Five-year outcomes with anti-vascular endothelial growth factor in neovascular age-related macular degeneration: results of the Comparison of Age-related Macular Degeneration Treatments Trials

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in industrialized countries (1,2). Current treatments for AMD are severely limited and only the wet form can be treated with anti-vascular endothelial growth factor (anti-VEGF). Although anti-VEGF is a palliative treatment, this drug dramatically improves the prognosis for patients with this disease (3). For example, in a population-based study in Denmark, the incidence of legal blindness from AMD was reduced by 50% after 2006 (4). Currently, all patients diagnosed with neovascular AMD are treated with intravitreal injections of one of the three drugs available in clinical practice that target VEGF: bevacizumab, the most widely used in the USA, ranibizumab and aflibercept (5).

The Comparison of Age-related macular degeneration Treatments Trials (CATT) study was the first head-to-head trial to compare 1.25 mg bevacizumab and 0.5 mg ranibizumab injected under either a monthly or as-needed regimen over a 2-year period (6). This study showed equivalent clinical functional efficacy between the two drugs at 1 and 2 years. However, in this study, the as-needed regimen seems to be associated with a slight poorer outcome regardless of the drug used. Several subsequent studies have confirmed the functional equivalence of the molecules but few investigators have addressed outcomes after 4 years or more, and long-term results vary considerably across studies (7-10).

The CATT Research Group recently reported the clinical outcomes of participants enrolled in the CATT study at 5 years after the initiation of treatment (11). The authors contacted all patients enrolled in the original trial to schedule an appointment at a CATT clinical center or interviewed the patient and their external ophthalmologist, asking them about past care, treatment, visual acuity (VA), imaging and serious medical events. Only patients with a VA measurement between 51 months (4.3 years) and 85 months (7.1 years) were included. Finally, 647 participants were enrolled in the follow-up study out of the 914 patients still alive (71%) (1,117 patients alive at the end of the original trial) with average follow-up of 5.5 years.

At 5 years, participants lost around three letters from baseline and 11 letters from 2 years. After the end of the clinical trial, the mean number of examinations was 8 for the third year, 7 for the fourth year and 6 for the fifth year with a mean number of injections of 5, 5 and 4, respectively. Most patients still had an active neovascular lesion with persistent fluid on the OCT (83%) and a few had active leakage on the fluorescein angiography (24.5%). Moreover, out of 467 eyes with fluorescein angiography, the mean total lesion area was 12.9 mm², a mean 4.8 mm² larger than at 2 years. In addition, geographic atrophy was present in 41% of gradable eyes at 5 years (subfoveal in 17%), compared to 21% at 2 years. These data highlight the under-dosing of patient treatment, despite the fact that 85.5% of patients were followed-up at a CATT center after the 2-year trial. Most importantly, 50% of eyes had VA of 20/40 or better and 20% VA of 20/200 or worse. This result could firstly be interpreted as normal, but it is actually remarkable when comparing VA outcomes in neovascular AMD before the anti-VEGF era during which 2 years after diagnosis, less than 10% of patients retained vision of 20/40 or better with no treatment and 15% of patients with photodynamic therapy (PDT) (12,13).

The SEVEN-UP study, another long-term follow-up study of patients from ANCHOR/MARINA (monthly ranibizumab versus sham or PDT in the study eye), and HORIZON study [open-label extension trial of patients from ANCHOR and MARINA study with patients treated with ranibizumab under a pro re nata (PRN) regimen], showed similar results or worse, with a mean change from baseline of −8.6 letters and from year 2 (end of original trial) of −19.8 letters (9). Similarly, the mean number of injections after the phase III trial was dramatically reduced between year 4 and year 7 at 6.3. These long-term studies highlight that insufficient treatment is responsible for a long-term loss of VA after the monthly injection phase.

The loading dose of three anti-VEGF injections generally dries the macula. Retaining this gain is challenging because it is difficult to propose monthly injections. A PRN regimen requires a monthly follow-up consultation with repeat visits. Despite a strict protocol, several studies have demonstrated that the gain in VA obtained at the beginning of the study is not maintained over time (IVAN, CATT, HARBOR) (6,14,15).

Pro-active regimens, such as the Treat & Extend (T&E) protocol, are an attractive alternative for patients. Rayess et al. used the T&E protocol to treat 212 eyes diagnosed with treatment-naïve-neovascular AMD with a mean follow-up of 1.88 years. Mean best corrected VA significantly improved in the first year of treatment and was maintained at the 2- and 3-year follow-up visits (16). Recently, the TREX-AMD study revealed the non-inferiority of the T&E regimen compared to monthly injections (17).

These long-term studies have demonstrated that anti-VEGF therapy has revolutionized the prognosis for patients with neovascular AMD. A pro-active approach adapted to each patient would appear to be a good compromise for controlling the disease and decreasing the numbers of visits required.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by Section Editor Zhihua Cui, MD, PhD (Department of Ophthalmology, the First Hospital of Jilin University, Jilin, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes.2017.02.04). L Kodjikian is the coordinator and PI of the GEFAL study (avastin versus lucentis in exsudative AMD in France) and is consultant for Abbvie, Alcon, Allergan, Bayer, Kris, Novartis and Théa laboratories; T Mathis has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Klein R, Peto T, Bird A, et al. The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137:486-95. [Crossref] [PubMed]
2. Bressler NM. Age-related macular degeneration is the leading cause of blindness... JAMA 2004;291:1900-1. [Crossref] [PubMed]
3. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31. [Crossref] [PubMed]
4. Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular degeneration in denmark: year 2000 to 2010. Am J Ophthalmol 2012;153:209-13.e2. [Crossref] [PubMed]
5. Stein JD, Hanrahan BW, Comer GM, et al. Diffusion of technologies for the care of older adults with exudative age-related macular degeneration. Am J Ophthalmol 2013;155:688-96, 696.e1-2.
6. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119:1388-98. [Crossref] [PubMed]
7. Rasmussen A, Bloch SB, Fuchs J, et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2013;120:2630-6. [Crossref] [PubMed]
8. Gillies MC, Campain A, Barthelmes D, et al. Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study. Ophthalmology 2015;122:1837-45. [Crossref] [PubMed]
9. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013;120:2292-9. [Crossref] [PubMed]
10. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2012;119:1175-83. [Crossref] [PubMed]
11. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. 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;123:1751-61. [Crossref] [PubMed]
12. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology 2009;116:57-65.e5. [Crossref] [PubMed]
13. Bressler NMTreatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol 2001;119:198-207. [PubMed]
14. 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;382:1258-67. [Crossref] [PubMed]
15. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013;120:1046-56. [Crossref] [PubMed]
16. Rayess N, Houston SK 3rd, Gupta OP, et al. Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen. Am J Ophthalmol 2015;159:3-8.e1. [Crossref] [PubMed]
17. 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;122:2514-22. [Crossref] [PubMed]