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SETTINGIOP TARGETS
Setting IOP targets
I. Establishing a target IOPII. Evidence from clinical trialsIII. Key points
Establishing a target IOP
IndividualisedHow?
On initial visit and review periodicallyWhen?
Set target IOP rangeWhat?
To maintain functional visionthroughout the patients lifetime witha minimal effect on quality of life
Why?
Establishing a target IOP
Based on pressure reduction required to slowor retard disease progression
Target IOP needs to be individualised The benefits of further pressure reduction
need to be weighed against the risks When the target is achieved, the patient
needs continued monitoring for structural andfunctional changes
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
IOP control in glaucomamanagement
Population studies indicate:13 Incidence, severity and progression of glaucoma
consistently correlate with elevated IOP IOP reduction is currently the only treatment
available for decreasing the risk of diseaseprogression4
Accurate understanding of individual patientIOP affects treatment decisions and guidestreatment plans
1. Quigley HA et al. Am J Ophthalmol 1996; 122: 35563; 2. Leske MC et al. Arch Ophthalmol 2001; 119: 8995;3. Heijl A et al. Arch Ophthalmol 2002; 120: 126879; 4. Lichter PR et al. Ophthalmology 2001; 108: 194353.
Treatment categories: Group 1
Glaucoma with high risk of progressivevisual loss Definite glaucomatous optic neuropathy
(GON) with correlating visual field loss Includes moderate-to-advanced normal
pressure glaucoma (NPG)
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
Treatment categories: Group 2
Glaucoma with moderate risk of visual loss orglaucoma suspect with high risk of visual loss
Mild GON with correlating early visual field loss Mild-to-moderate NPG Ocular hypertension 30 mmHg with suspicious
disc Primary angle closure with high IOP or peripheral
anterior synechiae Angle neovascularisation
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
Treatment categories: Group 3
Moderate risk of visual loss fromglaucoma Glaucoma-like disc appearance without
detectable visual field loss Fellow eye with established GON (exclude
secondary unilateral glaucomas) Ocular hypertension with suspicious disc
and/or low central corneal thickness
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
Treatment categories: Group 4
Low risk of visual loss from glaucoma* More important
Ocular hypertension (OHT), older age, occludableangles, pigment dispersion syndrome, pseudoexfoliationsyndrome, disc haemorrhage, glaucoma suspect disc,family history of glaucoma, glaucoma gene(s)
Less important Steroid responder or user, myopia, peripapillary atrophy,
diabetes mellitus, uveitis, systemic hypertension
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
* Risk factors in patients with anotherwise normal disc. The presenceof multiple factors compounds the risk.
Treatment categories
Low risk of visual lossfrom glaucoma
Moderate risk of visualloss from glaucoma
Glaucoma(moderate risk);
glaucoma suspect(high risk)
Glaucoma (high risk)
Monitor; no treatmentGroup 4
Monitor closely for change; if risk increases, treat with target
pressure reduction ofat least 20%
Group 3
Target pressure reduction ofat least 20%Group 2
Target pressure reduction ofat least 30%, or near episcleralvenous pressure (712 mmHg if
achievable safely)
Group 1
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
IOP is dynamic
IOP may be higher than measured inthe clinic due to: lack of patient compliance with treatment normal variations in IOP
Consider Fluctuation over time1,2
Maximum IOP Circadian IOP
1. Asrani S et al. J Glaucoma 2000; 9: 13442; 2. Hughes E et al. J Glaucoma 2003; 12: 2326.
IOP fluctuations increase the riskof glaucomatous progression
0
20
40
60
80
100
Patients with circadian
IOP range > 11.8 mmHg
Patients with circadian
IOP range < 7.7 mmHg
Pati
en
ts (
%)
Stable visual field
Visual field loss
Asrani S et al. J Glaucoma 2000; 9: 13442.
Factors to consider in settingthe target IOP
Baseline/presenting IOP Circadian IOP IOP in fellow normal eye Population mean and standard deviation IOP
for normal eyes Central corneal thickness Severity of disease Extent and rate of disease progression
Factors to consider in settingthe target IOP
Patient age and life expectancy Family history Race Systemic illness Costs and risks of treatment
Resetting IOP in thepresence of progression
Need to get IOP even lower Re-adjust for lower target IOP and treat
more effectively Check compliance Check circadian curve
Evidence from clinical trials
AGIS5 (NEI)
CIGTS4 (NEI)
CNTGS3 (GRF)
EMGT2 (NEI)
OHTS1 (NEI) The Ocular Hypertension Treatment Study
The Early Manifest Glaucoma Trial
The Collaborative Normal-TensionGlaucoma Study
The Collaborative Initial GlaucomaTreatment Study
The Advanced Glaucoma Intervention Study
1. Kass MA et al. Arch Ophthalmol 2002; 120: 70113; 2. Heijl A et al. Arch Ophthalmol 2002; 120: 126879;3. CNTG Study Group. Am J Ophthalmol 1998; 126: 48797; 4. Lichter PR et al. Ophthalmology 2001; 108: 194353;
5. AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
Glaucoma clinical trials: titles
GRF, Glaucoma Research Foundation; NEI,National Eye Institute
Glaucoma clinical trials: designs
ALT, argon laser trabeculoplasty; NTG, normal tension glaucoma; OAG, open-angle glaucoma
8 yearsALT versus surgeryOAG738eyesAGIS5
5 yearsMedical treatment versussurgeryOAG607ptsCIGTS
4
7 yearsMedical treatment and/orsurgery versus observationNTG140eyesCNTGS
3
49 yearsTreatment (ALT + betaxolol)versus observationOAG255ptsEMGT
2
5 yearsMedical treatment versusobservationOHT1636ptsOHTS
1
Follow-upRandomisationDxNTrial
1. Kass MA et al. Arch Ophthalmol 2002; 120: 70113; 2. Heijl A et al. Arch Ophthalmol 2002; 120: 126879;3. CNTG Study Group. Am J Ophthalmol 1998; 126: 48797; 4. Lichter PR et al. Ophthalmology 2001; 108: 194353;
5. AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
Glaucoma clinical trials: results
No progression (average)< 18 mmHg targetAGIS5No progression (average)~46% (average)CIGTS4 (surg)
No progression (average)~38% (average)CIGTS4 (med)
12% vs 35% (over 7 years)30% targetCNTGS345% vs 62% (over 6 years)25% (average)EMGT24.4% vs 9.5% (over 5 years)20% targetOHTS1
% Progression(treatment vs no treatment)
IOPreduction
Study
1. Kass MA et al. Arch Ophthalmol 2002; 120: 70113; 2. Heijl A et al. Arch Ophthalmol 2002; 120: 126879;3. CNTG Study Group. Am J Ophthalmol 1998; 126: 48797; 4. Lichter PR et al. Ophthalmology 2001; 108: 194353;
5. AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
OHTS: treatment reduces incidenceof glaucoma in OHT patients
1636 patients with OHT Medical treatment versus
observationTarget IOP 20% reduction, 24 mmHg Average IOP drop: 22.5% vs
4.0% in untreated controlsResults Cumulative probability of
primary open-angle glaucoma(POAG)
4.4% in treated group vs9.5% in observation group(p < 0.001)
Conclusion Medical therapy effective in
delaying/preventing onset ofPOAG in subjects withelevated IOP
Kass MA et al. Arch Ophthalmol 2002; 120: 70113.
Follow-up monthFollow-up month
Prop
ortio
n of
par
ticip
ants
Prop
ortio
n of
par
ticip
ants
dev
elop
ing
POAG
dev
elop
ing
POAG
Medical treatment group
Observation group
00
0.050.05
0.100.10
0.150.15
66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666 7272 7878 8484
OHTS: lowering IOP by 20%reduces incidence of POAG
Kass MA et al. Arch Ophthalmol 2002; 120: 70113.
0%
5%
10%
15%
20%
25%
Untreated patients(n = 819)
9.5%
Treated patients(n = 817)
4.4%
53.7%differential
Cum
ulat
ive
prob
abili
ty o
fde
velo
ping
PO
AG
OHTS: additional results
All-cause reproducible abnormalitiesin visual fields and/or optic discs weresignificantly reduced in the medication group
Hazard ratio 0.58 (95% CI, 0.440.76);p = 0.00008
Little evidence of increased ocular or systemicrisk in the medication group
Kass MA et al. Arch Ophthalmol 2002; 120: 70113.
OHTS: possible misinterpretations
Treat all patients with elevated IOP Risk of POAG is low in this population Glaucoma medications are harmless Risk factors for developing POAG are clearly
delineated; the influence of race, gender,hypertension, heart disease, family history,blood pressure and diabetes are all clear
20% lowering of IOP is the correct targetfor OHT
Drug X is proven to prevent glaucoma in OHT
OHTS: summary
Not every patient with OHT should be treated Offer treatment to OHT patients at moderate-
to-high risk, taking into consideration: age medical status life expectancy likely treatment benefit
Consider corneal thickness in all patients withOHT or glaucoma
EMGT: early treatment reduces anddelays glaucoma progression
255 patients with newlydetected glaucoma
(ALT + medical treatment)versus observation
Target IOP No target set Mean IOP decrease 25%
(range 029%)Results Disease progression in 45% of
treated vs 62% of untreatedpatients (p = 0.007)
Conclusion Treatment significantly delays
disease progression
Inci
denc
e of
pro
gres
sion
(%)
0
20
40
60
80
Untreated
62%
Treated
45%
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
EMGT: early treatment reduces anddelays glaucoma progression
Median time to progression was 66 months in treated patientscompared with 48 months in controls
00
20
40
60
80
100
12 24 36 48 60 72 84 96 108
Follow-up month
UntreatedTreated
Pro
gres
sion
(%)
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
N atrisk:
T: 68C: 64
6761
6353
5443
4537
3022
1713
86
30
N atrisk:
T: 61C: 62
5552
4840
4329
3724
2114
109
65
23
N atrisk:
T: 8C: 15
711
67
53
33
20
00
N atrisk:
T: 121C: 111
115102
10586
9269
7958
4936
2722
1411
53
IOP < 21 mmHgIOP < 21 mmHg IOP IOP 21 mmHg 21 mmHg
ExfoliationsExfoliations No exfoliationsNo exfoliations
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
N atrisk:
T: 69C: 77
6774
6462
5748
5040
2925
1515
89
33
N atrisk:
T: 60C: 49
5539
4731
4024
3221
2211
127
62
20
N atrisk:
T: 63C: 57
6053
5548
4940
4233
2922
1412
88
31
N atrisk:
T: 66C: 69
6260
5645
4832
4028
2214
1310
63
22
MD better than MD better than 4.5 dB4.5 dB MD worse than MD worse than 4.5 dB4.5 dB
Age < 68 yearsAge < 68 years Age Age 68 years 68 years
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.MD, mean deviation
EMGT: LOCS II scores
6 12 18 24 30 36 42 480
5
10
15
20
25Treatment
Control
0
5
10
15
20
25Treatment
Control
6 12 18 24 30 36 42 480
5
10
15
20
25Treatment
Control
6 12 18 24 30 36 42 48
LOCS
II S
core
2
(%)
Base
line
Follow-up (months)
Base
line
Base
line
Follow-up (months) Follow-up (months)
Nuclear Cortical Posterior subcortical
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
LOCS, Lens Opacities Classification System
Treatment groupTreatment groupoutcomeoutcome
Control groupControl groupoutcomeoutcome
45%45%55%55%38%38% 62%62%
ProgressionProgression
Non-progressionNon-progression
Visual field onlyVisual field only
Visual field and optic discVisual field and optic disc
Optic disc onlyOptic disc only
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
Mode of progressionMode of progression
EMGT: summary
First randomised trial comparing long-termoutcomes between treated and untreatedpatients to clearly show that IOP reductiondecreases the risk of glaucoma progression
Provides new information on diseaseprogression rates, with and without treatment,in different patient subgroups
Demonstrates very large inter-patient variationin disease progression rates
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
EMGT: conclusions
Progression was more common in: patients with higher IOP older patients patients with more advanced baseline
damage exfoliation glaucoma
Treatment was associated withprogression of nuclear lens opacities
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
EMGT: implications
Treatment of newly diagnosed POAGand NTG reduces the risk of furthervisual field loss
In EMGT, the average sustained IOPreduction was 25%
IOP reductions of 30% or 35% will preservevisual function in many patients
The goal of therapy should be to achievepressures as low as is safely possible
Heijl A et al. Arch Ophthalmol 2002; 120: 126879.
CNTGS: lowering IOP reducesvision loss in NTG patients
145 eyes with NTG Medical treatment surgery
versus observationTarget IOP 30% IOP reductionResults 80% progression-free survival
in treated group versus 60%in control arm at 3 years(p = 0.0018)
Visual field progression 18%in treated versus 30% inuntreated
Conclusion Lowering IOP reduces risk of
vision loss in NTG
Pro
porti
on s
urvi
ving
Time (years)
UntreatedTreated
00
0.2
0.4
0.6
0.8
00
1.0
11 22 33 44 55 66 77 88E
yes
that
pro
gres
sed
(%)
35%
12%
00
15
30
45
Untreated eyes Treated eyes
CNTG Study Group. Am J Ophthalmol 1998; 126: 487497 and 498505.
CNTGS: cataract development
0.311200 6941443 785Mean SD time (days)from randomisation to
cataract
0.001123 (38%)11 (14%) Developed cataract[n (%)]
Pvalue
Treatedgroup
(n = 61)
Controlgroup
(n = 79)
Patientcharacteristics
CNTG Study Group. Am J Ophthalmol 1998; 126: 48797.
CNTGS: discussion
IOP is a factor in deterioration of visionfrom NTG
This study shows that lowering IOP in suchpatients decreases the risk of progressivevisual loss
Since 65% of untreated patients did notprogress during follow-up, factors otherthan IOP influence progression inindividual patients
CNTG Study Group. Am J Ophthalmol 1998; 126: 48797.
CNTGS: conclusion
In NTG patients, lowering IOP by atleast 30% led to a lower rate of visualfield loss than was seen in NTG patientswho did not receive treatment
Therapy that lowers IOP effectivelywith no side-effects is likely to benefitpatients at risk of visual field lossfrom NTG
CNTG Study Group. Am J Ophthalmol 1998; 126: 48797.
CIGTS: lowering IOPminimises visual field loss
607 patients with newlydiagnosed OAG
Medical treatment versussurgery
Target IOP Low target pressure set by
formulaResults Both medical treatment and
surgery lower IOP andprevent visual field loss
Conclusion With aggressive therapy
aimed at IOP-lowering, visualfield loss in general is minimal
Mea
n vi
sual
fiel
dsc
ore
Time (months)
2
12 24 36 48 600 18 30 42 54
4
67
5
3
10
Medicine
Mea
n IO
P (m
mH
g) Surgery
15
20
25
30
12 24 36 48 606 18 30 42 54108
6
0
Lichter PR et al. Ophthalmology 2001; 108: 194353.
CIGTS: lowering IOP minimisesclinically significant visual field loss
0
10
20
30
0 12 24 36 48 60
Time (months)
Medicine
Surgery
Patie
nts
with
3
uni
t inc
reas
ein
vis
ual f
ield
sco
re (%
)
Lichter PR et al. Ophthalmology 2001; 108: 194353.
CIGTS: adverse events insurgery group
73 (14.2)61 (11.9)61 (11.9)58 (11.3)54 (10.5)
After 1 month of follow-up (n = 517) Shallow/flat anterior chamber Encapsulated bleb Ptosis Serous choroidal detachment Anterior chamber bleeding/hyphema
n (%)
37 (7.1)
5 (1.0)
Trabeculectomy (n = 525) Intraoperative bleeding (anterior
chamber) Buttonhole
Lichter PR et al. Ophthalmology 2001; 108: 194353.
CIGTS: summary
Both medical and surgical treatment reducedIOP by an average of > 30% in patients withnewly diagnosed OAG
Mean reduction: approximately 37% and 47% withmedical treatment and surgery, respectively
Few patients in either treatment groupprogressed
Risk of progression over 5 years: 10.7% and 13.5%with medical treatment and surgery, respectively
Target pressures used were aggressive
Lichter PR et al. Ophthalmology 2001; 108: 194353.
CIGTS: implications
The results of this trial suggest thatglaucoma progression will be minimalif patients are treated aggressively toachieve low target pressures
Lichter PR et al. Ophthalmology 2001; 108: 194353.
AGIS: definition of IOP groups
Predictive analysis IOP averaged over the
first three 6-month visits < 14 mmHg 1417.5 mmHg > 17.5 mmHg
Associative analysis
10075 to < 10050 to < 75 0 to < 50
ABCD
Visits with IOP< 18 mmHg (%)IOP group
AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
AGIS: IOP needs to beconsistently low
738 eyes with uncontrolledglaucoma
ALT versus surgeryTarget IOP < 18 mmHgResults 100% of visits at which IOP
< 18 mmHg: no change invisual field
< 50% visits at which IOP< 18 mmHg: worsening ofvisual field by 0.63 units
Conclusion Consistently low IOP
associated with reducedprogression of visual fielddefect
Associative analysis< 50% of visits IOP < 18 mmHg
2
1
0
1
2
3
4
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Follow-up (months)
Mea
n ch
ange
invi
sual
fiel
d de
fect
sco
re
100% of visits IOP < 18mmHg
75100% of visits IOP < 18 mmHg5075% of visits IOP < 18 mmHg
20.216.914.7
12.3
Mean IOP(mmHg)
AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
-1
0
1
2
3
4
24 36 48 60 72 84 96
Follow-up month
Mean
ch
an
ge in
vis
ual
field
defe
ct
sco
re
< 14 mmHg
1417.5 mmHg
> 17.5 mmHg
AGIS: very low IOP slows orhalts glaucomatous vision loss
3
Predictive analysis
AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
AGIS: discussion
The association between low IOP and reducedprogression of visual field defects persistedthroughout follow-up
IOP levels often considered adequate (1417.5mmHg) were associated with greater visual fieldloss than low IOP levels (< 14 mmHg), although thedifference was not statistically significant
A proportion of eyes in the < 14 mmHg groupexperienced visual field loss, even though on averagethe change in visual field defect score was closeto zero
AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
AGIS: conclusions
Low IOP is associated with reducedprogression of optic neuropathy, asmeasured by deterioration in the visualfield defect score
The association between low IOP andreduced glaucomatous progressionpersists during long-term follow-up
AGIS Investigators. Am J Ophthalmol 2000; 130: 42940.
Key points
IOP is a significant, modifiable risk factorin glaucoma
Lowering IOP to a target level is helpfulacross the spectrum of disease statesand IOP levels:
advanced glaucoma normal tension glaucoma newly diagnosed glaucoma
Target IOP range must be: individualised re-evaluated periodically