Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes

Ophthalmic Res. 2015;55(2):84-90. doi: 10.1159/000440886. Epub 2015 Dec 5.
Chang AA 1 , Broadhead GK, Hong T, Joachim N, Syed A, Schlub TE, Toth L, Peto T, Zhu M.


To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD).

This prospective, non-randomized clinical trial included 49 patients with treatment-resistant nAMD who received 2 mg intravitreal aflibercept as 3 monthly loading doses, followed by injections every 2 months over 12 months. Inclusion criteria included active nAMD on fluorescein angiography at baseline and persistent intra- or subretinal fluid on optical coherence tomography (OCT) for; 6 months prior to baseline with a minimum of 4 injections of bevacizumab and/or ranibizumab. Patients were assessed monthly for best-corrected visual acuity (BCVA), central retinal thickness (CRT) measured with OCT and occurrence of adverse events. Retinal pigment epithelium atrophy (RPEA) was assessed at baseline and at 12 months.

Mean BCVA improved by 4.7 letters (95% CI: 2.1-7.3, p < 0.001) and CRT decreased by 97.2µm (95% CI: 54.4-140.1, p < 0.001) at 12 months compared to baseline. Median RPEA area increased by 0.48 mm2 (range = -0.1 to 19.9, p < 0.001). There was 1 arterial thromboembolic event and 2 cases of submacular haemorrhage.

In this cohort of treatment-resistant nAMD patients, intravitreal aflibercept was effective in improving vision and reducing exudation. Early visual and anatomic outcomes may predict longer-term response to treatment, but further assessment is required.


Response of pigment epithelial detachments to intravitreal aflibercept among patients with treatment-resistant neovascular age- related macular degeneration 

Retina. 2015 May;35(5):975-81. doi: 10.1097/IAE.0000000000000409.
Broadhead GK 1 , Hong T, Zhu M, Li H, Schlub TE, Wijeyakumar W, Chang AA.


To assess the effect of intravitreal aflibercept on pigment epithelial detachment (PED) in patients withtreatment-resistant neovascular age- related macular degeneration.

Forty-six patients with vascularized PEDs participating in a wider, prospective clinical trial of treatment-resistant neovascular age-related macular degeneration received 2mg aflibercept as 3 loading doses 1 month apart, followed by further 2 monthly doses over a total 12-month period. Change in PED dimensions and reflective properties were assessed by optical coherence tomography. Reflectivity was subclassified as solid (hyperreflective), hollow (hyporeflective), or mixed (elements of both).

Aflibercept reduced PED height, width, and length at 48 weeks compared with baseline values (P ≤ 0.01 for all). Reductions in PED height were correlated with reductions in central macular thickness at 48 weeks (R = 0.36, P ≤ 0.001). There was no significant correlation between PED height decrease and visual acuity changes at 48 weeks. Solid PEDs were less likely to experience reductions in all three dimensions than either hollow or mixed PEDs.

Aflibercept is effective in reducing PED dimensions in treatment-resistant patients and is most effective in PEDs demonstrating some hyporeflective optical coherence tomography characteristics. Reduction in PED dimensions correlated with central macular thickness, but not with visual acuity changes. The role of PEDs as markers of disease requires further investigation; however, lesions should be monitored for retinal fluid recurrence.


Intravitreal aflibercept for treatment-resistant neovascular age-related maculardegeneration.

Ophthalmology. 2014 Jan;121(1):188-92. doi: 10.1016/j.ophtha.2013.08.035. Epub 2013 Oct 18.
Chang AA 1 , Li H 2 , Broadhead GK 3 , Hong T 2 , Schlub TE 4 , Wijeyakumar W 3 , Zhu M 5.


To assess the effectiveness of intravitreal aflibercept in patients with neovascular age-relatedmacular degeneration (AMD) previously resistant to treatment with other anti-vascular endothelial growth factor agents.

Prospective, open-label, noncontrolled, registered clinical trial.

Forty-nine patients with treatment-resistant neovascular AMD.

A dose of 2 mg intravitreal aflibercept was administered as 3 initial loading doses every 4 weeks (week 0, week 4, and week 8), followed by further injections every 8 weeks (weeks 16 and 24) across a 24-week period in total. All patients underwent a complete ophthalmic examination, including measurement of Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), intraocular pressure assessment, adverse event monitoring, and spectral-domain optical coherence tomography at every visit. Baseline fluorescein angiography and indocyanine green angiography also were performed.

Main outcome measures
Outcomes assessed included proportions of patients with a gain or loss of more than 5 ETDRS letters and a decrease or increase in central retinal thickness (CRT) of more than 150μm at week 24 compared with baseline, change in mean BCVA and CRT between baseline and week 24, and descriptive safety data.

The BCVA improved and CRT was reduced significantly at all follow-up visits compared with baseline (P ≤ 0.001), with a mean improvement of 6.9 letters of BCVA and a decrease of 89.4μm in CRT at week 24. Spacing of injections from every 4 weeks to 8 weeks resulted in an increase of 37.4 μm in CRT (P < 0.001); however, this was not correlated with a significant change in vision. There was 1 (2%) patient who lost more than 5 ETDRS letters, and 27 (55%) patients who gained more than 5 letters. Two (4%) patients had a more than 150 μm increase in CRT at week 24, and 10 (20%) patients showed a decrease in CRT of more than 150 μm.

Intravitreal aflibercept is effective in previously treatment-resistant neovascular AMD. Further follow-up is required to determine whether these improvements can be maintained.


The role of aflibercept in the management of diabetic macular edema.

Drug Des Devel Ther. 2015 Aug 6;9:4389-96. doi: 10.2147/DDDT.S62778. eCollection 2015.
Chang AA 1 , Hong T 2 , Ewe SY 2 , Bahrami B 2 , Broadhead GK 1 .


Diabetic macular edema (DME) represents one of the leading causes of visual impairment in working-age adults. Although there are several proven treatments available for this condition, pharmacotherapy through the use of intravitreal antivascular endothelial growth factor agents has revolutionized the management of DME over the past decade with superior outcomes compared to laser therapy. This review summarizes the pathophysiology and available treatment options for the management of DME, with an emphasis on the efficacy and safety profile of a single particular intravitreal antivascular endothelial growth factor agent, aflibercept.


Dietary modification and supplementation for the treatment of age-related macular degeneration.

Nutr Rev. 2015 Jul;73(7):448-62. doi: 10.1093/nutrit/nuv005. Epub 2015 Apr 28.
Broadhead GK 1 , Grigg JR 2 , Chang AA 2 , McCluskey P 2 .


Age-related macular degeneration (AMD) causes a significant proportion of visual loss in the developed world. Currently, little is known about its pathogenesis, and treatment options are limited. Dietary intake is one of the few modifiable risk factors for this condition. The best-validated therapies remain oral antioxidant supplements based on those investigated in the Age-Related Eye Disease Study (AREDS) and the recently completed Age-Related Eye Disease Study 2 (AREDS2). In this review, current dietary guidelines related to AMD, along with the underlying evidence to support them, are presented in conjunction with current treatment recommendations. Both AREDS and AREDS2 are discussed, as are avenues for further research, including supplementation with vitamin D and saffron. Despite the considerable disease burden of atrophic AMD, few effective therapies are available to treat it, and further research is required.

© The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail:


Intravitreal Ranibizumab for neovascular Age-related macular degeneration in clinical practice: five-year treatment outcomes.

Graefes Arch Clin Exp Ophthalmol. 2015 Aug;253(8):1217-25. doi: 10.1007/s00417-014-2799-8. Epub 2014 Sep 10.
Zhu M 1 , Chew JK, Broadhead GK, Luo K, Joachim N, Hong T, Syed A, Chang AA.


Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are the established standard of care for neovascular age-related macular degeneration (nAMD). However, data on long-term outcomes of this therapy are limited. The purpose of this study was to assess the visual and anatomical outcomes and safety profile of intravitreal ranibizumab in treating nAMD over a period of five years.

208 patients (208 eyes) were included in this retrospective case series study. Intervention was an "as-needed" treatment model. Visual acuity (VA), central macular thickness (CMT), ophthalmic examination, and adverse events (AEs) were assessed in each visit. Snellen VA was converted to Early Treatment Diabetic Retinopathy Study letters for analysis.

The average VA improved by 1.9 letters after one year (p ≤ 0.017), and decreased by 2.4 letters over five years of treatment (p = 0.043). At the end of year five, 11.1 % of patients (23/208) had improved VA by more than 15 letters and 68.8 % (143/208) had VA improvement or loss less than or equal to 15 letters, while 20.2 % of patients (42/208) had a loss of more than 15 letters. Patients with VA of less than 35 letters at baseline showed significant VA improvement after five years of treatment. There was a positive relationship between injection numbers and VA improvement over the five-year period, after adjusting for age and baseline VA (p ≤ 0.0005). Mean CMT decreased by 28.3 μm (p ≤ 0.0005) over five years. Ocular AEs, serious adverse events (SAEs), and systemic SAEs occurred in 4.6 %, 0.48 %, and 2 % of patients, respectively, during the follow-up period.

The use of intravitreal ranibizumab in an as-needed treatment regimen over a five-year period was effective in maintaining vision in patients with nAMD and in reducing macular thickness, with a relatively low rate of adverse and serious adverse events.


Treating the untreatable patient: current options for the management of treatment-resistant neovascular age-related macular degeneration.

Acta Ophthalmol. 2014 Dec;92(8):713-23. doi: 10.1111/aos.12463. Epub 2014 Jun 12.
Broadhead GK 1 , Hong T, Chang AA.


Anti-vascular endothelial growth factor (anti-VEGF) agents represent the current standard of care for neovascular age-related macular degeneration (nAMD). Although effective in a majority of cases, a significant proportion of patients have persisting retinal exudation despite regular anti-VEGF therapy. This exudation is considered to produce poorer visual outcomes in these patients. Some of these patients may have misdiagnosed nAMD variants such as polypoidal choroidal vasculopathy; however, the majority of these eyes have what has been termed treatment-resistant nAMD. Currently, the best way to care for these patients is uncertain. Here, we review the evidence for different approaches to the management of treatment-resistant nAMD, including high-dose anti-VEGF therapy, combination regimes and switching of anti-VEGF agents, and discuss possible therapeutic approaches for patients with treatment-resistant nAMD.