Vascular Endothelial Growth Factor Promotes Progressive Retinal Nonperfusion in Patients with Retinal Vein Occlusion

doi:10.1016/j.ophtha.2012.09.032

Ophthalmology

Volume 120, Issue 4, April 2013, Pages 795-802

Portions of these data were presented at the American Academy of Ophthalmology Annual Meeting, October 22–25, 2011, Orlando, Florida.

https://doi.org/10.1016/j.ophtha.2012.09.032 Get rights and content

Objective

Central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO) causes hypoperfusion, high levels of vascular endothelial growth factor (VEGF), macular edema, and loss of vision. Many patients also show areas of complete closure of retinal vessels (retinal nonperfusion [RNP]) that increase over time. The objective was to assess the effect of blocking VEGF on progression of RNP.

Design

Retrospective analysis of prospectively collected data from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials.

Participants

A total of 392 and 397 patients with macular edema due to CRVO or BRVO.

Methods

An independent reading center measured the area of RNP on fluorescein angiograms (FAs) in 2 phase III trials investigating the effect of ranibizumab (RBZ; Lucentis; Genentech, Inc, South San Francisco, CA) in patients with CRVO or BRVO.

Main Outcome Measures

The percentage of patients with no posterior RNP at months 0, 3, 6, 9, and 12.

Results

There was no difference among treatment groups at baseline, but at the month 6 primary end point the percentage of patients with CRVO and no RNP was significantly greater in the RBZ groups (0.3 mg, 82.0%, P = 0.0092; 0.5 mg, 84.0%, P = 0.0067) versus the sham group (67.0%). Reperfusion of nonperfused retina was rare (1%) in sham-treated patients with CRVO, but occurred in 6% to 8% of patients with CRVO treated with RBZ (30% of those who had RNP and could improve). Results in patients with BRVO mirrored those in patients with CRVO. Crossover to 0.5 mg RBZ from sham at month 6 halted the progression of RNP and resulted in improvement in both CRVO and BRVO.

Conclusions

Treatment with RBZ did not worsen RNP in patients with RVO, but rather reduced its occurrence compared with sham. These data provide an important new insight regarding the pathogenesis of RVO; the initial vein occlusion is a precipitating event that causes baseline ischemia and release of VEGF, which then contributes to progression of RNP and thus worsening of ischemia. Timely, aggressive blockade of VEGF prevents the worsening of RNP, promotes reperfusion, and eliminates a positive feedback loop.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Materials and Methods

The BRAVO and CRUISE were 6-month phase III, multicenter, randomized, injection-controlled studies, with an additional 6 months of follow-up (total 12 months), designed to evaluate efficacy and safety of intraocular injections of RBZ in patients with macular edema following RVO. The study included a 28-day screening period (days –28 to –1); a 6-month treatment period (day 0 to month 6), during which patients received monthly intraocular injections of 0.3 mg or 0.5 mg RBZ or sham injections; and

Area of Retinal Nonperfusion at Baseline

The area of RNP in the posterior retina at baseline was gradable in the majority of patients with RVO. In patients with CRVO, 112 of 130 (86%) in the sham group, 113 of 132 (86%) in the 0.3 mg RBZ group, and 109 of 130 (84%) in the 0.5 mg RBZ group had FAs that were gradable, and in the corresponding BRVO groups, 124 of 132 (94%), 125 of 134 (93%), and 118 of 131 (90%) had gradable FAs (Table 1). The mean area of posterior RNP at baseline was low in patients with CRVO—0.27, 0.17, and 0.55 DA in

Discussion

It has been recognized for many years that some patients with CRVO or BRVO experience an increase in RNP over time. This has been characterized as conversion from a perfused to a nonperfused RVO. The mechanism by which this occurs was unknown, and it was postulated that it might be explained by worsening of the venous occlusion. Measurement of the area of RNP in clinical trials has confirmed that increases in RNP over time occur in patients with CRVO or BRVO and in fact are the rule rather than

Acknowledgments

Support for third-party editing assistance for this manuscript, provided by Linda Merkel, PhD, of Envision Scientific Solutions, was provided by Genentech, Inc.

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Month 60 Imaging Findings and Relationship to Treatment Outcomes Following Anti-VEGF Therapy for Macular Edema Due to Central or Hemi-Retinal Vein Occlusion
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To evaluate imaging findings from SCORE2 participants through 60 months, to describe the degree of resolution or progression of these variables, and to correlate changes in these imaging findings to treatment outcomes such as visual acuity and the number of treatments administered.
SCORE2 participants were followed for up to 60 months. Visual acuity, injection frequency and imaging tests color fundus photography (CFP), optical coherence tomography (OCT), and ultra-widefield fluorescein angiography [UWFA]) were performed throughout this period.
Less than 6% of eyes had subretinal fluid at month 60. Disorganization of the retinal inner layers (DRIL) was the most likely finding to persist, present in 96% of eyes at baseline and unchanged at 95% at month 60. For UWFA, at baseline, there was a mean of 5.0% non-perfusion area (95% CI: 3.3%-6.8%) in the NETWORC grid with little change to month 60. For the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, at baseline, there was a mean of 2.3% non-perfusion area (95% CI: 0.7%-3.9%) with little change to month 60. There was no correlation between any of the imaging variables at baseline and change in visual acuity to month 60 or in the number of injections following the variable treatment timeframe (month 12 to month 60).
These analyses provide an anatomic explanation for persistent functional deficits many years following initial treatment. Clinical practice patterns should consider evaluation with these imaging tests to help explain persistent functional deficits in many eyes. Additionally, these 8 baseline imaging variables generally should not be relied on to predict visual acuity or intensity of treatment. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Comparison of anti-VEGF results between non-ischemic branch retinal vein occlusion and ischemic branch retinal vein occlusion with early sector panretinal photocoagulation
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Citation Excerpt :
The ME is closely associated with increased vascular endothelial growth factor (VEGF) [13]. Anti-VEGF agents are commonly used to treat the ME, reduce the severity of anterior segment neovascularization, and lower the risk of ocular angiogenesis [14,15]. Laser photocoagulation is a procedure that ablates nonperfusion areas [16].
To compare the need for anti-vascular endothelial growth factor (VEGF) in treating macular edema (ME) in patients with non-ischemic branch retinal vein occlusion (BRVO) and patients with ischemic BRVO with early peripheral photocoagulation.
Patients with BRVO with ME were included in the retrospective study. The patients were divided into two groups according to peripheral ischemic status: a non-ischemic BRVO group and an ischemic BRVO group. All patients received three initial monthly 0.50 mg ranibizumab injections followed by a pro re nata (PRN) regimen. In the ischemic BRVO group, early peripheral laser photocoagulation was applied in the area of capillary nonperfusion as defined by fluorescein angiography. The mean change in central macular thickness (CMT), best-corrected visual acuity (BCVA), and number of injections were evaluated.
Fifty-seven eyes of 57 patients were included in the study (32 nonischemic BRVO; 25 ischemic BRVO). Mean follow-up was 20.0 (SD,4.9) months. The mean number of injections from baseline to final visit was 5.3 (SD 3.4) and 4.6 (SD 2.6) for the nonischemic BRVO group and ischemic BRVO group, respectively. This difference was not statistically significant (P = 0.48). There was no significant difference in CMT and BCVA between groups.
No difference in the need for anti-VEGF therapy was observed between patients with non-ischemic BRVO and patients with ischemic BRVO with early laser photocoagulation.
Comparer le besoin d’anti-facteur de croissance endothélial vasculaire (VEGF) dans le traitement de l’œdème maculaire (EM) chez les patients présentant une occlusion de branche veineuse rétinienne non ischémique (OBVR) et les patients atteints d’OBVR ischémique avec photocoagulation périphérique précoce.
Les patients atteints d’OBVR avec EM ont été inclus dans l’étude rétrospective. Les patients ont été divisés en deux groupes selon le statut ischémique périphérique : groupe OBVR non ischémique et groupe OBVR ischémique. Tous les patients ont reçu trois injections mensuelles initiales de ranibizumab de 0,50 mg suivies d’un schéma pro re nata (PRN). Dans le groupe BRVO ischémique, la photocoagulation laser périphérique précoce est appliquée dans la zone de non-perfusion capillaire telle que définie par l’angiographie à la fluorescéine. La variation moyenne de l’épaisseur maculaire centrale (CMT), de la meilleure acuité visuelle corrigée (MAVC) et le nombre d’injections ont été évalués.
Au total, 57 yeux de 57 patients ont été inclus dans l’étude (32 BRVO non ischémique ; 25 BRVO ischémique), respectivement. Le suivi moyen était de 20,0 (ET, 4,9) mois. Le nombre moyen d’injections entre le départ et la visite finale était de 5,3 (ET, 3,4) et de 4,6 (ET, 2,6) pour le groupe BRVO non ischémique et le groupe BRVO ischémique, respectivement. Cette différence n’était pas statistiquement significative (P = 0,48). Il n’y avait pas de différence significative de CMT et de MAVC entre les groupes.
Il n’y avait aucune différence dans la nécessité d’un traitement anti-VEGF entre les patients atteints d’OBVR non ischémique et les patients atteints d’OBVR ischémique avec photocoagulation laser précoce.
Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy
2022, Ophthalmology Retina
Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR).
Prospective, randomized clinical trial with treatment crossover in the second year.
Eyes with PDR and RNP.
At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing.
Change in total RNP area (mm²) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated.
Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm² to 402 mm² (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm² at baseline to 386 mm² (P < 0.0001) at year 2 in arm 1 and from 207 mm² at baseline to 421 mm² (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively.
Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.
Foveal Thickness Fluctuation in Anti-VEGF Treatment for Branch Retinal Vein Occlusion: A Long-term Study
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Branch retinal vein occlusion (BRVO) causes macular edema (ME), which can be controlled with anti-VEGF treatments. However, these treatments are not curative, necessitating additional anti-VEGF treatments at recurrence. Long-term results, optimal anti-VEGF treatment regimens, and the comprehensive effects of ME recurrence are largely unknown. Thus, we aimed to examine the effects of foveal thickness (FT) fluctuation (FTF) on the visual and morphologic outcomes of anti-VEGF treatments for BRVO-ME administered via a pro re nata regimen.
A retrospective, observational case series.
This study analyzed 309 treatment-naïve patients (309 eyes) with BRVO-ME between 2012 and 2021 at a multicenter retinal practice.
The FT was assessed using OCT at each study visit.
We evaluated the logarithm of the minimal angle of resolution (logMAR) best corrected visual acuity (BCVA) and the defect length of the foveal ellipsoid zone (EZ) band using OCT.
At baseline, the mean logMAR BCVA was 0.30 ± 0.30 and the mean FT was 503 ± 162 μm. The number of anti-VEGF injections for BRVO-ME was 5.8 ± 4.6 during the mean follow-up period (50.6 ± 22.2 months). At the final examination, the mean logMAR BCVA and FT values were significantly improved compared with those at the baseline. Multiple regression analyses showed that age, baseline logMAR BCVA, and FTF were significantly associated with the final logMAR BCVA (β = 0.20, 0.35, and 0.30, respectively). Foveal thickness fluctuation (divided into groups 0–3 in ascending order of FTF) was significantly associated with logMAR BCVA and the defect length of the foveal EZ band at the final examination. The defect lengths of the foveal EZ band were longitudinally shortened in groups 0 and 1 and were slightly prolonged in groups 2 and 3. The logMAR BCVA showed improvements in groups 0 and 1 and worsened slightly in groups 2 and 3.
Foveal thickness fluctuation was significantly associated with visual acuity and foveal photoreceptor status. Thus, the morphologic and functional prognoses of eyes with BRVO may improve with the identification of the characteristics of eyes with greater FTF and consequently controlling the FTF more strictly.
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: Manuscript no. 2012-834.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): P.A.C. serves as a consultant for Genentech, GlaxoSmithKline, Regeneron, and Aerpio Therapeutics, for which his employer, Johns Hopkins University, receives compensation; currently serves on the data and safety monitoring committee for stem cell trials sponsored by Advanced Cell Technology; previously served on the Data and Safety Monitoring Committee for the View1 trial sponsored by Regeneron; serves as a consultant for Elan, Gene Signal, and Norvorx, for which he receives personal compensation; receives funding through Johns Hopkins School of Medicine for clinical research studies from Genentech, GlaxoSmithKline, Genzyme, and Oxford BioMedica; and has equity in Graybug, Inc. R.B.B. serves as consultant for Santen, Inc, and ActiveSite Pharmaceuticals; serves on an advisory board for ISTA Pharmaceuticals; serves on the speakers' bureau of Genentech, Inc; and receives funding for clinical research from Genentech, Inc. H.S. is an employee of Genentech, Inc.

: R.G.R. is an employee of Genentech, Inc.

: Genentech, Inc, provided support for the study and participated in study design; conducting the study; and data collection, management, and interpretation.

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Original articleVascular Endothelial Growth Factor Promotes Progressive Retinal Nonperfusion in Patients with Retinal Vein Occlusion

Objective

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Materials and Methods

Area of Retinal Nonperfusion at Baseline

Discussion

Acknowledgments

Mol Ther

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study

Ophthalmology

Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study

Ophthalmology

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 5

Arch Ophthalmol

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 6

Arch Ophthalmol

Original article
Vascular Endothelial Growth Factor Promotes Progressive Retinal Nonperfusion in Patients with Retinal Vein Occlusion