Switching Treatment from One Anti-VEGF Agent to Another: Does It Improve Outcomes in Patients with Neovascular AMD?
Anti-VEGF therapy has revolutionized the treatment of exudative age-related macular degeneration (AMD). The three most widely used anti-VEGF therapies, ranibizumab (Lucentis, Genentech; S. San Francisco, CA/Roche; Basel, Switzerland), bevacizumab (Avastin, Genentech; S. San Francisco, CA/Roche; Basel, Switzerland), and aflibercept (Eylea, Regeneron; Tarrytown, NY/Bayer; Leverkusen, Germany), have each been shown in large, prospective clinical trials to be effective in reducing vision loss in patients with treatment-naïve exudative AMD.1,2 However, after these initial visual gains, long-term studies have shown visual decline despite close monitoring.3,4 The SEVEN-UP study found that patients in the MARINA and ANCHOR trials had lost an average of 19.8 letters at a mean follow-up of 5.3 years after the completion of the trials.3 Outside of clinical trials, there have been various practice patterns among retina specialists administering long-term anti-VEGF therapy, including decreasing treatment intervals, increasing the dosage of drug, or switching to different drugs within the same class.
Many practicing retina specialists do not adhere to the strict monthly dosing regimens utilized in the ANCHOR and MARINA trials which initially established ranibizumab as the standard of care and, instead, have moved to a “treat and extend” dosing regimen despite the lack of large, randomized trials supporting its efficacy.5 In the 2014 Preferences and Trends Survey administered by the American Society of Retina Specialists, 77.9% of practicing retina specialists reported using a treat-and-extend protocol. Only 2.0% reported seeing and treating wet AMD patients monthly while 16.4% reported seeing patients monthly and treating only for active leakage.6
One tactic to try to improve outcomes and/or decrease treatment frequency is increasing the dosage of drug administered. In the HARBOR trial, 2.0-mg ranibizumab showed no benefit over the FDA-approved 0.5 mg dose in treatment-naïve eyes with neovascular AMD.7 In the SAVE trial, treatment non-naïve eyes with persistent fluid on OCT despite monthly 0.5 mg ranibizumab therapy were randomized to 2.0 mg ranibizumab monthly or every 6 weeks (Q6) on an as-needed (PRN) basis. An average gain of 4.1 ETDRS letters in best-corrected visual acuity was maintained in both treatment groups over 1 year; however, the majority of patients were treated with the maximum number of PRN injections and initial anatomic gains were lost over time in the Q6 week group.8
Switching to another anti-VEGF therapy is another strategy to try to improve long-term visual outcomes. The currently available anti-VEGF agents differ from each other with respect to such characteristics as molecular weight and binding affinity. Switching treatment from one anti-VEGF agent to another may help to prevent or minimize tachyphylaxis, defined as diminished therapeutic response to a drug after repeated administration over time.2,9 Several retrospective case series have shown improved anatomic outcomes in patients with refractory or recurrent neovascular AMD who were switched from bevacizumab or ranibizumab to aflibercept.10-12 Additionally, Gasperini et al found that, in patients who were treated previously with either ranibizumab or bevacizumab for exudative AMD, 81% showed anatomic improvement when switched to the other anti-VEGF agent.13
Although the results of studies evaluating outcomes after switching anti-VEGF agents appear promising, a number of factors make them difficult to interpret. Most of the studies are retrospective in nature with variable retreatment criteria, follow-up, and indications for switching therapy. More recently, the ASSESS study prospectively investigated the response of patients with active exudative AMD treated previously with anti-VEGF therapy when switched to aflibercept using a fixed-dose regimen. Intravitreal aflibercept was shown in the VIEW studies to have similar efficacy to ranibizumab in treatment-naïve patients with neovascular AMD using a less frequent dosing schedule.14 In the ASSESS study, the 6-month interim analysis demonstrated a statistically significant mean decrease in central subfield thickness of 38.6 microns and a mean increase in ETDRS visual acuity of +5.9 letters.15
Since the phase III randomized controlled trials have reported results only in patients treated with a single anti-VEGF agent, we currently lack outcome data from large prospective trials regarding outcomes associated with switching from one anti-VEGF agent to another. Additionally, there is some inherent bias in that we tend to switch patients who are not doing well, but there is no standardized definition of treatment failure. Prospective clinical trials with predetermined entry criteria and follow-up are needed to explore the role of switching anti-VEGF therapy in clinical practice.
1. Martin DF, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012 Jul;119(7):1388-98.
2. Farooghian F, et al. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009; 29(6):723-731.
3. Rofagha S, et al. Seven-Year Outcomes in Ranibizumab-Treated Patients in ANCHOR, MARINA, and HORIZON. Ophthalmology 2013;120:2292-2299.
4. Singer MA, et al. HORIZON: An Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. Ophthalmology 2012;119:1175-1183.
5. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009; 29:1424-1431.
7. 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. Epub ahead of print 2013 Jan 23. Doi:10.1016/j.ophtha.2012.10.014
8. Wykoff CC, Brown DM, Chen E, et al. SAVE (super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related macular degeneration: 1-year results. Ophthalmic Surg Lasers Imaging Retina. 2013; 44(2):121-126.
9. Schaal S, Kaplan HJ, Tongalp HT. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115(12):2199-2205.
10. Cho, Hyung, et al. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 2013; 97:1032-1035.
11. Yonekawa, Yoshihiro, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 2013; 156:29-35.
12. Bakall B et al. Aflibercept Therapy for Exudative Age-related Macular Degeneration Resistant to Bevacizumab and Ranibizumab. Am J Ophthalmol 2013; 156:15-22.
13. Gasperini JL, Fawzi AA, et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 2012 96: 14-20.
14. Heier JS et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-2548.
15. Singh RP, Srivastava S, Ehlers JP, et al. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 2014;98:i22-i27.
About our author(s):
Angela Bessette, MD
Flaum Eye Institute, University of Rochester
Rishi P. Singh, MD
Cole Eye Institute,