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Ophthalmology Management

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Intravitreal anti-VEGF in advanced glaucoma

Tailor your risk-benefit analysis to the individual.

Ophthalmology Management August 1, 2017

An 83-year-old male with a history of neovascular age-related macular degeneration (nAMD) of his right eye (RE), who was receiving quarterly ranibizumab (Lucentis, Genentech) injections at an outside clinic, was referred for continued management of his nAMD. Additional relevant history included bilateral trabeculectomy for end-stage glaucoma as well as a remote history of an ischemic central retinal vein occlusion of his left eye (LE). Notable findings included visual acuities of 20/200 RE and light perception LE, and IOP of 9 mm Hg in each eye with functioning trabeculectomy blebs. A Humphrey 10-2 visual field RE (Figure 1) showed a generalized depression with a small island of remaining vision. Macular optical coherence tomography (OCT) RE (Figure 2) revealed no exudation but did reveal significant thinning of the retina, due in part to severe glaucomatous ganglion cell atrophy. Fluorescein angiography was not available.

Figure 1. Humphrey 10-2 central threshold visual field of the patient’s right eye: The test was reliable based on false-positive, false-negative and fixation loss criteria. The mean deviation was -30.44 DB. A dense, generalized depression can be seen with a small island of remaining vision.
Figure 1. Humphrey 10-2 central threshold visual field of the patient’s right eye: The test was reliable based on false-positive, false-negative and fixation loss criteria. The mean deviation was -30.44 DB. A dense, generalized depression can be seen with a small island of remaining vision.
Figure 2. Spectral-domain OCT of the patient’s right macula: The central subfield thickness was 241 μm. Examination of multiple macular cross sections revealed generalized thinning of the retina, drusen, minimal subretinal hyper-reflective material (SHRM) and no exudation.
Figure 2. Spectral-domain OCT of the patient’s right macula: The central subfield thickness was 241 μm. Examination of multiple macular cross sections revealed generalized thinning of the retina, drusen, minimal subretinal hyper-reflective material (SHRM) and no exudation.

This case mandated careful consideration of the risks and benefits of additional intravitreal anti-VEGF therapy. Heightened risks of treatment included acute and chronic ocular hypertension with additional ganglion cell loss, while benefits were questionable given the inactivity of the choroidal neovascular membrane (CNV) on OCT.

DISCUSSION

Acute IOP after anti-VEGF injections

Intravitreal anti-VEGF therapy has been associated with both acute and chronic ocular hypertension. Immediately following injection, IOP rises sharply to an average of approximately 46 mm Hg and returns to pre-injection levels within 30 to 60 minutes.1-14 Risk factors for a higher IOP spike and slower decline in IOP include the absence of postinjection subconjunctival reflux, smaller needles, tunneled injection techniques and a prior diagnosis of glaucoma.12,15-19

Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy. These medications include apraclonidine, timolol, dorzolamide-timolol, brimonidine-timolol and brinzolamide-timolol, all of which modestly decrease the postinjection IOP spike by an average of approximately 6 mm Hg.20-24 No study has demonstrated a superior efficacy of one topical agent over other topical agents in this setting. Two studies have assessed oral acetazolamide prior to injection and noted no IOP lowering effect, although it is possible that the dosing and timing were not optimized for this indication.20,25 More effective than topical and oral treatments, anterior chamber paracentesis effectively prevents a postinjection IOP spike but introduces additional risks of infection and iatrogenic injury.26

Chronic IOP after anti-VEGF injections

In addition to the short-term IOP spike with each intravitreal injection, some patients are susceptible to chronic, low-grade ocular hypertension following multiple injections.27-30 Post-hoc analyses of some of the major anti-VEGF trials in nAMD and diabetic macular edema have demonstrated this.31,32 On analysis of the MARINA and ANCHOR study results, Bakri et al. noted that the proportion of patients who had at least one visit with an increase in IOP of 6 mm Hg or more from baseline with a concurrent IOP ≥21 mm Hg was 26.1% in the 0.5-mg ranibizumab group, in comparison to 23.6% in the 0.3-mg ranibizumab group and 13.6% in the sham/photodynamic therapy (PDT) groups.32 The proportion of patients with at least one IOP measurement of 21 mm Hg or more was 39.9% in the 0.5-mg ranibizumab group, in comparison to 37.0% in the 0.3-mg ranibizumab group and 29.1% in the sham/PDT groups.32

Risk factors for the development of sustained ocular hypertension include a prior diagnosis of glaucoma, a greater number of injections and a higher injection frequency.33-35 Potential mechanisms for this sustained ocular hypertension include the direct adverse effect of VEGF blockade on trabecular meshwork and collector channel function, damage to the trabecular meshwork from the repeated acute elevations in IOP and damage to the trabecular meshwork from preservatives or other chemicals in the anti-VEGF vials.32

OF SIDE EFFECTS AND RISKS

Possible unintended effects of chronic VEGF blockade on the retina

In addition to the acute and chronic ocular hypertension associated with anti-VEGF injections, long-term VEGF blockage may exert primary untoward effects on the retina. Anti-VEGF therapy appears to dose-dependently increase the risk of geographic atrophy (GA) development and progression, as demonstrated on analysis of three landmark trials.36 The Comparison of AMD Treatments Trials (CATT) showed that injection frequency correlated with new atrophy: 13 injections were associated with a 15% rate of GA, 17 injections were associated with an 18% rate of GA and 23 injections, a 24% rate of GA.37 The Inhibit VEGF in Age-related Choroidal Neovascularization study (IVAN) found that continuous therapy was associated with a 34% risk of new GA in comparison to a 26% risk in discontinuous therapy.38 The HARBOR study revealed similar results.

VEGF-A is known to be a survival factor for endothelial cells and has been shown to protect cultured neuronal cells from ischemic insult.39 Also, VEGF-A has been demonstrated to have a protective effect on retinal ganglion cells.39-41 The specific mechanism through which VEGF isoforms affect the neuronal and glial elements has not been elucidated but may be related to VEGF interaction with neuropilins 1 and 2, which are nontyrosine kinase receptors with roles in nerve cell homeostasis.40

Despite these concerns, no studies have conclusively demonstrated progression of visual field loss or nerve fiber layer loss in patients receiving repeated anti-VEGF injections. However, a subgroup analysis of low-biased studies in a recent meta-analysis found retinal nerve fiber layer thinning with chronic anti-VEGF therapy.42 Further studies are necessary to clarify the long-term effects of anti-VEGF medications on glaucomatous optic neuropathy as well as which patients are at increased risk of damage.

Risks of foregoing anti-VEGF therapy

Foregoing anti-VEGF therapy risks progression of nAMD. The MARINA study demonstrated a dramatic improvement in mean visual acuity of 7.2 ETDRS letters after one year of ranibizumab therapy compared to a loss of 10.4 ETDRS letters without treatment; at one year, monthly treatment decreased the risk of losing 15 ETDRS letters from 37.8% to 5.5%.43 Even a decreased intensity of anti-VEGF treatment in an as-needed regimen may yield an inferior result, as the CATT study demonstrated a mean difference of 2.4 ETDRS letters in favor of the monthly vs. the as-needed regimen after two years.44 The benefit of anti-VEGF therapy has been similarly demonstrated in macular edema due to diabetic retinopathy and vein occlusions.45-47

Recommendations

Numerous studies have demonstrated the dramatic benefits of anti-VEGF therapy in nAMD and other retinal pathologies; further, the therapy is well tolerated in the vast majority of patients. However, in patients with significant glaucomatous optic neuropathy, anti-VEGF therapy may pose increased risks, so practitioners may consider consulting a glaucoma specialist early in its course. Intermittent OCT assessment of the optic nerve may be prudent in patients who develop sustained ocular hypertension following multiple injections.

The benefits of pretreatment with ocular anti-hypertensive agents in these patients has not been well studied. In patients known to experience transient vision loss related to severe acute ocular hypertension following intravitreal injection, an anterior chamber paracentesis would be appropriate. In the future, new glaucoma and retinal therapies as well as delivery systems may limit the risk of clinically significant ocular hypertension in susceptible patients. OM

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About the Author

Peter Bracha, MD, is a resident and Thomas A. Ciulla, MD, MBA, is a volunteer clinical professor of Ophthalmology at Indiana University School of Medicine.

Peter Bracha, MD, is a resident and Thomas A. Ciulla, MD, MBA, is a volunteer clinical professor of Ophthalmology at Indiana University School of Medicine.

Dr. Ciulla is on the Board of Directors of Midwest Eye Institute, an ophthalmic subspecialty tertiary center. He can be reached via e-mail at thomasciulla@gmail.com.

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