Research drives treatment options for macular edema secondary to RVO


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. A multipronged approach may be warranted due to the multiple contributing disease factors.

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

Lucentis (ranibizumab, Genentech) 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 the 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 to a press release from Genentech.

The dexamethasone implant and ranibizumab are treatment advances that significantly affect the outcome of the disease, according to Seenu M. Hariprasad, MD, OSN Retina/Vitreous Board Member.

“Both are absolutely incredible treatments that have revolutionized the way we manage macular edema secondary to retinal vein occlusion,” Hariprasad said. “Prior to these treatments, eyes with this condition have gone blind, and now we hit home runs — we can actually save many of these eyes.”

Treatments for macular edema secondary to CRVO and BRVO also include off-label intravitreal triamcinolone acetonide and Avastin (bevacizumab, 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 for macular edema secondary to CRVO or BRVO. Investigators at Wills Eye Institute in Philadelphia are launching a clinical trial comparing ranibizumab monotherapy with combined ranibizumab and dexamethasone implant. Patients will receive either a dexamethasone implant injection with an as-needed monthly regimen of ranibizumab or monotherapy of once-monthly ranibizumab. The primary outcome measure will be mean change from baseline best corrected visual acuity after 6 months of treatment.

According to Bandello, the growth of treatment options begs 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 with the 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 combined treatment regimen may ultimately be more favorable in terms of clinical outcome, cost, durability, side effect profile and patient acceptance, according to Hariprasad.

“Since it’s a multifactorial disease, why use just anti-VEGF or just steroids instead of using a combination? There is good evidence that inflammation and high VEGF levels are implicated in the pathophysiology of macular edema secondary to RVO,” he said. “By using a combination, you can decrease the number of Lucentis injections you need and increase the efficacy of Ozurdex, allowing you to decrease the injection burden while hopefully maintaining efficacy. I eagerly await the results of the Wills Eye Institute Ozurdex-Lucentis combination therapy study.”

By using both treatments, physicians are able to address patients who have inflammation-mediated disease as well as patients who have anti-VEGF-mediated disease, Hariprasad said.

For some patients, anti-VEGF monotherapy does not work and the macular edema persists. According to Andrew A. Moshfeghi, MD, MBA, OSN Retina/Vitreous Board Member, these patients may benefit from the addition of dexamethasone and/or laser therapy.

“I believe that combination therapy with laser and anti-VEGF therapy or laser and Ozurdex may result in a greater sustainability for selected patients,” Moshfeghi said. “I do not believe that this type of combination therapy, however, will result in a more favorable visual outcome.”

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.”

Moshfeghi noted that BRVO and CRVO respond differently to treatment.

“I prefer anti-VEGF monotherapy for BRVO as a first-line therapy, and then I add in either Ozurdex or grid laser photocoagulation for patients who do not show a robust early response or for those who I believe I might be able to get a longer duration of action with the additional adjuvant therapy,” he said. “I am mindful of the potential side effects of Ozurdex, such as cataract development and intraocular pressure elevation, and therefore choose Ozurdex for CRVO more often than BRVO.”

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.”

The two treatment options also differ in terms of clinical results, Moshfeghi said.

“Ozurdex offers the possibility of having a longer duration in between planned intravitreal treatments than one might expect with ranibizumab monotherapy,” he said. “However, the side effect profile is less favorable for Ozurdex, and the visual acuity outcomes tend to favor ranibizumab, as least in the pivotal clinical trials.”

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.

“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,” Coscas 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.

“For these patients, after 1 or 2 years the macular edema will have regressed and will always be less accentuated,” Coscas 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.”

The current role of focal laser treatment in conjunction with the dexamethasone implant or ranibizumab is not precisely known, according to Hariprasad.

“The SCORE-BRVO trial as well as the BVOS studies lend support to the use of focal laser for macular edema secondary to BRVO. In addition, even CVOS showed that laser had a trend towards benefit in younger patients with macular edema secondary to CRVO. It is too early to dismiss the role of focal laser for the treatment of this disease if used in combination with either Ozurdex or Lucentis,” he said.

The future of treatment

Researchers are conducting a clinical trial to examine the use of Eylea, formerly known as VEGF Trap-Eye (aflibercept, Regeneron), for the treatment of macular edema secondary to CRVO.

“[Aflibercept’s] binding affinity for VEGF is substantially greater than that of either bevacizumab or ranibizumab, leading to a mathematical model predicting that it could have a substantially longer duration of action in the eye and allowing for less frequent dosing, as supported by early clinical trials,” the researchers said in a study reporting 6-month results of the COPERNICUS trial.

Patients received 0.2 mg of aflibercept once a month for 24 weeks and continued treatment on an as-needed basis. Treated patients gained an average of 16.2 letters by week 52, vs. an average gain of 3.8 letters in a sham treatment group (P < .001), according to information presented at the American Society of Retina Specialists meeting.

Moshfeghi and Hariprasad said FDA approval of aflibercept for macular edema secondary to CRVO is likely in the near future.

“The outcomes with Eylea are magnificent, from what we can see in the COPERNICUS and GALILEO clinical trials, and we eagerly anticipate the FDA’s decision in terms of the approval of this drug for the treatment of this disease,” Hariprasad said.

The largest problem with current anti-VEGF therapies is the numerous injections patients must receive, he said, and it may be beneficial to develop sustained delivery through the use of miniature ocular pumps or other devices.

“It would be nice to have a more durable treatment,” he said. “Ozurdex is good. You can get away with about 4 months in between treatments. It would be nice, however, to have a steroid that has about 6 months of durability if possible.”

Further clinical trials examining various combination treatments would also be valuable, Moshfeghi said.

“It will be useful to have additional clinical trial data integrating both drugs together to see if a particular long-term combination regimen may have long-term visual and treatment duration benefits,” he said. – by Matt Hasson and Ashley Biro

 

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 (Regeneron) 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 in these 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. 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.

 

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, Wisc. Disclosure: Kulkarni has no relevant financial disclosures.