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