Glaucoma studies, IOP and treatment rationale W. H. Morgan RPH, LEI and PMH

The importance of IOP A Sommer, Arch Ophthalmol, 1991; 109:1090, <= >= 35 IOP (mmHg) Relative risk of POAG at 5 years IOP IOP in normals and glaucoma Graham and Hollows normal glaucoma It is the most potent risk factor, but one third of glaucoma patients have a pressure reading of less than 21mmHg.

Typical problem Mrs G, 1999 referred with Hx IOPs yo lady FH - Mother Dx 40, surgery –Sister Dx 18, surgery IOP 18, 18 Angles open Fields HFA 24-2 normal Disks

Mrs G HFA, 1999

Mrs G – B/Y HFA, 2000

Mrs G optic disks, 2000

What is the knowledge? OHTS – IOPs 21 – 32 OU (5 years) –Follow up 5 years –4.4% risk in treated group (IOP 19.3) –9.5% in untreated group (IOP 23.9) –Mean 20% IOP reduction –Rel risk per mmHg IOP = 1.11 –Corneal thickness per 40um = 1.88 »613um - RR 1.0 »571um - RR 1.7 »530um - RR 3.4 –83um approx 3.5mmHg IOP change (2mmHg/50um) –Age, VCDR, Oral Ca ++ blockers, Heart disease –NOT migraine, FH, BP –Diabetes appeared protective! Gordon MO, OHTS study group. Archives Ophthalmol 2002

% conversion to glaucoma by IOP and CCT IOP > %13%6% IOP >23.7 < %10%7% IOP < %9%2% <555>555 <588 >588

What is the Evidence that IOP Reduction in OHT Reduces the Occurrence of Glaucoma? Module 2 Lowering IOP in OHT significantly reduces the risk of progression to glaucoma IOP, intraocular pressure; OHT, ocular hypertension. Peeters et al. Acta Ophthalmol. 2010; 88:5-11.

% conversion to glaucoma by VCDR and CCT VCDR ≥ 0.522%16%8% VCDR > 0.3 < %16%4% VCDR ≤ 0.315%1%4% <555>555 <588 >588

Can think in terms of Numbers needed to treat to prevent conversion to Glaucoma NNT for average OHT is 20 –100 / (9.5 – 4.4) from OHTS NNT for OHT with IOP ≥ 26 is 6 NNT for OHT with IOP ≥ 26 and CCT < 555 is 3.5 Thomas R, J Glaucoma, 2005

What else did we do? Corneal thickness 530um Genetic studies –I still take FH seriously –Myocilin 2%, Optineurin 0.2% –Other unknown haplotypes Reviewed 12 monthly Annual HFA, later B/Y Disk photos every 2 nd year

Disk photos late 2002

Disk photo 2000

FDT

Diagnosis POAG Disk change on flicker and FDT ? NTG Lets call it POAG - NTG

Is this NTG Results from CNTGS Progression more common in –Women rr = 1.85 –Migraine rr = 2.58 –Disk Hgerr = 2.72 Not significant was –Initial (untreated) level of IOP –Age 35% of controls progressed 12% of treated progressed –Protocol defined endpoint Collaborative normal tension glaucoma study group, AJO, 1998

CNTGS and therapy Treatment = 30% IOP reduction –Medical or surgical Data removed if cataract occurred More likely with surgery 2:1 ratio

Natural history NTG Follow up just > 3 years Mean MD loss –0.41dB/yr

Should we treat this There is disk damage occuring There is some benefit in therapy NTG really a continuum with POAG Worth looking at EMGTS

We want to stop more loss! EMGTT (IOP < 30, MD < 10 & 16, 6 yrs) Randomized to Rx or No Rx Rx Laser + betaxolol –IOP = 1.11 /mmHg –Disk rim haemorrhages 1.02 /%visits –Pseudo-exfoliation –MD > 4, RR = 1.46 –Corneal thickness < 548um, RR 1.25 Progression in 62% controls –Vs 45% treated NNT 6 Reduction of IOP and Glaucoma progression EMGTT, Heijl, Archives Ophthalmol 2002

EMGTT Progression in 62% controls –Vs 45% treated NNT 6 Average IOP reduction was 5.1mmHg –Or 25%

Evidence that IOP is an Important Risk Factor for Progression in Glaucoma Module 2 Relationship between IOP and risk for progression TrialRisk Hazard ratio (95% CI) Early Manifest Glaucoma Trial 1 10–13% decrease per mmHg 0.90 (0.86–0.94) Ocular Hypertension Treatment Study 2 10%* increase per mmHg1.11 (1.04–1.17) European Glaucoma Prevention Study 3 12%* increase per mmHg1.12 (1.03–1.23) Canadian Glaucoma Study 4 19%* increase per mmHg1.19 (1.05–1.36) IOP, intraocular pressure. *Increased risk per mmHg of higher follow-up IOP.

Evidence that Intraocular Pressure is a Risk Factor in Glaucoma Module 2 Increased IOP is the most important and the only treatable risk factor for both development and progression of glaucoma Jiang et al. Ophthalmology 2012;119:2245–53. IOP, intraocular pressure.

Evidence that Intraocular Pressure is a Risk Factor in Glaucoma Jiang et al. Ophthalmology 2012;119:2245–53.

Main thing is IOP! Rather – we don’t understand or are able to alter others Curve shifting “fragility” factors Disk Hges Severity of G Others Neurotoxicity Vessels Lamina  Migraine Myopia

Medical or Surgical CIGTS interim results (4.5yrs) No sig diff in field change VA drop with surgery –Evens out at 4 years Cataract surgery 17% vs 6% in Sx Lets go medical to start with! Collaborative initial glaucoma treatment study, Lichter P,

Practical tips May treat one eye first –Especially if IOP low –Depends how urgent the other eye is Use the other eye as a control Try to pick a target IOP –Below 20 –25% reduction –  15 if NTG or severe G –Tending to go for IOP based upon severity »And modified by CCT

Side Effects Prostaglandin antagonists Iris darkening + lash growth Conjunctival hyperaemia Uveitis (Lat + Trav, probably Bimat) CME (Lat, Trav, Bimat & Unoprost) Reactivation of HSK (rare) Don’t add one on top of another! –Eg Bimat + Lat ?Less effect in pseudophakes –Much less in aphakes

 -Blockers Asthma Depression, loss of energy etc Impotence, –mention this one because they won’t!

Brimonidine Allergic conjunctivitis –You can tell who is on alphagan Useful in those with  -Blocker problems Can lower BP ? Depression Has additive effect on top of  -Blockers

Dorz & Brinzolamide Least effective aqueous suppressants But safest Brinzolamide ? Better tolerated However Cosopt is quite useful

Miotics Very useful in aphakes & capsule loss pseudophakes Phospholine Iodide was the best –No longer available Carbachol has longer ½ life cf pilocarpine

In Mrs G Probably a Prostaglandin antagonist Treat RE first and watch Aim for IOP  15 Check fields (which type)

Risk of going blind from Glaucoma Review of 423 subjects who Died between 2006 – 2010 And who had definite glaucoma Field testing by HFA Looking at Who went blind Baseline and other risk factors Peters et al. Am J Ophthalmology 2013;156:724–30.

What is the Risk of Blindness in Glaucoma? Module 2 Unilateral and bilateral blindness from glaucoma linked to duration of disease; After 15 years, there is a 50% risk of blindness in one eye This is the total risk that an individual has of developing blindness from glaucoma during the whole of the 15-year span from diagnosis The risk of blindness in both eyes is ~20% Peters et al. Am J Ophthalmology 2013;156:724–30. Lifetime risk for blindness since diagnosis; 16% - Both eyes 43% - One eye

Baseline Factors Associated with Lifetime Risk of Open-Angle Glaucoma Blindness Module 2 Higher IOP Worse visual field status at baseline Peters et al. Acta Ophthalmol ; 92: Risk factorsReferenceOR (95% CI)p GenderMen1.43 (0.81–2.50)0.216 IOP (at diagnosis)*,† Per mmHg higher1.10 (1.06–1.15)< IOP (untreated)*,‡ Per mmHg higher1.08 (1.04–1.12)< Exfoliations*No1.74 (0.97–3.14) 1.80 (0.99–3.28) § 1.34 (0.71–2.55) ¶ Bilateral glaucomaNo2.23 (1.30–3.83)0.004 Age at time of diagnosisPer year older age0.99 (0.96–1.02) 0.97 (0.93–1.00) 0.97 (0.94–1.01) ** †† Disease stage*Per MD stage2.16 (1.64–2.84)< IOP, intraocular pressure; MD, mean deviation; OR, odds ratio.

Factors Associated with Lifetime Risk of Open-Angle Glaucoma Blindness Module 2 Rates of glaucoma blindness for different levels of IOP and mean deviation at the time of diagnosis For example, if MD is –12 dB and IOP > 25 mmHg, then rate of blindness is 50% Higher IOP and MD result in a greater risk of blindness IOP, intraocular pressure; MD, mean deviation. Peters et al. Acta Ophthalmol. 2014; 92:

Factors Associated with Lifetime Risk of Open-Angle Glaucoma Blindness Module 2 Higher IOP Worse visual field status at baseline Older age Peters et al. Acta Ophthalmol. 2014; 92: Risk factorReferenceOR (95% CI)p IOP* (at diagnosis)Per mmHg higher1.08 (1.03–1.13)0.001 Disease stage* (at diagnosis) Per MD stage1.80 (1.34–2.41)< Age at time of deathPer year older age1.09 (1.03–1.14)0.001 IOP, intraocular pressure; MD, mean deviation; OR, odds ratio. *Values are based on the perimetrically better eye at the time of diagnosis.

Prognosis Retrospective study of 295 patients with newly diagnosed open-angle glaucoma in Olmsted County, MN –Newly diagnosed glaucoma –Probability of blindness after 20 years » 54% in one eye; 22% in both eyes –Of 114 patients initially treated for OHT »Probability of blindness after 20 years 14% in one eye and 4% in both eyes But used GOLDMANN Fields to diagnose OHT=ocular hypertension. Hattenhauer MG et al. Ophthalmology. 1998;105:

Risk of going blind in both eyes 20 years after diagnosis

Risk of going blind in one eye after diagnosis

Absolute IOP and %IOP reduction in those going Blind vs not Blind

Rates of blindness in WA from glaucoma Yong, Morgan, Cooper et al Ophthalmic Epidemiology 2006

Summary IOP clearly related to –Development of glaucoma –Progression (worsening) of glaucoma –Therapy to lower IOP improves this But, patients still go blind –25 – 50% in one eye at 20 years –This is scary –Rates of blindness have halved in WA in 20 years –But some people have bad disease and while Rx slows it – it does not stop