Anti-VEGF Injection IOP Elevations
Anti-VEGF agents have been employed for a variety of uses in the treatment of ocular disease, and several reports have shown both acute and chronic increases in intraocular pressure (IOP) following injection of these drugs. This article will review these data and their relevance to glaucoma.
In 2004, pegatinib (Macugen) was the first anti-VEGF agent approved for intravitreal injection (IVI) for the treatment of neovascular age-related macular degeneration (ARMD). Since then, a host of other agents including ranibizumab (Lucentis), bevacizumab (Avastin), aflibercept (Eylea), and more recently, Faricimab (Vabysmo) have been approved for the treatment of macular edema secondary to diabetes, branch retinal vein occlusion, and central retinal vein occlusions as well as degenerative myopia. 
Soon after the introduction of these drugs, reports of acute spikes in IOP began to emerge and have been reported in multiple studies.              Nonetheless, the MARINA and ANCHOR clinical trials, which demonstrated the efficacy of Bevacizumab for treatment of neovascular age-related macular degeneration, found that these spikes were transient.  However, in a post-hoc analysis by Bakri et al, patients treated with anti-VEGF agents were found to have a greater likelihood of an increase in pre-injection IOP ≥6 mmHg from baseline and a concurrent IOP of ≥21 mmHg or ≥25 mmHg at ≥2 consecutive visits compared to those who received sham injections over a 24-month follow up period. Since then, a host of studies have been conducted demonstrating a sustained increase IOP following anti-VEGF injection. Given that the same aging population for which these drugs are most often employed is also at risk for developing glaucoma, understanding the potential for short- and long-term IOP spikes and the impact of anti-VEGF injections on glaucomatous progression is of critical importance. In this article, we will discuss data on the post-injection spike, long-term sustained IOP elevation, the impact on glaucomatous progression in susceptible eyes, and possible prophylactic measures that may be taken.
Post-injection spike in IOP
A post-injection spike in IOP is a logical outcome as the eye undergoes volume expansion. Summing the effect of 14 studies on short-term pressure effects of anti-VEGF injections (median 60 injected eyes, 12-853), Hoguet et al found 100% of patients had an increase in IOP (mean ≤18 mmHg pre-injection) to 28.3-55.2 at 1 minute; at 10-15 minutes the IOP decreased to 22.8-25.8 mmHg, and at 30 minutes it further decreased to 17.6-24.5 mmHg2. IOP continued to decrease over time in studies that captured longer time points, suggesting these IOP spikes were transient. Typically, post-injection IOP returned to baseline within 1 hour.
These findings were also supported by a recent large meta-analysis of 46 articles (2872 eyes), that reported that the mean difference in IOP after anti-VEGF injection (rise above pre-injection) was 23.41 mm Hg immediately after injection, 2.51 mm Hg at 30 minutes, −0.63 one day after injection, and back to baseline by 1 week. 
Long-term sustained IOP elevation
The best evidence for sustained IOP elevation following anti-VEGF injections comes from a post-hoc analysis of the MARINA and ANCHOR trials by Bakri et al which found the incidence of a >6 mmHg IOP spike from baseline in at least one visit with a simultaneous IOP ≥21 mmHg was 23.6% in the 0.3mg ranibizumab group, 26.1% in the 0.5 mg ranibizumab group, and 13.6% in the sham injection groups. Several studies have replicated these findings in different populations as shown in the table below.           Several cases have also been documented in which sustained IOP elevation following injection necessitated surgical filtration procedures.   In fact, a case-control study in Canada found that eyes with ≥7 annual injections had a significantly greater odds ratio of undergoing glaucoma drainage surgery than controls. This finding is bolstered by several studies showing total number of injections to be a risk factor for sustained IOP elevation as well as greater frequency of injections and pre-existing diagnosis of glaucoma prior to initiation of IVIs.     
|Author||Definition of IOP elevation||# Eyes||Mean # Injections||Mean Follow-Up (Weeks)||Preinjection IOP (Mean)||IOP at Study End (Mean)||% With Sustained IOP Elevation|
|Al-Abdullah 2015||IOP ≥6 mmHg above baseline, increase >20%, or IOP >24 mmHg on ≥2 consecutive visits||760||3.4||78.0||17.2||17||5.8%|
|Atchison 2018||IOP ≥6 mmHg above baseline and >21 mmHg on ≥2 consecutive visits||23776||7.9||96.6||15.3||14.4||2.6%|
|Choi 2011||IOP >25 mmHg on 2 separate visits||155||7.0||57.4||14.4||15.3||5.5%|
|Freund 2015||IOP >21 mmHg for ≥2 consecutive visits||595||16.0||96.0||15||NR||8.4%|
|Hoang 2012||IOP >5 mmHg above baseline on ≥2 consecutive visits||207||20.8||148.6||NR||NR||11.6%|
|Kim 2014||IOP >5 mmHg above baseline on ≥2 consecutive visits||629||9.5||151.7||14.1||14.2||3.7%|
|Mathalone 2012||IOP ≥22 mmHg and change from baseline of ≥6 mmHg recorded on ≥2 consecutive visits and lasting ≥30 days||201||4.0 (median)||68.0||14.8||15.5||11.0%|
|Bilgic 2020||IOP ≥6 mmHg above baseline and/or >24mmHg on 2 or more consecutive visits||1021||NR||183.7||NR||NR||8.9%|
|Gabrielle 2020||IOP ≥6 mmHg above baseline and >21mmHg at a single visit||3429||NR||52.0||14.4||13.9||4.9%|
|Cui 2019||having filled a prescription for IOP-lowering medication or having a new diagnosis of glaucoma, glaucoma suspect, or ocular hypertension||17113||NR||135.2||NR||NR||12.0%|
NR = not recorded
A handful of reports have been published in which no increased risk of IOP elevation over a 1-40 month period was found.      Only one of these studies, however, explicitly defines IOP elevation. Wehrli et al found no significant difference in sustained IOP elevation between 270 injected eyes and 195 control eyes with sustained IOP elevation defined as ≥22mmHg on 2 consecutive visits or >26mmHg on a single visit over a 5 year period. Compared to the studies which did find an increased risk of IOP elevation in anti-VEGF-treated eyes, these studies were limited by smaller sample sizes (average 111 vs 4,372 eyes) and shorter follow-up periods (72 vs. 106 weeks). Several risk factors have been shown to be associated with sustained IOP elevation following injection. First, and perhaps least surprisingly, is total number of injections. In a multitude of studies the total number of injections has been shown to be associated with an increased risk of sustained IOP elevation.       Some have suggested that the an accumulation of some component of the injection may effectively clog the trabecular meshwork, which is supported by the decrease in outflow facility seen by Schiøtz tonography. Importantly, a pre-existing glaucoma diagnosis was found to be associated with sustained IOP elevation defined as ≥22 mmHg lasting ≥30 days, recorded on at least two separate visits and a change from baseline of >6 mm Hg. Another study similarly found an association with preexisting glaucoma and sustained IOP elevation defined as a rise in IOP above baseline by ≥6 mmHg and/or >24 mmHg on 2 or more consecutive visits. Other risk factors studied have included higher injection volume and specific anti-VEGF agents, with two studies finding ranibizumab to be associated with more IOP elevation than aflibercept.
Development of Open-Angle Glaucoma
Whether or not the use of anti-VEGF agents is associated with the development of glaucoma is of great interest. Cui et. al demonstrated that patients receiving more injections (14 or more injections at 2 y follow-up and 20 or more injections at 3 y follow-up) had higher odds of initiating IOP-lowering therapy or having a new diagnosis of glaucoma. Filek et al found an increased cup-to-disc ratio and cup volume was observed over a 2 year study period in patients undergoing treatment with ranibizumab for diabetic macular edema, however there was no significant trend in deterioration of visual fields. Similarly, Gómez-Mariscal et al found significant cup widening, deepening, and RNFL thinning seen in eyes treated with anti-VEGF agents. Regarding a diagnosis of glaucoma, Wingard et al found the incidence of glaucoma or ocular hypertension diagnosis was significantly higher in patients undergoing a higher frequency of anti-VEGF injection for AMD for each additional injection over the most injection-intense 6 month period for any given subject. Furthermore, several studies have found an increased incidence of surgical filtration surgeries among patients undergoing repeated anti-VEGF injections.  
Development of Angle-Closure Glaucoma
Several case reports describe acute angle-closure glaucoma temporally related to intravitreal injection. Jeong et al described a case in a hyperopic eye and proposed that eyes with short axial lengths are at higher risk due to less room to accommodate for the injected volume of fluid. They performed a prophylactic peripheral iridotomy in the contralateral eye to prevent future post injection attacks. Alkin et al suggested that anterior chamber depth might shallow after intravitreal injection in correlation with the acute rise in IOP due to increased posterior chamber volume. Kim and Baek described a case of angle closure in an eye that was not hyperopic, however they suggested that zonulopathy and mydriasis might have contributed to the patient’s angle-closure. These reports indicate that it might be prudent to assess eyes for risk of angle closure, including gonioscopy, before initiating intravitreal injections.
Exacerbation of Glaucoma
Exacerbation of glaucoma following the use of anti-VEGF agents has been documented. In 2017, Eadie et al used a big-data approach to investigate the risk of necessitating glaucoma surgery in all patients in British Columbia receiving bevacizumab injections for ARMD over a four-year period. Using 10:1 matched controls for age, glaucoma diagnosis, data, and follow-up time, there was an adjusted risk ratio of 2.48 for undergoing glaucoma surgery in patients receiving bevacizumab. Furthermore, 7 or more injections was associated with an increased risk of surgery.
It has been proposed that glaucoma patients have a larger and more persistent IOP spike after injections which may result in progression of disease. Kim et al found that eyes with preexisting glaucoma take longer to recover from the acute spike after injection. They found that fewer eyes with glaucoma had reached an IOP < 30 mm Hg at 5, 10, and 15 minutes after injection compared with non-glaucomatous eyes.
In 2019, Du et al found a higher rate of visual field decline, glaucoma surgery, and RNFL thinning in injected glaucomatous eyes over an eight year period compared to those not undergoing injection. This study was limited by a small sample size and a high percentage of retinal vein occlusions in the glaucomatous group (which are associated with RNFL thinning). Nonetheless, significant RNFL thinning and cup widening following repeated injections has been observed in another study by Gómez-Mariscal et al in which ARMD was the primary indication for anti-VEGF injection.
Post-Injection Changes to Retinal Nerve Fiber Layer
Given the risk of IOP spike after multiple IVIs, the impact of injections on RNFL loss has also been studied, with mixed results. A meta-analysis by de Vries et al included 4 studies on this topic and concluded that RNFL was significantly reduced by −3.34 µm at 1 year. This being said, only 1 of the 4 individual studies (Martinez-de-la-Casa et al) inferred that injections were associated with thinning.
In the prospective study by Martinez-de-la-Casa et al, 49 treatment eyes and 17 control eyes were compared over a span of one year. They demonstrated significant RNFL thinning in IVI treated eyes, while no change was noted in the control group.  Jo et al found that RNFL was not reduced in eyes treated with ranibizumab and suggested that areas of RNFL thinning might more likely be related to the macular lesion rather than the injections. Entezari et al also found that RNFL was similar to baseline at 1 year in eyes injected with bevacizumab, but similarly concluded that temporary RNFL thinning might be related to changes in macular edema. Parlak et al found thinning in both injected eyes and control eyes without a difference between the groups.
Outside of de Vries and colleagues’ meta-analysis, other studies have largely failed to show an association of IVIs and RNFL loss. Valverde-Megias et al followed 20 injected eyes and their contralateral control eyes for 8 years and demonstrated RNFL loss in both groups but no difference in RNFL thickness between injected and control eyes. Horsley et al reported no RNFL loss in a retrospective study of injected eyes that underwent RNFL measurement over the span of at least 1 year. Swaminathan et al reported no difference in RNFL thinning per year in a retrospective study of 53 injected eyes versus fellow eye controls. Soheilian et al randomized patients undergoing IVI to receive a prophylactic anterior chamber paracentesis or standard protocol without paracentesis. They noted acute IOP spikes and RNFL loss at 3 months in eyes undergoing standard IVI protocols, while this was prevented in eyes receiving a prophylactic anterior chamber paracentesis.
If there is an association between injections and RNFL loss, then it is likely that some but not all eyes are susceptible, and that larger studies are necessary to adequately describe this relationship. It must also be noted that interpretation of these studies is difficult given that RNFL thickness might be impacted by injections as well as the underlying retinal pathology.
Proposed Mechanism for sustained IOP increase following anti-VEGF Injection
Multiple mechanisms have been proposed to explain a sustained increase in IOP following anti-VEGF injections. A decrease in outflow facility has been one proposed mechanism secondary to either obstruction by some component of the injection or an inflammatory response. Supporting this theory is one study which found outflow facility to be significantly decreased in eyes receiving anti-VEGF therapy as measure by Schiøtz tonography when patients had ≥20 intravitreal injections. Microparticle obstruction of the trabecular meshwork is one possibility that has been explored by multiple groups, whether due to high-molecular weight protein aggregates from medication packaging or silicone microdroplets from syringes.   Alternatively, a direct inflammatory effect of anti-VEGF agents on trabecular meshwork cells has been explored. Kahook et al demonstrated 4 mg/ml bevacizumab slows the metabolism and replication of trabecular meshwork cells in vitro, possibly contributing to decreased outflow facility. Additionally, an inflammatory response to monomer antibodies, protein aggregates or high molecular weight molecules may lead to a trabeculitis with impaired aqueous humor outflow. 
Another proposed mechanism is related to the inhibition of nitric oxide synthase by anti-VEGF agents. This results in a decrease in nitric oxide which results in a downstream movement of potassium and calcium in trabecular meshwork cells, alteration of trabecular meshwork cell contractility, and ultimately decreased aqueous outflow through intercellular spaces. Nitric oxide’s effect on smooth muscle contractility has been linked to systemic hypertension in patients receiving anti-VEGF injections, and thus has also been proposed to increase outflow resistance in the eye.
Management and Prevention
Several prophylactic measures have been suggested to prevent the acute post-injection IOP spike in patients for whom large IOP fluctuations pose a risk such as those with advanced glaucomatous disease. Pre-injection topical glaucoma medications have proven successful in limiting post-injection IOP elevation in several studies.      Additionally, the presence of vitreous reflux following injection has been associated with a lower IOP spike.  Other factors found to prevent acute IOP spikes include ocular decompression by cotton swabs, a history of glaucoma surgery, pseudophakia, and anterior chamber paracentesis.
Regarding sustained IOP elevation following long-term anti-VEGF therapy, no successful mitigation strategy has been thoroughly investigated. Regarding the theory that silicone oil originating from coating on syringes ultimately occludes the trabecular meshwork, Lode et al has described a method of compounding anti-VEGF agents in silicone-free syringes, however more research needs to be done on its efficacy. Wingard et al suggested that patients with known risk factors for sustained IOP elevation should consider lower frequency injections at initiation of therapy and extension of the inter-injection interval. Nonetheless, foregoing anti-VEGF therapy or extending the intervals of injection risks progression of the diseases these agents treat. Ultimately, patients should be monitored for development of ocular hypertension, and those who develop a sustained increase in IOP should be evaluated periodically for glaucomatous changes via an optic nerve OCT and visual field testing. Referral to a glaucoma specialist should be considered in patients with concerning features.
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