A commonly used treatment paradigm in the management of neovascular age-related macular degeneration (nAMD) is the treat-and-extend (TE) strategy, which uses serial optical coherence tomography (OCT) and visual acuity results for adjustment of intravitreal anti-VEGF agent treatment intervals. This strategy is backed by strong evidence.¹  

The treat-extend-stop (TES) variant of the treat-and-extend protocol allows for withdrawal of ongoing anti-VEGF treatment for nAMD when the treatment interval reaches 12 weeks and the lesion remains inactive for 3 consecutive visits.² The possibility of withdrawal of anti-VEGF treatments is attractive to patients, giving them a “goal” and a hope for conclusion of ongoing treatment. It is also an attractive idea for physicians, because there are possible side effects associated with long-term anti-VEGF administration, including geographic atrophy.³  

However, withdrawal of periodic anti-VEGF dosing may be complicated by breakthrough reactivation of choroidal neovascularization (CNV) when total regression of CNV has not occurred. There is likely to be a delay between reaching subtherapeutic anti-VEGF levels in the vitreous (which we do not currently measure) and “disease recurrence” as measured by anatomy on OCT.  

Currently there is insufficient evidence regarding withdrawal of anti-VEGF treatment for nAMD, including patients with (1) good visual potential who have been extended to treatment periods at consecutive 12-week intervals or (2) those with end-stage disease with widespread macular photoreceptor disruption/disciform scarring (due to the exclusion of these end-stage AMD eyes in clinical trials).  

In eyes with better visual potential, there are studies indicating that vision can be regained if reactivation occurs and is detected and treated. One such study with the TES regimen reported a 30% recurrence of CNV after treatment suspension (mean follow-up 14 months) with good recovery of vision after resumption of treatment.⁴ Additionally, a separate retrospective analysis examining treatment suspension in eyes that had received 3 consecutive injections at 16-week intervals found promising results, with only a 13% recurrence rate (after a mean follow-up of 37 weeks).⁵  

In contrast to this, withdrawal in eyes with better vision potential may be harmful due to consequences of breakthrough reactivation of CNV. One report observing results of withdrawal of treatment in eyes in which the neovascular lesion was inactive for at least 3 months indicated a 91% rate of recurrent lesion activity over a mean follow-up of 18 months, with a mean consequential vision loss of approximately 2 Snellen lines at the time of reactivation discovery.⁶  

In those with advanced nAMD and vision less than or equal to 20/400 with a treatment pause of at least 6 months, a recent study suggests that withdrawal of treatment after serial anti-VEGF injections may be a reasonable strategy, if the treating physician deems additional treatment is unlikely to provide benefit.⁷ However, in that study, 7.5% of eyes needed a restart in treatment after a mean of 977 days after treatment suspension, for reasons which included recurrent active CNV and new hemorrhage. 

Ideally, in the future, the issue of whether to discontinue⁸ anti-VEGF treatment for neovascular AMD may be irrelevant if constitutive anti-VEGF expression following a session of gene therapy becomes a reality.  The reality of today, however, is that this is not an option. Therefore, the controversy is whether eventual withdrawal of anti-VEGF therapy should be a goal with current agents. We are fortunate to have the commentary of Anat Lowenstein, MD, MHA, and Diana Do, MD, FASRS, regarding their thoughts on this issue.

The Treat-Extend-Stop Protocol

Anat Loewenstein, MD, MHA

The treatment paradigm using mainly a TE regimen with anti-VEGF for AMD is well established. There is no consensus among experts, however, regarding clear criteria to determine treatment futility and timing to stop treatment. One obvious reason to stop treatment is when the response to treatment is not sufficient because the diagnosis of neovascular AMD was made incorrectly, for example in a case that is actually MacTel or central serous chorioretinopathy. A less obvious scenario is where there is lack of treatment benefit in a correctly diagnosed patient with neovascular AMD. 

The TES protocol was proposed by Adrean et al, aiming to prevent unnecessary injections.¹ They found that only 9.9% of study population lost 3 lines or more while being followed up for 8 years, agnostic to the anti-VEGF utilized. The researchers’ TES protocol is performed as follows:

Therapy begins with at least 3 monthly injections of an anti-VEGF agent, until a relatively “dry” macula is confirmed by OCT.

If the macula remains free of fluid, the intervals between injections are extended by 1 to 2 weeks between consecutive visits, until a 12-week time interval is reached.

If the patient has received at least 7 total injections, and if OCT at 3 consecutive 12-week visits confirms that CNV has not recurred, the injections are stopped.

Patients return 1 month later and then successively longer by 2-week intervals until 12 weeks is reached. These patients are then monitored quarterly for signs of recurrence.

The TES regimen alleviates treatment burden and cost. If and when one employs an exit strategy from a TE regimen, the exit criteria should be scientifically acceptable among experts, and in this case, there is still no consensus.  

Arendt et al proposed these criteria: 3 consecutive injections 16 weeks apart with stable findings with a follow-up of 3 to 4 months without treatment. Still, recurrence of disease activity occurred among 13% after 37 weeks, and with a higher rate of pigment epithelial detachment.⁶ Thus, one should use this exit strategy with caution and maintain strict patient monitoring. 

Another study conducted by Nguyen et al⁵ found that around 40% of included eyes showed reactivation of CNV within 1 year of treatment suspension, increasing to about 80% at 5 years. It is crucial to ensure minimal risk of CNV reactivation before deciding to stop treatment, to avoid significant vision loss, as some patients can lose vision even if the treatment is resumed eventually. In general, eyes with lower vision and longer treatment duration have a lower risk of reactivation. 

Retina specialists should be highly aware of the danger of CNV reactivation when using the exit criteria in the TES regimen. Further studies are needed to reach a large consensus regarding the definition of the exit criteria.

Eliminating Disease Activity Is the Goal in Managing Neovascular AMD

Diana V. Do, MD, FASRS

Clinical trials have repeatedly proven the vision and vision-related quality of life benefits associated with  long-term anti-VEGF treatment of nAMD, a chronic disease driven by VEGF.^9-12 Dr. Michael Colucciello thoughtfully asks whether eventual withdrawal of anti-VEGF therapy should be a goal with our current agents.

If a medicine is safe and effective in controlling a progressive disease, why stop it? The burden of frequent office visits and intravitreal anti-VEGF injections has led to injection fatigue and undertreatment. Retrospective studies have shown that undertreatment of neovascular AMD in clinical practice leads to suboptimal visual acuity outcomes.¹³ 

Most retina specialists prefer the TE regimen when using intravitreal anti-VEGF therapy. Treat-and-extend allows a personalized approach to each patient, finding the appropriate interval between anti-VEGF injections and hopefully reducing unnecessary office visits and injections.^14,15 The goal of therapy is to eliminate and suppress choroidal neovascularization activity and preserve or improve vision. The goal is not necessarily to withdraw anti-VEGF agents over time.

As Dr. Colucciello noted, there is insufficient evidence regarding withdrawal of anti-VEGF treatment for neovascular AMD. Most individuals with neovascular AMD need chronic and often lifelong monitoring and treatment. Although many physicians may have a minority of patients that can be weaned off anti-VEGF therapy due to inactive CNV, macular atrophy, or fibrosis, most patients still require monitoring and treatment for active disease, albeit at longer intervals.^5,6 Cessation of anti-VEGF therapy could put the patient at risk of vision loss due to breakthrough hemorrhages or reactivation of the CNV.

With the advent of new FDA-approved medicines such as aflibercept 8 mg and faricimab, the intervals between treatments could possibly reach 12, 16, or even greater than 20 weeks during the first 2 years of treatment.^16,17 Longer term follow-up studies with these new anti-VEGF agents will give retina specialists more insight on the durability of these medicines at years 3 and beyond. In addition, clinical trials evaluating the use of gene therapy to produce anti-VEGF antibodies within the eye or use of novel anti-angiogenic targets may provide other durable treatment option for patients. 

The most important goal of treatment for neovascular AMD is to eliminate or suppress the destructive activity of the CNV. The aim is not to wean off anti-VEGF injections, especially because these medicines are essential to control the pathology behind the disease. Individualizing the frequency of anti-VEGF injections is important to engaging the patient while effectively treating their eye disease. New medicines will help answer the unmet need for durability and disease control. RP

Michael Colucciello, MD, is a clinical associate at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia and a retina specialist with the South Jersey Eye Physicians Division of Prism Vision Group in Moorestown, New Jersey.

References 

Chaikitmongkol V, Sagong M, Lai TYY, et al. Treat-and-extend regimens for the management of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy: consensus and recommendations from the Asia-Pacific Vitreo-retina Society. Asia Pac J Ophthalmol (Phila). 2021;10(6):507-518. doi:10.1097/APO.0000000000000445

Adrean SD, Chaili S, Ramkumar H, Pirouz A, Grant S. Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol. Ophthalmology. 2018;125(7):1047-1053. doi:10.1016/j.ophtha.2018.01.012

Colucciello M. Controversies in care: examining the evidence for macular atrophy as a complication of anti-VEGF therapy for wet AMD. Retinal Physician. 2022;19(10):42-46. 

Adrean SD, Chaili S, Grant S, Pirouz A. Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat-extend-stop protocol. Ophthalmol Retina. 2018;2(3):225-230. doi:10.1016/j.oret.2017.07.009

Nguyen V, Vaze A, Fraser-Bell S, 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):623-628. doi:10.1016/j.oret.2019.05.013

Arendt P, Yu S, Munk MR, Ebneter A, Wolf S, Zinkernagel MS. Exit strategy in a treat-and-extend regimen for exudative age-related macular degeneration. Retina. 2019;39(1):27-33. doi:10.1097/IAE.0000000000001923

Awh KC, Mahmoudzadeh R, Salabati M, et al. Outcomes of intentionally suspending treatment in eyes with advanced neovascular age-related macular degeneration. Am J Ophthalmol. 2023;256:20-26. doi:10.1016/j.ajo.2023.07.022 

Wong DT, Lambrou GN, Loewenstein A, Pearce I, Okada AA; Vision Academy Steering Committee. Suspending treatment of neovascular age-related macular degeneration in cases of futility. Retina. 2020;40(6):1010-1020. doi:10.1097/IAE.0000000000002713

Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. doi:10.1056/NEJMoa062655

Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. doi:10.1056/NEJMoa054481

Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration [published correction appears in Ophthalmology. 2013 Jan;120(1):209-10]. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006

CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908. doi:10.1056/NEJMoa1102673

Ciulla TA, Hussain RM, Pollack JS, Williams DF. Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients: a real-world analysis of 49 485 eyes. Ophthalmol Retina. 2020;4(1):19-30. doi:10.1016/j.oret.2019.05.017

Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122(1):146-152. doi:10.1016/j.ophtha.2014.07.041

Wykoff CC, Croft DE, Brown DM, et al. Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results. Ophthalmology. 2015;122(12):2514-2522. doi:10.1016/j.ophtha.2015.08.009

Brown DM; on behalf of the PULSAR study investigators. Aflibercept 8 mg in patients with nAMD: 48-week results from the phase 3 PULSAR trial. Data presented at: Angiogenesis 2023; February 11, 2023.

Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-740. doi:10.1016/S0140-6736(22)00010-1