Elsevier

Survey of Ophthalmology

Volume 63, Issue 3, May–June 2018, Pages 281-295
Survey of Ophthalmology

Major review
The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review

https://doi.org/10.1016/j.survophthal.2017.08.008Get rights and content

Abstract

The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.

Introduction

Antivascular endothelial growth factor (anti-VEGF) therapy has proliferated over the past decade. In 2004, intravitreal pegaptanib (Macugen) was the first anti-VEGF agent approved for any ophthalmic indication after administration every 6 weeks was shown to decrease vision loss by half compared to sham injections in the treatment of neovascular age-related macular degeneration AMD (nAMD).41 Subsequently, in Genentech's MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of nAMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration Study) trials investigating monthly intravitreal ranibizumab (Lucentis) in nAMD, subjects experienced a mean improvement in visual acuity of 7.2 and 11.3 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, respectively, at 1 year, compared to a mean loss of 10.4 and 9.5 ETDRS letters in the sham and verteporfin control groups, respectively.16, 96 Ranibizumab 0.5 mg was approved for the treatment of nAMD in 2006, a major milestone because, for the first time, a treatment improved vision in nAMD, as opposed to simply ameliorating decline. Several years later, Regeneron's VIEW (Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration) randomized control trials of intravitreal aflibercept (Eylea) demonstrated monthly and bimonthly regimens of aflibercept that were noninferior to monthly ranibizumab over a 1-year time period44 and led to the approval of aflibercept 2 mg for the treatment of nAMD in 2011. Simultaneously, off-label intravitreal bevacizumab 1.25 mg (Avastin) was found to be noninferior to ranibizumab in the Comparison of AMD Treatments Trials, a National Institutes of Health sponsored randomized control trial.77

Anti-VEGF therapy for the treatment of diabetic macular edema and macular edema due to retinal vein occlusions was subsequently adopted, after several studies demonstrated a significant benefit for these indications.15, 18, 27 Because of the remarkable benefit of anti-VEGF therapies in these disorders, their use has exploded from essentially 0 in 2004 to over 16 million intravitreal anti-VEGF injections performed in 2016, comprising a global market of over $8 billion annually (www.market-scope.com). Coinciding with this burst in anti-VEGF therapy, reports of associated sustained ocular hypertension surfaced. Confounding this issue, however, is an aging population at risk of both developing glaucoma and acquiring pathologies necessitating anti-VEGF therapy. In addition, both vein occlusion and diabetes are known risk factors for glaucoma. Consequently, the acute and chronic ocular hypertensive effects of repeated anti-VEGF therapy have not been effectively characterized.55, 56, 63 We review the short- and long-term effects of intravitreal anti-VEGF injections on intraocular pressure (IOP) and the optic nerve, as well as the prophylactic measures that have been investigated to reduce immediate postinjection IOP spikes. In addition, this review presents the theoretical mechanisms for anti-VEGF–related chronic ocular hypertension.

Section snippets

Short-term ocular hypertensive effects of intravitreal anti-VEGF injections

Anti-VEGF regimens typically involve long-term monthly or periodic intravitreal injections (IVIs) of 50 μL of therapy via a small gauge needle, most often without paracentesis. As expected, ocular hypertension immediately follows from a volume effect, but this is generally transient and well tolerated in the vast majority of patients.

Studies associating sustained ocular hypertension with chronic anti-VEGF injections

Repeated intravitreal anti-VEGF injections have been associated with chronic ocular hypertension, distinct from the short-term acute ocular hypertension following each injection, in a subset of patients. Numerous case reports and case series have suggested this phenomenon, and those with incidence rates are summarized in Table 3.2, 3, 4, 6, 19, 34, 59, 76, 79, 80, 93, 99, 110 In some cases, the ocular hypertension was severe enough to warrant surgical filtration.23, 104

Post hoc analyses of

Macular disease and the risks of forgoing anti-VEGF therapy

Foregoing anti-VEGF therapy risks progression of various macular diseases. The MARINA study demonstrated a dramatic improvement in mean visual acuity of 7.2 ETDRS letters after 1 year of ranibizumab therapy compared to a loss of 10.4 ETDRS letters without treatment (for a net 17.6 ETDRS letter benefit); at 1 year, monthly treatment decreased the risk of losing 15 ETDRS letters from 37.8% to 5.5%.96 Unfortunately, a decreased intensity of anti-VEGF treatment in an as-needed regimen may yield an

Conclusion

Although anti-VEGF therapy is well tolerated in the vast majority of patients, acute and chronic ocular hypertension following treatment merits consideration. We have discussed the degree and timing of ocular hypertension immediately following anti-VEGF IVIs. IOP typically rises acutely following IVI with normalization within 30–60 minutes. In glaucomatous patients, this ocular hypertension is more dramatic and of longer duration. Numerous medications have been investigated to reduce

Disclosures

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

References (114)

  • M.B. Horsley et al.

    Retinal nerve fiber layer thickness in patients receiving chronic anti-vascular endothelial growth factor therapy

    Am J Ophthalmol

    (2010)
  • H. Jampel et al.

    Anti-Vascular Endothelial Growth Factor Injections and Intraocular Pressure Measurement: Should We Throw the Baby out with the Bath Water?

    Ophthalmology

    (2015)
  • W. Kiddee et al.

    Intraocular pressure monitoring post intravitreal steroids: a systematic review

    Surv Ophthalmol

    (2013)
  • J.E. Kim et al.

    Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents

    Am J Ophthalmol

    (2008)
  • Y.J. Kim et al.

    Long-term effects of multiple intravitreal antivascular endothelial growth factor injections on intraocular pressure

    Am J Ophthalmol

    (2014)
  • D.F. Martin et al.

    Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results

    Ophthalmology

    (2012)
  • K.M. Perkumas et al.

    Protein markers and differentiation in culture for Schlemm's canal endothelial cells

    Exp Eye Res

    (2012)
  • Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group

    Am J Ophthalmol

    (1984)
  • R.A. Adelman et al.

    Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections

    J Ocul Pharmacol Ther

    (2010)
  • A.A. Al-Abdullah et al.

    Intraocular pressure trends after intravitreal injections of anti-vascular endothelial growth factor agents for diabetic macular edema

    Retina

    (2015)
  • A. Azuara-Blanco et al.

    Infectious keratitis in a paracentesis tract

    Ophthalmic Surg Lasers

    (1997)
  • S.U. Baek et al.

    Long-term intraocular pressure changes after intravitreal injection of bevacizumab

    Cutan Ocul Toxicol

    (2016)
  • S.J. Bakri et al.

    Intravitreal silicone oil droplets after intravitreal drug injections

    Retina

    (2008)
  • S.J. Bakri et al.

    Persisent ocular hypertension following intravitreal ranibizumab

    Graefe's archive Clin Exp Ophthalmol

    (2008)
  • S.J. Bakri et al.

    Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab

    Eye (London, England)

    (2009)
  • J. Beato et al.

    Long-Term Effect of Anti-VEGF Agents on Intraocular Pressure in Age-Related Macular Degeneration

    Ophthalmic Res

    (2016)
  • D.S. Boyer et al.

    Effect of pegaptanib sodium 0.3 mg intravitreal injections (Macugen) in intraocular pressure: posthoc analysis from V.I.S.I.O.N. study

    Br J Ophthalmol

    (2014)
  • S.B. Bressler et al.

    Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment

    JAMA Ophthalmol

    (2015)
  • A.M. Brooks et al.

    Ocular beta-blockers in glaucoma management. Clinical pharmacological aspects

    Drugs Aging

    (1992)
  • D.M. Brown et al.

    Ranibizumab versus verteporfin for neovascular age-related macular degeneration

    N Engl J Med

    (2006)
  • A. Cacciamani et al.

    Intravitreal injection of bevacizumab: changes in intraocular pressure related to ocular axial length

    Jpn J Ophthalmol

    (2013)
  • D.Y. Choi et al.

    Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib

    Retina

    (2011)
  • V.S. Dedania et al.

    Sustained Elevation of Intraocular Pressure After Intravitreal Anti-VEGF Agents: What is the evidence?

    Retina (Philadelphia, Pa)

    (2015)
  • S. Demirel et al.

    The effect of multiple injections of ranibizumab on retinal nerve fiber layer thickness in patients with age-related macular degeneration

    Curr Eye Res

    (2015)
  • S. Demirel et al.

    Intraocular pressure changes related to intravitreal injections of ranibizumab: analysis of pseudophakia and glaucoma subgroup

    Int Ophthalmol

    (2015)
  • B.D. Eadie et al.

    Association of Repeated Intravitreous Bevacizumab Injections With Risk for Glaucoma Surgery

    JAMA Ophthalmol

    (2017)
  • M.F. El-Ashry et al.

    Evaluation of the effect of intravitreal ranibizumab injections in patients with neovascular age related macular degeneration on retinal nerve fiber layer thickness using optical coherence tomography

    Clin Ophthalmol (Auckland, NZ)

    (2015)
  • H. El Chehab et al.

    Intraocular Pressure Spikes after Aflibercept Intravitreal Injections

    Ophthalmologica

    (2016)
  • H. El Chehab et al.

    Effect of topical pressure-lowering medication on prevention of intraocular pressure spikes after intravitreal injection

    Eur J Ophthalmol

    (2013)
  • M. Entezari et al.

    Changes in Retinal Nerve Fiber Layer Thickness after Two Intravitreal Bevacizumab Injections for Wet Type Age-related Macular Degeneration

    J Ophthalmic Vis Res

    (2014)
  • S. Esser et al.

    Vascular endothelial growth factor induces endothelial fenestrations in vitro

    J Cell Biol

    (1998)
  • I.A. Falkenstein et al.

    Changes of intraocular pressure after intravitreal injection of bevacizumab (avastin)

    Retina (Philadelphia, Pa)

    (2007)
  • Q.K. Farhood et al.

    Short-term intraocular pressure changes after intravitreal injection of bevacizumab in diabetic retinopathy patients

    Clin Ophthalmol (Auckland, NZ)

    (2014)
  • A.J. Foss et al.

    Changes in intraocular pressure in study and fellow eyes in the IVAN trial

    Br J Ophthalmol

    (2016)
  • T. Fujimoto et al.

    Vascular Endothelial Growth Factor-A Increases the Aqueous Humor Outflow Facility

    PLoS One

    (2016)
  • J. Gavard et al.

    VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin

    Nat Cell Biol

    (2006)
  • M. Georgopoulos et al.

    Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin)

    Br J Ophthalmol

    (2009)
  • M. Gismondi et al.

    Short-term effect of intravitreal injection of Ranibizumab (Lucentis) on intraocular pressure

    J Glaucoma

    (2009)
  • A. Goktas et al.

    Short-term impact of intravitreal ranibizumab injection on axial ocular dimension and intraocular pressure

    Cutan Ocul Toxicol

    (2013)
  • T.J. Good et al.

    Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents

    Br J Ophthalmol

    (2011)
  • Cited by (0)

    View full text