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Retinal Physician

Article

Clinical Trials in Retinal Vein Occlusion

Recent trials have explored a variety of interventions to minimize vision loss.

By: Neesurg Mehta, MD, Susanna S. Park, MD, PhD
Retinal Physician May 1, 2022 Vol 19, Issue May 2022 Page(s): 27-32

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Retinal vein occlusion (RVO) is the second most common retinal vascular cause of vision loss after diabetic retinopathy.1 An obstruction may occur at a branch or central retinal vein, resulting in branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), respectively. Vision loss associated with RVO can occur from macular edema, macular ischemia, and/or complications of retinal or iris neovascularization. The extent of vision loss and retinal ischemia varies depending on the severity and location of the obstruction. Macular edema occurs in 5% to 15% over 1 year in eyes with BRVO and in most eyes with CRVO.1 The 36-month incidence of retinal neovascularization is 8.8% and 7.6% of eyes with BRVO and CRVO, respectively.2 This article summarizes the clinical trials have been completed or ongoing exploring various interventions to minimize vision loss associated with RVO (Table 1).

Table 1: Landmark Clinical Trials in Retinal Vein Occlusion
STUDY INTERVENTION NUMBER OF EYES FOLLOW-UP RESULTS
BRVO
BVOS Study Group, 19953
  1. Macular grid argon laser or sham
  2. Scatter laser or no laser in eyes with ≥5 disc diameters of nonperfusion without NV
  3. Scatter laser or no laser in eyes with NV
  1. 139
  2. 319
  3. 82
 3 years
  1. 2 more lines VA gain: 65% in treated eyes (gained 1.33 lines) vs 17% untreated eyes (gained 0.23 lines).
  2. Developed NV: 12% in treated eyes vs 22% in untreated eyes (no change in VA from baseline).
  3. Incidence of vitreous hemorrhage: 29% in treated eyes vs 61% in untreated eyes.
Scott et al, 2009 (SCORE)9 Intravitreal triamcinolone 1 mg and 4 mg vs macular grid photocoagulation 411 12 months 15 or more letters VA gain: 26%, 27%, and 29% in the 1 mg, 4 mg, and grid groups, respectively. Improved OCT thickness in all 3 groups. IOP >10 mmHg above baseline in 12%, 50%, and 1% for 1 mg, 4 mg, and grid groups, respectively.
Campochiaro et al, 2010 (BRAVO)13 Monthly 0.3 mg or 0.5 mg ranibzumab vs sham 397 6 months 15 or more letters VA gain: 55%, 61%, and 29% in the 0.3 mg, 0.5 mg, and sham groups, respectively. Mean change from baseline VA was 16.6, 18.3, and 7.3, respectively. Mean reduction in foveal thickness significantly higher in ranibizumab groups.
Brown et al, 2011 (BRAVO)16 0.3 mg or 0.5 mg ranibzumab vs sham if retreatment criteria met 397 12 months 15 or more letters VA gain: 56%, 60%, and 44% in the 0.3 mg, 0.5 mg, and sham groups, respectively. Mean change from baseline VA was 16.4, 18.3, and 12.1 for 0.3 mg, 0.5 mg, and sham groups, respectively.
Clark et al, 2016 (VIBRANT)21 2mg aflibercept (IAI group) vs grid laser at baseline with possible IAI therapy after 24 weeks (laser/IAI group)   12 months 15 or more letters VA gain at 6 months: 53% vs 27% in IAI and laser/IAI group, respectively.
15 or more letters VA gain at 12 months: 57% vs 41% in IAI and laser/IAI groups, respectively.
BRVO and CRVO
Haller et al, 2010, 2011 (GENEVA)11,12
  1. 0.7 mg and 0.35 mg DEX vs sham
  2. At 6 months, retreated with 0.7 mg DEX if retreatment criteria met
  1. 1,267
  2. 997
  1. 6 months
  2. 12 months
  1. 15 or more letters VA gain: 41%, 40%, and 23% in 0.7 mg DEX, 0.35 mg DEX, and sham groups, respectively. Mean decrease in CST significantly greater in DEX groups vs sham at 3 months but not 6 months. IOP peaked at 2 months in DEX groups, but no change compared to sham at 6 months.
  2. 15 or more letters VA gain: 30% and 32% at day 60 after first and second 0.7 mg DEX, respectively. Cataract progression in 30% vs 6% in those who received 2 DEX implants vs sham, respectively. Greater than 10 mmHg IOP increase from baseline was observed in 12.6% after the first treatment, and 15.4% after the second.
CRVO
CVOS Study Group, 19954,5
  1. Nonperfused group: immediate prophylactic PRP vs PRP when NV develops
  2. Macular edema group: grid pattern photocoagulation vs no treatment
  1. 181
  2. 155
 3 years
  1. Regression of NV: 22% in eyes with immediate prophylactic PRP vs 56% in eyes with PRP after NV developed.
  2. Final VA: 20/200 vs 20/160 in laser-treated eyes vs 20/160 in untreated eyes. Angiographic edema did improve in laser treated eyes, though no VA benefit.
Ip et al, 2009 (SCORE)10 Intravitreal triamcinolone 1 mg and 4 mg vs observation 271 12 months 15 or more letters VA gain: 27%, 26%, and 7% in the 1 mg, 4 mg, and observation groups, respectively. Improved OCT thickness in triamcinolone groups; IOP >10 mmHg above baseline in 15%, 24%, and 2% in 1 mg, 4 mg, and observation groups, respectively.
Brown et al, 2010 (CRUISE)14 Monthly 0.3 mg or 0.5 mg ranibzumab vs sham 392 6 months 15 or more letters VA gain: 46%, 48%, and 17% in the 0.3 mg, 0.5 mg, and sham groups, respectively. Mean change from baseline VA was 12.7, 14.9, and 0.8 for 0.3 mg, 0.5 mg, and sham groups, respectively. Mean reduction in foveal thickness significantly higher in ranibizumab groups.
Campochiaro et al, 2011 (CRUISE)17 0.3 mg or 0.5 mg ranibzumab vs sham if retreatment criteria met 392 12 months 15 or more letters VA gain: 47%, 51%, and 33% in the 0.3 mg, 0.5 mg, and sham groups, respectively. Mean change from baseline VA was 13.9, 13.9 and 7.3 in the 0.3 mg, 0.5 mg, and sham groups, respectively.
Brown et al, 2013 (COPERNICUS)22 Monthly 2 mg aflibercept vs sham; after 6 months as-needed aflibercept given in both groups 189 12 months 15 or more letters VA gain at 6 months: 56% vs 12% in aflibercept and sham groups, respectively.15 or more letter VA gain at 12 months: 55% vs 30%, in aflibercept and sham groups, respectively.
Korobelnik et al, 2014 (GALILEO)23 Monthly 2 mg aflibercept vs sham for 20 weeks; from week 24 to 48 aflibercept group received as-needed injections and sham group continued to receive sham injections 177 12 months 15 or more letters VA gain at 12 months: 60% vs 32% in aflibercept and sham groups, respectively.
Scott et al, 2017 (SCORE2)27 Monthly 2 mg aflibercept vs 1.25 mg bevacizumab 362 6 months Mean gain from baseline VA: 18.9 and 18.6 letters in aflibercept and bevacizumab groups, respectively (P=.001 for noninferiority).
Hykin et al, 2019 (LEAVO)28 0.5 mg ranibizumab vs 2 mg aflibercept vs 1.25 mg bevacizumab 463 100 weeks Mean gain from baseline VA: 12.5, 15.1, and 9.8 letters in ranibizumab, aflibercept, and bevacizumab groups, respectively.
Aflibercept was noninferior to ranibizumab (intention-to-treat–adjusted mean VA difference, 2.23 letters; 95% CI, -2.17 to 6.63 letters; P < .001).
Bevacizumab was not noninferior to ranibizumab (intention-to-treat–adjusted mean VA difference, –1.73 letters; 95% CI, -6.12 to 2.67 letters; P = .07).
BRVO, branch retinal vein occlusion; CI, confidence interval; CRVO, central retinal vein occlusion; CST, central subfield thickness; DEX, intravitreal dexamethasone implant; IAI, intravitreal aflibercept; IOP, intraocular pressure; NV, neovascularization; PRP, panretinal laser photocoagulation; VA, visual acuity.

LASER PHOTOCOAGULATION

Laser photocoagulation can be applied to peripheral ischemic retina as panretinal photocoagulation (PRP) to minimize neovascular complications or as macular grid photocoagulation to treat macular edema associated with RVO. The Branch Vein Occlusion Study (BVOS) demonstrated visual benefit of macular grid argon laser photocoagulation over observation in eyes with angiographic macular edema from BRVO, intact foveal vascularity, and best corrected visual acuity (BCVA) of 20/40 vision or worse.3 Sectoral PRP was also recommended to help regress retinal neovascularization and minimize risk of vitreous hemorrhage.3 In contrast, the Central Vein Occlusion Study (CVOS) demonstrated that macular grid photocoagulation improved macular edema angiographically without visual benefit.4 Panretinal photocoagulation was recommended when at least 2 hours of iris neovascularization or any angle neovascularization are noted.5 Prophylactic PRP did not always prevent iris neovascularization but was recommended in eyes with >10 disc areas of retinal ischemia from CRVO to reduce devasting complications of neovascular glaucoma.6,7

INTRAVITREAL CORTICOSTEROID

Intravitreal Triamcinolone

Upregulation of vascular endothelial growth factor (VEGF) associated with RVO increases retinal capillary permeability, leading to macular edema. Intravitreal corticosteroids have shown to decrease induction of VEGF by proinflammatory mediators.8 The SCORE study compared efficacy of 2 different doses of intravitreal triamcinolone (1 mg and 4 mg) with macular grid laser in treating macular edema due to BRVO.9 No significant difference was noted among the study groups in vision gains, but higher rates of elevated intraocular pressure (IOP) and cataract formation were noted in the 4 mg triamcinolone group. In eyes with macular edema from nonischemic CRVO, either dose of intravitreal triamcinolone resulted in a higher proportion of eyes with improvement in BCVA after 1 year when compared to untreated eyes.10

Intravitreal Dexamethasone Implant

Dexamethasone implant (DEX, Ozurdex; Allergan/Abbvie) was developed to deliver a longer lasting and more effective dose of intravitreal corticosteroid than triamcinolone. The GENEVA study evaluated the efficacy of 0.7 mg and 0.35 mg implants compared to sham in treatment of macular edema due to RVO.11 The mean BCVA gain and percentage of eyes gaining 15 or more letters at 6 months was significantly higher in both groups. Sixteen percent of DEX-treated eyes had IOP of 25 mmHg or higher at day 60 (both doses), although IOP was not different from sham group by day 180. The 12-month results showed that a repeated treatment after 6 months with DEX resulted in sustained BCVA gain and a favorable safety profile except for cataract progression.12

INTRAVITREAL ANTI-VEGF THERAPY

Intravitreal Ranibizumab

Ranibizumab (Lucentis; Genentech) was the first anti-VEGF drug to be approved by the Food and Drug Administration (FDA) for treatment of macular edema from RVO. Results from the BRAVO and CRUISE studies showed that the proportion of eyes gaining 15 or more letters of BCVA at month 6 was higher with ranibizumab 0.3 mg or 0.5 mg when compared to sham.13-15 The 12-month results of the BRAVO and CRUISE studies showed that visual gains were sustained with a pro re nata (PRN) regimen in the ranibizumab groups. Furthermore, starting PRN injections in the sham group resulted in visual and anatomic improvement, but not to the extent of the ranibizumab groups.16,17 Results from the SHORE study further validated the efficacy of a PRN regimen after 7 monthly injections.18

In an open-label 12-month extension trial of the BRAVO and CRUISE trials, patients were evaluated at least every 3 months and given 0.5 mg ranibizumab if they met a prespecified retreatment criteria.19 At the end of the second year, mean change from baseline BCVA was decreased in both the 0.3 mg and 0.5 mg ranibizumab groups, highlighting the importance of more frequent follow-up and ranibizumab treatment in these eyes to sustain visual gain.

The RETAIN study conducted a prospective 4-year extension study in a subgroup of eyes from the BRAVO and CRUISE trials, and patients were retreated with ranibizumab as needed.20 About half of eyes required injections in year 4 for persistent macular edema, of which the mean number was 3.2 for BRVO and 5.9 for CRVO eyes. Not surprisingly, eyes with resolved macular edema at year 4 had greater increase in BCVA from baseline than eyes requiring ongoing ranibizumab for persistent macular edema.

Intravitreal Aflibercept

Aflibercept (Eylea; Regeneron) is FDA approved for treating macular edema due to RVO. Several clinical trials showed that aflibercept therapy resulted in a higher rate of improvement in BCVA when compared to grid laser for BRVO and sham for CRVO. The VIBRANT study evaluated the efficacy of aflibercept vs grid laser with deferred as-needed aflibercept in eyes with macular edema from BRVO and found that the mean change from baseline BCVA was better with aflibercept at weeks 24 and 52.21 The COPERNICUS study evaluated intravitreal aflibercept in eyes with macular edema from CRVO and found that the proportion of eyes gaining 15 or more letters BCVA was significantly greater with aflibercept when compared to sham at 12 months.22 The GALILEO study revealed similar 1-year results.23 Both studies show that monthly aflibercept followed by a PRN regimen resulted in sustained visual gains.

Intravitreal Bevacizumab

Intravitreal bevacizumab (Avastin; Genentech) can be used off-label as an alternative anti-VEGF therapy to treat macular edema due to RVO. Several studies showed noninferiority of bevacizumab to ranibizumab in treatment of macular edema associated with RVO in terms of BCVA gain and reduction of foveal thickness after 6 months.24-26

The SCORE2 and LEAVO studies compared the relative efficacy of various anti-VEGF therapies for macular edema associated with RVO. The SCORE2 trial showed that monthly intravitreal bevacizumab was noninferior to monthly intravitreal aflibercept with respect to BCVA gains after 6 months in patients with macular edema secondary to CRVO.27 The LEAVO study compared the efficacy of intravitreal ranibizumab, bevacizumab, and aflibercept in patients with macular edema due to CRVO and reached a slightly different conclusion using a slightly different study design than SCORE2.28 Patients received 3 monthly injections followed by as-needed injections every 4 to 8 weeks if prespecified treatment criteria was met. The mean (SD) gain in the BCVA letter score was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. The intention-to-treat analysis showed that aflibercept was noninferior but not superior to ranibizumab; bevacizumab was not noninferior compared with ranibizumab.28

A recent post hoc analysis of the LEAVO trial revealed that eyes with persistent macular edema were associated with worse BCVA when compared with eyes with dry macula at 52 and 100 weeks.29 By 100 weeks, more eyes treated with bevacizumab had persistent macular edema than those treated with aflibercept, suggesting aflibercept may be superior to bevacizumab.

CLINICAL TRIALS EXPLORING ALTERNATIVE THERAPIES FOR RVO

There are several ongoing clinical trials investigating alternative approaches to minimizing vision loss associated with RVO. The TRUST trial is a phase 1/2 randomized, sham controlled, double-masked study sponsored by the National Eye Institute (NEI) exploring the safety and potential efficacy of intravitreal injection of autologous CD34+ stem cells from bone marrow for vision loss from CRVO. Preliminary phase 1 study results showed that this cell therapy is feasible and appears well tolerated.30 Improvement in BCVA and retinal perfusion was noted in an eye with CRVO (Figure 1). CD34+ cells include endothelial progenitor cells; preclinical studies show retinal vascular incorporation of these cells after intravitreal injection with preservation of the retinal vasculature in eyes with retinal vasculopathy.31,32

Figure 1. Fundus photography of the right eye of a patient with 9 months duration of vision loss from a combined central retinal vein and artery occlusion and BCVA of 20/800 (A). No macular edema was noted. Vision improved to 20/40 at 3 months after intravitreal injection of autologous CD34&amp;#x2B; stem cells from bone marrow and remained improved at 20/63 at 6 months follow-up visit (B). Marked resolution of retinal hemorrhages are noted with some improvement in retinal perfusion on fluorescein angiography.
Figure 1. Fundus photography of the right eye of a patient with 9 months duration of vision loss from a combined central retinal vein and artery occlusion and BCVA of 20/800 (A). No macular edema was noted. Vision improved to 20/40 at 3 months after intravitreal injection of autologous CD34+ stem cells from bone marrow and remained improved at 20/63 at 6 months follow-up visit (B). Marked resolution of retinal hemorrhages are noted with some improvement in retinal perfusion on fluorescein angiography.31

A phase 1 open-labeled study enrolled eyes with ischemic CRVO and aims to reopen occluded central retinal veins by intra-arterial thrombolysis with tissue plasminogen activator via the ophthalmic artery. This therapy has been previously explored as a therapy for central retinal artery occlusion.33,34

An NEI-sponsored phase 1 study is evaluating oral minocycline as a therapy for BRVO. Minocycline is anti-inflammatory and is a known inhibitor of microglia in animal models of RVO.35 Inhibition of inflammation and microglial activation may limit the retinal damage associated with RVO.

CONCLUSION

Various clinical trials have shown that vision loss associated with RVO can be limited and partially reversed by treating associated macular edema with intravitreal anti-VEGF drugs or corticosteroids. Laser photocoagulation has also been shown to be beneficial in treating macular edema associated with BRVO and limiting neovascular complications associated with RVO. Currently there is no treatment for vision loss resulting from retinal ischemia and associated retinal damage. Ongoing clinical trials are exploring various novel therapies to limit or reverse damage to the retina and retinal vasculature associated with RVO. RP

Neesurg Mehta, MD, and Susanna Park, MD, PhD, are with the department of ophthalmology and vision science at the University of California Davis Health in Sacramento, California. This work is supported in part by the Barbara A. & Alan M. Roth, MD, Endowed Chair in Discovery, Education and Patient Care in Visual Science (Dr. Park) from University of California Davis. Dr. Park serves as study chair and principal investigator for the NEI-sponsored TRUST study (UG1 EY026876). Dr. Mehta reports no disclosures. Reach Dr. Park at ssscpark@ucdavis.edu. Editor’s note: Listen to discussion of this article at www.retinapodcast.com .

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