INFLUENCE OF AXIAL LENGTH AND POSTINJECTION REFLUX ON SUSTAINED INTRAOCULAR PRESSURE ELEVATION AS A RESULT OF INTRAVITREAL ANTI– VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY QUAN V. HOANG, MD, PHD,*†‡§ JESSE J. JUNG, MD,*†‡§ SARAH MREJEN, MD,*† K. BAILEY FREUND, MD*†‡§ Purpose: To assess an association of axial length (AL) or postinjection reflux with transient or sustained intraocular pressure (IOP) elevation in patients with neovascular agerelated macular degeneration receiving anti–vascular endothelial growth factor injections. Methods: One hundred and forty-seven eyes from 74 consecutive patients with neovascular age-related macular degeneration who presented to a single physician over a 2-month period had ALs measured by IOLMaster. Twenty-one patients had preinjection and immediate postinjection IOP measured and immediate reflux assessed. Results: Overall, 9.5% of eyes had been identified with sustained IOP elevation in our previous study. Axial length did not significantly differ between eyes that had (AL, 23.96 ± 0.66 mm; n = 14) and had not experienced sustained IOP elevation (AL, 23.44 ± 1.24 mm; n = 133; P = 0.12, t-test). By linear regression analysis, the relationship between experiencing sustained IOP elevation and AL was not statistically significant (R2 = 0.0165; P = 0.121). The relationship between AL and immediate postinjection IOP elevation was also not statistically significant (R2 = 0.0001; P = 0.97). Immediate postinjection IOP increase did differ between eyes without reflux (30.2 ± 9.3 mmHg; n = 12) and those with reflux (1.1 ± 7.2; n = 9; P , 0.001). Conclusion: Axial length does not seem to be a predictor of transient or sustained IOP elevation. Repeated trabecular meshwork trauma related to the absence or presence of reflux and immediate postinjection IOP elevation may be a contributing factor. RETINA 34:519–524, 2014
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within 30–60 minutes).3–6 Sustained elevations of IOP as a complication of anti-VEGF injections were not noted in the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) trials1,2 or the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial,7,8 but recent reports including a post hoc analysis of data from the ANCHOR and MARINA trials (Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP in Eyes Treated With Monthly Ranibizumab: A Post Hoc Analysis of Data From the MARINA and
ntravitreal anti–vascular endothelial growth factor (anti-VEGF) agents, including ranibizumab (Lucentis; Genentech, San Francisco, CA), bevacizumab (Avastin; Genentech, San Francisco, CA), and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY), are used to treat choroidal neovascularization and retinal vascular disorders with rarely reported ocular adverse events, such as intraocular inflammation, retinal tears, vitreous hemorrhage, endophthalmitis, and lens changes.1,2 Studies have shown that with the addition of fluid into the vitreous cavity, transient increases in intraocular pressure (IOP) may occur (range reported from baseline levels up to 80 mmHg immediately after injection, with return to ,25 mmHg 519
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ANCHOR Trials. Paper presented at: AAO Annual Meeting, October 17, 2010; Chicago) suggest that sustained ocular hypertension can occur following treatment with intravitreal ranibizumab or bevacizumab.9–17 In the current article, we assess if axial length is a predictive factor for transient or sustained IOP elevation in neovascular age-related macular degeneration (NVAMD) eyes undergoing intravitreal antiVEGF therapy and whether the absence or presence of immediate postinjection fluid reflux out of the eye can predict the degree of postinjection IOP elevation.
Methods Western Institutional Review Board (Olympia, WA) approval was obtained for this Health Insurance Portability and Accountability Act–compliant prospective study, and all research adhered to the tenets of the Declaration of Helsinki. We previously reported that 7.1% of our patient population experienced sustained IOP elevation among a consecutive series of 449 eyes from 328 NVAMD patients followed for at least 9 weeks.17 These patients had been treated along their course with at least 3 intravitreal injections of ranibizumab (0.5 mg/0.05 mL) and/or bevacizumab (1.25 mg/ 0.05 mL) based on a “treat-and-extend” dosing regimen18 by a single physician (K.B.F.) at 2 offices of the Vitreous-Retina-Macula Consultants of New York. Patients with a baseline diagnosis of glaucoma were excluded if their baseline IOP (defined as the preinjection IOP on the day of their initial injection of ranibizumab or bevacizumab in either eye) was .21 mmHg. In this study, preinjection bilateral IOP measurements before the instillation of dilating agents were recorded on the day of first treatment and at each subsequent office visit. All IOP measurements were taken using Goldmann applanation tonometry (Haag-Streit, Mason, OH) by certified ophthalmic technicians who were not masked to previous IOP measurements. “Sustained IOP elevation” From the *Vitreous-Retina-Macula Consultants of New York, New York, New York; †LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York; ‡Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York; and §Department of Ophthalmology, New York University Medical Center, New York, New York. Supported by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, and The Macula Foundation. Financial disclosure received from Genentech (Consultant, Research Support for K.B.F.), Regeneron (Consultant for K.B.F.), and Bayer (Consultant for K.B.F.). None of the authors have any financial/conflicting interests to disclose. Reprint requests: K. Bailey Freund, MD, Vitreous-RetinaMacula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
while under treatment was defined as meeting one of the following criteria on at least 2 consecutive office visits: an absolute IOP .25 mmHg, an increase above baseline IOP of .10 mmHg, or an absolute IOP . 21 mmHg and an increase above baseline IOP of .5 mmHg. Using patients from this previous study, including those with sustained IOP elevation, a prospective study was performed 1 year after the original study on 147 eyes from 74 consecutive NVAMD patients who presented to a single physician (K.B.F.) over a 2-month period. It was confirmed that none of the control patients included in the present study had developed sustained IOP elevation in the interim. All patients had axial lengths measured by IOLMaster (Carl Zeiss Meditec, Inc, Dublin, OH). Axial lengths of patients previously identified as having sustained IOP elevation were compared by a two-tailed t-test for the presence of NVAMD patients who did not have a history of sustained IOP elevation. Linear regression analysis was also performed to assess the association of axial length with sustained IOP elevation. Of these patients, 21 also had preinjection and immediate postinjection IOP measured by Goldmann applanation tonometry, and immediate postinjection reflux assessed by a single experienced retinologist (K.B.F.). Trace to no reflux is was denoted as “absence of reflux,” whereas any reflux greater than trace was denoted as “presence of reflux.” All 21 patients represented NVAMD patients receiving anti-VEGF injection by a single investigator (K.B.F.) at a single office over a span of 1 week. Immediate postinjection IOP elevation among eyes without appreciable postinjection reflux and those with reflux was compared by a two-tailed t-test. Linear regression analysis was performed to assess the association of axial length with immediate postinjection IOP, immediate postinjection change in IOP, experiencing sustained IOP elevation, and experiencing immediate postinjection reflux. Linear regression analysis was also performed to assess the association of immediate postinjection reflux with sustained IOP elevation and the presence of a posterior vitreous detachment (PVD). Analysis was performed using Stata 12 software (StataCorp, College Station, TX). Significance was accepted at P # 0.05. All injections were administered under topical anesthesia. Before injection, the eye was treated with antibiotic drops: topical proparacaine hydrochloride (0.5%) and topical 5% povidone–iodine solution. Injections were administered 3.5 mm to 4.0 mm posterior to the limbus. The type of syringes and needles used were uniform. All bevacizumab (1.25 mg/0.05 mL) injections were bought from the same compounding pharmacy (Rockwell, Rye, NY) in prefilled 31-gauge BD insulin syringes (Becton, Dickinson and Company,
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Franklin Lakes, NJ). All ranibizumab (0.5 mg/0.05 mL) was drawn up at the time of injection from the singleuse glass vials supplied by Genentech. A 32-gauge injection needle was used for ranibizumab (32.5-gauge, TSK STERIJECT; Tochigi Seiko KK, Tochigi, Japan). Additionally, the 19-gauge filter needle used to draw up ranibizumab, 31-gauge injection needle for bevacizumab injections, and syringes for ranibizumab were purchased from Becton Dickinson. Results Among the 147 eyes studied, 9.5% had been identified as having sustained IOP elevation in our previous studies. Axial length did not correlate with the occurrence of sustained IOP elevation, nor did it correlate with immediate postinjection IOP or IOP change in the subset of 21 eyes (Figures 1 and 2). Specifically, eyes that had experienced sustained IOP elevation showed an axial length of 23.96 ± 0.66 mm (n = 14; range, 23.08–25.13 mm), which was not significantly different from the axial length found in eyes that had not experienced sustained IOP elevation (23.44 ± 1.24 mm; n = 133; range, 21.11–29.80 mm) with P = 0.12 (2-tailed t-test). Also, by linear regression analysis, the relationship between experiencing sustained IOP elevation and axial length was not found to be statistically significant (R2 = 0.0165; P = 0.121). Axial length also did not correlate with the degree of transient IOP elevation. Eyes with axial length of #23.5 mm had an immediate postinjection IOP elevation of 18.4 ± 17.4 mmHg (n = 9), which was not significantly different from that found in eyes with axial length of .23.5 mm (17.8 ± 16.7 mmHg; n = 12), with P = 0.94 (2-tailed
Fig. 2. Scatter plot of immediate postinjection change in IOP (in millimeters of mercury) versus axial length (in millimeters) of 21 eyes of 18 patients who underwent Goldmann applanation tonometry both before and immediately after intravitreal injection of 0.05 mL of antiVEGF agent. Axial length was measured by IOLMaster.
t-test). The relationship between axial length and immediate postinjection IOP increase was not statistically significant (linear regression analysis, R2 = 0.0001; P = 0.97). Eyes without postinjection reflux had an immediate postinjection IOP elevation of 30.2 ± 9.3 mmHg (n = 12), which was significantly higher than those with reflux (1.1 ± 7.2 mmHg; n = 9), with P , 0.001 (2-tailed t-test). Of the 12 patients without appreciable reflux, 2 had a history of sustained IOP elevation. Of the 9 patients with appreciable reflux, none had a history of sustained IOP elevation. By linear regression analysis, the relationship between experiencing sustained IOP elevation and the presence of reflux was not found to be statistically significant (R2 = 0.0789; P = 0.217). By linear regression analysis, the relationship between experiencing immediate postinjection reflux and axial length was not found to be statistically significant (R2 = 0.0542; P = 0.31). Of the 12 eyes that did not display appreciable immediate postinjection reflux, 2 (16.7%) had a PVD. Of the 9 eyes that did display appreciable immediate postinjection reflux, 5 (55.6%) had a PVD. The presence of PVD is associated with a 43% point (P = 0.066) increase in the likelihood of the presence of immediate postinjection reflux. This result is marginally significant at the 10% level. Discussion
Fig. 1. Scatter plot of immediate postinjection IOP (in millimeters of mercury) versus axial length (in millimeters) of 21 eyes of 18 patients who underwent Goldmann applanation tonometry both before and immediately after intravitreal injection of 0.05 mL of anti-VEGF agent. Axial length was measured by IOLMaster.
Recent evidence has shown that sustained elevations in IOP may be a significant complication of repeated intravitreal injections.9–15 Our group reported on 207 patients who received unilateral ranibizumab and/or bevacizumab intravitreal injections and showed that 11.6% of injected versus 5.3% of contralateral, uninjected
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control eyes experienced preinjection IOP elevation of $6 mmHg on $2 consecutive visits.16 Elevations in IOP were not noted to be a complication of ranibizumab injections in the ANCHOR and MARINA trials, as determined by mean monthly preinjection measurements during the 2 year follow-up,1,2 but a post hoc analysis of data from the ANCHOR and MARINA trials by Bakri et al showed a greater likelihood of preinjection IOP of $6 mmHg from baseline and a preinjection IOP of $25 mmHg at $2 consecutive visits in eyes treated with 0.3 mg (5.4%) or 0.5 mg (4.5%) ranibizumab versus those receiving sham injections (1.3%) over the 24-month follow-up period of these studies. Additionally, 11.4% of all ranibizumab-treated patients experienced at least one ocular hypertension or glaucoma-related event in the study eye compared with 6.4% of sham/photodynamic therapy control patients over 24 months (P = 0.008; Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP in Eyes Treated With Monthly Ranibizumab: A Post Hoc Analysis of Data From the MARINA and ANCHOR Trials. Paper presented at: AAO Annual Meeting, October 17, 2010; Chicago). Similarly, a study from our group reported that 32 of 449 eyes (7.1%) experienced sustained IOP elevation and showed that a greater number of injections and a history of intravitreal steroid injections were predictive factors.17 The mechanism by which sustained IOP is induced in these susceptible eyes is still unclear. Before the widespread use of intravitreal anti-VEGF therapy, Jager et al19 reported that sustained ocular hypertension occurred in 2.4% of eyes receiving intravitreal injections of any chemical, excluding triamcinolone acetonide, with the majority occurring in eyes receiving intravitreal fomivirsen for cytomegalovirus retinitis. In the previous reports of sustained ocular hypertension occurring in eyes receiving intravitreal ranibizumab or bevacizumab, the frequency of sustained IOP elevation was reported to be between 3.5% and 6% with IOP elevations ranging from 22 mmHg to 58 mmHg.9–13 Several theories have been proposed regarding possible mechanisms for how intravitreal anti-VEGF injections could lead to sustained IOP elevation including a pharmacologic effect of VEGF blockade, an inflammatory mechanism/trabeculitis, impaired outflow because of protein aggregates/silicone droplet debris, and damage to outflow pathways as a result of repeated trauma and/ or IOP spikes associated with the injection procedure.9– 13 Another hypothesis was based on the observations in the uveitis literature that an increase in concentration of aqueous humor protein can increase IOP.1,2,20 Therefore, it has been suggested that an immunologic reaction may be induced by anti-VEGF agents, resulting in inflammation and subsequent IOP elevation.21 Adelman
et al12 proposed that anti-VEGF injections may decrease trabecular meshwork function, either mechanically or physiologically, but Kernt et al22 reported no in vivo toxicity to the trabecular meshwork with standard concentrations of bevacizumab. Good et al9 noted a difference in rates of sustained IOP elevation between two different study centers and suggested that this may be the result of differences in the preparation, shipment, and storage of prefilled bevacizumab syringes or the differences in injection techniques. Additionally, it has been suggested that a disruption of the anterior hyaloid or zonules may allow access for high-molecular-weight proteins to enter the anterior chamber, and multiple doses of these proteins may mechanically or physiologically disrupt the normal outflow of aqueous humor.12 Others have theorized that silicone oil used to lubricate the components of syringes or the accumulation of protein aggregates may play a role in these sustained IOP elevations.23,24 Although these may be possible mechanisms, these are less likely given that there is no increase in risk for sustained IOP in those who are pseudophakic or aphakic, or those who have had YAG (yttrium aluminum garnet) capsulotomy compared with those who still possess their natural lens, which would possibly allow the proteins or silicone oil access to the anterior chamber.17 A previous report from our group suggested that a greater number of injections may increase the risk for sustained IOP elevation in eyes with neovascular agerelated macular degeneration receiving intravitreal anti-VEGF therapy.17 No other demographic factors included in this study, including age at first anti-VEGF injection, sex, history of hypertension, family or personal history of glaucoma, history of photodynamic therapy, lens status at time of first or last injection, history of YAG capsulotomy, and history of peripheral iridotomy, had an association with sustained elevation in IOP. Only eyes having received previous intravitreal steroid injections and an increased total number of consecutive injections had a greater risk for this complication of treatment. Good et al9 demonstrated that patients with preexisting glaucoma experienced higher rates of elevated IOP when compared with those without preexisting glaucoma (33% vs. 3.1% respectively; P , 0.001). Mathalone et al25 also reported that shorter intervals between anti-VEGF injections, for example, ,8-week intervals (P = 0.009), are a significant risk factor for sustained IOP elevation after Avastin injections. The present study examined whether axial length correlated with the risk of sustained IOP elevation or the degree of transient IOP elevation in a series of NVAMD eyes, and whether the absence or presence of immediate postinjection reflux correlated with postinjection IOP. There have been several published reports demonstrating
EFFECT OF AXIAL LENGTH AND REFLUX ON IOP HOANG ET AL
short-term, transient increases in IOP after intravitreal anti-VEGF agents, which were shown to return to ,25 mmHg within 30 minutes to 60 minutes without IOP-lowering therapy.3–6 These studies suggested that increase in IOP tended to be higher in phakic patients3 and that eyes with a history of glaucoma were thought to take more time to return to baseline IOP.4 In these studies, no predictive value was found for baseline IOP, age, gender, refractive error, and the number of previous intravitreal injections in determining postinjection IOP level.3–6 Gismondi et al26 reported that the relationship between shorter axial length and IOP increase after 5 seconds was significant (linear regression analysis, R2 = 0.28; P = 0.007) in the 24 eyes studied. Whereas in our study, we did not find a correlation between axial lengths and transient or sustained IOP elevations. This suggests that the overall size of the eye based on axial length measurements does not likely increase the risk of sustained IOP after intravitreal anti-VEGF therapy. Although it would seem a shorter axial length (and therefore smaller the initial eye volume) may predispose the eye to a greater immediate IOP increase after injection of the standard volume of anti-VEGF and potentially increase the risk of sustained IOP elevation after repeated injections, the results of the linear regression analysis did not show a correlation between shorter axial length and transient or sustained IOP elevation. This observation led the authors to examine other factors that could influence the level of immediate postinjection IOP, including immediate postinjection reflux. Not surprisingly, eyes without appreciable postinjection reflux had an immediate postinjection IOP elevation that was significantly higher than the negligible elevation seen in eyes with appreciable postinjection reflux. Based on our analysis, the presence of a PVD increased the likelihood of postinjection reflux. Using smaller caliber needles, such as a 31-gauge or 32-gauge needle, decreases the amount of postinjection reflux and can result in higher immediate postinjection IOP elevation. We have noted that sustained IOP elevation is virtually nonexistent in our patient population following a switch to larger 30-gauge needles and reducing the injection volume in eyes with borderline or high preinjection IOPs (unpublished data). Based on these observations, our hypothesis is that repeated injections with low reflux may cause mechanical expansile stress on the trabecular meshwork and may lead to sustained IOP elevation. Further studies including histopathologic evaluation of the trabecular meshwork in those who have received more injections versus those who have received fewer could further support this hypothesis. In addition to monitoring the amount of postinjection reflux, other groups have also suggested lowering preinjection IOP with glaucoma drops27 or
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softening the eye with pressure during anesthetic preparation of the globe28,29 to reduce the levels of immediate postinjection IOP. In summary, axial length does not appear to be a predictor of subsequent transient or sustained IOP elevation. Repeated trabecular meshwork trauma related to the absence or presence of postinjection reflux and immediate postinjection IOP elevation may be a contributing factor. In light of these results, one could consider avoiding excessively small-gauged needles, preinjection instillation of IOP-lowering agents or softening of the eye, or using lower injection volumes of anti-VEGF agents in those patients who have already experienced or who are at the risk of experiencing sustained IOP elevation. Key words: axial, bevacizumab, injection, IOP, length, pressure, ranibizumab, reflux, transient, sustained. Acknowledgments The authors would like to thank Jessica Y. Pan, PhD, MBA, for her statistical assistance. References 1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 3. Hollands H, Wong J, Bruen R, et al. Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol 2007;42:807–811. 4. 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;146:930–934. 5. 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. 6. Bakri SJ, Pulido JS, McCannel CA, et al. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23:181–185. 7. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816. 8. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D’Amico DJ, Masonson HN, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 2006;113:992–1001. 9. Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol 2011;95:1111–1114.
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10. Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persistent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:955–958. 11. Kahook MY, Kimura AE, Wong LJ, et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging 2009;40:293–295. 12. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther 2010;26:105–110. 13. Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma 2012;21:241–247. 14. Loukianou E, Brouzas D, Apostolopoulos M. Sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 ml ranibizumab. Int Ophthalmol 2011;31:211–213. 15. Choi D, Ortube M, McCannel C, et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib. Retina 2011;31: 1028–1035. 16. Hoang QV, Mendonca LS, Della Torre KE, et al. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology 2012;119:321–326. 17. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal antivascular endothelial growth factor therapy. Retina 2013;33: 179–187. 18. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009;29:1424–1431. 19. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676–698.
20. Ladas JG, Yu F, Loo R, et al. Relationship between aqueous humor protein level and outflow facility in patients with uveitis. Invest Ophthalmol Vis Sci 2001;42:2584–2588. 21. Georgopoulos M, Polak K, Prager F, et al. Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin). Br J Ophthalmol 2009;93:457–462. 22. Kernt M, Welge-Lüssen U, Yu A, et al. Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells [in German]. Ophthalmologe 2007;104:965–971. 23. Sniegowski M, Mandava N, Kahook MY. Sustained intraocular pressure elevation after intravitreal injection of bevacizumab and ranibizumab associated with trabeculitis. Open Ophthalmol J 2010;4:28–29. 24. Liu L, Ammar DA, Ross L, et al. Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. Invest Ophthalmol Vis Sci 2011;52:1023–1034. 25. 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;250:1435–1440. 26. Gismondi M, Salati C, Salvetat ML, et al. Short-term effect of intravitreal injection of ranibizumab (Lucentis) on intraocular pressure. J Glaucoma 2009;18:658–661. 27. Kim GN, Han YS, Chung IY, et al. Effect of dorzolamide/timolol or brinzolamide/timolol prophylaxis on intravitreal anti-VEGF injection-induced intraocular hypertension. Semin Ophthalmol 2013;28:61–67. 28. Kim KS, Jee D. Effect of the Honan intraocular pressure reducer on intraocular pressure increase following intravitreal injection using the tunneled scleral technique. Jpn J Ophthalmol 2011;55:632–637. 29. Gregori NZ, Weiss MJ, Goldhardt R, et al. Ocular decompression with cotton swabs lowers intraocular pressure elevation after intravitreal injection. J Glaucoma 2013. Epub ahead of print.
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within 30–60 minutes).3–6 Sustained elevations of IOP as a complication of anti-VEGF injections were not noted in the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) trials1,2 or the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial,7,8 but recent reports including a post hoc analysis of data from the ANCHOR and MARINA trials (Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP in Eyes Treated With Monthly Ranibizumab: A Post Hoc Analysis of Data From the MARINA and
ntravitreal anti–vascular endothelial growth factor (anti-VEGF) agents, including ranibizumab (Lucentis; Genentech, San Francisco, CA), bevacizumab (Avastin; Genentech, San Francisco, CA), and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY), are used to treat choroidal neovascularization and retinal vascular disorders with rarely reported ocular adverse events, such as intraocular inflammation, retinal tears, vitreous hemorrhage, endophthalmitis, and lens changes.1,2 Studies have shown that with the addition of fluid into the vitreous cavity, transient increases in intraocular pressure (IOP) may occur (range reported from baseline levels up to 80 mmHg immediately after injection, with return to ,25 mmHg 519
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ANCHOR Trials. Paper presented at: AAO Annual Meeting, October 17, 2010; Chicago) suggest that sustained ocular hypertension can occur following treatment with intravitreal ranibizumab or bevacizumab.9–17 In the current article, we assess if axial length is a predictive factor for transient or sustained IOP elevation in neovascular age-related macular degeneration (NVAMD) eyes undergoing intravitreal antiVEGF therapy and whether the absence or presence of immediate postinjection fluid reflux out of the eye can predict the degree of postinjection IOP elevation.
Methods Western Institutional Review Board (Olympia, WA) approval was obtained for this Health Insurance Portability and Accountability Act–compliant prospective study, and all research adhered to the tenets of the Declaration of Helsinki. We previously reported that 7.1% of our patient population experienced sustained IOP elevation among a consecutive series of 449 eyes from 328 NVAMD patients followed for at least 9 weeks.17 These patients had been treated along their course with at least 3 intravitreal injections of ranibizumab (0.5 mg/0.05 mL) and/or bevacizumab (1.25 mg/ 0.05 mL) based on a “treat-and-extend” dosing regimen18 by a single physician (K.B.F.) at 2 offices of the Vitreous-Retina-Macula Consultants of New York. Patients with a baseline diagnosis of glaucoma were excluded if their baseline IOP (defined as the preinjection IOP on the day of their initial injection of ranibizumab or bevacizumab in either eye) was .21 mmHg. In this study, preinjection bilateral IOP measurements before the instillation of dilating agents were recorded on the day of first treatment and at each subsequent office visit. All IOP measurements were taken using Goldmann applanation tonometry (Haag-Streit, Mason, OH) by certified ophthalmic technicians who were not masked to previous IOP measurements. “Sustained IOP elevation” From the *Vitreous-Retina-Macula Consultants of New York, New York, New York; †LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York; ‡Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York; and §Department of Ophthalmology, New York University Medical Center, New York, New York. Supported by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, and The Macula Foundation. Financial disclosure received from Genentech (Consultant, Research Support for K.B.F.), Regeneron (Consultant for K.B.F.), and Bayer (Consultant for K.B.F.). None of the authors have any financial/conflicting interests to disclose. Reprint requests: K. Bailey Freund, MD, Vitreous-RetinaMacula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
while under treatment was defined as meeting one of the following criteria on at least 2 consecutive office visits: an absolute IOP .25 mmHg, an increase above baseline IOP of .10 mmHg, or an absolute IOP . 21 mmHg and an increase above baseline IOP of .5 mmHg. Using patients from this previous study, including those with sustained IOP elevation, a prospective study was performed 1 year after the original study on 147 eyes from 74 consecutive NVAMD patients who presented to a single physician (K.B.F.) over a 2-month period. It was confirmed that none of the control patients included in the present study had developed sustained IOP elevation in the interim. All patients had axial lengths measured by IOLMaster (Carl Zeiss Meditec, Inc, Dublin, OH). Axial lengths of patients previously identified as having sustained IOP elevation were compared by a two-tailed t-test for the presence of NVAMD patients who did not have a history of sustained IOP elevation. Linear regression analysis was also performed to assess the association of axial length with sustained IOP elevation. Of these patients, 21 also had preinjection and immediate postinjection IOP measured by Goldmann applanation tonometry, and immediate postinjection reflux assessed by a single experienced retinologist (K.B.F.). Trace to no reflux is was denoted as “absence of reflux,” whereas any reflux greater than trace was denoted as “presence of reflux.” All 21 patients represented NVAMD patients receiving anti-VEGF injection by a single investigator (K.B.F.) at a single office over a span of 1 week. Immediate postinjection IOP elevation among eyes without appreciable postinjection reflux and those with reflux was compared by a two-tailed t-test. Linear regression analysis was performed to assess the association of axial length with immediate postinjection IOP, immediate postinjection change in IOP, experiencing sustained IOP elevation, and experiencing immediate postinjection reflux. Linear regression analysis was also performed to assess the association of immediate postinjection reflux with sustained IOP elevation and the presence of a posterior vitreous detachment (PVD). Analysis was performed using Stata 12 software (StataCorp, College Station, TX). Significance was accepted at P # 0.05. All injections were administered under topical anesthesia. Before injection, the eye was treated with antibiotic drops: topical proparacaine hydrochloride (0.5%) and topical 5% povidone–iodine solution. Injections were administered 3.5 mm to 4.0 mm posterior to the limbus. The type of syringes and needles used were uniform. All bevacizumab (1.25 mg/0.05 mL) injections were bought from the same compounding pharmacy (Rockwell, Rye, NY) in prefilled 31-gauge BD insulin syringes (Becton, Dickinson and Company,
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Franklin Lakes, NJ). All ranibizumab (0.5 mg/0.05 mL) was drawn up at the time of injection from the singleuse glass vials supplied by Genentech. A 32-gauge injection needle was used for ranibizumab (32.5-gauge, TSK STERIJECT; Tochigi Seiko KK, Tochigi, Japan). Additionally, the 19-gauge filter needle used to draw up ranibizumab, 31-gauge injection needle for bevacizumab injections, and syringes for ranibizumab were purchased from Becton Dickinson. Results Among the 147 eyes studied, 9.5% had been identified as having sustained IOP elevation in our previous studies. Axial length did not correlate with the occurrence of sustained IOP elevation, nor did it correlate with immediate postinjection IOP or IOP change in the subset of 21 eyes (Figures 1 and 2). Specifically, eyes that had experienced sustained IOP elevation showed an axial length of 23.96 ± 0.66 mm (n = 14; range, 23.08–25.13 mm), which was not significantly different from the axial length found in eyes that had not experienced sustained IOP elevation (23.44 ± 1.24 mm; n = 133; range, 21.11–29.80 mm) with P = 0.12 (2-tailed t-test). Also, by linear regression analysis, the relationship between experiencing sustained IOP elevation and axial length was not found to be statistically significant (R2 = 0.0165; P = 0.121). Axial length also did not correlate with the degree of transient IOP elevation. Eyes with axial length of #23.5 mm had an immediate postinjection IOP elevation of 18.4 ± 17.4 mmHg (n = 9), which was not significantly different from that found in eyes with axial length of .23.5 mm (17.8 ± 16.7 mmHg; n = 12), with P = 0.94 (2-tailed
Fig. 2. Scatter plot of immediate postinjection change in IOP (in millimeters of mercury) versus axial length (in millimeters) of 21 eyes of 18 patients who underwent Goldmann applanation tonometry both before and immediately after intravitreal injection of 0.05 mL of antiVEGF agent. Axial length was measured by IOLMaster.
t-test). The relationship between axial length and immediate postinjection IOP increase was not statistically significant (linear regression analysis, R2 = 0.0001; P = 0.97). Eyes without postinjection reflux had an immediate postinjection IOP elevation of 30.2 ± 9.3 mmHg (n = 12), which was significantly higher than those with reflux (1.1 ± 7.2 mmHg; n = 9), with P , 0.001 (2-tailed t-test). Of the 12 patients without appreciable reflux, 2 had a history of sustained IOP elevation. Of the 9 patients with appreciable reflux, none had a history of sustained IOP elevation. By linear regression analysis, the relationship between experiencing sustained IOP elevation and the presence of reflux was not found to be statistically significant (R2 = 0.0789; P = 0.217). By linear regression analysis, the relationship between experiencing immediate postinjection reflux and axial length was not found to be statistically significant (R2 = 0.0542; P = 0.31). Of the 12 eyes that did not display appreciable immediate postinjection reflux, 2 (16.7%) had a PVD. Of the 9 eyes that did display appreciable immediate postinjection reflux, 5 (55.6%) had a PVD. The presence of PVD is associated with a 43% point (P = 0.066) increase in the likelihood of the presence of immediate postinjection reflux. This result is marginally significant at the 10% level. Discussion
Fig. 1. Scatter plot of immediate postinjection IOP (in millimeters of mercury) versus axial length (in millimeters) of 21 eyes of 18 patients who underwent Goldmann applanation tonometry both before and immediately after intravitreal injection of 0.05 mL of anti-VEGF agent. Axial length was measured by IOLMaster.
Recent evidence has shown that sustained elevations in IOP may be a significant complication of repeated intravitreal injections.9–15 Our group reported on 207 patients who received unilateral ranibizumab and/or bevacizumab intravitreal injections and showed that 11.6% of injected versus 5.3% of contralateral, uninjected
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control eyes experienced preinjection IOP elevation of $6 mmHg on $2 consecutive visits.16 Elevations in IOP were not noted to be a complication of ranibizumab injections in the ANCHOR and MARINA trials, as determined by mean monthly preinjection measurements during the 2 year follow-up,1,2 but a post hoc analysis of data from the ANCHOR and MARINA trials by Bakri et al showed a greater likelihood of preinjection IOP of $6 mmHg from baseline and a preinjection IOP of $25 mmHg at $2 consecutive visits in eyes treated with 0.3 mg (5.4%) or 0.5 mg (4.5%) ranibizumab versus those receiving sham injections (1.3%) over the 24-month follow-up period of these studies. Additionally, 11.4% of all ranibizumab-treated patients experienced at least one ocular hypertension or glaucoma-related event in the study eye compared with 6.4% of sham/photodynamic therapy control patients over 24 months (P = 0.008; Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP in Eyes Treated With Monthly Ranibizumab: A Post Hoc Analysis of Data From the MARINA and ANCHOR Trials. Paper presented at: AAO Annual Meeting, October 17, 2010; Chicago). Similarly, a study from our group reported that 32 of 449 eyes (7.1%) experienced sustained IOP elevation and showed that a greater number of injections and a history of intravitreal steroid injections were predictive factors.17 The mechanism by which sustained IOP is induced in these susceptible eyes is still unclear. Before the widespread use of intravitreal anti-VEGF therapy, Jager et al19 reported that sustained ocular hypertension occurred in 2.4% of eyes receiving intravitreal injections of any chemical, excluding triamcinolone acetonide, with the majority occurring in eyes receiving intravitreal fomivirsen for cytomegalovirus retinitis. In the previous reports of sustained ocular hypertension occurring in eyes receiving intravitreal ranibizumab or bevacizumab, the frequency of sustained IOP elevation was reported to be between 3.5% and 6% with IOP elevations ranging from 22 mmHg to 58 mmHg.9–13 Several theories have been proposed regarding possible mechanisms for how intravitreal anti-VEGF injections could lead to sustained IOP elevation including a pharmacologic effect of VEGF blockade, an inflammatory mechanism/trabeculitis, impaired outflow because of protein aggregates/silicone droplet debris, and damage to outflow pathways as a result of repeated trauma and/ or IOP spikes associated with the injection procedure.9– 13 Another hypothesis was based on the observations in the uveitis literature that an increase in concentration of aqueous humor protein can increase IOP.1,2,20 Therefore, it has been suggested that an immunologic reaction may be induced by anti-VEGF agents, resulting in inflammation and subsequent IOP elevation.21 Adelman
et al12 proposed that anti-VEGF injections may decrease trabecular meshwork function, either mechanically or physiologically, but Kernt et al22 reported no in vivo toxicity to the trabecular meshwork with standard concentrations of bevacizumab. Good et al9 noted a difference in rates of sustained IOP elevation between two different study centers and suggested that this may be the result of differences in the preparation, shipment, and storage of prefilled bevacizumab syringes or the differences in injection techniques. Additionally, it has been suggested that a disruption of the anterior hyaloid or zonules may allow access for high-molecular-weight proteins to enter the anterior chamber, and multiple doses of these proteins may mechanically or physiologically disrupt the normal outflow of aqueous humor.12 Others have theorized that silicone oil used to lubricate the components of syringes or the accumulation of protein aggregates may play a role in these sustained IOP elevations.23,24 Although these may be possible mechanisms, these are less likely given that there is no increase in risk for sustained IOP in those who are pseudophakic or aphakic, or those who have had YAG (yttrium aluminum garnet) capsulotomy compared with those who still possess their natural lens, which would possibly allow the proteins or silicone oil access to the anterior chamber.17 A previous report from our group suggested that a greater number of injections may increase the risk for sustained IOP elevation in eyes with neovascular agerelated macular degeneration receiving intravitreal anti-VEGF therapy.17 No other demographic factors included in this study, including age at first anti-VEGF injection, sex, history of hypertension, family or personal history of glaucoma, history of photodynamic therapy, lens status at time of first or last injection, history of YAG capsulotomy, and history of peripheral iridotomy, had an association with sustained elevation in IOP. Only eyes having received previous intravitreal steroid injections and an increased total number of consecutive injections had a greater risk for this complication of treatment. Good et al9 demonstrated that patients with preexisting glaucoma experienced higher rates of elevated IOP when compared with those without preexisting glaucoma (33% vs. 3.1% respectively; P , 0.001). Mathalone et al25 also reported that shorter intervals between anti-VEGF injections, for example, ,8-week intervals (P = 0.009), are a significant risk factor for sustained IOP elevation after Avastin injections. The present study examined whether axial length correlated with the risk of sustained IOP elevation or the degree of transient IOP elevation in a series of NVAMD eyes, and whether the absence or presence of immediate postinjection reflux correlated with postinjection IOP. There have been several published reports demonstrating
EFFECT OF AXIAL LENGTH AND REFLUX ON IOP HOANG ET AL
short-term, transient increases in IOP after intravitreal anti-VEGF agents, which were shown to return to ,25 mmHg within 30 minutes to 60 minutes without IOP-lowering therapy.3–6 These studies suggested that increase in IOP tended to be higher in phakic patients3 and that eyes with a history of glaucoma were thought to take more time to return to baseline IOP.4 In these studies, no predictive value was found for baseline IOP, age, gender, refractive error, and the number of previous intravitreal injections in determining postinjection IOP level.3–6 Gismondi et al26 reported that the relationship between shorter axial length and IOP increase after 5 seconds was significant (linear regression analysis, R2 = 0.28; P = 0.007) in the 24 eyes studied. Whereas in our study, we did not find a correlation between axial lengths and transient or sustained IOP elevations. This suggests that the overall size of the eye based on axial length measurements does not likely increase the risk of sustained IOP after intravitreal anti-VEGF therapy. Although it would seem a shorter axial length (and therefore smaller the initial eye volume) may predispose the eye to a greater immediate IOP increase after injection of the standard volume of anti-VEGF and potentially increase the risk of sustained IOP elevation after repeated injections, the results of the linear regression analysis did not show a correlation between shorter axial length and transient or sustained IOP elevation. This observation led the authors to examine other factors that could influence the level of immediate postinjection IOP, including immediate postinjection reflux. Not surprisingly, eyes without appreciable postinjection reflux had an immediate postinjection IOP elevation that was significantly higher than the negligible elevation seen in eyes with appreciable postinjection reflux. Based on our analysis, the presence of a PVD increased the likelihood of postinjection reflux. Using smaller caliber needles, such as a 31-gauge or 32-gauge needle, decreases the amount of postinjection reflux and can result in higher immediate postinjection IOP elevation. We have noted that sustained IOP elevation is virtually nonexistent in our patient population following a switch to larger 30-gauge needles and reducing the injection volume in eyes with borderline or high preinjection IOPs (unpublished data). Based on these observations, our hypothesis is that repeated injections with low reflux may cause mechanical expansile stress on the trabecular meshwork and may lead to sustained IOP elevation. Further studies including histopathologic evaluation of the trabecular meshwork in those who have received more injections versus those who have received fewer could further support this hypothesis. In addition to monitoring the amount of postinjection reflux, other groups have also suggested lowering preinjection IOP with glaucoma drops27 or
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softening the eye with pressure during anesthetic preparation of the globe28,29 to reduce the levels of immediate postinjection IOP. In summary, axial length does not appear to be a predictor of subsequent transient or sustained IOP elevation. Repeated trabecular meshwork trauma related to the absence or presence of postinjection reflux and immediate postinjection IOP elevation may be a contributing factor. In light of these results, one could consider avoiding excessively small-gauged needles, preinjection instillation of IOP-lowering agents or softening of the eye, or using lower injection volumes of anti-VEGF agents in those patients who have already experienced or who are at the risk of experiencing sustained IOP elevation. Key words: axial, bevacizumab, injection, IOP, length, pressure, ranibizumab, reflux, transient, sustained. Acknowledgments The authors would like to thank Jessica Y. Pan, PhD, MBA, for her statistical assistance. References 1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 3. Hollands H, Wong J, Bruen R, et al. Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol 2007;42:807–811. 4. 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;146:930–934. 5. 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. 6. Bakri SJ, Pulido JS, McCannel CA, et al. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23:181–185. 7. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816. 8. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D’Amico DJ, Masonson HN, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 2006;113:992–1001. 9. Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol 2011;95:1111–1114.
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10. Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persistent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:955–958. 11. Kahook MY, Kimura AE, Wong LJ, et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging 2009;40:293–295. 12. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther 2010;26:105–110. 13. Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma 2012;21:241–247. 14. Loukianou E, Brouzas D, Apostolopoulos M. Sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 ml ranibizumab. Int Ophthalmol 2011;31:211–213. 15. Choi D, Ortube M, McCannel C, et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib. Retina 2011;31: 1028–1035. 16. Hoang QV, Mendonca LS, Della Torre KE, et al. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology 2012;119:321–326. 17. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal antivascular endothelial growth factor therapy. Retina 2013;33: 179–187. 18. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009;29:1424–1431. 19. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676–698.
20. Ladas JG, Yu F, Loo R, et al. Relationship between aqueous humor protein level and outflow facility in patients with uveitis. Invest Ophthalmol Vis Sci 2001;42:2584–2588. 21. Georgopoulos M, Polak K, Prager F, et al. Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin). Br J Ophthalmol 2009;93:457–462. 22. Kernt M, Welge-Lüssen U, Yu A, et al. Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells [in German]. Ophthalmologe 2007;104:965–971. 23. Sniegowski M, Mandava N, Kahook MY. Sustained intraocular pressure elevation after intravitreal injection of bevacizumab and ranibizumab associated with trabeculitis. Open Ophthalmol J 2010;4:28–29. 24. Liu L, Ammar DA, Ross L, et al. Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. Invest Ophthalmol Vis Sci 2011;52:1023–1034. 25. 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;250:1435–1440. 26. Gismondi M, Salati C, Salvetat ML, et al. Short-term effect of intravitreal injection of ranibizumab (Lucentis) on intraocular pressure. J Glaucoma 2009;18:658–661. 27. Kim GN, Han YS, Chung IY, et al. Effect of dorzolamide/timolol or brinzolamide/timolol prophylaxis on intravitreal anti-VEGF injection-induced intraocular hypertension. Semin Ophthalmol 2013;28:61–67. 28. Kim KS, Jee D. Effect of the Honan intraocular pressure reducer on intraocular pressure increase following intravitreal injection using the tunneled scleral technique. Jpn J Ophthalmol 2011;55:632–637. 29. Gregori NZ, Weiss MJ, Goldhardt R, et al. Ocular decompression with cotton swabs lowers intraocular pressure elevation after intravitreal injection. J Glaucoma 2013. Epub ahead of print.
