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Retinal Vein Occlusion: Major Trials, Clinical Features, and Treatment Updates

Overview

• BRVO (Branch RVO) - most common, ~3-6x more prevalent than CRVO; affects a sector drained by a branch vein, usually at an A-V crossing
• CRVO (Central RVO) - occlusion at or behind the lamina cribrosa
• HRVO (Hemiretinal) - a variant of CRVO involving superior or inferior branch at the disc
• MRVO (Macular RVO) - a minor macular branch variant

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BRANCH RETINAL VEIN OCCLUSION (BRVO)

Clinical Features

• Flame-shaped and dot/blot hemorrhages confined to the sector drained by the occluded vein; hemorrhages do not cross the horizontal raphe
• Superotemporal quadrant most commonly affected
• Dilated, tortuous affected venous segment; cotton-wool spots; retinal edema
• Occlusion typically occurs at an arteriovenous crossing point
• Acute signs resolve within 6-12 months, leaving venous sheathing and sclerosis
• Collateral vessels form near ischemic areas after weeks to months - their presence is a better prognostic sign
• Chronic macular edema is the most common cause of persistent poor VA

• Retinal neovascularization (NVE > NVD) in ~8% by 3 years; risk markedly higher if >5 disc areas of non-perfusion on FA
• NVI and NVG are uncommon (2-3% at 3 years) - much less than CRVO
• Vitreous hemorrhage, tractional retinal detachment

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CENTRAL RETINAL VEIN OCCLUSION (CRVO)

Classification

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THE BIG NAMED CLINICAL TRIALS

BRVO Trials

BVO Study (BVOS) - 1984 (The Original Trial)

• Multicenter RCT; the foundational branch vein occlusion study
• Macular edema arm: Grid laser photocoagulation significantly improved VA vs observation; gain of ~1.33 lines at 3 years
• NV arm: Sector PRP reduced vitreous hemorrhage from 61% to 29% over 3 years
• Prevention arm: Prophylactic laser to areas of non-perfusion did NOT prevent NVE
• Established sector PRP for NVE/NVD and grid laser for macular edema as standard of care for decades

BRAVO Trial (2010-2012) - Ranibizumab

• Phase III RCT; 397 patients with BRVO-associated macular edema
• Arms: ranibizumab 0.3 mg vs. 0.5 mg vs. sham injection monthly x 6 months; then PRN (all groups could receive rescue laser after month 3)
• Results at 6 months: Mean BCVA gain +16.6 letters (0.5 mg) vs. +7.3 letters (sham); p<0.001
• Results at 12 months: Gains maintained; ranibizumab 0.5 mg group gained +18.3 letters
• Confirmed ranibizumab superior to laser; BRAVO + CRUISE collectively supported FDA approval of ranibizumab for RVO macular edema (2010)
• The Wills Eye Manual (p. 797) notes these trials validated early anti-VEGF for better visual outcomes

VIBRANT Trial (2014-2015) - Aflibercept vs. Laser

• Phase III; 181 patients with BRVO macular edema
• Arms: aflibercept 2 mg Q4W x 6 doses, then Q8W (yr 1); vs. laser photocoagulation (with rescue aflibercept option after week 24)
• At 24 weeks: +17.0 letters (aflibercept) vs. +6.9 letters (laser); p<0.001
• At 52 weeks: Gains maintained and laser group showed improvement after crossing to aflibercept
• Supported FDA approval of aflibercept (Eylea) for BRVO (2014) - Kanski 10th ed., p. 541

SHORE Study - Treat-and-Extend for BRVO

• Ranibizumab PRN vs. treat-and-extend (TAE) in BRVO
• TAE dosing reduced injection frequency while maintaining equivalent visual outcomes
• Supported adoption of TAE regimen as an alternative to monthly dosing

BALATON Trial (2024) - Faricimab vs. Aflibercept (BRVO)

• Phase III, global, double-masked RCT; N=553 patients, treatment-naive BRVO macular edema
• Arms: faricimab 6.0 mg Q4W vs. aflibercept 2.0 mg Q4W x 24 weeks
• Primary endpoint (week 24): Faricimab non-inferior to aflibercept (+16.9 vs. +17.5 letters, 95.03% CI)
• CST reduction comparable: -311.4 µm (faricimab) vs. -304.4 µm (aflibercept)
• Key superiority finding: Greater proportion achieved absence of FA-based macular leakage with faricimab vs. aflibercept at week 24 (33.6% vs. 21.0%; p=0.0023)
• Safety profiles comparable
• Source: Tadayoni et al., Ophthalmology 2024 [PMID: 38280653]

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CRVO Trials

CVOS (Central Vein Occlusion Study) - 1993-1995 (The Original Trial)

• Multicenter RCT; the foundational CRVO study
• Macular grid laser: Did NOT improve visual acuity despite reducing angiographic leakage (no vision benefit); grid laser not recommended for CRVO macular edema
• Prophylactic PRP: Did NOT prevent NVI/NVG in ischaemic CRVO
• Therapeutic PRP: Effective at causing regression of NVI when given after NVI detected
• Key lesson: Monitor ischaemic CRVO monthly for first 6 months, treat NVI promptly with PRP - EyeWiki CRVO

SCORE Trial (2009) - Triamcinolone vs. Observation

• Phase III RCT comparing intravitreal triamcinolone acetonide (1 mg and 4 mg) vs. standard care (observation for CRVO)
• Result: Triamcinolone 1 mg superior to standard care at 12 months for CRVO macular edema
• 4 mg dose had higher rates of IOP elevation and cataract without additional visual benefit
• Established triamcinolone as an alternative but limited by side effects

CRUISE Trial (2010-2012) - Ranibizumab (CRVO)

• Phase III RCT; 392 patients, CRVO-associated macular edema
• Arms: ranibizumab 0.3 mg vs. 0.5 mg vs. sham monthly x 6 months, then PRN
• At 6 months: +14.9 letters (0.5 mg) vs. +0.8 letters (sham); p<0.001
• At 12 months: Mean gain of +13.9 letters (0.5 mg arm)
• Together with BRAVO, led to FDA approval of ranibizumab for CRVO (2010)

COPERNICUS Trial (2012) - Aflibercept (CRVO)

• Phase III; 188 patients with CRVO macular edema
• Arms: aflibercept 2 mg Q4W vs. sham x 24 weeks
• At 24 weeks: +17.3 letters (aflibercept) vs. -4.0 letters (sham); p<0.001
• 56.1% gained ≥15 ETDRS letters vs. 12.3% sham
• Parallel GALILEO trial (Europe, similar design): +18.0 vs. -1.2 letters at 24 weeks
• Together led to FDA approval of aflibercept for CRVO (2012)

SCORE2 Trial (2017) - Bevacizumab vs. Aflibercept (CRVO)

• Phase III RCT (NEI-funded); 362 patients with CRVO macular edema
• Arms: bevacizumab 1.25 mg Q4W vs. aflibercept 2 mg Q4W x 6 months, then TAE
• Primary result at 6 months: +18.6 letters (bevacizumab) vs. +18.9 letters (aflibercept) - non-inferior (p<0.001 for non-inferiority)
• However: CST reduction was significantly greater with aflibercept (-434 µm vs. -338 µm); aflibercept had better anatomic outcomes
• TAE dosing (months 6-12) = ~1-2 fewer injections vs. monthly with comparable VA outcomes
• Switching from poor bevacizumab responders to aflibercept improved both VA and CST; fewer poor responders to aflibercept
• Supported bevacizumab as a cost-effective option but showed aflibercept's anatomic superiority - EyeWiki, CRVO

LEAVO Trial (2019) - Bevacizumab vs. Ranibizumab vs. Aflibercept (CRVO)

• Large UK-based RCT; 463 patients with CRVO macular edema
• Arms: bevacizumab 1.25 mg vs. ranibizumab 0.5 mg vs. aflibercept 2.0 mg (PRN after loading)
• Result: Aflibercept non-inferior to ranibizumab; bevacizumab vs. ranibizumab comparison was inconclusive (could not confirm non-inferiority)
• Aflibercept showed greater CST reductions than ranibizumab and bevacizumab
• Confirmed aflibercept as a strong first-line choice; left bevacizumab's position vs. ranibizumab uncertain

COMINO Trial (2024) - Faricimab vs. Aflibercept (CRVO/HRVO)

• Phase III, global, double-masked RCT; N=729 patients, treatment-naive CRVO/HRVO macular edema
• Arms: faricimab 6.0 mg Q4W vs. aflibercept 2.0 mg Q4W x 24 weeks
• Week 24: Faricimab non-inferior (+16.9 vs. +17.3 letters)
• CST reduction comparable: -461.6 µm (faricimab) vs. -448.8 µm (aflibercept)
• Key superiority finding: Greater FA-based macular leakage resolution with faricimab (44.4% vs. 30.0%; p=0.0002)
• Source: Tadayoni et al., Ophthalmology 2024 [PMID: 38280653]

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RECENT ADVANCES AND UPDATES (2023-2026)

1. Faricimab (Vabysmo) - Dual Ang-2/VEGF Inhibitor

• VA and anatomic gains achieved at week 24 were fully maintained through week 72
• BALATON: 64.1% (prior faricimab arm) vs. 56.9% (prior aflibercept arm) achieved ≥Q12W dosing at week 68
• COMINO: 45.5% (faricimab) vs. 50.1% (aflibercept) at ≥Q12W
• Mean BCVA gains at weeks 64-72: +18.1 letters (BALATON/faricimab) and +16.9 letters (COMINO/faricimab)
• Supports extended dosing intervals up to Q16W in some patients, reducing injection burden
• Source: Danzig et al., Ophthalmol Retina 2025 [PMID: 40107501]

2. Aflibercept 8 mg (High-Dose Eylea HD) - QUASAR Trial

• Phase III QUASAR trial: aflibercept 8 mg vs. aflibercept 2 mg monthly in RVO (including BRVO, CRVO, HRVO)
• N=892 patients; primary endpoint was mean BCVA change at week 36
• Result: 8 mg arms were non-inferior to 2 mg monthly
• 8 mg arms required significantly fewer injections through week 36 (mean 6.1-6.9 vs. 8.8 injections)
• FDA approved aflibercept 8 mg (Eylea HD) for macular edema due to RVO - the most recent FDA approval in this space
• Extended dosing: Q8W after 3-5 loading doses; can reduce injection burden substantially
• EyeWiki CRVO (current)

3. Treat-and-Extend (TAE) as the Standard Approach

• Both faricimab and aflibercept 8 mg support TAE protocols in RVO
• BALATON/COMINO 72-week data confirm TAE with faricimab achieves Q12-16W dosing in 45-64% of patients
• SCORE2 showed TAE saved ~1-2 injections vs. monthly from months 6-12 without significant VA difference
• NHS England (2025 pathway update) recommends aflibercept 2 mg (switching to biosimilar once available) or ranibizumab biosimilar as first-line; faricimab as second-line option; TAE as preferred maintenance strategy for both BRVO and CRVO

4. Biosimilars

• Ranibizumab biosimilars (NICAS/BYOOVIZ) now available and guideline-endorsed as first-line alternatives
• Aflibercept 2 mg biosimilars entering market (loss of exclusivity ~Nov 2025 in UK)
• NHS England specifically recommends switching to aflibercept biosimilar once available to reduce costs while maintaining efficacy

5. Anti-VEGF + Dexamethasone Combination

• 2025 RCT (Cai et al., Int Ophthalmol, PMID: 41128968): ranibizumab + dexamethasone intravitreal implant vs. ranibizumab alone - combination showed enhanced CST reduction and fewer injections at 12 months; combination approach may be useful in recalcitrant edema or patients requiring fewer visits

6. Emerging: Anti-VEGF Monoclonal Antibody 601 (2026)

• Phase IIa RCT (Zhao et al., Br J Ophthalmol 2026, PMID: 41448868) evaluated a novel anti-VEGF mAb 601 in BRVO and CRVO
• Phase IIa results showed efficacy and safety; further Phase III data awaited

7. Long-Term Real-World Data (5-Year)

• Real-world 5-year follow-up of aflibercept in CRVO (reported 2025) showed sustained VA gains and anatomic improvement in ~50% of patients
• Favorable outcomes linked to baseline retinal integrity and ability to extend dosing intervals
• Good response at year 1 is the strongest predictor of long-term benefit

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TREATMENT ALGORITHM (Current, 2025-2026)

BRVO - Macular Edema

CRVO - Macular Edema

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KEY DIFFERENCES: BRVO vs. CRVO Trials and Management

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Summary Table: All Major Trials

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