Are Improvements in Diabetic Retinopathy Severity Clinically Meaningful? Insights from Studies of Intravitreal Ranibizumab (RBZ) in Patients with Diabetic Macular Edema (DME)

Abstract

Purpose: Worsening of diabetic retinopathy (DR) severity, seen by step changes in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR severity scale, is clinically important because even a single step worsening implies a markedly increased risk for proliferative DR and/or DME in the future. However, the clinical relevance of DR improvement is not well understood because it has not been commonly observed in controlled trials. We have reported that intravitreal RBZ not only reduces the likelihood of DR worsening, but also improves DR severity in many patients, providing an opportunity to study the clinical significance of improvement. We explored associations between DR improvement and clinical outcomes using data from Phase III studies of DME patients.

Methods: Twenty-four month outcomes from 468 RBZ-treated patients in RIDE (NCT00473382) and RISE (NCT00473330) were used; these were patients randomized to monthly 0.3mg or 0.5mg RBZ who had baseline DR severity data. Best-corrected visual acuity (BCVA) was assessed by ETDRS testing; contrast sensitivity (CS) by a Pelli-Robson chart; central foveal thickness by optical coherence tomography (OCT); and ETDRS DR severity levels by evaluation of photos at a reading center. BCVA, CS, and OCT outcomes across groups experiencing varying levels of change in DR severity were displayed along with the incidence of DR-associated clinical events. Durability of DR severity changes following cessation of RBZ therapy was examined.

Results: At month 24, significant BCVA gain (≥15 ETDRS letters) was more common in patients with 2 or ≥3-step DR improvement compared to those with no change or 1 step DR improvement or worsening (Table). Similarly, the magnitude of mean BCVA and CS changes were greater with 2 or ≥3-step DR improvement, and resolution of macular edema (OCT ≤250 um) was more common.

Conclusions: Patients with substantial DR improvement (2 or ≥3 steps) were more likely to show significant gains in vision, and also trend to better mean improvements in BCVA, visual function, and anatomic outcomes compared to those with either no change or worsening in DR severity. Substantial improvement in DR severity is thus a clinically important outcome.

Keywords: 499 diabetic retinopathy • 505 edema • 748 vascular endothelial growth factor