Important trials in Glaucoma

IMPORTANT TRIALS IN GLAUCOMA
Presenter-Dr Ravneet
Moderator- Dr Hetal Shah
Dr Rita Dhamankar
Dr Vijay Shetty

Landmark studies in glaucoma
 Ocular Hypertension Treatment study (OHTS)
 Collaborative Initial Glaucoma treatment Study (CIGTS)
 Advanced Glaucoma Intervention Study (AGIS)
 Early Manifest Glaucoma trial (EMGT)
 Collaborative Normal Tension Glaucoma (CNTGS)
 Tube versus Trabeculectomy study (TVT)
 European Glaucoma prevention study(EGPS)
 Low Tension Glaucoma prevention Study(LoGTS)

Ocular Hypertension Treatment
study (OHTS)
3
Arch Ophthalmol 120: 701-713, 2002.

Ocular Hypertension Treatment study (OHTS)
Objective:
 To evaluate the safety and efficacy of topical ocular
hypotensive medications in preventing or delaying onset
of visual field loss and or optic nerve damage in subjects
with ocular hypertension.
 Identify baseline demographic and clinical factors that
predict which participants will develop POAG
4

Participants:
 1637 patients with ocular hypertension recruited
between 1994 and 1996
Study design:
 Multicentre randomized controlled clinical trial
comparing observation with medical therapy for
ocular hypertension.
5

Methods:
 1637 participants
 no evidence of glaucomatous damage,
 40 to 80 years
 IOP 24 mmHg - 32 mmHg in one eye
21mmHg and 32 mmHg in other eye
 The goal in the medication group was to reduce the IOP
by 20% or more and to reach an IOP of 24 mmHg or less.

OHTS Phase 1
Begins February 28, 1994
Eligibility Criteria
Medication
Topical treatment to lower IOP 20%
and IOP < 24 mm Hg
Observation
No topical treatment to lower IOP
Randomization
Reproducible Abnormality
3 consecutive visual fields and/or 2 consecutive sets of optic disc photographs
Monitoring
Humphrey 30-2 q6 months
Stereoscopic disc photos annually
POAG
Visual field and/or optic disc changes attributed to
POAG
Adjust therapy if
target not met

Results :
At 5 years followup
 Incidence of POAG
9.5% in controls
4.4% in treatment group
 22.5% decrease in IOP in the treatment group
8

OHTS Summary of results
CCT < 555 & IOP > 25 CCT < 555 & CD > 0.5
Risk 36% Risk 22%
CCT > 588 &IOP > 25 CCT > 588 & CD >0.5
Risk 6% Risk 8%

Increased risk of the onset of POAG was associated
with:
 Increased age
 Vertical and horizontal cup disc ratio
 Pattern standard deviation
 IOP at baseline
 Central corneal thickness (CCT) was found to be a
powerful predictor for the development of POAG.

 The corneas in OHTS subjects were thicker
 lower corneal thickness in black subjects than
whites.
 The effect of CCT may influence the accuracy of
applanation tonometry in the diagnosis, screening
and management of patients with glaucoma and
ocular hypertension.
1
2

Clinical useful points from OHTS
 OHT – What to do
* Treat all
* Treat no one
* Treat some
-- Is treatment effective
DOES OHTS HAVE ANSWERS FOR THIS

Clinical useful points from OHTS
 Treat only patients at high risk.
 Risk factors – risk calculator
www.discoveriesinsight.org
 Importance of CCT
 ONH & VF monitoring at every FU
 Study – Rx effective , of the 9.6% that
converted half could be prevented by Rx
 OHTS - ? Conversion after longer FU
Age Vertical
C/D
IOP DM+
CCT PSD
If not high risk waiting to treat OHT till
conversion- better strategy ( vision related
QOL)

OHTS PHASE2
March
OHTS Phase 2
Medication Group
N = 694
Medication is continued
in the Medication group
OHTS Phase 2
N = 672
Medication is Initiated
in the Observation group

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.

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

OHTS PHASE 2 RESULTS
 Median Time to develop POAG:
Observation group-6 yrs
Medication group-8.7 yrs
 Increased cumulative incidence of POAG at 13 yrs
(22% vs 16%)
 More eyes with structural and functional damage(8%
vs 5%)
 More participants with bilateral disease (6% vs 4%)

 The primary purpose of the follow up study was to
determine whether delaying treatment resulted in
persistently increased risk of conversion to
glaucoma, even after the initiation of therapy.
2
0

Implications:
 Ocular hypertensives can be seperated into
categories of high,medium & low risk.
 People with high risk factors may benefit from
close followup and early treatment
 Low risk patients can have less frequent followup
and may not need early treatment.
2
1

Ocular Hypertension Treatment study (OHTS
 Subjects with corneal thickness of 555μm or less had
three times the risk of developing primary open-angle
glaucoma compared with those who had corneal
thickness of 588μm or more.
 Therefore, measure central corneal thickness of all
new glaucoma suspects.

Early Manifest Glaucoma trial
(EMGT)
2
4

Early Manifest Glaucoma trial (EMGT)
Purpose:
 To compare the effect of immediate therapy to lower
the intraocular pressure versus late or no treatment
on the progression of newly detected open-angle
glaucoma,as measured by increasing visual field loss
and or optic disc changes
2
5

Participants:
 Newly diagnosed POAG patients (255)
 50 to 80 years of age
 255 patients were randomized between 1993
and 1997.
2
6

Early Manifest Glaucoma trial
(EMGT)
Study design:
 Multicenter randomized controlled clinical trial
comparing observation with betaxolol and argon
laser trabeculoplasty for OAG.
2
7

EMGT
• Randomised to
-ALT and betaxolol
-No treatment
• If IOP >25mmHg in treated (>35 untreated)
→ Latanoprost added
• If remains high
→ individualised treatment

Results:
 At 6 years, 62% of untreated patients showed
progression, whereas 45% of treated patients progressed.
Treatment reduced IOP by 25%.
 Median time to progression 66 months in treated versus
48 months in untreated .
2
9

EMGTS – results
 Progression
 62% - control
 45% - treated group
 25% IOP - risk of
progression by 50%
 Risk of progression less
with larger initial IOP
drop
 Risk of progression by
10% / mm Hg IOP from
baseline

 In the control group , the rate of visual field
progression was fastest in the subgroup of
patients with exfoliation and slowest in those
with normal IOPs at baseline.
3
1

Baseline risk factors:
 Higher IOP
 Exfoliation
 Older age
 Lower systolic perfusion pressure
 Lower CCT among patients with higher IOPs
 follow up higher IOP,
 disc hemorrhages.
3
2

Implications:
 In eyes with glaucoma ,IOP that was lowered by
an average of 25%, treatment was of benefit
versus no treatment .
 There is beneficial effect of immediate therapy to
lower the intraocular pressure versus late or no
treatment on the progression of newly detected
OAG
3
3

Clinical Implications
 Even small reductions in IOP can make a difference.
 Every 1mm of IOP reduction was associated with a
risk reduction of 10% to 13%, depending on the
analysis,
 But that doesn't necessarily mean all patients must be
treated, because we can't know which patients will
progress, in some cases, we can observe closely and
tailor management to the individual patient
 It's beneficial to lower pressure in patients
progressing quickly, even if IOP levels have been in
the range of 15 to 18mm Hg,

Clinical useful points from EMGTS
 25% IOP - progression from 62 – 45%
 Regular FU every 3 – 6 months with ONH & VF
must – not commonly practiced.
 Pts with low risk of progression left untreated –
no effect on QOL till lifetime
 Drawbacks – Rx options limited – better drugs
now

Collaborative Initial Glaucoma
treatment Study (CIGTS)
Am J Ophthalmol 1998;126:498-505

Collaborative Initial Glaucoma treatment Study (CIGTS)
Purpose:
 To determine whether patients with newly
diagnosed open angle glaucoma (OAG) are better
treated by initial treatment with medications or
by immediate filtering surgery.
 In addition, a secondary measure—a health-
related quality of life questionnaire—looked at
how the treatment affected the patient's lifestyle.3
9

Collaborative Initial Glaucoma treatment Study
(CIGTS)
Participants:
 607 patients with OAG ( primary, pigmentary, or
pseudoexfoliative) recruited between 1993 and 1997.
Study design:
comparing initial medical with initial surgical
therapy for OAG.
4
0

 First time the concept of Target IOP was used.
March
CIGTS
MEDICATION GROUP
N = 307
SURGICAL GROUP
N = 300

CIGTS
 RESULTS
 At 5 yrs both effective
 Control of IOP lower by
surgery (48%), medical
(35%)
 VF loss greater in
surgery (cataract)
 QOL initially better
with medical group

CIGTS – Results at 5yrs
Medical
Treatment
Surgical
Treatment
IOP reduction 28mmHg→17-18mmHg
(38%)
27mmHg→14-15mmHg
(46%)
Progression at 5 years No progression No progression
• Surgical group is at increased risk of visual loss initially
but by 4yrs both groups are comparable
•The rate of cataract removal was greater in the surgically
treated group.

Results
 Patients with diabetes were more likely to
progress if treated with surgery first.
 The quality of life (QOL) impact reported by the
2 treatment groups was very similar.
 Increased impact of local eye symptoms reported
by the surgery group
4
5

Results
 The overall rate of progression of OAG in CIGTS
was lower than in many clinical trials, potentially
the result of more aggressive IOP goals and the
stage of the disease.

CIGTS summary
 Surgery resulted in
 Lower IOP
 More cataract
 More ocular side effects
 Initial ↓ vision
 Initial ↓ visual field

Collaborative Initial Glaucoma treatment Study
(CIGTS)
Implications
 In moderate to advanced disease initial surgical
therapy may be preferred.
 The results also revealed that either treatment had a
remarkably similar effect on patients' quality of life.
 Though not associated with a particular treatment
group, the fear of blindness was common, affecting
34% at diagnosis.
 Patients who reported a decrease in visual
functioning were more likely to experience depression
and mood changes
4
8

Clinical useful points from CIGTS
 Early POAG – medical Rx effective
 Our scenario – compliance/cost – deciding factor for
either modality
 Concept of target IOP – must in our management.
 Drawback – study duration too short for Rx
recommendation.

Advanced Glaucoma
Intervention Study (AGIS)
5
1

Advanced Glaucoma Intervention Study (AGIS)
Purpose:
To compare the clinical outcomes of 2 treatment
sequences in cases of advanced glaucoma
5
2

Advanced glaucoma intervention
study (AGIS)
 Objective – to determine if ALT or surgery is
preferred Rx for advanced glaucoma on max
tolerated medical Rx.
789 eyes
ALT
TRAB
TRAB
(ATT)
TRAB
ALT
TRAB
(TAT)

Participants:
 789 eyes of 591 patients with medically
uncontrolled OAG recruited from 1988 to 1992.
 POAG uncontrolled on maximum accepted and
tolerated medical therapy(IOP ≥ 18 mm Hg)
 35 to 80 yr
5
4

Study design:
comparing 2 treatment sequences (TAT and ATT ) for
patients with OAG uncontrolled by medical therapy.

Results:
 Black patients had less combined visual acuity and visual
field loss if treated with the ATT sequence.
 White patients had less combined visual acuity and visual
field loss at 7 years if treated with the TAT sequence.
 Visual function scores improved after cataract surgery.
5
6

AGIS - Results
 Relationship of IOP & VF progression.
 Predictive analysis – IOP < 14 mm Hg did better
 Associative analysis – low IOP & low IOP
fluctuation - Decreased progression

Advanced Glaucoma Intervention Study (AGIS
Results:
 Lower IOP was associated with less visual field loss.
 First 18 months after the first surgical intervention, or
eyes with IOP of 18mmHg or less at all visits throughout
the study had significantly less visual field loss
 Approximately half of the study patients developed
cataract in the first 5 years of follow up.
 Trabeculectomy increases the relative risk of cataract
formation by 78%.
5
8

Results
 ALT failure is associated with
-younger age
-higher IOP.
 Trabeculectomy failure associated with
-younger age,
-higher IOP,
-diabetes, and postoperative complications such as particularly elevated
IOP and marked inflammation.
-IOP fluctuation was an independent predictor of progression of OAG in
eye with lower baseline IOPs.

Results - AGIS
 TAT
 IOP
 Better for whites
 ATT
 Failure
 Better for blacks
Risk of cataract after TRAB after 5 years – 78 %

AGIS
 Effects of IOP on visual field progression were also
specifically evaluated from AGIS data, and it was
found that patients with an average IOP of greater
than 17.5mm Hg had greater worsening of their visual
fields than those with an average IOP of less than
14mm Hg.
 AGIS was one of the first studies to show that lower
mean IOP results in a decreased risk of visual field
progression.

AGIS
 Each patient requires individualized care.
 AGIS demonstrated that race is an important
consideration for surgical intervention in advanced
glaucoma.
 This is not to say, for instance, that a white patient
with medically-uncontrolled glaucoma should only be
offered the option of trabeculectomy.
 Potential operative complications associated with the
more invasive surgery may sway the patient toward
laser intervention as a first option.

AGIS
 Conversely, a black patient presented with the option
of laser intervention should be warned of the likely
future need for both additional medications and
additional glaucoma surgery after the laser procedure
is completed.

AGIS
 There is no magic number for target IOP.
 Patients in the AGIS group who consistently
maintained IOP less than 18mm Hg at every visit over
six years, with mean IOP of 12.3mm Hg as a group,
had good preservation of visual field—yet a number of
patients in this group still showed progressive visual
field loss.

Implications:
 Keep race in mind when choosing therapy.
 Lower IOP was associated with less visual field loss
 IOP fluctuation was an independent predictor of
progression of OAG in eye with lower baseline IOPs.
6
5

Collaborative Normal Tension
Glaucoma (CNTGS)
6
6

 Lowering IOP in patients with normal-tension
glaucoma (NTG) can be challenging.
 Is it even worth trying to lower an already-low IOP?

Collaborative Normal Tension Glaucoma (CNTGS)
Purpose:
 To determine if IOP plays a part in the pathogenic
process of NTG by comparing a treatment group (with
a 30% reduction in IOP) to a no treatment group. .
6
8

Participants :
 230 patients
 20-90 yrs
 Patients had unilateral or bilateral NTG
 Three reliable visual fields within 1 month
 Average IOP ≤20 mmHg,no reading above 24 mmHg
6
9

NTGS - methods
 Randomised immediately if
 VF defect threatening fixation
 Previously documented disease progression
 Others randomised when evidence of progression

NTGS
 145 (of 239) patients randomised
 One eye randomised to
 Treatment
 Drops, ALT or surgery to achieve 30% reduction in
IOP
 No treatment until evidence of
progression
 Other eye could be treated in this group

Study design:
 In both arms, neither eye could receive beta-
adrenergic blockers or adrenergic agonists, because
they might have systemic cardiovascular effects that
could conceivably alter the course of the treated or
untreated disease, confounding the analysis of data.
7
2

CNTGS
RESULTS
 30% drop achieved in half without surgery
 Once 30% drop achieved rate of progressive field loss
was lower than group that did not receive treatment
(after allowing for cataract effect which was higher in
treated group)

CNTGS
RESULTS:
 Rate of progression in untreated NTG highly variable
 Half did not progress on VF in 5 years
 Factors associated with progression
 Female
 Migraine
 Disc haemorrhages on presentation

CNTG – results
 Prog in 12% of Rxed eyes & 35% in untreated group.
 30% reduction possible even by medicines.
 Treated pts that progressed
 Non IOP related
 target IOP wrong

CNGTS
 Overall, lowering IOP in NTG slows progression.
 However, over half of patients did not progress
without treatment at 5 years.

IMPLICATIONS:
 The natural course of NTG is quite variable, some
cases slow enough that they may never need
treatment, but others progressing rapidly to
potential blindness.
7
7

 Because of the variable natural course of NTG, it is
important to distinguish between patients who have
progressive vs. non-progressive disease.
 In cases of mild NTG, consider monitoring until
progression is confirmed.
 However, factors that weigh more heavily for
treatment are female gender, history of migraine and
disc hemorrhage at diagnosis.

 When you suspect progression, be sure to confirm
that it is actual progression and not testing variability.
 This may require multiple visual fields to prevent
over-diagnosing progression.
 Once the decision is made to begin treatment, set a
goal (at least 30% IOP reduction) and be diligent in
attaining it.
 The large arsenal of IOP-lowering medications
available today makes this goal much more achievable
without surgery

TVT
 PURPOSE: To report 5 year treatment outcomes in
the tube versus trabeculectomy study.
 DESIGN: Multicenter randomized clinical trial

TVT
 STUDY POPULATION:
-Patients 18 to 85 years
-Prior cataract or glaucoma filtering surgery
- Uncontrolled glaucoma with IOP of 18mmHg to 40
mmHg on maximum tolerated medical therapy
 OUTCOME MEASURES
-IOP, Visual acuity, visual fields, surgical complications,
glaucoma medications and treatment failure

TVT
 RESULTS:
-Trabeculectomy with MMC and tube-shunt surgery
both produced sustained IOP reduction to the low
teens during 5 years of followup
-Tube-shunt surgery was associated with use of more
glaucoma medications than trabeculectomy with
MMC during the first 2 yrs of study,but medical
therapy equalized with longer followup

TVT
 RESULTS
-Trabeculectomy with MMC had a higher failure rate
(46.9%)compared with tube shunt surgery(29.8%)
-Higher rate of reoperation for glaucoma(29%)
compared to tube group(9%0
-vision loss occurred at similar rate in both groups
-Early postoperative complications occurred more
frequently after trabeculectomy with MMC relative to
tube shunt surgery.similar rate for late complications

TVT
 Implications
-No procedure superior for treating glaucoma
-Factors for selecting surgical procedure
o Surgeons skill and experience
o Patients willingness to undergo repeat glaucoma
surgery
o Surgeons planned surgical approach should failure
occur

 The researchers maintain that the TVT study does not
demonstrate clear superiority of one glaucoma
operation over the other, but that both surgeries are
viable options.
 Potential pitfalls exist with the use of tube shunts.
Subsequent surgical options after failure of tube-
shunt devices become limited—surgeons are left with
the choice of a second, inferiorly placed tube or
cyclophotocoagulation.

 The TVT Study supports the expanding use of tube
shunts beyond the surgical management of refractory
glaucoma.
 Tube shunt surgery was shown to be effective in a
patient population at lower risk of surgical failure
than has traditionally been designated for this
procedure.

 Trabeculectomy is not without its travails. It requires
the surgeon to tailor the procedure to each patient
(i.e., number of scleral flap sutures and dosage of an
antifibrotic agent) whereas tube-shunt surgery is a
more standardized procedure
 Also, trabeculectomies require more frequent and
more vigilant postoperative care than tube shunts.

EUROPEAN GLAUCOMA PREVENTION
STUDY
 OBJECTIVE
Efficacy of reduction of IOP by dorzolamide versus
placebo in preventing or delaying POAG in patients
affected by Ocular hypertension

EGPS
 PARTICIPANTS:
-1081 patients
-Age ≥30 yrs
-IOP 22 to 29 mmHg
-2 normal and reliable visual fields
-Normal optic discs
 Outcome measures:
Safety end point was IOP >35 mmHg on 2 consecutive
examinations

EGPS
 RESULTS
-Dorzolamide reduced IOP by 15-22% in 5 yrs period
-At 60 months ,cumulative probability of converting to
an efficacy end point was
13.4%(dorzolamide group)
14.1%(placebo group)
-No statistically significant difference between medical
therapy and placebo group in reducing incidence of
POAG

EGPS
 Risk factors for progression
1.Older age
2.Thinner CCT
3.Higher vertical cup disc ratio
4.Higher Pattern standard deviation

EGPS
 The role of systemic blood pressure appears
important
 Regression to the Mean
 Minimised by multiple IOP measurements at different
times of the day (diurnal variation) or on a different
day.
 For each mm Hg higher IOP per 12 months, the risk
of converting to POAG in increased by 9% in the next
5 years.

LOW TENSION GLAUCOMA
PREVENTION STUDY
 OBJECTIVE
To evaluate visual field stability in low-pressure
glaucoma patients randomized to intraocular pressure
reduction in both eyes with topical twice daily
brimonidine tartrate 0.2% versus twice daily timolol
maleate 0.5%

LOGTS
 PARTICIPANTS
-Low-pressure glaucoma patients
- 30 years of age or older
-untreated pressure of more than 21 mmHg and
advanced visual field loss were excluded
 Randomization of both eyes to double-masked
monotherapy with brimonidine or timolol.

LOGTS
 Follow-up visits included Humphrey 24-2 full-
threshold perimetry, tonometry every 4 months, and
annual optic disc photography.
 MAIN OUTCOME MEASURE:
- Progression of visual field loss.

LOGTS
RESULTS
 showed similar IOP reduction for each medication.
 patients on brimonidine had less visual field loss
(9.1%) compared with patients on timolol (39.2%)
during an average of 30 months
 28 of the 99 patients in the brimonidine arm of the
study dropped out due to drug-related adverse events,
compared with only 9 of the 79 timolol patients

LOGTS
RESULTS
 low-pressure glaucoma patients treated with
brimonidine are less likely to have field progression
than patients treated with timolol
 Conclusion:
Brimonidine better than Timolol??

 The study attempted to find correlations between
many other baseline factors of the 2 study groups and
the slower progression of glaucoma in the group that
received brimonidine.
 Age, sex, family history, diabetes mellitus, risk factors
for low-tension glaucoma (such as migraine and the
Raynaud phenomenon), and ocular perfusion
pressure were investigated..

LOGTS
 Drawbacks
-Data may have been skewed due to the high number of
patients dropping out of the brimonidine group.
-No therapeutic goal for either medication
-Baseline untreated IOP was just over 15mm Hg and the
mean treated IOP was around 14mm Hg

LOGTS
 For now,we should use the therapy that reduces
IOP in normal-tension patients to significant
levels (minimum 30%), and modify treatment if
the optic nerve, retinal nerve fiber layer or visual
field changes.
 Prostaglandins have superb efficacy and less effect
than other agents in lowering heart rate. These
should be used as a first-line treatment whenever
possible.

 Remember to check blood pressure and heart rate before
initiating treatment with a beta-blocker such as timolol.
 Also, check if the patient is already taking a systemic beta-
blocker.
 Be sure that patients use timolol earlier in the evening
rather than before bedtime to avoid the hypotensive effect
that might compromise ocular blood flow and induce
systemic hypotension.

TAKE HOME MESSAGE
In OHT cases:
 Not all OHT need treatment – assess risk on
individual basis and then decide
 People with high risk factors may benefit from close
followup and early treatment
 Low risk patients can have less frequent followup and may
not need early treatment.

TAKE HOME MESSAGE
In NTG cases:
 Rate of progression in NTG highly variable
 Only proven treatment is reducing IOP
 Treat if risk factors present

TAKE HOME MESSAGE
POAG cases
 Start early treatment in diagnosed cases of POAG
 Choice of medical therapy first – change only if target
IOP not achieved.
 Surgical therapy safe
 In moderate to advanced disease initial surgical therapy
may be preferred

TAKE HOME MESSAGE
 Efficient patient care – practice of evidence based Rx
 IOP is the main risk factor for all glaucomas
 Recognize threat – lower IOP – lower risk of progression
 Set a target IOP after assessing risk factors for progression

Important trials in Glaucoma

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