Macular edema in retinal vein occlusion (RVO) is the second most common cause of vision loss due to retinal vascular disease.1-3 The two major types of RVO are branch retinal vein occlusion (BRVO) and central retina vein occlusion (CRVO). BRVO is more common than CRVO, with a 5-year incidence in 0.6% of the general population, compared with a 0.2% 5-year incidence of CRVO.3

BRVO presents with dilated and tortuous retinal venous system in a particular quadrant or hemisphere of the retina, and it is often associated with macular edema. Cotton wool spots, disc edema, and neovascularization may also be present. CRVO presents with hemorrhagic changes in all four quadrants of the retina and dilated and tortuous retinal veins, often described as a “blood and thunder” fundus. As with BRVO, associated cotton wool spots, optic disc edema, and neovascularization may also be present.

The exact pathogenesis is not known, but possible causes of RVO include external vascular compression, disease of the vein wall, or intravascular thrombus formation.1-3 Once an obstruction has occurred, increased vascular pressure behind the occlusion can cause fluid and small molecules to leak across the vascular wall and into the surrounding retinal tissue, causing macular edema. Macular edema is a common complication of RVO.4 Low-grade, chronic inflammation may also play a role in exacerbating the disease process.3,4 This includes the production of inflammatory mediators (such as prostaglandins and IL-6), increased amounts of vascular permeability factors such as vascular endothelial growth factor (VEGF),5 and may also include the loss of endothelial tight junction proteins.6

The natural history of CRVO was described first in the CVOS (Central Vein Occlusion Study), which showed that patients with perfusion who had good visual acuity at baseline, 20/40 or better, had the tendency to have better visual acuity later on.7 Patients with baseline visual acuity worse than 20/200 for example, tended not to show improvement—80% could be expected to have visual acuity of 20/200 or worse over time. Those in the intermediate category of 20/50 to 20/200 generally stayed the same or worsened. Only about 20% would improve with better visual acuity over 3 years.7 The natural history of BRVO is more variable, as shown in the BVOS (Branch Vein Occlusion Study). One-third to one-half of untreated patients can return to a visual acuity of 20/40 or better within the first 6 months, and as many as 70% of patients can gain some vision over time in the first year.8

Diagnostic evaluation of patients with RVO includes fluorescein angiography to identify areas of leakage and also to identify areas of nonperfusion. In addition, optical coherence tomography (OCT) has become an essential tool, allowing physicians to monitor macular edema, which causes swelling and visual dysfunction and can be associated with lipid exudation and hemorrhage, and the effectiveness of therapy.

CLINICAL TRIALS IN RVO

Until recently, treatments for BRVO and CRVO were primarily guided by the BVOS and CVOS, studies that were published in the 1980s and 1990s, respectively. Over the past 2 years, there have been no fewer than five randomized clinical trials evaluating the use of pharmacologic agents for RVO. The SCORE (Standardized Care vs Corticosteroid for Retinal Vein Occlusion) BRVO and CRVO studies tested the standard of care, laser photocoagulation (BRVO) or observation (CRVO), to intravitreal triamcinolone (Trivaris, Allergan Inc.) injections; the Geneva study evaluated the use of the dexamethasone intravitreal implant (Ozurdex, Allergan Inc.) vs sham for CRVO and BRVO; and BRAVO (A phase 3, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in patients with macular edema secondary to BRVO) and CRUISE (A phase 3, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in patients with macular edema secondary to CRVO) evaluated ranibizumab (Lucentis, Genentech) vs sham for BRVO and CRVO, respectively. Most recently, the Copernicus study evaluated aflibercept (VEGF Trap-Eye, Regeneron) vs sham for CRVO.

The rationale for using steroids to treat macular edema secondary to RVO is that corticosteroids provide stabilization of the blood-retinal barrier, thereby reducing macular edema. Steroids may also have an anti-angiogenic effect, reducing the vascular endothelial growth factor (VEGF) mediated increase in vascular permeability.

SCORE

SCORE compared 1 mg triamcinolone acetonide with 4 mg triamcinolone vs laser photocoagulation for BRVO and CRVO. The results of SCORE-BRVO showed that over the period of 3 years, the laser produced superior visual acuity results when compared to either 1 mg and 4 mg triamcinolone acetonide (Figure 1).9 Additionally, the safety profile of laser was better, with fewer cataracts or increased intraocular pressures (IOPs), leading to the recommendation that laser remain the standard of care for BRVO.

The results of SCORE-CRVO showed that both triamcinolone acetonide groups achieved results superior to the observation group for vision at 12 months.10 The visual benefit was enjoyed as early as 4 months and continued to 24 months (Figure 2). The 1 mg dose had a better safety profile than the 4 mg dose and therefore, the 1 mg dose was recommended over observation.

GENEVA

There are other steroids that have been explored for macular edema due to RVO. The 6-month Geneva trial compared the dexamethasone 0.7 mg or 0.35 mg intravitreal implant to sham for the treatment of macular edema following BRVO and CRVO.

The dexamethasone intravitreal implant at both doses provided a benefit to patients, and the time to a 15-letter gain was significantly shorter for patients in the dexamethasone groups than in the sham groups from day 30 through day 90, with peak efficacy of dexamethasone at day 60 (Figure 3).11 Additionally, sustained-release dexamethasone reduced the incidence of 15-letter vision loss by 50% compared with sham by day 90. The persistence of efficacy was 21% for patients with BRVO and 17% CRVO at month 12.

The incidence of adverse events was relatively low, with increased IOP being the most frequently reported (25% of patients vs 1% with sham), but this is consistent with steroid therapy.

BRAVO AND CRUISE

BRAVO was a phase 3, 6-month trial with 6 months of follow-up. Patients with BRVO were randomized to treatment with either 0.3 mg or 0.5 mg ranibizumab monthly or sham for the first 6 months and then as-needed (PRN) ranibizumab in the second 6 months, with the sham group being converted to PRN 0.5 mg ranibizumab. Rescue laser was available during the first 6 months beginning at month 3 and PRN in the second 6 months beginning at month 9.

Patients in the ranibizumab 0.5 mg group achieved a mean 18.3-letter gain at month 6, compared with 7.3 letters in the sham group, which was statistically significant (Figure 4).12 Visual acuity improvement and anatomic improvement was evident as early as day 7 for the patients treated with ranibizumab.

The horizontal and vertical OCTs of a patient from baseline to month 6 are shown in Figure 5 and are demonstrative of the typical response of patients treated with ranibizumab in BRAVO. During the 6-month period, the patient's centerpoint thickness decreased from 539 μm at baseline to 142 μm at month 6. Overall, this patient's visual acuity improved from 20/80 to 20/40.

Sixty-one percent of patients in the ranibizumab 0.5 mg group gained three or more lines of vision from baseline to month 6, compared with 29% in the sham treatment group.

Adverse events in the BRAVO study showed comparable safety side-effects and are consistent with the safety of ranibizumab for patients with AMD.

Like BRAVO, CRUISE randomized patients to either 0.3 mg or 0.5 mg ranibizumab or sham and also had a 6-month treatment period and a 6-month follow-up period with PRN dosing of ranibizumab for all groups (0.5 mg for the crossover sham group).

Patients in the 0.5 mg group achieved a 15-letter improvement at 6 months, compared with a less than 1 letter gain in the sham group (Figure 6). As with BRAVO, the change in visual acuity and anatomic improvement occurred as early as day 7 in the ranibizumab group.13

Figure 7 shows the horizontal and vertical OCTs from baseline to month 6 in a patient with CRVO treated with ranibizumab. The patient's center point thickness decreased from 695 μm at baseline to 148 μm at month 6, and the visual acuity improved from 20/100 to 20/40.

When patients in the CRUISE sham group converted over to the PRN ranibizumab phase in the second 6 months, there was some improvement in visual acuity, but the benefit was not nearly as great as it was for those patients who received ranibizumab in the first 6 months (Figure 8).

Adverse events in CRUISE were comparable between the sham and the ranibizumab groups.

COPERNICUS

Recently, the 6-month results of a trial comparing aflibercept to sham for CRVO were released. Copernicus randomized patients with CRVO to receive 2 mg aflibercept every 4 weeks vs sham.

At 6 months, 56% of patients in the aflibercept group gained three or more lines of vision compared with only 12% in the sham group.14 The mean change in visual acuity for patients in the aflibercept group was a gain of 17.3 letters at 6 months vs a loss of four letters in the sham group. There was also significant and rapid reduction in retinal thickness on OCT in the aflibercept group, whereas although there was some reduction in the sham group, it was not significant.

SUMMARY

The recent data that are available have changed our thinking about the treatment of macular edema RVO. When treating macular edema secondary to RVO, we have historically been guided by data that are decades old. It is the hope that we will soon have several treatment options at our disposal so that our patients may benefit by improved outcomes.

Allen C. Ho, MD, is a Professor of Ophthalmology at Thomas Jefferson University Retina Service and Wills Eye Hospital in Philadelphia. Dr. Ho is the Chief Medical Editor of Retina Today. Dr. Ho can be reached at acho@att.net.

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