One of the primary clinical goals in the treatment of neovascular age-related macular degeneration (nAMD) is drying the intraretinal fluid (IRF) and subretinal fluid (SRF) that is detected via optical coherence tomography (OCT). In addition to OCT features of IRF and SRF driving more than 90% of U.S. retina specialists’ treatment decisions,¹ there are data supporting that extinguishing the fluid—especially IRF—leads to better visual outcomes.^2,3

There are several small and/or retrospective studies that have shown that pure SRF may not have a detrimental impact on vision,^4,5 and there has been a recent, moderately large randomized controlled trial supporting tolerance of SRF.⁶

In the clinical setting, it can be difficult to translate a tolerance of SRF into effective clinical practice. There are large, real-world data sets showing that fewer injections lead to poorer visual outcomes in broad populations,⁷ and tolerating fluid inherently supports less-frequent treatment. Prescribers must remain vigilant for disease activity and our data suggest that clinicians must beware of under-treatment.

In the clinic, almost 99% of U.S. retina specialists practice either treat-and-extend (TAE) or as-needed (PRN) injections, with the majority practicing TAE.¹ The indication for retreatment with these dosing plans is often OCT detection of exudative disease activity, specifically the persistence or recurrence of IRF and/or SRF. In the common TAE setting, the injecting surgeon has the option to either contract the injection interval or change the injectable agent upon the detection of exudative activity. For a patient who cannot extend to a tolerable interval with a dry OCT on any given agent, the injecting surgeon will often decide to switch the patient to a different available agent.

ASSESSING SWITCHING AGENTS

There have been a variety of clinical trials assessing switching patients from one agent to another. Most of these are uncontrolled retrospective case series, and have several limitations.⁸ Even with the limitations in the data, there is only a single class of commercially available therapeutic agents to treat nAMD in 2021 to date, and there is some rationale that switching may lead to better anatomic and visual outcomes for a subset of patients with particular genetic features favoring one drug over another, or for whom design-related or pharmacodynamic characteristics of a specific anti-VEGF drug might be beneficial.

In the clinic, I practice as a fairly typical TAE prescriber. There is a good amount of randomized, controlled, prospective data supporting gradual extension,^9-11 and there is data supporting 2-week extensions as superior to 4-week extensions.¹² However, in all of the TAE literature, patients only extend out to 12 weeks or more about 15% to 50% of the time regardless of agent, with a large range of successful 12-week extension, depending upon the criteria of the study. Most patients still require relatively frequent treatment, and I do switch between commercially available agents when extension cannot be achieved to an interval tolerable for the patient.

Fortunately, we have four readily available commercial agents in 2021—including off-label bevacizumab (Avastin; Genentech) and excluding FDA-approved pegaptanib-sodium (Macugen; Bausch + Lomb)—with brolucizumab (Beovu; Novartis) expanding our options following its approval in October 2019.

ASSESSING DOSING

The goal with anti-VEGF treatment is to achieve the best possible visual outcome. With that in mind, my typical dosing for a treatment-naïve patient is to start with monthly induction injections until there is both a plateau in anatomy and a plateau in vision. The ARIES trial¹³ showed that there was a significant visual benefit in initiating TAE dosing later after a period of fixed dosing, so I err toward more induction doses rather than fewer. There are some patients who do not achieve a dry macula even with monthly loading doses of their initially selected anti-VEGF agent, and those are the easiest patients to select for a switch. I will often initiate a switch after about 2 or 3 loading doses, if there is persistent IRF and/or SRF with monthly dosing.

There is a larger group of patients who fail extension at relatively short intervals. If a patient cannot extend to 6 or 8 weeks without recurrent fluid, that patient may be a good candidate for a switch to another anti-VEGF agent.

The largest group of patients for a potential switch is those who have established that they can tolerate extension without OCT exudative activity out to 8 to 10 weeks, but show a recurrence at longer intervals and have a difficult time maintaining their ongoing appointments, or they express a desire to extend further. I talk with these patients about the option of switching, and some of them want to try an alternative treatment with attempted further extension.

CONCLUSION

It is important for patients to understand that anti-VEGF therapy for nAMD is a chronic maintenance treatment for a chronic disease, and that all of our data supports q12 to q16 week treatment as a reasonable maximum maintenance target interval for many patients in 2021.

It is also important to explain to patients that an extension to that interval is an aspirational goal, and fewer than half of patients can achieve these longer extension intervals over time. I assure my patients that I will try to reduce their treatment burden as much as possible while maintaining vision. I also tell them that anatomic maintenance is more important than fewer injections.

The chronicity of nAMD and the ongoing need for VEGF suppression is the standard of care in 2021, but we can hope for a further reduction in treatment burden with novel mechanisms of action, delivery devices, and the promise of gene therapy in the years to come.

CASE STUDY

Nov. 30, 2020: A 79-year-old pseudophakic male presents as a seasonal resident complaining that his vision remains poor despite 4 to 5 years of bilateral monthly aflibercept (Eyelea; Regeneron) injections. He reports difficulty reading and driving, and states that: “I want to try anything else to improve my vision.”

Dec. 30, 2020: The patient is 1 month from his last aflibercept injection OU. His vision is 20/50- OD and 20/100 OS. OCT OD shows a pigment epithelial detachment (PED) with intraretinal hyperreflectivity and trace SRF at the apex of the PED. OCT OS shows a shallow bilobed PED with significant SRF and mild IRF (Figure 1). The patient and I discuss the option of trying brolucizumab in his worse-seeing eye. We talk about the risk of intraocular inflammation and vascular occlusion associated with a small percentage of brolucizumab patients. He elects to proceed with aflibercept injection OD and brolucizumab injection OS.

Jan 27, 2021: Upon return to the clinic, the patient reports that: “My vision in the left eye is much better.” Acuity is now 20/40- OD and 20/50 OS. There is essentially unchanged stable anatomy OD, consistent with the patient’s reports of stability with regular aflibercept injection, and improved anatomy with a reduction of PED, essentially resolved SRF, and organization of the retina OS (Figure 2). The patient elects to proceed with brolucizumab injection OU. ◆

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