Value of Anti-VEGF Therapy for Neovascular Age-Related Macular Degeneration
By Gary C. Brown, MD, MBA, and Melissa M. Brown, MD, MN, MBA
The three anti-vascular endothelial growth factor (anti-VEGF) agents currently available, and commonly used, for intravitreal injection to treat neovascular age-related macular degeneration (NVAMD) in the United States include: 1) ranibizumab (Lucentis),1,2 2) aflibercept (Eylea)3,4 and 3) bevacizumab (Avastin).5-7 Ranibizumab and aflibercept are approved by the U.S. Food and Drug Administration (FDA), while bevacizumab demonstrated noninferior efficacy compared to ranibizumab in the non-industry sponsored Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).5-7 Primary data and meta-analyses show the three drugs are associated with similar visual acuity outcomes when used for the treatment of NVAMD.8-12 Medicare 2017 data reveal that, for all indications, bevacizumab was used for 71% of intravitreal injections, aflibercept for 24% and ranibizumab for 5%.13
Quality-of-life gain. Clinical trials show that pre-treatment visual acuity among patients with NVAMD is typically 20/63 to 20/80.1-5 When such eyes are treated aggressively with anti-VEGF therapy, some achieve ≥ 20/63 long-term mean visual acuity.1-7,14 But compared to what? Untreated NVAMD control cohorts from anti-VEGF clinical trials have only 24-month follow-up. The average CATT patient age-matched individual, however, has an 11-year life expectancy.15 A Lineweaver-Burke meta-analysis of six untreated cohorts from early NVAMD clinical trials modeled long-term, NVAMD natural history and found that vision progressively deteriorated to a mean, end-stage vision of 20/640 beginning at eight to nine years after presentation.16
Given this information, the value gain (improvement in quality-of-life and/or length of life) from anti-VEGF therapy can be calculated; it is approximately 26%.17 Part of the gain comes from NVAMD therapy increasing mean length of life by 1.2 years; the mean life expectancy among patients with NVAMD treated with anti-VEGF therapy is 11 years, compared to 9.8 years among individuals with the poorer vision associated with untreated NVAMD.15 The value gain associated with anti-VEGF therapy is considerable when compared to the 3% to 5% value gain from statins used to treat hyperlipidemia and the 1% value gain from bisphosphonates used to treat osteoporosis.17
Treating earlier. Boyer and colleagues18 reported that anti-VEGF treatment of patients with NVAMD and a baseline vision of 20/40 to 20/80 (early treatment) was associated with a 24-month vision of 20/40 to 20/50, while anti-VEGF treatment of patients with NVAMD and a baseline vision of 20/160 to 20/320 (late treatment) was associated with a 24-month visual acuity of 20/160. The value gain associated with early treatment is approximately 29%, while the value gain associated with late treatment is 12%.15 Early treatment is also 2.5 times as cost-effective as late therapy.15 Data from the SEVEN-UP14 Study showed that if a person had a visual acuity outcome of ≥ 20/63 at 7.3 years following initiation of anti-VEGF treatment for NVAMD, there was a 96% chance that his/her baseline vision was ≥ 20/63 as well. Early treatment rocks!
SEVEN-UP14 data also showed that eyes undergoing ≥ 11 ranibizumab injections between five years and 7.3 years after baseline (a 2.3-year period) had a mean 3.9 letter gain versus a 10-letter loss with zero to five injections. Thus, it seems that a greater number of intravitreal anti-VEGF injections is associated with better long-term visual acuity outcomes. This is also suggested in a systematic review comparing pro re nata (PRN) therapy to the greater number of injections received with treat-and-extend therapy.19
Financial return-on-investment. Select interventions deliver a favorable financial return-on-investment for the direct medical costs expended. The mean 11-year anti-VEGF treatment (drug + physician) cost for NVAMD is approximately $15,000 for bevacizumab, $60,000 for aflibercept and $105,000 for ranibizumab.5-7,15 Yet each generates an 11-year, $390,000 return in revenue to society (patients, insurers, etc.) from decreased wage loss, caregiver costs, depression, trauma, facility admissions and so forth.15 Anti-VEGF therapy for NVAMD increases the gross domestic product and makes the country wealthier. This is consistent with the belief of Nobel prize winner William Nordhaus, who postulated that medical advances were responsible for 50% of the wealth created in the United States in the 20th century.20
Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
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;355:1432-1444.
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;119:2537-2548.
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121:193-201.
CATT Research Group; Martin DF, Maguire MG, Ying GS, Grunwalkd JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388-1398.
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group Writing Committee; Maguire MG, Martin DF, Ying G, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration. The comparison of age-related macular treatments trials. Ophthalmology. 2016;123:1751-1761.
Rao P, Lum F, Wood K, et al. Real-world vision in age-related macular degeneration patients treated with a single anti-VEGF drug type for 1 year in the IRIS Registry. Ophthalmology. 2018;256:522-528.
Nguyen CL, Oh LJ, Wong E, Wei J, Chilov M. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration: a meta-analysis of randomized controlled trials. BMC Ophthalmol. 2018;18:130.
Sawar S, Clearfield E, Soliman MK, et al. Aflibercept for age-related macular degeneration. Cochrane Database Syst Rev. 2016 Feb 8:2:CD011346.
Chen G, Li W, Tzekov R, Jiang F, Mao S, Tong Y. Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a meta-analysis of randomized controlled trials. Retina. 2015;35:187-193.
Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014 Sep 15;(9):CD011230.
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.
Brown GC, Brown MM, Rapuano S, Christ SL, Boyer D. A cost-utility analysis of bevacizumab, ranibizumab and aflibercept monotherapy for neovascular age-related macular degeneration. Submitted for publication.
Sah AP, Del Priores LV. Progressive visual loss in subfoveal exudation in age-related macular degeneration: A meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol. 2007;143:83-89.
Brown MM, Brown GC, Sharma S. Evidence-Based to Value-Based Medicine. Chicago, AMA Press, 2005:1-324.
Boyer DS, Antoszyk AN, Awh CC, Bhisitkul RB, Acharya NR; MARINA Study Group. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007;114:246-252.
Chin-Yee D, Eck T, Fowler S, Hardi A, Apte RS. A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment for patients for neovascular age-related macular degeneration. Br J Ophthalmol. 2016;100:914-917.
Nordhaus WD. The health of nations: The contribution of improved health to living standards. Working paper 8881. Cambridge, MA, National Bureau of Economic Research. 2002:37-38.
About our author(s):
Dr. Gary Brown is chief medical officer at the Center for Value-Based Medicine, a 20-year-old, healthcare economic research organization. Former chief of the Retina Service and director of the Retinal Vascular Unit at Wills Eye Hospital, he is a professor at Thomas Jefferson Medical University and adjunct professor in the Department of Ophthalmology at the Emory University School of Medicine. He has authored or edited 12 books and more than 600 scientific and healthcare economic writings.
Dr. Melissa Brown, CEO of the Center for Value-Based Medicine and former Wills Eye Hospital clinician and surgeon, is now in the Research Department at Wills Eye Hospital, a professor at Thomas Jefferson Medical University and adjunct professor in the Department of Ophthalmology at the Emory University School of Medicine. Author of more than 300 scientific, political and healthcare economic articles, she was twice a U.S. Congressional nominee, former board member at the National Institute of Aging and currently sits on the Council of Councils at the National Institutes of Health.