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  • New treatments for central retinal vein occlusion

    Retina/Vitreous
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    Central retinal vein occlusion (CRVO) is a sight-threatening condition with an annual incidence of 30,000 eyes in the United States,1 while macular edema (ME) is a frequent cause of vision loss in eyes with CRVO with limited therapeutic options.2 Until recently, there were no effective treatments to manage ME associated with CRVO, with the Central Vein Occlusion Study finding no difference in visual outcomes among patients with ME secondary to CRVO randomized to undergo grid photocoagulation or observation.3 However, over the past year, four therapeutic modalities have been reported to improve vision in patients with CRVO and supported with level 1 evidence: the dexamethasone intravitreal implant (Ozurdex, Allergan), intravitreal triamcinolone acetonide (IVTA; Trivaris, Allergan), ranibizumab (Lucentis, Genentech) and afilbercept (VEGF Trap-Eye, Regeneron, Bayer HealthCare).

    Dexamethasone implant treats for three months

    The dexamethasone intravitreal implant was approved by the U.S. Food and Drug Administration (FDA) in June 2009 for macular edema secondary to CRVO. The six-month GENEVA study Phase III trial randomized patients with either branch retinal vein occlusions (BRVOs) or CRVOs 1:1:1 to sham treatment or treatment with the 0.35 mg or 0.7 mg dexamethasone intravitreal implant. The results showed that 29 percent of patients with CRVOs treated with dexamethasone implant improved more than three lines at two months.4

    It is important to note that most patients (83 percent) had chronic macular edema (longer than 90 days). Elevated intraocular pressure (IOP) greater than 10 mmHg occurred at two months in 15 percent of patients who received the dexamethasone implant but normalized at six months. The benefits of the implant lasted for approximately three months, after which it lost its effect. These results were replicated in the six-month open-label study that followed.5

    Intravitreal triamcinolone acetonide effective with lower dose

    The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study is a randomized clinical trial that compared the efficacy and safety of two doses (1 mg and 4 mg) of preservative-free IVTA (Trivaris, Allergan) with observation among patients with macular edema secondary to nonischemic CRVO. At one year, 27 percent of those in the 1 mg IVTA group and 26 percent of those in the 4 mg IVTA group gained three lines compared with 7 percent of the observation group.6 Patients needed an average of two treatments over 12 months.

    However, elevated IOP of greater than 10 mmHg was more common at twelve months in the 4 mg IVTA group (26 percent) compared with the 1 mg IVTA group (16 percent) or observation group (2 percent). The authors concluded that CRVOs should be treated with the 1 mg IVTA dose because of the improved side effect profile yet similar efficacy compared with the 4 mg IVTA dose.

    Ranibizumab effective but requires frequent injections

    Another effective option for treating CRVOs is anti-vascular endothelial growth factor (VEGF) therapy involving ranibizumab, which was approved by the FDA in June 2010 for the management of macular edema secondary to vein occlusions. The CRUISE study, a Phase III clinical trial in which patients were randomized to 1:1:1 to either sham treatment or 0.3 mg or 0.5 mg of ranibizumab, demonstrated its effectiveness for CRVOs.

    Patients treated with ranibizumab underwent six monthly injections. At six months, 46 percent of patients who received 0.3 mg ranibizumab and 48 percent who received 0.5 mg ranibizumab gained three lines compared with 17 percent given sham injections.7 After the initial six months, patients were treated with ranibizumab as needed. The visual gains were maintained at 12 months, with patients averaging four injections from months six through eleven.8

    Studies find afilbercept effective

    Another anti-VEGF agent, afilbercept, has also been found to be effective at treating CRVOs. Regeneron intends to submit a regulatory application for U.S. marketing approval for VEGF Trap-Eye for CRVO before the end of 2011.

    In two similar phase III trials (GALILEO and COPERNICUS), patients with macular edema secondary to CRVOs were randomized 3:2 to either 2 mg afilbercept or sham treatment for six months. In the GALILEO study, 60 percent of patients who received afilbercept improved by three lines at six months compared with 22 percent who received sham injections. Similarly in the COPERNICUS study, 56 percent of patients treated with afilbercept gained three lines compared with 12 percent given sham injections.9

    Comparing and combining treatments

    The clinical studies I've described above are different in design and endpoints, making head-to-head comparisons between the various treatment modalities difficult. However, in my practice, anti-VEGF therapy is the first-line treatment for CRVOs, with its superior efficacy and benign safety profile regarding ocular hypertension and cataract formation compared to steroid options.

    The limitation of anti-VEGF therapy is the need for frequent injections, as demonstrated in the CRUISE trial in which patients received on average 10 treatments over a year. For patients unable to make frequent visits or tolerate frequent injections or who have contraindications to anti-VEGF therapy, I recommend steroids as an alternative.

    Some physicians have explored combination therapy involving anti-VEGF therapy and steroids in order to stretch out the intervals between anti-VEGF injections10 Another intriguing option involves targeted panretinal photocoagulation treatment of ischemic areas based on the rationale that decreasing the VEGF load will minimize the number of treatments. Prospective studies examining these options are under way. The ideal treatment regimen is not known and may include a combination approach to optimize outcomes.

    References

    1. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4):513-518.
    2. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997;115(4):486-491.
    3. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):1425-1433.
    4. Haller JA, Bandello F, Belfort R, Jr., et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-46.e3.
    5. Haller JA, Bandello F, Belfort R, Jr., et al. Dexamethasone Intravitreal Implant in Patients with Macular Edema Related to Branch or Central Retinal Vein Occlusion Twelve-Month Study Results. Ophthalmology. July 15, 2011 [Epub ahead of print].
    6. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114.
    7. 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(6):1124-33 e1.
    8. 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. June 27, 2011 [Epub ahead of print].
    9. Boyer D. Anti-VEGF therapy for CRVO: Copernicus Study. Paper presented at: Angiogenesis, Exudation and Degeneration 2011; Feb. 12, 2011; Miami, Fla.
    10. Singer M, Bell, DJ, Woods P. Combination therapy in retinal vein occlusion. Paper presented at: American Society of Retina Specialists. August 28 to September 1, 2010. Vancouver, British Columbia.