Pharmacotherapy sets new standard of care for retinal vein occlusion, but questions remain

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For the last 2 decades, there has been little debate about the preferred treatment of retinal vein occlusion.

With the publication of the Branch Vein Occlusion Study in 1984, gold standard therapy has called for grid laser photocoagulation to treat vision-reducing macular edema caused by branch retinal vein occlusion (BRVO).

Almost a decade later, researchers in the Central Vein Occlusion Study established that careful monitoring instead of laser yielded equivalent, if not better, visual acuity for macular edema due to central retinal vein occlusion (CRVO).

Those two studies established the standard of care, which remained unchanged until the Retina Congress 2009, when three separate clinical trial programs reported data challenging the status quo. Suddenly, retinal specialists had at their disposal a plethora of data on new and effective pharmacological treatments for the second-leading cause of vision loss due to retinal vascular disorders.

Francesco Bandello, MD, said choosing the appropriate treatment for BRVO and CRVO is complicated because of differing study designs and results. Image: Bandello F

The SCORE study supported the use of triamcinolone over observation for CRVO and confirmed the superior safety profile of laser in BRVO; the two study groups of the GENEVA trial presented strong, positive data on the use of dexamethasone-containing Ozurdex implant (Allergan) for both BRVO and CRVO; and the BRAVO and CRUISE studies demonstrated the positive impact of Lucentis (ranibizumab, Novartis/Genentech) on BRVO and CRVO, respectively.

“It was a huge step forward. The advantage of pharmacological therapy is that it is not destructive for retinal tissue. Function could be improved, and the sequelae of laser photocoagulation could be avoided,” Frank G. Holz, MD, said.

In 2009 and 2010, Ozurdex and ranibizumab were approved by the U.S. Food and Drug Administration (FDA) for treatment of BRVO and CRVO, respectively. In Europe, the European Medicines Agency (EMA) approved Ozurdex in 2010, while ranibizumab was approved for diabetic macular edema in January and is currently awaiting approval for RVO. Results of the GALILEO and COPERNICUS studies evaluating the efficacy of VEGF Trap-Eye (aflibercept ophthalmic solution, Regeneron) in the treatment of macular edema secondary to CRVO are expected early this year. Additionally, new evidence has emerged about the natural history of BRVO and CRVO. However, retinal specialists now find themselves with a problem: a deluge of data, but no head-to-head comparisons to know which treatment or combination of treatments is the most appropriate.

Frank G. Holz

“Different study populations and different inclusion and exclusion criteria make the results of the various studies difficult to compare when it comes to making choices for clinical practice,” Francesco Bandello, MD, FEBO, said.

Moreover, in Europe, the amount of time for approval and funding of pharmacotherapies by national agencies and national health systems presents large discrepancies between countries. This often creates the paradox of having evidence-based treatments approved by the EMEA, but physicians still having to resort to off-label drugs.

Natural history

In the Branch Vein Occlusion Study, about one-third of untreated patients had spontaneously improved vision, and photocoagulation doubled the odds of improved vision compared with observation. Based on that study, it has been assumed that a subset of BRVO patients would improve regardless of intervention. However, according to Tien Y. Wong, MD, PhD, whose research group published meta-analyses on the natural history of BRVO and CRVO, these assumptions may need to be re-evaluated.

“Although vision generally improves among patients with BRVO, improvement beyond 20/40 is uncommon. In addition, the natural history of BRVO is associated with significant morbidity, namely macular edema, vitreous hemorrhage and retinal neovascularization,” he said.

In both BRVO and CRVO, the main causes of visual loss are macular edema and macular ischemia. In BRVO, macular edema, even if present, may not involve the foveal center and is generally less severe, but in CRVO, when present, macular edema is generally diffuse, central and severe, leading to a poorer visual prognosis.

“CRVO more frequently is ischemic in nature, which portends a more severe clinical course,” he said.

In their analysis, Prof. Wong and colleagues found that about one-third of untreated eyes affected by CRVO initially diagnosed in the medical literature as non-ischemic CRVO later converted to ischemic CRVO. The ischemic subtype, in turn, was associated with substantial complication rates: 20% developed neovascularization and 60% developed glaucoma.

Corticosteroids

Corticosteroids, as a class, have been researched for RVO disorders because they are thought to have several effects on the multiple causes of blocked vasculature. Namely, they have anti-inflammatory effects and help regulate associated inflammatory immune responses and may reduce vascular permeability, limiting fibrin deposition. Also, they inhibit the synthesis of natural chemicals important in the formation of new blood vessels, specifically VEGF.

But progress in using corticosteroids has been trumped by safety concerns. Research over the past decade has been aimed at finding the right formulation of the right corticosteroid in the right dosage strength to improve vision after onset of RVO, while limiting adverse outcomes.

Because of its association with high rates of cataract and IOP elevation, triamcinolone has not been approved in Europe for intraocular use. Researchers are currently working on a new formula of fluocinolone with a higher safety profile.

Meanwhile, following the positive outcomes of the GENEVA study, Ozurdex has been licensed and is gradually abating the skepticism about the use of corticosteroids in the eye.

“The safety profile of Ozurdex is definitely better, with a much lower incidence of complications,” Dr. Bandello said. “Efficacy is remarkable. In the GENEVA trial, 41% of BRVO and CRVO patients achieved a 15-letter gain at 6 months compared with 23% of patients who received a sham injection. We need to change our attitude to corticosteroids now.”

The active principle used in Ozurdex is dexamethasone, a potent corticosteroid with a short half-life. The biodegradable implant, injected via the pars plana in the vitreous, provides sustained release of the drug in situ for about 3 months, with possible extended effect for up to 6 months, the study suggested.

Dr. Bandello, one of the principle investigators in the European group of the trial, said that an effective treatment has been found for CRVO, although results are better with BRVO.

“It’s a mere fact of size: The larger the occluded vessel, the worse the prognosis. Branch vessels do better because they are smaller, and best outcomes are always obtained with the occlusion of small, peripheral vessels that in many cases resolve spontaneously,” he explained.

Anti-VEGFs

Vascular hyperpermeability and subsequent breakdown of the blood-retinal barrier that generates macular edema are due, in RVO, to increased expression of VEGF.

“Here is the rationale for using anti-VEGF agents in retinal vein occlusion,” Jean-François Korobelnik, MD, said.

Jean-François Korobelnik

All four currently available VEGF inhibitors — pegaptanib, bevacizumab, ranibizumab and aflibercept ophthalmic solution — have been applied successfully to RVO. The CRUISE and BRAVO clinical trials have been successful in demonstrating the positive effects of ranibizumab in both BRVO and CRVO, with a response rate approaching 50%, higher than the response rate in age-related macular degeneration cases.

“These studies have taught us that response might be delayed a lot more than in wet AMD. Before the results of the trials, we used to inject once, see the patient 1 month later, and if results were disappointing, we’d classify this patient as a nonresponder. Now we know that we need at least three injections to judge the effects of the treatment because some patients respond very quickly, within a week, but other patients start getting better after the second or even third injection,” Dr. Korobelnik said.

In the CRUISE trial, mean gain in best corrected visual acuity at 6 months was 12.7 letters after treatment with 0.3 mg of ranibizumab and 14.9 letters after 0.5 mg of ranibizumab, but just 0.8 letters after sham injections. The percentage of patients gaining 15 or more letters was significantly higher among treated patients, as was reduction in central foveal thickness and the percentage of patients with final vision greater than 20/40.

In the BRAVO trial, BCVA increased by a mean of 16.6 letters in the 0.3-mg group and 18.3 letters in the 0.5-mg group, compared with 7.3 letters in the sham group. Again, the percentage of patients ending the study with vision better than 20/40, the reduction in macular thickness and percentage gaining 15 or more letters of vision were all significantly higher among treated patients.

While potential complications related to the injection procedure exist, the safety profile of anti-VEGFs is high, as confirmed by a study published by Curtis and colleagues in the October issue of Archives of Ophthalmology.

“Particularly for ranibizumab, the associated risks of mortality, myocardial infarction, bleeding and stroke were extremely low,” Dr. Korobelnik said. “Such reassuring data make us even more confident with the use of these therapies.”

VEGF Trap-Eye is a novel, investigational anti-VEGF therapy with high-binding affinity for VEGF-A and placental growth factor, two proteins involved in the abnormal growth of new blood vessels.

According to Dr. Holz, one of the investigators of the GALILEO and COPERNICUS studies, there are reasons to believe that this approach might demonstrate superior efficacy and more long-lasting effects compared with other anti-VEGF agents.

Both studies are investigating the effect of this treatment on CRVO. Patients who are randomized to receive the active treatment are administered VEGF Trap-Eye 2 mg every 4 weeks for 24 weeks. An as-needed regimen is then adopted for 1 year. The control group receives sham injection for 52 weeks in the GALILEO study and for 24 weeks in the COPERNICUS study, then switches to active therapy until endpoint at week 76 and week 100, respectively.

“Primary endpoint will be the proportion of patients who gain at least 15 letters (three or more lines) in BCVA at week 24 compared to baseline. There are secondary endpoints, including change in central retinal thickness assessed by OCT at 24 weeks, proportion of patients progressing to neovascularization, and subjectively reported lifestyle and vision changes,” Dr. Holz said.

Treatment schedules

Each of the recently proposed treatment options comes with questions yet to be answered. With regard to anti-VEGF therapy, those questions parallel experiences in treating AMD: How often does treatment need to be repeated, is as-needed therapy sufficient, and when can therapy be discontinued?

Treatments of AMD and RVO, however, do not have a direct correlation. Unlike AMD, RVO is an acute condition, which runs its course over a limited span of time.

“There is a specific and limited time during which we can treat and, therefore, a limited number of therapeutic interventions we can perform over that time. The problem of when and how often to re-treat is somewhat more contained,” Dr. Bandello said.

One fact has emerged thus far: Early treatment is more beneficial. There is accumulating evidence that prompt initiation of treatment with both corticosteroids and anti-VEGFs might yield better visual results.

In the BRAVO and CRUISE studies, as well as in the GENEVA study, patients initially treated with sham before crossing over to active treatment did not achieve the same degree of visual gain as patients treated with the active agents from enrollment.

Apart from this initial statement, there are no well-established landmarks for re-treatment, according to Dr. Holz.

“There is a huge patient-to-patient variability in the response to treatment and progression of the disease. Some patients need more frequent treatment, and some have resolution of [macular edema] with just one injection. This applies to both steroids and anti-VEGFs,” he said.

As far as anti-VEGFs are concerned, a fixed regimen with monthly injections has been shown effective in trials, but monthly injections are not likely to be needed for all patients.

“For sure, as for AMD, most of us want to be able to treat on an as-needed basis after a first loading phase,” Dr. Korobelnik said. “But we don’t know yet what the parameters for re-treatment should be. Should we re-treat as soon as OCT shows signs of edema, or should we wait for vision loss? At the moment, I look both at OCT and visual acuity, but criteria might change following the results of further trials. The same happened with AMD. We used to wait until visual acuity decreased, and now we treat based on simple OCT data, including eyes with 20/20 vision.”

Dosing schedule is also unclear with corticosteroid therapy, Dr. Bandello said. The Ozurdex implant is designed to be delivered every 6 months, and clinical trials evaluated its efficacy at 6-month intervals. However, although 20% of patients maintained the results of the treatment for up to 1 year with a single injection, several relapses were reported at 3 months to 4 months by study investigators.

“We now have a problem of consistency with the study outcomes. The FDA and EMA have granted marketing authorization for Ozurdex on the basis of the available evidence provided by studies that entailed administration every 6 months. Having reached the conclusion that more frequent administrations are needed will inevitably lead us to try different arbitrary treatment schedules that are not evidence-based,” he said.

A similar situation was created by the studies on anti-VEGFs in AMD that used a fixed regimen of monthly administration, which is too onerous to be used in a daily practice; hence, discretionary variable-dosing regimens were adopted.

“As in many other cases, in our clinical practice, we end up using treatment schedules that are different from those validated by official trials, with unpredictable consequences also in terms of legal responsibility. The applicability of study protocols to real-life practice should be a prerequisite of clinical trials,” Dr. Bandello said.

Setting a new standard

The onset of new information for treating RVO, it seems, calls into question the current standard of care. But it also leaves open the question as to what the new standard should be.

From a data-analysis perspective, anti-VEGF therapy appears to have the edge over steroids. Visual outcomes are better, and although Ozurdex has a higher safety profile than other steroids, the rate of complications of anti-VEGFs is still significantly lower.

However, comparing clinical trial data can be misleading. In the specific case of RVO treatment trials, the study populations in which Ozurdex was tested exhibited unfavorable baseline conditions compared with the population of anti-VEGF trials.

“Only a head-to-head study could provide us with useful data to decide on which, between anti-VEGFs and corticosteroids, should be considered as first-line therapy,” Dr. Bandello said.

From a pragmatic standpoint, steroids retain considerable appeal, mainly due to their easier dosing schedule. Even in cases of shorter duration of therapeutic effects, the number of injections will not approach the monthly dose of anti-VEGFs.

Another point in favor of corticosteroids is their homogeneous efficacy.

“In the majority of cases, you do have a result. The same cannot be said about anti-VEGFs. In RVO more than in AMD, there are many nonresponders, and we don’t have the criteria to identify them yet,” Dr. Bandello said.

The number of injections required for anti-VEGF treatment might indeed be onerous in terms of time and money for both the patient and health provider. Ongoing research is aimed at finding an agent with more long-lasting effects.

“VEGF Trap is the best we have in the pipeline at the moment. It’s one step better in regard to duration, but we need to go further,” Dr. Korobelnik said.

However, he strongly disagrees with using corticosteroids to reduce the burden of repeated procedures. Patients do not need as many injections but are seen just as frequently to prevent potential complications such as increased IOP, he said.

In his opinion, anti-VEGFs should be used as first-line treatment because their safety profile is high, despite the number of injections.

According to Dr. Holz, treatment choice should remain open to all options, including laser. In his patients with CRVO, he uses anti-VEGFs or steroids. In BRVO, he still considers laser an option, particularly if patients cannot return for a second treatment.

Outside clinical trials, off-label drugs such as Avastin (bevacizumab, Genentech) are used, while the new evidence-based pharmacotherapies are awaiting approval and/or funding in several countries in Europe. The high costs remain an issue that, hopefully, will not cause too many delays. – by Bryan Bechtel and Michela Cimberle

Is there a role for observation before initiating treatment for BRVO, perhaps to avoid the need for pharmacotherapy?

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• Francesco Bandello, MD, FEBO, can be reached at Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Via Olgettina, 60 Milano 20132, Italy; +39-02-26433598; fax: +39-02-26433643; e-mail: bandello.francesco@hsr.it.
• Frank G. Holz, MD, can be reached at University of Bonn, Ernst-Abbe-Strasse 2, D-53105 Bonn, Germany; +49-22828715647; fax: +49-22828715603; e-mail: Frank.Holz@ukb.uni-bonn.de.
• Jean-François Korobelnik, MD, can be reached at Groupe Hospitalier Pellegrin, Place Amelie Raba Leon, 33076 Bordeaux (Gironde), France; +33-5-56795679; e-mail: jean-francois.korobelnik@chu-bordeaux.fr.
• Tien Y. Wong, MD, MPH, PhD, can be reached at Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751; +65-63224571; fax: +65-63231903; e-mail: ophwty@nus.edu.sg.
• Disclosures: Dr. Bandello is an advisory board member for Novartis, Allergan Pfizer, Bayer and Thea. Dr. Holz is a consultant for Acucela, Bayer, Genentech, GSK, Novartis and Pfizer. Dr. Korobelnik is a consultant for Alcon, Allergan, Bayer and Novartis. Dr. Wong is on the advisory boards of and has served as a consultant for Novartis, Allergan and Pfizer.