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Anti-vascular endothelial growth factor (VEGF) therapy is a viable alternative to panretinal photocoagulation (PRP) in eyes with proliferative diabetic retinopathy (PDR).
The Diabetic Retinopathy Clinical Research (DRCR) Network Protocol S found that injections of intravitreous ranibizumab (Lucentis, Genentech) were non-inferior to panretinal photocoagulation (PRP) at the 2-year follow-up evaluation; the CLARITY Study reported that aflibercept (Eylea, Regeneron Pharmaceuticals) was superior to PRP at the 1-year follow-up examination; and the extended DRCR Protocol S study found no significant differences between intravenous ranibizumab and PRP at the 5-year evaluation.
“Anti-VEGF is a viable alternative to PRP in eyes with PDR,” said Anthony Obeid, MD, MPH, research fellow, Retina Service, Wills Eye Hospital, Philadelphia.
However, as with all things, anti-VEGF therapy also has its downsides, specifically, its half-life ranges from 2.5 to 5 days, which results in a concomitant exponential decrease in the drug’s concentration in the vitreous, he noted.
This becomes problematic, according to Dr. Obeid, because of the large percentage of patients who may become lost to follow-up after treatment. The DRCR Protocol S Study found that over 30% of patients did not return for the 5-year follow-up visit.
In a study performed in a private retina practice, he and his colleagues reported that of 2,304 patients seen over a 4-year period, they estimated conservatively that over 25% were treated and did not return for 1 year, if they returned at all. Of that 25%, 22% treated with an anti-VEGF drug and 28% with PRP were lost to follow-up (Ophthalmology. 2018;125:1386-1392).
In light of this, the investigators wanted to compare differences between PRP and anti-VEGF injections. They compared the anatomic and functional outcomes in eyes with PDR that were lost to follow-up after more than 6 months following treatment and returned for a documented reexamination. All patients were treated between September 2013 and September 2016. Eyes were excluded that had another retinal pathology and were treated in other clinics as well as those in the anti-VEGF group who underwent PRP and eyes that had anti-VEGF treatment 3 months before loss to follow-up in the PRP group, Dr. Obeid recounted.
The study evaluated the visual acuity (VA) and the presence of macular edema, retinal neovascularization, vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma in 76 eyes of 59 patients; 30 eyes of 20 patients had been treated with ranibizumab, aflibercept, or bevacizumab (Avastin, Genentech) and 46 eyes of 39 patients underwent PRP. The two treatment groups were similar at baseline; however, the PRP group had significantly more patients with type 1 diabetes and a higher percentage of men in the anti-VEGF group, Dr. Obeid explained.
The average number of treatments in the anti-VEGF and PRP groups before loss to follow-up were, respectively, five injections and two sessions. Both groups were lost to follow-up for about 12 months. Upon their return for a re-examination, the patients undergoing anti-VEGF therapy received an average of four additional injections and had one PRP session over 321 days of follow-up and those undergoing PRP had one injection and one additional PRP session over 233 days of follow-up.
The mean baseline VA of 20/50 in the two groups had decreased significantly to about 20/200 and 20/80, respectively, in the anti-VEGF and PRP groups. The poor VA in the anti-VEGF group persisted and was worse than in the PRP group, in which the VA returned to the baseline level, Dr. Obeid reported.
The prevalence of diabetic macular edema was high in the anti-VEGF group throughout the study, which was expected because most physicians are likely to treat with an intravitreous anti-VEGF drug when patients have PDR and macular edema.
The prevalence rates of vitreous hemorrhage were similar between the two treatment groups at all evaluations and four eyes in each group underwent vitrectomy to clear the hemorrhage by the end of the study.
“The incidence of tractional retinal detachments was much higher in the anti-VEGF group than in the PRP group, i.e., 30% versus 2%. Six eyes in the anti-VEGF group underwent vitrectomy to repair the detachment in contrast to no eyes in the PRP group,” Dr. Obeid commented.
He also pointed out that the prevalence of iris neovascularization in the anti-VEGF group was worrisome. The disorder developed in three and four eyes, respectively, at the time of the reexamination and final visit. Of those eyes, one and two, respectively, developed neovascular glaucoma as a result. No eyes in the PRP group developed iris neovascularization.
Strict compliance with follow-up seems to be mandatory to achieve the relatively similar outcomes seen when anti-VEGF drugs and PRP were compared in the large clinical trials. The Early Treatment of Diabetic Retinopathy Study reported that PRP seems to have a durable effect, with 84% of patients maintaining 20/40 vision over 16.5 years. The long-term effect of anti-VEGF drugs is unclear if the treatments are stopped.
However, one intriguing finding was that eyes in the study under discussion, which received more anti-VEGF injections (on average, 6) prior to being lost to follow-up had a lower incidence of tractional retinal detachment after returning from being lost to follow-up.
“However, real-world outcomes do not necessarily mimic the results of large randomized clinical trials. And this may be secondary to the poor adherence with medical recommendations,” Dr. Obeid said.
“Eyes with PDR that were lost to follow-up and had received anti-VEGF therapy had worse anatomic and functional outcomes compared with the patients treated with PRP. Considering the high rates of patients lost to follow-up, careful consideration is needed when choosing a treatment for PDR. Future studies should verify these results and tackle some of the barriers to follow-up in this sensitive population,” Dr. Obeid concluded.
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Anthony Obeid, MD, MPH
Dr. Obeid has no financial interest in any aspect of this report.
Jason Hsu, MD
Dr. Hsu is associate professor of ophthalmology, Retina Service, Wills Eye Hospital, Thomas Jefferson University, and affiliated with Mid-Atlantic Retina
He has received grant support from Genentech/Roche and Ophthotech.