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Review Article

A Review of Randomized Trials of Approved Pharmaceutical Agents for Macular Edema Secondary to Retinal Vein Occlusion

Wang, Jia-Kang MD

Author Information
Asia-Pacific Journal of Ophthalmology: March/April 2016 - Volume 5 - Issue 2 - p 159-164
doi: 10.1097/APO.0000000000000168
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Abstract

Retinal vein occlusion (RVO) is a common retinal vascular disorder in which macular edema is the main cause of vision loss.1 The pathophysiology of macular edema involves both the presence of inflammation and susceptibility to angiogenic stimulation by vascular endothelial growth factor (VEGF).2,3 Intravitreal injections of anti-VEGF—including ranibizumab,4–9 bevacizumab,10,11 pegaptanib,12,13 and aflibercept14–16—have shown benefits in treating macular edema resulting from RVO. Intravitreal injections of potent anti-inflammatory agents in the form of corticosteroids, such as dexamethasone implants,17–19 triamcinolone acetonide,20 and fluocinolone acetonide implants,21 have been shown to reduce RVO-related macular edema. The US Food and Drug Administration (FDA) and the European Medicines Agency have approved the use of intravitreal dexamethasone implants, injected ranibizumab, and injected aflibercept for treating macular edema secondary to RVO. Herein, clinical outcomes assessed in randomized controlled trials of these approved pharmaceutical agents will be reviewed.

DEXAMETHASONE IMPLANT

Ozurdex (Pharm Allergan Inc, Irvine, Calif) is an intraocular implant that slowly releases dexamethasone. The implant is a capsule of polylactic-co-glycolic acid (a biodegradable copolymer) filled with 0.7 mg of dexamethasone and can be delivered into the vitreous cavity through a 22-gauge needle. The antiedematous effect of Ozurdex is apparent as early as 7 days after implantation19 and may persist as long as 4 to 6 months after a single injection.17,18

The global evaluation of implantable dexamethasone in RVO with macular edema (GENEVA) study collected 1267 patients with visual impairment due to macular edema associated with RVO and randomized them into groups receiving Ozurdex 0.7 mg, Ozurdex 0.35 mg, or sham injections.17 Visual improvement in response to a single intravitreal injection of Ozurdex 0.7 or 0.35 mg was maximal (nearly 10 letters and significantly better than the 3-letter gain in the sham group) 2 months after Ozurdex implantation, and the decrease in central retinal thickness was also significantly greater in the treatment group 90 days after Ozurdex implantation. The effect of Ozurdex diminished 6 months after the injection. From month 6 to 12, the sham group was switched to Ozurdex treatment. The maximal response also occurred 2 months after repeated injections of Ozurdex with visual gains of 10 letters18 and peak visual improvement of approximately 7 letters. For 12 months, cataract progression occurred in nearly one third of phakic eyes, and an increase in intraocular pressure by 10 mm Hg from baseline was observed in 15.4% of the study eyes 60 days after the second implant of Ozurdex 0.7 mg. The increases in intraocular pressure were usually transient and controlled with medication or observation. A laser or surgical procedure to reduce intraocular pressure was required for only 14 study eyes. A total of 17 GENEVA study patients had a mean long-term follow-up of 50.5 months.22 After the initial 12-month study period, no patient received Ozurdex injections. Comparing the initial and final visual acuity, patients with branch RVO (BRVO) but not central RVO (CRVO) improved significantly even in the absence of continuous treatment. The authors concluded that the prognosis was more favorable in patients with BRVO than CRVO and that longer duration of macular edema at the time of the first Ozurdex treatment was associated with a significantly lower likelihood of achieving clinically meaningful improvements in vision or macular thickness 6 or 12 months after treatment.23 This suggests that prompt Ozurdex treatment improves clinical outcome. The proportion of BRVO eyes with active neovascularization increased from baseline to day 180 in the sham group but stayed relatively constant in the Ozurdex-treated group of the GENEVA study.24 It is hypothesized that corticosteroids are associated with the downregulation of VEGF and the inhibition of ocular neovascularization.

An institutional trial collected 30 eyes with macular edema due to RVO and randomly assigned them to receive either combination therapy or bevacizumab monotherapy.25 All patients received intravitreal bevacizumab at baseline, followed by Ozurdex or sham injections 1 week later. In cases of anatomical deterioration, monthly bevacizumab was injected in all patients, and the combined group received a second implant at month 4 or 5. At 6 months, bevacizumab with dexamethasone implants produced greater improvements in macular thickness, and patients on this treatment required fewer bevacizumab injections compared with those on bevacizumab monotherapy.

A randomized multicenter study compared the clinical outcome of Ozurdex monotherapy and Ozurdex combined with macular grid laser in 50 patients with macular edema associated with BRVO.26 The combination of the Ozurdex implants and macular grid laser was synergistic for visual improvement and lengthened the time between Ozurdex injections.

A single-center study randomly assigned 60 eyes with macular edema secondary to CRVO to either intravitreal dexamethasone implantation or pro re nata (PRN) bevacizumab injection for 6 months.27 Both drugs provided comparable visual improvement and macular thickness reduction, but intraocular pressure was statistically higher with Ozurdex at months 3 to 6.

RANIBIZUMAB

Ranibizumab (Lucentis; Genentech, Inc, South San Francisco, Calif, and Novartis Pharma AG, Basel, Switzerland) is an antibody fragment that binds with high affinity to all forms of VEGF-A and can effectively inhibit intraocular levels of VEGF-A. The ranibizumab for the treatment of macular edema after BRVO (BRAVO) study included 397 patients with macular edema after BRVO and randomized them 1:1:1 to receive 6 intraocular ranibizumab 0.3 or 0.5 mg or sham injections.4 At month 6, ranibizumab 0.3 and 0.5 mg resulted in a mean gain of 16.6 and 18.3 letters, respectively, which was significantly better than the gain of 7.3 letters in the sham group. The decrease in central foveal thickness was also significantly greater in the treatment group than in the sham group. No significant ocular or nonocular safety events were identified. All patients, including those in the sham group, received PRN ranibizumab injections from month 6 to 12.5 The mean number of intravitreal ranibizumab injections was nearly 3 in the treatment group between month 6 and 12. At month 12, ranibizumab 0.3 and 0.5 mg resulted, respectively, in a mean gain of 16.4 and 18.3 letters, which was significantly better than the mean gain of 12.1 letters in the sham group. In the extension trial of the BRAVO trial (HORIZON), 304 patients with BRVO treated with PRN ranibizumab according to the protocol of the BRAVO study completed 2 years of follow-up.8 The mean number of intravitreal ranibizumab injections was 2.1 in the 0.5 mg ranibizumab group between month 12 and 24. At month 24, ranibizumab 0.5 mg injections resulted in a mean gain of 17.5 letters, which maintained the visual outcome noted at month 6 and 12. In the extension trial of the HORIZON study (RETAIN), 34 BRVO eyes treated with ranibizumab (according to the BRAVO study protocol) completed 4 years of follow-up.9 Half of the patients required frequent injections, and the edema in the other half resolved without further treatment. There was a trend toward more visual improvement in patients with resolved macular edema than in those with unresolved edema (ie, a gain in 25.9 vs 17.1 letters).

The ranibizumab for the treatment of macular edema after CRVO (CRUISE) study included 392 patients with macular edema after CRVO and randomized them 1:1:1 to receive 6 monthly intraocular ranibizumab injections of 0.3 or 0.5 mg or sham injections.6 At month 6, ranibizumab 0.3 and 0.5 mg resulted, respectively, in a mean gain of 12.7 and 14.9 letters, which was significantly better than the 0.8 letters in the sham group. The decrease in central foveal thickness was also significantly greater in the treatment group. No significant ocular or nonocular safety events were identified. All patients, including the sham group, received PRN ranibizumab injections from month 6 to 12.7 The mean number of intravitreal ranibizumab injections was approximately 3 to 4 between month 6 and 12. At month 12, ranibizumab 0.5 mg resulted in a gain of 16.2 letters, significantly better than the gain of 9.4 letters in the sham group. In the extension trial of the CRUISE trial (HORIZON), 304 patients with CRVO treated with PRN ranibizumab (according to the CRUISE study protocol) completed 2 years of follow-up.8 The mean number of intravitreal ranibizumab injections was 3.5 in the 0.5 mg ranibizumab group between month 12 and 24. At month 24, ranibizumab 0.5 mg injections caused a mean gain of 12.0 letters, which was inferior to the gain at month 12. Reduced follow-up (every 3 months) and fewer injections in the second year of treatment were associated with a decline in vision in eyes with CRVO. The authors recommended more frequent follow-up in the second year for macular edema after CRVO. In the RETAIN study, 32 CRVO eyes treated with ranibizumab (according to the CRUISE study protocol) completed a 4-year follow-up protocol.9 Most (56%) of the patients required frequent injections, and 44% of them had edema resolution without further treatment. Visual improvement was greater in patients with resolved macular edema than unresolved edema (25.2 vs 4.3 letters).

The retrospective analysis of the BRAVO and CRUISE studies suggested that initiating ranibizumab injection immediately after diagnosis of RVO, rather than delaying it, provides greater vision gain.28 Another analysis of the BRAVO and CRUISE studies found that nearly 70% to 80% of patients with RVO were categorized as early ranibizumab responders (ie, had central foveal thickness < 250 μm 3 months after treatment and better visual outcome at months 6 and 12 than late or incomplete responders). The BRAVO and CRUISE trials also showed that ranibizumab injections (compared with sham injections) blocked VEGF production, prevented the worsening of retinal nonperfusion, and even promoted reperfusion of the ischemic area.29 Patients with macular edema and RVO treated with ranibizumab in these 2 trials had better reading speed and self-reported visual functions at month 6 than those receiving the sham treatment.30,31

The ranibizumab dose comparison (0.5 and 2.0 mg) and the role of laser in the management of RVO (RELATE) study included 39 patients with CRVO and 42 with BRVO complicated by macular edema who were randomized into groups receiving 0.5 or 2.0 mg monthly ranibizumab for 6 months.32 Mean visual gains were nearly 12 to 15 letters in both the 0.5 and 2.0 mg groups. For CRVO but not BRVO, reduction of macular thickness was significantly greater in the 2.0 mg versus the 0.5 mg group. From month 6 to 24, subjects were rerandomized into PRN ranibizumab plus scatter and grid laser photocoagulation or ranibizumab alone. The 2-year results demonstrated no significant difference in visual improvement and macular thickness change between the group receiving ranibizumab plus laser and the one receiving ranibizumab alone. The authors concluded that there was no short-term clinically significant visual benefit from monthly ranibizumab injections of higher doses compared with standard doses in patients with macular edema resulting from RVO, but there was greater anatomical success from high-dose ranibizumab than standard-dose ranibizumab in patients with CRVO. They also found no long-term benefit in vision improvement, resolution of edema, or number of ranibizumab injections from the addition of laser treatment to ranibizumab.

The evaluating dosing regimens for treatment with intravitreal ranibizumab injections in subjects with macular edema after RVO (SHORE) study collected subjects with macular edema after RVO initially treated with monthly ranibizumab injections for 7 months.33 Thirteen patients did not meet stability criteria and received monthly injections until month 15. One hundred sixty-two patients with edema resolution were randomized into groups receiving PRN versus monthly injections from month 7 to 15. At month 15, the mean visual gains were comparable in the PRN group (+21 letters) and monthly group (+18.7 letters) and less in the nonrandomized group (+14.5 letters). Thus, PRN ranibizumab treatment was sufficient for macular edema control if edema was stabilized in patients with RVO after the initial 7 monthly injections.

A single institutional study randomized 30 patients with macular edema secondary to BRVO into the following 3 groups: group 1 received a single dose of intravitreal ranibizumab followed by grid laser treatment, group 2 received a single dose of intravitreal bevacizumab followed by grid laser treatment, and group 3 received grid laser alone.34 At month 6, 6 eyes (60%) in group 1, 4 eyes (40%) in group 2, and 2 eyes (20%) in group 3 had statistically significant gains of more than 3 lines of Snellen acuity. The authors concluded that both ranibizumab and bevacizumab combined with laser treatment resulted in better visual outcomes than grid laser alone.

The ranibizumab for BRVO-associated macular edema (RABAMES) study randomized 30 patients with macular edema after BRVO to receive grid laser or 3 monthly injections of ranibizumab or both followed by 3 months of observation.35 At month 6, mean visual changes were greater in the ranibizumab group (+17 letters) than in the combined group (+6 letters) and in the laser group (+2 letters). The results suggested that ranibizumab was superior to grid laser for improving vision in patients with macular edema associated with BRVO. Combined laser and ranibizumab neither enhanced functional and morphological improvement of ranibizumab nor did it prevent or prolong recurrence of edema.

One multicenter study randomized 36 patients with macular edema after BRVO to receive 6 monthly injections of ranibizumab and thereafter PRN injections or to receive monthly sham injections for 1 year.36 The PRN protocol was defined as ranibizumab treatments when visual loss was more than 5 letters or mean central subfield thickness increased by greater than 150 μm on optical coherence tomography from the month 5 visit. Grid laser treatment was allowed in both groups. At month 6, laser treatment was administered to more patients in the sham group (50%) than in the ranibizumab group (8.3%). At month 12, mean visual gains were greater in the ranibizumab group (+12.5 letters) than in the sham group (−1.6 letters). The authors found that compared with macular grid laser, intravitreal ranibizumab provided more significant and sustained visual and anatomic improvement in eyes with macular edema secondary to BRVO.

A single-center trial randomized 30 patients with macular edema secondary to BRVO into the following 3 groups: group 1 received grid laser treatment alone, group 2 received a single intravitreal ranibizumab injection combined with laser, and group 3 received 3 monthly ranibizumab injections combined with laser.37 At 6-month follow-up, mean visual gains were significantly better in groups 2 (+17.5 letters) and 3 (+19 letters) than in group 1 (+12 letters). The authors demonstrated greater visual and anatomical improvement after combined ranibizumab and laser than after grid laser alone. A single dose of intravitreal ranibizumab with grid laser was sufficient to control macular edema secondary to BRVO.

A multicenter trial of macular edema due to CRVO included 58 patients who were randomized into groups receiving isovolemic hemodilution with either prompt or deferred injections of ranibizumab 0.5 mg (for >2 months) and evaluated the 12-month effectiveness.38 At month 12, isovolemic hemodilution with either prompt or deferred ranibizumab treatments resulted in comparable visual gains (28.1 vs 25.2 letters). In addition, most eyes in the isovolemic hemodilution with deferred ranibizumab group needed fewer injections, and 30% of them required none. The authors concluded that initial isovolemic hemodilution may be a first treatment option for macular edema associated with CRVO in patients anxious about intraocular injection, and ranibizumab can serve as an effective adjunct.

A recent study randomized 22 patients with macular edema and nonischemic CRVO into 2 arms.39 Patients in one arm received ranibizumab and laser photocoagulation to the peripheral retinal areas of nonperfusion, whereas patients in the other arm received ranibizumab alone. All patients received 3 initial monthly ranibizumab injections followed by a PRN regimen. At month 6, more pronounced visual improvements were seen in the combined treatment group than in the ranibizumab group (median, +14 vs +6.5 letters). The authors observed that combined treatment compared with ranibizumab monotherapy led to additional visual improvement in patients with macular edema secondary to CRVO.

The comparing ranibizumab with sham in patients with macular edema secondary to CRVO (ROCC) study randomized 32 subjects to receive 3 monthly injections of ranibizumab or 3 monthly sham injections and demonstrated that 3 monthly injections of ranibizumab significantly improved vision and macular thickness.40 If macular edema persisted, patients underwent further monthly injections. At month 6, the ranibizumab group had greater mean visual gains (+12 letters) than the sham group (−1 letter) and 80% of them required more than 3 initial injections (mean, 4.3).

Three unpublished randomized studies associated with ranibizumab for macular edema secondary to RVO were identified on the Web site Clinicaltrials.gov. The efficacy and safety of ranibizumab with or without laser in comparison with laser in BRVO (BRIGHTER) study compared 0.5 mg ranibizumab using PRN dosing administered with or without adjunctive laser treatment versus macular laser alone up to 6 months in patients with macular edema in BRVO. The trial results are still pending. The efficacy and safety of ranibizumab intravitreal injections versus dexamethasone intravitreal implants in patients with BRVO (COMRADE-B) and CRVO (COMRADE-C) studies compared the efficacy of ranibizumab with that of Ozurdex for 6 months in patients with macular edema associated with BRVO and CRVO, respectively. In these studies, treatment with ranibizumab was PRN for 126 and 124 patients, and Ozurdex was administered once in the beginning for 118 and 119 cases, respectively. In the ranibizumab and Ozurdex groups at month 6, the COMRADE-B study showed mean visual gains of +14.9 and +10.1 letters and a decrease in mean central retinal thickness of 230.6 and 112.3 μm. The COMRADE-C study showed mean visual gains of +14.6 and +4.8 letters and a decrease in mean central retinal thickness of 376.7 and 168.7 μm. Because the outcomes of the COMRADE-B and C studies were not published, the statistical comparisons of visual acuity and macular thickness between groups are unknown.

AFLIBERCEPT

Aflibercept (Eylea, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, and Bayer Pharma AG, Berlin, Germany) is a decoy receptor fusion protein composed of the second domain of human VEGF receptor 1, the third domain of VEGF receptor 2, and the Fc domain of human IgG1.41 Aflibercept can downregulate VEGF-A, VEGF-B, and placental growth factor, which are synergistic for pathologic angiogenesis.42 The binding affinity of VEGF is higher for this drug than for ranibizumab and bevacizumab.43 Vascular endothelial growth factor inhibition in retinal pigment epithelium/choroid organ cultures is longer lasting for aflibercept than for the other VEGF antagonists ranibizumab and bevacizumab.44

The intravitreal aflibercept for macular edema after BRVO (VIBRANT) study, a randomized controlled trial, demonstrated the efficacy of intravitreal aflibercept 2 mg over macular grid laser treatment for 183 patients with macular edema associated with BRVO.14 The authors used monthly injections for 6 months. The 6-month results showed significantly greater vision improvement (mean gain of 17.0 vs 6.9 letters) and a more prominent decrease in macular thickness in the aflibercept group than in the laser group, without accompanying serious ocular and systemic adverse events. The authors concluded that aflibercept was superior to macular laser for managing macular edema related to BRVO.

The intravitreal aflibercept injection for macular edema secondary to CRVO (COPERNICUS and GALILEO) studies, 2 randomized controlled trials, compared the efficacy of intravitreal aflibercept 2 mg with that of sham injections for macular edema associated with CRVO.15,16 In the former study, monthly aflibercept was given to 114 patients and sham injections to 74 patients for the first 6 months.15 Visual improvement from baseline to month 6 was significantly greater in the aflibercept group (mean, +17.3 vs −4 letters). From month 6 to 24, all the patients received PRN aflibercept injections. At the end of 2 years, the aflibercept group had better results (mean, +13 vs +1.5 letters). In the latter study, 6 monthly (and then PRN) aflibercept injections were given to 106 patients and 6 monthly (and then PRN) sham injections were given to 71 patients for the first year; all patients received PRN aflibercept injections for the subsequent 6 months.16 The aflibercept group had improved vision (mean, +16.9 vs +3.8 letters at 12 months and +13.7 vs +6.2 letters at 18 months) and all groups of both studies had a prominent decrease in macular thickness. The authors concluded that aflibercept was superior to sham for managing macular edema associated with CRVO. Early aflibercept treatment can lead to superior visual improvement.

Serious ocular adverse effects, such as endophthalmitis and retinal detachment, are rarely reported in randomized trials of anti-VEGF injections for macular edema in RVO.5,7,14–16 The population-based rate of endophthalmitis after anti-VEGF injections in the United States from 2011 to 2013 was 391/740,757 (0.053%). One institution reported an incidence of 6 endophthalmitis events after ranibizumab (0.018%) and 6 endophthalmitis events after aflibercept (0.031%) per 121,285 injections.45 Endophthalmitis was found in 0% to 0.8% of patients in large-scale randomized trials of ranibizumab and aflibercept for macular edema in RVO.5,7,14–16 Rhegmatogenous retinal detachment developed in 1 eye (0.0026%) after 38,503 intravitreal ranibizumab injections were carried out in 1 Danish center and in 5 eyes (0.013%) after 35,942 anti-VEGF injections were carried out in several German centers.46,47 Rhegmatogenous retinal detachment or retinal tears were demonstrated in 0% to 1.6% of patients in anti-VEGF for RVO-related studies.5,7,14–16 Sterile intraocular inflammation (including sterile endophthalmitis) was found in 0.033% to 2.9% of patients after intravitreal anti-VEGF therapy.48 Fifty-six cases of aflibercept-related sterile inflammation were reported in the United States from 2011 to 2014.49 In most of the cases, initial visual impairment was accompanied by intraocular inflammation without prominent redness, severe pain, or hypopyon. Nearly two thirds of the patients were treated with topical corticosteroids and/or observation alone. Although vision remained overall unchanged, some patients developed permanent visual loss. Sterile intraocular inflammation was found in 0% to 2.3% of patients in randomized trials of ranibizumab and aflibercept for macular edema secondary to RVO.5,7,14–16 Other severe complications, including lens injury, macular ischemia, vitreous hemorrhage, and ocular neovascularization, were also uncommon.5,7,14–16

Although intravitreal ranibizumab and aflibercept (compared with placebo) may contribute to systemic thromboembolic events (eg, stroke and myocardial infarction), the incidence of events was as low as 1% to 2% after anti-VEGF injections50,51 in a series of more than 8000 patients with age-related macular degeneration, which was nearly equal to the incidence of thromboembolic events in the population older than 65 years. Systemic adverse effects such as thromboembolic events and gastrointestinal bleeding were uncommon, with an incidence of 0% to 0.8% in the above anti-VEGF for RVO studies.5,7,14–16

CONCLUSIONS

In summary, 3 pharmaceutical agents (dexamethasone, ranibizumab, and aflibercept) have been approved by the US FDA for treating macular edema secondary to BRVO. The results of randomized controlled trials of these pharmaceutical agents are summarized in Table 1. All of them improve vision and reduce macular thickness when compared with sham injections or macular grid laser treatment at 6- or 12-month follow-up. Prompt treatment with these agents can lead to a better outcome. Severe ocular or systemic adverse effects of anti-VEGF for macular edema after RVO are rare. Intraocular pressure elevation and cataract aggravation should be addressed after intravitreal dexamethasone implants. The antiedematous response to a single intravitreal dexamethasone implant is maximal 1 to 3 months after the injection. Protocols for aflibercept or ranibizumab injections vary. They include either 3 to 6 monthly injections as loading doses and then injections on an “as needed” basis from the beginning or according to functional and anatomical changes. Although the “treat-and-extend” regimen is frequently applied in anti-VEGF treatment for age-related macular degeneration, this protocol is not yet mentioned in randomized studies associated with anti-VEGF for RVO. Follow-up for as long as 4 years showed that frequent injections are needed in nearly half of patients with macular edema due to RVO treated with ranibizumab, and no further treatment is required in the rest. For such patients, monthly ranibizumab injections of higher doses offer no short-term benefit over standard doses. Ozurdex and ranibizumab reduce not only macular edema but also the probability of retinal ischemia and neovascularization, and Ozurdex or ranibizumab combined with macular grid laser show similar treatment effects to Ozurdex or ranibizumab monotherapy.

TABLE 1
TABLE 1:
Randomized Controlled Trials Leading to US FDA Approval for Macular Edema Secondary to RVO

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Have a vision. It is the ability to see the invisible. If you can see the invisible, you can achieve the impossible.

— Shiv Khera

Figure
Figure
Keywords:

intravitreal injection; aflibercept; ranibizumab; macular edema; branch retinal vein occlusion; Ozurdex; central retinal vein occlusion

© 2016 by Asia Pacific Academy of Ophthalmology