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Figure 1.  Best-Corrected Visual Acuity (BCVA) Change in the Total Laser Control Populations in VISTA and VIVID
Best-Corrected Visual Acuity (BCVA) Change in the Total Laser Control Populations in VISTA and VIVID

Shown are the mean Early Treatment Diabetic Retinopathy Study letters in analyses with and without censoring values obtained after the initiation of intravitreal aflibercept injection treatment (last observation carried forward [LOCF] and ancillary LOCF [aLOCF], respectively) among 154 eyes in VISTA and 132 eyes in VIVID. Laser control indicates macular laser photocoagulation treatment control; VISTA, Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema; VIVID, Intravitreal Aflibercept Injection in Vision Impairment Due to DME.

Figure 2.  Visual Outcomes in Laser Control Eyes That Received Intravitreal Aflibercept Injection Treatment (Ancillary Last Observation Carried Forward)
Visual Outcomes in Laser Control Eyes That Received Intravitreal Aflibercept Injection Treatment (Ancillary Last Observation Carried Forward)

Shown are the mean best-corrected visual acuity (BCVA) change from baseline (63 eyes in VISTA and 46 eyes in VIVID) (A), the mean BCVA change synchronized at the time of intravitreal aflibercept injection treatment initiation (B), and the proportions of eyes that gained at least 10 letters (C) and at least 15 letters (D) from the time of intravitreal aflibercept injection treatment initiation through the end of the study. Laser control indicates macular laser photocoagulation treatment control; VISTA, Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema; VIVID, Intravitreal Aflibercept Injection in Vision Impairment Due to DME.

Figure 3.  Central Subfield Thickness (CST) Change in the Total Laser Control Population in VISTA and VIVID
Central Subfield Thickness (CST) Change in the Total Laser Control Population in VISTA and VIVID

Shown are the mean values in analyses with and without censoring values obtained after the initiation of intravitreal aflibercept injection treatment (last observation carried forward [LOCF] and ancillary LOCF [aLOCF], respectively) among 154 eyes in VISTA and 132 eyes in VIVID. Laser control indicates macular laser photocoagulation treatment control; VISTA, Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema; VIVID, Intravitreal Aflibercept Injection in Vision Impairment Due to DME.

Figure 4.  Central Subfield Thickness (CST) Change in Laser Control Eyes That Received Intravitreal Aflibercept Injection Treatment (Ancillary Last Observation Carried Forward)
Central Subfield Thickness (CST) Change in Laser Control Eyes That Received Intravitreal Aflibercept Injection Treatment (Ancillary Last Observation Carried Forward)

Shown are the mean CST change from baseline (among 63 eyes in VISTA and among 46 eyes in VIVID) and the mean CST change from baseline synchronized at the time of intravitreal aflibercept injection treatment initiation through the end of the study. Laser control indicates macular laser photocoagulation treatment control; VISTA, Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema; VIVID, Intravitreal Aflibercept Injection in Vision Impairment Due to DME.

Table.  Baseline Demographics and Characteristics in Laser Control Eyes in VISTA and VIVID From the Full Analysis Set
Baseline Demographics and Characteristics in Laser Control Eyes in VISTA and VIVID From the Full Analysis Set
1.
Bourne  RR, Jonas  JB, Flaxman  SR,  et al; Vision Loss Expert Group of the Global Burden of Disease Study.  Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990-2010.  Br J Ophthalmol. 2014;98(5):629-638.PubMedGoogle ScholarCrossref
2.
Early Treatment Diabetic Retinopathy Study Research Group.  Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1.   Arch Ophthalmol. 1985;103(12):1796-1806.PubMedGoogle ScholarCrossref
3.
Nguyen  QD, Brown  DM, Marcus  DM,  et al; RISE and RIDE Research Group.  Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.  Ophthalmology. 2012;119(4):789-801.PubMedGoogle ScholarCrossref
4.
Korobelnik  JF, Do  DV, Schmidt-Erfurth  U,  et al.  Intravitreal aflibercept for diabetic macular edema.  Ophthalmology. 2014;121(11):2247-2254.PubMedGoogle ScholarCrossref
5.
Brown  DM, Schmidt-Erfurth  U, Do  DV,  et al.  Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies.  Ophthalmology. 2015;122(10):2044-2052.PubMedGoogle ScholarCrossref
6.
Boyer  DS, Yoon  YH, Belfort  R  Jr,  et al; Ozurdex MEAD Study Group.  Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema.  Ophthalmology. 2014;121(10):1904-1914.PubMedGoogle ScholarCrossref
7.
Campochiaro  PA, Brown  DM, Pearson  A,  et al; FAME Study Group.  Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema.  Ophthalmology. 2012;119(10):2125-2132.PubMedGoogle ScholarCrossref
8.
Elman  MJ, Aiello  LP, Beck  RW,  et al; Diabetic Retinopathy Clinical Research Network.  Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;117(6):1064-1077.e35. doi:10.1016/j.ophtha.2010.02.031PubMedGoogle ScholarCrossref
9.
Mitchell  P, Bandello  F, Schmidt-Erfurth  U,  et al; RESTORE Study Group.  The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.  Ophthalmology. 2011;118(4):615-625.PubMedGoogle ScholarCrossref
10.
Elman  MJ, Bressler  NM, Qin  H,  et al; Diabetic Retinopathy Clinical Research Network.  Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2011;118(4):609-614.PubMedGoogle ScholarCrossref
11.
Boyer  DS, Hopkins  JJ, Sorof  J, Ehrlich  JS.  Anti–vascular endothelial growth factor therapy for diabetic macular edema.  Ther Adv Endocrinol Metab. 2013;4(6):151-169.PubMedGoogle ScholarCrossref
12.
Elman  MJ, Ayala  A, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.  Ophthalmology. 2015;122(2):375-381.PubMedGoogle ScholarCrossref
13.
Brown  DM, Heier  JS, Clark  WL,  et al.  Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study.  Am J Ophthalmol. 2013;155(3):429-437.e7. doi:10.1016/j.ajo.2012.09.026PubMedGoogle ScholarCrossref
14.
Campochiaro  PA, Brown  DM, Awh  CC,  et al.  Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study.  Ophthalmology. 2011;118(10):2041-2049.PubMedGoogle ScholarCrossref
15.
Campochiaro  PA, Heier  JS, Feiner  L,  et al.  BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study.  Ophthalmology. 2010;117(6):1102-1112.e1. doi:10.1016/j.ophtha.2010.02.021PubMedGoogle ScholarCrossref
16.
Ip  MS, Domalpally  A, Hopkins  JJ, Wong  P, Ehrlich  JS.  Long-term effects of ranibizumab on diabetic retinopathy severity and progression.  Arch Ophthalmol. 2012;130(9):1145-1152.PubMedGoogle ScholarCrossref
17.
Campochiaro  PA, Wykoff  CC, Shapiro  H, Rubio  RG, Ehrlich  JS.  Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema.  Ophthalmology. 2014;121(9):1783-1789.PubMedGoogle ScholarCrossref
18.
Early Treatment Diabetic Retinopathy Study Research Group.  Focal photocoagulation treatment of diabetic macular edema: relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report No. 19.  Arch Ophthalmol. 1995;113(9):1144-1155.PubMedGoogle ScholarCrossref
19.
American Society of Retina Specialists. ASRS PAT survey. http://www.asrs.org/content/documents/_2012asrspatsurveyresults.pdf. Published 2012. Accessed April 2016.
20.
clinicaltrials.gov. Treatment for CI-DME in Eyes With Very Good VA Study (Protocol V). https://clinicaltrials.gov/ct2/show/NCT01909791. Accessed January 2016.
Original Investigation
Clinical Trial
February 2017

Intravitreal Aflibercept Injection in Eyes With Substantial Vision Loss After Laser Photocoagulation for Diabetic Macular Edema: Subanalysis of the VISTA and VIVID Randomized Clinical Trials

Author Affiliations
  • 1Retina Consultants of Houston, Houston, Texas
  • 2Southeast Retina Center, Augusta, Georgia
  • 3Department of Ophthalmology, University of Padova, Padova, Italy
  • 4Service d’Ophtalmologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  • 5University Bordeaux, Institut de Santé Publique, d’Epidémiologie et de Développement (ISPED), Bordeaux, France
  • 6Institut National de la Santé et de la Récherche Médicale Unité 1219, Bordeaux Population Health Research Center, Bordeaux, France
  • 7Regeneron Pharmaceuticals, Inc, Tarrytown, New York
  • 8Bayer HealthCare Pharmaceuticals, Berlin, Germany
  • 9University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 10Ophthalmic Consultants of Boston, Boston, Massachusetts
JAMA Ophthalmol. 2017;135(2):107-114. doi:10.1001/jamaophthalmol.2016.4912
Key Points

Question  In a post hoc analysis of the VISTA and VIVID trials, was there visual acuity improvement with intravitreal aflibercept injection after substantial visual acuity loss at least 24 weeks after macular laser photocoagulation treatment for persistent diabetic macular edema?

Findings  In these randomized clinical trials, eyes with substantial visual acuity loss at least 24 weeks after macular laser photocoagulation treatment subsequently receiving intravitreal aflibercept injection had mean gains from baseline to week 100 of 2.2 (VISTA) and 3.8 (VIVID) letters. After initiating intravitreal aflibercept injection, the mean gain was 17.4 (VISTA) and 13.6 (VIVID) letters through week 100.

Meaning  Intravitreal aflibercept injection results in substantial visual acuity gains among eyes with substantial visual acuity loss at least 24 weeks after macular laser photocoagulation treatment for diabetic macular edema.

Abstract

Importance  Information on the effect of anti–vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable.

Objective  To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection.

Design, Setting, and Participants  This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials—VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)—in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included.

Interventions  Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline.

Main Outcomes and Measures  Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection.

Results  Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 μm in VISTA and a decrease of 3.0 μm in VIVID), after which further mean (SD) reductions of 285.6 (202.6) μm (VISTA) and 313.4 (181.9) μm (VIVID) occurred through week 100.

Conclusions and Relevance  Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME.

Trial Registration  clinicaltrials.gov Identifiers: NCT01363440 and NCT01331681

Introduction

Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy (DR) and the most common cause of blindness among working-age populations in the United States.1 The first validated treatment for DME, focal or grid laser photocoagulation of the macula (hereafter referred to as macular laser photocoagulation), was established by the Early Treatment Diabetic Retinopathy Study2 (ETDRS) in the 1980s.

More recently, pharmacologic management with anti–vascular endothelial growth factor (VEGF) agents has progressively replaced macular laser photocoagulation as the primary treatment of center-involving DME with visual acuity (VA) loss.3-9 Multiple large, randomized clinical trials directly comparing macular laser photocoagulation with anti-VEGF pharmacotherapies have confirmed superior visual and anatomic outcomes with VEGF blockade.4,5,8-10 In the protocol I8 and the RESTORE study9 among the subgroup of eyes with prior macular laser photocoagulation or previous treatment for DME, no significant interaction was identified between prior macular laser photocoagulation or prior treatment for DME and the superiority of anti-VEGF therapy compared with additional macular laser photocoagulation for DME. However, reported subgroup analyses did not specifically consider eyes that received macular laser photocoagulation and subsequently experienced substantial declines in VA.8,9

Two large phase 3 trials—VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)—concluded that intravitreal aflibercept injection was superior to macular laser photocoagulation through 100 weeks of treatment in patients with baseline VA of 20/40 or worse.4,5 A key component of VISTA and VIVID was the opportunity for additional treatment beginning at week 24 if there was substantial vision loss, defined per protocol in all treatment arms.4,5 This report analyzes visual and anatomic outcomes of these eyes initially randomized to macular laser photocoagulation that subsequently received treatment with intravitreal aflibercept injection per protocol-defined criteria through week 100.

Methods
Study Design

The phase 3 VISTA and VIVID studies were 2 similarly designed, double-masked, randomized, active-controlled trials, described previously.4,5 Briefly, adults with type 1 or 2 diabetes with center-involving DME (retinal thickening involving the spectral-domain optical coherence tomography 1-mm central subfield thickness [CST]) were eligible for enrollment if study eye best-corrected VA (BCVA) was between 73 and 24 letters (20/40 to 20/320 Snellen equivalent). Patients with prior anti-VEGF or macular laser photocoagulation treatment for DME were required to have at least a 90-day period between the last anti-VEGF or macular laser photocoagulation treatment and enrollment in the study. Each clinical site’s respective institutional review board or ethics committee approved the study. Institutional names for each site have been previously published.4 All patients provided written informed consent. The study dates were May 2011 to May 2014. Eyes were randomized in a 1:1:1 ratio to receive either 2 mg of intravitreal aflibercept injection every 4 weeks, 2 mg of intravitreal aflibercept injection every 8 weeks after 5 initial monthly doses with sham injections on nontreatment visits, or macular laser photocoagulation treatment control (hereafter laser control) at baseline and at each visit during which an eye met laser retreatment criteria, with sham injections at each study visit. Eyes were treated in this fashion through week 100. Laser photocoagulation was applied according to a commonly used modified ETDRS treatment protocol using approximately a 50-µm spot size and green to yellow laser light applied for 0.01 to 0.1 seconds to create barely visible (light gray) burns in the areas of retinal edema.

Study eyes in the laser control group were assessed for laser retreatment criteria beginning at week 12. They received macular laser photocoagulation if ETDRS-defined, clinically significant DME was present (defined as thickening of the retina or hard exudates at ≤500 µm of the center of the macula or ≥1 zone of retinal thickening 1 disc area or larger, any part of which was within 1 disc diameter of the center of the macula) but not more frequently than every 12 weeks.

Study eyes in the laser control group could also receive additional intravitreal aflibercept injection treatment (“rescue” treatment4,5) from week 24 onward if DME worsened, causing at least a 10-letter VA loss from the best previous measurement at 2 consecutive visits or at least a 15-letter VA loss from the best previous measurement at 1 visit, with BCVA not better than measurements at baseline. Anatomic worsening or improvement per a specific optical coherence tomography CST was not required to receive additional treatment. Eyes meeting these criteria received 5 doses of 2 mg of intravitreal aflibercept injection every 4 weeks, followed by 2 mg of intravitreal aflibercept injection every 8 weeks, and continued to receive active macular laser photocoagulation per laser retreatment criteria. Eyes could receive both laser and intravitreal aflibercept injection, when applicable, at the same visit.

Outcome Measures and Statistical Analysis

Efficacy end points were evaluated in the full analysis set, which included eyes that received study treatment and had a baseline and at least 1 postbaseline BCVA assessment. Missing values were imputed using the last observation carried forward (LOCF) method. The following 2 approaches were prespecified for computing outcomes of eyes that received treatment with intravitreal aflibercept injection in the laser control group: (1) the last value before treatment with intravitreal aflibercept injection was used for analyses, censoring values after treatment with intravitreal aflibercept injection was given (LOCF), and (2) values after treatment with intravitreal aflibercept injection were included in the analyses (ancillary LOCF). A post hoc analysis was conducted to specifically evaluate visual and anatomic outcomes in the subgroup of eyes originally randomized to laser control that received treatment with intravitreal aflibercept injection.

Results

Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (safety analysis set) (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. In VISTA, of the 63 laser control eyes in VISTA that would ultimately receive intravitreal aflibercept injection, 30.2% (19 of 63) initiated treatment with intravitreal aflibercept injection at week 24, the earliest possible time point at which treatment could be initiated, and a total of 76.2% (48 of 63) initiated treatment through week 52 (not inclusive of week 52). In VIVID, of the 46 laser control eyes ultimately receiving intravitreal aflibercept injection, 26.1% (12 of 46) received treatment at week 24, and 69.6% (32 of 46) received treatment by week 52 (not inclusive of week 52). The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 days in VISTA and 83.5 days in VIVID.

Before initiating treatment with intravitreal aflibercept injection, a mean of 2.7 (range, 1-7) and 2.3 (range, 1-5) laser treatments had been applied to these eyes in VISTA and VIVID, respectively. After the initiation of treatment with intravitreal aflibercept injection, eyes received a mean of 8.9 (range, 1-12) and 8.8 (range, 1-12) injections of intravitreal aflibercept through week 100 in VISTA and VIVID, respectively.

Overall baseline characteristics in the subgroup of laser control eyes that received treatment with intravitreal aflibercept injection were similar to those of the total laser control population and the laser control population who did not meet these requirements in both VISTA and VIVID except for CST (Table). The mean baseline CST was greater in the subgroup of laser control eyes that received intravitreal aflibercept injection in both VISTA and VIVID by 40 and 60 µm, respectively, compared with the subgroup of laser control eyes that did not receive intravitreal aflibercept injection.

Visual Outcomes

The mean changes in BCVA through week 100 for the total laser control population are shown in Figure 1 with and without censoring values after the initiation of treatment with intravitreal aflibercept injection in the subgroup meeting criteria. In VISTA, the mean change in BCVA from baseline at week 100 was 0.9 letters after censoring values obtained after the initiation of treatment with intravitreal aflibercept injection compared with 6.3 letters when including values obtained after the initiation of treatment with intravitreal aflibercept injection. The corresponding BCVA changes from baseline at week 100 in VIVID were 0.7 and 5.5 letters, respectively.

The mean changes in BCVA in the subgroup of laser control eyes that received treatment with intravitreal aflibercept injection are shown in Figure 2 using 2 approaches. Figure 2A demonstrates the mean change in BCVA from baseline regardless of the time of the initiation of treatment. These eyes lost a mean of 4.5 and 3.5 letters from baseline in VISTA and VIVID, respectively, through week 24 and then, on average, gained vision from week 24 onward, with an ultimate mean (SD) BCVA gain from baseline to week 100 of 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters (Figure 2A). Figure 2B demonstrates the mean change in BCVA from the time that treatment with intravitreal aflibercept injection was initiated in each study eye. This analysis shows that eyes in this subgroup had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline at the time of treatment initiation with intravitreal aflibercept injection. Although vision gain was not achieved in all eyes after the initiation of treatment with intravitreal aflibercept injection, these eyes subsequently gained a mean (SD) of 17.4 (9.7) (range, −4 to +34) letters (VISTA) and a mean (SD) of 13.6 (8.6) (range, −4 to +24) letters (VIVID) from the initiation of treatment with intravitreal aflibercept injection through week 100 (Figure 2B). The proportions of patients who gained at least 10 letters from the time of treatment initiation with intravitreal aflibercept injection at week 100 were 78.9% (15 of 19) and 69.2% (9 of 13) in VISTA and VIVID, respectively (Figure 2C). The corresponding proportions of patients who gained at least 15 letters at week 100 were 63.2% (12 of 19) and 53.8% (7 of 13), respectively (Figure 2D).

Anatomic Outcomes

The mean reduction in CST through week 100 for the total laser control population is shown in Figure 3 with and without censoring values after the initiation of treatment with intravitreal aflibercept injection. In VISTA, the mean reduction in CST from baseline at week 100 was 83.9 μm, censoring the values obtained after the initiation of treatment with intravitreal aflibercept injection, compared with 178.6 μm when including values obtained after the initiation of treatment with intravitreal aflibercept injection. The corresponding CST reductions from baseline at week 100 in VIVID were 85.7 μm and 178.4 μm, respectively.

The mean change in CST in the subgroup of laser control eyes that received treatment with intravitreal aflibercept injection is shown in Figure 4 using the same approaches described for BCVA. Figure 4A shows CST changes compared with baseline regardless of the time of the initiation of treatment with intravitreal aflibercept injection, demonstrating that this subgroup of eyes experienced a minimal reduction in CST through week 24 (5.8 and 16.0 μm in VISTA and VIVID, respectively) but subsequently experienced progressive CST reductions after week 24 through week 100 (Figure 4A). The mean changes in CST from the time that treatment with intravitreal aflibercept injection was initiated in each study eye are shown in Figure 4B. This analysis demonstrates that the subgroup of eyes that ultimately received treatment with intravitreal aflibercept injection had no meaningful CST change from baseline until the time of the initiation of treatment with intravitreal aflibercept injection, producing an increase of 3.9 μm (VISTA) and a decrease of 3.0 μm (VIVID) (Figure 4B). These eyes demonstrated mean (SD) CST reductions of 285.6 (202.6) (range, −696.0 to +6.0) μm (VISTA) and 313.4 (181.9) (range, −637.0 to −47.0) μm (VIVID) from the initiation of treatment with intravitreal aflibercept injection through week 100.

In VISTA, 31.7% (20 of 63 eyes) of laser control eyes that received treatment with intravitreal aflibercept injection had at least a 2-step improvement in Diabetic Retinopathy Severity Scale score from baseline through week 100. The corresponding proportion in VIVID was 22.6% (7 of 31 eyes).

Discussion

While previous studies8,9 of anti-VEGF treatment demonstrated a superiority over macular laser photocoagulation treatment for DME among eyes that underwent prior macular laser photocoagulation for DME, the phase 3 VISTA and VIVID trials offer a unique opportunity to analyze outcomes of eyes with center-involving DME with baseline VA of 20/40 or worse that were randomized to macular laser photocoagulation and subsequently met prespecified criteria to receive additional treatment with intravitreal aflibercept injection. More than one-third of eyes randomized to macular laser photocoagulation met these substantial vision loss criteria and received treatment with intravitreal aflibercept injection, with most initiating treatment within the first 6 months of eligibility.

During initiation of treatment with intravitreal aflibercept injection, this subgroup of eyes had lost a mean of 2 lines of vision from baseline. Subsequently, these eyes rapidly regained this lost vision, returning to their baseline mean vision after approximately 3 months of treatment with intravitreal aflibercept injection, and continued to gain additional vision above their baseline through week 100. These results indicate that the VA changes occur with the initiation of treatment with intravitreal aflibercept injection among eyes with vision loss after treatment with macular laser photocoagulation for DME. Despite substantial visual gains in some eyes after initiating treatment with intravitreal aflibercept injection, the mean final VA was less than that achieved in eyes initially randomized to intravitreal aflibercept injection.5 This finding may indicate that delaying treatment with intravitreal aflibercept injection in center-involving DME could limit optimal VA outcomes. Potential reasons for suboptimal visual outcomes after delayed anti-VEGF treatment in DME management may be related to the damaging permeability effects from long-term VEGF overexpression that results in persistent retinal edema11,12 and possible vision-limiting effects of thermal laser damage.

The final anatomic response as measured by changes in CST after the initiation of treatment with intravitreal aflibercept injection was robust and comparable to the response seen among eyes initially randomized to intravitreal aflibercept injection. Other DME studies have demonstrated a robust anatomic response, accompanied by limited visual gains after delayed treatment with an anti-VEGF.3 The phenomenon of suboptimal visual outcomes with delayed anti-VEGF treatment in the presence of significant anatomic response also has been documented in retinal venous occlusive disease.13-15 These studies did not require criteria-based vision loss before implementation of anti-VEGF treatment.

Earlier anti-VEGF treatment initiation in the management of patients with DME may be beneficial through mechanisms other than simple edema mitigation. Anti-VEGF treatments in eyes with DME can significantly improve Diabetic Retinopathy Severity Scale scores and reduce the risk of DR worsening.4,5,10,16 Consistent with these previously reported outcomes, improvement in DR was observed in approximately 23% to 32% of the eyes that received treatment with intravitreal aflibercept injection herein. Therefore, treating patients with DME early in the course of disease may improve the underlying DR and therefore decrease risks of long-term, vision-threatening complications. Such VEGF blockade may significantly reduce the development and progression of retinal capillary nonperfusion involving the posterior pole.17

Strengths of the present analysis include the robust randomized design of VISTA and VIVID, masked VA examiners, independent masked reading centers, the use of strict prespecified VA criteria for the initiation of treatment with intravitreal aflibercept injection starting at week 24 (thus allowing enough time for a potential therapeutic effect with macular laser photocoagulation), and a uniform treatment regimen. Evaluation of the eyes in this analysis provides clinical guidance distinct from that inferred from other studies in which a mandated crossover to anti-VEGF occurred at a predefined time point, without specific evaluation of vision loss.3

Limitations

A limitation of the present subgroup analysis is the post hoc exploratory approach. All patients originally randomized to laser control who met criteria of substantial vision loss received treatment with intravitreal aflibercept injection. The present analysis does not provide information on outcomes of these patients had intravitreal aflibercept injection treatment been initiated with lesser vision loss or at an earlier time point than required by the prospective protocol. In addition, outcomes in these patients if they had not received treatment with intravitreal aflibercept injection cannot be determined by this analysis. Even though treatment with intravitreal aflibercept injection was initiated at different time points, approximately 70% to 76% of laser control eyes received treatment with intravitreal aflibercept injection before week 52, allowing for an adequate follow-up interval for most eyes to manifest the full treatment effect of intravitreal aflibercept injection on visual and anatomic outcomes.

The optimal clinical point at which to initiate anti-VEGF therapy in the management of DME is uncertain in patients with VA better than the enrollment criteria used in the phase 3 trials establishing the efficacy of anti-VEGF agents.3-5 This population is particularly relevant because many patients with DME may be initially seen with better than 20/40 VA.18 For clinically significant DME that is not center involving in which many patients have well-preserved VA, macular laser photocoagulation remains a commonly used treatment strategy and is applied in this clinical scenario by 75.9% of US and Canadian retina specialists responding to the American Society of Retina Specialists Patterns and Trends Survey.19 In patients having center-involving DME with preserved VA, the appropriate use of macular laser photocoagulation and anti-VEGF medication is being actively investigated.20

Conclusions

Treatment with intravitreal aflibercept injection led to rapid, substantial, and sustained visual and anatomic benefit among a subgroup of eyes with substantial visual loss that were initially randomized to macular laser photocoagulation in VISTA and VIVID. However, despite substantial VA gains in most of these eyes, ultimate VA appeared to be limited because of the requirement for substantial vision loss before treatment with intravitreal aflibercept injection was allowed. The findings of this study suggest that the initiation of treatment with intravitreal aflibercept injection in eyes with substantial vision loss after macular laser photocoagulation treatment for DME may be beneficial.

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Article Information

Accepted for Publication: October 26, 2016.

Corresponding Author: Charles C. Wykoff, MD, PhD, Retina Consultants of Houston, 6560 Fannin St, Ste 750, Houston, TX 77030 (ccwmd@houstonretina.com).

Published Online: December 22, 2016. doi:10.1001/jamaophthalmol.2016.4912

Author Contributions: Dr Wykoff had full access to all the data in study and takes responsibility for the integrity of the data and the accuracy of data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Schmelter.

Obtained funding: Zeitz.

Study supervision: Marcus, Midena, Korobelnik, Vitti, Berliner, Zeitz, Metzig.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Wykoff reported being a consultant for Alcon, Allergan, Alimera, Bayer HealthCare Pharmaceuticals, Clearside, DORC (Dutch Ophthalmic Research Center) International, Genentech, ONL Therapeutics, Regeneron Pharmaceuticals, Inc, and ThromboGenics and reported receiving research funding from Acucela, Alcon, Allegro Ophthalmics, Allergan, Ampio, Apellis Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Clearside, Genentech, Iconic Therapeutics, National Eye Institute, National Institute of Health, Ophthotech, Pfizer, pSivida, Regeneron Pharmaceuticals, Inc, Santeen, ThromboGenics, and XOMA. Dr Marcus reported being a consultant for Alimera, Genentech, and Regeneron Pharmaceuticals, Inc and reported receiving research funding from Acucela, Alcon, Alimera, Allegro, Allergan, Appellis, Astellas, Genentech, GSK, Iconic, Lpath, Neurotech, Ohr, Ophthotech, Pfizer, Regeneron Pharmaceuticals, Inc, ThromboGenics, and Tyrogenex. Dr Midena reported that Padova University Hospital (Padova, Italy) has received research funding from Bayer HealthCare Pharmaceuticals. Dr Korobelnik reported being a consultant for Alcon, Alimera, Allergan, Bayer HealthCare Pharmaceuticals, Horus, Novartis, Roche, Thea, and Zeiss. Dr Schmelter reported owning stock in Bayer HealthCare Pharmaceuticals. Dr Heier reported being a consultant for Acucela, Aerpio Therapeutics, Allegro Ophthalmics, Allergan, Avalanche Biotechnologies, CoDa Therapeutics, Eleven Biotherapeutics, EyeGate Pharmaceuticals, Foresight Biotherapeutics, ForSight Vision 4, Genentech, Icon Therapeutics, Janssen R&D, Kala Pharmaceuticals, Kanghong, Kato Pharmaceuticals, Lpath, Nano Retina, Ohr Pharmaceuticals, Regeneron Pharmaceuticals, Inc, RestorGenex, RetroSense, SciFluor Life Sciences, Shire, Stealth Biotherapeutics, ThromboGenics, and Valeant Pharmaceuticals and reported receiving research funding from Acucela, Apellis, Astellas, Corcept, Daiichi, EyeGate, Genentech, Genzyme, Kala Pharmaceuticals, Neurotech, Novartis, Ophthotech, Regeneron Pharmaceuticals, Inc, Stealth Biotherapeutics, and ThromboGenics. No other disclosures were reported.

Funding/Support: The VISTA and VIVID trials were funded by Regeneron Pharmaceuticals, Inc, Tarrytown, New York, and by Bayer HealthCare Pharmaceuticals, Berlin, Germany.

Role of the Funder/Sponsor: The sponsors participated in the design and conduct of the study, analysis and interpretation of the data, preparation and review of the manuscript, and decision to submit the manuscript for publication.

Additional Contributions: Editorial and administrative assistance to the authors was provided by Hadi Moini, PhD, Regeneron Pharmaceuticals, Inc (without compensation).

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