Choroidal neovascularization, the hallmark of neovascular AMD, is the major cause of severe vision loss in the disease, and research has shown that the development of CNV lesions is stimulated by increased secretion of vascular endothelial growth factor A.1,2 The goal of anti-VEGF therapy is to stabilize or improve vision by inhibiting the growth of CNV, which reduces the complications induced by the neovascular complex that can lead to loss of vision, such as macular hemorrhage, macular edema and subretinal fluid (SRF). Although anti-VEGF therapy has improved the visual prognosis for patients with AMD, not all eyes with exudative disease experience full anatomic resolution of macular hemorrhage, macular edema or intraretinal fluid/SRF on OCT with standard-dose
Figure 1. An 83-year-old man who had suboptimal response to anti-VEGF monotherapy for six months (vision 20/25 at baseline and six months). After switching to a double-dose regimen the subretinal fluid resolved and vision improved to 20/20.
therapy (ranibizumab 0.5 mg, bevacizumab 1.25 mg or aflibercept 2 mg). Using a higher dose of anti-VEGF therapy may enhance the effectiveness of these drugs in some cases of neovascular AMD. In this article, we’ll explain what we know so far about this treatment option.

The response to anti-VEGF therapy depends on a variety of factors, including the patient’s age, lesion characteristics, lesion duration, baseline best-corrected visual acuity and anatomic improvement on optical coherence tomography. We know from clinical trials that anti-VEGF therapies given as a standard regimen of monthly injections fail to control exudation in all patients. For example, the Comparison of Age-Related Macular Degeneration Treatment Trials research group reported that despite a monthly dosing regimen with anti-VEGF for a year, 53.2 percent of patients receiving ranibizumab 0.5 mg and 70.9 percent of patients receiving bevacizumab 1.25 mg had evidence of persistent subretinal fluid on OCT.3

Because of the lack of complete response to standard therapy in some patients with AMD, some clinicians and researchers have investigated the possibility of using higher-dose treatment. The LAST trial, the first prospective clinical trial of neovascular AMD to publish results of high-dose (2 mg) ranibizumab, reported that it has the potential to maintain or improve BCVA and anatomical outcomes in some patients with persistent or recurrent SRF or IRF secondary to neovascular AMD despite prior monthly intravitreal anti-VEGF therapy with the standard dose.4 Bascom Palmer retina specialist Phil Rosenfeld and his colleagues examined the tolerability of higher dose ranibizumab (up to 2 mg) and found that increasing the dose was well-tolerated, with a 40-percent rate of improvement in visual acuity that was similar to the standard regimen.5 Another study recently demonstrated
Figure 2. A case of good response after switching to a double-dose regimen of anti-VEGF therapy. The images show resolution of subretinal fluid in a 73-year old woman with wet AMD and large pigment epithelial detachment despite many injections of anti-VEGF agents on a monthly regimen. Vision remained stable at 20/100 at all visits.
improved visual acuity and anatomic response with 2-mg ranibizumab injections in patients who demonstrated persistent disease despite standard dosing therapy.6 Other researchers reported the use of double-dose ranibizumab in a retrospective chart review of 10 eyes (eight subjects) with exudative AMD that had persistent macular fluid on spectral-domain OCT after at least three monthly intravitreal ranibizumab (0.5 mg) or bevacizumab (1.25 mg) injections. In this cohort, central macular thickness was significantly lower after two monthly double-dose intravitreal ranibizumab injections (0.1 mg, DDR) (324 ±77 µm at baseline vs. 248 ±50 µm, p=0.02). All eyes demonstrated improvement on SD-OCT after the first two doses of DDR. Central macular thickness demonstrated a statistically significant decrease following the second DDR injection, while the decrease was smaller and not significant after the third double dose of ranibizumab. Paracentesis was performed frequently for acute intraocular pressure elevation or as prophylaxis in eyes receiving DDR, due to the higher volume injected intravitreally, but no other ocular or systemic adverse effect was noted with double-dose ranibizumab.7  

In our clinical practice, we’ve used high-dose anti-VEGF agents with some success in a small cohort of cases of recalcitrant exudation in neovascular AMD (See Figures 1 and 2). This has provided us with an additional treatment option to consider in patients with an unsatisfactory response to standard therapy. A larger prospective, randomized clinical study will be necessary to validate this therapeutic approach and to identify features predicting a response to a high dose anti-VEGF therapy regimen.  REVIEW

Dr. Sukpen is a fellow and Dr. Stewart a professor in the Department of Ophthalmology at the University of California, San Francisco Medical Center. Dr. Stewart can be reached at

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