1
Practical Implications of the The Ocular
Hypertension Treatment Study (OHTS)
G. Richard Bennett, M.S., O.D., F.A.A.O.
Professor and Chief, The Glaucoma Service
The Eye Institute of Salus University
The Ocular Hypertension Treatment Study Group (OHTS)
National Eye Institute, National Center for Minority Health and Health
Disparities, NIH grants EY09307, EY09341, EY02687, Unrestricted Grant from
Research to Prevent Blindness, Merck Research Laboratories and Pfizer, Inc.
August 2010
National Eye Institute
Clinical Trials Across the
Ongoing trials
Spectrum of Glaucoma
Interim results
Completed trials
CIGTS
OHTS
Ocular
Hypertension
Early
Glaucoma
AGIS
GLT
EMGT
Brandt JD. Large prospective glaucoma trials: Where are we now?
Presented at: American Glaucoma Society Annual Meeting 2002.
March 2, 2002; San Juan, Puerto Rico.
Advanced
Glaucoma
FFSS
2
Ocular Hypertension
A common condition




What to do with these patients?
How often should they be examined?
Is preventative treatment effective?
Who should be treated?
August 2010
3
Ocular Hypertension
1.
2.
3.
4.
5.
IOP > 21 mmHg
No detectable visual field loss
No detectable optic disc or nerve
fiber layer damage
Open angles
No ocular or systemic cause of
increased IOP
August 2010
4
Ocular Hypertension
 119
million people in US over age 40
(Census 2000)
 4%-8%
of people in the United States
over age 40 (4.8 – 9.5 million people)
have OHT
 The
number of affected people will
increase with the aging of the population
 Managing
this large group of people is
associated with substantial costs for
examinations, tests and treatment
August 2010
5
Ocular Hypertension
 Elevated
IOP is a leading risk factor
for development of POAG
 Only
modifiable risk factor for POAG
 Patients
can lose a substantial
proportion of their nerve fiber layer
before POAG is detected by standard
clinical tests
Quigley HA, et al. Arch Ophthal
1981;99:635
August 2010
6
Does Treatment of
Ocular Hypertension Prevent POAG?
Protective
Investigator
Protective
Graham
no
Becker & Morton
yes
Norskov
no
Shin et al.
yes
Levine
no
Kitizawa
yes
David et al.
no
Epstein et al.
yes
Chisholm
no
Kass et al.
yes
Schulzer et al.
no
Heijl et al.
no
Limitations of previous studies:
Kamal et al.
no

Miglior et al.
no

Investigator

Varying endpoints
Limited treatment regimens
Small sample size
August 2010
7
Ocular Hypertension Treatment Study (OHTS)
Primary Goals

Evaluate the safety and efficacy of
topical ocular hypotensive medication in
delaying or preventing the development of
POAG in individuals with elevated IOP

Identify baseline demographic and
clinical factors that predict which
participants will develop POAG
Kass, et al. 2002
8
The OHTS Entry Criteria


Age 40 - 80
Normal visual fields
 Humphrey 30-2


Normal optic discs
Untreated IOP:
 24 to 32 mm Hg in one eye
 21 to 32 mm Hg in fellow eye
Kass, et al. 2002
9
OHTS Phase 1
Begins February 28, 1994
Eligibility Criteria
• 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
Adjust therapy if
target not met
Observation
No topical treatment to lower IOP
Monitoring
Humphrey 30-2 q6 months
Stereoscopic disc photos annually
Reproducible Abnormality
3 consecutive visual fields and/or 2 consecutive sets of optic disc photographs
as determined by masked readers at ODRC or VFRC
POAG
Visual field and/or optic disc changes attributed to
POAG by masked Endpoint Committee
Kass, et al. 2002
10
Baseline Characteristics
Baseline Characteristics
N=1,636
Age (mean ±SD)
55.4 ±9.6 SD
White
70%
African American
25%
Hispanic
4%
Other
1%
Sex
Male
43%
Female
57%
IOP, mm Hg
24.9 ±2.7 SD
Vertical CD
0.39 ±0.2 SD
CCT
572 ±38.4 SD
Kass, et al. 2002
11
OHTS Phase 1: Primary POAG Endpoints
Log rank P-value<0.001, hazard ratio 0.40, 95% confidence interval (0.27, 0.59)
Cumulative proportion POAG at 60 months, 9.5% in OBS and 4.4% in MEDS
Proportion of participants developing POAG
0.4
Medication
Observation
0.3
0.2
0.1
0.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Months
Kass, et al. 2002
12
OHTS Phase 1: First Optic Disc POAG Endpoint
Log rank P-value<.0001, hazard ratio 0.36, 95% confidence interval (0.23, 0.56)
Cumulative proportion POAG at 60 months, 7.7% in OBS and 3.2% in MEDS
Proportion of participants developing POAG
0.4
Medication
Observation
0.3
0.2
0.1
0.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Months
Kass, et al. 2002
13
OHTS Phase 1: First Visual Field POAG Endpoint
Log rank P-value=0.002, hazard ratio 0.45, 95% confidence interval (0.26, 0.76)
Cumulative proportion POAG at 60 months, 5.2% in OBS and 2.1% in MEDS
Proportion of participants developing POAG
0.4
Medication
Observation
0.3
0.2
0.1
0.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Months
Kass, et al. 2002
15
OHTS Phase 1: Cumulative Proportion
Developing POAG by Race
African Americans
Others
 12.7% POAG
endpoints in
observation group
 10.2% POAG
endpoints in
observation group
 6.9% POAG endpoints
in medication group
 3.6% POAG endpoints
in medication group
 Hazard Ratio 0.54
 Hazard Ratio 0.34
 P value 0.26
Kass, et al. 2002
17
OHTS Phase 1: Summary
 Medication produced about a 20% reduction
in IOP.
 Medication reduced incidence of POAG in OHT
participants by more than 50% at 5 years from
9.5% in the Observation Group to 4.4% in the
Medication Group.
 Little evidence of safety concerns.
Kass, et. al. 2002
18
OHTS Phase 2: Rationale
 OHTS Phase 1 provides proof of concept:
medication reduces the incidence of POAG.
 OHTS Phase 1 does not indicate when
medication should begin.
 OHTS Phase 1 does not indicate if all OHT
patients should receive early medication.
 Is there a penalty for delaying medication in
OHT?
August 2010
19
OHTS Phase 2
Begins 06/01/2002
Medication Group
Observation Group
N = 694
N = 672
Medication is continued
in the Medication group
Medication is Initiated
in the Observation group
August 2010
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OHTS Phase 2: Methods
 After 7.5 years of observation, participants originally
randomized to observation group start medication.
 This creates:
Delayed treatment group
Observation group followed for 7.5 years then treated for 5.5 years
Early treatment group
Medication group treated for median of 13 years from the beginning
 Compare incidence of POAG at 13.0 years
Kass, et al. 2010
21
Median IOP thru 13 Yrs by Randomization Group
Medication
30
Observation
28
mm Hg
26
24
22
20
18
16
14
0
12
24
36
48
60
72
84
96
108 120 132 144 156
Months
Kass, et al. 2010
22
Kass, et al. 2010
OHTS: Cumulative Incidence of POAG by Randomization Group
24
Complementary log log at 13 years, p=0.009
Cumulative proportion POAG at 13 years, 22% in OBS and 16% in MEDS
Proportion of participants developing POAG
0.4
Medication
Observation
0.3
0.2
0.1
0.0
6
18
30
42
54
66
78
90 102 114 126 138 150 162
Months
Kass, et al. 2010
25
Median Time to Develop POAG
Observation Group
6.0 years
Medication Group
8.7 years
P ≤ .001
Kass, et al. 2010
26
OHTS Phase 1
Incidence of POAG is nearly 60% lower in
the Medication Group
Hazard ratio for medication group at 60 months
0.40 (0.27-0.59); P ≤ .001
Kass, et al. 2002
OHTS Phase 2
Incidence of POAG is not different between
observation and medication groups
Hazard Ratio for medication group
1.06 (0.74-1.50); P = .77
Kass, et al. 2010
29
Cumulative Proportion Developing
POAG at 13 Yrs. by Race
African Americans 0.28
(0.23-0.33)
Others
(0.14-0.19)
0.16
P = .001
Kass, et al. 2010
OHTS: Cumulative Proportion POAG at 13 yrs by Race
30
Other Races: 19.5% OBS and 13% MEDS
African Americans: 29% OBS and 26% MEDS
Other race/Med
Other race/Obs.
African American/ Med
African American/Obs
Proportion of participants developing POAG
0.4
0.3
0.2
0.1
0.0
6
18
30
42
54
66
78
90
102 114 126 138 150 162
Months
Kass, et al. 2010
31
 Self-identified race not significant predictor
of POAG in a multivariate model.
 Race not significant when central corneal
thickness and baseline cup-disc ratio
included.
Kass, et al. 2010
32
Baseline Predictive Factors for
the Development of POAG
 Age
IOP
 CCT
 Vertical C/D Ratio
 PSD

OHTS/EGPS,2007
Multivariate Hazard Ratios for Predictors of POAG
33
OHTS Observation group, EGPS Placebo group, DIGS and OHTS/EGPS
Age Decade
OHTS
EGPS
DIGS
OHTS-EGPS
IOP (mm Hg)
OHTS
EGPS
DIGS
OHTS-EGPS
CCT (40 µm decrease)
OHTS
EGPS
DIGS
OHTS-EGPS
PSD (per 0.2 dB increase)
OHTS
EGPS
DIGS
OHTS-EGPS
Vertical CD ratio
OHTS
EGPS
DIGS
OHTS-EGPS
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
OHTS/EGPS 2007
34
Accuracy of Prediction Models for POAG
compared to Framingham Heart Study*
Prediction Models
C-statistic
Framingham Heart Study
prediction model applied to different studies
0.63 - 0.83
D’Agostino et. al. JAMA, 2001.
OHTS observation group
0.76
OHTS/EGPS Ophthal, 2007.
EGPS placebo group
0.73
OHTS/EGPS Ophthal, 2007.
Pooled OHTS EGPS sample
0.74
OHTS/EGPS Ophthal, 2007.
August 2010
35
Using the OHTS/EGPS Prediction
Model for the Development of POAG


Available on web free of charge
http://ohts.wustl.edu/risk
OHTS/EGPS, 2007
36
August 2010
37
Baseline Risk of Developing POAG by Race
At each level of risk. the percent of African Americans and “Other” participants developing POAG is similar.
Percent of Participants Developing POAG to study end on top of bars
Others
African American
Percent of participant by race
40
35
30
25
20
15
10
5
0
<5%
>5% - 10% >10% - 15% >15% - 20% >20% - 25%
Baseline Predicted 5 year Risk
>25%
Kass, et al. 2010
38
Cumulative Incidence of POAG in the “Lowest”, “Middle” and
“Highest” Tertiles of Baseline Risk for Developing POAG*
Lowest <6%
Medication
Observation
Observation
Medication
0.5
0.4
0.3
0.2
0.1
0.4
0.3
0.2
0.1
0.0
0.0
6
18
30
42
54
66
78
90 102 114 126 138 150 162
Months
Observation
0.5
Proportion of participants developing POAG
Proportion of participants developing POAG
0.5
Proportion of participants developing POAG
(n=484)
(n=482)
(n=482)
Medication
Highest >13%
Middle 6% - 13%
6
18
30
42
54
66
78
90 102 114 126 138 150 162
Months
0.4
0.3
0.2
0.1
0.0
6
18
30
42
54
66
78
90 102 114 126 138 150 162
Months
* Risk estimated by OHTS/EGPS risk calculator, 2007
Kass, et al. 2010
39
Cumulative 13 year Incidence of POAG for
“Lowest”, “Middle” and “Highest” Baseline Risk Group*
Medication group
Observation group
P-Value
Lowest Risk
< 6%
(n=482)
Middle Risk
6% - 13%
(n=482)
Highest Risk
13%
(n=484)
7%
14%
28%
4% - 11%
9% - 18%
22% - 34%
8%
19%
40%
4% - 11%
14% - 25%
33% - 46%
0.81
0.11
0.009
* OHTS/EGPS Risk Calculator, 2007
Kass, et al. 2010
40
Mean PSD Before and After POAG
Patients who developed POAG had worse PSD at entry and worsened over time
 Patients who did not develop POAG did not change
4.75
Non-POAG OBS, n=494
Non-POAG MEDS, n=558
4.50
POAG OBS, n=164
POAG MEDS, n=117
4.25
4.00
Time of POAG diagnosis is time “0”
Time before POAG is “-”
Time after POAG is “+”
3.50
PSD
Median time to POAG of 7 years
is “0” for participants who do not
develop POAG.
3.75
3.25
3.00
2.75
2.50
2.25
2.00
1.75
-7 -6 -5 -4 -3 -2 -1 0
1
2
3
Median Follow-Up or Years since POAG
4
5
6
7
Kass, et al. 2010
42
Safety
No safety differences between
randomization groups
 Mortality
 Adverse events
 Glaucoma Symptom Scale
 NEI VFQ
 MOS-SF 36
Kass, et. al. 2010
43
Delaying Treatment of OHT
1.
Increased cumulative incidence of POAG
at 13 years (22% vs.16%)
2.
More eyes with structural and functional
damage (8% vs. 5%)
3.
More participants with bilateral disease
(6% vs. 4%)
Kass, et. al. 2010
44
Delaying Treatment of OHT …
4.
Shorter time to develop POAG
(6.0 vs. 8.7 years)
5.
Waiting does not have a large effect on
MD and PSD (0.5db for PSD) within 5
years of developing POAG.
Kass, et. al. 2010
DRANCE HEMORRHAGES

Optic Disc Hemorrhages
– observed in glaucoma
– perhaps noticed particularly in NTG
– linked to progression of disease not
adequately controlled
– An endpoint of glaucoma
progression??
Drance
Hemorrhages

Glaucomatous Optic Disc
Hemorrhages
– characteristically in the axon bundles
– therefore, splinter-shaped and
superficial
» crossing the disc boundary, or
» over a peripapillary crescent or halo
– or within the disc, not flame-shaped
Drance Hemorrhage?
OHTS DATA

Data from the Ocular
Hypertension Treatment Study
(OHTS) used to see:
– what makes disc hemorrhage
likely?
– how predictive are they of the
future course (incident glaucoma)
in OHT?
Definition of
“Glaucomatous” ODH
 Flame- or splintershaped hemorrhage
– radially oriented and
– perpendicular to
disc margin
Definition of
“Glaucomatous” ODH
Flame- or splintershaped hemorrhage
 Not associated with
disease other than
glaucoma

– Vascular occlusive disease
– Diabetic retinopathy
– Ischemic optic neuropathy
Results: Cumulative Incidence
of Disc Hemorrhage prior to
POAG
0.15
0.10
0.05
0.00
0
12
24
36
48
60
72
84
96
Months Since Randomization
Cumulative Incidence of Disc
Hemorrhage prior to POAG endpoint

12 months between disc photos

Disc hemorrhages may come and
disappear between photographs

Therefore previous graph almost
certainly underestimates the true
incidence of ODH
Comments
To our surprise Tx IOP lowering
medicine did not reduce risk of ODH.
 Q: What does this mean?
 A: We don’t know

– ODH marks inadequate IOP lowering
– ODH marks pathogenic mechanism
» mechanism is still there
» but it no longer causes harm
– ODH had lower incidence than POAG and
analysis has insufficient power
ODH prediction of POAG
in multivariate analysis
Hazard ratio 3.7 [2.1 – 6.6]
After adjusted for:
– Treatment Group
– Age
– Vertical cup/disc ratio
– Pattern standard deviation (visual
field)
– Baseline IOP
– Central corneal thickness
Summary: Why do you get Drance
Hemorrhages?


OHTS participants who developed ODHs
– Similar to those who develop POAG
– including older age, thinner corneas, and
larger vertical C/D, higher PSD
EXCEPT THAT.. ODH not less frequent with
– lower baseline IOP
– assignment to treatment
Summary: What if you get ODH?
ODH is an additional independent risk
factor for developing POAG
 But ODH is not synonymous with
developing POAG
– 87% of OHT participants with ODH did
NOT develop POAG endpoint during
follow-up period
– 153 eyes of 168 who developed POAG
did so without prior ODH

Conclusions
ODH are difficult to find,
 but a diligent search is worthwhile,
because they represent one of the risk
factors to be taken into account when
making clinical decisions.

45
How to Incorporate
Information From OHTS Into
Clinical Practice?
August 2010
46
 Most OHT patients are at low risk.
Most low risk OHT patients can be
followed without medication.
 Delaying treatment for 7.5 years
resulted in only a small absolute
increase in POAG in low risk
participants.
 Starting treatment of POAG at
diagnosis has no major negative
effect on prognosis over 5 years.
August 2010
47
 High risk OHT patients may benefit
from more frequent examinations
and early treatment taking into
consideration:
 Patient age
 Health status
 Life expectancy
 Personal preference
August 2010
48
 Some clinicians may elect to follow
all OHT patients without treatment.
•
Requires timely visits,
appropriate tests and
interpretation.
•
Risk status changes over time.
•
Patient education is key
August 2010
49
Limitations of OHTS
1.
Study IOP goal was 20% reduction. May
not be sufficient.
2.
No measure of medication adherence.
3.
Convenience sample, not populationbased epidemiologic study.
4.
Participants healthy and “squeaky clean”
at baseline.
5.
High threshold for diagnosing POAG.
August 2010
50
OHTS Summary
1. Early medical treatment reduces the
cumulative incidence of POAG.
2. The absolute effect is greatest in high
risk individuals.
3. There is little absolute benefit of early
treatment in low risk individuals.
August 2010
51
OHTS Summary
4. There are safe and effective treatment
options for most ocular hypertensive
patients.
5. The risk of developing POAG continues
over at least a 15 year follow-up.
August 2010
52
OHTS Summary
6. African Americans develop POAG at a
higher rate despite similar treatment
and similar levels of IOP. Higher
incidence is related to baseline risk
factors.
7. Individualized assessment of risk is
useful to patients and clinicians.
August 2010
53
Key References

Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JK, Miller JP, Parrish, RK, Wilson MR,
Gordon MO for the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment
Study: A Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or
Prevents the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol 2002; 120:701-713.
PMID:12049574

Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JK, Miller JP,
Parrish RK, Wilson MR, Kass MA for the Ocular Hypertension Treatment Study Group. The Ocular
Hypertension Treatment Study: Baseline Factors That Predict The Onset of Primary Open-Angle
Glaucoma. Arch Ophthalmol 2002; 120:714-720. PMID:12049575

The Ocular Hypertension Treatment Study (OHTS) Group and the European Glaucoma Prevention
Study (EGPS) Group. A validated Prediction Model for the Development of Primary Open-Angle
Glaucoma in Individuals with Ocular Hypertension. Ophthalmology 2007; 114(1):10-19.
PMCID:1995665

Kass MA, Gordon MO, Gao F, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JK, Miller JP,
Parrish RK, Wilson MR, and the Ocular Hypertension Treatment Study (OHTS) Group. Delaying
Treatment of Ocular Hypertension. Archives of Ophthalmology 2010; 128(3):276-287.
PMID:20212196
August 2010
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OHTS Clinical Centers
















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
August 2010
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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
August 2010
OHTS
1,636 participants
880 individuals certified for OHTS:
– Clinicians
– Coordinators
– Perimetrists
– Photographers
– Technicians
August 2010