Treatment of Retinal Vein Occlusion
The first of two parts
HUSSEIN ALMUHTASEB, MD, MSC, FEBO • ANDREW LOTERY, MD, FRCOphth
Globally, an estimated 16.4 million adults are affected by retinal vein occlusion: 13.9 million by branch RVO and 2.5 million by central RVO.1 Macular edema associated with RVO causes a significant decrease in vision-related quality of life, with increased healthcare costs and resource use.2,3 Over a one-year period, between 5% and 15% of BRVO eyes developed macular edema.4 In contrast, the majority of CRVO patients have macular edema at presentation.
There are now multiple treatment options available for retinal venous occlusive disease. Thus, healthcare professionals face new challenges in deciding on the most appropriate treatment strategy for their patients. To address these challenges, this review discusses the latest clinical trials addressing treatment options for RVO-associated macular edema (Tables 1 and 2).
|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|
|GENEVA-BRVO||Dexamethasone implant, 0.35 mg and 0.7 mg||Sham, 0.7-mg implant at 6 months||830||12 months||0.7 mg||0.35 mg||Sham||0.7 mg/0.7 mg||Sham/0.7 mg||0.7 mg||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|
|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|
|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)|
|VIBRANT||Aflibercept, 2 mg||Grid-pattern laser/aflibercept (post week 24)||183||12 months||Aflibercept||Grid-pattern laser||Aflibercept||Grid-pattern laser/aflibecept||Aflibercept||Grid-pattern laser/aflibercept|
|8.7||No injections before week 24||17.1||12.2||57%||41%|
|Brighter||Ranibizumab, 0.5 mg stabilization criteria-driven PRN with/without laser||Laser||455||24 months (results at month 6)||Ranibizumab||Ranibizumab + laser||Laser||Ranibizumab||Ranibizumab + laser||Laser||Ranibizumab||Ranibizumab + laser||Laser|
|Laser in Brighter||N/A||0.8||1.2|
|MARVEL||Bevacizumab||Ranibizumab, 0.5 mg||75||6 months||3||3.2||15.6||18.1||57.80%||59.40%|
|THESE VALUES ARE NOT DIRECTLY COMPARABLE BECAUSE STUDY POPULATIONS VARIED DUE TO DIFFERENT ENTRY CRITERIA AND INDIVIDUAL STUDY DURATION; BCVA = BEST-CORRECTED VISUAL ACUITY|
|STUDY||DRUG||CONTROL||NUMBER OF EYES||DURATION||MEAN # INJECTIONS||CHANGE IN BCVA (MEAN NUMBER OF LETTERS)*||% OF EYES GAINING ≥15 LETTERS*|
|SCORE-CRVO||Triamcinolone, 1 mg and 4 mg||Observation||271||12 months||1 mg||4 mg||Observation||1 mg||4 mg||Observation||1 mg||4 mg||Observation|
|GENEVA-CRVO||Dexamethasone implant, 0.35 mg and 0.7 mg||Sham, 0.7 mg implant at 6 months||437||12 months||0.7 mg||0.35 mg||Sham||0.7 mg/0.7 mg||Sham/0.7 mg||0.7 mg||0.35 mg||Sham|
|1.86||1.85||0.83||2||-1||18% (6 months)||17% (6 months)||12% (6 months)|
|CRUISE||Ranibizumab, 0.3 mg and 0.5 mg||Sham, PRN 0.5 mg ranibizumab after week 24||392||12 months||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg|
|HORIZON-CRUISE||Ranibizumab, 0.5 mg (months 12-24)||Sham||304||24 months||3.8||3.5||2.9||12||8.2||7.6||38.60%||45.10%||38.30%|
|RETAIN-CRVO||Ranibizumab, 0.5 mg||-||32||49.7 months||4.5 (year 2), 3.6 (year 3), and 3.3 (year 4)||12.6||≥20/40; 64.3% (no edema), 27.8% (persistent edema)|
|SHORE-CRVO||Ranibizumab, 0.5 mg PRN vs monthly (months 7-15)||-||87||15 months||Monthly||PRN||Monthly||PRN||Monthly (both CRVO/BRVO)||PRN (both CRVO/BRVO)|
|COPERNICUS||Aflibercept, 2 mg||Sham, PRN aflibercept after week 24||189||12 months||2 mg||Sham||2 mg||Sham||2 mg||Sham|
|Crystal||Ranibizumab, 0.5 mg stabilization criteria-driven||Single arm||357||24 months (results at month 12)||0.5 mg 8.1||Single arm||12.3||Single arm||49.20%||Single arm|
|VALUES ARE NOT DIRECTLY COMPARABLE BECAUSE STUDY POPULATIONS VARIED DUE TO DIFFERENT ENTRY CRITERIA AND INDIVIDUAL STUDY DURATION; BCVA = BEST-CORRECTED VISUAL ACUITY|
For many years, effective treatment options for RVO were limited to observation, laser photocoagulation, or corticosteroids. The standard of care was dictated by the pivotal trials — the Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study (CVOS) — which recommended grid-pattern laser photocoagulation for perfused macular edema in eyes with BRVO and observation of the macular edema in eyes with CRVO.2,5
Sectoral or panretinal laser photocoagulation was the recommended treatment for neovascularization.3,6 Laser was also useful for reducing the risk of neovascular glaucoma, but its effectiveness for the treatment of macular edema in eyes with CRVO was not established.
Hussein Almuhtaseb, MD, MSc, FEBO, and Andrew Lotery, MD, FRCOphth, serve on the faculty of the University Hospital Southampton of the National Health Service of the United Kingdom. Neither author reports any financial interests in products mentioned in this article. Dr. Lotery can be reached via e-mail at email@example.com.
INTRAVITREAL ANTI-VEGF AGENTS
Pharmacologic therapy with intravitreal medications has significantly modified the management options for macular edema secondary to RVO. Several lines of evidence have suggested that vascular endothelial growth factor (VEGF) is a major mediator of macular edema in RVO.7-11
The ischemic retina expresses VEGF, and the severity of RVO is correlated with VEGF concentration in the vitreous. This concentration in eyes with CRVO is higher than in BRVO cases.7,12,13 Numerous studies have demonstrated the resolution of macular edema and improvement of vision in response to pharmacologic VEGF inhibition.14
Bevacizumab and RVO
Bevacizumab (Avastin, Genentech, South San Francisco, CA) is a monoclonal, humanized, full-length antibody that binds to VEGF. No drug-sponsored clinical trials were conducted to evaluate its role as a treatment option for macular edema secondary to RVO. However, much of our knowledge about VEGF inhibition in the eye is derived from the numerous studies and anecdotal reports with regard to bevacizumab, driven by the many clinicians who use this drug due to its pharmacological similarities yet economic advantages when compared with ranibizumab (Lucentis, Genentech).15
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.16-23
Ongoing Studies in CRVO
LEAVO. This is a multicenter, phase 3, double-masked, randomized, controlled noninferiority trial comparing the clinical and cost-effectiveness of intravitreal therapy with ranibizumab vs aflibercept (Eylea, Tarrytown, NY) vs bevacizumab for macular edema due to CRVO. The LEAVO study is currently ongoing in the United Kingdom with a targeted recruitment of 459 patients.
The primary objective of the study is to determine whether bevacizumab is noninferior to ranibizumab or aflibercept in treating visual impairment due to macular edema from CRVO.
The secondary objectives are to determine the differences among the three arms for changes in visual acuity at 12 months, proportions with ≥15- and ≥10-letter improvements at 12 and 24 months, proportions with ≥73 letters at 12 and 24 months, changes in central subfield thickness and macular volume on optical coherence tomography, the relative cost-effectiveness, and changes in the area of nonperfusion.
No exclusions are being made of ischemic or nonperfused eyes. The treatment regimen is a mandated course of four injections administered four weeks apart, followed by an as-needed phase guided by retreatment criteria of VA gain of 6 letters or more, VA loss of 6 letters or more associated with an increase in central subfield thickness, central subfield thickness of more than 0 µm, and central subfield thickness increase of 50 µm or more, compared to the lowest measurement.
SCORE2. The SCORE2 study is currently ongoing in the United States. With a noninferiority design, the study is comparing four weekly intravitreal bevacizumab injections with four weekly intravitreal aflibercept injections in 362 targeted participants.
The primary objective of the SCORE2 study is to determine whether the VA change at six months of bevacizumab is noninferior to aflibercept in the treatment of macular edema from CRVO. The inferiority margin is set at 5 letters.
Secondary objectives include the change in central subfield thickness between the two arms at month 6. Other than the usual parameters studied, the SCORE2 group has also set out to assess the outcomes at month 12 with regard to different dosing strategies after month 6 for participants who respond well. These different dosing regimens include randomization to continued monthly treatment or to a treat-and-extend regimen with two-week increments.
For participants who respond poorly to aflibercept after 6 months, this group will receive the intravitreal dexamethasone implant (Ozurdex, Allergan, Irvine, CA), while patients who respond poorly to bevacizumab will receive aflibercept.
With the recent literature suggesting that anti-VEGF therapy modifies the progression or even promotes retinal reperfusion in CRVO, there is an additional need to study the area of retinal nonperfusion, which is being studied in SCORE2, along with the risk of neovascular conversion.24 The cost-effectiveness of aflibercept and bevacizumab and the economic implications will also be studied in the SCORE2 study.
The results of these two large clinical trials, SCORE2 and LEAVO, will shed some light on the safety of bevacizumab. In addition, it will enhance our understanding of the relative clinical and cost-effectiveness of the various drugs that are available for macular edema secondary to CRVO.25
Ongoing Studies in BRVO
MARVEL. A randomized, single-center, masked trial called MARVEL was conducted to directly compare bevacizumab with ranibizumab for BRVO-associated macular edema.26 In this study, intravitreal injections were administered on a PRN basis. After six months, both groups had comparable best-corrected VA and central retinal thickness. The mean number of injections was 3.2 for ranibizumab and 3.0 for bevacizumab.
However, MARVEL failed to demonstrate noninferiority of bevacizumab based on a 5-letter mean difference in VA. Given the results of the study, it remains unclear whether noninferiority for functional outcomes, which were established for bevacizumab against ranibizumab for age-related macular degeneration in the CATT study,27 might also apply to eyes with BRVO.15
In the MARVEL trial,26 researchers found a mean VA difference of only -2.5 letters between bevacizumab- and ranibizumab-treated eyes but with a broad 95% confidence interval that extended from −8.0 to +5.0 letters. The broad CI resulted from a larger variance in VA changes than had been predicted a priori.26
Because the CI included the noninferiority limit (-5 letters), the researchers were unable to demonstrate the noninferiority of bevacizumab. The noninferiority analysis and its outcome in the MARVEL trial should be reviewed carefully, taking into account the small sample size of the MARVEL trial (75 patients), compared to both the CATT (1,208 patients; noninferiority limit of 5 letters) and IVAN studies (628 patients; noninferiority limit of 3.5 letters). The small sample size and the larger variance in VA changes in the MARVEL trial might explain the noninferiority analysis outcome.
In addition, despite its structural similarities to ranibizumab, bevacizumab’s systemic safety has been questioned in persons with RVO who may be more prone to systemic vascular events.15 However, Protocol T from the DRCRnet, which was a head-to-head study among bevacizumab, ranibizumab, and aflibercept for diabetic macular edema, did not demonstrate increased systemic adverse events for any of the drugs,28 nor did the CATT study highlight these concerns.27 Despite its widespread national and international use for an array of retinal conditions, bevacizumab use remains off-label.
RANIBIZUMAB AND RVO
Questions From BRAVO
The development of ranibizumab, a monoclonal Fab fragment designed for intraocular use that specifically binds to 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 The benefits of ranibizumab for eyes with RVO were generally maintained at one year, as stated in the 12-month outcome reports.31,32
However, the initial decline in BCVA after instituting PRN therapy raised questions regarding whether visual outcomes at one year could have been even better had the eyes 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.33
Patients who completed the BRAVO trial were eligible for the HORIZON open-label, multicenter extension study,34 and 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.35
The 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 curve in BCVA between months 7 and 15 in the PRN vs monthly treated eyes.36
RANIBIZUMAB IN CRVO
The efficacy of ranibizumab in eyes with CRVO was confirmed by the double-masked, multicenter, randomized, phase 3 CRUISE study.37 The benefits of ranibizumab for CRVO observed in the first six months were generally maintained at one year.
The mean changes from baseline BCVA letter score at month 6 were 12.7 and 14.9 in the 0.3-mg and 0.5-mg ranibizumab groups, respectively, and 13.9 letters in both the 0.3-mg and 0.5-mg ranibizumab groups at month 12.
HORIZON-CRVO and RETAIN-CRVO addressed the use of long-term treatment with ranibizumab. However, the SHORE-CRVO clinical trial compared ranibizumab use implementing different treatment regimens.
The BRIGHTER38 and CRYSTAL39 studies tried to address two issues. The first was to establish the efficacy of a stability-driven individualized PRN treatment regimen. The second was to evaluate the macular status at baseline (ischemic vs. nonischemic), and whether that would have implications for the anatomic or visual outcome of ranibizumab in vein occlusion patients.
BRIGHTER. In the BRIGHTER study, a 24-month, prospective, open-label, randomized, active-controlled, multicenter, phase 3b study in patients with visual impairment due to macular edema secondary to BRVO, patients were randomized 2:2:1 to receive ranibizumab (n=183), ranibizumab with laser (n=180), or laser only (n=92).38
Patients treated with ranibizumab with or without laser received a minimum of three initial monthly ranibizumab injections until VA stabilization and VA-based PRN dosing thereafter. In the ranibizumab with laser and laser-only groups, laser was performed at the investigator’s discretion at a minimum interval of four months and if VA was <79 letters.
In the recently published six-month results of BRIGHTER, ranibizumab with or without laser was superior to laser only in improving mean BCVA from baseline at month 6 (14.8 and 14.8 vs 6.0 letters; both P<.0001; primary end point met).
Patients with a shorter BRVO duration at baseline had a higher mean BCVA gain than those with a longer BRVO duration. Patients with a poor baseline VA had a better BCVA gain than those with a higher baseline VA, although final BCVA was lower in those with poor baseline VA.
In the ranibizumab with or without laser groups, the presence of some macular ischemia at baseline did not influence mean BCVA gains. There were no new ocular or nonocular safety events.38
CRYSTAL. The CRYSTAL study is a 24-month, prospective, open-label, single-arm, multicenter study to assess the efficacy and safety profile of an individualized regimen of ranibizumab 0.5 mg driven by stabilization criteria in patients with macular edema secondary to CRVO.
The treatment was initiated with monthly consecutive intravitreal ranibizumab 0.5-mg injections starting on day 1 (baseline). Per design, at least three initial injections were required (baseline, month 1, month 2) until a stable maximum VA (based on the investigator’s judgment) was observed over three consecutive visits with treatment (months 1, 2, and 3).39
Patients were treated with monthly ranibizumab 0.5-mg injections (minimum of three injections) until stable VA was maintained for 3 consecutive months. Thereafter, ranibizumab 0.5 mg was dosed as needed if monthly monitoring indicated a loss of VA resulting from disease activity.
Mean change from baseline at month 12 in BCVA (the primary end point) and safety over 12 months were examined. The efficacy of this regimen in subgroups categorized by baseline BCVA score, CRVO duration, or presence of macular ischemia (exploratory analysis) was analyzed.
Ranibizumab 0.5-mg treatment resulted in a statistically significant mean gain in BCVA from baseline at month 12 of 12.3 letters. The mean number of ranibizumab injections up to month 12 was 8.1.
At month 12, mean BCVA gains were similar with or without macular ischemia at baseline (11.6 vs 12.1 letters); the mean BCVA gain was higher with baseline CRVO duration of less than three months (13.4 letters) than with a longer duration (≥3 to <9 months, 11.1 letters; ≥9 months, 10.9 letters).
Patients with lower baseline BCVA had larger mean BCVA gains at month 12 than those with higher baseline BCVA (≤39/40-59/≥60 and 18.0/12.7/8.9 letters, respectively), although the absolute BCVA at month 12 was higher with higher baseline BCVA. No new ocular or nonocular safety events were observed.39
An individualized dosing regimen of ranibizumab 0.5 mg driven by stabilization criteria for up to 12 months resulted in significant BCVA gain in a broad population of patients with macular edema secondary to CRVO, including those with macular ischemia at baseline.
IN PART TWO
In the next issue of Retinal Physician, we will continue our update on the use of anti-VEGF agents to treat RVO. We will summarize data related to the use of aflibercept in the management of RVO. In addition, we will discuss which anti-VEGF agent to start with, when to switch between agents, and whether there is utility in using anti-VEGF therapy in combination with steroids. RP
1. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117:313-319.
2. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102:1425-14.
3. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34-41.
4. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117:1094-1101.
5. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271-282.
6. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102:1434-1444.
7. Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Vascular endothelial growth factor upregulation in human central retinal vein occlusion. Ophthalmology. 1998;105:412-416.
8. Noma H, Funatsu H, Mimura T, Harino S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor in macular edema with central retinal vein occlusion. Ophthalmology. 2009;116:87-93.
9. Noma H, Funatsu H, Yamasaki M, et al. Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion. Eye (Lond) 2008;22:42-48.
10. Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol. 2011;56:281-299.
11. Ehlers JP, Fekrat S. Differential effects of triamcinolone and bevacizumab in central retinal vein occlusion. Can J Ophthalmol. 2011;46:88-89.
12. Ehlken C, Rennel ES, Michels D, et al. Levels of VEGF but not VEGF(165b) are increased in the vitreous of patients with retinal vein occlusion. Am J Ophthalmol. 2011;152:298-303.
13. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.
14. Hahn P, Fekrat S. Best practices for treatment of retinal vein occlusion. Curr Opin Ophthalmol. 2012;23:175-181.
15. Oellers P, Grewal DS, Fekrat S. Role of aflibercept for macular edema following branch retinal vein occlusion: comparison of clinical trials. Clin Ophthalmol. 2016;10:411-418.
16. Funk M, Kriechbaum K, Prager F, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci. 2009;50:1025-1032.
17. Zhang H, Liu ZL, Sun P, Gu F. Intravitreal bevacizumab for treatment of macular edema secondary to central retinal vein occlusion: Eighteen-month results of a prospective trial. J Ocul Pharmacol Ther. 2011;27:615-621.
18. Costa RA, Jorge R, Calucci D, Melo LA Jr, Cardillo JA, Scott IU. Intravitreal bevacizumab (avastin) for central and hemicentral retinal vein occlusions: IBeVO study. Retina. 2007;27:141-149.
19. Decroos FC, Ehlers JP, Stinnett S, Fekrat S. Intravitreal bevacizumab for macular edema due to central retinal vein occlusion: perfused vs. ischemic and early vs. late treatment. Curr Eye Res. 2011;36:1164-1170.
20. Ehlers JP, Decroos FC, Fekrat S. Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. Retina. 2011;31:1856-1862.
21. Ferrara DC, Koizumi H, Spaide RF. Early bevacizumab treatment of central retinal vein occlusion. Am J Ophthalmol. 2007;144:864-871.
22. Kriechbaum K, Michels S, Prager F, et al. Intravitreal Avastin for macular oedema secondary to retinal vein occlusion: a prospective study. Br J Ophthalmol. 2008;92:518-522.
23. Pai SA, Shetty R, Vijayan PB, et al. Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion. Am J Ophthalmol. 2007;143:601-606.
24. Epstein DL, Algvere PV, von Wendt G, Seregard S, Kvanta A. Benefit from bevacizumab for macular edema in central retinal vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology. 2012;119:2587-2591.
25. Nicholson L, Sivaprasad S, Hykin P. Anti-VEGF therapy for macular edema secondary to CRVO. A review of the data and ongoing head-to-head clinical trials. Retin Physician. 2016;13(2):26-29.
26. Narayanan R, Panchal B, Das T, et al. MARVEL Study Group A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J Ophthalmol.2015;99(7):954-959.
27. Martin DF, Maguire MG, Ying GS, et al. CATT Research Group Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
28. Diabetic Retinopathy Clinical Research Network. Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-1203.
29. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther. 2008;16:791-799.
30. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102-1112
31. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118:1594-1602.
32. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118:2041-2049.
33. Grewal DS, Fekrat S. Evidence-based treatment of RVO with anti-VEGF drugs. In the second of two parts, we review the evidence for treating central RVO. Retin Physician. 2014;11(9):25-32.
34. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119:802-809
35. Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology. 2014;121:209-219.
36. Campochiaro PA, Wykoff CC, Singer M, et al. Monthly versus as-needed ranibizumab injections in patients with retinal vein occlusion: The SHORE study. Ophthalmology. 2014;121:2432-2442.
37. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1124-1133.
38. Tadayoni R, Waldstein SM, Boscia F, et al; BRIGHTER study group. Individualized stabilization criteria-driven ranibizumab versus laser in branch retinal vein occlusion: six-month results of BRIGHTER. Ophthalmology. 2016;123:1332-1344.
39. Larsen M, Waldstein SM, Boscia F, et al; CRYSTAL Study Group. Individualized ranibizumab regimen driven by stabilization criteria for central retinal vein occlusion: twelve-month results of the CRYSTAL study. Ophthalmology. 2016;123:1101-1111.