A real or theoretical concern?

Intravitreal VEGF inhibitors have revolutionized the management of neovascular AMD, DME, and macular edema associated with retinal vein occlusion. Steroid agents tend to be associated with an increase in intraocular pressure (IOP) — some more than others — when injected in the vitreous cavity. As experience with intravitreal anti-VEGF agents grows (now more than 10 years!), we wonder whether they may also be associated with increased IOP (though perhaps not to the degree associated with some of the steroid agents).

A recent report indicated that 7 or more intravitreous injections of bevacizumab annually was associated with a higher risk of glaucoma surgery.¹

Since we use these agents so frequently and on a daily basis in our practice, this is an important issue to address. Pertinent questions would include the following:

1. What is the incidence (if any) of sustained increased IOP with serial intravitreal anti-VEGF injections?
2. What are possible mechanisms of increased IOP with these agents?
3. Should we expect a greater tendency with one agent vs another?

Retina specialists who have investigated this issue provide their expert commentary on the subject below.

REFERENCE

1. Eadie BD, Etminian M, Carleton BC, Maberley DA, Mikelberg FS. Association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery. JAMA Ophthalmol. 2017;135(4):363-368.

Long-Term IOP Elevations Are of Minimal Concern

SEENU M. HARIPRASAD, MD

Seenu M. Hariprasad, MD, is Shui-Chin Lee Professor of Ophthalmology and Visual Science, chief of the vitreoretinal service, and director of clinical research at the University of Chicago Medicine & Biological Sciences.

The effect of anti-VEGF injections on IOP has been under critical review over the past few years given the increasing use of these drugs. A short-term increase in IOP after intravitreal injections has been described in several papers.^1-5 In each of these studies, a significant elevation in IOP was found 30 minutes post injection, but returned to baseline levels by the first follow-up clinic visit. These studies challenged the need to perform IOP checks shortly after injection due to the transient nature of the IOP increase. This increase has been theorized to be due to an increase in volume and most often normalizes after 30 minutes, although eyes with glaucoma may take longer to normalize.

Sustained long-term elevation in IOP has been reported with several anti-VEGF agents in a variety of diagnoses.^6-9 While many hypotheses have been generated regarding the pathophysiology behind sustained IOP elevation, a clear understanding of this phenomenon is lacking.^9,10 Proposed associations and risk factors for sustained IOP elevation include total number of injections, interval between injections, and a history of glaucoma or ocular hypertension.^9,11

Notably, large clinical trials have shown that intravitreal injections do not (or very rarely) lead to a sustained increase in IOP.^10,12-14 Post hoc analysis of the MARINA and ANCHOR ranibizumab trials showed that most ranibizumab-treated eyes did not experience a sustained elevation of IOP over 24 months.¹³ Similarly, a large long-term study of anti-VEGF injections did not identify a history of multiple intravitreal anti-VEGF injections as a significant risk factor for IOP elevation.¹⁴ However, a recent survey of retina specialists revealed that 53% still believe that intravitreal injections may cause sustained IOP elevation.¹⁵ Thus, debate surrounding long-term sustained elevation in IOP after intravitreal injections persists.

We recently published our research regarding the long-term effects of anti-VEGF injections on IOP.¹⁶ We performed a retrospective study to investigate how the number and timing of intravitreal injections in patients with AMD and DME affect IOP over time. Patients were grouped according to indication as well as number of injections received. IOP measurements were then placed into various time points and compared with the pre-injection average IOP. Our data suggest that when using a treat‑and‑extend dosing regimen, the administration of anti‑VEGF intravitreal injections is not a significant risk factor for an increase in IOP – regardless of how many injections the patient receives. Clinicians should use anti‑VEGF agents with the confidence that long‑term IOP elevations are of minimal concern, and routine evaluation specifically for IOP elevation may not be necessary. Of course, clinical judgment is advised.

REFERENCES

1. Kim JE, Mantravadi AV, Hur EY, Covert DJ. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol. 2008;146(6):930-934.e1.
2. Falkenstein IA, Cheng L, Freeman WR. Changes of intraocular pressure after intravitreal injection of bevacizumab (Avastin). Retina. 2007;27(8):1044-1047.
3. Mazzulla DA, Hariprasad SM, Jager RD, Mieler WF. Short-term intraocular pressure trends after intravitreal injection of bevacizumab (Avastin). Retina Cases Brief Rep. 2008;2(3):234-235.
4. Mojica G, Hariprasad SM, Jager RD, Mieler WF. Short-term intraocular pressure trends following intravitreal injections of ranibizumab (Lucentis) for the treatment of wet age-related macular degeneration. Br J Ophthalmol. 2008;92:584.
5. Hariprasad SM, Shah GK, Blinder KJ. Short-term intraocular pressure trends following intravitreal pegaptanib (Macugen) injection. Am J Ophthalmol. 2006;141(1):200-201.
6. Segal O, Ferencz JR, Cohen P, Nemet AY, Nesher R. Persistent elevation of intraocular pressure following intravitreal injection of bevacizumab. Isr Med Assoc J. 2013;15(7):352-355.
7. Mathalone N, Arodi-Golan A, Sar S, et al. Sustained elevation of intraocular pressure after intravitreal injections of bevacizumab in eyes with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2012;250(10):1435-1440.
8. Hoang QV, Mendonca LS, Della Torre KE, Jung JJ, Tsuang AJ, Freund KB. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology. 2012;119(2):321-326.
9. Singh RSJ, Kim JE. Ocular hypertension following intravitreal anti-vascular endothelial growth factor agents. Drugs Aging. 2012;29(12):949-956.
10. Abedi G, Adelman RA, Salim S. Incidence and management of elevated intraocular pressure with antivascular endothelial growth factor agents. Semin Ophthalmol. 2013;28(3):126-130.
11. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013;33(1):179-187.
12. Yu AL, Seidensticker F, Schaumberger M, Welge-Lussen U, Wolf A. Evaluation of intraocular pressure elevation after multiple injections of intravitreal ranibizumab. Clin Ophthalmol. 2014;8:743-747.
13. Bakri SJ, Moshfeghi DM, Francom S, et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials. Ophthalmology. 2014;121(5):1102-1108.
14. Kim YJ, Sung KR, Lee KS, et al. Long-term effects of multiple intravitreal antivascular endothelial growth factor injections on intraocular pressure. Am J Ophthalmol. 2014;157(6):1266-1271.e1.
15. Yannuzzi NA, Patel SN, Bhavsar KV, Sugiguchi F, Freund KB. Predictors of sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2014;158(2):319-327.e2.
16. Nariani A, Williams B, Hariprasad SM. Long-term effect of anti-vascular endothelial growth factor injections on intraocular pressure. Indian J Ophthalmol. 2016;64:643-647.

Real-World Data on the Effect of Anti-VEGF on IOP

MATHEW W. MACCUMBER, MD, PHD • ELIZABETH ATCHISON, MD

Mathew W. MacCumber, MD, PhD, is professor and associate chair for research at Rush University Medical Center and Illinois Retina Associates, S.C., in Chicago. Elizabeth Atchison, MD, is a vitreoretinal surgery fellow at Rush University Medical Center and Illinois Retina Associates, S.C.

Our review examined 23,262 patients in the American Academy of Ophthalmology IRIS Registry (Intelligent Research in Sight) who received anti-VEGF agent injections in their right eye. A total of 16,025 (69%) were being treated for exudative AMD, 4,525 (20%) for DME, 2,109 (9%) for edema secondary to vein occlusion, and 603 (3%) for a combination of diagnoses. Three samples were examined: all patients, those with a diagnosis of AMD only, and those who were treatment naive for at least 1 year prior to the start of the study. We also examined a group including all diagnoses but excluding those who had a diagnosis of glaucoma or underwent cataract surgery during the study period to ensure they did not have an undue influence on the data. All patients were followed for at least 1 year and had at least 1 IOP measurement before the first injection and greater than 1 year after. By drug, 14,774 (62%) received only bevacizumab, 4,138 (17%) only aflibercept, and 4,961 (21%) only ranibizumab; all eyes that had received intravitreous steroid were excluded. Patients received an average of 6.9 injections over the course of the study, including 7.8 for those with AMD, 3.8 for those with DME, and 7.1 for those with macular edema after vein occlusion. In all groups, we found a decrease in average IOP from baseline ranging in magnitude from 0.04 mmHg to 0.52 mmHg, which was statistically significant for all groups except for ranibizumab in the treatment-naive group.

Using a generalized linear model to control for confounding factors, we found that in most groups there was a tendency for bevacizumab to have less of an IOP decrease from baseline than aflibercept or ranibizumab. These effects were less than 0.5 mmHg. At the start of the study, 540 patients (2%) had a diagnosis of glaucoma that was associated with an increase of 1 mmHg compared with those without glaucoma in the generalized linear model. Overall, 1.6% of patients received a new diagnosis of glaucoma over the course of our study. The proportion of patients having an IOP rise of >6 mmHg to a new IOP measurement >21 mmHg was 2% to 3% for all 3 anti-VEGF agents in all groups. However, when given over 25 times, bevacizumab caused this sustained pressure rise in an even higher percentage of patients, up to 9.5%; ranibizumab and aflibercept did not have a similar effect.

Although there are several case reports and studies of elevated IOP after starting intravitreous anti-VEGF treatment, our study does not support this as a common phenomenon in clinical practice. There are several reasons our findings may have differed from those of previous studies. Our study examines real-world findings, with fewer injections on average per year than the 12 that 4-week dosing regimens used in most clinical trials. It is also possible that we would pick up more increases if we examined more IOP data points. Additional research presented at ARVO this year further examines the frequency of clinically significant IOP rises.

Sustained IOP Elevation With Serial Anti-VEGF Injections Reported; More Rigorous Studies Necessary

SOPHIE J. BAKRI, MD • VAIDEHI S. DEDANIA, MD

Sophie J. Bakri, MD, is professor of ophthalmology at the Mayo Clinic in Rochester, MN. Vaidehi S. Dedania, MD, is a vitreoretinal surgery fellow at Kellogg Eye Center, University of Michigan, Ann Arbor.

There is growing evidence in the literature that intravitreal anti-VEGF agents can be associated with sustained elevation of IOP. Multiple studies have reported persistent IOP with intravitreal anti-VEGF therapy with incidence varying from 3.45%¹ to 11.6%² and being 4.7% overall.³ Unfortunately, the reported incidence in different studies may not be comparable because there are no uniform criteria for defining sustained elevation of IOP.

Some studies defined elevated IOP as ≥21 mmHg and/or a change from baseline of ≥6 mmHg, while others specified IOP as ≥30 mmHg. Additionally, although the incidence of sustained elevation of IOP with serial intravitreal anti-VEGF injections is not insignificant, it does vary according to the study population. There is a greater tendency to develop sustained elevation of IOP in patients who already carry a diagnosis of glaucoma and possibly in patients with a family history of glaucoma.^3,4

While the exact mechanism underlying the development of sustained elevation of IOP in eyes treated with intravitreal anti-VEGF agents has yet to be elucidated, multiple theories exist. One such theory implicates subclinical inflammation immediately post injection. Such inflammation may cause scar formation and fibroblast proliferation in the trabecular meshwork, impeding aqueous outflow.⁴

A second theory suggests that the transient post-injection IOP rise, which usually resolves within 30 minutes to 60 minutes, can cause chronic damage to the trabecular meshwork with recurrent intravitreal injection. If this theory prevails, we may be able to prevent persistent IOP elevation with the use of preinjection IOP-lowering medications. Support for recurrent and cumulative damage from serial intravitreal injections comes from data that suggest an increased risk of IOP elevation with more injections.

Some data suggest mechanical obstruction of the trabecular meshwork from silicone microdroplets and/or protein aggregates.⁴ There are reports of high-molecular-weight protein aggregates in different samples of compounded/repackaged bevacizumab.

Additionally, reports have shown silicone microdroplets in the anterior chamber after intravitreal injection. These particles may be introduced intraocularly via the delivery equipment, such as the injection syringe.⁴ Because bevacizumab is the only anti-VEGF agent that is compounded/repackaged, some studies have sought to evaluate for a potentially increased risk of IOP elevation in patients treated with bevacizumab vs ranibizumab or aflibercept, although there are no definitive data to date.

There may be a predisposition to IOP elevation with particular anti-VEGF agents, although we feel there are limited data at this time to support any particular medication. Some theories suggest patients treated with bevacizumab may be more likely to develop sustained IOP elevation for not only the reasons above but also because bevacizumab is a larger molecule, with a longer serum and vitreous half-life. No randomized, controlled trials have confirmed an increased incidence of sustained IOP elevation in patients treated with bevacizumab compared with ranibizumab and/or aflibercept.

Retrospective analysis of the VIEW studies of aflibercept vs ranibizumab showed a mean change in IOP to be consistently higher in the ranibizumab group than in all aflibercept groups.⁵ Retrospective analysis of the MARINA and ANCHOR trials of ranibizumab also showed a large subset of patients receiving ranibizumab to have IOP rises, vs those receiving photodynamic therapy or sham treatment.⁶

Sustained elevation of IOP with serial intravitreal anti-VEGF injections has been reported with varying frequency and is likely a multifactorial process, but more rigorous studies are necessary to better understand this association and which subgroups of patients may be more susceptible. RP

REFERENCES

1. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther. 2010;26:105-110.
2. Hoang QV, Mendonca LS, Della Torre KE, Jung JJ, Tsuang AJ, Freund KB. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology. 2012;119:321-326.
3. Zhou Y, Zhou M, Xia S, Jing Q, Gao L. Sustained elevation of intraocular pressure associated with intravitreal administration of anti-vascular endothelial growth factor: a systematic review and meta-analysis. Sci Rep. 2016;6:39301.
4. Dedania VA, Bakri SJ. Sustained elevation of intraocular pressure after intravitreal anti-VEGF agents: what is the evidence? Retina. 2015;35:841-858.
5. Freund KB, Hoang QV, Saroj N, Thompson D. Intraocular pressure in patients with neovascular age-related macular degeneration receiving intravitreal aflibercept or ranibizumab. Ophthalmology. 2015;122(9):1802-1810.
6. Bakri SJ, Moshfeghi DM, Francom S, et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials. Ophthalmology. 2014;121(5):1102-1108.