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Treatment and re-treatment of macular edema secondary to retinal vein occlusion

Issue: October 2013

ByAnat Loewenstein, MD

ByElad Moisseiev, MD

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Retinal vein occlusion, or RVO, is the second most common vascular retinopathy that causes visual loss, surpassed only by diabetic retinopathy.

Both branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) are often associated with macular edema, causing visual loss. The pathogenesis of macular edema in RVO is complex, and causative factors include increased hydrostatic venous pressure, inflammation, endothelial dysfunction and increased vascular permeability factors, such as VEGF. BRVO has a more favorable natural history than CRVO. Significant improvement in visual acuity occurs in many BRVO patients even without treatment, but it should be noted that spontaneous improvement better than 20/40 is not common. CRVO patients have a much higher rate of visual loss and neovascular complications.

Evolution of treatment

Until recently, treatment of macular edema in patients with RVO had been guided by the Branch Vein Occlusion Study and Central Vein Occlusion Study. According to the results of these studies, treatment included grid laser photocoagulation for BRVO, if no spontaneous regression occurred 3 months after presentation, and mere observation for CRVO. However, significant advances in the management of macular edema in RVO have been made in recent years, and the previous established guidelines for treatment are now obsolete. Several effective treatment modalities are available nowadays for macular edema secondary to RVO, and they are broadly classified into two groups: steroids and anti-VEGF agents.

Steroids

The SCORE study has demonstrated that intravitreal injection of triamcinolone acetate is superior to observation for macular edema in CRVO but not in BRVO. At 12 months, approximately 26% of RVO patients who received this treatment gained 15 letters in visual acuity. This was significantly better than observation in CRVO patients but no different than the results of observation and macular grid laser treatment in BRVO patients. Intravitreal triamcinolone was associated with relatively high rates of complications, with cataract progression documented in up to 33% of patients and IOP elevation requiring medical treatment in up to 35% of patients.

Ozurdex, an intravitreal slow-release dexamethasone implant (Allergan), has been demonstrated to be effective in the treatment of macular edema in both BRVO and CRVO in the GENEVA study and is currently approved by the U.S. Food and Drug Administration for these indications. Ozurdex’s peak effect is achieved 60 days after its injection, with about 30% of patients gaining more than 15 letters at that time. At 12 months after two injections, 40% of patients enjoyed a gain of 15 letters or more. It also has a good safety profile, and its main complications are cataract progression and transient IOP elevation.

Anti-VEGF agents

Intravitreal Lucentis (ranibizumab, Genentech/Novartis) has been shown to be an effective treatment for macular edema in both BRVO and CRVO, in the BRAVO and CRUISE studies, respectively. Twelve monthly injections resulted in a mean improvement of 18.3 letters in BRVO patients, with 60% gaining more than 15 letters. The same regimen resulted in a mean improvement of 13.9 letters in CRVO patients, with 50% gaining more than 15 letters by 12 months.

Avastin (bevacizumab, Genentech/Roche) is also commonly used off label for these indications, although it should be noted that its efficacy has not been proven in large multicenter randomized controlled studies.

The recent COPERNICUS and GALILEO studies have shown that Eylea (aflibercept, Regeneron/Bayer Healthcare) is also effective in the treatment of macular edema in CRVO. In these studies, mean visual acuity improvement after 12 months was 17 letters, with 55% to 60% of patients gaining more than 15 letters.

Initial treatment

Although many modalities have been shown to be effective in the treatment of macular edema in RVO, there are no clear guidelines for their use. The efficacy and safety studies were short term, and they did not address the issue of long-term monitoring and repeated treatment. For example, the GENEVA study was 12 months long and included up to two Ozurdex injections, and the BRAVO and CRUISE studies were 6 months long and included six ranibizumab injections. Another important point is that, as of yet, no study comparing these new agents directly to one another has been published, so their relative efficacy is unknown. Until this issue is resolved by prospective randomized controlled studies, a European consensus paper has suggested a practical algorithm for the selection of the initial therapy.

Re-treatment

There are currently no criteria for re-treatment of persistent or recurrent macular edema in RVO and no established guidelines for the monitoring and treatment of such patients. As mentioned earlier, the major studies on treatment of macular edema in RVO were focused on the short-term efficacy and safety of the new agents. However, evidence is currently being gathered on the long-term usefulness of these treatments.

The HORIZON study was an extension of the BRAVO and CRUISE trials and investigated long-term re-treatment with intravitreal ranibizumab for macular edema in RVO. Patients were treated on an as-needed basis, and the results have shown that visual acuity remained stable in BRVO but decreased in CRVO. In addition, there are smaller studies that reported long-term improvements in visual acuity with close follow-up and reinjections with ranibizumab and bevacizumab in both BRVO and CRVO.

Similarly, there is significant accumulation of evidence showing rationale for using Ozurdex for long-term re-treatment of RVO. These studies have shown good visual acuity results, with 30% to 50% of patients achieving improvement of visual acuity and presenting a good safety profile.

Future studies should evaluate the efficacy of long-term treatment with steroids and anti-VEGF agents, and establish protocols for continuous monitoring and clear indications for re-treatment. Until such guidelines are established, it is our recommendation to consider re-treatment as long as macular edema persists or no improvement in visual acuity is noted. After the initial treatment has been chosen, monitoring should be tailored for each patient according to the therapeutic agent and biologic response. For the anti-VEGF agents, after a loading phase of three injections, monitoring should be done monthly and reinjection considered if macular edema is present or visual acuity has not improved. For Ozurdex, monitoring the patient for IOP elevation should be done between 4 to 8 weeks after the injection. A repeated complete examination should be done 4 months after injection and monthly thereafter, and re-treatment should be considered if macular edema is present or visual acuity has not improved.

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• Anat Loewenstein, MD, and Elad Moisseiev, MD, can be reached at the Department of Ophthalmology, Tel Aviv Medical Center, 6 Weizmann St., Tel Aviv 64239, Israel; +972-36973408; fax: +972-36973870; email: anatlow@tasmc.health.gov.il, elad_moi@netvision.net.il.

Disclosures: Loewenstein is a consultant for Teva, Ora Bio, Novartis, Notal Vision, Lumenis, ForSight Labs, Bayer, Allergan and Alimera. Moisseiev has no relevant financial disclosures.