Ranibizumab

Ranibizumab (Lucentis, Genentech) is a humanized Fab fragment that binds and neutralizes all isoforms of VEGF-A. Ranibizumab was the first anti-VEGF agent to receive Food and Drug Administration (FDA) approval (in June 2010) for the treatment of ME secondary to BRVO.

In the BRanch Retinal Vein Occlusion (BRAVO) study ²⁴ (a phase III, multicenter, prospective clinical trial comparing the efficacy and safety of intravitreal injections of ranibizumab 0.3 mg, intravitreal injections of ranibizumab 0.5 mg, and sham injections), 397 patients with center-involved ME from a BRVO occurring within 12 months of study entry were randomized to receive monthly intraocular injections of 0.3 mg (n =134) or 0.5 mg (n =131) of ranibizumab or sham injections (n = 132). A gain of =15 Early Treatment Diabetic Retinopathy Study (ETDRS letters in best-corrected visual acuity (BCVA) at 6 months compared to baseline (the primary study endpoint) was achieved in 55.2% (0.3 mg) and 61.1% (0.5 mg) of patients in the ranibizumab groups and 28.8% in the sham group (p < 0.0001 for each ranibizumab group versus sham). There was greater resolution of ME in the ranibizumab groups compared to the sham group; central subfield thickness (CST) was reduced by 337.3 µm in the 0.3 mg group; 345.2 µm in the 0.5 mg group; and 157.7 µm in the sham group (p < 0.0001 for each ranibizumab group versus sham). Rescue grid laser therapy was performed in 18.7% of patients in the 0.3 mg ranibizumab group, 19.8% of patients in the 0.5 mg ranibizumab group, and 54.5% of patients in the sham group. After 6 months, all the patients were evaluated monthly and, if study eye Snellen equivalent BCVA was =20/40 or mean CST was =250 µm, patients received intravitreal ranibizumab; patients in the ranibizumab groups received their assigned dose and patients in the sham group received 0.5 mg of ranibizumab. Between 6 and 12 months, the vision was maintained in the ranibizumab groups, and there was substantial improvement in the sham group (an improvement in VA letter score of =15 compared to baseline was achieved in 28.8% of patients in the sham group at month 6 and in 43.9% of patients in the sham group at month 12). ²⁵ In the BRAVO study, patients in the sham group showed a substantial improvement in vision after receiving ranibizumab as needed, but their vision at month 12 was not as good as that in patients in the ranibizumab groups. ²⁵ This indicates that a delay in instituting treatment may affect the final visual gain. ²⁵

Bevacizumab

Bevacizumab (Avastin, Genentech) is a full-length humanized monoclonal antibody to VEGF-A. Although bevacizumab is not FDA approved for intravitreal use, numerous case reports and case series have reported that intravitreal bevacizumab is associated with improvement in VA and retinal thickening in eyes with ME due to BRVO. ^{26 ,​ 27 ,​ 28} Fung et al concluded that physician reporting of adverse events after intravitreal bevacizumab injections did not show an increased rate of drug-related ocular or systemic events. ²⁹ There are concerns about tolerance and tachyphylaxis with intravitreal bevacizumab therapy, which may be addressed by switching to other anti-VEGF agents. ³⁰

Aflibercept

Aflibercept (Eylea, Regeneron) is a small soluble VEGF receptor that acts as a decoy receptor binding free-VEGF. Aflibercept was approved by the FDA for treatment of ME secondary to BRVO in October 2014. ³¹ In the VIBRANT study ³¹ (a phase III, multicenter, prospective clinical trial comparing the efficacy and safety of intravitreal aflibercept with macular grid laser for treatment of ME after BRVO), 183 treatment-naive eyes with ME after BRVO of less than 12 months’ duration and BCVA between 20/40 and 20/320 Snellen equivalent were randomized to receive either intravitreal aflibercept 2 mg every 4 weeks (n = 91) from baseline to week 20 or grid laser (n = 92) at baseline with a single grid laser rescue treatment, if needed, from weeks 12 through 20. Rescue treatment criteria included (a) a >50-µm increase in central retinal thickness (CRT) compared with the lowest previous measurement; (b) presence of new or persistent cystic retinal changes, subretinal fluid, or persistent diffuse edema in the central OCT subfield; or (c) loss of =5 ETDRS letters compared with the best previous measurement because of BRVO in conjunction with any increase in CRT. If =1 rescue treatment criterion was met, eyes in the intravitreal aflibercept group received sham laser at either week 12, 16, or 20. Eyes in the laser group eligible for rescue treatment before week 24 received one additional laser treatment from week 12 to 20. A gain of =15 ETDRS letters in BCVA at 24 weeks compared to baseline (the primary study endpoint) was achieved in 52.7% of eyes in the aflibercept group compared to 26.7% in the laser group (p = 0.0003). The mean reduction in CRT at week 24 compared to baseline was 280.5 µm in the aflibercept group and 128.0 µm in the laser group (p < 0.0001). There were no cases of intraocular inflammation or endophthalmitis.

Triamcinolone Acetonide (TA)

According to a pharmacokinetics study of human nonvitrectomized eyes, a single 4 mg intravitreal injection of TA has a mean half-life of 18.6 days with measurable concentrations expected to last approximately 3 months. ³⁸ Reported side effects include cataract, increased IOP, and injection-related complications including noninfectious and infectious endophthalmitis, retinal detachment, vitreous hemorrhage, and lens injury. ^{33 ,​ 34 ,​ 35 ,​ 36 ,​ 37} The SCORE Study, a multicenter, randomized, phase III National Eye Institute–sponsored study, investigated the efficacy and safety of standard care versus intravitreal injection(s) of TA for ME secondary to BRVO and CRVO. ^{39 ,​ 40} Individuals with BRVO or CRVO with associated ME of up to 24 months’ duration and BCVA between 19 and 73 ETDRS letters (corresponding to a Snellen VA equivalent of approximately 20/40–20/400) were eligible for participation in the SCORE Study. ^{39 ,​ 40 ,​ 41} The two primary study objectives of the SCORE-BRVO trial were (1) to determine whether intravitreal TA at 1 and 4 mg doses produces greater visual benefit, with an acceptable safety profile, than grid laser (standard care), when appropriate, for the treatment of vision loss associated with ME secondary to BRVO; and (2) to compare the efficacy and safety of the 1- and 4-mg TA doses. ⁴⁰ The results of the SCORE-BRVO trial demonstrated no significant differences among the three treatment groups for a gain in VA letter score of =15 at 12 months (29, 26, and 27% in the standard care, and 1- and 4-mg TA groups, respectively). ⁴⁰ An early positive treatment response of a gain in VA letter score of =15 was observed at month 4 in the 4-mg TA group compared with the 1-mg TA and standard care groups. After month 12 and through month 36, the mean improvement from baseline VA letter score was greatest in the standard care group compared with the two TA groups. With respect to OCT-measured center point thickness, all three groups showed a decrease from baseline to month 12. Analogous to the VA results, only at month 4 did the 4-mg TA group demonstrate a greater treatment effect on center point thickness than the 1-mg TA and standard care groups; at all other times investigated (months 8–36), the standard care group demonstrated the greatest overall median decrease in center point thickness from baseline. The rates of adverse events were higher in the 4-mg TA group compared with the 1-mg and standard care groups. There was a dose-dependent higher frequency of initiating IOP-lowering medications in the TA groups (41% in 4 mg and 8% in 1 mg) compared with the standard care group (2%). The proportion of phakic eyes that had new-onset lens opacity or progression of an existing opacity through 12 months based on assessment at the clinical center was greater in the two TA groups (35% in 4 mg and 25% in 1 mg) compared with the standard care group (13%). Most cataract surgeries were performed during the second year of the study and occurred with the highest frequency in the 4-mg TA group (n = 35). The rates of adverse events with respect to cataract surgery and elevated IOP were similar between the standard care and 1 mg TA groups. Thus, the SCORE Study results, at the time of publication, supported grid laser as the standard of care for patients with decreased VA attributable to ME secondary to BRVO. ⁴⁰

Dexamethasone Implant

Dexamethasone is a glucocorticoid which is three times more potent than TA. ⁴¹ However, it is cleared rapidly from the vitreous cavity (half-life of 5.5 h) in humans. Ozurdex (Allergan) is an extended delivery bioerodable dexamethasone polylactic acid polyglycolic acid (PLGA) copolymer complex. ⁴¹ A specially designed proprietary instrument is used for the intravitreal injection of the Ozurdex dexamethasone implant, thus obviating the need for surgery. The Ozurdex dexamethasone implant is approved by the FDA for ME associated with BRVO or CRVO. ⁴² Two identical, randomized, prospective, multicenter, masked, sham-controlled, phase 3 clinical trials investigated the efficacy of the dexamethasone implant compared with sham treatment for ME associated with BRVO or CRVO. ⁴² The trials enrolled 1,267 patients aged =18 years with a BCVA between 20/50 and 20/200 secondary to ME of =300 µm in the central 1-mm macular subfield associated with either BRVO or CRVO. The study consisted of a 6-month primary phase followed by a 6-month, open-label, follow-up phase. ⁴³

In the primary phase, enrolled patients were randomized 1:1:1 to receive either a 700-µg dexamethasone implant (n = 427), a 350-µg dexamethasone implant (n = 412), or a sham injection (n = 423). Ninety-four percent of patients completed the study through day 180, and 997 patients continued in the open-label phase. One-third of patients in each group had a diagnosis of CRVO, whereas the remaining two-thirds had a diagnosis of BRVO. The duration of ME was similar among groups. Patients did not receive grid laser in the control arm. All patients were examined at baseline, and at 1, 7, 30, 60, 90, and 180 days after treatment. The primary outcome for the first 6 months was the proportion of eyes achieving at least a 15-letter VA improvement from baseline. The FDA later changed the primary outcome for the second study to be the time to reach a 15-letter improvement from baseline. Following completion of the first portion of the study, patients were eligible to have open-label retreatment with the 700-µg dexamethasone implant regardless of which initial treatment group they were in (sham, 350 µg, or 700 µg), provided that they demonstrated evidence of ME >250 µm on OCT examination and VA was worse than 20/20 at 6 months.

Both dexamethasone implant groups showed significantly greater improvement in vision than the sham treatment. The cumulative response rate was 41% in the 700-µg group, 40% in the 350-µg group, and 23% in the sham group (p < 0.001). Although the proportion of eyes achieving at least a 15-letter improvement from baseline BCVA was greater in the treatment groups at month 1 (21% in the 700-µg group vs. 18% in the 350-µg group vs. 8% in the sham group; p < 0.001) and month 3 (22% in the 700-µg group vs. 23% in the 350-µg group versus 13% in the sham group; p < 0.001), this effect was not statistically significant at month 6. The reduction in mean OCT central subfield retinal thickness was greater in the 700-µg (208 ± 201 µm) and 350-µg (177 ± 197 µm) groups than in the sham group (85 ± 173 µm) at month 3 (p < 0.001), but not statistically significant at month 6. It should be noted that 21% of BRVO and 17% of CRVO eyes required only a single treatment through 12 months. The dexamethasone implant was well tolerated and most eyes had no significant increase in IOP at the 6-month follow-up. Only 0.2% of eyes in either dexamethasone group had an IOP >35 mm Hg and 1.2% had an IOP >25 at 6 months. Overall, 29.7% of eyes were treated with IOP-lowering medication at day 90 and the IOP returned to baseline by day 180 in all groups. Five eyes (0.7%) underwent surgical intervention for IOP control, and three of these were for NVG secondary to RVO. Rates of cataract progression up to 1 year did not differ significantly among the groups. The side effect profile was similar during the 6-month open-label extension, during which all eyes received a first (in the case of sham-treated eyes) or second dexamethasone implant. In the extended follow-up, 32.8% of retreated dexamethasone 700-µg/700-µg group patients had at least a 10-mm Hg increase in IOP from baseline at some point over the 12-month period. In this retreatment group, 14 eyes underwent laser or surgery to reduce IOP. Cataracts were reported in 29.8% of phakic study eyes in the retreated dexamethasone 700-µg/700-µg group, 19.8% of the dexamethasone 350-µg/700-µg group, and 10.5% of the delayed treatment (sham/700-µg) group (p = 0.001). A total of 11 patients underwent cataract surgery. The results from these two “phase 3” trials have important clinical implications. Earlier treatment was associated with a better VA outcome across subgroups. A three-line VA gain following treatment with the 700-µg implant was seen in 48% of eyes with BRVO =90 days and in 67% of eyes with baseline BCVA worse than 55 letters in the =90-day subset. In addition, there was up to a twofold greater risk of three-line VA loss in sham-treated eyes compared with the 700-µg implant group. Risk of vision loss persisted at 12 months even after the sham group was treated with a 700-µg implant at the 6-month visit. ⁴³