Evidence-based Treatment of RVO With Anti-VEGF Drugs
In the first of two parts, we cover the evidence for treating branch RVO.
DILRAJ S. GREWAL, MD • SHARON FEKRAT, MD, FACS
Each year in the United States, there are approximately 150,000 new cases of branch retinal vein occlusion and 30,000 new cases of central retinal vein occlusion.1 Globally, an estimated 16.4 million adults are affected by retinal vein occlusion: 13.9 million by BRVO and 2.5 million by CRVO.2
When one eye develops a CRVO, the estimated chance of developing a CRVO in the fellow eye is approximately 1% per year.3 Ten percent of patients with BRVO in one eye may experience an RVO of any type in the fellow eye over a three-year period.4-7
Treatment of RVO has been primarily directed at two vision-threatening sequelae — macular edema and neovascularization — rather than on the etiology of the disease itself. Macular edema associated with RVO causes a significant decrease in vision-related quality of life, with increased healthcare costs and resource use.8,9 Over a one-year period, between 5% and 15% of BRVO eyes develop macular edema.6 In contrast, the majority of CRVO patients have macular edema at presentation.
INITIAL TREATMENT STUDIES
Approximately 10 years ago, effective treatment options for RVO were limited to observation, laser photocoagulation, or corticosteroids. The standard of care had been dictated by the pivotal trials — the Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study, which recommended grid-pattern laser photocoagulation for perfused macular edema in eyes with BRVO and observation of the macular edema in eyes with CRVO.7,8 Sectoral or panretinal laser photocoagulation was the recommended treatment of neovascularization.9,10
Dilraj S. Grewal, MD, is a vitreoretinal surgery fellow and Sharon Fekrat, MD, FACS, is on the faculty of the Duke Eye Center of Duke University in Durham, NC. Neither author reports any financial interests in products mentioned in this article. Dr. Fekrat can be reached via e-mail at fekra001@mc.duke.edu. The authors acknowledge grant support from the Heed Ophthalmic Foundation in San Francisco, CA.
Such laser was useful for reducing the risk of neovascular glaucoma, but grid-pattern laser was not effective for the treatment of macular edema in eyes with CRVO. The Central Vein Occlusion Study classification of initial perfusion status as perfused (<10 disc areas of retinal capillary nonperfusion), nonperfused (≥10 disc areas), or indeterminate was used to categorize the natural history of each subtype.3
Subsequent trials, such as the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) and the Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion With Macular Edema (GENEVA) studies, evaluated the role of intravitreal corticosteroids. Triamcinolone acetonide, dexamethasone, and fluocinolone have all shown potential to reduce edema in RVO.11-13 However, the efficacy of steroids comes at the expense of elevated intraocular pressure and progression of lens opacity in some eyes.11
VEGF Enters the Picture
Evidence that VEGF plays an important role in RVO pathogenesis prompted the development of anti-VEGF agents for the treatment of RVO. Expression of VEGF mRNA is upregulated in ischemic retina,14,15 and intraocular VEGF levels correlate with the severity of ocular findings, including macular edema and neovascularization.16,17
These advances in our understanding of the pathogenesis of RVO and the role of the VEGF cascade, along with the development of intravitreal anti-VEGF pharmacotherapy, have now expanded our treatment armamentarium for RVO-associated macular edema to include pegaptanib (Macugen, Eyetech, Melville, NY), bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY).
Being distinct clinical entities, we review separately the evidence-based treatment of BRVO- and CRVO-associated macular edema with anti-VEGF drugs.
In this first part of this two-part series, we will review the data for use of these drugs in BRVO, saving our analysis of the data for CRVO for the second part.
THE ANTI-VEGF AGENTS
Bevacizumab
Much of the early work in understanding the role of anti-VEGF agents in the treatment of retinal disease comes from studies with bevacizumab. While bevacizumab is not FDA-approved for intravitreal use, there are numerous studies with level II and level III evidence demonstrating its safety and efficacy for RVO-associated macular edema.18-25
A Japanese study evaluated 105 BRVO eyes with macular edema that received intravitreal bevacizumab.26 Best-corrected visual acuity improved from 0.64±0.24 to 0.39±0.22 logMAR one month after the first injection. One year after the first injection, BCVA improved to 0.33±0.21 and remained 0.34±0.21 logMAR until two years after the first injection. Over this two-year follow-up, a mean of 3.8±1.5 injections were administered.
Russo and colleagues compared 1.25 mg bevacizumab to grid-pattern laser photocoagulation in 30 eyes with a perfused BRVO (>3 months duration) over a 12-month period.27 They found a gain of 15.5 letters in bevacizumab-treated eyes and 10 letters in grid-pattern laser-treated eyes (P<.05) achieved by a mean number of 1.7 bevacizumab injections and 1.5 grid applications.
Despite its reported efficacy and widespread use, bevacizumab remains off-label for use in eyes with vitreoretinal disease. The lack of large, randomized, controlled clinical trials limits the safety profile data for bevacizumab, and it is difficult to quantify theoretical systemic risks, such as stroke and myocardial infarction.
It is unclear whether the safety results of the Comparison of Age-related macular degeneration Treatment Trials (CATT) are generalizable to the treatment of those with RVO. In retrospective studies, the side effect profile of bevacizumab has been found to be similar to that of ranibizumab.28-33
Ranibizumab
BRAVO. The development of ranibizumab, a monoclonal Fab fragment designed for intraocular use that specifically binds all active isoforms of VEGF, made it possible to test the effect of neutralizing VEGF in eyes with RVO.29 Its efficacy in BRVO was confirmed by the double-masked, multicenter, randomized phase 3 clinical trial called BRAVO.30
BRAVO assigned 397 patients to three treatment arms: ranibizumab 0.3 mg; ranibizumab 0.5 mg; and sham for six months, followed by PRN ranibizumab 0.5 mg for all eyes until month 12. Grid-pattern laser photocoagulation was allowed as rescue therapy (in all groups) but not earlier than three months after study entry. Sixty-five percent of patients were treated within three months of the BRVO onset, with a mean of 3.5 months.
Monthly ranibizumab resulted in a gain of 16.6 (0.3 mg) and 18.3 letters (0.5 mg) compared to 7.3 letters in the sham group at six months; 55% (0.3 mg) and 61% (0.5 mg) of ranibizumab-treated eyes gained ≥15 letters, compared to 28.8% in the sham group. At month 12, mean visual improvement was 16.4 (0.3 mg) and 18.3 letters (0.5 mg) in the ranibizumab groups and 12.1 letters in the sham/0.5 mg group.
More eyes treated with ranibizumab from study entry gained ≥15 letters (56% and 60.3% for the 0.3- and 0.5-mg groups, respectively) than those with sham injections followed by ranibizumab 0.5 mg (43.9%) for months 6-12. The mean number of injections did not differ among groups (mean of 8.3, 8.4, and 9.4 injections, respectively).
The 0.3-mg and 0.5-mg treatment groups each showed a substantial decrease in mean BCVA between months 6 and 7. The benefits of ranibizumab for eyes with BRVO observed in the first six months were generally maintained at one year.31,32
However, the initial decline in BCVA after instituting PRN therapy raised questions as to whether visual outcomes at one year could have been even better if the eyes had continued to receive monthly injections over the second six months, as well as whether providing additional monthly injections before a PRN regimen could eliminate this initial loss in VA.
HORIZON. To determine the long-term effects of ranibizumab on macular edema from BRVO, patients who completed the BRAVO trial were eligible for the HORIZON open-label, multicenter extension study.33 In this trial, patients were followed quarterly for the next year, and reinjections were performed at the investigator’s discretion.
Half of the BRVO eyes had resolution of edema, and 80% achieved ≥20/40. The other 50% still required an average of three injections during the last year of follow-up, but 80% of them nevertheless achieved ≥20/40. The use of grid-pattern laser may have contributed to this visual stability because almost half enrolled in the HORIZON-BRAVO study received grid-pattern laser photocoagulation.
The mean BCVA change during the second year compared to year 1 was -2.3 letters (0.3/0.5 mg), -0.7 letters (0.5/0.5 mg), and +0.9 letters (sham/0.5 mg). The mean difference in BCVA score between baseline and month 24 was +14.9 letters, +17.5 letters, and +15.6 letters, respectively in these same groups.
Fifty percent, 60.3% and 51.5% of eyes, respectively, gained ≥ 15 letters at 12 months. The frequency of intravitreal injections was considerably lower during year 2, with eyes receiving 2.4 (0.3/0.5 mg), 2.1 (0.5/0.5 mg), and 2.0 (sham/0.5 mg) injections.
RETAIN. A cohort of patients from HORIZON continued for an additional two years in the RETAIN study, an investigator-initiated trial sponsored by the Macula Foundation and Genentech.34 The RETAIN study followed 34 BRVO patients monthly during the first year of the study and at least every three months during the second year. Reinjections were performed if any intraretinal fluid involving the fovea was identified.
With a mean follow-up of 49 months, 17 of 34 BRVO eyes (50%) had edema resolution, defined as no intraretinal fluid for ≥6 months after the last injection, which was given within two years of treatment initiation in 76% of eyes. At the last visit, 62% of eyes had improved ≥3 lines from BRAVO baseline, and 80% were ≥20/40.
Some eyes are likely to demonstrate chronic or recurrent edema that may require treatment for years.35 These eyes would be candidates for sustained delivery of a VEGF-binding protein if that were available, but we could currently make a case for a treat-and-extend protocol.
To address this question, the recent randomized, open-label, 15-month SHORE trial compared PRN and monthly 0.5 mg ranibizumab in BRVO and CRVO eyes stabilized with monthly injections.36 Two hundred two subjects received monthly ranibizumab for seven months, and those meeting stability criteria between months 7 and 14 (171, 84.7%) were randomized (1:1) to PRN treatment vs continued monthly injections. There was no difference in the slope of change in BCVA between months 7 and 15 in the PRN vs monthly treated eyes.
Compared with the BRVO eyes treated monthly, BRVO PRN patients had slightly better BCVA at month 7 and maintained that difference at month 15 (18.7 letters gained in the monthly injection group and 21 in the PRN group). These results were comparable to the 19.2-letter gain seen in the 0.5 mg ranibizumab-treated group in BRAVO.
Aflibercept
Aflibercept is a fusion protein that binds multiple isoforms of human VEGF-A and placental-derived growth factor (PDGF) with a higher affinity than either bevacizumab or ranibizumab.37,38 The aflibercept supplemental Biologics License Application for BRVO, currently under review by the FDA, was based on the positive results from the phase 3 VIBRANT trial, which was a double-masked, randomized, active-controlled study of 183 patients with macular edema following BRVO.
Patients received either aflibercept 2 mg every four weeks or grid-pattern laser treatment for 24 weeks, with the primary objective being the comparison of visual improvement at week 24. At week 24, 53% of aflibercept eyes gained ≥15 letters, compared with 27% in the laser group. In addition, aflibercept-treated eyes gained 17 letters, compared with 6.9 letters in laser-treated eyes. The study is ongoing through week 52.
Previous studies have examined anti-VEGF with laser treatment delayed for up to 90 days, but this study is the first to compare them head-to-head. The results also raise the question of combination therapy as a potential approach for BRVO, including whether grid-pattern laser can increase the interval between anti-VEGF injections while maintaining the visual gains.
Pegaptanib
Pegaptanib sodium, a 40-kDa RNA aptamer, binds to the 165 isoform of VEGF and was first approved for intravitreal therapy in wet AMD. A possible beneficial effect on visual acuity in eyes with macular edema due to BRVO was investigated.39 Fifteen subjects received 0.3 mg of intravitreal pegaptanib, and five received 1 mg of pegaptanib.
Improvement in VA was similar in both the 0.3- (14 letters) and 1-mg (13 letters) groups at week 54. Improvement in OCT thickness was also similar between the two groups. Pegaptanib has not been approved by the FDA for use in eyes with BRVO.
CORTICOSTEROIDS
Intravitreal Triamcinolone
The SCORE-BRVO trial included 411 patients and compared 1 mg and 4 mg of intravitreal triamcinolone acetonide (IVTA; Kenalog, Bristol-Myers Squibb, New York, NY) with grid-pattern laser photocoagulation in eyes with BRVO. The patients were randomly assigned to grid-pattern laser (n=137), IVTA 1 mg (n=136), or IVTA 4 mg (n=138).
The time span to treatment initiation in SCORE-BRVO was four months. Participants in the grid-pattern laser treatment group received an average of 1.5 treatments in the first 12 months of the study, and participants in the corticosteroid groups received an average of two injections in the first 12 months.
After one year, 29% in the laser treatment group, 26% in the 1-mg IVTA group, and 27% in the 4-mg IVTA group gained ≥15 letters. The mean gain in BCVA was 4 to 5 letters in all groups, which was achieved with a mean of 2.2 injections (for 1 mg of IVTA), 2.1 injections (for 4 mg of IVTA), and 1.5 applications of grid-pattern laser for the laser treatment group.
Patients who received either dose of IVTA were more likely to develop a cataract or elevated IOP than those who received laser treatment. The SCORE-BRVO trial results support grid-pattern laser as the treatment for perfused macular edema secondary to BRVO because there was a similar efficacy in all three treatment arms up to month 12, improved efficacy for laser beyond month 12, and a superior safety profile of grid-pattern laser over 1-mg and 4-mg IVTA.
Dexamethasone Implant
The GENEVA study evaluated the safety and efficacy of the intravitreal dexamethasone implant (Ozurdex, Allergan, Irvine, CA), evaluating a 0.35-mg vs a 0.7-mg implant vs sham injection in eyes with RVO. A total of 1131 patients completed the trial, 34.5% of whom had CRVO and 65.5% BRVO.
The primary outcome measurement was time to visual improvement of ≥15 letters or more, which was pooled for BRVO and CRVO patients. The subgroup analyses examining BRVO and CRVO groups separately provided the information most relevant to patient care.
In the BRVO eyes, injection of either a 0.35-mg or 0.7-mg dexamethasone implant showed no efficacy at six months. The peak effect was seen at two months, and there was a substantial drop-off between two and three months. At two months, 26% in the 0.35-mg group gained ≥15 letters, compared to 30% in the 0.7-mg group and 13% in the sham group. These numbers decreased to 23%, 24%, and 15%, respectively, at three months and to 21%, 23%, and 20% at six months.
Two hundred twenty-seven BRVO eyes were retreated with the 0.7-mg implant, and 210 eyes received delayed treatment (sham/0.7-mg group) if BCVA was <84 letters or central retinal thickness was >250 μm.
At six months, the mean gain in BCVA was 7.5 letters in the 0.7 mg/0.7 mg group and 5 letters in the sham group. The mean gain at 12 months was ~6 letters in the 0.7 mg/0.7 mg group, as well as in the sham/0.7 mg group.
The Table (pages 56 and 57) summarizes the study characteristics and visual outcomes of the BRVO trials.
| STUDY | DRUG | CONTROL | NUMBER OF EYES | DURATION | MEAN # OF INJECTIONS | CHANGE IN BCVA (MEAN NUMBER OF LETTERS)* | % OF EYES GAINING ≥15 LETTERS* | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SCORE-BRVO | Triamcinolone, 1 mg and 4 mg | Grid-pattern Laser | 411 | 12 months | 1 mg | 4 mg | Grid-pattern laser applications | 1 mg | 4 mg | Grid | 1 mg | 4 mg | Grid |
| 2.2 | 2.1 | 1.5 | +5.7 | +4 | +4.2 | 26% | 27% | 29% | |||||
| GENEVA-BRVO | Dexamethasone implant, 0.35 mg and 0.7 mg | Sham, 0.7-mg implant at 6 months | 830 | 12 months | 0.7 | 0.35 | Sham | 0.7 mg/0.7 mg | Sham/0.7 mg | 0.7mg | 0.35 mg | Sham | |
| 1.86 | 1.85 | 0.83 | ~+6 | ~+6 | 23% (6 months) | 21% (6 months) | 20% (6 months) | ||||||
| BRAVO | Ranibizumab, 0.3 mg and 0.5 mg | Sham (PRN 0.5 mg ranibizumab for all after 6 months, rescue grid ≥3 months) | 397 | 12 months | 0.3 mg | 0.5 mg | Sham | 0.3 mg | 0.5 mg | Sham | 0.3 mg | 0.5 mg | Sham |
| 8.3 | 8.4 | 5.7 | +16.4 | +18.3 | +12.1 | 56% | 60.3% | 43.9% | |||||
| HORIZON-BRAVO | Ranibizumab, 0.3 mg and 0.5 mg | Sham, followed by 0.5 mg PRN, grid-pattern laser | 205 | 24 months | 0.3 mg | 0.5 mg | Sham | 0.3 mg | 0.5 mg | Sham | 0.3/0.5 mg | 0.5/0.5 mg | Sham/0.5 mg |
| 2.4 | 2.1 | 2 | +14.9 | +17.5 | +15.6 | 50% | 60.3% | 51.5% | |||||
| RETAIN-BRVO | Ranibizumab; 0.5 mg | - | 34 | 49 months | 2.6 (year 2), 2.1(year 3), and 2.0 (year 4) | +20.1 | 62%; 71.3% ≥20/40 | ||||||
| SHORE-BRVO | Ranibizumab, 0.5 mg PRN vs monthly (months 7-15) | - | 115 | 15 months | Monthly | PRN | Monthly | PRN | Monthly (both CRVO and BRVO) | PRN (both CRVO and BRVO) | |||
| 7.6 | +3.8 | +18.7 | +21.0 | 66.3% | 70.7% | ||||||||
| VIBRANT | Aflibercept, 2 mg | Grid-pattern laser | 183 | 6 months | Aflibercept | Grid-pattern laser | Aflibercept | Grid-pattern laser | Aflibercept | Grid-pattern laser | |||
| 5.7 | - | +17 | +6.9 | 53% | 27% | ||||||||
| * These values are not directly comparable because study populations varied due to different entry criteria and individual study duration; BCVA = best corrected visual acuity | |||||||||||||
GRID-PATTERN LASER
Combination therapy with grid-pattern laser and anti-VEGF therapy may lessen the treatment burden and also increase efficacy in incomplete responders to anti-VEGF monotherapy. A combination of an intravitreal steroid injection with grid-pattern laser may also result in synergistic effects because such a combination targets both the inflammatory component and VEGF-related drivers of macular edema at multiple points along the pathway. However, varying results have been reported.
Pielen and colleagues40 demonstrated that 0.5 mg of ranibizumab was superior to grid-pattern laser in improving VA. Parodi and coworkers investigated subthreshold micropulse 810-nm grid-pattern laser photocoagulation in combination with 4 mg IVTA vs subthreshold grid laser photocoagulation combined with sham injection in 24 patients with BRVO.41 The mean time from symptoms to treatment was eight months (range, 3-18 months).
At 12 months, 54% of the combination group (micropulse laser and IVTA) and 38% of controls (micropulse laser with sham injection) gained ≥15 letters after a single combination treatment. Mean VA increased by 17 letters (combination group) and 6.5 letters (control group) at month 12.
SECTOR SCATTER LASER PHOTOCOAGULATION
In the era of anti-VEGF pharmacotherapy, scatter laser photocoagulation may find a niche, other than for the treatment of neovascularization, for macular edema in eyes with BRVO, because if production of VEGF by ischemic peripheral retina was contributing to recurrent and/or persistent macular edema, one would expect laser photocoagulation to the midperipheral and peripheral retina to promote resolution of edema.34
In the RETAIN study, laser photocoagulation was directed primarily to areas of retinal nonperfusion and to the far periphery, where it can be challenging to assess perfusion status. Retinal nonperfusion is not an ideal marker for retinal ischemia because hypoperfused retina may be ischemic but still appear perfused on fluorescein angiography.
Fluorescein angiograms in eyes with recurrent edema often show telangiectatic vessels in the macula that leak. Such abnormal vessels may be particularly sensitive to the leakage-promoting effects of VEGF, so that even small patches of ischemic retina in the posterior pole are sufficient to cause recurrent bouts of edema, a situation in which sector scatter photocoagulation to peripheral retina may have little effect.
CONCLUSION
In the next issue, our update on the data for the use of anti-VEGF agents to treat RVO will continue, with our specific emphasis turning to CRVO. In addition, we will offer some advice on choosing the right agent for a patient. RP
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