Anti-VEGF Injection IOP Elevations

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Introduction 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 following injection of these drugs. This article will review these data and their relevance to glaucoma. History In 2004, pegatinib (Macugen) was the first anti-VEGF agent approved for intravitreal injection for the treatment of neovascular age-related macular degeneration1. Since then, a host of other agents including ranibizumab (Lucentis), bevacizumab (Avastin), aflibercept (Eylea), and more recently brolucizumab (Beovu) 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 myopia2, 3. Soon after the introduction of these drugs, reports of acute spikes in intraocular pressure (IOP) began to emerge and have been reported in multiple studies4-17. 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 transient18, 19. 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 period20. 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. 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 groups20. Several studies have replicated these findings in different populations as shown in the table below21-31. Several cases have also been documented in which sustained IOP elevation following injection necessitated surgical filtration procedures32-34. In fact, a recent case-control study in Canada found that eyes with ≥7 annual injections had a significantly greater odds ratio of undergoing glaucoma drainage surgery than controls32. 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.25, 27, 35-40 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% Silva 2013 NR 210 6.1 104.0 NR NR 6.4% 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 found41-46. 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 period45. 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 elevation25, 29, 32, 35-37, 39. 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 tonography47. Importantly, a pre-existing glaucoma diagnosis was found to be associated with sustained IOP elevation with sustained IOP defined as ≥22 mm Hg lasting ≥30 days, recorded on at least two separate visits and a change from baseline of >6 mm Hg38. Another study similarly found an association with preexisting glaucoma with sustained IOP defined as a rise in IOP above baseline by ≥6 mmHg and/or >24 mmHg on 2 or more consecutive visits29. 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 aflibercept24, 29. Development of Glaucoma Whether or not the use of anti-VEGF agents is associated with the development of glaucoma is of great interest. 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 fields48. Similarly, Gómez-Mariscal et al found significant cup widening, deepening, and RNFL thinning seen in eyes treated with anti-VEGF agents49. 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 subject50. Furthermore, several studies have found an increased incidence of surgical filtration surgeries among patients undergoing repeated anti-VEGF injections32-34. 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 bevacizumab32. Furthermore, 7 or more injections was associated with an increased risk of surgery. Additionally, 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 injection34. 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)51. Nonetheless, significant RNFL thinning and cup widening following repeated injections has been observed in another study by Gómez-Mariscal et al in which age-related macular degeneration was the primary indication for anti-VEGF injection49. 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 response52. 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 injections47. 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 syringes53-55. 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 facility56. Additionally, an inflammatory response to monomer antibodies, protein aggregates or high molecular weight molecules may lead to a trabeculitis with impaired aqueous humor outflow57, 58. Disruption of nitric oxide signaling secondary to VEGF blockade has also been proposed to disrupt aqueous outflow and contribute to ocular hypertension59. 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 studies60-65. Additionally, the presence of vitreous reflux following injection has been associated with a lower IOP spike65-67. Other factors found to prevent acute IOP spikes include ocular decompression by cotton swabs68, a history of glaucoma surgery69, pseudophakia29, 50, and anterior chamber paracentesis70. Regarding sustained IOP elevation following long-term anti-VEGF therapy, no successful mitigation strategy has been thoroughly investigated. 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 interval50. 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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