Ocular and Systemic Risk Factors for Disease Worsening Among Patients with NPDR: Post Hoc Analysis of the PANORAMA Trial

Purpose: Identify baseline systemic and ocular characteristics associated with nonproliferative diabetic retinopathy (NPDR) worsening and the impact of intravitreal aflibercept injection (IAI) on these associations. Design: Post hoc analysis of PANORAMA. Participants: Patients with moderately severe to severe NPDR enrolled in the prospective PANORAMA phase III trial. Methods: Associations between baseline systemic and ocular factors with events indicative of NPDR worsening at week 100 were evaluated by multivariable analysis in sham-treated eyes. Nonproliferative diabetic retinopathy worsening was defined as the development of (1) vision-threatening complications (VTCs; comprising proliferative diabetic retinopathy and/or anterior segment neovascularization), (2) center-involved diabetic macular edema (CI-DME), or (3) ≥ 2-step Diabetic Retinopathy Severity Scale (DRSS) worsening. The impact of IAI on identified baseline factors was evaluated using univariable analysis in combined IAI groups. Main Outcomes Measures: Baseline systemic and ocular factors associated with events indicative of NPDR worsening at week 100. The cumulative incidence and risk of developing such events at week 100 among sham versus IAI-treated eyes. Results: Using multivariable analyses among sham-treated eyes, 5 baseline factors associated with increased risk of NPDR worsening were identified: fluorescein leakage, retinal nonperfusion area, thicker central subfield thickness, eosinophil level, and proteinuria. Considering baseline fluorescein leakage area as a prognostic indicator in detail, the risk of developing VTCs alone, VTCs and/or CI-DME, or ≥ 2-step DRSS worsening increased with increasing fluorescein leakage area in the sham group (all P < 0.05). Considering baseline retinal nonperfusion area as a prognostic indicator in detail, the risk of developing VTCs alone, CI-DME alone, or VTCs and/or CI-DME increased with increasing baseline retinal nonperfusion area in the sham group (all P < 0.05). In contrast, among IAI-treated eyes, increasing baseline fluorescein leakage or retinal nonperfusion areas did not increase the risks of NPDR worsening. Conclusions: Within the PANORAMA trial, increased areas of fluorescein leakage and retinal nonperfusion at baseline were identified as key ocular biomarkers associated with events indicative of NPDR worsening among sham-treated patients. Intravitreal aflibercept injection treatment seemed to mitigate the effect of these baseline risk factors and reduced the likelihood of NPDR worsening. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.