In the United States, neovascular age-related macular degeneration (nAMD; Figures 1 and 2) is a leading cause of legal blindness, and anti-VEGF therapy is currently the standard of care. In randomized clinical trials (RCTs), 3 anti-VEGF agents, ranibizumab (Lucentis; Genentech), aflibercept (Eylea; Regeneron Pharmaceuticals), and off-label bevacizumab (Avastin; Genentech), have achieved dramatic results in treatment of nAMD.
However, in large “real-world” studies of anti-VEGF therapy in nAMD, based on chart reviews, electronic medical records (EMR) or claims analyses, the results fall far short of RCTs.1-15 Although the cause of the discrepancy is unknown, possibilities include patient characteristics and undertreatment associated with variable frequency treatment regimens.
REAL-WORLD AMD EXPERIENCE WITH ANTI-VEGF THERAPY AMONG US RETINA SPECIALISTS
In a recent study, my colleagues and I assessed real-world nAMD experience with anti-VEGF therapy in a large database of aggregated, longitudinal EMRs from a geographically and demographically diverse sample of US retina specialists (Vestrum Health Retina Database).16 Treatment-naïve nAMD patients who underwent anti-VEGF injections between January 1, 2012, and October 31, 2016, were eligible if follow-up data were available before October 31, 2017. Based on the inclusion criteria, 49,485 eyes were analyzed. The mean age was 80.9 years, 36% male and 64% female. The mean baseline VA was 53.8 letters. Initial anti-VEGF agent was 25% aflibercept, 35% ranibizumab, and 39% bevacizumab.
REAL-WORLD OUTCOMES WITH ANTI-VEGF THERAPY ARE MEANINGFULLY WORSE THAN RCTS
Mining EMR data has numerous limitations, including the retrospective nature and the utilization of aggregated data, as well as nonstandardized VA assessment from multiple sites. Nevertheless, the resulting data can yield important longitudinal insights to better understand patient outcomes in clinical practice. Overall, our US-based study demonstrated worse visual outcomes and fewer anti-VEGF injections on average, compared to patients receiving fixed, frequent therapy in RCTs. Specifically, at 1 year, after a mean of 7.3 injections, there was a mean gain of only 1 letter (0.95 letter, 95% confidence interval for change in VA: +0.77 to +1.13 letter, P<.001). In contrast, registration trials for ranibizumab (monthly) and aflibercept (every 2 months after 3 monthly loading doses), and the monthly ranbizumab and bevacizumab arms of CATT, show an average 1-year improvement of 8.5 letters across these studies.17-20
Cross-trial comparisons have limitations. Also, real-world studies are prone to worse therapeutic outcomes, given the more diverse patient presentations, likely including advanced disease states that are not consistently eligible with RCT inclusion criteria. A specific limitation of our study was classification of nAMD patient eyes based on initial anti-VEGF agent, without accounting for switching between agents, and it is not surprising that there was no difference between agents.
Numerous real-world studies of anti-VEGF therapy in nAMD have reported similar poor visual outcomes.1-15 In one particularly relevant real-world study using a database of American Academy of Ophthalmology members (the Intelligent Research in Sight [IRIS] registry), 13,859 nAMD patients received an average of 6.1 injections and experienced a mean improvement of 0.05 logMAR (2.5 letters).15 Cross-trial comparisons are difficult, as this IRIS registry study differed in several aspects (ie, the IRIS database is not confined to referral-based retina practices, the protocol excluded patients with fewer than 3 injections, and baseline VA was slightly better than current real-world study), but nevertheless, the results are not dissimilar to our study.
UNDERTREATMENT MAY LIMIT OUTCOMES
A common explanation for poor visual outcomes in real-world studies is undertreatment. In our study, patients received an average of only 7.3 injections. A prior large US-based retrospective analysis of medical claims from 2006 to 2011 similarly showed that, compared to RCTs, patients in the United States received fewer anti-VEGF treatments and less frequent monitoring.21 One reason for fewer injections in the real world compared to RCTs involves the adoption of variable-frequency anti-VEGF treatment regimens that aim to decrease treatment burden for nAMD patients. The 2015 American Society of Retina Specialists “Preferences and Trends” survey of more than 2,700 retina specialists in 60 countries revealed that more than 90% of retina specialists, both in the United States and internationally, utilize OCT-guided variable frequency anti-VEGF treatment protocols for nAMD. In our real-world study, patients received a mean number of injections similar to that in the prior US claims analysis, similar to that in the IRIS registry real-world study,15 and similar to that in the as-needed treatment arms of CATT.18,21,22 These findings confirm that US physicians are generally employing variable-frequency treatment regimens for nAMD.
Our study showed a linear relationship between mean letters gained and mean number of injections, between 4 and 10 injections over 1 year, after which the relationship plateaued. Nearly 15% of patients received 11 to 13 injections in the first year, gaining approximately 3 letters on average. However, more than 15% were severely undertreated, having received just 1 to 4 injections in the first year and losing approximately 2 letters on average. Those who received the fewest injections tended to be older and have worse baseline VA.
Multiple reports have suggested a relationship between the number of injections and visual outcome, with fewer injections associated with worse VA.2-4,8,11,23,24 In the PIER RCT of ranibizumab vs sham, patients received 6 treatments (monthly for 3 months followed by quarterly) and experienced a loss of VA of 0.2 letters from baseline by month 12,25 a result similar to our study. Consequently, attempts to limit treatment burden through the adoption of less frequent or variable-frequency anti-VEGF treatment regimens must be approached cautiously. Multiple prospective RCTs have demonstrated that variable frequency anti-VEGF therapy for nAMD results in a less favorable visual outcome compared to fixed, frequent anti-VEGF suppression.22,25-29 In CATT, for example, patients assigned to monthly treatment regimens of ranibizumab or bevacizumab experienced a statistically significant greater benefit in VA gain compared to those receiving “as-needed” therapy (difference of 2.4 ETDRS letters at 2 years; P=.046).22
Another variable frequency regimen, “treat and extend” (T&E), appears based on retrospective studies to perform relatively well in practice. Two studies that evaluated T&E are the large, noncomparative LUCAS study, which compared ranibizumab and bevacizumab for nAMD,30 and the small prospective, controlled TREX study, which analyzed T&E vs monthly dosing.31 The level of evidence is not as strong because these were not large-scale, controlled trials. However, the mean number of treatments in the first year was 10.1 in the TREX study,31 and the mean number of treatments in the first year was 8.0 for ranibizumab and 8.9 for bevacizumab in the LUCAS study.30 Like the fixed, frequent regimens, the treatment intensity in these T&E studies also exceeds that of the current study, further supporting the relative undertreatment in the real world.
In our study, patients who were extremely undertreated, receiving 4 or fewer injections in 1 year, had lower baseline mean VA and greater baseline mean age. Paradoxically, these patients with poor baseline VA have most to gain from anti-VEGF therapy, as several studies have shown that patients with poor baseline VA gain more vision than those patients with better baseline VA. It is unclear if these patients received fewer injections because of the advanced nature of their disease, or advanced age associated with comorbidities precluding frequent visits and more intense therapy.
In our study, patients who received more intense therapy, meaning 10 or more injections in 1 year, had greater baseline mean VA and lower baseline mean age. Patients with greater baseline VA are at greater risk of vision loss, and more intense therapy appears to prevent vision loss, although there is a relative ceiling effect in VA gains. This ceiling effect highlights a limitation of anti-VEGF therapy. Frequent injections of antipermeability agents such as anti-VEGF therapy may control exudation, but do not address other causes of vision loss in AMD, such as geographic atrophy (GA) and subretinal fibrosis.
Given the limited outcomes of anti-VEGF therapy highlighted by real-world AMD studies, along with the burdensome need for repeated intravitreal injections to sustain efficacy, long-acting formulations of anti-VEGF drugs and therapies that address other pathways will be developed. Sustained-delivery systems, new classes of therapies, and combinations of therapies may meaningfully enhance outcomes for nAMD patients, especially for those older patients and those with poor baseline VA who may be particularly prone to undertreatment and poor outcomes. RP
- Arevalo JF, Lasave AF, Wu L, et al; Pan-American Collaborative Retina Study Group (PACORES). Intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration: 5-Year Results of The Pan-American Collaborative Retina Study Group. Retina. 2016;36(5):859-867.
- Cohen SY, Mimoun G, Oubraham H, et al; LUMIERE Study Group. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study. Retina. 2013;33(3):474-481.
- Hjelmqvist L, Lindberg C, Kanulf P, Dahlgren H, Johansson I, Siewert A. One-year outcomes using ranibizumab for neovascular age-related macular degeneration: results of a prospective and retrospective observational multicentre study. J Ophthalmol. 2011;2011:405724.
- Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99(2):220-226.
- Krüger Falk M, Kemp H, Sørensen TL. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. Am J Ophthalmol. 2013;155(1):89-95.
- Rakic JM, Leys A, Brié H, et al. Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study. Clin Ophthalmol. 2013;7:1849-1858.
- 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(12):2630-2636.
- Souied EH, Oubraham H, Mimoun G, et al; TWIN Study Group. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the TWIN study. Retina. 2015;35(9):1743-1749.
- Talks JS, Lotery AJ, Ghanchi F, et al. First-year visual acuity outcomes in the united kingdom of providing aflibercept according to the VIEW study protocol for age-related macular degeneration. Ophthalmology. 2016;123(2):337-343.
- van Asten F, Evers-Birkenkamp KU, van Lith-Verhoeven JJ, et al; HELIOS study group. A prospective, observational, open-label, multicentre study to investigate the daily treatment practice of ranibizumab in patients with neovascular age-related macular degeneration. Acta Ophthalmol. 2015;93(2):126-133.
- Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity. Ophthalmology. 2014;121(5):1092-1101.
- Zarranz-Ventura J, Liew G, Johnston RL, et al; United Kingdom Age-Related Macular Degeneration Electronic Medical Records Users Group. The neovascular age-related macular degeneration database: report 2: incidence, management, and visual outcomes of second treated eyes. Ophthalmology. 2014;121(10):1966-1975.
- Ross AH, Donachie PH, Sallam A, et al. Which visual acuity measurements define high-quality care for patients with neovascular age-related macular degeneration treated with ranibizumab? Eye (Lond). 2013;27(1):56-64.
- Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States. Ophthalmol Retina. 2018;2(7):645-653.
- Rao P, Lum F, Wood K, et al. Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS Registry. Ophthalmology. 2018;125(4):522-528.
- Ciulla TA, Pollack JS, Williams D. Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular AMD patients: a “real world” analysis in 49,485 eyes. Invest Ophthalmol Vis Sci. 2018;59(9):1623-1623.
- Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
- 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.
- Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.
- Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
- Holekamp NM, Liu Y, Yeh WS, et al. Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration. Am J Ophthalmol. 2014;157(4):825-833.
- Martin DF, Maguire MG, Fine SL, et al; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
- Dadgostar H, Ventura AA, Chung JY, Sharma S, Kaiser PK. Evaluation of injection frequency and visual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration. Ophthalmology. 2009;116(9):1740-1747.
- Hussain RM, Hariprasad SM, Ciulla TA. Treatment burden in neovascular AMD: visual acuity outcomes are associated with anti-VEGF injection frequency. Ophthalmic Surg Lasers Imaging Retina. 2017;48(10):780-784.
- 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(2):239-248.
- Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010;150(3):315-324.
- Busbee BG, Ho AC, Brown DM, et al; HARBOR Study Group. 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(5):1046-1056.
- Chakravarthy U, Harding SP, Rogers CA, et al; IVAN study investigators. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267.
- Schmidt-Erfurth U, Eldem B, Guymer R, et al; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology. 2011;118(5):831-839.
- 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.
- Wykoff CC, Croft DE, Brown DM, et al; TREX-AMD Study Group. 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.