Research drives treatment options for macular edema secondary to retinal vein occlusion

Retinal vein occlusion is the second most common retinal vascular disease after diabetic retinopathy. Associated macular edema frequently causes vision loss and is notably difficult to treat.

Available treatment options include anti-angiogenic agents, corticosteroids, laser treatment, vitrectomy and observation. Anti-angiogenics and steroids are injected into the vitreous.

Macular edema secondary to central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) was virtually untreatable until recently, according to Francesco Bandello, MD, FEBO. 

“Generally, we had unhappy patients because the functional improvement was usually very bad,” 
Bandello said. “During these last years, the first advance was triamcinolone, steroids and the advance of anti-VEGF drugs. Then the new steroidal approaches such as Ozurdex were able to significantly modify the results of treatment. This is one of the fields where these new therapies are most effective.”

Ozurdex (dexamethasone intravitreal implant, Allergan) has received the CE mark in Europe for macular edema secondary to CRVO and BRVO. In addition, the United Kingdom’s National Institute for Health and Clinical Excellence issued final guidance recommending the implant for this indication in July 2011. The implant is the first treatment approved by the U.S. Food and Drug Administration for macular edema secondary to CRVO and BRVO.

Lucentis (ranibizumab, Genentech/Novartis) is also approved for this indication and for wet age-related macular degeneration. It has CE mark approval for diabetic macular edema, an indication recently approved by the FDA as once monthly 0.3-mg intravitreal ranibizumab. In addition, the drug has regulatory approval for treatment of diabetic macular edema in more than 75 countries, wet AMD in 100 countries and retinal vein occlusion in more than 70 countries, according a press release from Genentech.

Treatments for macular edema secondary to CRVO and BRVO also include off-label intravitreal triamcinolone acetonide and bevacizumab (Avastin, Genentech). Grid laser photocoagulation is indicated for BRVO without dense hemorrhage.

Recent research has focused on combination treatment with ranibizumab injections and the dexamethasone implant. Investigators at Wills Eye Institute in Philadelphia, U.S.A., are launching a clinical trial comparing ranibizumab monotherapy with combined ranibizumab and dexamethasone implant for macular edema secondary to CRVO or BRVO.

According to Bandello, the growth of treatment options raises the question of what the optimal treatment strategy is for each unique case.

“The main problem today, and this may be one of the most interesting aspects of this problem, is that we do not know which treatment is best for these kinds of diseases,” Bandello said. “Is it better to use steroids? Is it better to use anti-VEGF? At the moment, we do not have answers for these questions. Nobody can answer these questions in a competent way. In fact, studies will be done using anti-
VEGF vs. steroids in order to have the information that we need to answer these questions.”

The choice of treatment hinges on a clear distinction between CRVO and BRVO in terms of pathology and prognosis, Gabriel Coscas, MD, said.

“In branch retinal vein occlusion, the disease is usually more stable and there is no worsening of the situation,” he said. “And if the patient has good vision, even if he has macular edema, we could suggest observation for a few weeks. But if the vision is decreasing and the patient is symptomatic, then we could suggest treatment with intravitreal injection.”

Image-guided treatment

Advanced imaging technologies have improved disease diagnosis, tracking and treatment, according to Coscas.

Angiography provides clear images of macular perfusion and the presence of ischemia in the macula and periphery, Coscas said.

However, Bandello noted that the number of angiographies performed for retinal examination has diminished amid the burgeoning growth of optical coherence tomography.

We reserve fluorescein angiography for a small number of cases compared with what we did before,” Bandello said. “If you consider the number of angiographies we were doing some years ago, before the advent of OCT, it’s a huge reduction. Today we do hundreds of OCTs per day and we do some fluorescein angiographies. It was completely different some years ago, before OCT’s introduction.”

OCT, particularly spectral-domain OCT, helps clinicians assess fluid accumulation with a high degree of accuracy. OCT enables close observation of morphology associated with many retinal diseases.

“The results help us to know the presence or absence of not only cystoid macular edema but also subretinal fluid,” Coscas said. “In the follow-up, these data become very relevant and very important. It has been shown that if we consider treatment, we have to consider first of all the changes in vision and the presence or absence of these fluids associated or not with angiographic cystoid macular edema.”

OCT also enables clinicians to accurately target fluid accumulation with injections.

“The most important thing is that now we have some kind of parameter for the activity of the lesions, which is leakage into the retina on the basis of OCT measures,” Bandello said. “This capability to recognize the activity of the disease using this noninvasive diagnostic technique is a milestone. This milestone became more important because, as a consequence of the activity of the lesion, we are now able to do something that we were not able to do before. This is to inject patients with some new drug.”

Monotherapy vs. combination treatment

A multipronged approach to treatment is called for because retinal vascular disease has multiple contributing factors, according to Pravin U. Dugel, MD, OSN U.S. Edition Retina/Vitreous Board Member.

“It doesn’t make sense to try to solve this process by inhibiting only one factor, which is VEGF, even if it’s the most important factor,” Dugel said. “Intuitively, it would make sense that combination treatment would be most effective. That’s been shown over and over in other specialties.”

Based on clinical outcomes and early research, combination treatment is superior to other strategies, Dugel said.

“Because of better efficacy, because it makes physiologic sense … because of sustainability, I think a rational combination treatment algorithm is the only treatment model that we can sustainably adopt,” Dugel said.

A small percentage of patients respond to anti-VEGF monotherapy permanently, but macular edema persists and often recurs in the majority, Dugel said.

“In those patients, and that’s a majority of patients, combination treatment would be my next step,” he said.

Even when it proves effective, anti-VEGF monotherapy is unsustainable in the treatment of retinal vein occlusion, Dugel said.

“The question is not whether anti-VEGF monotherapy works or not. It certainly does. The question is whether anti-VEGF monotherapy is sustainable,” Dugel said.

Bandello said he uses combination therapy in eyes that do not respond to steroid or anti-VEGF injections.

“I must say that in all these cases, the results are really much better than was thought before,” Bandello said. “Unfortunately, we are using this combined approach only in the most advanced cases, where the chance to have an improvement is very low. We have anatomic responses and we have few functional responses. But I think that this approach could be very good in the most aggressive forms of retinal vein occlusion.”

Combination therapy should not be the first line of treatment for macular edema secondary to retinal vein occlusion, Coscas said.

“We do not recommend combined treatment as front line, and only with nonresponsive patients or possibly nonresponsive patients,” he said. “Usually, this is good for branch retinal vein occlusion and when the macula is well-perfused. When the macula is not well-perfused but there is still some vision and not very accentuated ischemia, we could also suggest this treatment knowing that the result could be less efficient in terms of vision.”

Combination treatment hinges on the presence, type and location of fluid, Gaurav Shah, MD, said.

“I may start with anti-VEGF therapy and then give them steroids once some of the blood has gone away,” he said. “The anti-VEGF therapy is exclusively good at getting rid of blood. Sometimes it is also good at getting rid of fluid, but steroids may be better at getting rid of fluid. If you have intraretinal fluid, that may respond better to anti-VEGF therapy. … It’s not the presence or absence of fluid. It’s really the location.”

Shah emphasized the importance of monitoring disease progression in any treatment scenario.

“You always have to re-evaluate, retest and see exactly what you are treating,” Shah said.

Laser photocoagulation

The role of grid laser photocoagulation has diminished in recent years, except in cases involving retinal ischemia and potential neovascular glaucoma, Bandello said.

“The number of patients I’m now treating with laser for retinal vein occlusion is very small,” he said.

Laser treatment may be considered in cases of BRVO involving peripheral ischemia, Coscas said.

“If there is extensive ischemia, we have to consider laser treatment in the periphery guided by the angiograms in order to avoid this, based on the idea that this ischemia could induce accentuated expression of VEGF and could accentuate the macular edema,” he said.

In CRVO, laser treatment may be suggested after patients have received multiple steroid or anti-VEGF injections over a 1- or 2-year period, Coscas said.

“For these patients, after 1 or 2 years the macular edema will have regressed and will always be less accentuated,” he said. “We could suggest grid laser in the area of the macular edema to stop the disease and to allow the patient to have less treatment and less frequent visits for follow-up.”

Dugel said he would consider using a dexamethasone implant instead of laser photocoagulation in cases of BRVO and diffuse macular edema with hemorrhage and involvement of the fovea. A similar strategy may apply to CRVO but without laser photocoagulation as an option, he said.

Sustained drug delivery

The dexamethasone implant, which is made of a solid biodegradable polymer, is the ideal drug delivery medium for retinal vein occlusion because it is minimally invasive and enables sustained but tapered drug delivery, Dugel said.

"Because it’s biodegradable, cavitations form around the entire implant," he said. "After a few days and certainly a few weeks, these cavitations dramatically increase the surface area. So, what you do get is sort of a pulse response not dissimilar to an injection but much more tapered. An initial pulse is then followed by a very gradual decline over a period of 2 or 3 months. That’s the pharmacokinetic profile of Ozurdex."

In a recent study, Shah and colleagues reported that the implant provided a rapid and sustained therapeutic effect in eyes that responded to treatment.

"We found that eyes that responded after their first Ozurdex injections after anti-VEGF therapy continued to respond to subsequent Ozurdex therapy," he said. "We learned something very important: If you’re going to respond, you’re going to respond fairly quickly and you’re going to continue to respond." – by Matt Hasson

References:

Brown DM, Campochiaro PA. Singh RP. Ranibizumab for macular edema following central retinal vein occlusion. Ophthalmology. 2010;117(6):1124-1133.

Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion. Ophthalmology. 2010;117(6):1102-1112.

Chan A. Leung S, Blumenkranz MS. Critical appraisal of the clinical utility of the dexamethasone intravitreal implant (Ozurdex) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion. Clin Ophthalmol. 2011;5:1043-1049.

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

For more information:

Haller JA, Lally D, London N. Ozurdex with rescue Lucentis for treating macular edema secondary to retinal vein occlusion. http://www.clinicaltrials.gov/ct2/show/NCT01581151?term=NCT+01581151&rank=1. Accessed August 23, 2012.

Shah G. Anatomic outcomes following Ozurdex injections. http://www.clinicaltrials.gov/ct2/show/NCT01282411?term=01282411&rank=1. Accessed August 23, 2012.

Francesco Bandello, MD, FEBO, can be reached at the Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Via Olgettina, 60 Milano 20132, Italy; +39-02-26432648; fax: +39-02-26433643; email: bandello.francesco@hsr.it.

Gabriel Coscas, MD, can be reached at Centre Hospitalier Intercommunal de Créteil, 40 Avenue de Verdun, 94000 Créteil, France; + 33-1-45-17-52-25; fax: + 33-1-45-17-52-27; email: gabriel.coscas@gmail.com.

Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, Ltd., 1101 E Missouri Ave., Phoenix, AZ 85014, U.S.A.; +1-602-222-2221; fax: +1-602-682-2740; email: pdugel@gmail.com.

Gaurav Shah, MD, can be reached at Barnes Retina Institute, Center for Advanced Medicine, 4921 Parkview Place, Suite B, Floor 12, St. Louis, MO 63110, U.S.A.; email: gkshah1@gmail.com.

Disclosures: Bandello serves on the advisory boards of Alcon, Allergan, Bausch + Lomb, Genentech, Novartis, Farmila-Thea, Bayer Schering, Alimera Sciences, Sanofi Aventis and ThromboGenics. Coscas serves as a consultant and advisory board member for Allergan and Novartis. Dugel is a consultant for Allergan and Genentech. Shah is a consultant for Abbott Medical Optics, Alcon, Allergan, Bausch + Lomb, DORC, Regeneron and Synergetics.

In patients who do not respond to intravitreal injection of ranibizumab for macular edema associated with CRVO or BRVO, when is it appropriate to introduce combination treatment with the dexamethasone implant?

Combine therapies if response regresses at 30 days

Everyone — I repeat, everyone — with RVO responds to ranibizumab. In those cases in which no response is seen at 1 month, examination and OCT should be performed 3 to 7 days after ranibizumab injection because in almost every eye, there is marked reduction in edema from the anti-VEGF effects, but the VEGF levels may be so high that the effects have worn off by 1 month. If the eye looks great at 7 days but is totally back to baseline by 30 days, this is a perfect eye for Ozurdex because the Ozurdex duration of effect is much longer between treatments. Another indication is when monthly injections of anti-VEGF are required but the patient and family want to go longer. Typically inthese cases, Ozurdex will give you 2 to 3 months of response.

David M. Brown, MD, FACS, is an ophthalmologist practicing at Retina Consultants of Houston and Methodist Hospital, Houston, U.S.A. Disclosure: Brown is a consultant for Allergan, Genentech/Roche and Regeneron/Bayer.

Start combination treatment at 3 months

It is important to differentiate between a partial response (more common) and non-response (rare) to intravitreal ranibizumab based on anatomic findings. Persistent macular edema, despite monthly ranibizumab injections for at least 6 months (partial response), can be appropriately considered for combination treatment with the dexamethasone implant or intravitreal triamcinolone. In these patients, a visual acuity of 20/30 or worse, retinal thickness greater than 350 µm and visual symptoms are indications to introduce corticosteroid therapy. Furthermore, in patients with macular edema associated with BRVO, laser photocoagulation should be considered before use of intraocular corticosteroids. The monthly ranibizumab injections should continue after introduction of the implant in partial responders.

Amol D. Kulkarni Patients with no changes in baseline visual acuity, central retinal thickness and macular morphology on OCT despite monthly ranibizumab injections for 3 months are considered non-responders. In these non-responders, switching the anti-VEGF agent (eg, changing from bevacizumab to ranibizumab or vice versa) with use of the dexamethasone implant may be employed.

Unfortunately, long-term studies on the safety and efficacy of dexamethasone implant are not yet available, and further studies need to be performed showing long-lasting improvement in vision.

Amol D. Kulkarni, MD, is a vitreomacular fellow and clinical instructor, Department of Ophthalmology, University of Wisconsin, Madison, U.S.A. Disclosure: Kulkarni has no relevant financial disclosures.