RVO and Macular Edema: Challenges and Opportunities

The likelihood of preserving vision increases with new treatment options.

Seenu M. Hariprasad, MD: Retinal vein occlusion (RVO) is one of the most common causes of reduced vision due to retinal vascular disease.¹ Unlike some of the other vitreoretinal conditions we encounter in our practices, RVO can affect both younger and older patients. Without timely treatment, macular edema, macular ischemia, neovascularization and other potential sequelae of RVO can lead to photoreceptor cell death, permanent cystoid and other structural changes and irreversible vision loss.

Fortunately, we have more options for treating RVO-associated macular edema today than at any time in the past. Treatments recently approved by the FDA for this indication include the VEGF inhibitor ranibizumab (Lucentis, Genentech), the VEGF and placental growth factor inhibitor aflibercept (Eylea, Regeneron Pharmaceuticals), and a dexamethasone-releasing intravitreal implant (Ozurdex, Allergan). These new treatments are enabling us to preserve vision for many RVO patients who could not have expected such favorable results just 5 or 6 years ago. However, not every treatment is effective for every patient, and whether one option is superior to another or a combination of options is superior to monotherapy have yet to be definitively determined.

Here, leading vitreoretinal specialists share their insights on these important issues. In particular, they discuss how they manage macular edema secondary to RVO that is not responding adequately to initial therapy.

One challenge we face in deciding how best to manage patients is that we still lack a complete understanding of whether inflammation or VEGF is the primary driver of macular edema associated with RVO. Based on what is currently known, and your experience, what are your thoughts on this issue?

Michael M. Singer, MD: Simplistically speaking, with RVO we have the original event and the body’s response to the event. A decrease in blood circulation and turbulent blood flow leading to thrombus formation constitute the original compressive injury. The response is capillary permeability, fluid backup and edema. Anti-VEGF agents and steroids can each be effective treatments because they stop that secondary swelling of blood vessels.

John W. Kitchens, MD: It’s clear that VEGF is a major player in most typical vein occlusions. We have seen outstanding results from the BRAVO, CRUISE, GALILEO and COPERNICUS studies, all of which evaluated anti-VEGF therapy for macular edema secondary to RVO. However, it appears that a subset of cases have an inflammatory component. We see these eyes in our practices. They may get 50% better with anti-VEGF injections, but they never get to the point of having the fluid-free, flat macula we want to see on OCT. We also see mixed cases where VEGF seems to be the main driver but inflammation results in persistent leakage.

Pravin U. Dugel, MD: It’s clear to most of us that VEGF is a very important factor in all forms of macular edema but it’s not the only factor. In any complicated physiologic process such as angiogenesis or edema, hundreds, if not thousands, of chemical factors are involved. Also, we know from anti-VEGF monotherapy studies in various diseases that permanent structural advantages are not necessarily conferred, even after months or years of treatment. We know in RVO, for instance, that when we stop treatment, fluid has a propensity to return. All of this suggests that more than VEGF is involved.

Preferences for First-Line Treatment

Dr. Hariprasad: What is your preferred first-line treatment for RVO?

Dr. Kitchens: For most of my patients I start with an anti-VEGF agent, either ranibizumab, aflibercept or bevacizumab (Avastin, Genentech). The studies have been very convincing on their effectiveness. In BRAVO,² 61% of branch retinal vein occlusion (BRVO) patients treated monthly with the 0.5-mg dose of ranibizumab gained 15 or more letters in best-corrected visual acuity (BCVA) from baseline to 6 months compared with 29% who received sham. In CRUISE,³ those results for patients with central retinal vein occlusion (CRVO) were 48% vs. 17%. Similarly, in COPERNICUS,⁴ 56% percent of CRVO patients receiving aflibercept (2 mg) monthly gained at least 15 letters of vision from baseline to 6 months compared with 12% in the sham group. In GALILEO,⁵ those results were 60% vs. 22%.

In my practice, I begin with 3 monthly anti-VEGF injections before deciding whether it’s necessary to switch directions and perhaps add a steroid or laser treatment.

Dr. Singer: Our primary goal is for patients to achieve the best vision possible, and based on the relevant clinical trials, I believe that monthly anti-VEGF injections are the best way to accomplish that.

Dr. Hariprasad: I typically have a discussion with the patient regarding the number of treatments that anti-VEGF vs. dexamethasone steroid will require in year one. I also discuss side effects and cost. Depending on our discussion, we pick either the dexamethasone implant, aflibercept or ranibizumab. I also explain to the patient that it is very likely that he or she will receive treatment with both classes of drugs during the course of therapy.

Dr. Dugel: When the macula is involved, my first-line approach are anti-VEGF agents because they tend to work well and quickly.

A Closer Look at the RVO Clinical Trials

Dr. Hariprasad: In terms of guiding first-line treatment for RVO, what do you consider important take-home points from the latest RVO clinical trials?

Dr. Singer: The BRAVO and CRUISE studies of ranibizumab showed that achieving the best possible vision in BRVO and CRVO requires monthly injections. When injections were given at longer intervals following monthly loading doses, about 20% of visual potential was left on the table. The HORIZON extension trial bore this out for CRVO in particular in that the visual gains and the reduction in OCT thickness started to slip with prn dosing.⁶

Also interesting is that in COPERNICUS and GALILEO, aflibercept provided a very good response in eyes with CRVO that were considered ischemic. While it would have been possible to exclude ischemic eyes using diagnostic parameters similar to those developed by Hayreh,⁷ that was not done in these two trials. Therefore, a fairly significant number of ischemic eyes were enrolled. For example, in GALILEO, 7% of eyes were nonperfused and 7% were only intermediately perfused. In COPERNICUS, 15% of eyes were nonperfused and 17% were intermediately perfused, and they did very well on aflibercept. In contrast, ischemic eyes were screened out of BRAVO and CRUISE for the most part, so we don’t know their response to ranibizumab.

Applying that data to my practice, I am currently evaluating whether I can replicate the aflibercept results in ischemic eyes. For non-ischemic eyes, with all else being equal, my first treatment choice is usually ranibizumab because I have more experience with it. Also, aflibercept is not yet FDA-approved for BRVO. I rarely use bevacizumab for RVO patients. In my experience, it is not effective enough. Soon I will be presenting data from a study in my practice in which both CRVO and BRVO patients did better with ranibizumab than with bevacizumab in terms of edema reduction, and twice as many ranibizumab patients had dry retinas within 2 weeks of initial injection.

The GENEVA studies, which evaluated the use of the dexamethasone intravitreal implant vs. sham for CRVO and BRVO, represent another relevant clinical trial.⁸ The steroid implant improved BCVA in both groups of patients. Top-line data from the 12-month results included that 30% of patients had achieved a gain in BCVA of 15 or more letters compared with baseline 60 days after implantation. Sixty days after receiving a second implant, 32% had achieved a BCVA gain of 15 or more letters from baseline.⁹ The steroid implant definitely has a place in the treatment of RVO patients. It can work synergistically with an anti-VEGF agent, allowing us to attack the disease from more than one angle. I personally tend to use it exclusively in combination with anti-VEGF therapy.

Dr. Kitchens: BRAVO and CRUISE demonstrated how effective anti-VEGF agents can be against RVO-associated macular edema. They set the standard for what we should expect from a treatment. They also showed that the disease responds quickly to ranibizumab injections. Most eyes gain a line or more of vision by the end of the first week therapy is initiated. The trials also reinforced that vein occlusion is a chronic disease, edema recurs and preserving vision requires repeat injections.

GALILEO AND COPERNICUS demonstrated that aflibercept is as effective as ranibizumab for macular edema secondary to RVO, so it’s nice that we have an additional option. All of us have patients who respond to one anti-VEGF agent but not another.

A main point I take from GENEVA is the dexamethasone implant has fewer side effects than intravitreal triamcinolone and we can expect it to have a positive effect for 3 or 4 months per insertion.⁸ In my experience, it is a useful option for reducing the treatment burden in patients who would otherwise require monthly anti-VEGF injections and for patients who may be refractory to all of the anti-VEGF agents.

Dr. Dugel: One key point to glean from the RVO trials is whether the treatment is steroids or an anti-VEGF drug, the sooner we start treatment, the better our results will be. This was evident in the RISE and RIDE studies of ranibizumab for diabetic macular edema (DME) as well. With delayed initiation of treatment, we may see improvement but not to the same extent as with earlier treatment. Also, what we consider good vision is not necessarily good for patients. We may measure 20/40, but that’s in the controlled, artificial setting of bright letters in a dark room. Many patients feel debilitated at 20/40.

For these reasons, I tend to treat early and with a low threshold. I don’t hesitate to start treatment for a patient with 20/40 visual acuity or even for someone who is 20/30 but has any level of macular edema. As I said, when the macula is involved, my first-line treatment is an anti-VEGF agent. In a minority of cases, that is sufficient. However, in a significant number of cases, monotherapy is not sufficient so I supplement with the dexamethasone implant. I treat the vast majority of patients with both.

We should keep in mind, too, that we can’t crosstrial compare. We have a tendency to think that because vision improved in one trial vs. another that one drug is better than the other. A look at the sham groups in the RVO trials is a good illustration of why we should not compare results. The rate of ocular serious adverse events in the CRUISE sham group was 0.78%, while the rates in the COPERNICUS and GALILEO sham groups were 13.51% and 8.45%, respectively. The rate of systemic adverse events was 0.77% in the CRUISE sham group and 2.70% in the COPERNICUS sham group. It’s clear from the sham group data that the patient populations in the trials were quite different, which highlights why results can’t be directly compared across studies.

Variation in Patient Response to Treatment

Dr. Hariprasad: At this time, we don’t have enough knowledge or the tools to predict which treatment will be most effective for each patient. Some do very well with an anti-VEGF agent but not steroids and vice versa. Also, some patients don’t respond as well as others to initial anti-VEGF therapy. What might be the reasons for this?

Dr. Singer: One theory for why some patients don’t respond as well to initial treatment is that they may have significant ischemia, much of which may be in the peripheral retina. We have only recently begun to consider the potential effects of peripheral ischemia. We use Optos wide-field fluorescein angiography (FA) in our practice now and we are working on a protocol for determining how our treatments affect ischemia. We’re finding that eyes with more edema also have more peripheral ischemia, and anti-VEGF injections decrease both, essentially restoring circulation to some areas that were ischemic. However, when the treatment wears off, the peripheral ischemia and the edema often recur.

Peter Campochiaro, MD, is conducting a study called RELATE, which is evaluating whether higher doses of anti-VEGF agents could be more effective in some patients and whether laser treatment of peripheral ischemia could reduce the need for injections. Based on his results thus far, he believes chronic edema prior to treatment and closed perifoveal capillaries in patients with BRVO may be predictors of subpar final outcomes.

Dr. Kitchens: Differences in response among patients are multifactorial. Each presents with a different degree and duration of disease. An occlusion can be acute or 6 months old. BRVO can be quadrantic or hemiretinal. Macular ischemia may be present or not, and so on. For the clinician, it is a matter of quickly determining and effectively why a particular patient is not responding adequately to first-line treatment.

Dr. Dugel: In my experience, the severity of an RVO patient’s macular edema is a good indication of whether or not anti-VEGF monotherapy will be successful. I find that patients fall into three general categories. One type presents with very little edema and good visual acuity, although they may be bothered by decreased vision. These are the patients for whom anti-VEGF monotherapy is most likely to be sufficient for controlling the disease process. They are the minority, however, in my practice. A second type has mild to moderate macular edema, which seems to make the possibility of successful monotherapy less likely. I may try anti-VEGF monotherapy in these patients, but if edema reduction is not adequate after a few monthly injections, I don’t hesitate to add the dexamethasone implant. I tell them from the start that combination therapy may be part of their treatment plan. The third type of patient, the majority in my practice, has diffuse, dense macular edema. Anti-VEGF monotherapy is rarely sufficient for such patients. Therefore, I recommend using a combination of anti-VEGF and the steroid implant from the start. In these cases, I believe the severity of their edema\stems from a large inflammatory component at the cellular level, which anti-VEGF drugs do not address.

I will mention, too, that the dexamethasone implant is a much more attractive steroid option than intravitreal triamcinolone. While triamcinolone was our only option for quite some time and did confer some benefit, delivering steroid as a large bolus that dissipates quickly is not an elegant strategy. Patients often had to deal with all of the side effects without maximizing the benefits.

Dr. Hariprasad: Near the end of last year, the FDA approved ocriplasmin (Jetrea, Thrombogenics) for the treatment of symptomatic vitreomacular adhesion (VMA). This is the first pharmacological agent to be approved for this indication. Might this be of help in treating our RVO patients?

Dr. Kitchens: One of our considerations is whether traction such as VMA could be contributing to persistent macular edema. We know that in some cases, performing a vitrectomy and peeling the internal limiting membrane provides long-term freedom from edema. We also know that surgery has not been shown to be very effective in treating macular edema due to RVO. Ocriplasmin may release traction without the need for a vitrectomy. However, like a vitrectomy, ocriplasmin may change the pharmacokinetics of drugs in the eye. I don’t think we know for sure at this time whether the change will be positive or negative. Perhaps drugs will move more quickly out of the eye, creating a need for more frequent anti-VEGF or steroid injections. On the other hand, liquefying the vitreous near the macula may facilitate delivery of drugs to that area.

Dr. Singer: Ocriplasmin will be a very valuable drug. In the clinical trial, complete release of VMA occurred in nearly 25% of eyes by 28 days after injection.¹⁰ In addition, in 40% of eyes that had small macular holes, the holes completely closed. My practice was part of the clinical studies and have already started using ocriplasmin in practice. Our early results are encouraging. I think the spectrum of indications for which it will work best will be determined over time, although the number of RVO patients who have traction or VMA is relatively small.

References

1. Laouri M, Chen E, Looman M, Gallagher M. The burden of disease of retinal vein occlusion: review of the literature. Eye 2011;25(8):981-988.

2. Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC, Murahashi WY, Rubio RG; BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117(6):1102-1112.

3. Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117(6):1124-1133.

4. Boyer D, Heier J, Brown DM, Clark WL, et al. Vascular endothelial growth factor trap-eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology 2012;119(5):1024-1032.

5. Korobelnik JF. The 6-month (primary endpoint) results of the phase 3 GALILEO study: VEGF Trap-Eye in CRVO. Presentation at the annual meeting of the American Society of Retina Specialists, Aug. 22, 2011, Boston, Mass.

6. Heier JS, Campochiaro PA, Yau L, Li Z, Saroj N, Rubio RG, Lai P. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology 2012;119(4):802-809.

7. Hayreh SS. Central retinal vein occlusion. July 15, 2010 lecture, University of Iowa Health Care, Ophthalmology and Visual Sciences. Accessed Jan. 9, 2013. Available at: http://webeye.ophth.uiowa.edu/dept/CRVO/.

8. Haller JA, Bandello F, Belfort R Jr, et al., the Ozurdex GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117(6):1134-1146.

9. Haller JA, Bandello F, Belfort R Jr, et al., the Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118(12):2453-2460.

10. Stalmans P, Benz MS, Gandorfer A, et al., the MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606-615.