Table 5.

Recommendations Matrix of clinical practice guidelines for the diagnosis and management of RVO (Guideline clinical recommendation meta-synthesis).

	RCO	EURETINA	PPP	SERV	CEC
GENERAL FEATURES
Risk factor for RVO	Stroke: conflicting Peripheral venous disease	NR	NR	Open angle glaucoma (level 1) Hypertension (level 2) Blood hyperviscosity (level 2), Hyperlipidaemia (level 3), Thrombophilia (level 3–4).	Hypertension (OR 3.5) Diabetes (OR 1.5) Hyperlipidaemia (OR 2.5) The previous need to be addressed and treated (consensus/level III)
Diabetes	No: No more common than the general population. Testing at diagnosis for detecting undiagnosed diabetes.	No: Diabetes is associated with RVO, but this may be because both diabetes and RVO are associated with cardiovascular risk factors.	Yes.	No: Probably not directly, but increase other risk factors.	Yes: Diabetes (OR 1.5).
Antiphospholipid syndrome	No rutinary unless other recognised Anti-Phospholipid Syndrome (APS) clinical associations.	No rutinary.	NR	In the absence of risk factors, in patients under 50 years of age, or in bilateral cases.	All patients with RVO
Thrombophilia tests	No rutinary. Thrombophilic abnormality does not alter management options or predict prognosis.	No rutinary. Screen in younger patients in whom no common risk factors have been identified Women with oestrogen-containing hormone replacement: continue therapy, but no commence if absent.	NR	Assess Hiperhomocisteinemia in all patients with RVO, in the absence of risk factors, in patients under 50 years of age, or in bilateral cases	All patients with RVO
Anticoagulation or antiplatelet therapy	No high-quality evidence.	NR	NR	Not enough effectiveness.	NR
Ophthalmology role	Initial assessment by ophthalmologist and additional assessment by primary care physician.	Initial assessment by ophthalmologist and additional assessment by primary care physician.	Refer patients to a primary care physician.	Initial assessment by ophthalmologist and additional assessment by primary care physician.	Standardised communication between family doctors, internists, and ophthalmologists. RVO might be a hypertensive crisis, so patients should be managed and referred for urgent follow-up (consensus/level III).
Medical treatment
Anti-VEGF therapy	If no iris or angle NV and OCT evidence of MO: If visual acuity is 6/96 or better, commence intravitreal anti-VEGF. Bevacizumab: MO due to CRVO and BRVO Ranibizumab: MO due to CRVO and BRVO Aflibercept: MO due to CRVO and BRVO Comparison: The proportion of patients achieving >15 letter gains were similar (47%, 52 and 45% for ranibizumab, aflibercept and bevacizumab respectively) Bevacizumab was not non-inferior to ranibizumab. Aflibercept non-inferior but not superior to ranibizumab Aflibercept had a superior drying effect of the macula compared to the other 2 agents. Switch: No evidence that switching to another anti-VEGF agent may be effective.	Bevacizumab: Macular oedema due to CRVO (monthly and PRN regimens). Ranibizumab: Macular oedema secondary to BRVO and CRVO Aflibercept: Macular oedema secondary to BRVO and CRVO	Macular oedema secondary to BRVO and CRVO with minimal side effects. (I++, Good quality, Strong recommendation)	Bevacizumab Useful in initial phase of CRVO but no recommendation can be done (Level of evidence 4/Grade of recommendation D) No recommendation can currently be made in BRVO. (Level of evidence 4/Grade of recommendation D) Ranibizumab Macular oedema secondary to CRVO and BRVO. (Level of evidence 1/Grade of recommendation A). Aflibercept: Patients with macular oedema secondary to CRVO and BRVO. (Level of evidence 1/Grade of recommendation A). Comparison Bevacizumab and Ranibizumab offer similar results in BRVO (Level of evidence 4/Grade of recommendation D). Ranibizumab the safer in patients with a cardiovascular event adverse less than 3 months ago (Level of evidence 3/Grade of recommendation C)	Bevacizumab: First-line therapy. Macular oedema secondary to CRVO (level IIb) and BRVO (Level IIb). Ranibizumab: First-line therapy. Macular oedema secondary to CRVO (Level I) and BRVO (Level I). Aflibercept: First-line therapy. Macular oedema secondary to CRVO (Level I) Also considered in cases of vitreous haemorrhages, associated with anterior or posterior segment neovascularization, following detailed B-scan imaging to rule out tractional changes (consensus/level III).
Intravitreal steroids	Dexamethasone: MO secondary to CRVO and BRVO.	Dexamethasone: First-line for patients with recent history of a major cardiovascular event or who are unwilling to come for monthly injections (and/or monitoring) in the first 6 months of therapy. IOP needs to be monitored every 2 to 8 weeks following injection (first cycle after implantation need close monitoring after every 2 weeks to see the patients IOP response). Reasonable in anti-VEGF nonresponders.	Insufficient evidence to determine if steroids are beneficial or not. (I+, Good quality, Strong recommendation) No difference in macular oedema secondary to CRVO with bevacizumab, ranibizumab, aflibercept and triamcinolone. Steroid and IOP risks make anti-VEGF more favourable as initial therapy. (I+, Good quality, Strong recommendation)	Dexamethasone: First choice macular oedema secondary to CRVO, with good perfusion. (Level of evidence 1/Grade of recommendation A) In BRVO for macular oedema in anti-VEGF nonresponders (Level of evidence 4/Grade of recommendation D). Combined with bevacizumab or ranibizumab is superior monotherapy. (Level of evidence 4/grade of recommendation D) Triamcinolone: No proven protective effect on anterior neovascularization. (Level of evidence 4/Grade of recommendation D)	Steroids in CRVO but not BRVO (consensus/level III). IOP should be monitored every 4–6 weeks (consensus/level III).
Laser photocoagulation
Pan Retinal Photocoagulation (PRP)	Iris new vessels (NVI) or angle new vessels (NVA) are visible. PRP may be useful in preventing vitreous haemorrhage.	Neovascular complications (retinal and disc neovascularization secondary to BRVO or CRVO as well as iris neovascularization)	CRVO: Peripheral PRP in iris o angle neovascularization.	Ischaemic OVCR When the first sign of NVI or NVA appears. (Level of evidence 1/Grade of recommendation A) Prophylactic when controls cannot be carried out (Level of evidence 3/Grade of recommendation C) Neovascular glaucoma (Level of evidence 3/Grade of recommendation C).	Scatter or PRP, choice in neovascularization secondary to RVO (level III).
Sectorial laser	BRVO: Disc or retinal neovascularization		BRVO: Sectoral PRP for neovascularization in vitreous haemorrhage or iris neovascularization.	Retinal and papillary neovascularization (in the area of ischaemic retina). (Level of evidence 1/Grade of recommendation A).
Grid laser	No evidence of benefit from macular grid laser + intravitreal anti-VEGF or steroids for macular oedema secondary to CRVO.	Focal laser photocoagulation as a second-line in MO secondary to BRVO	BRVO, macular perfusion, and macular oedema with a visual acuity of 20/40 or worse. If anti-VEGF failure or inadequate response.	No benefit and is not recommended in MO secondary to CRVO (Level of evidence 1/Grade of recommendation A) but could be used in MO secondary to BRVO. BRVO: In the area of capillary diffusion, after a period of 3 to 6 months from the onset of the disease and when most of the haemorrhagic component has already been reabsorbed. (Level of evidence 1/Grade of recommendation A)	Second-line over intravitreal steroids for BRVO patients with suboptimal response to anti-VEGF (consensus/ level III) and/or persistent oedema and vision <20/40 after 3–4 monthly injections of anti-VEGF (level I)
Complications
Neovascularization	Iris/angle neovascularization (NV): Open anterior chamber angle: urgent anti-VEGF with PRP within the same day (prior to anti-VEGF treatment) or within 2 weeks initially. PRP plus intravitreal bevacizumab (off license) can be repeated if NVI/NVA persist. Closed angle and raised intraocular pressure: Urgent PRP with cyclodiode laser therapy/tube shunt surgery.	PRP only after iris neovascularization was visible, with weekly or biweekly follow-up of patients with extensive capillary non-perfusion. PRP for neovascular complications (retinal and disc neovascularization secondary to BRVO or CRVO as well as iris neovascularization)	Iris or angle neovascularization: Complete peripheral PRP	Ischaemic CVRO: PRP when the first sign of NVI or NVA appears. (Level of evidence 1/Grade of recommendation A) PFC for Papilar NV or Retinal NV without Iridian/angle NV to prevent anterior segment neovascularization. The protective effect of intravitreal triamcinolone acetonide (TAIV) on anterior neovascularization is not proven. (Level of evidence 4/Grade of recommendation D). BRVO: Photocoagulation Retinal and papillary neovascularization (in the area of ischaemic retina). (Level of evidence 1/Grade of recommendation A).	Anti-VEGF agents should be considered in cases when anterior segment neovascularization is present or before the initiation of laser treatment (consensus/level III).
Follow up
Follow-up/Stop/Stability	Cessation: Maybe: No VA improvement after first 3 injections Recommended: after 6 injections. Ranibizumab/aflibercept if after 3 consecutive monthly treatments, visual acuity has not improved and CMT has not reduced from baseline If visual acuity stability: Treat and extend regimen or PRN regimen. PRN regimen: Monitored at monthly (or bi-monthly) intervals. If Ozurdex is the first line of treatment, re-treatment may be required at 4–6 monthly intervals until visual stability is obtained. Non-ischaemic CRVO: Follow-up every 3 months is recommended in the first 6 months in eyes not requiring treatment In ischaemic CRVO or eyes with >10DA of posterior pole nonperfusion: Monthly monitoring for 6 months and subsequently every 3 months for a year if anti-VEGF therapy is not commenced.	Monthly follow-up period for at least 1 year.	Iris examination for early iris or angle NV: monthly for 6 months in eyes with CRVO and in eyes with ischaemic CRVO after discontinuing anti-VEGF to detect neovascularization.	Ischaemic CRVO: Monthly controls to rule out iridian neovascularization (INV) or neovascularization of the angle (NVA). Could be every 2–3 months, unless there are particular risk factors. (Level of evidence 1/Grade of recommendation A) Non-ischaemic CRVO: Periodic controls for 3 years.	Successful treatment: After 3–4 monthly injections, vision is stable or is progressively improving and OCT shows reduction in retinal fluid. Consider PRN treatment with frequent (ideally monthly) monitoring, or a treat-and-extend approach. Patients should be followed for at least 3 years (consensus/level III). CRVO patients should be followed and monitored more frequently than BRVO patients. Monthly followup is recommended until they present with relatively stable vision and reduced fluid on OCT (level I).
Economic issues
Economic recommendation	NR	NR	When looking at the dollars per QALY, this was $824 for bevacizumab versus $1,572 for grid laser, $5,536 for Ozurdex, and $25,566 for ranibizumab. The dollars per line-year saved followed along similar lines, with bevacizumab at $25, grid laser $68, Ozurdex $162, and ranibizumab $754.	NR	Data regarding treatment patterns and the economic burden associated with RVO are sparse.

Bold: grade of recommendation.

RCO Royal College of Ophthalmologists, EURETINA European Society of Retina Specialists, PPP Preferred Practice Pattern, SERV Sociedad Española de Retina y Vítreo, CEC Canadian Expert Consensus.