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Baseline data: Age, CCT, PSD, VCD
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F/up of >4 visits (< 3 unstable results)
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Eye to develop POAG or random eye
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Censored data after:
Initiation of topical hypotensive medication
Eye surgery
POAG
IOP Variables
POAG eye or random eye
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Mean f/up IOP:
Baseline & 6 mo. follow-up in Obs. group
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Standard deviation of f/up IOP
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Maximum f/up IOP
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Range of f/up IOP
(maximum – minimum)
Definition of POAG
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3 consecutive reliable, abnormal visual fields
and/or 2 consecutive stereo-optic disc
photographs showing progression per Reading
Center
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Masked Endpoint Committee (DH, EH, RP)
adjudicated if change could be attributable to
POAG.
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Optic disc progression also had to be “clinically
significant” (JND not adequate)
Result: Analysis Dataset
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Median 16 visits
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84% (687 of 819) Observation pts.
(no CCT, censored< 4 visits, < 4 visits)
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12% (84 of 687) pts developed POAG
in 1 or both eyes
Description of F/up IOP Variables
N=687 Obs. pts.
Mean + SD
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Mean IOP
SD IOP
Max IOP
Range IOP
24.0 + 3.1
2.5 + 1.0
28.4 + 3.9
8.5 + 3.5
Correlation of IOP Variables
Mean IOP
SD IOP
Max IOP
Range IOP
Mean
IOP
-----
SD
Max
Range
0.08
0.69
0.06
-----
0.34
0.79
-----
0.34
-----
Analysis Plan
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Cox proportional hazards model for each
measure of IOP variability
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Univariate Cox proportional hazards model
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Multivariable Cox proportional hazards
models: Age, CCT, mean IOP, VCD, PSD + Var
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C statistic for predictive accuracy
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Calibration chi-square for model fit
Quartiles Mean IOP (baseline & f/up)
Obs. Group Cox Proportional Hazards
Univariate
Mean IOP Quartiles
HR
95% CI
Multivariable+
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
P-Value
C-statistic and Calibration χ2
<0.0001
4.3 -27.1
<0.0001
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 SD
Obs. group Cox Proportional Hazards
Univariate
IOP Standard Deviation
HR
95% CI
Multivariable
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
C-statistic and Calibration χ2
0.0021
0.0376
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 Max
Obs. group Cox Proportional Hazards
Univariate
HR
IOP Maximum
95% CI
Multivariable
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
C-statistic and Calibration χ2
<0.0001
0.96
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 Range
Obs. group Cox Proportional Hazards
Univariate
HR
IOP Range
95% CI
Multivariable
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
C-statistic and Calibration χ2
0.56
0.19
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.
Summary
(replicated w > 4,5,6 visits in Obs. group)
Multivariable
P-Value
<0.0001
C Statistic
0.81
Calibration
Chi-Square
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
Mean 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)
> 26.0
22%
24%
29%
36%
> 23.9 to <26.0
6%
19%
6%
15%
>21.9 to <23.9
2%
8%
8%
< 21.9
3%
<1.9
4%
>1.9 to <2.4
0%
>2.4 to <3.0
Standard Deviation of f/up IOP
5%
> 3.0
4%
Conclusions
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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
OHTS Clinical Centers
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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
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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 Resource Centers
Study Chairman’s Office
&
Coordinating Center
Washington University
St. Louis, MO
Optic Disc Reading Center
Visual Field Reading Center
Bascom Palmer Eye Institute
University of Miami
Miami, FL
University of California, Davis
Sacramento, CA
Thank-you!
QUESTIONS?