A recent study suggesting that 31% of patients with neovascular age-related macular degeneration (nAMD) can safely stop eye injections is dangerously misleading.
Response durability of anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (nAMD) is highly variable among patients. Although clinical trials have shown efficacy for the three Pharmaceutical Benefits Scheme (PBS) listed anti-VEGF agents ranging from four-weekly (ranibizumab) to eight-weekly (aflibercept) to eight-12-weekly (brolucizumab), in the real world some patients still have neovascular activity at four weeks, while others can last up to four months between injections.1 This has led to a preference for the proactive treat-and-extend regimen (T&E) in Australia and the USA. With T&E, patients are treated at each visit, but injection intervals are lengthened if the macula remains dry, and shortened if there are signs of neovascular activity.
This is dangerously misleading. Currently management of nAMD remains a life-long process…
The article, by Cao et al,2 published in the Journal of Clinical Investigation, suggested that 31% of patients who were stable on 12-weekly injections of intravitreal anti- VEGF were able to enter a treatment pause of 30 weeks or greater, one year after initiation of treatment. In addition, the investigators performed proteomic analysis on aqueous fluid to identify proteins that may be associated with treatment need. Apolipoprotein-B100 (ApoB100), found in drusen of non-neovascular AMD, was associated with less frequent injections.
The press release reporting on the article was titled “Study Finds Up to 30% of Patients with Macular Degeneration Can Safely Stop Eye injections”.3 This is dangerously misleading. Currently, management of nAMD remains a lifelong process. A recent prospective cohort study of 102 patients stable on 12-weekly injections with a T&E regimen showed that 52.9% demonstrated recurrence within 12 months.4
Importantly, only 40.7% of patients with recurrent disease showed symptoms of visual loss or metamorphopsia. The Fight Retinal Blindness! Registry showed, in 434 patients, that reactivation rates for nAMD lesions in which treatment had been ceased after three months of inactivity were as high as 41% in the first year and 79% by five years.5 Patients permanently lost over three letters of vision despite reinstatement of treatment. Given that in the majority of nAMD patients, macular neovascularisation recurs if given sufficient time, often initially without symptoms and with irreversible vision loss, it makes sense to continue intravitreal anti- VEGF treatment indefinitely, unless management is considered futile due to extremely poor vision from subretinal fibrosis or atrophy.
Currently, there are no biomarkers to predict the required treatment intensity in patients with nAMD. The finding of aqueous humour protein differences between patients who respond differently to anti-VEGF therapy is valuable and highlights the heterogeneity of this disease. Aqueous humour sampling, however, is not a very practical approach to identifying treatment need in nAMD. In the future, two avenues of research may guide decisions regarding treatment frequency. Firstly, there is emerging evidence that artificial intelligence (AI) algorithms can help predict low-treatment demand even at the first visit, prior to treatment.6 An observational, multicentre, multinational, open-label study (RAZORBILL) is underway to assess the benefit and operational feasibility of AI optical coherence tomography (OCT) segmentation and fluid quantification measurements for treatment of nAMD.7 Secondly, remote (home) OCT monitoring combined with automated analysis may shift the preference for treatment regimen to pro re nata (PRN), where patients are only treated reactively when fluid activity recurs. A pilot study on four patients with nAMD using the Notal Vision Home (spectral-domain) OCT (NVHO) device has already shown that daily self-imaging at home can produce satisfactory scan images and high agreement of automated analysis compared to human grading.8 This still needs to be validated in a larger study, and barriers to this approach include the high cost, device regulation, difficulties for some patients in operating the OCT machine and lag time from when fluid is detected to when a clinic visit can be arranged for an anti-VEGF injection.
In the future, a cure for nAMD may eventually be found. But until then, intravitreal anti- VEGF therapy remains our best effective treatment that must not be stopped.
Adrian T. Fung MMED, FRANZCO, is Clinical Professor, Department of Ophthalmology, Macquarie University Hospital and Clinical Associate Professor, Specialty of Clinical Ophthalmology & Eye Health, University of Sydney.
- Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y, et al. Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR : A Randomized Controlled Trial. Adv Ther. 2020;37(3):1173-87.
- Cao X, Sanchez JC, Dinabandhu A, Guo C, Patel TP, Yang Z, et al. Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy. J Clin Invest. 2022;132(2):18.
- Available from: www.hopkinsmedicine.org/news/newsroom/ news-releases/study-finds-up-to-30-of-patients-with-wetmacular- degeneration-can-safely-stop-eye-injections.
- Aslanis S, Amren U, Lindberg C, Epstein D. Recurrent Neovascular Age-Related Macular Degeneration after Discontinuation of Vascular Endothelial Growth Factor Inhibitors Managed in a Treat-and-Extend Regimen. Ophthalmol Retina. 2022;6(1):15-20.
- Nguyen V, Vaze A, Fraser-Bell S, Arnold J, Essex RW, Barthelmes D, et al. Outcomes of Suspending VEGF Inhibitors for Neovascular Age-Related Macular Degeneration When Lesions Have Been Inactive for 3 Months. Ophthalmol Retina. 2019;3(8):623-8.
- Gallardo M, Munk MR, Kurmann T, De Zanet S, Mosinska A, Karagoz IK, et al. Machine Learning Can Predict Anti-VEGF Treatment Demand in a Treat-and-Extend Regimen for Patients with Neovascular AMD, DME, and RVO Associated Macular Edema. Ophthalmol Retina. 2021;5(7):604-24.
- Holz FG, Abreu-Gonzalez R, Bandello F, Duval R, O’Toole L, Pauleikhoff D, et al. Does real-time artificial intelligence-based visual pathology enhancement of three-dimensional optical coherence tomography scans optimise treatment decision in patients with nAMD? Rationale and design of the RAZORBILL study. Br J Ophthalmol. 2021;06:06.
- Keenan DL, Goldstein M, Goldenberg D, Zur D, Shilman S, Loewenstein A. Prospective, Longitudinal Pilot Study: Daily Self-Imaging with Patient-Operated Home OCT in Neovascular Age-Related Macular Degeneration. Ophthalmology Science. 2021;1(2):100034.