Intraocular Pressure Changes and Vascular Endothelial Growth Factor Inhibitor Use in Various Retinal Diseases: Long-Term Outcomes in Routine Clinical Practice: Data from the Fight Retinal Blindness! Registry

Written by: Rehan M. Hussain, MD

December 2020

Gabrielle PH, Nguyen V, Wolff B, et al. Intraocular Pressure Changes and Vascular Endothelial Growth Factor Inhibitor Use in Various Retinal Diseases: Long-Term Outcomes in Routine Clinical Practice: Data from the Fight Retinal Blindness! Registry. Ophthalmol Retina 2020 Sep;4(9):861-870. doi: 10.1016/j.oret.2020.06.020. Epub 2020 Jun 20.

It is well established that a transient rise in IOP occurs immediately after an intravitreal injection, however the degree to which anti-VEGF agent injections contribute to long-term IOP changes is debated.

The purpose of this study was to report long-term changes in IOP in eyes receiving VEGF inhibitors for various retinal conditions (AMD, DME, RVO) over 12 and 24 months in routine clinical practice. The study design was a retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project. Participants in this analysis included patients from practices in Australia, France, New Zealand, Singapore, and Switzerland.

The data set included 3429 treatment-naïve eyes (395 receiving bevacizumab, 1138 receiving aflibercept, and 1896 receiving ranibizumab) with complete IOP data from 3032 patients with 12 months of follow-up data, of which 2125 (62%) had 24 months of follow-up data. Patients had at least 3 injections from December 2013 through December 31, 2018. Eyes with pre-existing glaucoma were identified at baseline.

The primary outcome was the mean change in IOP (in mmHg) at 12 months. The following secondary IOP outcome measures were investigated at 12 and 24 months: (1) mean change in IOP from baseline and (2) proportion of clinically significant IOP increase defined as an elevation of at least 6 mmHg to an IOP of more than 21 mmHg at any point during the follow-up.

The overall mean IOP change was –0.5 mmHg (at 12 months and –0.4 mmHg at 24 months, whereas the proportions of clinically significant IOP increases were 5.6% and 8.8%, respectively. A lower mean IOP change and fewer IOP elevations at 12 and 24 months was observed in eyes receiving aflibercept than in those receiving bevacizumab and ranibizumab ( P ≤ 0.01 for both comparisons at each time point and outcome). No difference was found between bevacizumab and ranibizumab at 12 and 24 months.

Clinically significant IOP elevations during 12 and 24 months of follow-up were less likely to occur in aflibercept-treated eyes than eyes treated with bevacizumab (odds ratio [OR] 2.2; P=0.015 and 2.7 [P < 0.01], respectively) or ranibizumab (OR 2.8; P < 0.01] and 2.6 [P < 0.01], respectively). The rates of clinically significant elevated IOP were 2.4% and 3.9% in the aflibercept group, 5.2% and 9.7% in the bevacizumab group, and 6.4% and 9.4% in the ranibizumab group during 12 and 24 months of follow-up, respectively.

Treated eyes with RVO tended to be significantly more at risk of IOP elevations during the first 12 months of follow-up than eyes treated for AMD (OR 1.9,  P = 0.039), although this association was not statistically significant at 24 months.

Eyes with pre-existing glaucoma demonstrated more IOP increases over 12 and 24 months (OR 2.2 [P = 0.012] and 2.1 [P = 0.025], respectively), consistent with previous reports. A trend was found for an increasing rate of IOP elevations with more injections during both 1 and 2 years of follow-up; however, this was not statistically significant.

There are numerous theories regarding the pathophysiology of sustained IOP elevations associated with anti-VEGF therapy. It may be related to a decrease in aqueous outflow by chronic mechanical damage to the trabecular meshwork resulting from repeated injection-related IOP spikes, direct toxicity of anti-VEGF medication, obstruction resulting from accumulation of protein aggregates or silicone droplets, or even trabecular meshwork constriction mediated by inhibition of nitric oxide synthesis.

As for why aflibercept patients were less likely to experience clinically significant IOP elevations, the authors propose that its unique inhibition of placental growth (PlGF) factor may control against an inflammatory response that occurs secondary to upregulated PlGF in patients receiving repeated anti-VEGF injections.

This study found no significant difference in IOP outcomes between the prefilled and non-prefilled syringe time periods. This is not consistent with the theory that droplets of silicone oil, applied to lubricate the components of the insulin syringe used for bevacizumab or non-prefilled ranibizumab packing, play a role in IOP elevations.

One major limitation of this study is that no specific protocol for IOP measurements was defined. They did not record which instrument was used to measure the IOP, so this was not adjusted for in the analysis. Also, data on glaucoma treatment during follow up such as introduction of IOP-lowering drops, laser therapy, or incisional glaucoma surgery were not recorded systematically, and hence the authors could not address the influence of these factors on results. There was no analysis on the influence of IOP changes on onset or progression of glaucoma.

In conclusion, mean IOP did not change significantly from baseline to 12 and 24 months in eyes receiving anti-VEGF injections, whereas clinically significant IOP elevations occurred in a small proportion of eyes. Aflibercept may be safer than bevacizumab or ranibizumab in eyes with glaucoma or ocular hypertension that require treatment for exudative retinal disease.