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Quantitative assessment of retinovascular features on ultra-widefield angiography images showed significant improvements in leakage and ischemia following treatment with aflibercept in patients with diabetic macular edema and retinal vein occlusion.
By Lynda Charters; Reviewed by Justis P. Ehlers, MD
Anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for physicians who treat patients with diabetic macular edema (DME) and macular edema related to retinal vein occlusion (RVO). The precise changes in the retinal vascular dynamics that occur during therapy have remained undetermined until recently.
The PERMEATE study evaluated how aflibercept (Eylea, Regeneron Pharmaceuticals) affected the peripheral and macular angiographic features, using quantitative ultra-widefield angiography. The study identified significant changes in retinal vascular leakage, retinal ischemia, and microaneurysms in eyes undergoing treatment with intravitreal aflibercept, which previously had not been quantified.
“Multiple phase III studies have demonstrated the impact of anti-VEGF drugs on various disease characteristics, including decreased retinal hemorrhages, improved vascular dynamics such as presence of leakage, potential reduction in ischemia, and changes in the severity of diabetic retinopathy using standard angiography and seven-field photography,” Justis Ehlers, MD, said. “Quantitative and qualitative assessments also have found improved leakage and ischemia resulting from anti-VEGF therapy using these conventional imaging modality.”
Dr. Ehlers noted, however, that a full understanding of the retinal dynamics is not available from previous clinical trials regarding the performance of anti-VEGF therapy because of the limited availability of quantification tools and lack of ultra-widefield imaging data. Utilizing ultra-widefield angiography, a near-panretinal assessment of disease burden and activity is feasible.
Multiple groups are working to improve quantitative assessment, such as correcting the peripheral distortion stereographically, providing automatic leakage segmentation, and assessing retinal vessel permeability, according to Dr. Ehlers, The Norman C. and Donna L. Harbert Endowed Chair for Ophthalmic Research, Cleveland Clinic Lerner College of Medicine, Cleveland.
In this prospective, open-label trial, the investigators used ultra-widefield angiography and a novel quantification tool developed at the Cleveland Clinic to assess the longitudinal retinal vascular dynamics in patients with DME and RVO.
The key inclusion criteria were foveal-involving retinal edema secondary to DME or RVO and a best-corrected visual acuity (BCVA) of 20/25 or worse in the study eye. Patients were excluded who had been treated previously with intravitreal pharmacotherapy or laser photocoagulation in the study eye.
All eyes received intravitreal aflibercept monthly for the first 6 visits and then every other month for the next 6 visits. The patients were evaluated quarterly with ultra-widefield angiography to determine changes in ischemia, leakage, and microaneurysms.
Dr. Ehlers presented the interim data that included 26 patients who were divided evenly between the 2 retinal pathologies and who completed the 6-month evaluation. At baseline, the mean visual acuity was 20/80 and the mean central subfield thickness (CST) was 500 µm.
“As expected, the visual acuity outcomes were excellent, with a mean gain of about 17 letters of vision,” Dr. Ehlers reported. “About 38% of eyes achieved a 3-line or greater gain in vision.”
The anatomic improvements also were significant, with a decrease in the mean CST to 265 µm. More than half (54%) of the retinas were dry, as seen on optical coherence tomography (OCT) images at 6 months. Subretinal fluid resolved in all eyes by the 6-month evaluation, according to Dr. Ehlers.
Dr. Ehlers pointed out that the ultra-widefield angiography images showed qualitative improvements in leakage, microaneurysms, and macular and peripheral ischemia in the study eyes.
“Quantitatively, we observed a reduction in microaneurysms between baseline and the 6-month evaluation,” he added. “Interestingly, we saw this predominantly in the posterior pole.”
Regarding leakage, Dr. Ehlers noted significant improvements from baseline to month 6 in both the number of leakage foci and the leakage index in the posterior pole and in the periphery. The leakage index showed an 83% reduction over 6 months. Ischemic index also decreased by a mean of 53%.
Dr. Ehlers cautioned that the changes must be considered in the context of the overall improvements in angiographic appearance. For example, subtle hypofluorescence associated with ischemia may be apparent more in the presence of significant leakage. As the leakage improves, the hypofluorescence may be less recognizable, but not necessarily “reperfused.”
He cautioned that this study was a preliminary analysis of a subset eyes and that the study had no control group. The complete 6-month dataset is expected to be available in early 2018.
The investigators expect to conduct additional analyses of the underlying diagnosis and treatment response and their implications related to the vascular dynamics and how they might be used to help in the understanding of the patient responses to anti-VEGF therapy. Fluid burden assessment with higher order quantitative OCT assessment will also be evaluated with quantitative ultra-widefield angiographic features, Dr. Ehlers said.
He commented on the importance of identifying an objective, easy-to-follow measurement tool for treating diabetic retinopathy. In particular, as new therapies emerge for diabetic retinopathy, an objective and quantifiable metric for gauging treatment response and need for ongoing treatment may be required to facilitate physician decision-making.
“Overall, intravitreal aflibercept resulted in significant improvements in visual acuity and macular edema in this cohort,” Dr. Ehlers explained. “Additional ultra-widefield quantitative parameters showed significant reductions in microaneurysms, especially in the posterior pole, and in leakage and ischemia seen on the ultra-widefield angiography images.
“Quantitative segmentation presents a unique opportunity for potential endpoints and for understanding some of the changes that occur in patients,” he added. “ In addition, higher order assessment of these imaging features, including potential machine learning, may provide new imaging biomarkers to better characterize these common retinal vascular diseases.”
Justis Ehlers, MD
This article was adapted from a presentation that Dr. Ehlers delivered at the 2017 American Society of Retina Specialists meeting. Dr. Ehlers is an investigator for Regeneron Pharmaceuticals, which provided a research grant to fund this study.