Research limited on role of combination therapy for CRVO-related ME

Table courtesy of Lihteh Wu, MDMore data are needed to determine the use of combination therapy for treatment of macular edema (ME) secondary to central retinal vein occlusion (CRVO) and to identify whether there is an ideal strategy. For now, however, combination therapy may be a reasonable approach to manage eyes that are not responding to intravitreal monotherapy with an anti-vascular endothelial growth factor (VEGF) agent or corticosteroid, said Lihteh Wu, MD, at the inaugural Retina World Congress.

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“Intravitreal treatment with a corticosteroid or anti-VEGF agent alone is currently the first-line treatment for ME secondary to CRVO, and there is no evidence to support the use of combination therapy as primary intervention,” said Dr. Wu, consulting surgeon, Asociados de Macula, Vitreo y Retina de Costa Rica, San José, Costa Rica.

“There have also been very few studies investigating combination therapy for management of refractory or recurrent ME therapy, and those that have been published are small and short-term, include retrospective reviews, and have generated inconsistent results," Dr. Wu said. "Based on theory and limited clinical data, however, combination therapy with an anti-VEGF agent corticosteroid or laser therapy should be considered in eyes that do not respond to intravitreal monotherapy.”

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Interest in the role of combination therapy as initial or second-line intervention for ME secondary to CRVO arises from data showing that a sizeable proportion of eyes do not respond to monotherapy despite receiving multiple continuous injections.

Citing results from large-scale, randomized studies investigating intravitreal anti-VEGF agents and intravitreal triamcinolone, Dr. Wu noted that up to 25% of eyes suffered a best-corrected visual acuity (BCVA) loss of ≥15 letters and up to 52% had residual ME.

Reducing injection burden, side effects

In addition to improving these functional and anatomic outcomes, combination therapy could possibly reduce the burden of injections and therefore treatment-related side effects.

A scientific rationale for combining anti-VEGF and corticosteroid treatment derives from studies that show RVO is associated with elevated levels of VEGF and other growth factors and inflammatory cytokines that might be controlled by corticosteroid treatment.

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Reviewing the literature for reports on combination anti-VEGF/corticosteroid therapy, Dr. Wu discussed a randomized study comparing intravitreal bevacizumab (Avastin, Genentech) alone or combined with triamcinolone as primary therapy. The study found no difference between the two treatment groups in visual outcomes, ME resolution, or frequency of re-treatment.   

Another group of investigators reported findings from a series of 62 eyes treated initially with an anti-VEGF injection followed 2 weeks later by placement of the dexamethasone implant (Ozurdex, Allergan). They reported a mean re-injection interval of 135 days, mean peak change in BCVA of nearly 14 letters, and a 3-line or greater BCVA gain in almost one-half of the treated eyes. The study, however, had no monotherapy comparator group, noted Dr. Wu, who is a member of the member of the Pan-American Collaborative Research Study Group.

Laser plus pharmacotherapy

Interest in adding laser treatment to anti-VEGF therapy stems from understanding that VEGF upregulation occurs in areas of capillary non-perfusion.

“Destruction of this source of VEGF secretion with laser photocoagulation could potentially limit edema recurrence and lead to better visual acuity outcomes with fewer intravitreal injections,” Dr. Wu explained.

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The published reports of this approach include a trial that reported no benefit from adding scatter laser photocoagulation for treatment of eyes with CRVO requiring ongoing ranibizumab (Lucentis, Genentech) injections.

However, laser treatment was not started until 40 months after initiating anti-VEGF therapy, and the investigators noted they could not rule out a possible benefit of earlier laser treatment.

Effect of panretinal photocoagulation

The effect of panretinal photocoagulation to peripheral areas of retinal nonperfusion in eyes with previous CRVO was assessed in a prospective single-investigator study including 10 eyes. Analyses of data collected 6 months before and 6 months after the laser treatment showed it had no significant benefit for improving visual acuity or reducing injection frequency.

In a comparative study, eyes with recurrent ME while receiving intravitreal bevacizumab treatment were randomly assigned to panretinal photocoagulation with a pattern scan laser system or a control group. The results showed eyes receiving laser treatment required significantly fewer bevacizumab injections during subsequent follow-up when compared with the controls, but there were no significant differences between the two study groups in visual outcomes or foveal thickness. 

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One prospective, randomized study compared outcomes of treatment with ranibizumab alone (three consecutive monthly doses followed by monthly follow-up and PRN injections) or combined with laser photocoagulation to the areas of retinal non-perfusion. At 6 months, median BCVA gain was greater in the combination group compared with the eyes receiving ranibizumab alone (14 letters versus 6.5 letters), but the difference was not statistically significant.

Dr. Wu has received lecture fees from Bayer Health, Heidelberg Engineering, Novartis, and Quantel Medical.