Lower treatment burden with aflibercept for CRVOs


Cystoid macular edema (CME) might become less problematic in patients with non-ischemic central retinal vein occlusions (CRVOs).

Take-home: In chronic central retinal vein occlusions, aflibercept (Eylea, Regeneron Pharmaceuticals) showed to increase the cystoid macular edema-free interval. 

Reviewed by Rahul N. Khurana, MD

Dr. KhuranaCystoid macular edema (CME) might become less problematic in patients with non-ischemic central retinal vein occlusions (CRVOs).

The 1-year results released from the NEWTON Study (Intravitreal AflibErcept Injection of previously treated Macular Edema Associated With Central ReTinal Vein Occlusion) indicated that intravitreal aflibercept injections (Eylea, Regeneron Pharmaceuticals) staved off recurrences of CME for a longer period in patients who had been treated with anti-vascular endothelial growth factor (anti-VEGF) drugs.

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“Even though anti-VEGF therapy is effective for treating CME associated with CRVOs, the treatment is chronic and the treatment interval with ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) is limited,” according to Rahul Khurana, MD, who is in private practice in Mountain View, CA.

CRVOs have received a lot of attention over the last 20 years with limited success until 2009 with the introduction of intravitreal corticosteroids and anti-VEGF injections.

“Anti-VEGF treatments are extremely effective for CME secondary to CRVOs,” Dr. Khurana explained. “However, in the pivotal phase III clinical trials, the primary endpoint was only at 6 months, compared to 2 years with diabetic macular edema and neovascular age-related macular degeneration; and it begs the question, “Is macular edema associated with CRVOs really a 6-month disease?” 

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Long-term outcomes of patients treated with ranibizumab show that it is indeed a chronic disease in many patients requiring frequent injections.  Dr. Khurana recounted that the RETAIN Study by Peter Campochiaro, MD, of the Wilmer Eye Institute/Johns Hopkins University and colleagues who looked at 32 patients with CRVOs from the original CRUISE Study. These patients were followed for 4 years after treatment, and 56% required frequent injections at the rate of every 8 weeks and they had reduced visual potential (Ophthalmology 2014; 121: 209-219).

Courtesy of Rahul N. Khurana, MDAlong with considerations of the available therapies, questions about dosing strategies also arose, with consideration given to monthly, as-needed, and treat-and-extend options, Dr. Khurana said.

In the 2015 American Society of Retina Specialists Preferences and Trends Survey, Dr. Khurana pointed out that the treat-and-extend regimen was favored by 56% of retina specialists, in contrast to 40% who opted for as-needed treatment, and 1% who still hung on to a monthly dosing strategy.




Aflibercept is the latest anti-VEGF drug to enter the market and investigators have been testing it in the treatment of various retinal diseases.

The NEWTON Study–a phase IV, prospective, single arm, interventional, single-center trial–set out to determine if injecting intravitreal aflibercept would be more beneficial to patients by providing longer CME-free intervals than ranibizumab or bevacizumab had been able to do in patients with CRVOs.

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Patients were included in the study if they had macular edema secondary to non-ischemic CRVOs, had a best-corrected visual acuity (BCVA) level between 20/25 and 20/320, and had been treated for at least 6 months with 3 initial doses of ranibizumab or bevacizumab and had recurrent edema when the treatment was extended beyond 4 weeks.

Unlike previous switch studies with intravitreal aflibercept injections, these patients were doing well with anti-VEGF therapy, except that they needed frequent treatments.

The study used a treat-and-extend regimen, in which scheduled visits were extended by 2 weeks if the patients had no evidence of CME. Scheduled visits were shortened by 1 week if there was evidence of activity in the retina.

The primary study end point was a CME-free interval between treatments, and the secondary end points were the BCVA and the central subfoveal thickness measured by optical coherence tomography.

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Twenty patients were recruited, of whom 65% (n=13) had received previous treatment with ranibizumab and 35% (n=7) with bevacizumab. The baseline data showed that the mean duration of CRVO was 22 months, the mean number of injections was 15, the mean baseline visual acuity was 20/63, the average CME-free interval was 37 days, and the baseline retinal thickness was 427 µm.

Dr. Khurana reported that 17 (80%) of patients completed the 1-year follow-up visit. The other 3 were lost to follow-up. Sixteen of the 17 patients who completed follow-up had a greater CME-free interval because of aflibercept therapy. The CME-free interval was 9.6 weeks compared with 5.7 weeks with the previous anti-VEGF treatments.

“With intravitreal aflibercept injections, the mean CME-free interval increased from 37 days to 64 days, a difference that reached significance (P = 0.00001),” Dr. Khurana said of the primary study end point.

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Regarding the secondary end points, the mean BCVA improved by 6 letters (Snellen equivalent change of 20/63 to 20/40), and the mean central retinal thickness decreased by 152 µm to a mean of 275 µm. Both results were significant at P = 0.02 and P = 0.001, respectively.

One ocular adverse event developed, a combined macular hole and rhegmatogenous retinal detachment that was unrelated to the treatment. One patient died from metastatic cancer.

Treatment relevance


Treatment relevance

Compared with treatment of intravitreal ranibizumab or bevacizumab injections, patients treated with intravitreal aflibercept injections had a reduction of about 4 injections over the course of 1 year, Dr. Khurana pointed out. “With ranibizumab and bevacizumab, patients had a greater treatment burden of 10 visits and injections, compared with about 6 visits and injections,” he added.

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The study limitations include a small number of patients and the single-arm design without a comparative arm.

 “In patients with non-ischemic CRVOs who had previously been treated with ranibizumab or bevacizumab, treatment with aflibercept injections resulted in a longer CME-free interval,” Dr. Khurana concluded. “This extended interval will help minimize the patients’ treatment burden.”

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Rahul N. Khurana, MD

E: rnkhurana@gmail.com

Dr. Khurana was joined in this study by James Palmer, MD; Mark Wieland, MD; Alok Bansal, MD; and Louis Chang, MD, all from the Northern California Retina Vitreous Associates, Mountain View, CA. Dr. Khurana is on the advisory board and is an investigator for Regeneron and has received honoraria and grants from the company. The NEWTON Study was supported by an Investigator Initiated Study funded by Regeneron.



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