Effect of Vascular Endothelial Growth Factor Blockers on Aqueous Humor Dynamics

Effect of Vascular Endothelial Growth Factor Blockers on Aqueous Humor Dynamics

The objective of this research is to determine the effects of anti-VEGF drugs (bevacizumab, ranibizumab or aflibercept) on aqueous humor dynamics (AHD) in patients with retinal vascular disease. The underlying hypothesis is that anti-VEGF drugs increase intraocular pressure (IOP) by increasing aqueous inflow, decreasing uveoscleral outflow or both. The specific aim is to evaluate the changes produced in AHD after 1 baseline and a subsequent 1 monthly injection of anti VEGF agents.

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.