Systematic review of clinical practice guidelines for the diagnosis and management of retinal vein occlusion

Abstract

Background/objectives

To assess the methodological quality of Clinical Practice Guidelines (CPG) for the diagnosis and management of Retinal Vein Occlusion (RVO).

Methods

A systematic review of CPGs for the diagnosis and management of RVO was carried out with a search in databases, metasearch engines, CPG development institutions, ophthalmology associations and CPG repositories until April 2022. Search update was performed on April 2023, with no new record available. Five CPGs published in the last 10 years in English/Spanish were selected, and 5 authors evaluated them independently, using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument. An individual assessment of each CPG by domain (AGREE-II), an overall assessment of the guide, and its use with or without modifications were performed. Additionally, a meta-synthesis of the recommendations for the most relevant outcomes was carried out.

Results

The lowest score (mean 18.8%) was for domain 5 ‘applicability’, and the highest score (mean 62%) was for domain 4 ‘clarity of presentation’. The 2019 American guideline (PPP) presented the best score (40.4%) in domain 3 ‘rigour of development’. When evaluating the overall quality of the CPGs analysed, all CPGs could be recommended with modifications. In the meta-synthesis, anti-VEGF therapy is the first-choice therapy for macular oedema associated with RVO, but there is no clear recommendation about the type of anti-VEGF therapy to choose. Recommendations for diagnosis and follow-up are similar among the CPGs appraised.

Conclusion

Most CPGs for the diagnosis and management of RVO have a low methodological quality assessed according to the AGREE-II. PPP has the higher score in the domain ‘rigour of development’. Among the CPGs appraised, there is no clear recommendation on the type of anti-VEGF therapy to choose.

Introduction

Retinal vein occlusion (RVO) is a retinal vascular condition that may cause significant ocular morbidity and visual acuity impairment, with a prevalence of 0.77% in people aged 30–89 years old (28.06 million worldwide in 2015) and an incidence of 0.86%, being more frequent in 60–69 years old patients [1]. Several risk factors have been described, like hypertension [1], heart failure, ischaemic heart disease, peripheral artery disease, stroke and others [2]. The correct diagnosis and treatment continue to be a challenge for the clinician in training, for which different clinical practice guidelines (CPG) have been developed to ensure a uniform evidence-based practice, with the best standards of care.

CPG are ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances’ [3]. Institute of Medicine (IOM) published a set of 8 standards required for a CPG to be considered trustworthy [3, 4]. However, the most applied method to assess CPG methodological quality is the ‘Appraisal of Guidelines for Research & Evaluation’ (AGREE) Instrument [5, 6].

Several studies have assessed the quality of CPG in ophthalmology, for diseases like glaucoma [7–10], cornea/surface/refraction [11–14], and retina (Age-Related macular degeneration [15, 16], diabetic macular oedema [17], or myopic macular degeneration [18], however no previous systematic review of CPG for the diagnosis and management of RVO has been published. Considering that a CPG with high methodological quality should include better recommendations, based on strongest evidence, it is important to assess the methodological quality of the available CPGs. The aim of this paper was to assess the methodological quality of CPGs for the diagnosis and management of RVO.

Materials and methods

A systematic review of CPGs was conducted in compliance with methodology reports [19–21].

Systematic literature search

Two authors (JGO and ISO) conducted a systematic literature search, with no date limit, on April 2022 (eTable 1 and eTable 2). Search update was performed on April 2023, with no new record available.

Table 1.

Selected CPG for the diagnosis and management of RVO.

Denomination	Title	Year of Publication	Organisation	Language
RCO [22]	Retinal Vein Occlusion (RVO) Guidelines	2022	The Royal College of Ophthalmologists	English
EURETINA [23]	Guidelines for the Management of Retinal Vein Occlusion by the European Society of Retina Specialists (EURETINA)	2019	European Society of Retina Specialists	English
PPP [24]	Retinal Vein Occlusions Preferred Practice Pattern (PPP)®	2019	American Academy of Ophthalmology	English
SERV [25]	Manejo de las oclusiones venosas de la retina	2015 (2021a)	Sociedad Española de Retina y Vítreo	Spanish
CEC [26]	Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus	2015	SNELL Medical Communication Inc.	English

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.

^aAvailable at SERV website (only for SERV member) report: ‘Last modification: 17/09/2021’.

Table 2.

Characteristics of CPG for the diagnosis and management of RVO.

Characteristic	Sub-characteristic	RCO	EURETINA	PPP	SERV	CEC
Guideline status		Update	New	Update	Update	New
Developer organization		Society	Society	Society	Society	Private
Funding		NR	NR	Yes	NR	Novartis Pharmaceuticals Canada
Development group	Number	5	8	7	8	11
	Affiliation details	Yes	Yes	No	Yes	Yes.
	Specialty/sub-specialty details	No	No	No	No	No
	Non-physician specialist	No	No	No	No	No
	Haematologist	Yes	No	No	No	No
	Population representative	No	No	No	No	No
	Methodologist	No	No	Yes	No	No
External review		NR	NR	Yes	Yes	NR
General features	Objective	Yes	NO	Yes	Yes	No
	Scope	Yes	No	Yes	No	No
	Target users	Yes	No	Yes	No	Yes
	Population	Yes	No	Yes	No	Yes
Evidence search	Search strategy	Yes	No	Yes	No	No
	Number of referenced citations	140	158	111	174	117
Update	Previous guide	2015	NA	2015 (2021a)	2010	NA
	Next update	2025	NA	2024	NR	NA
Detailed declaration of conflict of interest		Yes	Yes	Yes	Yes	No
Monitoring and/or auditing criteria		Yes	No	No	No	No
Evidence and grading of recommendations		NR	NR	Level of evidence: SIGN Recommendation: GRADE	US Agency for Health Research and Quality	Own level of evidence system

NR not reported, NA not applicable, 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.

^aAvailable at SERV website (only for SERV member) report: ‘Last modification: 17/09/2021’.

CPG screening

Two authors (JGO and ISO), independently screened titles and abstracts. Discrepancies were resolved through discussion and reviewed by a third author (TGO).

Guideline selection and data extraction

CPGs were selected if they were written in English/Spanish, published in the last 10 years, and full text was available. If a consensus document was retrieved, a global assessment was performed by authors (JGO and ISO), and it was selected if the consensus reported some relevant characteristics of a CPG (development group, scope, search strategy and a list of recommendations).

CPG details were extracted, and were not excluded on the basis of overall quality. In the case of updated CPG, previous CPG (1 or 2 previous editions), supplements and additional files were searched and data extracted.

Guideline quality critical appraisal

Five authors (JGO, RBE, ISO, HPH, CBM) critically appraised the quality of the guidelines using the AGREE II instrument [5, 6].

Guideline clinical recommendation meta-synthesis

A meta-synthesis of most clinically relevant recommendations was performed. Two authors (JGO and RBE) extracted independently the key recommendations and built a recommendations matrix, reviewed by a third author (CBM). Selected recommendations items were reviewed additionally by two authors with experience in retina (HPH and MZM) and in glaucoma (TGO). Authors discussed, selected and summarised global clinical recommendations for management of RVO based on the CPG, and clinical recommendations applicable for developing countries.

Results

Guideline selection

Literature search through databases and metasearch engines retrieved 1018 records, from those, 326 were deleted using the duplicate detection tool of Rayyan web application. Next, 689 records were screened by title and abstract using Rayyan web application, and 12 records were selected for full-text review. Eight articles were excluded due to the following reasons: wrong study design (n = 4), language not English/Spanish (n = 1) and old version of included guidelines (n = 3). 17 records were found through GPGs developers or Ophthalmology organisations webpages, one CPG was selected from the ‘Sociedad Española de Retina y Vítreo’ (SERV) webpage, the rest were excluded due to the following reasons: language not English/Spanish (n = 1), health technology assessments (n = 4), wrong topic (n = 7) and already included (n = 4). No additional study was identified by manual search. (eFig. 1).

Finally, five CPG were selected (four CPG and one consensus recommendation). The selected guidelines were developed by The Royal College of Ophthalmologists (RCO) [22], European Society of Retina Specialists (EURETINA) [23], Preferred Practice Pattern (PPP) from the American Academy of Ophthalmology (AAO) [24], Sociedad Española de Retina y Vítreo (SERV) [25] and the Canadian Expert Consensus (CEC) [26] (Tables 1 and 2).

Guideline quality

Regarding the quality of evidence, RCO and EURETINA did not report the used system for rating quality of evidence and grading recommendation, unlike PPP that used SIGN (Scottish Intercollegiate Guidelines Network) for rating the evidence and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) for grading recommendation. SERV used US Agency for Health Research and Quality system and CEC used its own system (Table 2).

Of the six domains from AGREE II (Table 3), the lowest score (mean 18.8%) was for domain 5 ‘applicability’, and the highest score (mean 62%) was for domain 4 ‘clarity of presentation’. About single domains scores, the EURETINA guideline had the lowest score (3.3%) in the ‘applicability’ domain. The RCO had the highest score (87.8%) for the ‘scope and purpose’ domain; followed by the SERV guideline score (77.8%) for the ‘clarity of presentation’. The 2019 American guideline (PPP) presented the best score (40.4%) in domain 3 ‘rigour of development’ (Tables 3 and 4).

Table 3.

Domain scores (%).

Domain	RCO	EURETINA	PPP	SERV	CEC	MEAN
1: Scope and Purpose	87.80%a	21.10%	42.20%	25.60%	30.00%	41.30%
2: Stakeholder Involvement	44.40%	8.9%	52.20%	18.90%	31.10%	31.10%
3: Rigour of Development	17.90%	12.50%	40.40%	16.70%	29.60%	23.40%
4: Clarity of Presentation	74.40%a	43.30%	41.10%	77.80%a	73.30%a	62.00%a
5: Applicability	29.20%	3.30%	32.50%	6.70%	22.50%	18.80%
6: Editorial Independence	58.30%	43.30%	85.00%a	31.70%	11.70%	46.00%
Overall Guideline Assessment	3	3	4	3	3	-
Recommendation	Yes, with modifications	Yes, with modifications	Yes, with modifications	Yes, with modifications	Yes, with modifications	-

High-quality CPG (at least 3/6 domains >60% including domain 3). Moderate quality CPG (≥3 domains score >60%, except Domain 3) [19].

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.

^aScore ≥ 60%.

Table 4.

Summary of Appraisers’ Comments on the Retinal Vein Occlusion Clinical Practice Guidelines assessed, organised by AGREE II Domains.

AGREE II domain	Strength	Weaknesses
1. Scope and Purpose	• The objective is well defined only in one CPG (RCO). • Population to whom the guideline is meant to apply, is partially reported (RCO, PPP, CEC).	• Guideline objective is partially or not clearly stated (EURETINA, PPP, SERV, CEC) • Partial statements about health questions are reported (RCO). • Health questions are not clearly stablished (EURETINA, SERV, CEC). • Population to whom the guideline is meant to apply, is not specifically described (EURETINA, SERV).
2. Stakeholder Involvement	• Guideline development group included individuals from relevant professional groups: Methodologist (PPP) or Haematologist (RCO). • Target users were reported (RCO, PPP, CEC).	• Guideline development group does not include individuals from all relevant professional groups (no methodologist, no patient representative) (RCO, EURETINA, SERV, PPP, SERV, CEC). • Target users were not reported (EURETINA, SERV). • No reference to views and preferences of the target population was reported (RCO, EURETINA, SERV, CEC, partially in the PPP).
3. Rigour of development	• Details of the search strategy used were reported (RCO, PPP, CEC). • Some criteria for selecting the evidence are described (PPP). • An explicit link between the recommendations and the supporting evidence was reported (RCO, EURETINA, partially in SERV and CEC). • The guideline was externally reviewed (PPP, SERV). • Health benefits, side effects, and risks were considered (RCO, CEC, partially in SERV). • Update details are reported (RCO and PPP).	• Criteria for selecting the evidence was not clearly described (RCO, EURETINA, SERV, CEC). • No clear description of the strengths and limitations of the body of evidence (RCO, EURETINA, PPP, SERV, CEC). • No clear description of the methods for formulating the recommendations (RCO, EURETINA, PPP, SERV, CEC). • No clear description of health benefits, side effects, and risks (RCO, EURETINA,). • No external review details were reported (RCO, EURETINA, CEC). • No update details were reported (SERV, EURETINA, CEC).
4. Clarity of presentation	• Key recommendations are easily identifiable (RCO, PPP, SERV, CEC). • Recommendations are specific and unambiguous, different options for management of the condition or health issue are clearly presented (RCO, EURETINA, SERV, CEC; highlighted findings and recommendations for care in PPP).	• Key recommendations are not easily identifiable only in one CPG (EURETINA).
5. Applicability	• Present monitoring and/or auditing criteria (RCO reports ‘service evaluation measures’, PPP describes some criteria for monitoring and/or auditing). • Includes several algorithms (SERV, CEC). • An economic section is included (PPP, CEC). • Facilitators and barriers to its application were described (PPP, CEC). • Guideline includes recommendations to put into practice (PPP).	• Don’t describe facilitators and barriers to its application (RCO, EURETINA, SERV). • The guideline doesn’t provide advice and/or tools on how the recommendations can be put into practice (RCO, EURETINA, SERV). • Potential resource implications of applying the recommendations have not been considered (RCO, EURETINA, SERV). • No monitoring and/or auditing criteria is included (EURETINA, CEC).
6. Editorial independence	• Views of the funding body were reported (PPP, partially in RCO) • Competing interests of guideline development group members have been recorded and addressed (RCO, EURETINA, PPP, SERV). • Guideline report details about funding body (CEC).	• No report of the views of the funding body was reported (EURETINA, SERV). • No description of competing interests was reported (CEC).
7. Overall Guideline Assessment	• RCO: 3, with modification. • EURETINA: 3, with modification. • PPP: 4, with modification. • SERV: 3, with modification. • CEC: 3, with modification.

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.

Guideline clinical recommendation meta-synthesis

A meta-synthesis of most clinically relevant recommendations is presented in Table 5. Selected recommendations included; general features (risk factors, diabetes, antiphospholipid syndrome, thrombophilia tests, anticoagulation or antiplatelet therapy, ophthalmology role), medical treatment (anti-VEGF therapy and Intravitreal steroids), laser photocoagulation (pan retinal photocoagulation (PRP), sectorial laser and grid laser), complications (neovascularization), follow-up/stop/stability and economic recommendations). A summary of global clinical recommendations for the management of RVO based on the CPG is presented in eTable 3, and clinical recommendations applicable for developing countries are presented in eTable 4.

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.

Discussion

Methodological quality

A large number of systems for grading evidence and making recommendations are available, most of them consisting of hierarchical grading systems based on the design and biases of the studies, leading to assign a specific grade of recommendation. SIGN was one of the most widely used methods [27]; but in the last few years, SIGN implemented the GRADE approach within its guideline development methodology and since 2020 SIGN adopted GRADE to address intervention questions in guidelines [28]. GRADE is a system used in systematic reviews and CPG [29], has been adopted by several organisations worldwide (more than 110 organisations from 19 countries) [4, 30] like Cochrane Collaboration, the WHO, UpToDate®, Dynamed, and since 2013 the UK National Institute for Health and Clinical Excellence [31]. PPP was the only CPG that used SIGN and GRADE. The use of a structured system to for grading evidence and making recommendations is necessary, considering that the quality of a CPG, is based on the available evidence related to each clinical question, that should be answered preferably with a well-designed systematic review or high-quality primary studies.

None of the CPG assessed reached the minimum suggested for a high or moderate quality CPG (at least 3/6 domains >60% including domain 3) or moderate quality CPG (≥3 domains score >60%, except Domain 3) [19]. Even when RCO CPG included a haematologist and PPP CPG scored the better methodological quality items (Domain 3: Rigour of development = 40.4%), all the CPG are considered ‘Low-quality CPG’ (≥2 domain score <60% and domain 3 score < 50%) [19]. Previous studies have assessed and gave some suggestion to improve PPP quality: ‘The inclusion of a diverse representation of clinical, scientific, and methodological experts, record the inclusion of patients or patient representatives in CPG development, and ensure that patients, patient organisations, and interested members of the public have an opportunity to review the CPG and describe how their comments were addressed’ [32].

In item 9 (Strengths/limitations of the body of evidence are clearly described), guideline development group must assess the risk of bias and the certainty of the evidence of the included studies (i.e systematic reviews) or in the case of not available, not performed, or low quality; assess primary studies (clinical trials, observational studies or even expert opinion). None of the CPG provided detailed description of the strengths and limitations of the evidence, so readers do not know quality of included studies, the magnitude of the effect or whether they have methodological limitations. Most of the guidelines had lower scores, that could be due to lack of high-quality evidence in ophthalmology, primarily in systematics reviews [33–35], however retina is the sub-specialty with more published systematic reviews, followed by cornea, glaucoma and cataract surgery [33]. Also, constant development of new and several types of anti-angiogenics can be a reason.

Item 10 (methods for formulating the recommendations) is the most important about clinical relevance, however only PPP and SERV reported a method for evidence and grading of recommendations (SIGN/GRADE for PPP and US Agency for Health Research and Quality for SERV). CEC reports its own level of evidence. In recent years, most of the developer organisations are including the GRADE framework [4, 30]. Not including how evidence was assessed nor how the recommendation was formulated could be a problem with consensus-based recommendations. However, even in this case, a complete description of the percent of agreement between members, will give transparency to the CPG [36]. Transparency in a CPG is a very important matter and includes several issues contained in AGREE assessment like: a complete description of the questions, retrieved evidence, who assessed the evidence (including conflict of interest), benefit/harms balance, judgments for or against recommending a specific intervention, and who peer-reviewed the draft guidance [37].

Including the date of update is a very important issue assessing CPGs, especially considering that recommendations become outdated after 3 years [38]. RCO and PPP guidelines detailed the update date (2025 and 2024, respectively). Waiting more than 3 years to review a CPG is not recommended [38], so an efficient way is to implement systematic updating, with the possibility of performing partial updating [39]. A special committee/working group focused on the disease, can lead to annual updates, as in other CPG development groups like hypertension [40]. The RCO was the unique CPG that included criteria for monitoring and/or auditing. Having an accessible CPG with an adequate description of audit criteria, useful to audit the implementation of the CPG in the future as has been done in glaucoma [41, 42] and Herpes Simplex Keratitis [43].

On an overall Guideline Assessment, all guidelines except for PPP (Score 4) were scored 3 and recommended with modifications. This recommendation is based mainly on methodological assessment, but also on content recommendations. Even when AGREE II scores were low for all the guidelines, some of these guidelines are useful tools for the diagnosis and management of RVO. SERV and CEC have simple and useful algorithms.

Guideline clinical recommendation meta-synthesis

When assessing the evidence matrix (Guideline clinical recommendation meta-synthesis), risk factor reports are different between assessed guidelines. The most important risk factor for RVO is hypertension (meta-odds ratio of 2.82%), followed by advanced age (1.60 for every decade increase), heart attack history (2.23), stroke history (2.07), total cholesterol (1.32 for every mmol/L increase) and creatinine (1.04 for every 10-mmol/L) [1]. Other authors report different OR for several risk factors: hypertension (OR = 1.10), heart failure (OR = 1.30), ischaemic heart disease (OR = 1.37), peripheral artery disease (OR = 1.89), and stroke (OR = 2.21) [2]. Atrial fibrillation is also a risk factor for RVO [44], however, other factors like non-O blood groups are known risk factors for thrombotic and cardiovascular disease, but not for RVO [45].

Some authors report that arterial hypertension, high-density lipoprotein level, hyperlipidaemia, peripheral artery disease, stroke, anticoagulation, aspirin use, age-related macular disease, glaucoma, intraocular pressure, refractive errors, diabetes, liver disease, and renal disease are risk factors with an effect exceeding 10% [46]. Other studies report that in patients under 50 years old, hypertension and hyperlipidaemia were the most frequent cardiovascular risk factors for RVO, however congenital thrombophilic disorder was the third in frequency [47].

Diabetes is one of the risk factors still in doubt (Table 4). A meta-analysis showed that diabetes is associated with RVO (OR = 1.68), with CRVO (OR = 1.98), but not with BRVO (OR = 1.22, CI: 0.95–1.56) [48]. Antiphospholipid syndrome and Thrombophilia test recommendations vary between guidelines, especially with CEC. Based on guidelines, there’s not enough evidence to recommend anticoagulation or antiplatelet therapy, but new studies suggest that anticoagulation could lead to better VA improvement and fewer recurrences compared with antiplatelet therapy, considering the bleeding risk [49]. Recommendations for systemic diagnosis in patients with RVO is an important outcome that must be issued by an internal medicine/haematology/primary care specialist [50, 51].

Diagnosis or monitoring criteria were not included in the evidence matrix. However, OCT markers are reported in some of the guidelines. Also, some studies report that ‘baseline central subfield thickness (CST) < 464 μm, absence of subretinal fluid, absence of hyperreflective foci (HF). intact ellipsoid zone (EZ) and external limiting membrane (ELM), absence of epiretinal membrane (ERM) and absence of macular ischaemia on FFA, were associated with a better response to intravitreal treatment at 12 months [52]. Mean central retinal thickness (CRT) decreased from 554.3 μm (603.1 μm for CRVO and 496.7 μm for BRVO) to 314.4 μm after 2 years, and to CRT for CRVOs was 254.2μm (for CRVO) and to 147.8 μm for BRVO after 5 years. A formal comparison between drugs was not performed, however available data at 5 years show that most patients were receiving mixed treatment [53].

Most of the guidelines show enough evidence to recommend anti-VEGF as first line treatment and intravitreal steroids as second-line treatment. A recent meta-analysis reported that BVCA improved from baseline to 2 years, 3 years (with a decline for CRVO) and 5 years (for both BRVO and CRVO) [49] with anti-VGEF or Dexamethasone. Treat and extend is a viable regimen for the treatment of macular oedema (MO) secondary to RVO [54]. In some reports, there’s no significant difference between treat and extend with monthly and PRN treatment, but treat and extend had significant increase of injection frequency compared with PRN and fewer injections compared with monthly [55]. Even when Bevacizumab is not approved for the treatment of MO in RVO, several studies show that in the real-world setting, Bevacizumab can be effective at improving vision in patients with MO secondary to RVO [56]. There are no available clinical trials (head-to-head trials) to clearly state the best treatment for RVO patients. Some economic studies show better cost-effectiveness for Ranibizumab compared with Aflibercept [57]; however, network meta-analysis showed slightly better visual outcomes for Aflibercept compared with Ranibizumab [58], while others show no difference between available anti-VEGF in efficacy [59–61] or in IOP [62]. Recently anti-VEGF available like Faricimab is being evaluated in RVO (BALATON and COMINO clinical trials) [63], or Brolucizumab in some available case reports [64].

Comparing new anti-VEGF with Dexamethasone, there’s not enough evidence to conclude which of them is better (in terms of VA and adverse effects) for the treatment of MO [65], or if combination therapy has the better safety profile compared with steroids alone [66]. A recent meta-analysis showed that combination therapy with intravitreal anti-VEGF and steroid (intravitreal/subtenon triamcinolone or dexamethasone implant) has a slightly better effect on improving BCVA in cases with BRVO or CRVO at 6 months compared to monotherapy [67]. Network meta-analysis showed that anti-VEGF (Aflibercept and Ranibizumab) were superior to Dexamethasone for the treatment of MO associated with CRVO [58, 68–70]. Other studies reported that Dexamethasone intravitreal has better efficacy than anti-VEGF in the treatment of MO associated with RVO, but the safety profile (cataract development or exacerbation and high intraocular pressure) is inferior to other anti-VEGF [71]. Currently, there are no published cost-analysis of Dexamethasone compared with anti-VEGF in RVO, however available studies in Diabetic macular oedema report that when Bevacizumab is available, Dexamethasone increases economic costs [72], but in other contexts, eye care-related medical costs are lower for Dexamethasone compared with anti-VEGF [73], especially as an early switch when there is no response to anti-VEGF [74].

SERV recommends that Ranibizumab is the safer anti-VEGF in patients with an adverse cardiovascular event less than 3 months ago. Some recent studies, including MA, reported that anti-VEGF treatment for RVO doesn’t increase risk of CV events, hypertension, or arrythmias, and that comparing Aflibercept with Ranibizumab has no difference in cardiovascular events [75]. A French nationwide cohort study reported that for retinal diseases indications, Ranibizumab and Aflibercept have the same risk for myocardial infarction, stroke, or all-cause death, with a small stroke risk increase (not significant) in diabetic patients for Aflibercept [76].

Laser photocoagulation is an issue where views differ. Two meta-analyses showed no difference between the combination of intravitreal injections and retinal laser photocoagulation compared with single intravitreal injections in the treatment of MO associated with RVO, however, laser photocoagulation with intravitreal injections decrease number of intravitreal injections in patients with BRVO but not in patients with CRVO [59, 77].

Few guidelines included details about follow-up, a relevant issue, considering that most patients with RVO will continue to receive anti-VEGF 5 years after initial treatment [78]. It may be related to lower visual and anatomical gain in the real-world with anti-VEGF treatment, because of not achieving frequency of injections compared with clinical trials results [79].

A limitation of this systematic review was language inclusion criteria just for Spanish or English, however, just one guideline in another language (German) was available.

Finally, results do not show which CPG is better, but we can report that PPP has the higher score in the domain ‘Rigour of Development’, which can mean that it has a better methodological quality compared with the other CPG.

Most of the CPGs for the diagnosis and management of RVO have a low methodological quality according to the AGREE-II.

PPP has the highest score in the domain ‘Rigour of Development’; however, they do score well in the ‘clarity of presentation’ domain.

Among the CPGs evaluated, there is no clear recommendation about the type of anti-VEGF therapy to choose.

High methodological quality CPG ensure a uniform evidence-based practice, high standards of care and represent a benchmark against which standards of care can be assessed/ audited, especially in retinal diseases like RVO.

Based on CPG and the best available evidence, anti-VEGF agents should be considered as first line therapy for eyes with MO due to CRVO or BRVO; steroids as second line therapy, and laser photocoagulation to manage neovascular complications.

Summary

What was known before

• Several studies have assessed the quality of CPG in ophthalmology, however, no previous systematic review of CPG for the diagnosis and management of RVO has been published.

What this study adds

• In this systematic review, four of the five CPGs assessed scored low in domain 3 (rigour of development), and the highest score (mean 62%) was for domain 4 (clarity of presentation).

• In the meta-synthesis, anti-VEGF therapy is the first-choice therapy for macular oedema associated with RVO, but there is no clear recommendation about the type of anti-VEGF therapy to choose.

Author contributions

JGO: Conceptualisation, Validation, Formal analysis, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing. RBE: Validation, Formal analysis, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing. ISO: Validation, Formal analysis, Investigation, Data Curation, Writing - Review & Editing. HPH: Validation, Formal analysis, Investigation, Data Curation, Writing - Review & Editing. MCM: Conceptualisation, Writing - Review & Editing. CBM: Validation, Investigation, Data Curation, Writing - Review & Editing. TGO: Conceptualisation, Investigation, Writing - Review & Editing.

Funding

Self-funded.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

JGO was peer reviewer of CPG, CPG critical appraisal tools, and SR of CPG, for Annals of Internal Medicine, Journal of Evidence Based Medicine and Journal of Affective Disorders. JGO has received speaker fees from Novelty Technology Care and Angelini. JGO has received Travel and meeting support from Esteve, Bausch and Lomb, Thea, Equipsa, Alcon, Zeiss, Angelini. RBE has received Travel and meeting support from Novartis Spain, Angelini, Thea, Roche, Alcon, Esteve and AbbVie. CBM has received Travel and meeting support from Bausch. ISO, HPH, MCM, MZM and TGO have nothing to disclose.

Supplementary information

The online version contains supplementary material available at 10.1038/s41433-024-03008-1.