Setting IOP Targets

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)



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



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



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


* 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


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



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



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


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


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

(%)


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


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


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


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


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


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


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


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


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 (%

)


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


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


CIGTS: implications

The results of this trial suggest thatglaucoma progression will be minimalif patients are treated aggressively toachieve low target pressures


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)


-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: 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: 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


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

Documents

Setting IOP Targets