Identifying Long-term Treatment Patterns of Anti-VEGF for DME and the Ideal Dosing Paradigm

Anti–vascular endothelial growth factor (VEGF) therapy is the current first-line treatment for patients with diabetic macular edema (DME), and those patients who have poor responses on therapy are switched to a different anti-VEGF agent. However, many patients do not follow-up treatment appropriately or discontinue their anti-VEGF treatment, explained Theodore Leng, MD, MS, FASRS, director of Clinical and Translation Research and director of Ophthalmic Diagnostics in the Department of Ophthalmology at Stanford University School of Medicine.

During the American Society of Retina Specialists 40th Annual Scientific Meeting, Leng presented the results of a study reviewing long-term treatment patterns with anti-VEGF therapies using the IRIS Registry. The patients included in the study had DME and had no prior anti-VEGF intravitreal therapy (IVT) in the previous 12 months. They initiated therapy on anti-VEGF IVT between January 1, 2015, and December 31, 2019.

A total of 190,345 eyes from 147,687 patients were included in the analysis. The majority (64%) of patients were White, 49% were female, and the mean age was 64 years. Half (50%) of the eyes included had nonproliferative diabetic retinopathy and 46% had proliferative diabetic retinopathy.

Most (77%) of the eyes had only received 1 type of anti-VEGF during the mean follow-up of 2.3 years. Off-label bevacizumab was the most commonly used agent in 53% of eyes, followed by aflibercept in 21%. As each year passed, the use of off-label bevacizumab decreased by a mean of 5.6% while use of on-label agents increased by a mean of 6.9%. After a mean of 53 weeks, 15% of eyes switched to a different anti-VEGF agent with 74% switching from bevacizumab to an on-label agent after of mean of 50 weeks. Only 10% of eyes were switched from an on-label agent to bevacizumab after a mean of 65 weeks.

More than half (54%) of eyes discontinued anti-VEGF treatment after a mean of 24 weeks; however, 33% reinitiated anti-VEGF treatment after a mean of 91 weeks. Leng noted that the rates of discontinuation, switching, and reinitiation were mostly similar regardless of baseline best visual acuity. “Although discontinuation with no reinitiation of injections during follow-up was highest in patients with a vision of 20/200 or worse at baseline.”

He noted some limitations, including that the researchers were unable to differentiate between patients who discontinued their treatment and those who were lost to follow-up before 12 months. Since the study relied on electronic health record data, the timing of therapy stop and start might not be precise, and other comorbid conditions impacting treatment persistence might not have been captured.

He concluded that this study was the longest and largest follow-up study in patients with DME on anti-VEGF therapy to date, with outcomes of up to 6 years being evaluated. “The reasons for switching and discontinuation should be further explored,” he concluded.

Although anti-VEGF therapy is the first-line treatment for center involving DME, there is no consensus on the ideal dosing of anti-VEGF. In a second presentation, Varun Chaudhary, MD, chief of ophthalmology and professor of surgery at the Hamilton Regional Eye Institute of McMaster University in Ontario, Canada, reviewed the findings of a meta-analysis comparing treat and extend (T&E) versus other fixed dosing or pro re nata (PRN or “as needed”) dosing.

For the meta-analysis, Chaudhary and his colleagues looked at studies in which 1 arm received anti-VEGF in a T&E setting while the other arm received fixed dosing or PRN. There were a total of 22 unique studies included, 8 of which were randomized controlled trials, 7 prospective single-arm studies, and 7 retrospective studies.

When comparing T&E with fixed dosing, the “gold standard in terms of DME management,” the pooled results showed “no difference between treat and extend and gold standard,” Chaudhary said. The results were similar for T&E vs PRN.

However, those findings alone shouldn’t be enough to satisfy clinicians, he said. The researchers then carried out a certainty of evidence analysis on an outcome by outcome basis. The certainty is very low to low for most outcomes and moderate for the remaining.

“We certainly need more prospective clinical trial data to increase the certainty behind these treatment algorithms and how we make decisions,” Chaudhary said.

For the meta-analysis, there were also areas they could not evaluate because there was not enough evidence, such as the ideal T&E paradigm to use.

Later in 2022, Chaudhary will be the principal investigator on the INSITE-DME Trial, a pragmatic, multinational, randomized controlled trial to determine if a 4-week pragmatic T&E regimen up to every 24 weeks versus fixed dosing at 8 weeks produces noninferior visual acuity outcomes from baseline to week 100. It will be a large trial with 450 patients across 4 countries (Australia, Canada, the United Kingdom, and the United States) to hopefully provide wide generalizability of the findings, he explained.