Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Short-Term Outcomes of Aflibercept Therapy for Diabetic Macular Edema in Patients With Incomplete Response to Ranibizumab and/or Bevacizumab

Edward H. Wood, MD; Peter A. Karth, MD; Darius M. Moshfeghi, MD; Theodore Leng, MD, MS

Abstract

BACKGROUND AND OBJECTIVE:

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of diabetic macular edema (DME). Currently, the effect of switching to aflibercept from other anti-VEGF agents for DME is unknown.

PATIENTS AND METHODS:

In this prospective, interventional case series, DME patients with persistent retinal fluid despite regular (every 4 to 6 weeks) intravitreal injection (IVI) with ranibizumab 0.3 mg, and/or bevacizumab 1.25 mg were switched to IVI aflibercept 2 mg. Collected data included visual acuity, central subfield foveal thickness (CSFT), and the area of thickest edema on registered spectral-domain optical coherence tomography (SD-OCT).

RESULTS:

At 1 month after the first aflibercept IVI, 79% (11 of 14 eyes) showed anatomic improvement with a 23% decrease in average CSFT from 421 µm to 325 µm (P < .0132).

CONCLUSION:

A majority of patients with DME with persistent fluid on SD-OCT despite regular ranibizumab 0.3 mg and/or bevacizumab 1.25 mg IVIs showed a positive anatomic response to IVI aflibercept 2 mg.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:950–954.]

Abstract

BACKGROUND AND OBJECTIVE:

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of diabetic macular edema (DME). Currently, the effect of switching to aflibercept from other anti-VEGF agents for DME is unknown.

PATIENTS AND METHODS:

In this prospective, interventional case series, DME patients with persistent retinal fluid despite regular (every 4 to 6 weeks) intravitreal injection (IVI) with ranibizumab 0.3 mg, and/or bevacizumab 1.25 mg were switched to IVI aflibercept 2 mg. Collected data included visual acuity, central subfield foveal thickness (CSFT), and the area of thickest edema on registered spectral-domain optical coherence tomography (SD-OCT).

RESULTS:

At 1 month after the first aflibercept IVI, 79% (11 of 14 eyes) showed anatomic improvement with a 23% decrease in average CSFT from 421 µm to 325 µm (P < .0132).

CONCLUSION:

A majority of patients with DME with persistent fluid on SD-OCT despite regular ranibizumab 0.3 mg and/or bevacizumab 1.25 mg IVIs showed a positive anatomic response to IVI aflibercept 2 mg.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:950–954.]

Introduction

Aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY) is an anti–vascular endothelial growth factor (VEGF) agent that was approved by the U.S. Food and Drug Administration (FDA) for neovascular age-related macular degeneration (AMD) in 2011, macular edema following central retinal vein occlusion (CRVO) in 2012, macular edema following branch retinal vein occlusion (BRVO) in 2014, and diabetic macular edema (DME) in 2014. The DA VINCI study demonstrated that aflibercept provided an 8.9-letter improvement over laser,1 and the DRCR. net Protocol T trial showed that patients with DME presenting with visual acuity of 20/50 or worse had improved outcomes with aflibercept when compared to both bevacizumab (Avastin; Genentech, San Francisco, CA) and ranibizumab (Lucentis; Genentech).2 However, the effect of switching to aflibercept from other anti-VEGF agents for DME is currently unknown, as is the effect of switching agents due to nonresponsiveness. The purpose of this study was to evaluate the anatomic and visual acuity outcomes of intravitreal aflibercept 2 mg in patient with DME with persistent fluid on spectral-domain optical coherence tomography (SD-OCT) despite regular intravitreal injections (IVI) of ranibizumab 0.3 mg and/or bevacizumab 1.25 mg.

Patients and Methods

One academic practice with two retinal specialists conducted this prospective, interventional case series that was approved by the institutional review board at Stanford University. Inclusion criteria included DME patients with persistent retinal fluid despite regular (every 4 to 6 weeks) injections of ranibizumab 0.3 mg and/or bevacizumab 1.25 mg who were switched to aflibercept 2 mg (Table 1). Exclusion criteria included patients with other vision-limiting conditions besides DME or other possible causes of macular edema. Collected data included details of prior treatments, best available visual acuity, central subfield foveal thickness (CSFT), and the area of thickest edema on registered SD-OCT scans before and after aflibercept. Data points prior to aflibercept injection, 4 to 6 weeks after aflibercept injection, and at last aflibercept injection were collected. A paired t test was used to generate the P values, and a value of less than .05 was deemed to be significant.

Spectral-Domain Ocular Coherence Tomography and Visual Acuity Primary Data Before and After Aflibercept Injection

Table 1:

Spectral-Domain Ocular Coherence Tomography and Visual Acuity Primary Data Before and After Aflibercept Injection

Results

A total of 14 eyes with persistent DME were included. All eyes had persistent fluid after at least three monthly ranibizumab or bevacizumab IVIs (range: 3 to 15 IVIs). At 1 month after the first aflibercept IVI, 79% (11 of 14 eyes) showed anatomic improvement, although none were fluid-free; 21% (three of 14 eyes) showed stable or worsening edema (Table 1). On average, CSFT decreased from 421 µm to 325 µm (23%; P < .0132) after one aflibercept IVI (Table 2). When measuring the thickest point in the macula on registered SD-OCT, the thickness decreased from 539 µm to 463 µm (14%; P < .0144) after one aflibercept IVI as illustrated (Figure). All eyes monitored during the course of multiple aflibercept injections (three eyes) showed further improvement. Visual acuity improved in three of 14 eyes 1 month after the first aflibercept IVI, but this change did not reach statistical significance (P < 1.0). Treatment was well-tolerated with no adverse events.

Spectral-Domain Ocular Coherence Tomography and Visual Acuity Analyzed Data Before and After Aflibercept Injection

Table 2:

Spectral-Domain Ocular Coherence Tomography and Visual Acuity Analyzed Data Before and After Aflibercept Injection

Improved diabetic macular edema as seen with spectral-domain optical coherence tomography after aflibercept injection.

Figure.

Improved diabetic macular edema as seen with spectral-domain optical coherence tomography after aflibercept injection.

Discussion

DME is the leading cause of vision loss in the working-age population in developed countries.3 DME may occur in both proliferative and nonproliferative diabetic retinopathy (DR), with 26% of patients with DR presenting with DME.4 DME is characterized as focal or diffuse, and preferred treatment patterns depend upon the amount, location, and chronicity of macular edema caused by leaking microaneurysms and dilated capillary beds.

For nearly three decades, focal/grid laser photocoagulation (F/G) was the standard of care for DME, reducing the risk of moderate vision loss by 50%.5 The parallel RISE and RIDE studies of ranibizumab injection in subjects with clinically significant macular edema with center involvement secondary to diabetes mellitus and the RESTORE study of ranibizumab monotherapy or combined with laser versus laser monotherapy for DME ushered in a paradigm shift in the management of DME, proving that anti-VEGF therapy with intravitreal ranibizumab was safe, efficacious, and ultimately superior to F/G in the treatment of DME.6,7 The higher relative cost of ranibizumab inspired the current widespread usage of anti-VEGF therapy with intravitreal bevacizumab to treat DME, with a cost per dose roughly 40-times less8,9 and data from the prospective randomized BOLT trial of intravitreal bevacizumab or laser therapy in the management of DME proving its comparable efficacy with laser.10 More recently, the VIVID study of aflibercept in vision impairment due to DME, the VISTA study of intravitreal administration of aflibercept in patients with DME, and DA VINCI demonstrated that anti-VEGF therapy with intravitreal aflibercept was superior to F/G in restoring visual acuity in eyes with DME,1,11 leading to the current FDA approval of intravitreal aflibercept for the treatment of DME.12 Intravitreal steroids including triamcinolone and sustained-release dexamethasone implant continue to have a limited role in the management of DME,3 particularly in pseudophakic patients with refractory edema, and subthreshold diode laser micropulse photocoagulation (SDM) provides a less destructive alternative to F/G or adjunct to anti-VEGF therapy.13 Current expert opinion generally regards focal DME as responsive to F/G and diffuse DME as best managed with anti-VEGF therapy.

Several studies have investigated the relative efficacy of anti-VEGF agents in the treatment of DME. One small prospective study showed that ranibizumab and bevacizumab were statistically equivalent in terms of efficacy in reducing CSFT in DME at 12 months, despite the bevacizumab group requiring more injections to reach this endpoint.14 This study, however, did not include aflibercept. The DRCR.net Protocol T trial showed that DME patients presenting with visual acuity of 20/50 or worse (fewer than 69 letters) had improved outcomes with aflibercept (18.9-letter improvement) compared to both bevacizumab (11.8-letter improvement) and ranibizumab (14.2-letter improvement).2

Although there are clearly several efficacious treatment options available to treat DME, no large studies have been done to investigate the efficacy of switching between anti-VEGF agents in the setting of suboptimal treatment response. It is known that the VISTA and VIVID phase 3 trials of aflibercept for the treatment of DME included eyes previously treated with anti-VEGF agents (prior to entering the VIVID/VISTA trial protocol). However, these studies required a wash-out period of 3 months for any patient enrolling in the trial, thereby allowing for possible fluid reaccumulation prior to switching to aflibercept. This wash-out period is not typically employed in clinical practice when considering a switch in pharmaceutical agents. The data presented here are novel in that this study included patients who did not undergo a wash-out period, thereby mimicking clinical practice patterns more closely. Along similar lines, patients in this study were reexamined every 4 to 6 weeks in a real clinical practice, as opposed to repeat examinations at exact 4-week intervals.

The data presented here suggest that in clinical practice, intravitreal aflibercept may provide additional short-term anatomic efficacy in the treatment of DME in cases in which three treatments with ranibizumab and/or bevacizumab resulted in suboptimal anatomic response. In this study, suboptimal response to treatment was defined as persistent intraretinal or subretinal fluid despite at least three monthly ranibizumab or bevacizumab injections, a time period often used in clinical practice by clinicians. A possible explanation for this is the higher binding affinity of aflibercept to VEGF relative to bevacizumab and ranibizumab.15,16

The data presented herein may add to the understanding of the loss of anti-VEGF agent efficacy over time, a phenomenon well known in the literature variably as tachyphylaxis, tolerance, or resistence.17 Studies analyzing the effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD have shown reduced edema following a switch to aflibercept.18 Although theoretically all VEGF should be bound by routine anti-VEGF therapy, it is possible that aflibercept’s higher affinity and faster association rate to VEGF-A, ability to entrap the VEGF dimer, and unique ability block the placental growth factor and VEGF-B produced the observed anatomical improvement.15 It is reasonable to assume that these same pharmacologic advantages are at least partially responsible for the data presented here for DME. Forooghian et al.19 built upon the work of Rosenfeld et al.20 to suggest that the formation of circulating neutralizing antibodies against anti-VEGF drug molecules produces decreased efficacy of anti-VEGF treatment over time. Perhaps alternating drug molecules with aflibercept’s potentially novel antigens avoids such neutralizing antibodies, thereby allowing for greater efficacy.

A majority of DME cases with persistent fluid on SD-OCT despite three regular ranibizumab 0.3 mg and/or bevacizumab 1.25 mg intravitreal injections showed a positive short-term anatomic response to aflibercept 2 mg IVI. With the widespread use of anti-VEGF therapy in the treatment of DME, the data presented here provide a greater understanding of management of DME cases exhibiting suboptimal early response to ranibizumab or bevacizumab.

References

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Spectral-Domain Ocular Coherence Tomography and Visual Acuity Primary Data Before and After Aflibercept Injection

Pre-Aflibercept (after IVB or IVR treatment)Post-Aflibercept (1 month after aflibercept)Change Analysis (change after aflibercept)
EyeCSFT (µm)Maximum Thickness (µm)Visual acuityInjection Number (IVB/IVR)CSFT (µm)Maximum Thickness (µm)Visual acuityCSFT (µm)Maximum Thickness (µm)Visual acuity (line)
150868420/703 (IVB)34365420/70(165)(30)0
229029020/404 (IVR)29029020/40000
338342020/307 (IVR)34139920/30(42)(21)0
447660320/1006 (IVB)55157320/10075(30)0
534453720/1006 (IVB)37854220/1003450
651151120/3004 (IVR)42451120/400(87)0(1)
761961920/403 (IVR)23623620/40(383)(383)0
838247820/705 (1 IVB, 4 IVR)28238720/60(100)(91)1
941477120/8004 (IVR)37873320/500(36)(38)1
1029947520/7015 (IVB)22340920/50(76)(66)1
1139561720/3007 (5 IVB, 2 IVR)29049520/300(105)(122)0
1245054620/1003 (1 IVB, 2 IVR)32446120/150(126)(85)(1)
1327741320/206 (IVR)25737220/25(20)(41)(1)
1455258820/1505 (3 IVB, 2 IVR)23442220/150(318)(166)0
Avg.42153920/1575.3 (2.9 IVB, 2.4 IVR)32546320/143(96)(76)

Spectral-Domain Ocular Coherence Tomography and Visual Acuity Analyzed Data Before and After Aflibercept Injection

Avg. CSFT (µm)Maximum Thickness (µm)Visual Acuity
CSFT Reduction22.86%14.14%
P value0.01320.0144
No. Improved11 of 1411 of 143 of 14
% Improved79%79%21%
# Stab/Worse3 of 143 of 1411 of 14
% Stab/Worse21%21%79%
No. Dry0 of 14
% Dry0%
Authors

From the Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA.

Presented in part at the American Society of Retinal Specialists meeting, on August 9, 2014, in San Diego, CA.

The authors report no relevant financial disclosures.

Dr. Moshfeghi did not participate in the editorial review of this manuscript.

Address correspondence to Theodore Leng, MD, MS, Byers Eye Institute at Stanford, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303; 650-498-4264; email: tedleng@stanford.edu.

Received: October 16, 2014
Accepted: August 26, 2015

10.3928/23258160-20151008-08

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