A 54-year-old black male presented with a history of decreased vision in his right eye that was associated with photopsia. Two months earlier, his best-corrected visual acuity measured 20/40 O.D.; however, it decreased to 20/100 at this visit. He had no afferent pupillary defect in either eye. His medical and ocular histories were unremarkable.
In-office blood pressure measurement was 118/74mm Hg, right arm sitting. His intraocular pressure measured 12mm Hg O.U. Dilated fundus examination revealed intraretinal and superficial hemorrhages distributed in the inferior quadrant and superior temporal arcade of the right eye that were associated with a vein occlusion (figure 1). Additionally, optical coherence tomography revealed a macular thickness of 350µm in his right eye, which contributed to the decreased visual acuity (figure 2).
So, what treatment options are available for this patient?
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1. Dilated fundus examination
revealed intraretinal and superficial hemorrhages distributed in the
inferior quadrant and superior temporal arcade of the right eye that
were associated with a vein occlusion.
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| 2. The optical coherence tomography scan indicated that our patient’s macular thickness measured 350µm in his right eye. |
CVOS and BVOS
To date, the Central Vein Occlusion Study (CVOS) and the Branch Vein Occlusion Study (BVOS) are regarded as two of the most influential analyses of management standards for patients with ME secondary to vein occlusion.1-4
Still, these studies have their limitations regarding treatment. For example, while BVOS showed that laser photocoagulation was an effective treatment for some patients who experienced ME secondary to branch retinal vein occlusion (BRVO), CVOS showed that laser photocoagulation for the treatment of ME secondary to central retinal vein occlusion (CRVO) was only moderately effective. More specifically, patients in CVOS who received laser treatment showed no statistically significant improvement in visual acuity compared to untreated patients.1
Anti-VEGF Therapy
Although vascular endothelial growth factor (VEGF) is the driving force behind angiogenesis, it also plays a role in permitting vascular permeability.5 High levels of VEGF have been found in the aqueous humor of patients with ME secondary to vein occlusion.6-8 Accordingly, patients with higher levels of VEGF often have more severe cases of ME. Therefore, anti-VEGF therapy would seem a reasonable treatment option in these cases.
Thus far, off-label use of anti-VEGF drugs has been shown to effectively target the underlying pathogenesis associated with the development of ME secondary to vein occlusion.9-11
CRUISE and BRAVO
Two recent phase III clinical trials bear this out. In both the Central Retinal Vein Occlusion (CRUISE) study and the Branch Retinal Vein Occlusion (BRAVO) study, subjects who received intravitreal injections of ranibizumab showed a statistically significant improvement in visual acuity compared to subjects in the sham group.10,11
• CRUISE. The CRUISE study was a 12-month clinical trial that evaluated the efficacy and safety of anti-VEGF injections in the treatment of macular edema secondary to CRVO. CRUISE researchers examined 392 subjects from 95 U.S. locations.
Subjects were initially randomized into a 0.3mg ranibizumab group, a 0.5mg ranibizumab group or a sham injection group. Participants received injections every month during the first six-months. During the observational period (months six to 12), the treatment groups were re-treated on an “as needed” basis, and the sham group received a single 0.5mg intravitreal injection of ranibizumab, followed by “as needed” basis treatment protocol.
The researchers began to see the initial effects of ranibizumab therapy within seven days after the first injections. At six-month follow-up, a visual acuity improvement of three or more lines was observed in 46% of the subjects in the 0.3mg ranibizumab group, 48% of the subjects in the 0.5mg ranibizumab group, and 17% of the subjects in the sham group.
Additionally, subjects in the 0.3mg ranibizumab group gained an average of 12.7 letters from baseline best-corrected visual acuity; subjects in the 0.5mg ranibizumab group exhibited gained 14.9 letters; and subjects in the sham group gained just 0.8 letters.10
Improvements were maintained in both treated groups at 12 months. Though subjects in the sham group did show some relative improvement in both visual acuity and macular thickness by month 12, the findings were not as significant as those from either treatment group.
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3. Following a single injection of
ranibizumab in our patient’s right eye, he experienced dramatic
resolution of his retinal hemorrhage and edema.
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| 4. Following treatment, our patient’s macular architecture normalized and his retinal thickness decreased to 210µm. |
• BRAVO. Like CRUISE, the BRAVO study was a 12-month clinical trial that evaluated the efficacy and safety of anti-VEGF therapy for macular edema associated with BRVO. The BRAVO researchers examined 397 subjects from 93 U.S. locations. The subjects were randomized into the same treatment groups as in the CRUISE study; however, subjects were eligible to receive rescue laser treatment during the clinical trial.
At six-month follow-up, a visual acuity improvement of three or more lines was observed in 55.2% of the subjects in the 0.3mg ranibizumab group, 61.1% of the subjects in the 0.5mg ranibizumab group, and 28.8% of the subjects in the sham group.11 Additionally, subjects in the 0.3mg ranibizumab group gained an average of 16.6 letters; subjects in the 0.5mg ranibizumab group gained 18.3 letters; and subjects in the sham group gained 7.3 letters.11
Although the effects were not permanent and the patients might require several re-injections, results from the BRAVO study showed a good safety profile. The 12-month evaluation revealed similar results to the CRUISE study.
The results from the BRAVO and CRUISE studies are encouraging because they will likely help to expand the therapeutic options for our patients as well as establish a new set of treatment protocols. The standard of care is continuing to evolve, and we must be aware of the potential ramifications of such landmark trials.
As For Our Patient...
Following a single injection of ranibizumab in our patient’s right eye, he experienced dramatic resolution of his retinal hemorrhage and edema (figure 3). Additionally, his macular architecture normalized and his retinal thickness decreased to 210µm (figure 4). And, most importantly, during the next month, his best-corrected visual acuity improved to 20/25 O.D.
1. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. Ophthalmology. 1995 Oct;102(10):1425-33.
2. The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol. 1984 Sep 15;98(3):271-82.
3. Lee HB, Pulido JS, McCannel CA, Buettner H. Role of inflammation in retinal vein occlusion. Can J Ophthalmol. 2007 Feb;42(1):131-3.
4. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133-41.
5. Derevjanik NL, Vinores SA, Xiao WH, et al. Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2462-7.
6. 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 Mar;50(3):1025-32.
7. Kinge B. A randomized study, comparing ranibizumab to sham in patients with macular edema secondary to CRVO. U.S. National Institutes of Health. Clinical Trial ID: NCT00567697. Available at: www.clinicaltrials.gov/ct2/show/NCT00567697?term=nct00567697&rank=1 (Accessed May 14, 2010).
8. Nghiem-Buffet S, Cohen SY. Retinal vein occlusion: anti-VEGF treatment. J Fr Ophtalmol. 2009 Nov;32(9):679-86.
9. Pieramici DJ, Rabena M, Castellarin AA, et al. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions. Ophthalmology. 2008 Oct;115(10):e47-54.
10. Brown DM. Safety and efficacy of intravitreal ranibizumab (Lucentis) in patients with macular edema secondary to central retinal vein occlusion. The CRUISE Study. Paper presented at The American Society of Retina Specialists Retina Congress, October 4, 2009; New York.
11. Campochiaro PA. Safety and efficacy of intravitreal ranibizumab (Lucentis) in patients with macular edema secondary to branch retinal vein occlusion. The BRAVO Study. Paper presented at The American Society of Retina Specialists Retina Congress, October 4, 2009; New York.