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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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Retinal Arterial Occlusion: Treatments, Thrombolysis Trials, and 2025-2026 Updates

Overview and Pathophysiology

• CRAO - Central retinal artery occlusion: occludes at or proximal to the lamina cribrosa
• BRAO - Branch retinal artery occlusion: sectoral, often at bifurcation points
• Arteritic CRAO - Due to giant cell arteritis (GCA): different pathophysiology and treatment
• Non-arteritic CRAO (naCRAO) - Embolic or thrombotic; the main target for thrombolysis

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CLINICAL FEATURES

CRAO (Kanski 10th ed., pp. 551-552)

• Sudden, profound, painless monocular vision loss (CF or worse); pain only in GCA
• RAPD: profound, sometimes amaurotic (total)
• Cherry-red spot: orange choroidal reflex at thin foveola contrasts with surrounding pale ischemic retina
• Emboli visible in ~20% of cases
• If a cilioretinal artery is present, a sector of macula is preserved (normal-appearing macular patch on fundus)
• Over weeks: cloudiness and cherry-red spot resolve; optic atrophy, attenuated vessels, inner retinal atrophy develop
• ~2% develop retinal/disc NV; rubeosis iridis up to ~20%, typically earlier than CRVO (4-5 weeks)
• FA: delayed/absent arterial filling; patent cilioretinal artery fills in early phase
• OCT: highly reflective embolic plaque in superficial optic nerve head; inner retinal thickening acutely

BRAO (Kanski 10th ed., pp. 549-550)

• Sudden profound painless altitudinal or sectoral visual field defect; may be asymptomatic if central vision spared
• "Cattle-trucking/box-car" appearance: segmentation and sludging of blood column in affected artery
• Cloudy white "ground-glass" retina in ischemic sector; one or more emboli often visible at bifurcation
• RAPD often present
• Rarely recovers unless obstruction relieved within hours

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ETIOLOGY AND WORKUP

• Systemic hypertension (most common)
• Atherosclerosis / carotid artery disease
• Cardiac emboli (atrial fibrillation, valvular disease, patent foramen ovale)
• Hyperlipidemia, diabetes mellitus
• Hypercoagulable states (especially in young patients)
• GCA (always consider in patients >55 years)

1. BP measurement, ECG, cardiac monitoring
2. CBC, ESR, CRP (ESR/CRP to rule out GCA)
3. Fasting glucose, HbA1c, lipid profile, coagulation screen
4. Carotid Doppler ultrasonography
5. Echocardiography (TTE/TEE)
6. Neurology/stroke team referral - CRAO carries 2-week stroke risk of ~10%
7. MRI brain (DWI) - concurrent acute ischemic lesions found in up to 25% of CRAO patients

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TREATMENT

A. Acute Interventions (within the therapeutic window)

1. Ocular Massage

• Three-mirror contact lens (allows direct artery visualization) or digital massage through closed eyelid
• Method: Apply positive pressure 10-15 seconds, then release; repeat for 3-5 minutes
• Goal: Mechanically collapse the arterial lumen, cause rapid flow changes, dislodge embolus
• Patient can self-massage through closed eyelids while awaiting specialist
• Evidence: No RCT evidence of benefit; considered low-risk and widely practiced as first-response

2. Anterior Chamber Paracentesis (AC Tap)

• 27-gauge needle withdraws 0.1-0.2 mL aqueous to acutely lower IOP
• Pre-treat with 5% povidone-iodine; short antibiotic course afterwards
• Goal: Sudden IOP drop creates a pressure gradient to improve perfusion pressure
• Evidence: No controlled trial evidence; occasional anecdotal reports of benefit
• Avoid vigorous ocular massage immediately after

3. IOP-Lowering Agents

• Topical beta-blockers (timolol), acetazolamide 500 mg IV or orally
• Goal: Lower IOP to improve ocular perfusion pressure
• No evidence of visual benefit in controlled studies

4. Carbogen Inhalation (95% O₂ + 5% CO₂) / Oxygen Therapy

• Induces vasodilation and increases retinal oxygen supply
• No controlled trial evidence of vision benefit

5. Rebreathing into a Paper Bag

• Increase pCO₂ to cause vasodilation
• No evidence base; generally discouraged

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B. Thrombolytic Therapy - The Central Debate

Intravenous tPA (IV-tPA / IVT)

• Standard AHA/ASA stroke protocol; emergency medicine familiar
• Can be given rapidly without specialized neurointerventional setup
• Time window mirrors ischemic stroke: within 4.5 hours of onset

• Multiple case series and meta-analyses (pre-2024) suggested visual improvement in 30-75% of patients treated within 4.5 hours - substantially better than conservative management's ~15-25% spontaneous recovery rate
• The Shahjouei et al. IPD meta-analysis (Int J Stroke 2024, PMID: 37424312) of 771 patients from 72 publications found:
  • Visual improvement ≥0.3 logMAR in 74.3% of patients receiving IV-tPA within 4.5 hours (95% CI: 60.9-86.0%)
  • VA of ≥20/100 achieved in 39% after IVT within 4.5 hours vs. 21.9% with IAT within 24 hours
  • Better outcomes associated with: shorter symptom-to-needle time, antiplatelet co-therapy, better presenting VA

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THE LANDMARK 2025-2026 RCTs - GAME-CHANGING NEGATIVE RESULTS

THEIA Trial (Lancet Neurology, 2025) [PMID: 41109232]

• Design: Phase 3, multicentre (16 French stroke units), double-dummy, patient/assessor-blinded RCT
• Patients: Adults with sudden severe monocular vision loss (Snellen <20/400) due to suspected non-arteritic CRAO, treated within 4.5 hours of onset
• Arms: Alteplase 0.9 mg/kg IV + oral placebo (n=35) vs. aspirin 300 mg oral + IV saline placebo (n=35)
• Primary endpoint: VA improvement ≥0.3 logMAR at 1 month
• Result:
  • Alteplase: 66% improved vs. aspirin: 48% improved (risk difference +17.4%, 95% CI -11.8 to +46.5; adjusted OR 1.1, p=0.95)
  • NO statistically significant difference
  • Mean treatment time: 232 minutes (~3 hrs 52 min) from symptom onset
  • One asymptomatic intracranial hemorrhage in the alteplase group
• Conclusion: IV alteplase within 4.5 hours was not associated with significant visual improvement vs. aspirin; trial was underpowered (enrolled only 70 of a planned larger cohort due to COVID and recruitment challenges)
• Source: Préterre et al., Lancet Neurol. 2025

TenCRAOS Trial (NEJM, 2026) [PMID: 41604638]

• Design: Phase 3, double-blind, double-dummy, multinational RCT (16 sites, 6 countries)
• Patients: Adults with acute non-arteritic CRAO, symptom onset within 4.5 hours before treatment
• Arms: Tenecteplase 0.25 mg/kg IV + oral placebo (n=40) vs. IV placebo + aspirin 300 mg oral (n=38)
• Primary endpoint: Vision recovery = BCVA ≤0.7 logMAR (≥20/100) in affected eye at 30 days
• Result:
  • Tenecteplase: 20% achieved vision recovery vs. aspirin: 24% (risk difference -3.7%, 95% CI -22.0 to +14.7; p=0.69)
  • NO significant difference - tenecteplase did NOT outperform aspirin
  • One fatal intracranial hemorrhage in the tenecteplase group
  • Greater incidence of adverse events overall in tenecteplase group
• Conclusion: IV tenecteplase within 4.5 hours did not produce significantly greater vision recovery at 30 days than aspirin and was associated with serious safety concerns
• Source: Ryan et al., NEJM 2026 - published January 2026

Clinical implication of THEIA + TenCRAOS: Both pivotal Phase 3 RCTs - the first ever in CRAO - failed to demonstrate benefit of IV thrombolysis over aspirin within 4.5 hours. The current evidence does NOT support routine IV thrombolysis for CRAO. Both trials were also limited by small sample sizes, reflecting the extreme difficulty of enrolling CRAO patients within narrow time windows.

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Individual Participant Data (IPD) Meta-Analysis 2025 (Stroke) [PMID: 40832714]

• Xie et al., Stroke 2025: 783 patients from 35 studies (IPD analysis)
• Key findings (observational data):
  • For every 1-hour earlier treatment: IV thrombolysis associated with 0.04 logMAR additional improvement; IAT 0.02 logMAR
  • IAT within 6 hours: OR 2.72 (95% CI 1.02-7.28) for recovery from severe vision loss vs. conservative
  • IVT within 4.5 hours: OR 3.32 (95% CI 1.24-8.92) vs. conservative
  • IAT had a changepoint at 8 hours: benefit drops sharply after this
  • Estimated: ~95 participants per arm needed in a properly powered RCT (neither THEIA nor TenCRAOS was large enough)
• Conclusion: Observational data support early thrombolysis; RCTs were underpowered; well-powered trials still needed

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Intra-Arterial Thrombolysis (IAT)

• Superselective catheterization of the ophthalmic artery; direct infusion of tPA or urokinase
• Potential time window extends to 24 hours (vs. 4.5 hrs for IV-tPA) due to local delivery
• Logistically complex; requires experienced neurointerventional team; not widely available
• German case series and EAGLE study data suggested benefit in select cases
• The IPD meta-analysis (Xie 2025) showed OR 2.72 for recovery within 6 hours
• Cochrane Review 2023 (Lin et al., PMID: 36715340): Only 6 RCTs, 223 patients total; all with significant heterogeneity; low certainty evidence for all interventions including tPA; tPA associated with higher serious adverse effects; NO single treatment can be recommended based on current RCT evidence

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Cochrane Systematic Review 2023 - Summary

• 6 RCTs, 223 patients; no meta-analyses possible due to heterogeneity
• Compared: tPA vs. saline; tPA vs. hemodilution+massage+IOP reduction; transcorneal electrical stimulation (TES) doses; ophthalmic artery retrograde vs. superselective IAT; pentoxifylline vs. placebo
• No evidence of important VA difference for any single intervention vs. comparator
• tPA associated with higher serious adverse events
• Conclusion: Proposed interventions do not have sufficient RCT support; treatments used remain based on expert opinion and observational evidence

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C. Hyperbaric Oxygen Therapy (HBOT)

• 100% oxygen at 2-3 atmospheres absolute (ATA)
• Mechanism: Increases dissolved oxygen in plasma, delivering O₂ to ischemic retina bypassing the blocked artery; buys time until spontaneous or thrombus-related reperfusion
• Traditional window: Most effective within 6-12 hours of onset; used up to 24 hours; some reports of benefit beyond 24-48 hours if residual retinal viability present
• 2026 systematic review (HBOT vs. IVT, PMID: 41976928, PMC13073387):
  • 25 observational studies, 781 patients (557 HBOT, 225 IVT)
  • Both HBOT and IVT associated with significant BCVA improvement: HBOT MD -0.57 logMAR vs. IVT MD -0.53 logMAR
  • Similar efficacy between the two approaches in observational studies
  • Note: No head-to-head RCT; observational data only
• AAO 2026 review (Paddock & Bakaeva, J Neuroophthalmol 2026, PMID: 41700954): Conservative management rarely beneficial and potentially harmful; prompt thrombolytic or HBOT intervention provides best chance for visual recovery
• Practical limitation: Availability is geographically restricted; most centers cannot offer HBOT within the critical window

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D. Nd:YAG Laser Embolysis

• Indication: Visible emboli in the retinal arteries (seen in ~20% of CRAO)
• A Nd:YAG laser pulse is applied directly to the visible embolus to fragment or dislodge it
• Evidence: Case reports and small series only; risk of vitreous hemorrhage, endophthalmitis; technique is specialist and high-risk
• Kanski notes this can be "considered" when emboli are visible, but no RCT evidence

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E. Transcorneal Electrical Stimulation (TCS/TES)

• Non-invasive electrical stimulation applied to the cornea
• Theorized to promote retinal neuroprotection and increase retinal blood flow
• Three-arm RCT included in Cochrane 2023: no significant benefit between different stimulation thresholds
• Investigational; not in routine practice

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F. Pentoxifylline

• Hemorheological agent; improves red cell deformability and reduces viscosity
• Included in one small RCT vs. placebo in Cochrane 2023: no significant VA difference
• No current role in evidence-based management

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G. Systemic Steroid Therapy (for Arteritic CRAO)

• GCA is the primary concern in patients >55 with CRAO
• Treatment: High-dose IV methylprednisolone 1g/day x 3 days, then oral prednisolone 1 mg/kg/day
• Goal: Prevent fellow eye involvement (which can occur within hours to days without treatment)
• IV thrombolysis is NOT indicated in arteritic CRAO - the underlying pathology is inflammatory/ischemic, not thromboembolic
• Temporal artery biopsy to confirm diagnosis (but do not delay steroids awaiting biopsy result)
• Tocilizumab (IL-6 inhibitor) now approved as steroid-sparing agent in GCA

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SECONDARY PREVENTION (Critical - Often Overlooked)

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THE REVISION TRIAL (Ongoing)

• Phase 3 RCT evaluating IV alteplase in CRAO within 4.5 hours (NCT04965038)
• German-led multicenter trial designed with the statistical power that THEIA and TenCRAOS lacked (~95 patients per arm)
• Also includes an observational arm evaluating OCT-based retinal viability markers and "retrobulbar spot sign" (a hyperechogenic lesion on orbital ultrasound predicted to identify treatable thrombus)
• Results awaited; this will be the most definitive trial to date

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CURRENT MANAGEMENT ALGORITHM (2026)

CRAO Presentation
        |
        v
< 4.5 hours from onset?
        |
   YES ─────────────────────────────────────────────────────────────────
   |                                                                    |
Rule out GCA (ESR, CRP, age)                              HBOT if available
   |                                                       within 6-12 hours
Non-arteritic?
   |
Stroke team activation + MRI brain (DWI)
   |
IV thrombolysis (alteplase 0.9 mg/kg):
  - THEIA + TenCRAOS = NOT proven superior to aspirin in RCTs
  - IPD meta-analysis (observational) = OR 3.32 for recovery vs. conservative
  - AHA 2026: Class IIb, C-LD ("uncertain benefit")
  - Decision: individualized risk-benefit; discuss risks (ICH) vs. uncertain benefit
  - If pursuing: multidisciplinary (neurology + ophthalmology)
   |
Simultaneously:
  - Ocular massage (low risk; widely practiced)
  - IOP lowering (topical/acetazolamide)
  - AC paracentesis if available/appropriate
   |
   > 4.5 hours or IVT contraindicated:
  - Consider HBOT (up to 24 hours; some benefit reported up to 48 hours)
  - Consider IAT if specialist available and within 8-24 hours
  - Conservative + secondary prevention
   |
ALL CASES:
  - Aspirin (if not anticoagulated)
  - Carotid imaging, cardiac monitoring, ECG
  - Urgent systemic workup; stroke prevention pathway
  - Follow-up 3-4 weeks (neovascularization monitoring)

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KEY TAKEAWAY TABLE

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