management of early glaucoma: evidence based medicine

Management of Primary

Open Angle Glaucoma:

Evidence Based MedicineBy

Hend M. Safwat

Asst. Lecturer of Ophthalmology

Al-Azhar University

2016

All Rights are Preserved

Closed angle glaucoma usually manifests

at early stages of functional damage.

Open angle glaucoma

usually not diagnosed

at early stages of

functional damage .

Should we need a screening system ?!

According to Preferred Practice Pattern of

American Academy of Ophthalmology

(2010):

(Population-based screening for glaucoma is

currently not cost-effective. Screening may

be more useful and cost-effective when it is

targeted at populations at high risk for

glaucoma, such as older adults, those with a

family history of glaucoma, and African

Americans and Hispanics.

Screening for glaucoma could be included in

general screening for eye disease, especially

among older populations).(American Academy of Ophthalmology Vision Rehabilitation Committee. Preferred Practice Pattern® Guidelines.

Primary Open Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2010. Available at:

www.aao.org/ppp).

We all are invited to catch the glaucoma as

early as possible !

Clinical tips in taking history; Always ask

about family history of glaucoma, as you

routinely ask about HTN and DM.

In examination, do not let normal IOP guide

you.

Remember, IOP is corneal biomechanics

dependant, and risk factor rather than a

cornerstone in the diagnosis.

The evaluation of ONH is by Volk 90 D with

(dilated) pupil; is recommend by AAO and

European glaucoma society.

If you suspect in the disc, document it, and

follow up after 6 months.

Documentation is by coloured

stereophtography, or computerized imaging

methods as cSLO/OCT.

Practice

Von Herick’s

technique as

a routine

for angle

assessment

as the gonioscopy

is not a routine.

Do not depend in one visual field in

conclusion of glaucoma diagnosis(OHTS

founded 86% of patients had normal field on

2nd repetition, learning curve effect).

Your patient is either a suspect or newlydiagnosed glaucoma.

What’s the border of the suspect?

Open angle glaucoma suspect (OAGS) ispatient of one of the following:

1- Ocular hypertension2- Suspect ONH; cupping, asymmetry, focal

notch,….3- Suspect perimetry as large PSD without

obvious scotoma, or abnormal FDT withnormal SAP.

(American Academy of Ophthalmology Vision Rehabilitation Committee. Preferred Practice Pattern® Guidelines.Primary Open Angle Glaucoma Suspect. San Francisco, CA: American Academy of Ophthalmology; 2010.Available at: www.aao.org/ppp).

Early Manifest Glaucoma Trial

(EMGT)

Purpose: comparing treatment (Betaxolol +

Argon laser trabeculoplasty, ALT) Vs. no

treatment in early diagnosed open angle

glaucoma. The 2ndry purpose is assessment of

risk factors for Progression.

Study Design: multicentre randomized

controlled clinical trial with 255 newly

diagnosed glaucoma (POAG, NTG, and PEX

glaucoma), from1993 to1997.

Assessment: guided by ONH changes and standardautomated perimetry.

Results:

• 25% decrease of IOP from the 1s visit baseline >>> 50 % decrease in progression.

• The less baseline IOP, the less rate of progression.

• Untreated group >>>> 62 % progression.

• Treated group >>>> 45 % progression

• IOP fluctuation is not risk factor for progression.

• Lens opacity increased in treated group vs.

untreated group.

• The risk factors for progression at base line

are:

1- higher baseline IOP

2- pseudoexfoliation

3- hypotension (in NTG)

4- lower central corneal thickness + high IOP

5- disc haemorrhage.

Clinical Applications:

Early treatment is associated of noprogression; but not all untreated patientsare associated with progression !!!

So, tailor the management for everypatient.

(Heijl A, Leske MC, Bengtsson B, et al, Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucomaprogression. Results from the Early Manifest GlaucomaTrial.Arch Ophthalmol 2002;120:1268-79.

Leske MC, Heijl A, Hussein M, et al, Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect oftreatment.The Early Manifest GlaucomaTrial.Arch Ophthalmol 2003;121:48-56.

Leske MC, Heijl A, Hyman L, et al, Early Manifest Glaucoma Trial Group. Predictors of long-term progression in the Early ManifestGlaucomaTrial. Ophthalmology 2007;114:1965-72. )

Collaborative Normal Tension

Glaucoma Study (CNTGS)

Purpose: comparing treatment vs. no

treatment in normotensive glaucoma.

Treatment aim was 30% reduction of baseline

IOP by drops (except beta blocker or alpha2

agonist),ALT, or surgery.

Study Design: randomized controlled trial

with 230 patients.

Assessment: Progression assessment was

either by field or coloured

stereophotography.

Results:

• 30 % reduction of IOP was associated with

12 % progression vs. 35% in untreated group

• Variable progression value means in

untreated group.

• Cataract increased with surgery.

• Risk factors associated with progression:

1- female sex

2- migraine

3- disc hge


The variable rates of NTG make some patients

need no treatment ... and others may progress

till blindness ...............................................................

.........................................................................................

So, NTG are 2 types:

progressive type.

non progressive type

• If you diagnosed your patient as early NTG

>>>> close follow up >>> if progression

occurs >>>> start treatment.

• 30 % reduction of initial IOP is a must.

(Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with

normal-tension glaucoma and patients with therapeutically reduced intraocular pressures.Am J Ophthalmol 1998;126:487-97.

Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-

tension glaucoma.Am J Ophthalmol 1998;126:498-505. )

Ocular Hypertension Treatment

Study (OHTS)

Purpose: Compare effect of ocular

hypotensive drugs on ocular hypertension vs.

no treatment.


prospective controlled clinical trial. It contains

1637 patients. It started 1994. It had 2 phases

Results:

• After 5 years (treated group vs. untreated

group):

4.4% in treated group showed onset of

glaucoma; vs. 9% in untreated group; 50%

reduction of risk.

• After 13 years (treated group from start vs.

treated group from phase 2):

16% converted to glaucoma from treated

group from the start; vs. 22% from the treated

group from phase 2.

• Risk factors for progression were: thinnerCCT (555 um or less), disc hge, higher IOP,older age, enlarged vertical cup/disc ratio,and larger PSD.

• Cataract was associated with treatedgroup.

• Disc hge missed from clinical examination,but detectable in coloredstereophotography in 87%.


Ocular hypertensives are either high risk or

low risk.

High risk group will have benefit from early

treatment.

Measurement of CCT for all glaucoma

suspect.

(Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the

onset of primary open-angle glaucoma.Arch Ophthalmol 2002;120:714-20; discussion 829-30. )

European Glaucoma Prevention

Study (EGPS)

Purpose: comparing dorzolamide eye dropsvs. placebo in OHT to delay onset ofglaucoma.

Study Design: multicentre randomizeddouble-masked placebo-controlled trial. 1081patients. Follow up for 55 months (4.6 years).

Assessment: visual field and optic discchanges.

Results:

After 6 months:

• Dorzolamide group >>> 15% IOP reduction.

• Placebo group >>> 9% IOP reduction.

After 5 years

• Dorzolamide group >>> 22% IOP reduction.

• Placebo group >>> 19% reduction.

• The risk factors for progression were as in

OHTS results + diuretics use.

Clinical application:

No clinical significant difference betweendorzolamide and placebo in delaying the onsetof glaucoma.

(Miglior S, Zeyen T, Pfelffer N, et al. Results of the European Glaucoma Prevention Study. Ophthalmology 2005; 112(3):366-75.)

Collaborative Initial Glaucoma

Treatment Study (CIGTS)

Purpose:

1- Comparing initial medical vs. surgical

(trabeculectomy with or without 5 FL)

treatment in newly diagnosed open angle

glaucoma (primary, PEX, and pigmentary).

2- Effect of treatment on quality of life (QoL).

Study Design: multicentre, randomized

study. 607 patients. 1993-1997.

Assessment: IOP reduction, field

progression, QoL, visual acuity, and cataract

formation.

Results:

• IOP reduction was 48% by surgical vs. 35%

by medical.

• After 5 years: no difference in field

progression in both groups.

• After 8 years: the stability of field was

better in surgical group (22% progression

vs. 25% progression in medical group).

• QoL was initially better with medical group.

• Cataract formation was twice in surgical group.

• Initial visual loss was with surgical group; but after 4 years, both groups are the same.

• The risk of endophthalmitis in surgical group was 1.1%.

• The reversal of ONH cupping was in surgical group

• The risk factors for progression are like

the other trials + higher baseline IOP,

worse initial field , and low educational

status.

• Diabetic patients shows more

progression if treated initially with

surgery.


Newly diagnosed open angle glaucoma +

early field changes = better initial medical

treatment.

Newly diagnosed open angle glaucoma +

moderate or sever field changes = better

initial surgical treatment.

OAG + DM >>> do not rush for surgery.

(Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing

initial treatment randomized to medications or surgery. Ophthalmology 2001;108:1943-53.

Musch DC, Gillespie BW, Lichter PR, et al. Visual field progression in the Collaborative Initial Glaucoma Treatment Study the impact of

treatment and other baseline factors. Ophthalmology 2009;116:200-7.

Parrish RK II, Feuer WJ, Schiffman JC, et al. Five-year follow-up optic disc findings of the Collaborative Initial Glaucoma Treatment Study.

Am J Ophthalmol 2009;147:717-24. )

Low Tension Glaucoma Treatment

Study (LoGTS)

Purpose: comparing twice timolol maleate

0.5% vs. brimonidine tartrate 0.2% in low

tension glaucoma, on IOP and stability of field.


monotherapy eye double-masked clinical trial.

Assessment: field, IOP, and coloured

stereophotography every 4 months.

Results:

• IOP reduction was the same in 2 groups.

• Visual field progression was 9.1% inbrimonidine group vs. 39.2% in timolol group.

• Adherence to brimonidine was bad due tolocal side effects.


• Brimonidine is better than B blockers.

• Don’t forget check heart rate, Bl Pr, andasking about systemic B blockers taking.

(Krupin T, Liebmann JM, Greenfield DS, Rosenberg LF, Ritch R, Yang JW. The Low-pressure Glaucoma Treatment Study (LoGTS) studydesign and baseline characteristics of enrolled patients.Ophthalmology. 2005;112:376–85)

Advanced Glaucoma Intervention

Study (AGIS)

Purpose: comparing ATT (Argon, Trab., Trab)

vs. TAT (Trab, Argon, Trab) regimens in

advanced glaucoma.

Advanced glaucoma here is patient not controlled with

maximum tolerated topical drugs (> 18 mmHg) with MD

less than 16 dB.

Study Design: multicentre, prospective,

randomized study. 789 eyes.

Assessment: visual acuity, IOP, visual

progression, and cataract formation.

Results:

After 1.5 years (3 visits):

less field progression if IOP < 14 mmHg.

More field progression if IOP > 17.5 mmHg.

After 7 years:

IOP reduction was grater with TAT protocol.

ATT worked well in African while TAT worked

well in Caucasians.

• Risk factors for progression were: older age,

longer follow up, and increasing number of

glaucoma interventions.

• Both ALT and SST failed in younger patients

with higher IOP.

• Reporting IOP fluctuation as a risk factor for

progression was debatable in this study.


• Keep race in your mind when choosing

therapy.

• Lower IOP was associated with less visual

field loss.

(The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure

and visual field deterioration. Am J Ophthalmol 2000;130:429-40.

The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 13. Comparison of treatment outcomes within race. Ten-year

results. Ophthalmology 2004;111:651-64. )

Tube Vs. Trabeculectomy (TVT)

Purpose: to report 5 year treatment

outcomes in the tube vs. trab.

Study Design: multicenter randomized

clinical trial.

The tube-shunt surgery using the 350-mm²

Baerveldt implant.

The trab with mitomycin-C in patients with

previous cataract extraction and/or failed

trabeculectomy .

Assessment: IOP, visual acuity, visual fields,surgical complications, glaucoma medications,and treatment failure.

Results:

Tube-shunt surgery had a higher success ratethan trab (85% vs. 69%) after 3 years of follow-up (no success was defined as: loss of vision,and/or IOP less than or equal to 5 mmHg orgreater than or equal to 21 mmHg).

Both surgical procedures were associated withsimilar IOP reduction and use of supplementalmedical therapy at 3 years.

• Postoperative complications occurred more

frequently after trab, compared with tube-

shunt surgery, but the rate of serious

complications associated with vision loss

and/or reoperation to manage the

complication was similar with both

procedures.


•The TVT Study supports the expanding use

of tube shunts beyond the surgical

management of refractory glaucoma.

•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 postoperative care than tube shunts.

(Gedde SJ, Schiffman JC, Feuer WJ, et al, Tube Versus Trabeculectomy Study Group. Three-year follow-up of the Tube

VersusTrabeculectomy Study.Am J Ophthalmol 2009;148:670-84. )

Minor Trials Comparing Surgeries

• Randomized clinical trials comparingviscocanalostomy with trab generally suggestgreater IOP reduction with trab, and morecomplications with viscocanalostomy.(Yalvac IS, Sahin M, Eksioglu U, et al. Primary viscocanalostomy versus trabeculectomy for primary open-angle glaucoma: three-yearprospective randomized clinical trial. J Cataract Refract Surg 2004;30:2050-7)

• One randomized clinical trial found thattrabeculectomy was more effective than nonpenetrating deep sclerectomy at lowering IOP.

And several others found that the twosurgeries were equally effective.(Chiselita D. Non-penetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma surgery. Eye (Lond)2001;15:197-201.

Cillino S, Di Pace F, Casuccio A, et al. Deep sclerectomy versus punch trabeculectomy with or without phacoemulsification: a randomizedclinical trial. J Glaucoma 2004;13:500-6).

Trials for Laser in Glaucoma

Glaucoma Laser Trial (GLT)

• Newly diagnosed POAG.

• Medical therapy vs. laser trabeculoplasty.

• Initial laser trabeculoplasty lowered IOP more (-9 mmHg)

than initial treatment with topical timolol maleate (-7

mmHg), over 2 years.

• Initial laser trabeculoplasty was at least as effective in

preserving visual field and optic disc status over 5.5 years.(Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study: 7. Results. Am J

Ophthalmol 1995;120:718-31. )

Moorfields Primary Treatment Trial 3

• Newly diagnosed POAG.

• Medical therapy vs. laser trabeculoplasty vs.trabeculectomy .

• Trabeculectomy lowered IOP the most (-60%);laser trabeculoplasty (-38%) and medical therapygroups (-49%).

• Medical group had more deterioration in visualfields than trabeculectomy group.(Migdal C, Gregory W, Hitchings R. Long term functional outcome after early surgery compared with laser and medicine in open-angle

glaucoma. Ophthalmology 1994;101:1651-7. )

All algorithms and tables data are from the European Glaucoma Society.

Terminology and Guidelines for Glaucoma. 4th ed. Savona, Italy: Editrice Dogma

S.r.l.; 2014:127.Available at: www.eugs.org/eng/EGS_guidelines.asp.

Prostaglandin analogues as 1st line of

treatment are based on some facts:

1- Some clinical trials (not multicentre)

2- Effective IOP lowering

3- Less systemic side effect

4- Adherence to therapy (once per day)

5- Introduction of preservative free (bimatoprost

(0.01%) and travoprost BAK-free).

6- Only10% non responders.

No clear evidence against use of beta

blockers as 1st line of therapy; except its

side effects, and twice use per day.

If you can achieve your patient IOP target

by use of beta blockers ........ Go.

Remember; alpha2 agonist or topical

carbonic anhydrase as monotherapy; must

used triple per day to avoid diurnal or

nocturnal IOP fluctuations.

Don’t start by combined therapy as 1st line.

Again .... don’t start by combined therapy as

1st line of treatment.

Unfortunately; adding another drug to PG

analogues don’t increasing its efficacy .... but

not vice versa.

(Higginbotham EJ, Feldman R, Stiles M, Dubiner H. Latanoprost and timolol combination therapy vs monotherapy:

one-year randomized trial.Arch Ophthalmol. 2002;120:915-922)

Anti Glaucoma during

Pregnancy

All IOP lowering drugs are class C (human

risk cannot be ruled out), except

bromindine is class B (no risk evidence on

human; but animal risk may be evidenced)

Laser therapy may be the

safest line for treatment

during pregnancy.

Glaucoma and Neuroprotection

Neurodegeneration occurs at 3 sites; axon,ganglion cell body (retina), andsynapses(brain).

Primary site of damage is debatable (axon orcell body).

Acute high rise in IOP causes damage in cellbody ... to save it; you have 45-90 minutes tointerfere (like CRAO).

Open angle glaucoma cause damage to axons1st; so you have time to interfere.

Drugs that emerged as neuroprotective is

based on interference with pathophysiology

(cannot be detailed here).

The evidence gives the power to

bromindine drops more than any drug.

(Data from Low-pressure GlaucomaTreatment Study, LoGTS).

PG analogues are still lacked clinical trials

evidence as neurorptective in glaucoma ....

However, intravitreal administration of

latanoprost has

demonstrated an

increase in RGC

survival following

trans-section of

the optic nerve !!

Memantine is NMDA receptor

antagonists tablets.

NMDA receptors are activated by glutmate

and nitric oxide, upregulated in POAG, and

increase intracelullar influx of Ca & Na.

The largest randomized, progressive, Phase3 clinical trial on neuroprotection studyingthe safety and efficacy of memantine foropen angle glaucoma has been completed,but it disappointingly failed to meet itsprimary endpoint.

(Osborne NN. Recent clinical findings with memantine should not mean that the idea of neuroprotection in glaucoma is abandoned.Acta Ophthalmol. 2009;87:450–4)

Antioxidants and vitamins E, C & B.

Calcium channel blockers as likenifedipine and verapamil may exertneuroprotection by increasing blood flowto the RGC.

Brain derived neurotrophic factors

(BDNF) drugs also show some clinical

promising but not yet evidence.

Others are still experimental as: anti

apoptotic, gene therapy, immunotherapy and

stem cell therapy.

management of early glaucoma: evidence based medicine

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