special report: retina

Gaining Ground on Retinal Vein Occlusion

New research reveals reasons to refer patients promptly for retinal evaluations.

Diane Donofrio Angelucci

The results of recently completed trials may bring new hope to patients who suffer from macular edema from retinal vein occlusion (RVO). This research, presented at the Retina Congress this fall, also offers compelling new reasons for optometrists to refer patients with venous occlusive disease to retina specialists as soon as possible.

In the past, research has shown that, compared with observation, macular grid laser photocoagulation increases the likelihood of visual improvement in patients with macular edema from branch retinal vein occlusion (BRVO). Yet studies have been slow to uncover new treatments for BRVO and viable therapies for central retinal vein occlusion (CRVO). However, recent trials have shown visual acuity gains in some of these patients who were treated with intravitreal anti-VEGF, triamcinolone injections, and a newly approved sustained-release dexamethasone implant.

This article summarizes the results of these trials and presents information to help you educate and refer patients so that they can potentially achieve better outcomes.

Ranibizumab in CRVO and BRVO

The Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion (CRUISE) trial studied 392 patients with CRVO, randomized to receive 0.3 mg or 0.5 ranibizumab (Lucentis, Genentech) or sham injection intravitreally each month for six months. Vision improved by 15 letters or more in:

► 46% of patients receiving 0.3 mg,
► 48% of those receiving 0.5 mg, and
► 17% of those receiving sham injections.

Recent study results show promising treatments for patients who have retinal vein occlusion, which is depicted in these fluorescein angiography images.

"By seven days, patients had a marked improvement in their optical coherence tomography (OCT) and, on average, eight-letter visual acuity gain. This increased to almost three lines of visual acuity gain by three months," says David M. Brown, M.D., retina surgeon, Methodist Hospital, Houston, who also operates a clinical trial center at Retina Consultants of Houston. Treated patients had few ocular or systemic side effects, with two patients in each treatment group having cataract progression.

"Basically, because the safety profile is so much better than steroids, and how robust the visual acuity improvement gains, I think this will change the standard of care for macular edema in CRVO to anti-VEGF therapy," Dr. Brown says.

Whether patients presented early or late, they benefited from therapy, Dr. Brown says. The study's findings also emphasize the importance of early referral of patients with macular edema to a retina specialist. "It's quite possible that early diagnosis would lead to even better visual acuity outcomes than we saw," he says.

The multicenter, randomized phase 3 Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion (BRAVO) trial studied 397 patients with macular edema resulting from BRVO. Improvements in vision of 15 letters or more were seen in:

► 55% of patients receiving 0.3 mg ranibizumab,
► 61% receiving 0.5 mg, and
► 29% receiving the sham injection.

These results expand treatment options for patients with BRVO, says Jeffry D. Gerson, O.D., F.A.A.O., in private practice at WestGlen Eyecare and Omni Eye Center, Kansas City, Mo. "There already was the option of traditional laser, but now we also know that Lucentis seems to be a fairly good option, although I think the warning with CRUISE and BRAVO is that these are six-month results, so these aren't one-year, two-year or three-year results. I'm not sure that's enough yet to change standard of care. It's probably enough to give the implication that there's probably a better option."

Despite potential benefits of anti-VEGF drugs in treating macular edema resulting from RVO, there is concern about the cost of ranibizumab and the need for frequent treatments even if bevacizumab (Avastin, Genentech) is used, says Mark T. Dunbar, O.D., F.A.A.O., director of optometric services, optometry residency supervisor, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. "The issue with Lucentis and Avastin is you're really looking at more frequent injections, perhaps monthly for some patients, compared with an intravitreal or implantable steroid that may last four to six months or longer," he says.

"These [anti-angiogenic] compounds do work," says Andrew Gurwood, O.D., F.A.A.O., professor of clinical sciences, Pennsylvania College of Optometry, Salus University, Philadelphia. "We know they work, and we know they offer the potential to improve vision rather than just stabilize it. However, the biggest problem with this modality of treatment is that the outcomes are not permanent." Therefore, he explains, "laser photocoagulation therapy remains the standard of care."

Weighing Corticosteroids

The Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) Study included two phase 3 prospective, randomized controlled clinical trials, one studying patients with CRVO and the other studying patients with BRVO.

In this study, 271 patients with CRVO received 1-mg or 4-mg intravitreal injections of tri-amcinolone acetonide or received the standard treatment of observation.

"The bottom-line results are that patients who received the triamcinolone injections were five times more likely to have substantial visual gain one year after initial treatment, and substantial visual gain meant that patients could read letters that were half the size as they could read previously," says Ingrid U. Scott, M.D., M.P.H., professor of ophthalmology and public health sciences, Penn State College of Medicine, Penn State Hershey Eye Center, Hershey, Pa. Patients receiving 1-mg doses had fewer side effects, such as increased intraocular pressure (IOP) and cataract formation, compared with those who received 4-mg doses.

The BRVO trial compared standard treatment — grid laser photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage cleared in eyes with dense macular hemorrhage — with 1-mg vs. 4-mg intravitreal injections of triamcinolone acetonide in 411 participants with BRVO. Rates of initiation of IOP-lowering medication and rates of cataract formation or progression were significantly higher in patients receiving triamcinolone compared with laser. "This study showed that laser treatment is as effective as, and safer than, corticosteroids for treating vision loss due to macular edema associated with BRVO," Dr. Scott says. In all three treatment groups, equal proportions of patients experienced substantial visual improvement — defined as a three-line or 15-letter or greater gain in visual acuity.

"For BRVO, the results indicate that, at this time, laser treatment should remain the standard care treatment for visual impairment due to macular edema secondary to BRVO and also that laser treatment should remain the benchmark against which treatments are compared in future clinical trials," Dr. Scott says.

"I think what was exciting about the SCORE Study is that it really did legitimize the use of steroids in these patients [with CRVO] because, to date, we really have no treatment for CRVOs," Dr. Dunbar says. Although the study showed laser to be more effective for BRVO, he believes clinicians still need to determine how all of these treatments might be used in conjunction in some patients to provide the best outcomes.

"Now, we have therapeutic options where for many years, at least within the realm of CRVO macular edema, there were no real options," says Diana L. Shechtman, O.D., F.A.A.O., associate professor, Nova Southeastern University College of Optometry, Fort Lauderdale, Fla. "The options we had were rather limited and we really didn't know the overall safety profile. With new available treatment options for our patients, we are now faced with new protocols. Optometrists need to be familiar with the various treatment options available for our patients in order to provide education and appropriate timely referral. Understanding efficacy and safety of such treatments is also prudent."

Dexamethasone implant

In June 2009, the U.S. Food and Drug Administration approved the dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) as the first drug treatment for macular edema from BRVO or CRVO.

A multi-center trial studied 1,267 patients with BRVO and CRVO randomized to receive the extended-release biodegradable implant at a 0.7-mg or 0.35-dose, or a sham injection. These were implanted at baseline and followed for six months to determine how long it took to achieve a 15-letter gain in best-corrected visual acuity. Within 60 days after implantation of the Ozurdex device, 20% to 30% of treated patients experienced a three-line improvement in BCVA, compared with 7% to 12% receiving sham injections. Some of the most common adverse reactions were increased IOP and conjunctival hemorrhage.

"The advantage of this particular treatment, of course, is that it's long lasting, so you don't have to go and do repeated injections as frequently as you do with Avastin, so that's a compelling advantage. But whether there are some people who would do better with more frequent injections, whether there are ways to combine the treatments, those are all very interesting areas of study that we need to work on," says Julia A. Haller, M.D., ophthalmologist-in-chief, Wills Eye Institute, and professor and chair of ophthalmology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.

Although Dr. Gerson believes Ozurdex has shown some benefits, he is concerned about the potential for glaucoma and cataracts. However, "I do think that some sort of sustained-release implant will be the treatment choice in the future, whether it's with dexamethasone, or if it's something else, I think that's headed down the right path," he says.

Optimizing Outcomes

"Given these results, in addition to always identifying the underlying cause, patients with RVO should promptly be referred to a retina specialist," Dr. Gurwood says. "Given the variety of new options in this area, clinicians discovering retinal vein occlusions should permit the experts in retinology an opportunity to provide their input rather than waiting for spontaneous resolution. Retinal specialists are uniquely positioned to be aware of the pertinent evidencebased reports, while through practice, are able to call upon anecdotal experience to identify unique circumstances which may indicate the need for one approach over another. This is a resurgent and fresh area of investigation. There [is] a subset of retinologists who have adopted an aggressive philosophy of intervention over observation in favor of improving vision and recovery."

However, experts urge caution in discussing results with patients. "While all of these studies demonstrate increasing promise, the referring practitioner must remember to present the options with cautious optimism. Clinicians should be conservative, explaining that these new treatments and technologies offer new hope for achieving stability," Dr. Gurwood says. "Patients should be educated that these interventions were designed to reduce the risk of things getting worse and while some patients get better (achieve an improvement in visual acuity), it's not an outcome that can be counted as a sure thing."

Dr. Dunbar suggests quoting results to patients. "At least from the SCORE Study and CRVO, you have a five times more likely chance of having an improvement in visual acuity, so it's encouraging to give patients an idea of the numbers," he says. "I think that's the best thing, to let them know this is the latest treatment and they offer you the best chance of having an improvement in visual acuity compared with no treatment at all."

Before referring patients, explain available options for treating their condition. "The main thing to stress would be the low incidence of side effects of the [anti-VEGF] injections because it's often nice for the patients to know that this may lead to a shot in the eye, but that they're very well tolerated and have much less side effects than one might imagine," Dr. Brown says.

In co-managing patients after treatment, optometrists will need to know the protocols for monitoring patients and understand potential benefits and complications of the treatment. "A lot of these treatments have short-term therapeutic effects, as well as associated complications, so you should follow-up with the patients carefully for the evaluation of any recurrence in macular edema, as well as associated complications — such as cataracts and increase in IOP," Dr. Shechtman says.

"For those O.D.s who have OCT imaging devices, I think that really is probably the best opportunity because you can follow these patients, and your OCT will be the barometer when these patients need to be referred back," Dr. Dunbar says.

"In older age groups or patients who have risks such as hypercoagulability syndrome or lupus, the optometrist might want to follow the patients a little more closely simply because of their risk," says Leo Semes, O.D., professor of optometry, University of Alabama, Birmingham.

Optometrists also should remind patients to control their systemic risk factors. "It really helps us when referring physicians encourage patients to work on things like their blood pressure," Dr. Brown says. Bright Outlook

Bright Outlook

"I think that the future looks a lot brighter for patients who have macular edema from vein occlusion, from macular degeneration or from diabetic changes because of the anti-VEGF agents," Dr. Semes says. "I think that's a real bright spot from when I started training and — even from some of the preliminary studies of 20 years ago in photocoagulation. Things are so much better now in terms of outcome and improvement in vision rather than just stabilization."

"What will probably evolve from all of this work is a 'cocktail' approach," Dr. Gurwood says. "That is, some variation of combinations of laser treatment, injectable or depot steroids and injectable anti-angiogenic substances. Investigations and trials determining head-to-head efficacies, along with reports that compare outcomes will permit us to eventually understand which entities respond best to which therapies and in which patients the treatments are best suited. With the primary goal being safety, outcomes, affordability, convenience of treatment and duration of benefits will ultimately determine which way the therapeutic path winds." OM

Editor's Note: Dr. Brown is a consultant for Allergan and Genentech and his trial center has received research support from Genentech (BRAVO, CRUISE), Allergan (Ozurdex trials), and the National Eye Institute (SCORE trials). Dr. Dunbar is on the Optometry Advisory Board for Allergan. Dr. Haller is a consultant for Allergan, Genentech, and Regeneron. Dr. Gurwood, Dr. Shechtman, Dr. Semes, Dr. Scott and Dr. Gerson have no financial interest related to this article.