Visual benefit is not seen during first 2 years of Protocol W study.
Periodic aflibercept (Eylea, Regeneron Pharmaceuticals) treatment for moderate to severe nonproliferative diabetic retinopathy (NPDR) resulted in fewer patients developing PDR or center-involving diabetic macular edema (DME), although no positive effect on the visual acuity (VA) was seen, according to Raj K. Maturi, MD, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, who reported the interim 2-year results of the DRCR Retina Network Protocol W study.
“Eyes with moderate to severe NPDR are at high risk for disease progression and development of vision-threatening complications,” Maturi stated, underscoring the importance of determining whether aflibercept prevents development of PDR and center-involved DME as well as the potential for a visual benefit at the later 4-year point.
Protocol W is a randomized multicenter clinical trial of adults with type 1 or 2 diabetes and severe NPDR in at least 1 eye. Included patients had no evidence of neovascularization on fluorescein angiography and a best-corrected VA letter score of 79 or higher, ie, Snellen acuity of 20/25 or better.
Patients were randomly assigned to receive either 2 mg of periodically administered intravitreous aflibercept or sham injection. Monthly injections were administered for the first 3 visits and followed by injections at months 4, 8, and 12. Before 2 years, injections were administered at each visit, with subsequent treatment with aflibercept only if the diabetic retinopathy exceeded mild NPDR.
The primary outcome was the cumulative probability of development of PDR or center-involving DME with vision loss. Treatment was deferred if the eye had no worse than mild NPDR. Aflibercept was administered in both groups if center-involving DME with vision loss or high-risk PDR developed.
A total of 399 eyes of 328 patients were included (mean age, 56 years), all of whom had moderate to severe NPDR. Of these, 200 were randomized to aflibercept and 199 to sham treatment; data from all these patients were included in the primary analysis.
At 2 years, more patients randomized to sham therapy developed DME or PDR compared with those randomized to aflibercept (44% vs 16%, respectively; adjusted HR, 0.32; P < .001), Maturi reported.
The time to development of PDR was 33% in the sham group and 14% in the aflibercept group. The time to development of DME was 15% in the sham group and 4% in the aflibercept group. “The criteria for the development of the first PDR and/or DME [were] met in 35 patients in the aflibercept group and 81 patients in the sham group,” Maturi said.
Most patients in both groups developed neovascularization of the disc and/or neovascularization elsewhere, 4 patients in each group developed vitreous hemorrhage, and 1 patient in the sham group developed neovascularization of the iris compared with no patients in the aflibercept group.
VEGF therapy was administered to 3 patients in each group, and focal or grid laser for DME was administered in 1 patient in the sham group.
Analysis conducted to determine a correlation between the baseline NPDR severity and development of DME or PDR indicated a definite relationship based on more severe disease.
“Among patients with the lowest levels of NPDR, only 3% in the aflibercept group went on to develop DME or PDR compared with 24% in the sham group,” Maturi said. “Among patients with severe NPDR, 36% went on to develop DME or PDR in the aflibercept group, and 68% did so in the sham group despite regular treatments.”
Analysis of the change in the severity of diabetic retinopathy at 2 years showed that 5% of patients in the aflibercept group had a 2-step worsening of disease compared with 12% in the sham group. Regarding improvement, 45% of patients in the aflibercept group had a 2-step or greater improvement compared with 14% in the sham group.
Comparison of the 2 treatment groups showed almost no difference in the adjusted mean VA over 2 years. The central subfield thickness improved slightly and nonsignificantly by –6 microns in the aflibercept group and –1 micron in the sham group.
About 5 injections of aflibercept were administered for DME and 0.3 in the sham group; over 2 years, the aflibercept patients received 8 injections and the sham-treated patients received 1.1 injections.
Adverse events associated with aflibercept included 3 cases of endophthalmitis, 2 of retinal detachment, 13 of IOP spikes of 10 mm Hg or higher, and 8 of IOP elevations of 30 mm Hg or higher. In the sham group, 2 patients had retinal detachments, 12 had IOP spikes of 10 mm Hg or higher, and 3 had IOP spikes of 30 mm Hg or higher.
Hypertension was the systemic event seen in more patients, with 18 in the aflibercept cohort and 13 in the sham group.
The major study findings indicated that among eyes with moderate to severe NPDR, the proportion that developed PDR or center-involving DME was lower with periodic aflibercept treatments compared with sham treatment through the 2-year point. Preventive treatment with aflibercept did not confer a VA benefit compared with anti-VEGF initiated after PDR or DME development.
Maturi pointed out that this 4-year study may be important to determine whether preventing PDR and center-involved DME improves the long-term outcomes.