Effect of Vascular Endothelial Growth Factor Blockers on Aqueous Humor Dynamics

Intravitreal injection of different anti-VEGF agents such as bevacizumab (Avastin, Genentech,
Inc., South San Francisco, CA, USA) ranibizumab (Lucentis; Genentech, Inc., South San
Francisco, CA, USA) and aflibercept (Eylea, Regeneron, Tarrytown, NY, USA) has been a widely
common practice for treatment of choroidal neovascularization and retinal vascular diseases
[1]. Several ocular and systemic adverse events have been reported with the use of anti-VEGF
agents [7]. Elevation of intraocular pressure (IOP) is a serious ocular adverse event that
may be associated with intravitreal injection of anti-VEGF agents. IOP elevation with
anti-VEGF injection may have variable presentation ranging from acute transient post
injection elevation to the development of persistent IOP elevation that mandates pressure
lowering therapy[8].

Patients with previously existing glaucoma may have a higher rate of persistent IOP elevation
associated with intravitreal injection of anti-VEGF agents. Good et al, reported the rate of
persistent IOP elevation after intravitreal anti-VEGF to be 33% in glaucoma patients versus
3.1% in eyes without previous diagnosis of glaucoma [9]. Tseng et al, reported 25 eyes with
sustained elevation of IOP after serial intravitreal injections of anti-VEGF agents (mean =
20injections). All the 25 eyes were normotensive prior to the study and 23 of them were not
previously diagnosed with glaucoma[10].

Multicenter clinical trials that studied the intravitreal injection of anti-VEGF agents, such
as MARINA and ANCHOR for ranibizumab, VISION for pegaptanib and PACORES for bevacizumab, did
not show sustained IOP elevation with the intravitreal injection of the study agents [12-15].
However, a subgroup analysis of the data of MARINA and ANCHOR trials showed at least 6 mm Hg
increase of IOP from baseline in 2.1% of eyes in MARINA trial and 3.6% of eyes in ANCHOR
trial [16]. A retrospective chart review of 207 patients over a 6-months follow up period
after serial intravitreal injections of anti-VEGF reported an IOP elevation greater than 5 mm
Hg in 2 consecutive visits compared to baseline in 11.6% of the treated eyes versus 5.3% in
control eyes [17].

The pathophysiology of the reported IOP elevation associated with intravitreal injection of
anti-VEGF is unknown. Anti-VEGF compounds might increase aqueous humor inflow by the
breakdown of the blood-aqueous barrier or reduce uveoscleral outflow by the ciliary body
vasculature. These potential changes could translate into elevated IOP and glaucoma.

Inclusion Criteria:

- Subjects must be at least 19 years of age and older

- Ability to give informed consent and attend the study visits

- Patients with established diagnosis of retinal vascular diseases (diabetic macular
edema, neovascular macular degeneration,presumed ocular histoplasmosis syndrome, high
myopia) who require intravitreal injection of anti-VEGF drugs such as
bevacizumab,ranibizumab or aflibercept and are likely to need three monthly doses.

- Patients who have not received intravitreal injections within 3 months of study entry

- No previous established diagnosis of glaucoma and consequently no previous history of
Argon Laser Trabeculoplasty (ALT) or Selective Laser Trabeculoplasty (SLT).

- No previous history of ocular surgery

- Patients who are not planning on and are unlikely to require an elective ocular
surgical or laser procedure within the study duration

- Open angle of the anterior chamber on clinical examination

- Ability to cooperate for aqueous humor dynamic studies

- Contact lenses removed prior to topical fluorescein instillation, and not used until
the end of each fluorophotometry session

- Able to participate on site over the multi-visit study period

Exclusion Criteria:

- Age less than 18 years of age

- Women who are pregnant or nursing

- Ocular hypertension or glaucoma

- Narrow angle with complete or partial closure (gonioscopy angle <2)

- Any previous surgical or laser procedures

- Secondary glaucoma including pigmentary, exfoliative, uveitic and traumatic glaucomas

- Any active neovascularization of the iris, angle, disc or retina

- Diagnosis of retinal arterial or vein occlusion

- Chronic or recurrent inflammatory eye disease

- Ocular trauma within the past 6 months

- Ocular infection or ocular inflammation in the past 2 months

- Any abnormality preventing reliable fluorophotometry of either eye,such as corneal
scarring or severe dry eye that results in punctuate fluorescein staining of the
cornea

- Intraocular surgery within 6 months

- Serious hypersensitivity to any components of the study medications or risk from
treatment with glaucoma medications, such as severe asthma or emphysema.

- Use of any glucocorticoid by any route. Subject must be washed out of the
glucocorticoid for at least 2 weeks before study entry.