Macular Edema Treatments Less Effective in the Real World

Laird Harrison

August 18, 2020

The improvement in visual acuity that patients with diabetic macular edema (DME) experienced after 2 years of treatment with anti-vascular endothelial growth factor (VEGF) injections in the Protocol T study had waned by year 5, findings from an extension study show.

Vision declined as patients transitioned from clinical trial to standard care, said investigator Dante Pieramici, MD, from California Retina Consultants in Santa Barbara.

"It's another piece of evidence looking at how patients do in typical clinical care," he told Medscape Medical News. "The outcomes don't always match up with what we see in a clinical trial."

The Diabetic Retinopathy Clinical Research Network (DRCR) Protocol T study compared effectiveness of the three anti-VEGF drugs commonly used to treat DME: aflibercept, bevacizumab, and ranibizumab.

During the 2-year study, all participants gained visual acuity. For those with the worst visual acuity at baseline, improvement was significantly better with aflibercept than with bevacizumab. Other differences were not significant.

For their extension study, Pieramici and his colleagues assessed how 317 (68%) of the original 558 Protocol T participants were faring 3 years later. Pieramici presented the 5-year findings at the virtual American Society of Retina Specialists (ASRS) 2020 Annual Meeting.

There was a balance between Protocol T patients who participated in the extension study and those who did not in terms of the type of anti-VEGF drug received and the mean central subfield thickness at baseline and at 2 years. However, mean ETDRS letter score was significantly higher for extension participants than for nonparticipants at baseline (66 vs 62; P < .001) and at 2 years (78 vs 74; P = 0.03).

"There might have been a bias that those who were tending to do better dropped out," Pieramici acknowledged.

In the 3 years after the Protocol T ended, 95% of extension participants received retinal care and 68% received at least one anti-VEGF injection. Patients received a median of four injections during a mean of 14 visits.

From baseline to year 2, central subfield thickness thinned by an average of 154 µm (95% CI, 142 - 166), but thinning during the subsequent 3 years was just 1 µm (95% CI, –12 to +9).

And mean improvement in visual activity from baseline reached a peak at 2 years of 12.2 letters, but then dropped by 4.7 letters over the next 3 years (95% CI, –3.3 to –6.0).

This pattern did not vary by anti-VEGF drug or by baseline visual acuity. And for patients with the worst visual acuity at baseline, aflibercept remained better than bevacizumab during the extension period.

This study reinforces research that has shown that patients don't fare as well in the real world as they do in the rarefied atmosphere of clinical trials, where coordinators call them before each appointment and sometimes arrange transportation, Pieramici said.

And COVID-19 has exacerbated the problem. "I've seen patients whose vision has gotten worse because they couldn't come in for 2 or 3 months," he said.

The finding lends urgency to research on new delivery mechanisms — such as implants, nanoparticles, and gene therapy — that can keep the drug present in the eye longer with fewer injections. "We need to find a better way to deliver these drugs over the long haul with these patients," he said.

However, "the fact that these patients retained a reasonable improvement over 5 years is quite remarkable," said Thomas Ciulla, MD, from the Indiana University School of Medical School in Indianapolis, who has conducted similar trials.

"The doctors involved in caring for these patients and the clinical investigators should be commended," he told Medscape Medical News.

Many patients with DME also lose visual acuity to cataract over time. This could explain why the Protocol T participants lost visual acuity during the extension period without an increase in central subfield thickness.

However, a post hoc analysis of Protocol T data showed only a weak correlation between central subfield thickness and visual acuity (Pearson correlation coefficient, 0.23; 95% CI, 0.15 - 0.31) at 2 years.

So cataract is not the only possible explanation, Ciulla said. "Central subfield thickness measures thickness. There could be other aspects of edema that aren't being measured. There could be ischemia. There could be just neuropathic dysfunction."

During the extension period, 38% of patients received aflibercept, 32% bevacizumab, 19% ranibizumab, 10% a corticosteroid, 10% pan-retinal photocoagulation, and 8% focal/grid laser.

In a separate post hoc analysis presented at the ASRS meeting, Jennifer Gallagher, MD, from UT Health in Austin, Texas, reported that focal/grid laser did not provide any additional benefit in patients with central subfield thicknesses of less than 250 µm after 24 weeks of treatment with an anti-VEGF drug.

After 2 years, visual acuity was worse in the 46 patients who underwent a laser procedure (at the clinician's discretion) than in the 162 who did not (73.7 vs 77.4 letters; P = .049).

In addition, the patients who underwent a laser procedure needed more injections than those who did not (15.7 vs 13.9; P = .045). A similar pattern held for those with an inner peripheral thickness less than 250 µm.

"It taught me that even though these patients are doing better, adding the laser doesn't clear them," Gallagher said. "They have to be monitored just as clearly."

Pieramici is a consultant for Genentech, Regeneron, and Novartis. Ciulla is chief medical officer of Clearside Biomedical. Gallagher has disclosed no relevant financial relationships.

American Society of Retina Specialists (ASRS) 2020 Annual Meeting. Presented July 25, 2020.

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