OCT permits detailed assessment and quantification of the degree and type of edema and is essential to determine whether visual impairment in patients with RVO is caused by macular edema. If patients do not experience any improvement in BCVA for the initial 3-monthly assessments while on treatment, continued treatment is not recommended. The attainment of stable VA for three consecutive months while on treatment (at least three injections when treatment is initiated and a minimum of two injections if treatment is restarted) is considered sufficient for a temporary interruption of treatment. Patients should continue to undergo monthly monitoring of VA. Monthly treatment is reinitiated when a loss of VA resulting from macular edema secondary to RVO is observed. No threshold for VA loss to trigger retreatment has been defined. OCT should be performed to determine the extent of macular edema; if VA has not changed but OCT clearly shows worsening, treatment may be considered on an individual basis [27].

When treating newly diagnosed RVO, physicians should be aware of common risk factors, to follow good clinical practice and refer patients to the appropriate specialist if necessary. Physicians should be aware of signs of rubeosis during follow-up of all RVO cases, particularly CRVO. The role of anti-VEGF therapy in the prevention and management of rubeosis is still unclear and requires further study. In the BRAVO and CRUISE studies, no patients from the BRAVO and only two patients from the CRUISE study met the generally accepted definition for ischemic RVO (≥10 disc areas of capillary non-perfusion) [25, 26].

Concerning macular ischemia, physicians are generally cautious to recommend anti-VEGF therapy for patients presenting with ischemic visual loss because of the limited availability of phase III trial data in this patient population. At present, physicians should use their own judgment in patients with macular ischemia affecting the fovea as to whether any functional improvement might be achieved with anti-VEGF treatment. However, the primary endpoint data of the CRYSTAL and BRIGHTER studies provided evidence for similar functional efficacy of ranibizumab regardless of the status of macular ischemia at baseline (Ref. Mones J, ARVO 2015) (see Fig. 4). Fluorescein angiography may be performed during follow-up of these patients to evaluate any progression of ischemia, but is not considered essential [27].

The extent of peripheral ischemia in RVO may be the driving force in recurrent edema after intravitreal injections by affecting the levels of intravitreal VEGF and, in turn, modulating the severity of macular edema and its response to therapy. Surprisingly, patients with a greater extent of retinal non-perfusion on presentation were more likely to experience a greater improvement in macular edema and visual acuity in a study by Singer et al. [33]. The authors also showed that the level of non-perfusion changes dynamically in response to intravitreal anti-VEGF or dexamethasone treatment and correlates with the severity of edema and visual acuity loss.

There is still a lack of prospective, randomized head-to-head trials comparing the efficacy of ranibizumab and aflibercept and the sustained-release dexamethasone (DEX) implant in patients with RVO. A systematic literature review published by Pielen et al. compared anti-VEGF agents (ranibizumab, bevacizumab, aflibercept) versus steroids (triamcinolone and Ozurdex) for macular edema in RVO [21]. All anti-VEGF agents showed a better visual acuity gain compared to steroids at month 12. The downside was that anti-VEGF therapy requires more frequent injections (around eight injections per year, compared to two injections in the steroid group). However, IOP increase and cataract progression are significantly higher in the patients treated with steroids compared to patients treated with anti-VEGF agents. These are substantial drawbacks for using steroids to treat macular edema in RVO. On the other hand, many affected patients may already be pseudophakic, and in these, the use of intraocular steroids may be reasonable [34]. Steroids may also have a place in the treatment pathway of patients who have failed on anti-VEGF therapy. Besides, the DEX implant may also be of value in vitrectomized eyes, where anti-VEGFs have shown significantly reduced half-life compared to non-vitrectomized eyes in previous reports [35], although some authors argue there is no difference [36].

Head-to-head trials comparing different anti-VEGF drugs are available for other conditions: Two similarly designed trials compared ranibizumab and aflibercept for the treatment of exudative age-related macular degeneration (VIEW 1 and 2) [37]. Similar efficacy and safety was found in both drugs. Aflibercept, compared with ranibizumab and bevacizumab, targets a wider range of cytokines and may have a stronger binding affinity [38]. Results suggested that aflibercept would require injections only every 8 weeks, which is fewer than ranibizumab, although ranibizumab was not tested every 8 weeks in VIEW. This was reflected in the FDA Dermatologic and Ophthalmic Drugs Advisory Committee recommendation that aflibercept should be given every 2 months following three initial monthly doses in neovascular age-related macular degeneration. Aflibercept also appeared to last longer in the eye than ranibizumab [39]. Age-related macular degeneration is a more aggressive condition than RVO, and so it is unlikely that more frequent dosing would be needed in RVO. Therefore, aflibercept may be preferred because it would reduce pressure on outpatient clinics [34]. Furthermore, there is some evidence from patients with age-related macular degeneration that aflibercept may be effective in patients who have not responded to ranibizumab [40, 41]. This may be due to the higher affinity and wider number of cytokines that are targeted. There is no reason to suspect that these effects are any different for the macular edema caused by RVO. However, there is as yet no evidence as to whether ranibizumab would be effective after aflibercept has failed [34].

There is little evidence that combining grid macular laser photocoagulation with anti-VEGF treatment provides additional clinical benefit for patients with visual impairment resulting from macular edema secondary to BRVO or CRVO [27, 42]. The randomized BRIGHTER study demonstrated similar functional efficacy for ranibizumab monotherapy versus ranibizumab combined with grid laser at the 6 months primary endpoint. Grid laser may lead to a reduced need for anti-VEGF injections; however, no prospective data are available as of yet. On the other hand, it has not been proven that anti-VEGF therapy may also treat peripheral ischemia. At present, anti-VEGF therapy should therefore be considered as supplemental therapy rather than replacement therapy in such cases. Some physicians recommend focal or pan-retinal laser photocoagulation in combination with anti-VEGF therapy for the treatment of ischemic retinal areas (for peripheral ischemia, most ophthalmologists consider a degree of ischemia of five disc diameters in BRVO and ten disc diameters in CRVO as significant). The rationale for this approach is to decrease the amount of VEGF by reducing the ischemic trigger. Although this approach seems logical, recent studies showed no benefit of laser treatment or combined treatment over anti-VEGF therapy in chronic RVO cases [42]. Furthermore, laser therapy should not be performed before initiation of intravitreal therapy because this may worsen macular edema [27].