Long-term Outcomes in Ranibizumab-Treated Patients With Retinal Vein Occlusion; The Role of Progression of Retinal Nonperfusion

Abstract

PURPOSE To determine the percentage of ranibizumab-treated patients with retinal vein occlusion (RVO) who had resolution of edema for at least 6 months after the last injection, along with factors and outcomes that correlate with resolution. DESIGN Post hoc analysis of open-label clinical trial. METHODS Twenty patients with branch RVO (BRVO) and 20 with central RVO (CRVO) received ranibizumab monthly for 3 months and as needed for recurrent/persistent macular edema, no more frequently than every 2 months. Patients still requiring injections after month 40 received scatter and grid laser photocoagulation to try to reduce the need for injections. Main outcome measures included the percentage of patients who had resolution of edema, change in best-corrected visual acuity (BCVA) from baseline, and change in area of retinal nonperfusion in central subfields. RESULTS Nine patients with BRVO (45%) had edema resolution from injections alone after a mean of 20.2 months, 4 resolved after addition of laser, 4 were unresolved through 72 months, and 3 exited prior to resolution. Five patients with CRVO (25%) resolved from injections alone after a mean of 14.0 months, 8 remained unresolved through 72 months despite addition of laser, and 7 exited prior to resolution. For BRVO or CRVO, there was a negative correlation between posterior retinal nonperfusion area and BCVA at months 18, 24, and 36 (P < .05). CONCLUSIONS In patients with RVO, infrequent ranibizumab injections to control edema may not be sufficient to prevent progression of retinal nonperfusion, which may contribute to loss of visual gains.

Changes in Retinal Microvasculature and Visual Acuity After Antivascular Endothelial Growth Factor Therapy in Retinal Vein Occlusion

“…While some reports demonstrate adverse vasoconstrictive effects on retinal perfusion that include a reduction in retinal vessel diameters and flow velocities, [31][32][33][34] there are others that demonstrate positive effects of anti-VEGF therapy on retinal perfusion, such as prevention of retinal nonperfusion. 35,36 In the current study, quantitative OCTA imaging identified that both VD and FAZ within the 3 3 3-mm area did not differ significantly during the course of anti-VEGF therapy for 12 months in patients with RVO. In addition, number of the anti-VEGF injections was not significantly associated with changes in the VD and FAZ area.…”

Reversible retinal vessel closure from VEGF-induced leukocyte plugging

“…However, measurement of area of retinal nonperfusion at several time points in RVO patients participating in clinical trials showed that progression of nonperfusion was the rule rather than the exception and that it did not occur abruptly, but rather progressed continuously through at least 24 months, the last measurement time point (30,31). In these and other clinical trials (32)(33)(34), it has been noted that subjects with substantial nonperfusion at baseline showed more rapid and often more severe worsening of nonperfusion than those with little or no nonperfusion at baseline. This suggests that all CRVOs are ischemic but to different degrees, resulting in different levels of VEGF expression, and it is eyes at the most severe end of the ischemia spectrum at baseline that tend to show the most rapid and extensive progression of retinal nonperfusion, which 5 Cyclophilin A transcripts for VCAM-1, ICAM-2, integrin β1, and integrin α4 (n in parentheses along x axis, *P < 0.05 by unpaired t tests).…”

“…In some patients, particularly those that are older, there is immediate closure of some retinal capillaries and/or arterioles, probably due to preexistent arterial disease. Regardless of the amount of retinal vessel closure that occurs immediately after thrombosis, it is frequently followed by additional closure of retinal vessels that can be reversed by VEGF suppression (32)(33)(34). In untreated eyes with CRVO, the worsening of retinal nonperfusion can be so profound that it leads to severe loss of vision due to widespread ischemic death of retinal cells, including those in the macula and/or neovascular glaucoma, a severe complication that often leads to loss of the eye.…”

“…Measurement of retinal nonperfusion in clinical trials have shown that progression of retinal nonperfusion is extremely common in untreated patients with CRVO or BRVO (30,31). Suppression of VEGF slowed progression of retinal nonperfusion and caused reopening of some previously closed retinal vessels in patients with CRVO or BRVO, whereas sham-treated patients or those in whom anti-VEGF treatment was stopped had progressive worsening of retinal nonperfusion (32)(33)(34). Some patients have nonperfusion that does not improve with VEGF suppression, and patients who show improvement in one region of nonperfusion may not in another, indicating that a substantial amount of nonperfusion is permanent, though the demonstration that some is reversible was surprising and exciting.…”

Intravitreal PRN ranibizumab treatment for macular edemadue to branch retinal vein occlusion

“…In this study, patients with BRVO received monthly intraocular ranibizumab injections for 6 months. Although previous studies (12)(13)(14) reported the efficacy of different dosing regimens in BRVO, an established therapeutic algorithm has not been reported yet. In addition, these studies did not address the issue of the ischemic or nonischemic nature of the retinal perfusion.…”