Considering the widespread prevalence of the conditions treatable with intravitreal injection of anti-VEGF agents, a question naturally arises: which ophthalmologists should administer this treatment? Should the use of intravitreal injections for blinding retinal diseases be the sole purview of fellowship-trained retina specialists, or should comprehensive ophthalmologists also administer these treatments?

In this article, I make the argument that the treatment of retinal diseases with anti-VEGF agents should be primarily done by retina specialists, with use of these treatments by comprehensive ophthalmologists relegated to special situations such as when a retinal specialist is not reasonably available to the patient.

ANTI-VEGF OVERVIEW

Prior to 2004, intravitreal injections were a relatively rare procedure. They were performed most commonly to administer intraocular steroids for macular edema and antibiotics to treat intraocular infections associated with viral, bacterial or fungal agents. The FDA’s December 2004 approval of the anti-VEGF agent pegaptanib (Macugen) for the treatment of neovascular AMD ushered in a new era for this procedure by opening up a new indication for the intraocular administration of therapeutic agents. Pegaptanib’s approval was followed by retina specialists’ rapid adoption of off-label intravitreal bevacizumab (Avastin, Genentech) in 2005 and the FDA approvals of ranibizumab (Lucentis, Genentech) in 2006, aflibercept (Eylea, Regeneron) in 2011 and brolucizumab (Beovu, Novartis) in 2019.

Since that first FDA approval of an anti-VEGF agent for neovascular AMD in 2004, these biopharmaceutical products have been approved for the treatment of additional conditions, including:

• Macular edema associated with retinal vein occlusions (Lucentis, 2010; Eylea, 2012)
• Diabetic macular edema (Lucentis, 2012; Eylea, 2014)
• Diabetic retinopathy in eyes with diabetic macular edema (Lucentis, 2015; Eylea, 2015)
• Myopic choroidal neovascularization (Lucentis, 2017)
• All forms of diabetic retinopathy (Lucentis, 2017; Eylea, 2019).

Anti-VEGF agents are also used off label for other ocular vascular diseases. These include iris neovascularization and retinal neovascularization secondary to other underlying conditions including (but not limited to) ocular ischemic syndrome, radiation retinopathy and retinopathy of prematurity.

The development of multiple anti-VEGF agents and the evolution to multiple treatment indications of these agents for relatively common retinal diseases gave rise to explosive growth in the number of intravitreal injections in the United States and around the world.

INTRAVITREAL INJECTIONS AND OPHTHALMOLOGISTS

Any ophthalmic surgeon should be capable of learning the basic technique of an intravitreal injection, and most ophthalmology residents gain experience with intravitreal injections of anti-VEGF agents during their residency. However, the technical ability to perform an intravitreal injection does not necessarily imply that one possesses, or can maintain, the full range of knowledge and judgment to properly manage intravitreal injections and the variety of complex retinal diseases encountered in clinical practice. For instance …

CONTRAINDICATIONS AND COMPLICATIONS

Those performing intravitreal injections should be aware of contraindications to treatment, such as active external eye infection, including conjunctivitis, meibomianitis and significant blepharitis. Such conditions may increase the risk of endophthalmitis; ideally, they should be treated and controlled prior to initiation of treatment. Proper preparation of the eye using adequate anesthesia, infection prophylaxis and safe injection technique is critical.

The clinician must have the experience to identify immediate post-injection complications (such as central retinal artery occlusion) and should be capable of recognizing when an immediate anterior chamber paracentesis is required. The ability to perform the paracentesis in a timely, safe and effective manner, especially in the high-pressure situation of an anxious patient whose eye has suddenly lost light perception, is imperative.

Other complications of intravitreal injections include intraocular inflammation, retinal detachment or perforation, traumatic lens damage, intraocular hemorrhage, sustained ocular hypertension and hypotony. The treating physician should ideally be capable of managing each of these complications should they occur.

While glaucoma is not a contraindication to intravitreal injections, a glaucoma-compromised optic nerve is more susceptible to the progressive visually significant changes associated with repeated elevations in IOP immediately following injections. Eyes without pre-existing glaucoma may develop progressive increased optic nerve cupping and vision loss with multiple injections. The treating physician should have a heightened sensitivity to these developments and be prepared to properly manage them.

Of all post-injection complications, endophthalmitis has the greatest potential to be visually devastating. Although uncommon, endophthalmitis may develop as soon as 1 day or as long as 1 to 2 weeks after an injection. Distinguishing between infectious endophthalmitis and sterile post-injection inflammation can be difficult.

The treating physician should be prepared to monitor inflamed eyes closely and have a low threshold to treat with immediate vitreous tap (for culture) and injection of intravitreal antibiotics. Urgent vitrectomy may be considered.

Pseudo-endophthalmitis has been reported with all of the anti-VEGF agents and may range from mild to severe. Recently, there have been reports of severe but delayed onset of retinal vasculitis and severe vision loss associated with one of the newer agents (https://www.aao.org/headline/brolucizumab-s-safety-under-review ).

DISEASE AND TREATMENT UNCERTAINTIES

The diseases treated with anti-VEGF agents are complex with varied presentations, natural courses and responses to treatment. Every case of neovascular AMD or retinal vein occlusion or diabetic retinopathy is not the same. What to treat, when to begin treatment, when and how frequently to treat or whether to discontinue treatment can be difficult decisions with major implications for the patient’s vision.

Determining when an eye has transitioned from dry to wet AMD can be challenging. Some eyes may have indolent occult neovascular AMD that may remain stable for a prolonged period without intervention. Previous experience and close monitoring of these eyes is imperative and can inform the treating physician when treatment is indicated.

An eye with a pigment epithelial detachment may or may not have associated choroidal neovascularization and may or may not benefit from treatment. Extensive experience with these eyes can help the clinician make an informed therapeutic decision. An eye with neovascular AMD may have type 1, 2 or 4 CNV, retinal angiomatous proliferation and/or polypoidal choroidal vasculopathy. Each of these subcategories of wet AMD may respond differently to anti-VEGF agents. Some are better treated with thermal laser or photodynamic therapy rather than with anti-VEGF agents.

Other uncertainties include:

• Whether to add an intraocular steroid to the regimen
• What to do in the event of a retinal pigment epithelial detachment
• Whether fibrosis in a lesion indicates stability
• Whether and how long to treat an eye with poor vision
• How to manage a well-seeing eye when the fellow eye has poor vision
• How to manage an eye with evidence of recurrent CNV.

Some eyes with macular edema, whether associated with retinal vascular occlusion or diabetic retinopathy, may have good visual acuity. Whether and when to treat these eyes is a challenging decision. Macular edema in some eyes may not respond well to anti-VEGF agents.

Some of these eyes may respond to a combination of intravitreal steroids in addition to ongoing anti-VEGF therapy. Adding steroids increases both the intensity of therapy and the risk of treatment side effects.

Eyes with retinal vascular occlusions and/or diabetic retinopathy often have significant associated capillary non-perfusion that impacts response to therapy and long-term prognosis. Many of these eyes can benefit from laser treatments in addition to anti-VEGF therapy. Whether, when and how to add laser to the treatment mix is another set of complex considerations best informed by extensive experience. Proliferative retinopathy will respond to anti-VEGF agents, but long-term stabilization cannot be achieved with anti-VEGFs alone. Panretinal photocoagulation (PRP) is still required — when and how to add PRP to the therapeutic mix is another challenge.

PRACTICE MANAGEMENT’S ROLE

The anti-VEGF drugs available in the United States are expensive, so careful financial management is imperative to the fiscal health of a practice. Navigating the wide variety and frequently changing insurance rules such as step therapy, pre-authorizations, deductibles and co-payments is a challenge that requires significant internal resources. Managing various patient assistance programs is extremely important to protect the practice’s financial status and to protect patients from unexpectedly large medical bills. This too requires robust practice resources.

While simply using bevacizumab as one’s default anti-VEGF agent may initially seem like an attractive way to avoid the complexities of the anti-VEGF agents, this approach seriously shortchanges patients with regard to choice, potential effectiveness and risk of complications.

ISSUES IN A COMPREHENSIVE OPHTHALMOLOGY ENVIRONMENT

More than ever, comprehensive ophthalmology practices are laser-focused on achieving near-perfect vision in their cataract and refractive patient population. The personnel, culture and even physical plant of the organization are all designed to serve this mission. Patients with blinding retinal diseases requiring anti-VEGF therapy are a very different category.

Their needs are unique and require a different set of practice imperatives for optimal care. Mixing a population of 20/15 multifocal IOL patients with one that includes disciform scars and legal blindness is simply incongruous.

CONCLUSION

Patients are best served with a highly focused, expert approach in an environment specially designed for their specific diseases. Within ophthalmology, a division of labor between retina specialists treating retinal diseases with anti-VEGF therapy and comprehensive ophthalmologists managing non-retinal diseases is in the best interest of patients. OM

About the Author

David F. Williams, MD, MBA, is a fellowship-trained retina specialist practicing with Vitreoretinal Surgery, PA in Minnesota. He is a past president of the American Society of Retina Specialists.