Optimal Treatment of Retinal Vein Occlusion: An Updated Canadian Review and Recommendations.

Introduction

Retinal vein occlusions (RVO) are a heterogeneous group of disorders that have in common impaired venous return from the retinal circulation. 1 RVO is a chronic condition and remains the second most common cause of vision loss, after diabetic retinopathy (DR), due to retinal vascular disease. 1 , 2

The global prevalence of RVO in people aged 30–89 years has been estimated at 0.77% in 2015, representing 28.06 million affected people, and the pooled 5- and 10-year cumulative incidence of RVO globally were 0.86% and 1.63%, respectively. 3 Epidemiology data for patients with RVO in Canada are scarce. A retrospective study of patient records from the Southwestern Ontario family practice database from 2008–2009 found that 73 of 47,166 patients aged >40 years had RVO (0.15%), including 0.11% with branch RVO (BRVO) and 0.04% with central RVO (CRVO); however, these data may severely underestimate incidence/prevalence due to the nature of the study. 4 The paucity of Canadian-based ophthalmological practice data underlines the need for a national registry or a populational eye health study to determine regional disease burden and treatment patterns to help guide policy and decision-making. In other countries, studies estimated prevalence rates of 0.50% in the United States (US; 2005–2008), 0.40% in Germany (study period not reported), and 2.1% in Japan (1998), as well as incidence rates of 48.09 per 100 000 population in Korea (2004–2015) and 1.9 per 100 persons in China (2001–2011). 5–9

As with all sight-threatening conditions, RVO imposes a substantial burden of illness that affects patients, caregivers, medical systems, and physicians. Among the complications associated with RVO, cystoid macular edema (CME) is the most common. 10 Other complications include retinal ischemia and neovascularization of the retina or of the anterior segment (iris and trabecular meshwork), which can lead to vitreous hemorrhage or to neovascular glaucoma respectively, potentially causing severe visual morbidity and/or blindness. 10 , 11 Vision loss can occur secondary to CME, macular ischemia, tractional retinal detachment, and secondary macular atrophy. 12 , 13 A retrospective study of patients with RVO in a US hospital estimated that 24.1% of patients would develop RVO in the fellow eye over their life expectancy (mean 16 years), with a conversion rate of 1.5% per year. 14

RVO-associated vision loss negatively impacts patients’ quality of life. 15–17 An online survey of 32 patients in Canada (March-April 2024) revealed that RVO led to visual complications that render certain daily activities (eg, reading and driving) problematic or impossible. 18 RVO was also associated with acute emotional and psychological burdens, such as elevated levels of fear or anxiety regarding accelerated vision loss or when receiving their intravitreal injections (IVI). 18 Patients living in rural and remote regions likely face a particularly increased burden for themselves and their caregivers if they are required to regularly travel long distances for their IVI appointments. 18

In response to the perceived need by retinal specialists, Berger et al developed a Canadian expert consensus in 2015 on optimal treatment of patients with RVO. 19 Since that time, improved understanding of the clinical picture of RVO and new advances in diagnosis and pharmacotherapy have refined these strategies ( Box 1 ). This article updates Canadian expert recommendations on the management of patients with RVO. Box 1 Summary of New Insights and Recommendations Since the 2015 Canadian Expert Consensus Clearer picture of the factors contributing to the development and exacerbation of RVO, notably the role of angiopoietin 2 Growing understanding and ongoing investigation of potential biomarkers for RVO, such as hyperreflective foci, endothelin-1, pentraxin 3, fatty acid-binding protein 4, and ellipsoid zone integrity Expanded imaging options, notably the emergence of OCT-A as a powerful visualization tool for retinal and choroidal microvasculature Confirmation in multiple large, real-world RVO studies of the safety and effectiveness of anti-VEGF agents, and evidence of their usefulness in patients with ischemic RVO Updated treatment strategies recommend consideration to switch anti-VEGF agents in patients with inadequate response Approval of faricimab as a bispecific (anti-VEGF and anti-Ang-2) treatment option Introduction and increasing availability of biosimilar agents for cost-effective anti-VEGF treatment Ongoing study of new molecules, including caspase-9 inhibitors, minocycline, rho-kinase inhibitors, CD 34+ stem cells, and gene therapies

Methods

An English-language literature search using the PubMed Library was performed with combinations of the terms “retinal vein occlusion”, “disease burden”, “classification”, “clinical features”, “epidemiology”, “etiology”, “imaging”, “history, complications”, “pathogenesis”, “pathophysiology”, “risk factors”, “anti-VEGF”, “ranibizumab”, “aflibercept”, “bevacizumab”, “faricimab”, “emerging therapies”, “steroid”, “triamcinolone acetonide”, “dexamethasone”, “diet”, “therapy”, “surgery”, and “laser” to identify studies published from January 2014 to January 2024. This was followed by a manual search of references cited in selected papers published in peer-reviewed journals, including the original consensus article. Older publications and trials were taken into consideration if deemed relevant and applicable to current practice and/or in cases where recently published evidence was insufficient to make sound conclusions. Meta-analyses, systematic reviews, and randomized clinical trials with at least 1 year of follow-up were selected as preferred sources.

References identified by the literature searches were further reviewed by the expert panel members. Each member was assigned a specific topic, on which they presented to the entire group during a meeting that took place in Toronto, Ontario, on September 28, 2024. During this meeting, the experts reviewed the evidence, highlighted new RVO data, and formulated recommendations to update current clinical considerations from the 2015 consensus. Agreement was sought on all recommendation points.

Classification

Lesion Area

RVO can be classified into 4 subtypes depending on the area of the lesion: CRVO, BRVO, hemiretinal (HRVO), and macular (MRVO). 20–24 RVO cases can evolve into more than one subtype. BRVO is the most common subtype, and includes HRVO and MRVO, with population-based estimates from the US, Europe, Asia, and Australia that BRVO is approximately 3–6 times more common than CRVO. 23–25 HRVO is retinal hemorrhage or other biomicroscopic evidence of RVO (eg telangiectatic capillary bed) and a dilated venous system (or previously dilated venous system) in 2 or 3 quadrants, typically 2 altitudinal quadrants. 22 While HRVO is often considered as a separate condition, its features are intermediate between BRVO and CRVO. 22 , 26 The literature on MRVO is sparse; studies by Hayreh et al identified MRVO as a distinct clinical entity from major BRVO. 21 MRVO refers to occlusion of a macular venule, 27 and it occurs primarily in the superior sector and manifests as retinal nerve fibre layer hemorrhages and CME. 20 , 28 , 29 Where previously there were specific therapeutic approaches for the RVO subtypes, current treatments have demonstrated efficacy in patients with CME secondary to both CRVO and BRVO. 30

Perfusion Status

RVO can also be broadly classified by perfusion status into ischemic and nonischemic types based on the area of capillary nonperfusion, and this distinction is useful for clinical management; 10 however, an indeterminate type also exists where the amount of intraretinal hemorrhages can mask the underlying perfusion status. 31 Most of these cases are subsequently identified as ischemic or nonperfused. Ischemic status is also indicated by the presence of retinal and iris neovascularization, which typically arise secondary to severe macular ischemia and extensive peripheral ischemia. 32 Rates of neovascular complications are notably higher in ischemic than nonischemic eyes (66.7% versus 2.8%, respectively). 29 Additionally, although nonischemic RVO may resolve without complications, it can also convert to an ischemic RVO in approximately 25–34% and 29% of CRVO and BRVO cases, respectively. 31 , 33 , 34

Pathogenesis and Pathophysiology

The pathogenesis and pathophysiology of RVO involve multiple factors and differ between CRVO and BRVO. Occlusion of the central retinal vein generally occurs posterior to or within the lamina cribrosa. 35–37 Because the vein and artery share a common adventitial sheath at the lamina cribrosa, CRVO pathogenesis is likely to be the result of mechanical narrowing of the vein’s lumen. 37 Venous compression in the form of a rigid and hyperplasic thick arterial wall is caused by arteriosclerosis. 37 BRVO is usually found at an arteriovenous (AV) junction 37 , 38 and potentially occurs due to a combination of vein compression at the AV junction, vessel wall degeneration, and abnormal hematological factors. 39 RVO-associated ischemia and inflammation lead to upregulation of vascular endothelial growth factor (VEGF) and expression of inflammatory cytokines; this also contributes to disruption of the blood-retina barrier (BRB) that is already compromised by fluid accumulation and tissue swelling caused by hydrostatic and osmotic pressure. 40 VEGF upregulation also increases endothelial cell proliferation, vascular permeability, and angiogenesis. 41 VEGF is expressed by retinal pigment epithelial (RPE), retinal glial, and vascular endothelial cells and is the main cytokine that induces neovascularization, exacerbating ischemia. 40 , 42 , 43 Both direct venous occlusion and subsequent compromised vascular integrity from inflammation and ischemia result in capillary nonperfusion.

Beyond VEGF, a host of cytokines and chemokines have been found to be significantly correlated with RVO and CME, including proinflammatory interleukins (including IL-1, IL-6, IL-8, IL-12, IL-15, and IL-18), matrix metalloproteinase, platelet-derived growth factor A, and lysophosphatidic acid and autotaxin. 40 , 42 Placental growth factor (PGF), a member of the VEGF family, has been found to be active in pathological retinal angiogenesis and inflammation. 44 While PGF is expressed primarily by the placental trophoblast during pregnancy, 45 its expression increases during pathologic conditions in RPE and choroidal cells. 46 , 47 Increased expression of PGF has been found in retinal diseases such as BRVO, 48 DR, 49 and diabetic macular edema (DME). 50 , 51 PGF facilitates angiogenesis via induction of crosstalk between VEGFR-1 and VEGFR-2 receptors, which increases cell sensitivity to VEGF-A activity. 44

More recently, the vascular destabilizing effects of angiopoietin 2 (Ang-2) have been studied, including increasing VEGF activity, weakening of endothelial cell junction integrity, and involvement in inflammatory cell recruitment. 52 , 53 Preclinical studies have also identified that Ang-2 negatively affects Tie2 integrin signaling, promoting angiogenesis and destabilization of the endothelium. 54 , 55 Intravitreal Ang-2 levels are higher in RVO compared to neovascular age-related macular degeneration (nAMD) and non-proliferative DR. 56

Risk Factors ( Table 1 )

General or Systemic Factors

Advanced age is a well-established primary risk factor for RVO; 6 , 24 , 57 , 58 odds ratios (OR) for RVO per 10-year increase have been estimated at 1.60–1.93 ( Figure 1 ). 3 , 5 , 25 The association between RVO prevalence and increased age may be partly attributed to the high prevalence of cardiovascular comorbidities among older patients, as the presence of systemic vascular and atherosclerotic diseases is a known risk factor for RVO. 3 , 8 , 9 , 58–64 Table 1 Risk Factors for RVO Modifiable Systemic Vascular/Atherosclerotic Diseases Ocular Patient Characteristics Medications and Recreational Drugs Hypertension Dyslipidemia Diabetes mellitus Peripheral artery disease Obstructive sleep apnea Multiple myeloma Polycythemia vera Leukemia Syphilis Glaucoma (open- and closed-angle) Ocular hypertension Diabetic retinopathy Retinal vasculitis Elevated body-mass index Smoking Low levels of folic acid Reduced levels of nitric oxide Antipsychotics Cancer therapies MEK inhibitors Systemic TK inhibitors Minoxidil Sildenafil Cigarette smoking Cocaine Nonmodifiable Systemic Diseases Mechanical Compression Ocular Thrombotic Patient Characteristics Chronic renal failure Systemic lupus erythematosus Sarcoidosis Stroke Atherosclerosis of retinal arteries (venous thrombosis at area of AV crossing) External compression or disease of retinal venous wall i.e vasculitis Changes in lamina cribrosa (CRVO) Hyperopia/short axial length Central serous chorioretinopathy Hyperhomocysteinemia Antiphospholipid syndrome Anticardiolipin antibody Prothrombin G20210A mutation Factor V Leiden Protein C/S deficiency Antithrombin III deficiency Age Abbreviations : AV, arteriovenous; MEK, Mitogen-activated protein kinase/extracellular signal-regulated kinase; POAG, primary open-angle glaucoma; TK, tyrosine kinase. Figure 1 Odds ratios of RVO by 10-year increment in age. Abbreviations : CI, confidence interval; OR, odds ratio.

Several studies have demonstrated that hypertension is among the strongest risk factors for RVO; 3 , 9 , 58 , 59 , 61 , 63 this association may be stronger in BRVO than in CRVO. 8 Other cardiovascular diseases positively associated with RVO include stroke and myocardial infarction, 60 , 62 and obstructive sleep apnea (OSA) has a high prevalence among patients with RVO. 65–67 Many patients with RVO present with undiagnosed conditions such as hypertension or OSA, 64 , 68 which highlights the importance of communication between specialists and primary-care providers. However, patients lacking a primary-care physician may not receive proper management of their comorbidities.

Ocular Factors

Ocular risk factors for RVO include ocular hypertension and glaucoma. 69–71 A meta-analysis found the OR for RVO in the presence of glaucoma to be 4.01 (95% confidence interval [CI] 3.28, 4.91), and stronger associations noted for CRVO (OR 6.21; 95% CI 4.64, 8.31) and HRVO (OR: 4.60; 95% CI 2.26, 9.35) than for BRVO (OR 2.38; 95% CI 1.77, 3.19). 70 The increased risk for RVO was significant in patients with primary open-angle glaucoma (OR 5.03; 95% CI 3.97, 6.37; P <0.001) but not for primary angle-closure glaucoma. 70 , 72 Signs of RVO such as hemorrhage or cotton wool spots are similar to those observed in DR; thus, RVO should be considered in patients with diabetes mellitus presenting with acute loss of vision and asymmetric signs of DR. 73

Thrombotic Factors

Data on the association between RVO and thrombotic risk factors appear conflicting. Patients with RVO have been reported to have higher prevalence of hyperhomocysteinemia and other thrombotic risk factors such as antithrombin, protein C or protein S deficiency, high factor VIII levels, and factor V Leiden, an R506Q mutation in the factor V gene; 63 , 71 , 74 however, other studies did not find significant differences in levels of these factors. 37 , 75 Coagulation disorders were found in 11.5% of 52 young (<40 years) patients with CRVO. 69

Pharmacological Factors

Certain medications and recreational drugs may increase the risk of developing RVO, as found in case reports and case series of antipsychotics, 76 , 77 cancer therapies (inhibitors of mitogen-activated protein kinase or tyrosine kinase), 78 , 79 sildenafil, 80 and minoxidil. 81 Cigarette smoking, cocaine, and methamphetamines have all been linked to an increased risk of RVO. 59 , 71 , 82–84 The association between oral contraceptive pills (OCP) or hormone replacement therapy (HRT) and RVO is unclear, and most data in the literature are derived from case reports. A population-based cohort study involving records of more than 2 million women from the Korea National Health Insurance Service found no association between a history of HRT or OCP use and the incidence of RVO, 85 as did an observational case series of 60 patients aged ≤49 years in the US. 86 A few studies found appreciable levels of OCP or HRT use in patients with RVO; however, no causal analyses were conducted. 87–89 Of note, the study by Kirwan et al with the objective of determining whether OCP or HRT were independent risk factors for RVO found that 11 of 588 women with RVO had a history of HRT or OCP use, including 6 of 9 patients aged <35 years with a history of OCP use. 89 The authors recommended that RVO be a contraindication to the use of OCP.

Clinical Features and Potential Diagnostic Markers

Beyond general findings such as low vision and visual field or pupillary defects, clinical features of RVO can be classified as acute or chronic conditions ( Box 2 and Figure 2 ). Ischemia is indicated by the presence of low vision (often 20/200 or worse), visual field defect including central scotoma, a relative afferent pupillary defect, and/or neovascularization of the iris. Box 2 Clinical Features of RVO Acute Dilated, tortuous retinal veins of affected area Deep and superficial retinal hemorrhages ± Cotton wool spots ± Cystoid macular edema ± Capillary nonperfusion Chronic ( Figure 3 ) Optic disc and retinal collateral vessels Telangiectatic capillary bed Perivenous sheathing Arteriolar narrowing Changes in macula; i.e chronic cystoid macular edema, retinal pigment epithelium mottling, exudate, epiretinal membrane, etc. Figure 2 Chronic RVO changes including optic disc collaterals (yellow arrowhead) and perivenous sheathing (white arrowhead). RPE mottling in the macula ( a ) and associated attenuation of ellipsoid (white arrowhead in b ) are noted. Images provided by Dr. Sivachandran. Abbreviation : RPE, retinal pigment epithelium. Figure 3 Representative fundus and OCT images for RVO. MRVO is shown where nerve fibre layer hemorrhages are limited to the superior macula below the arcade and does not involve the periphery ( a ) with associated CME ( b ). A dilated and tortuous superior retinal vein is noted secondary to arteriovenous nicking (yellow arrow) in superior BRVO ( c ) and associated CME ( d ). Cotton wool spots are indicated by white arrows in c and e. HRVO involving inferior nasal and temporal hemisphere ( e ) and associated CME with intra-and subretinal fluid is noted ( f ). CRVO is presented with retinal hemorrhages involving all 4 quadrants ( g ) and associated CME ( h ). Images provided by Dr. Sivachandran. Abbreviations : BRVO, branch retinal vein occlusion; CME, cystoid macular edema; CRVO, central retinal vein occlusion; HRVO, hemiretinal vein occlusion; MRVO, macular retinal vein occlusion; OCT, optical coherence tomography.

Potential diagnostic markers for RVO are listed in Box 3 . RVO causes inflammation, with increased expression of inflammatory factors such as VEGF and cytokines. 40 , 90 , 91 Endothelin-1 (ET-1) is the most potent vasoconstrictor in the cardiovascular system and is a proinflammatory peptide which promotes neutrophil adhesion to the endothelium and subsequent platelet aggregation. 92 , 93 Pentraxin 3 is produced by RPE cells in the presence of proinflammatory cytokines, and its plasma concentration was significantly higher in the RVO group than healthy controls. 94 , 95 Elevated vitreous levels of fatty acid-binding protein 4, which coordinates lipid responses in cells, was also shown to be significantly elevated in patients with RVO compared with control patients. 96 Box 3 Diagnostic Biomarkers Inflammatory cytokines Endothelin-1 Pentraxin 3 Fatty acid-binding protein 4 OCT Central retinal thickness Macular fluid Hyperreflective foci Serous retinal detachment OCT-A Capillary nonperfusion Foveal avascular zone morphology Neovascularization Vascular tortuosity, dilatation, and telangiectasias Microaneurysms Intraretinal hemorrhage Deep capillary plexus fractal dimension, vessel density, and lacunarity Fluorescein angiography Capillary nonperfusion Neovascularization Vessel density Peripheral ischemia (ischemic index) Deep capillary plexus fractal dimension, vessel density, and lacunarity Loss of integrity of ellipsoid zone, disorganization of retinal inner layers (DRIL), absence of a posterior vitreous detachment (PVD) are associated with poorer visual outcomes DRIL and ellipsoid zone integrity after first 3 loading doses with anti-VEGF are associated with long-term (1 year) visual outcomes

Optical coherence tomography (OCT) imaging has revealed diagnostic and prognostic biomarkers for RVO, the most established of which are central retinal thickness (CRT) and presence of macular fluid. 97–100

Increased levels of inflammatory factors in RVO (eg, IL-6, VEGF, and intercellular adhesion molecule 1) and the presence of subretinal fluid are associated with serous retinal detachment in patients with RVO. 97 Hyperreflective foci (HRF) are dot-liked lesions that are believed to represent activated microglial cells; they are an indicator of active inflammation. HRF in RVO-associated CME has been associated with an increased CRT and the presence of subretinal fluid. 97 , 98 Additional prognostic biomarkers for visual outcomes include disorganizations of the inner or outer retinal layers, particularly later during the treatment course, ellipsoid zone integrity, and absence of a posterior vitreous detachment. 97 , 98 , 101 , 102

Imaging

Fundus photography remains a primary imaging tool in the diagnosis of RVO. On fundoscopic examination, CRVO typically demonstrates enlargement and tortuosity of the central retinal vein and its branches with widespread retinal hemorrhages in all 4 quadrants ( Figure 3 ). 103

In contrast, BRVO presents as a wedge-shaped area arising from an AV crossing, more frequently in the superotemporal quadrant. 104 , 105 Additionally, RVO can present with cotton wool spots, retinal hemorrhages, and preretinal/subhyaloid hemorrhage (secondary to neovascularization). These findings can be imaged on fundus photography for diagnosis and monitoring. Macular changes that can be visualized with fundus photography include CME, exudate, epiretinal membrane (ERM), and degenerative changes in the RPE. Recent advances in deep learning and artificial intelligence to interpret fundus photographs have resulted in highly accurate diagnostic models for RVO. 106–108

Fluorescein angiography (FA) is used to identify the extent of vascular occlusion, degree of ischemia and leakage, and extent of CME. 109 , 110 Ultra-widefield (UWF) imaging up to an angle of 200° is helpful to visualize the peripheral retina and assess retinal capillary nonperfusion, 111 which is of particular importance in RVO to identify peripheral nonperfusion and ischemia ( Figure 4 ). 112 UWF FA is also used to identify abnormalities associated with CME, including area and extent of retinal nonperfusion. 113 Figure 4 Fluorescein angiography of a supertemporal BRVO in the left eye. ( a ) Evidence of capillary drop out and vascular remodeling in the location of the occlusion. ( b ) Widefield angiography reveals a larger area of nonperfusion in the peripheral retina. Images provided by Dr. Hasan.

OCT remains the most commonly used imaging device for the diagnosis and assessment of RVO-associated CME, including CRT and measurement of treatment effect ( Figure 3 ). 32 The introduction of spectral-domain OCT allows imaging of the macula with a much faster scan rate and at a higher scan resolution. 114 OCT angiography (OCT-A) visualizes the microvasculature of the retina and choroid. 115 OCT-A imaging of qualitative vascular abnormalities in RVO – such as capillary nonperfusion, enlargement of foveal avascular zone (FAZ), neovascularization, vascular tortuosity and dilatation, and microaneurysms – has been shown to be comparable with that of FA. 116 – 120 Swept-source OCT-A has greater definition than dye angiography and enables widefield imaging of the retina, which is particularly useful in evaluating RVO as capillary abnormalities often extend beyond the macula. 115 , 121 , 122 Quantitative imaging of metrics such as FAZ diameter and size and vessel density may contribute to prognosis of visual outcomes in patients with RVO. 123–127 Imaging of patients with RVO is also useful in the assessment of treatment responses, 121 , 128 , 129 as these techniques can identify areas of leakage and ischemia. Studies have shown that greater extent of peripheral ischemia drives persistent CME and need for ongoing anti-VEGF therapy in patients with concomitant diabetic retinopathy. 115

Treatment – General Principles

A clear understanding of the natural history of RVO is essential to determine optimal management strategies. As described by Berger et al, 19 the CVOS Group identified either good (>20/40) or poor (<20/200) baseline visual acuity (VA), but not intermediate, as a strong predictor of 3-year VA and of the risk of neovascularization. 31 This group also found that 34% of eyes developed ischemia over 3 years. Hayreh et al reported on natural history according to RVO classification. 130 In a cohort of 667 patients with CRVO seen within 3 months of onset, the investigators found a significant difference in the proportions of patients with VA ≥20/100 between nonischemic and ischemic cases (78% versus 1%; P <0.0001). Visual field defects were mild to moderate in a significantly higher proportion of patients without ischemia (91% versus 8%; P <0.0001). In patients with BRVO seen within 3 months of onset, VA improved or remained stable in 75% and 87% of patients with major and macular BRVO, respectively, and initial VA ≥20/60 and in 69% and 53%, respectively, of patients with initial VA ≤20/70. 21

General management of patients with RVO begins with identification and control of modifiable risk factors. Optimal risk-factor management will likely necessitate adopting a multidisciplinary approach with a primary-care provider and/or specialist. Undiagnosed or inadequately treated systemic risk factors have a negative effect on visual prognosis and associated ocular complications. Alternative strategies to rapid patient assessment may be required, including referral to a walk-in clinic for a prompt physical examination, review of vital signs, and bloodwork.

The use of antithrombotic therapy in patients with RVO is controversial and no large, randomized trials are available to assess their safety and efficacy in this patient population. A systematic review and meta-analysis of anticoagulant and antiplatelet therapy in patients with RVO (N=1422 patients from 15 studies) found that anticoagulant use was associated with a higher rate of VA improvement than antiplatelet use (64% versus 33%), and improvement by logarithm of the minimum angle of resolution (LogMAR) was significantly higher in patients receiving an anticoagulant than an antiplatelet (−0.20 versus 0.00; P =0.01). 131

The role of diet in the management of patients with RVO should not be overlooked, particularly to minimize baseline inflammatory states. Plant-based diets have been associated with a reduced risk for cardiovascular disease, including ischemic heart disease and cerebrovascular disease, 132–134 as well as anti-inflammatory properties. 135 Dietary considerations should also account for providing adequate levels of key minerals and vitamins that have been implicated in RVO, including iron, magnesium, folic acid, and vitamins B12 and D. 136–140

Updated treatment algorithms from Berger et al for patients with BRVO or CRVO are presented in Figures 5 and 6 . Recommendations for general treatment principles are presented in Box 4 . Figure 5 BRVO treatment algorithm. Bulleted text is subordinate to the text above it. Abbreviations : CME, cystoid macular edema; IVFA, intravenous fluorescein angiography; OCT, optical coherence tomography; OCT-A, optical coherence tomography angiography; PRP, panretinal laser photocoagulation; VA, visual acuity; VEGF, vascular endothelial growth factor. Figure 6 CRVO treatment algorithm. Bulleted text is subordinate to the text above it. Abbreviations : CME, cystoid macular edema; CRVO, central retinal vein occlusion; ERM, epiretinal membrane; IVFA, intravenous fluorescein angiography; OCT, optical coherence tomography; OCT-A, optical coherence tomography angiography; PRP, panretinal laser photocoagulation; RD, retinal detachment; VEGF, vascular endothelial growth factor; WF, wide-field. Box 4 Recommendations – General Treatment Principles Creation of a Canadian national RVO registry is desirable to inform clinical and regulatory decision-making. A multidisciplinary approach is important to achieve optimal control of modifiable risk factors of RVO.

Pharmacotherapy

Anti-VEGF Agents

Berger et al 19 presented the details of the Phase 3 trials involving ranibizumab 141–145 and aflibercept 146 , 147 ( Table 2 ) and the small-scale clinical trials with bevacizumab 148–151 that demonstrated their safety and efficacy versus sham injection in patients with CME secondary to BRVO or CRVO. Maintenance of visual and anatomic benefits was observed with ranibizumab and aflibercept in follow-up treat-and-extend studies up to 9 years, 152–156 and meta-analyses confirmed their superiority to steroids, laser therapy, or observation. 157–161 Based on these results, international guidelines support anti-VEGF agents as first-line therapy in patients with RVO-associated CME. 10 , 32 , 110 Table 2 Visual and Anatomical Outcomes in RVO Patients Treated with Ranibizumab, Aflibercept, and Faricimab Outcome Mean Change in BCVA from Baseline, ETDRS Letters Mean Change in CRT from Baseline, μm 6 Months 12 Months 24 Months 6 Months 12 Months 24 Months RANIBIZUMAB BRAVO (397 eyes with BRVO) 141 , 142 , 145 Ranibizumab 0.3 mg a +16.6 +16.4 +15.6 –337.3 –313.6 –291.4 Ranibizumab 0.5 mg +18.3 +18.3 +17.5 –345.2 –347.4 –330.6 Sham b +7.3 +12.1 +14.9 –157.7 –273.7 –304.2 CRUISE (392 eyes with CRVO) 143 , 144 Ranibizumab 0.3 mg a +12.7 +13.9 +8.2 –452.3 –452.8 –370.9 Ranibizumab 0.5 mg +14.9 +13.9 +12.0 –433.7 –462.1 –412.2 Sham b +0.8 +7.3 +7.6 –167.7 –427.2 –418.7 Aflibercept GALILEO (177 eyes with BRVO) 146 Aflibercept 2.0 mg c +18.0 +16.9 – –448.6 –423.5 – Sham c +3.3 +3.8 – –169.3 –219.3 – COPERNICUS (189 eyes with CRVO) 147 Aflibercept 2.0 mg c +17.3 +16.2 – –457.2 –413.0 – Sham c –4.0 +3.8 – –144.8 –381.8 – Faricimab BALATON (553 eyes with BRVO) 162 , 163 Faricimab 6.0 mg d +16.9 +18.1 e – –311.4 –310.9 e – Aflibercept 2.0 mg d +17.5 +18.8 e – –304.4 –307.0 e – COMINO (729 eyes with CRVO) 162 Faricimab 6.0 mg d +16.9 +16.9 e – –461.6 –465.9 e – Aflibercept 2.0 mg d +17.3 +17.1 e – –448.8 –460.6 e – Notes : a Switched to ranibizumab 0.5 mg after 12 months. b Switched to ranibizumab 0.5 mg after 6 months. c Patients received aflibercept or sham q4w for 20 weeks; from weeks 24–48, all patients received aflibercept on an as-needed basis, and patients who did not require injection at monthly evaluation received a sham injection. d Patients received faricimab or aflibercept q4w for 20 weeks; from weeks 24–72, all patients received faricimab up to q16w on a modified treat-and-extend regimen. e Outcomes were averages of measurements over weeks 64, 68, and 72. Abbreviations : BCVA, best-corrected visual acuity; BRVO, branch retinal vein occlusion; CRT, central retinal thickness; CRVO, central retinal vein occlusion.

Real-world outcomes supported the safety and effectiveness of anti-VEGF agents. 164–170 Evaluation of 3-year outcomes in treatment-naïve patients with CRVO from the international Fight Retinal Blindness Registry found a mean (95% CI) VA improvement of 12 (9, 15) letters and a mean reduction in central subfield thickness (CST) of 324 μm (291, 358 μm). 171 No significant differences in VA improvement were identified between aflibercept, ranibizumab, and bevacizumab; however, the differences in CST reductions between aflibercept (−310 mm) versus ranibizumab (−258 mm) versus bevacizumab (−216 mm) were significant ( P <0.001). It should be noted that nearly 50% of the original cohort was lost to follow-up. In the international, prospective, observational AURIGA study, 554 treatment-naïve and 65 previously treated patients who received aflibercept for RVO experienced improvements in their VA from baseline of 12.5 (10.8, 14.3) and 7.9 (3.3, 12.6) letters, respectively, at 12 months and 11.4 (9.4, 13.3) and 4.4 (- 0.6, 9.5) letters, respectively, at 24 months. 164 A treatment interval of Q≥12W at 12 months was achieved by 34.9% (187/536) of treatment-naïve and 39.3% (24/61) of treatment-experienced patients; at 24 months, 41.0% (220/536) and 41.0% (25/61), respectively, had achieved a Q≥12W treatment interval.

The exclusion of patients with a positive relative afferent pupillary defect in BRAVO and CRUISE likely prevented the participation in these trials of patients with ischemic RVO. The prospective, open-label Rubeosis Anti-VEGF (RAVE) trial enrolled 20 patients with CRVO who were at high risk of ischemia. 172 Patients received monthly doses to 8 months, were observed for 3 months, and then examined monthly on pro re nata (PRN) injection to 36 months. At 8 months, mean best-corrected VA (BCVA) was improved by 21.1 letters and mean central macular thickness (CMT) was reduced by 294 μm from baseline. During the 3-month observation, mean CMT increased by 203 μm and decreased by 191 μm during PRN dosing to 36 months. BCVA was +21.4 letters from baseline to 36 months. Neovascular complications were observed in 9 of the 18 patients completing the study at a mean of 24 months of follow-up. Thus, anti-VEGF therapy delayed but did not prevent neovascularization in 50% of patients.

Faricimab

Faricimab is a bispecific agent that provides dual inhibition of the Ang/Tie-2 and VEGF signalling pathways in patients with retinal diseases. 56 , 173 Inhibition of VEGF and Ang-2 demonstrated greater reductions in vessel lesion number, vascular permeability, retinal edema, and neuron loss than either component alone. 55 Synergistic activity of anti-inflammation and reduction of choroidal neovascularization leakage points to greater durability than with VEGF inhibition alone. 56 In an analysis of the vitreous of patients with newly diagnosed nAMD, DR, proliferative DR, or RVO; increases in Ang-2 levels were significant in all 4 subgroups and second highest (behind proliferative DR) in patients with RVO. 174

Faricimab was approved by Health Canada in July 2024 for the treatment of patients with CME secondary to RVO. 175 Approval was based on the results of the double-masked, multicentre, randomized, parallel-group, registrational phase 3 BALATON and COMINO trials, which showed that faricimab 6.0 mg was noninferior to aflibercept 2.0 mg for adjusted mean changes in BCVA (primary endpoint) or reductions in CST from baseline to week 24 ( Table 2 ). 162 Significantly more patients who received faricimab versus aflibercept experienced resolution of macular leakage at week 24 in BALATON (33.6% versus 21.0%; nominal P =0.0023) and COMINO (44.4% versus 30.0%; nominal P =0.0002). The incidence of ocular adverse events was similar between patients receiving faricimab and aflibercept in both studies. Longer-term data for BALATON and COMINO employing a modified treat-and-extend regimen found that the VA and anatomic gains achieved at 24 weeks were maintained at 72 weeks ( Table 2 ). 163 Dosing intervals of Q≥12W were achieved by 64% (BALATON) and 45% (COMINO) of treatment-naïve patients and by 57% (BALATON) and 50% (COMINO) of treatment-experienced patients.

Recommendations for the use of anti-VEGF agents are presented in Box 5 . Box 5 Recommendations – Anti-VEGF Agents Anti-VEGF agents remain the first-line treatment for patients with CME secondary to RVO. Anti-VEGF monotherapy such as aflibercept has been used extensively due its effectiveness in a treat & extend regimen. In this heterogeneous RVO population, different drugs may work differently in different patients so individualized treatment selection may be warranted or beneficial. Long-term and real-world studies with faricimab are warranted to confirm the added benefit of Ang-2 blockade as well as the Phase 3 trial results showing comparable visual outcomes, improved macular drying, and extensions of the treatment interval.

Biosimilars

Biosimilar anti-VEGF agents have been approved for the treatment of patients with nAMD and DME, and all provinces and territories have adopted switching requirements as cost-saving equivalents to brand-name agents. 176 Studies have demonstrated the equivalence of ranibizumab biosimilars with the originator agent in patients with nAMD; 177–181 however, there is a paucity of biosimilar data in patients with RVO. A subgroup analysis of the RE-ENACT 2 study involving 101 patients with RVO confirmed similar results for BCVA, CST, and presence of macular fluid, and no new safety signals; however, this study did not include a control group. 182

At present, 2 ranibizumab biosimilars and 7 aflibercept biosimilars are approved in Canada for RVO. 183–191 Biosimilar usage in patients with RVO is expected to be primarily guided by provincial regulations as per those adopted for the anti-VEGF treatment of patients with nAMD or DME.

Recommendations for the use of anti-VEGF agents are presented in Box 6 . Box 6 Recommendations – Biosimilars Real-world study evidence will be beneficial to confirm the safety and effectiveness of biosimilar anti-VEGF agents in patients with RVO.

Steroids

As described by Berger et al, 19 steroids continue to have a second-line role in the management of patients with RVO; however, they are limited by the risk of adverse events such as cataract formation or increased intraocular pressure (IOP). Although steroids have been shown to inhibit VEGF expression, 192 , 193 they may be most effective in VEGF-independent pathways promoting CME in RVO. 10 , 32 Steroids reduce levels of inflammatory cytokines such as IL-6, IL-10, IL-17, and platelet-derived growth factor AA, stabilize the blood retinal barrier, inhibit leukostasis, and modulate downstream effectors of VEGF. 194 , 195

Intravitreal triamcinolone acetonide was more efficacious in improving VA versus observation in the treatment of patients with CRVO in the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study Report 5. 196 Incidence of cataract and increased IOP were higher in the 4-mg group than the 1-mg group. The SCORE Study Report 6 in patients with BRVO found similar rates of VA improvement between triamcinolone acetonide and grid photocoagulation (standard of care). 197 Given the higher incidence of adverse events, triamcinolone acetonide was not recommended as standard of care in this patient population. Use of the sustained-release dexamethasone intravitreal implant was shown in the GENEVA trial to be associated with significantly higher proportions of eyes with CME secondary to RVO that achieved improvement in BCVA of ≥15 letters compared with sham implant. 198 IOP-lowering medication was required in 35% of patients who received the dexamethasone implant during the 12 months of study. Subsequent real-world studies found that the mean interval for dexamethasone implant reinjection was 4.5–5.9 months. 199 – 202 The SOLO study found that dexamethasone implant retreatment prior to the labelled 6-month interval was performed in 22 of 54 eyes (40.7%) with BRVO and 24 of 48 eyes (50.0%) with CRVO. 203 Other studies determined a mean of 1.9–2.2 implants during the first 12 months of treatment. 200 , 204

Although combination therapy with anti-VEGF and steroid was found in a systematic review and meta-analysis (10 studies) to be significantly superior to either agent alone in improving BCVA and CMT among patients with CME secondary to RVO, 30 the included studies were heterogeneous, using different anti-VEGF agents, steroids, and delivery methods. While combination therapy can be helpful in certain cases, there are insufficient data to support generalized usage to reduce the number of anti-VEGF injections.

Recommendations for the use of steroids are presented in Box 7 . Box 7 Recommendations – Steroids Intravitreal steroids should remain as a second-line option in patients with CME associated with RVO who experience an inadequate response to anti-VEGF agents and in subpopulations in whom biologic therapy should be avoided (eg, pregnant patients). The choice among available steroid options–triamcinolone acetonide, dexamethasone, and fluocinolone acetonide–is at the discretion on the treating physician’s preference. Close monitoring for cataracts or increased IOP of patients receiving intravitreal steroids is required. There are insufficient data to support the use of steroids to reduce the number of anti-VEGF injections.

Laser and Surgical Therapy

Before the advent of anti-VEGF agents, lasers were the mainstay of treatment in patients with RVO. Treatment protocols were based on the Branch Vein Occlusion and Central Vein Occlusion studies (BVOS and CVOS). 205–207

The BVOS found that grid laser photocoagulation was associated with a significantly higher proportion of eyes with CME secondary to BRVO (in eyes with baseline VA of ≤20/40) gaining ≥2 lines of VA; however, patients with baseline VA of ≤20/200 or who did not receive treatment for more than 1 year did not derive significant benefit. 205 Conversely, the CVOS determined that, while grid laser photocoagulation reduced angiographic evidence of CME, it did not improve VA relative to no treatment. 206 Laser scars expand and with excessive laser or treatment too close to the central fovea these scars may eventually grow to involve the fovea. Caution should be exercised when performing macular laser. Complications of laser therapy include foveal burns, scotomas, and rupture of Brüch’s membrane and the subsequent development of choroidal neovascular membranes.

Panretinal laser photocoagulation (PRP) was also shown in the BVOS to prevent vitreous hemorrhage. The investigators also found that prophylactic PRP only partially prevented neovascularization and therefore recommended careful observation of patients with ischemic CRVO and prompt PRP in the event of signs of neovascularization. 207 When neovascularization is present, prompt PRP should be considered to prevent further sequelae of ischemia-driven cascade.

Although laser photocoagulation has been shown to confer benefits such as promotion of collateral vessel formation, 208 additional value in combination with anti-VEGF therapy in patients with RVO has been variable. 209 – 211 Two meta-analyses found no significant difference between combination retinal laser photocoagulation and anti-VEGF therapy versus anti-VEGF alone in the treatment of patients with CME secondary to RVO. 212 , 213

Since its introduction by McAllister et al in 1995, 214 laser-induced chorioretinal venous anastomosis (CVA) has been shown to effectively bypass venous obstruction in eyes with ischemic and nonischemic CRVO, allowing the venous system to drain directly into the choroidal circulation. 215 , 216 This procedure was considered for nonischemic CRVOs with progressive vision loss; however, its use has dwindled due to complications including vitreous and retinal hemorrhage, rubeosis, scar tissue, traction, and choroidal neovascularization at the site of treatment.

Over the past 25 years, surgery has been performed in patients with RVO to target anatomic sites implicated in the pathoetiology. Limited benefits have been demonstrated for many surgical procedures. Surgery has become uncommon with the development of pharmacotherapies. Some surgical techniques that have been used at one time include adventitial sheathotomy for BRVO, surgical CVA, radial optic neurotomy, and vitrectomy with and without internal limiting membrane peeling for recalcitrant CME. The objective of adventitial sheathotomy is lysis of the adventitial sheath that binds vessels. It is optimally performed in patients with BRVO and VA of ≤20/200. 217 , 218 Vitrectomy was introduced for the management of patients with CME secondary to RVO in 1994 and has been shown to be effective with or without intraoperative combined procedures such as internal limiting membrane peeling and intravitreal triamcinolone acetonide at the completion of surgery. 219 This procedure is currently performed primarily in eyes with CRVO and nonclearing vitreous hemorrhage, ERM formation, and tractional retinal detachment. Some studies have supported the benefit of pars plana vitrectomy in patients with CME secondary to BRVO 220 and for resolution of vitreous hemorrhage in both BRVO and CRVO. 221

Surgical complications may occur, including elevated risks of cataract development or progression, 217 , 222–224 retinal detachment, 217 , 222 , 223 , 225 , 226 hypotony, 223 , 226–228 and vitreous hemorrhage. 215 , 222 , 223 , 226 , 227 Endophthalmitis is rare. 229 , 230

Recommendations for laser and surgical procedures are presented in Box 8 . Box 8 Recommendations – Laser and Surgery Consider focal or grid laser in patients with BRVO and persistent CME and inadequate response to anti-VEGFs and/or steroids. PRP should be used in patients with CRVO and neovascularization, and sectoral PRP in patients with BRVO and neovascularization. Vitrectomy with adjunctive PRP laser should be recommended as first-line therapy in patients with nonclearing vitreous hemorrhage with documented previous RVO from screening or referral. For neovascular RVO, PRP should be more robust than in other retinal conditions to minimize the risk of progression to neovascular glaucoma and preferably be completed in a single session. Patients with concurrent neovascularization and macular edema can be treated with anti-VEGF or a steroid in conjunction with scatter PRP laser. Widefield FA or OCT-A can help to identify ischemic areas or large microaneurysms.

Future Treatments and Delivery Routes

Emerging therapies are generally directed towards increasing treatment durability and the reduction of treatment burden of current anti-VEGF agents.

Early results of the Phase 3 QUASAR trial indicate that patients receiving aflibercept 8 mg q8w experienced noninferior gains in VA versus aflibercept 2 mg q4w (primary endpoint). 231 From baseline to 36 weeks, the mean observed BCVA improvements were 17.4 and 18.3 letters in treatment-naïve patients receiving aflibercept 8 mg q8w after 3 and 5 initial monthly doses, respectively, and 17.5 letters in patients receiving aflibercept 2 mg q4w. Mean reductions in CRT from baseline to 36 weeks were −371 μm, −370 μm, and −371 μm, respectively, and mean numbers of injections were 6.1, 6.9, and 8.8, respectively. There were no new safety signals with aflibercept 8 mg compared with 2 mg. Aflibercept 8 mg is not approved in Canada for the treatment of RVO.

Other potential therapeutic classes and molecules being studied include caspase-9 inhibitors, minocycline, rho-kinase inhibitors, and CD 34+ stem cells. 232 Caspase is active in initiation of the apoptotic pathway in inflammatory and degenerative pathologies, leading to neuromuscular dysfunction, edema, and gliosis. 233 , 234 Caspase-9 inhibition has been shown in murine models to increase the rate of reperfusion and reduction of hyperreflective foci compared to anti-VEGF. 235

Gene therapies such as ixoberogene soroparvovec (a single-dose gene therapy encoding for aflibercept) and ABBV-RGX-314 (an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment) have been shown to be safe and efficacious in Phase 1 studies of patients with nAMD, 236 , 237 and there is potential to expand study of the role of these agents in patients with RVO. The requirement of a single dose for these agents would represent a considerable reduction in patient treatment burden.

Conclusion

As the second most common cause of vision loss related to retinal vascular disease, the disease burden of RVOs to patients, caregivers, and the healthcare system remains high. This update to the 2015 Canadian Expert Consensus highlights advances in the diagnostic tools and therapeutic options for patients with RVO.

Acknowledgments

The authors wish to thank the following expert reviewers for their contributions to this article:

Kevin M. Colleaux, MD, FRCSC, Department of Ophthalmology, Saskatoon City Hospital and the University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Alan Cruess, MD, FRCSC, Department of Ophthalmology, QEII Hospital, Dalhousie University, Halifax, Nova Scotia, Canada. Peter J. Kertes, MD, CM, FRCSC, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada; John and Liz Tory Eye Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Wai-Ching Lam, MD, FRCSC, Department of Ophthalmology and Visual Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong; Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Ravi K Nrusimhadevara, MD, Department of Ophthalmology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Tom Sheidow, MD, FRCSC, Ivey Eye Institute, St. Joseph’s Hospital, London, Ontario, Canada. Eric Tourville, MD, FRCSC, Department of Ophthalmology, Hospital Saint-Sacrement, Laval University, Quebec, Quebec, Canada. The authors also thank Lindsay Craik and Jeff Alexander (SNELL Medical Communication) for their editorial assistance.

Disclosure

Dr. Sivachandran has been an Advisory Board member for Amgen, Apotex, Astellas, Bayer, Innova, and Roche; received research grants from Bayer, Roche, and Sentrex; and participated in an educational consortium for Apellis. Dr. Altomare has personal financial interest in Tracery Ophthalmics Inc. and Translatum Medicus Inc. Dr. Dookeran has been a consultant and/or speaker for Roche, Bayer, Bausch + Lomb and Apotex. Dr. Hasan has been an Advisory Board member for Novartis, Bayer, Apellis, Roche, AbbVie, and Biogen, received clinical trial support from Bayer and Roche, and received conference support from Bayer. Dr. Whelan has been an Advisory Board member for Apotex, Bayer, Novartis, and Roche; and received research grants from Novartis. The authors report no other conflicts of interest in this work.

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