We all know that age-related macular degeneration is the leading cause of blindness and visual disability in patients age 60 years and older in North America, and that neovascular AMD (nAMD) accounts for most AMD-related severe vision loss. In our practice in Toronto, patients with nAMD initially receive three monthly anti-VEGF injections followed by a treat-and-extend regimen. We base this management strategy on these 10 lessons we’ve learned from selected landmark nAMD trials. 

Lesson 1: Better than Photocoagulation
Laser photocoagulation was previously used to treat nAMD, but is no longer indicated for subfoveal disease. The Macular Photocoagulation Study showed, however, that it can be a treatment option for extrafoveal nAMD. After 18 months of follow-up, 60 percent of untreated eyes vs. 25 percent of treated eyes experienced severe visual loss, defined as a loss of more than 6 lines on an Early Treatment of Diabetic Retinopathy Study chart.1 However, 59 percent of patients in the treatment group demonstrated recurrent neovascularization in the form of either neovascularization contiguous with the treatment scar or independent neovascular membranes.2

Lesson 2: Variable Results With Photodynamic Therapy 
Photodynamic therapy (PDT) for nAMD is effective in preventing visual loss from nAMD, though there is doubt about the size of the effect. The TAP trial studied the effect of PDT on subfoveal, “classic” choroidal neovascular membranes (CNVM) on fluorescein angiography, while the VIP trial did a similar study on CNVM caused by pathological myopia.3,4 Participants received, on average, five treatments over two years, and patients who received PDT treatment had a 0.77 relative risk of losing 3 or more lines of visual acuity at 24 months.5 Alarmingly, severe acute visual loss occurred in about 2 percent of patients within seven days of treatment.

Lesson 3: Visual Acuity Improvement is Measurable
The advent of anti-VEGF treatment revolutionized our approach to nAMD and resulted in a paradigm shift in the way patients with nAMD are managed. The ANCHOR trial compared monthly ranibizumab (Lucentis, Roche/Genentech) therapy with PDT treatment for “predominantly classic” nAMD lesions, and the MARINA trial compared monthly ranibizumab therapy with sham injections for “minimally classic” or “occult” nAMD lesions.6,7 These trials showed that monthly ranibizumab injections for two years not only prevent visual loss, but also improved vision. 

In the ANCHOR trial, visual acuity improved by 15 letters or more in 40.3 percent of the 0.5-mg ranibizumab injection group, compared with 5.6 percent in the PDT group after one year. Similarly, visual acuity improved by 15 or more letters in 33.8 percent of the 0.5-mg ranibizumab injection group, compared with 5 percent of the sham injection group in the MARINA trial. These efficacy outcomes were achieved with a very low rate of serious ocular adverse events, including infectious endophthalmitis.

Similarly, the VIEW1 and VIEW2 studies compared monthly and bimonthly intravitreal aflibercept (Eylea, Regeneron) injections with monthly ranibizumab injections. The studies concluded that intravitreal aflibercept given monthly or bimonthly, after three initial monthly injections, produced similar efficacy and safety outcomes to monthly ranibizumab.24,25 

The VIEW trials demonstrated that aflibercept is an effective treatment for nAMD, with the bimonthly injection regimen offering the potential to reduce the treatment burden of monthly injections.

Lesson 4: Monthly Treatment Truly Works
Pivotal clinical trials reported that ranibizumab, bevacizumab (Avastin, Roche/Genentech) and aflibercept treatment achieved the best visual acuity outcomes with three initial consecutive monthly injections followed by continued monthly injections.9 For example, the PIER study evaluated the efficacy of three monthly injections followed by quarterly injections in patients with nAMD. Although mean visual acuity improved from baseline in the first three months with ranibizumab treatment, VA then declined an average of 2.2 letters over the two-year trial period,10 suggesting that quarterly treatment is, on average, inferior to monthly treatment and that more frequent monitoring is needed.
Lesson 5: Individualize Treatment Plans  
Patients with nAMD respond variably to the available anti-VEGF agents and treatment regimens, so individualizing treatment regimens is possible. The PRONTO study assessed three consecutive monthly injections followed by optical coherence tomography-guided variable dosing. Visual acuity improved 15 or more letters in 35 percent of patients and an average of 5.6 injections were administered over 12 months.11 

While PRONTO demonstrated similar visual outcomes to the MARINA and ANCHOR trials but with fewer intravitreal injections, substantial trial design differences limit comparisons. The SUSTAIN trial had a protocol very similar to the PRONTO study, with monthly visits following three initial monthly injections. Patients again achieved maximal visual acuity gain, on average, after the first three monthly injections. VA decreased slightly under a PRN regimen during the next two to three months, but was then sustained throughout the rest of the treatment period.12

Lesson 6: Prompt Initiation Of Therapy Preserves Vision
Treatment of nAMD should be initiated promptly because a longer delay from symptom onset was a significant predictor of poorer treatment outcome when controlling for age, sex and baseline visual acuity. Patients with a delay in treatment of 21 weeks or more had an odds ratio of 2.62 for worse vision after treatment, compared to patients with a delay of seven weeks or less.13 

In another retrospective review of 1,099 patients who began anti-VEGF therapy for nAMD, a two-week-earlier injection was associated with a 5-letter gain in mean VA at three months after initial presentation.14 Moreover, the preliminary results of the LUMINOUS study showed that patients with a better presenting visual acuity had a better one-year visual outcome.15

Lesson 7: Treat-and-Extend Is An Effective Protocol
Treat-and-extend (TREX) regimens offer similar anatomical and functional outcomes and can greatly reduce treatment burden. The TREX-AMD study group compared a TREX management strategy with monthly ranibizumab injections. The TREX patients were treated monthly for at least three doses, until resolution of clinical and OCT evidence of exudative disease activity. Thereafter, the interval between visits was individualized. 

At one year, the visual acuity gain was similar in the two groups and the mean number of injections was 13 in the monthly group and 10.1 in the TREX cohort. The mean maximum extension interval after the first three monthly injections was 8.4 weeks.16 The LUCAS study, which compared bevacizumab and ranibizumab injections in a treat-and-extend protocol, also showed that visual acuity results at one year were comparable to other clinical trials with monthly treatment. In this study, once patients achieved disease stability, the treatment interval was extended by two weeks at a time up to a maximum of 12 weeks. Disease recurrence meant shortening the treatment interval by two weeks at a time.17 

Interim results of the CANTREAT study in Canada also suggested that fewer injections and visits using a treat-and-extend strategy rather than monthly dosing can achieve comparable vision improvement in a real-world setting.18

Lesson 8: Ranibizumab vs. Bevacizumab, Monthly vs. PRN
Intravitreal bevacizumab, ranibizumab and aflibercept can be used to treat nAMD. The CATT and IVAN studies were non-inferiority trials, which assigned patients to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed (PRN) with monthly evaluation. The CATT study showed that monthly bevacizumab was equivalent to monthly ranibizumab, with 8 and 8.5 letters gained, respectively. 

Bevacizumab administered PRN was equivalent to ranibizumab PRN, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive.19 

Likewise, the IVAN study found that ranibizumab and bevacizumab have similar efficacy. However, these investigators found that reduction in the frequency of retreatment resulted in a small loss of efficacy, irrespective of the drug.20 The CATT study also found that the proportion of patients with serious systemic adverse events, primarily hospitalizations, was higher with bevacizumab than with ranibizumab treatment.

Lesson 9: GA and Monthly vs. PRN Treatments
Geographic atrophy (GA) has been shown to be more common with monthly treatment than with PRN regimens in retrospective analyses of the CATT and IVAN studies. Approximately 20 percent of patients in the CATT trial developed GA within two years of treatment. Independent baseline risk factors included poor vision, retinal angiomatous proliferation, foveal intraretinal fluid and monthly dosing.21 In the IVAN trial, the percentage of participants with new GA was no different between drug groups, but it was significantly lower in the arms that received PRN injections.20 

However, this is a subject of ongoing debate, as this association has not been replicated in other trials. Further studies, such as RIVAL, which will assess the development of GA with either ranibizumab or aflibercept treatment, will enhance our understanding of this problem.

Lesson 10: What the Long-term Data Tell Us
In long-term follow-up studies, nAMD patients remain at risk for substantial visual decline. 

SEVEN-UP is a follow-up study that reviewed 65 patients who received ranibizumab treatment from the MARINA and ANCHOR studies over a mean of 7.4 years. Of the study eyes, 37 percent had 20/70 vision or better and 37 percent had 20/200 vision or worse, which was a substantial decline compared to the initial two-year MARINA and ANCHOR study results.22 

Although vision gain was largely sustained in the VIEW1 Extension Study, which followed 323 patients from the original VIEW1 study over four years, on average vision loss of 3 letters occurred at four years.26 Active disease was still present in 68 percent of study eyes and 46 percent were receiving ongoing anti-VEGF treatments. 

Likewise, the five-year results of the CATT study found that the vision gains made in the first two years were not maintained at five years. However, 50 percent of eyes had VA of 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for nAMD.23

Although anti-VEGF therapy is not a cure for patients with nAMD, it has set a high standard for their care. Many treatment regimens exist, and the ideal regimen should be patient-specific. We hope that these 10 lessons shed light on our decision to adopt a treat-and-extend strategy, and that the final results of future landmark studies, such as the CANTREAT, LUMINOUS and RIVAL trials, will continue to guide our clinical practice.  RS

Dr. Mandelcorn is an assistant professor of ophthalmology at the University of Toronto. Dr. Yap is a vitreoretinal fellow and Dr. Yan a vitreoretinal surgeon at the University of Toronto.

1. No authors listed. Argon laser photocoagulation for senile macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol. 1982;100:912-918.
2. No authors listed. Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Macular Photocoagulation Study Group. Arch Ophthalmol. 1986;104:503-512.
3. No authors listed. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol. 1999;117:1329-1345.
4. Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial—VIP report no. 1. Ophthalmology. 2001;108:841-852.
5. Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2007:CD002030.
6. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
7. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
8. Fintak DR, Shah GK, Blinder KJ, et al. Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina. 2008;28:1395-9.
9. Mitchell P, Korobelnik JF, Lanzetta P, et al. Ranibizumab (Lucentis) in neovascular age-related macular degen-eration: evidence from clinical trials. Br J Ophthalmol. 2010;94:2-13.
10. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145:239-248.
11. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.
12. Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology. 2011;118:663-671.
13. Lim JH, Wickremasinghe SS, Xie J, et al. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol. 2012;153:678-686, 86 e1-2.
14. Rasmussen A, Brandi S, Fuchs J, et al. Visual outcomes in relation to time to treatment in neovascular age-related macular degeneration. Acta Ophthalmol. 2015;93:616-620.
15. Brand C. One-year outcomes with ranibizumab in treatment naïve patients with neovascular age-related macular degeneration. An interim analysis from the LUMINOUS study. Presented at: ARVO; May 1-5, 2016; Seattle, Washington.
16. 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;122:2514-2522.
17. Berg K, Pedersen TR, Sandvik L, Bragadottir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122:146-152.
18. Kertes P. Canadian treat and extend analysis trial with ranibizumab in patients with neovascular AMD: Interim analysis of the CANTREAT study. Presented at: EURETINA; September 7-10, 2017; Barcelona, Spain.
19. Group CR, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
20. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382:1258-1267.
21. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014;121:150-161.
22. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123:1751-1761.
23. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: 
a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120:2292-2299.