In recent years, new treatments have emerged to address CRVO and its complications.93 The development of macular edema is the most common cause of vision loss in people with CRVO94 and is a key target for treatment. Patients have the best outcomes when they are treated within two to four weeks after CRVO is detected.95
A major development in treating vision loss in people with CRVO has been the introduction of anti-VEGF drugs, which leverage recent advances in our understanding of the different mechanisms that cause CRVO. These drugs are designed to attack specific factors that contribute to CRVO development and are improving our ability to treat this condition.
Anti-VEGF agents target and block the glycoprotein VEGF (vascular endothelial growth factor). Lower levels of VEGF in the retina decrease its effects on retinal blood vessels, reducing macular edema96 and the occurrence of other complications, such as the growth of abnormal vessels (neovascularization). Anti-VEGF agents have been effective in treating macular edema for many CRVO patients, demonstrating improved visual acuity without risk of developing other major eye conditions.97
Currently, two anti-VEGF agents are approved for treating macular edema in RVO patients:
- Eylea (Aflibercept) is approved in the United States,100 the
European Union159, select countries in South America, and Japan.160
- Lucentis (Ranibizumab) is approved in the United States161 and the European Union.
Anti-VEGF treatment is relatively safe when administered correctly by a trained retinal specialist. Discuss with your eye care specialist if anti-VEGF therapy is the best option for your condition.
Eylea (Aflibercept) is a type of anti-VEGF drug known as a fusion protein which can stabilize and even improve vision in patients with retinal disease. For CRVO patients, it is directly injected into the eye.
The pivotal phase III COPERNICUS and GALILEO studies involved nearly 360 patients with macular edema from CRVO and demonstrated that after 24 weeks of treatment, monthly injections of 2 mg of Eylea had greatly improved vision compared to patients without treatment.115 At 24 weeks, 56% of patients in the COPERNICUS116 study and 60% of patients117 in the GALILEO study gained at least 15 letters in vision (compared to 12% of patients118 without treatment in the COPERNICUS study and 22%119 of patients without treatment in the GALILEO study). Retinal thickness decreased by an average of 457.2 µm120 in the COPERNICUS study, and by an average of 448.6 µm121 in the GALILEO study (compared to a reduction of only 144.8 µm in patients without treatment in the COPERNICUS study and a reduction of only 169.3 µm123 in the GALILEO study).
These benefits were maintained in the COPERNICUS trial at 52 weeks with injections of 2 mg of Eylea given between week 24 and week 52 on an as-needed basis to both groups of patients (those who did receive treatment for the first 24 weeks and those who did not in the COPERNICUS study).124 The benefits were also maintained at 52 weeks with injections of 2 mg of Eylea given between weeks 24 and 52 in GALILEO, where only the patients in the Eylea group were treated on an as-needed basis. The need for further injections was determined by the retreatment criteria: certain changes in visual acuity or in OCT findings.125
At week 52, 55% of patients126 in the COPERNICUS study and 60% of patients127 in the GALILEO study gained at least 15 letters in visual acuity (compared to only 30%128 of control patients who began Eylea injections at week 24 on an as-needed basis in the COPERNICUS study, and 32%129 of control patients not converted to Eylea in GALILEO). Retinal thickness decreased from the initial level of thickness by an average of 413 µm (compared to a reduction of 381.8 µm in control patients who began Eylea injections at week 24) in the COPERNICUS study130, and by an average of 423.5 µm (compared to a reduction of 219.3 µm in control patients at week 24) in the GALILEO study.131
The COPERNICUS study demonstrated that injections of Eylea were still beneficial at week 100 with 49% of patients gaining at least 15 letters in visual acuity (compared to only 23% in patients who began Eylea injections at week 24 on an as-needed basis). The GALILEO study demonstrated that injections of Eylea were still beneficial at 76 weeks, with 57% of patients gaining at least 15 letters in visual acuity (compared to only 29% in patients who began Eylea injections at week 52).
Side effects were rare. The most commonly reported side effects for Eylea include conjunctival hemorrhage, eye pain, reduced visual acuity, and increased intraocular pressure.133
European Dosing Schedule:
The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres. After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month. If there is no improvement in visual and anatomic outcomes over the course of the first three injections, continued treatment is not recommended. Monthly treatment continues until visual and anatomic outcomes are stable for three monthly assessments. Thereafter the need for continued treatment should be reconsidered. If necessary, treatment may be continued with gradually increasing treatment intervals to maintain a stable visual and anatomic outcome. If treatment has been discontinued, visual and anatomic outcomes should be monitored and treatment should be resumed if these deteriorate.
Usually, monitoring should be done at the injection visits. During treatment interval extension through to completion of therapy, the monitoring schedule should be determined by the treating physician based on the individual patient’s response and may be more frequent than the schedule of injections.
American Dosing Schedule:
It is directly injected into the eye at a recommended dose of 2 mg once a month.114
Lucentis (Ranibizumab) is a type of anti-VEGF drug called a monoclonal antibody fragment that was developed to treat retinal diseases and can stabilize and even improve vision. For CRVO patients, it is injected directly into the eye.
The pivotal phase III CRUISE study involved nearly 400 patients with macular edema from CRVO and demonstrated that after 24 weeks of treatment, monthly injections of 0.5 mg of Lucentis had greatly improved vision compared to patients without treatment.104
At 24 weeks, 48% of patients had gained at least 15 letters in vision (compared to 17% in patients without treatment), and retinal thickness had reduced on average by 452 µm (compared to a reduction of only 168 µm in patients without treatment).
These benefits were maintained at 52 weeks with injections of 0.5mg of Lucentis given between weeks 24 through 52 on an as-needed basis to both groups of patients (those who did receive treatment for the first 24 weeks and those who did not).106 The need for continuous injections was determined by the retreatment criteria: poor visual acuity or changes in retinal thickness as measured by OCT.107
At 52 weeks, 51% of patients gained at least 15 letters in visual acuity (compared to only 33% of patients who began Lucentis injections at 24 weeks on an as-needed basis). Commonly reported side effects of Lucentis injections include conjunctival hemorrhage and eye pain.
European Dosing Schedule:
The recommended dose for Lucentis is 0.5 mg given monthly as a single intravitreal injection. This corresponds to an injection volume of 0.05 ml. Treatment is given monthly and continued until maximum visual acuity is achieved, i.e. the patient’s visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment. Thereafter patients should be monitored monthly for visual acuity. If there is no improvement in visual acuity over the course of the first three injections, continued treatment is not recommended.
Treatment is resumed when monitoring indicates loss of visual acuity due to macular oedema secondary to RVO. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.
American Dosing Schedule:
It is directly injected into the eye at a recommended dose of 0.5 mg once a month.103
Steroids can stabilize the vessel wall, reduce vascular permeability and inhibit VEGF-expression—a promoter of macular edema.134 135 They can be received as an intravitreal injection or through a sustained-release implant.
Intravitreal Triamcinolone Acetonide (IVTA)
IVTA has been shown to offer temporary visual improvement in CRVO patients in the short-term.136
IVTA can significantly improve visual acuity within one year in CRVO patients when compared to no treatment.137, 138 These benefits are temporary and subsequent treatment every few months may be required to maintain vision gain.139 Also, a study found that IVTA did not reduce retinal thickness in 50% of the eyes tested,140 suggesting that the benefit of IVTA may be limited.141
IVTAs may increase risk of developing cataracts or elevated intraocular pressure in some patients. Cases of retinal detachment and endophthalmitis have not been reported.142
Sustained Corticosteroid Delivery Devices
Biodegradable sustained-release devices have been designed to prolong the benefit of corticosteroid therapy, and can provide medication for up to 6 months when implanted in the vitreous cavity in the back of the eye. They were granted approval for the treatment of macular edema in CRVO in the United States and the European Union.143
In a clinical trial of CRVO patients who received dexamethasone containing implants, patients achieved a 10-letter gain 2 months after implantation, returning to baseline values at 6 months. Implants also reduced central retinal thickness144 when compared to no treatment.145
Sustained-release devices do not seem to significantly affect the chances of developing cataracts in CRVO patients,146 though phakic patients (patients with a natural lens in the eyes)147 with CRVO may develop a cataract or glaucoma.148 In some cases, ocular hypertension and retinal detachment may develop when treated with sustained-release devices. Cases of endophthalmitis have not been reported.149
Grid laser photocoagulation has not been effective in treating macular edema in CRVO patients.150 While it can reduce thickening of the macula, it does not benefit vision when compared to patients without treatment, and is therefore not recommended for CRVO patients.151
Conclusions & Future Directions
The advent of anti-VEGF therapy has shifted the approach to treating retinal disease and offers new promise for maintaining a high quality of life for CRVO patients. However, further studies are needed to better understand the benefits and limitations of anti-VEGF therapy, and clinical trials for different anti-VEGF agents are ongoing. The long-term effects of anti-VEGF agents need to be examined further.152
Therapy may evolve to reduce the frequency of injections and visits required,153 which currently presents a burden to patients and their families.154 Combination approaches for treating CRVO are likely to develop and improve patient outcomes.155 156 Factors that play a role in CRVO formation other than VEGF are potential targets for treatment and need to be studied further.157
Risk factors for CRVO have yet to be understood clearly. Understanding the role of various risk factors in CRVO development, identifying individuals with a higher risk for this condition, and treating and monitoring individual risk factors, when possible, would help to prevent the development of CRVO, its complications and vision loss.158
Pursuing these questions further holds significant promise for providing each patient with the most effective treatment and greatly improving patient outcomes and quality of life.