Longitudinal Panretinal Leakage and Ischemic Indices in Retinal Vascular Disease after Aflibercept Therapy: The PERMEATE Study

Abstract

Purpose: To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs).

Design: Prospective open-label study (clinicaltrials.gov identifier, NCT02503540).

Participants: Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO.

Methods: Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected.

Main outcome measures: The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA.

Results: Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P < 0.0001), and central subfield thickness also improved significantly, with a mean reduction of 301.3±250.3 μm (P < 0.0001). Mean panretinal leakage index improved significantly, decreasing from 3.4% at baseline to 0.5% at month 6 (P <0.0001) and 0.4% at month 12 (P < 0.0001). Panretinal ischemic index did not demonstrate any significant change but showed a nonsignificant increase from 5.5% at baseline to 6.1% at month 6 (P = 0.315) and 8.7% at month 12 (P = 0.193). Eyes with DME showed a decrease in leakage index from 3.5±2.7% at baseline to 1.6±0.8% at month 12 (P = 0.018) and overall stability in ischemic index from 5.0±4.1% at baseline to 4.7±3.5% at month 12 (P = 0.689). Participants with RVO showed a decrease in leakage index from 3.3±1.1% at baseline to 0.02±0.03% at 12 months (P < 0.0001) and a nonsignificant increase in ischemic index from 5.9±4.5% at baseline to 12.6±9.8% at month 12 (P = 0.172).

Conclusions: Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening.

Figure 1:

Study Design. Additional treatment with intravitreal IAI injection at observation visits if criteria met. OCT-A is optional at month 0, 3, 6, 9 and 12.

Figure 2:

Ultra-widefield fluorescein angiograms from two representative PERMEATE subjects. A-C, Late-phase UWFA image of a patient diagnosed with CRVO. UWFA with overlay of the leakage in red (B), and binary mask containing the segmented leakage (C). D-F, Early phase UWFA of a patient diagnosed with PDR. UWFA with ischemia overlay in green (E), and binary mask containing the segmented ischemia (F).

Figure 3:

UWFA images from two PERMEATE subjects. The left column is the baseline visit, middle column shows month-6, and the right column is month-12. A-C, Late-phase UWFA images of a subject diagnosed with CRVO. D-F, Leakage overlay in red. G-I, Early-phase angiograms of a subject with PDR and a close-up view of the inferonasal quadrant presenting an area of ischemia which remains the same over the three time points. J-L, Ischemia overlay in green.

Figure 4:

Percentage of mean leakage index values (Top) and mean ischemic index values (Bottom) from baseline to month 12. Black lines show overall results; orange lines show results for subjects diagnosed with DME; blue lines show results for patients diagnosed with RVO. *P < 0.05, **P < 0.01, and ***P < 0.0001 versus baseline.

Figure 5:

Graphs showing the functional and anatomical outcomes of PERMEATE subjects. (Top) Mean change in best-corrected visual acuity (BCVA) from baseline to month 12. (Bottom) Mean change in central (OCT) subfield thickness (CST) at each study visit. Black lines represent overall results; orange lines are values for patients with DME; blue lines represent patients with RVO. *P < 0.05, **P < 0.01, and ***P < 0.0001 versus baseline.

Figure 6:

Additional key secondary endpoints. Bar graph showing functional outcomes after 6 months and 12 months of treatment for the full analysis set (A), patients diagnosed with DME (B), and patients diagnosed with RVO (C). Proportion of eyes that gained and lost ≥ 15 letters from baseline; proportion of eyes that had a best-corrected visual acuity (BCVA) ≥ 20/40 and ≤20/200. *P < 0.05, **P < 0.01, and ***P < 0.0001 versus baseline.