Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Abstract

Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15-40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.

Keywords: anti-VEGF; diabetic retinopathy; macular degeneration; resistant; retinal vein occlusion.

Figure 1

Diagram demonstrating the countering theories regarding the association of the inflammatory cascade and VEGF in the development of retinal pathologies. Hypothesis 1 theorizes that the inflammatory cascade and VEGF are both separate pathways resulting in a breakdown of the blood–retinal barrier, whereas Hypothesis 2 theorizes that the inflammatory cascade results in upregulation of VEGF which in turn leads to the breakdown of the blood–retinal barrier. Common therapeutic options and their targets within these pathways are demonstrated on the Hypothesis 2 diagram.

Figure 2

Example optical coherence tomography for a patient with branch retinal vein occlusion resistant to intravitreal anti-VEGF injections. (A,B) Macular cross-section and thickness map following multiple intravitreal anti-VEGF injections with visual acuity 20/80 and significant macular edema present. The decision was made to treat with a combination of intravitreal dexamethasone implant and anti-VEGF injection at this visit. (C,D) Macular cross-section and thickness map two months after the combination treatment with visual acuity now 20/20 and resolution of macular edema.

Figure 2

Example optical coherence tomography for a patient with branch retinal vein occlusion resistant to intravitreal anti-VEGF injections. (A,B) Macular cross-section and thickness map following multiple intravitreal anti-VEGF injections with visual acuity 20/80 and significant macular edema present. The decision was made to treat with a combination of intravitreal dexamethasone implant and anti-VEGF injection at this visit. (C,D) Macular cross-section and thickness map two months after the combination treatment with visual acuity now 20/20 and resolution of macular edema.

Figure 3

Flow chart of recommend management of anti-VEGF-resistant macular edema in exudative macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. If initial therapy with bevacizumab or ranibizumab fails, then ensuring patient adherence to injection schedule is a key first step. Following this would be a strict injection schedule, one injection every four weeks, and transition to aflibercept if still active. Topical therapy with nonsteroidal anti-inflammatory drugs and, if pseudophakic, steroids can be initiated if the macular edema remains resistant. Intravitreal steroid injections or implants can be added in those eyes without contraindications. Finally, in eAMD and diabetic retinopathy, the addition of laser therapy (photodynamic therapy for eAMD and focal/grid laser or panretinal photocoagulation in diabetic retinopathy) can be considered in those eyes that remain resistant to all of the aforementioned treatments.