Review SUSTAINED ELEVATION OF INTRAOCULAR PRESSURE AFTER INTRAVITREAL ANTI-VEGF AGENTS What Is the Evidence? VAIDEHI S. DEDANIA, MD,* SOPHIE J. BAKRI, MD† Purpose: To summarize the literature addressing sustained and delayed elevation of intraocular pressure (IOP) in patients with neovascular age-related macular degeneration being treated with intravitreal vascular endothelial growth factor (VEGF) inhibitors and to present possible mechanisms of effect. Methods: Analysis of current literature evaluating sustained and delayed elevation of IOP in patients receiving intravitreal anti-VEGF therapy for neovascular age-related macular degeneration. Results: Studies have demonstrated that patients undergoing treatment with intravitreal anti-VEGF agents may experience sustained and delayed elevation of IOP. The incidence of sustained elevation of IOP in patients with neovascular age-related macular degeneration varied from 3.45% to 11.6%, and few patients required surgical management to control IOP. Possible risk factors associated with sustained and delayed elevation of IOP include, but are not limited to, history of glaucoma, phakia, history of glucocorticoid use, and/or extended treatment duration. There are multiple theories explaining the pathogenesis of sustained elevation of IOP, including microparticle obstruction of the trabecular meshwork, intraocular inflammation, and transient elevation of IOP. Conclusion: Sustained and delayed elevation of IOP in patients undergoing treatment of neovascular age-related macular degeneration with intravitreal anti-VEGF agents is likely a multifactorial process. Further studies to prospectively investigate sustained elevation of IOP in large, randomized, controlled trials might lead to a better understanding of the longterm adverse events associated with intravitreal anti-VEGF therapy. RETINA 35:841–858, 2015

V

diseases of the posterior segment that are characterized by macular edema and/or neovascularization, including proliferative diabetic retinopathy, diabetic macular edema, and retinopathy of prematurity.1–6 Vascular endothelial growth factor has become the target of treatment for many of these conditions, and the emergence of intravitreal VEGF inhibitors has revolutionized the management of several of these conditions, including neovascular age-related macular degeneration, diabetic macular edema, and macular edema because of retinal vein occlusion.1,2,5,7–9 Commonly used anti-VEGF agents include ranibizumab (Lucentis; Genentech, Inc,

ascular endothelial growth factor (VEGF) upregulation has been shown to contribute to the pathogenesis of choroidal neovascularization and other

From the *Department of Ophthalmology, Albany Medical Center, Lions Eye Institute, Albany, New York; and †Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota. S. J. Bakri has, in the past, served as a consultant on advisory boards to Genentech, Regeneron, Allergan, SanBio, and Neumedics, but this work is not related to those consulting agreements. S. J. Bakri was supported by Research to Prevent Blindness, New York, NY. The remaining author has no conflicting interests to disclose. Reprint requests: Sophie J. Bakri, MD, Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905; e-mail: bakri. [email protected]

841

842

RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2015  VOLUME 35  NUMBER 5

South San Francisco, CA)—a humanized monoclonal antibody fragment, bevacizumab (Avastin; Genentech, Inc)—a recombinant full-length humanized monoclonal antibody (used off-label), and aflibercept (Eylea; Regeneron, Tarrytown, NY)—a soluble decoy receptor fusion protein.9–11 Although ocular adverse effects of ranibizumab, bevacizumab, and aflibercept are relatively rare, reported ocular adverse effects include endophthalmitis, cataract progression, vitreous hemorrhage, and retinal tears.8,12–14 Transient elevation of intraocular pressure (IOP) is a known immediate effect of any intravitreal injection, which rarely necessitates anterior chamber (AC) paracentesis for rapid decompression.15–17 This article discusses long-term elevations in IOP rather than the short-term increase in IOP after each injection, which is expected, and transient. In the Minimally Classic/Occult Trial of the AntiVEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA)8 and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR)18 trials, no long-term increase in the mean preinjection IOP from baseline was observed over a 2-year period. Similarly, in the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial19,20 evaluating pegaptanib, mean IOP was stable over a 2-year period. Although some studies report sustained elevation of IOP after intravitreal injection of VEGF inhibitors,21–29 others report lack of an association.30,31 The purpose of this review is to describe these findings and explore possible causes and mechanisms. Intravitreal steroids are known to cause long-term elevations in IOP; however, ocular hypertension (OHT) is rare after intravitreal ranibizumab. Although no evidence of an increase in mean IOP over time was reported in the MARINA and ANCHOR trials, Bakri et al21 noted a subset of patients in clinical practice without a history of glaucoma or steroid use who developed long-term increases in IOP. This finding prompted them to perform a subanalysis of the MARINA8 and ANCHOR18 trials, which had control patients and those receiving monthly injections, to corroborate this finding and report on risk factors.27 Others have noted similar findings and have performed retrospective chart reviews assessing for sustained elevation of IOP after intravitreal anti-VEGF injections. Of the studies examining sustained postinjection elevation of IOP reported in this review, 8 are retrospective cohort/chart reviews,22,24,26,28,31–34 6 are case series,21,23,25,29,30,35 and 127 is a post hoc analysis of the MARINA8 and ANCHOR18 trials

(Table 1). Mean follow-up duration ranged from 3 months23 to approximately 3.75 years33 (Table 2). Defining Sustained Elevation of Intraocular Pressure The definition of sustained elevation of IOP varied among the studies. In regard to threshold values defining sustained elevation of IOP, 3 studies did not report thesevalues,29,31,34 4 studies used .21 mmHg or $21 mmHg,21,23,27,35 3 studies used $22 mmHg and an increase of .6 mmHg from baseline,22,28,30 1 study used .29 mmHg,24 1 study used $24 mmHg or interocular asymmetry of $3 mmHg,25 1 study used .25 mmHg or any IOP .25 mmHg requiring IOPlowering therapy,26 1 study used .5, 10, or 15 mmHg above baseline,32 and 1 study used .25 mmHg with an increase of .10 mmHg above baseline or .21 mmHg with an increase of .5 mmHg above baseline.33 All except one study required threshold values to be attained at more than two visits. In some of these definitions, increase in IOP .6 mmHg was used, as published literature indicates that the normal fluctuation in IOP is less than this value.36 Peak IOP, reported in 9 studies, ranged from 23 mmHg to 70 mmHg,21–25,28–30,35 with mean peak IOP ranging from 25.9 mmHg to 42.6 mmHg in 8 studies (either reported or calculated).21–25,28,30,35 The number of injections before onset/detection of sustained elevation of IOP ranged from 121 to 20.35 Reported Incidence of Sustained Elevation of Intraocular Pressure The incidence of sustained elevation of IOP in patients with neovascular age-related macular degeneration varied from 3.45%23 to 11.6%.22,24,26–28,32,33,35 Good et al22 reported an incidence of 9.9% in patients treated with only bevacizumab and 3.1% in patients treated with only ranibizumab (P = 0.049). Wehrli et al30 failed to find statistically significant incidence of sustained elevation of IOP after intravitreal injection, reporting 0.51% incidence in VEGF inhibitor–treated eyes without glaucoma and 3.1% in treated eyes with glaucoma versus 1% in untreated eyes without glaucoma and 5.7% in untreated eyes with glaucoma (hazard ratio = 0.48; 95% confidence interval: 0.11–2.23 and hazard ratio = 0.59; 95% confidence interval: 0.10–3.60, respectively). Segal et al24 reported an incidence of 4.5% (24/528) when considering all eyes with an IOP from 24 mmHg to 70 mmHg and of 3.6% (19/528) when only considering those eyes with an IOP .29 mmHg. Bakri et al27 reported an incidence from 9.3% to 13.1%, with statistically significant sustained elevation of IOP over 2 consecutive visits in

Table 1. Summary of Studies Evaluating Sustained IOP Elevation After Intravitreal VEGF Inhibitor Injection

Study Bakri et al21

VEGF Inhibitor* Ranibizumab

Study Design

Incidence of sustained Elevation of IOP (Per Eye)

IOP .21 mmHg on several visits

—

Good et al22

Ranibizumab and/ 215 eyes of 195 or bevacizumab patients with neovascular AMD

Some patients can continue injection of anti-VEGF agent without recurrence of sustained elevation of IOP

Ranibizumab and/ 116 patients with IOP .21 mmHg or neovascular on 2 separate bevacizumab† AMD measurements

Heightened risk for Subgroup analysis in sustained IOP patients with elevation in patient preexisting with preexisting glaucoma and glaucoma those in (prevalence 33%) bevacizumabonly and ranibizumabonly groups Large study Bevacizumab only: 9.9% Total number of injections and interval between injections were not causative for elevated IOP Ranibizumab only: 3.1%

3.45%

Limitations

Small study Patients did not have a history of glaucoma or OHT Retrospective

IOP $22 mmHg Overall: 6% on $2 visits for $30 days and a change from baseline of .6 mmHg

Retrospective chart review

Adelman et al23

IOP normalized with treatment of glaucoma/OHT

Strengths

Large study Intravitreal antiVEGF agents can lead to sustained elevation of IOP in patients with no history of OHT or glaucoma

No control eyes Patients received multiple medications Retrospective

(continued on next page)

843

Retrospective case series

Conclusions

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

4 patients with neovascular AMD

Criteria for Elevated IOP

Unspecified follow-up period Patients were not treatment-naive Retrospective

Absence of randomization

844

Table 1. (Continued )

VEGF Inhibitor*

Study Design

Incidence of sustained Elevation of IOP (Per Eye)

Conclusions

Strengths

Retrospective case series

Wehrli et al30

Ranibizumab and/ 528 eyes or bevacizumab (including controls) with neovascular AMD

Retrospective chart review

Tseng et al35

Ranibizumab and/ 25 eyes of 23 or bevacizumab patients with neovascular AMD

IOP $22 mmHg Treated eyes without glaucoma: 0.51% on 2 consecutive visits with an increase of .6 mmHg from baseline or an IOP .26 mmHg on a single visit with initiation or augmentation of IOP-lowering treatment Untreated eyes without glaucoma: 1%

Low incidence of delayed IOP elevation after treatment with anti-VEGF agents and no difference between treated and control eyes

Treated eyes with glaucoma: 3.1% Untreated eyes with glaucoma: 5.7% IOP .21 mmHg Over previous 6 months: Most patients with 4.5%‡ sustained on $2 elevation of IOP consecutive can be managed visits and/or on medical elevation in IOP therapy requiring IOPlowering treatment

Noninjected fellow eyes served as controls

Subgroup of patients with preexisting glaucoma Large study

All patients were previously ocular normotensive

Limitations Patients were not treatment-naive Pretreatment IOP was not obtained in all patients Patients received multiple medications Retrospective

Absence of randomization Patients received multiple medications Small study

RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2015  VOLUME 35  NUMBER 5

Study

Criteria for Elevated IOP

Table 1. (Continued )

Study

VEGF Inhibitor*

Study Design

Criteria for Elevated IOP

Retrospective case series

83 patients with neovascular AMD

Over preceding 62 months: 3.4%10

—

—

Retrospective cohort study Menke et al34

Ranibizumab

Conclusions Occasional reversal of sustained elevation of IOP with longer intervals between injections

No significant sustained IOP elevation after multiple intravitreal injections, even in patients with increased number of injections and preexisting glaucoma

Strengths

Limitations Retrospective

20% of eyes had a remote history of intraocular corticosteroid use Patients received multiple medications Single medication Small study used

Retrospective

320 patients with neovascular AMD

—

—

Retrospective cohort study

—

—

Used noncontact tonometer Retrospective

Long-term elevation Large study of IOP after multiple intravitreal anti-VEGF injections Long-term elevation Single medication Did not assess use incidence of of IOP in eyes with glaucoma/OHT longer treatment duration (.12 months)

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

Kim et al31 Bevacizumab

Incidence of sustained Elevation of IOP (Per Eye)

(continued on next page)

845

846

Table 1. (Continued )

Segal et al24

Pershing et al25

VEGF Inhibitor*

Bevacizumab

Study Design

528 eyes of 424 patients with neovascular AMD

Retrospective chart review Ranibizumab and/ 21 eyes of 18 or bevacizumab patients with neovascular AMD

Retrospective

Incidence of sustained Elevation of IOP (Per Eye)

Conclusions

No correlation between the total number of injections and change in IOP IOP .29 mmHg 4.5% with IOP elevation Intravitreal injection of 24–70 mmHg of anti-VEGF agents is associated with persistent elevation of IOP 3.6% with IOP .29 mmHg — Delayed onset IOP $24 mmHg glaucoma/OHT within 60 days can occur after of intravitreal serial intravitreal injection or IOP injections of antiasymmetry of VEGF agents $3 mmHg at 3 consecutive visits High predominance of phakia with cataract in eyes with IOP elevation Odds of having IOP asymmetry of $3 mmHg after diagnosis of glaucoma/OHT were 9 times higher than previous diagnosis (P , 0.01)

Strengths

Large study

Limitations

Retrospective

Single medication Higher IOP threshold used for definition of OHT Large study Small study

Included patients Retrospective with diagnoses other than neovascular AMD Patients were not treatment-naive

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Study

Criteria for Elevated IOP

Table 1. (Continued )

Study

VEGF Inhibitor*

Study Design

Criteria for Elevated IOP

Incidence of sustained Elevation of IOP (Per Eye)

Conclusions

Strengths

Choi et al26

Ranibizumab, bevacizumab, and/or pegaptanib

155 eyes of 127 patients with neovascular AMD

Retrospective chart review

IOP .25 mmHg 5.5% on $2 separate visits or any IOP .25 mmHg requiring glaucoma medication or surgery

Sustained elevation of IOP after antiVEGF injection is not uncommon

Large study

Some patients received intravitreal corticosteroids in the past, and 2 eyes had a history of anatomically narrow angles Multiple methods to measure IOP: TonoPen XL and Goldmann applanation Did not assess incidence of glaucoma/OHT Retrospective

Sustained elevation Patients received Only used Goldmann applanation in multiple of IOP is patients with IOP medications independent of the .25 mmHg, frequency of otherwise used injections Tono-Pen XL No increase in IOP in Patients received fellow eyes of multiple medications treated eyes (continued on next page)

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

IOP normalized with treatment of glaucoma/OHT

Limitations

847

848

Table 1. (Continued )

Bakri et al27

VEGF Inhibitor* Ranibizumab§

Study Design 1,125 patients with neovascular AMD

IOP $21 mmHg on .2 consecutive visits

Incidence of sustained Elevation of IOP (Per Eye) 9.3%–13.1%

Post hoc analysis from 2 Phase III clinical trials (MARINA and ANCHOR)

Mathalone Bevacizumab et al28

201 eyes of 174 patients with neovascular AMD

IOP $22 mmHg and a change from baseline of $6 mmHg on $2 consecutive visits and lasting $30 days

11%

Conclusions

Strengths

Ranibizumab-treated Large study eyes were more likely than shamtreated or PDTtreated eyes to have an increase of $6 mmHg from baseline or a preinjection IOP of $25 mmHg at $2 consecutive visits IOP increase was not Control group related to the number of injections

Sustained elevation Large study of IOP can occur in normotensive eyes undergoing intravitreal treatment with bevacizumab

Limitations Post hoc analysis

Multiple methods used for IOP measurement: Tono-Pen XL, Goldmann applanation, and pneumotonometry (in some cases, no method was recorded) Unstandardized time of measurement of baseline and subsequent IOP Retrospective

RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2015  VOLUME 35  NUMBER 5

Study

Criteria for Elevated IOP

Table 1. (Continued )

Study

VEGF Inhibitor*

Study Design

Criteria for Elevated IOP

Incidence of sustained Elevation of IOP (Per Eye)

Retrospective cohort study

Hoang et al32

Bevacizumab

6 patients with neovascular AMD, myopic CNV, or CNV of unspecified etiology Retrospective case series

—

—

Ranibizumab and/ 207 patients with IOP .5, 10, or 15 11.6% of treated eyes or bevacizumab neovascular mmHg above AMD baseline on $2 consecutive visits

Strengths

Limitations

Excluded patients Shorter intervals with a history of between ocular surgery, injections, ,8 topical weeks, is corticosteroid associated with an use, and increased risk for previous sustained IOP treatment for elevation neovascular AMD Preexisting glaucoma and intraocular lens status is not associated with sustained IOP elevation Sustained elevation Single medication Small study used of IOP can occur in patients with and without a history of glaucoma

Positive correlation with number of injections of intravitreal antiVEGF agent and risk for sustained elevation of IOP

Patients were Retrospective treatment-naive Did not specify etiology of CNV in all cases Did not report baseline IOP in 2 patients Large study Retrospective

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

Kahook et al29

Conclusions

(continued on next page)

849

850

Table 1. (Continued )

VEGF Inhibitor*

Study Design Retrospective cohort study

Hoang et al33

Ranibizumab and/ 449 eyes of 328 or bevacizumab patients with neovascular AMD

Retrospective cohort study

Incidence of sustained Elevation of IOP (Per Eye)

Conclusions

5.3% of untreated/ control eyes

Absolute IOP .25 Overall: 9.5% mmHg, an increase above baseline IOP of .10 mmHg, or an absolute IOP of .21 mmHg and an increase above baseline IOP of .5 mmHg on $2 consecutive visits Injected unilaterally: 7.2%

Strengths Used contralateral untreated eye as a control

Positive correlation with number of injections of intravitreal antiVEGF agent and risk for sustained elevation of IOP

Large study

4 factors showed an Used contralateral association with untreated eye experiencing as a control a sustained IOP elevation: total number of injections, positive family history of glaucoma, phakia at last visit before sustained IOP elevation, or end of study and a history of intravitreal steroid injection

Limitations Excluded patients with glaucoma and poorly controlled IOP at baseline (IOP .21 mmHg) Excluded patients started on IOPlowering therapy after a single injection Patients received multiple medications Retrospective

Excluded patients with glaucoma and poorly controlled IOP at baseline (IOP .21 mmHg)

RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2015  VOLUME 35  NUMBER 5

Study

Criteria for Elevated IOP

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

Subgroup analysis of eyes treated unilaterally and bilaterally

Strengths

Limitations

patients with a highest preinjection IOP $21 mmHg and $25 mmHg (P = 0.01 and 0.014, respectively) and over 3 consecutive visits (P = 0.025) in patients with a highest preinjection IOP $25 mmHg. Hoang et al32 reported an incidence of 11.6% in treated eyes and 5.3% in untreated/control eyes (P = 0.02) and 7.2% in eyes injected unilaterally versus 1% of untreated eyes (P = 0.001) and 11.6% in eyes injected bilaterally (with IOP elevation in at least 1 eye).33 Tseng et al35 reported 3.4% (19/555) incidence for patients treated over the preceding 62 months and 4.5% (19/425) for patients treated over the previous 6 months (Figure 1). Methods of Intraocular Pressure Measurement

*Ranibizumab: 0.5 mg/0.05 mL, bevacizumab: 1.25 mg/0.05 mL, or pegaptanib: 1.6 mg/0.09 mL. †Bevacizumab: 1.5 mg per 0.06 mL. ‡Percent of patients. §Ranibizumab: 0.3 mg or 0.5 mg.

Study Design VEGF Inhibitor* Study

Injected bilaterally: 11.6%

Conclusions Incidence of sustained Elevation of IOP (Per Eye) Criteria for Elevated IOP

Table 1. (Continued )

851

Although most studies used only Goldmann applanation tonometry for IOP measurement, Kim et al31 report use of a noncontact tonometer and Choi et al26 and Pershing et al25 report use of Tono-Pen XL (Reichert Inc, Depew, NY). Method of IOP measurement was not specified in three studies.24,29,31 In the MARINA8 and ANCHOR18 trials, IOP was measured in 49.4% with applanation tonometry, 45.5% with Tono-Pen XL, and the remaining 5.1% with pneumotonometry, a combination of methods or unspecified. Control of Intraocular Pressure When IOP was unable to be controlled with topical IOP-lowering medication only, oral carbonic anhydrase inhibitor was used or laser trabeculoplasty, laser peripheral iridotomy, and filtration surgery were performed. Of all reported cases in the literature, laser trabeculoplasty was performed in three patients,22,25,35 and a filtration procedure was performed in seven.24–26,29,35 Bakri et al27 reported that four eyes in the ranibizumab group required laser peripheral iridotomy versus none in the sham/photodynamic therapy group. Initiation of IOPlowering therapy was avoided in two patients by implementing a “treat-and-extend” dosing regimen in one study.35 Menke et al34 reported significant sustained elevation of IOP, but no patients required IOPlowering therapy, as final IOP ranged from 21 mmHg to 25 mmHg, and Pershing et al25 reported spontaneous normalization of IOP in 19% of eyes. Overall, the rate of filtration surgery is low, and occasionally patients do not require any IOP-lowering therapy. What Are the Risk Factors? Some studies found no association of sustained elevation of IOP and total/cumulative number of injections,22,26,30,33,34 interval between injections,22 preexisting glaucoma,22,28,30 family history of glaucoma,33

Preinjection/Baseline IOP, mmHg

Bakri et al21 20, 18, 15, and 15 (mean 17) — Good et al22 Adelman 15, 14, 8, and 16 (mean et al23 13.25) Wehrli AMD without glaucoma: et al30 13, 15, and 11 (mean 13) AMD with glaucoma: 18 and 11 (mean 14.5) Tseng 16.9 (range 14–21) et al35 Kim et al31

Postinjection Peak IOP, mmHg

Mean Follow-up Duration —

30, 34, 46, and 50 (mean 40) 29.2 (range 23–36)

+10, +16, +31, and +35 (mean +23) +12

32, 31, 28, and 36 (mean 31.75) AMD without glaucoma: 25, 27, and 60 (mean 37.3)

+17, +17, +20, and +20 (mean +18.5) AMD without glaucoma: +12, +12, and +49 (mean +24.3)

AMD with glaucoma: 27 and 28 (mean 27.5) 35.8 (range 23–58)

AMD with glaucoma: +9 and +17 (mean +13) — 47.9 weeks (range 9–159)

29.8‡ (range 22–28) 14.11 ± 2.76 (range 8–20) 6 months: 13.61 ± 3.05§; 12 months: 13.74 ± 3.21§; 18 months: 14.01 ± 2.81§; 24 months: 13.94 ± 2.96§; last follow-up: 14.15 ± 2.71§ 14.2 ± 2.6 (range 7–21) 15.7 ± 3.0§ (range 7–25)

Menke et al34,** Segal 17.0 (range 10–20) et al24 — Pershing et al25 Choi et al26 15.2 ± 3.8 (range 10–22); entire cohort: 14.4 ± 3.4

Change in IOP,* mmHg

42.6 (range 30–70)

—

0.8 ± 3.1 (range −10 to +11) +25.5 (range +10 to +50)

Number of Injections Before Onset of Elevated IOP 2, 4, 11, and 1 (mean 4.5)

3 years

5†

3–36 months

16, 3, 12, and 12 (mean 10.75) AMD without glaucoma: 14, 5, and 14 (mean 11)

1.7–2.2 years

AMD with glaucoma: 8 and 2 (mean 5) 20 (range 8–40)

.2 years

3.71 ± 1.62** (range 1–9)

22.7 ± 14.1 months (range 2–51) —

13.0 ± 8.0** (range 2–35) 7.8 (range 3–13)

32 ± 8 (range 24–50)

—

—

20 ± 9.1§ (range 11–39); entire cohort: 15.3 ± 3.7

—

9.6 ± 7.7 (range 1–24); entire injected subgroup: 7 ± 7

Bakri et al27 Sham/PDT study eye: 15; Sham/PDT study eye: 29.1%††; ranibizumab 0.3 ranibizumab 0.3 mg: mg: 37%††; ranibizumab 15; ranibizumab 0.5 0.5 mg: 39.9%†† mg: 15.1 Mathalone 15.2 ± 2.2; entire cohort: 25.9 ± 3.3; entire cohort: 14.3 et al28 14.8 ± 2.2 ± 2.6§§

—

928 ± 489 days (range 210–1,564); entire cohort: 417 ± 388 days 2 years

15.7 ± 11.9 months; entire cohort: 15.7 ± 11.5 months —

5†,¶ (range 3–18); entire cohort: 4

183 weeks (range 48.1–260)

24.45¶ (range 9–39)

Kahook et al29 Hoang et al32

28, 42, 31, mid-30s, 30, and 15, 15, 11, 14, and not 25 mentioned for Cases 5 and 6 — —

— +13, +27, +20, $19, and unable to calculate for Cases 5 and 6 —

9.7 ± 11.2 (range 1–40)

—

2, 5, 1, 8, 7, and 10 (mean 5.5)

RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2015  VOLUME 35  NUMBER 5

Study

852

Table 2. Summary of Studies Evaluating Sustained IOP Elevation After Intravitreal VEGF-Inhibitor Injection

853

196 weeks (range 66.3– 25.8†† (range 11–40) 262.7)

or previous treatment with intravitreal and/or topical steroids.33 Other studies reported that an increased risk for sustained elevation of IOP was found to be associated with increased duration of treatment beyond 12 months,34 family history of glaucoma,33 number of injections,33 and history of use of intravitreal steroids.33 In the study by Bakri et al,27 a post hoc analysis of eyes receiving monthly ranibizumab for neovascular agerelated macular degeneration in the MARINA and ANCHOR trials, fellow eyes, and/or sham or photodynamic therapy-treated eyes served as controls, and treatment groups were well balanced with respect to glaucoma risk factors and ocular steroid use. In addition, IOP was monitored monthly. Is Preexisting Glaucoma a Factor?

*Peak IOP − preinjection IOP. †Median. ‡At first elevated IOP. §Not at peak IOP. ¶Total mean or median number of injections. **Entire cohort, including patients with sustained elevation of IOP. ††Patients with IOP $21 mmHg. §§At last follow-up.

— — Hoang et al33

—

Change in IOP,* mmHg Postinjection Peak IOP, mmHg Preinjection/Baseline IOP, mmHg Study

Table 2.

(Continued )

Mean Follow-up Duration

Number of Injections Before Onset of Elevated IOP

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

As previous studies have suggested that there is an increased risk for IOP elevation after intravitreal injection in patients with preexisting glaucoma,37 the role of preexisting glaucoma was evaluated in multiple studies. Eight studies included patients with a history of glaucoma and/or OHT,22,27,29–33,35 whereas seven studies excluded patients with a history of glaucoma and/or OHT.21,23–26,28,34 One study reported preexisting glaucoma in 9.8% of patients diagnosed with sustained elevation of IOP, with 33% of patients experiencing higher rates of IOP elevation when compared with patients without preexisting glaucoma (3.1%).22 In the original retrospective case series, Bakri et al21 reported the development of peripheral anterior synechiae soon after intravitreal injection in one patient with rapid sustained elevation of IOP. Hoang et al33 included patients with a personal and family history of glaucoma but only found a statistically significant association with sustained elevation of IOP in patients with a family history of glaucoma (P = 0.04), and Pershing et al25 excluded patients with a history of glaucoma and/or OHT but found that all 3 patients with an IOP .40 mmHg had showed signs of preexisting angle compromise, including mild peripheral anterior synechiae and/or heavy trabecular meshwork pigmentation. No association between personal history of glaucoma and sustained elevation of IOP was found by Hoang et al,32 but results might be confounded as three patients with preexisting glaucoma and poorly controlled IOP at baseline were excluded from this study. Although there are no conclusive data on the association of preexisting glaucoma, OHT or angle structure abnormality, and postinjection sustained elevation of IOP, all patients, especially those with a personal or family history of glaucoma or with a suspicion for glaucoma, should have gonioscopy and tonometry performed before

854

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Fig. 1. Comparison of number of patients in study, incidence of sustained elevation of IOP, and rigor of study design.

initiation of treatment and at regular intervals during treatment with intravitreal VEGF inhibitors. Is the Number of Injections a Factor? In all but 3 of the studies that reported the total and/ or mean number of injections before onset of sustained elevation of IOP, a mean of less than 10 injections were given, with a range from 1 to 40. Tseng et al35 identified a high proportion of eyes with significant elevations in IOP after many (.20) intravitreal injections. Hoang et al32 reported a positive correlation between the number of injections and sustained elevation of IOP, with a P-value threshold #0.10. Pershing et al25 found that 72% of patients had at least 1 previous visit with IOP asymmetry of $3 mmHg, and 11% had IOP asymmetry on 3 consecutive visits before diagnosis of elevation of IOP. Although Menke et al34 reported increased risk for sustained elevation of IOP with duration of treatment beyond 12 months, no significant correlation with total number of injections was found. Similarly, Hoang et al33 reported an

association of sustained elevation of IOP with a history of the use of intravitreal corticosteroids, whereas no significant association with the total number of intravitreal corticosteroid injections was found. Is Glucocorticoid Use Associated? Previous studies have explored the intraocular effects of glucocorticoids, including extracellular matrix deposition in the trabecular meshwork38 and altered aqueous dynamics39 and gene expression.40,41 In regard to previous or current use of intravitreal and/ or topical steroids, six studies included patients with a history of use,21,23,27,32,33,35 three studies excluded patients with a history of use,24,31,34 four studies did not report on this history,22,26,29,30 one study excluded patients with use in the three months preceding the study,25 and one study excluded patients with only a history of topical steroid use.28 A trend toward the sustained elevation of IOP in patients with previous or current systemic and/or topical steroid use was suggested by Bakri et al,21 Adelman et al,23 Hoang et al,32

SUSTAINED ELEVATION OF IOP AFTER ANTI-VEGF  DEDANIA AND BAKRI

and Tseng et al,35 and statistical significance (P , 0.05) with history of use was reported by Hoang et al33 (P = 0.002). In the aforementioned studies, patients with a history of the use of intravitreal, topical, or systemic corticosteroids seemed to have experienced a more rapid and greater increase in IOP postinjection or required more aggressive measures to manage IOP postinjection. During the time of ANCHOR18 trial, intravitreal corticosteroids may have been administered in patients undergoing photodynamic therapy. Previous or concurrent treatment with glucocorticoids likely alters aqueous outflow facility, increasing the likelihood of sustained or delayed IOP elevation after injection of anti-VEGF agents. Does Phakic Status Contribute? Studies examining the short-term postinjection elevation of IOP have found that transient elevation in IOP tended to be higher in phakic patients.42 Twelve of the 15 studies evaluating the sustained postinjection elevation of IOP included both phakic and pseudophakic patients, whereas 3 studies did not report and/or assess the lens status of patients. Of the studies reporting lens status, 1 study reported no association between the sustained elevation of IOP and lens status,32 and another study reported an association with being phakic at the last visit before the sustained elevation of IOP was diagnosed (P = 0.02).33 Choi et al26 reported that of the nine eyes with the sustained elevation of IOP, six were found to have cataracts, one was normal without sclerotic changes, and two were pseudophakic. Additionally, of the 21 eyes found to have the sustained elevation of IOP in the study by Pershing et al,25 there was a trend toward an association with phakia in 18 phakic patients and 3 pseudophakic patients. Lens status may play an important role in sustained elevation of postinjection IOP, or lack thereof, for numerous reasons. As there are reports suggesting that cataract extraction provides a lowering effect on long-term IOP, pseudophakic patients may be at lower risk for sustained elevation of IOP postinjection. However, as pharmacokinetic studies have shown that bevacizumab diffuses into the AC,43 pseudophakic patients, especially those who have had a Neodymiumdoped yttrium aluminum garnet (Nd:YAG) laser capsulotomy, may be at increased risk for sustained elevation of IOP postinjection. Furthermore, mechanical obstruction of the aqueous outflow channels by silicone microdroplets and protein aggregates from repackaged bevacizumab44–46 may contribute to sustained elevation of IOP in pseudophakic patients, as there may be a disruption of the anterior hyaloid or zonules, allowing access for silicone or high-molecular-weight proteins into the AC.23

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Hypotheses Microparticle Obstruction of the Trabecular Meshwork Earlier studies have shown that silicone microdroplets and protein aggregates from medication packaging and/or delivery equipment44–46 can obstruct aqueous outflow and result in IOP elevation. Concern for mechanical obstruction has been associated with bevacizumab, as at many centers, it is administered after being repackaged. Kahook et al44 reported variations in the concentration of high-molecular-weight protein aggregates in different samples of compounded/repackaged bevacizumab. Good et al22 found that a higher proportion of patients with a sustained elevation in IOP received intravitreal injections from the center obtaining repackaged bevacizumab than from the center receiving the medication in the original vial. As associations between repackaged bevacizumab and sustained elevation of IOP have been considered and supported by the aforementioned studies, the source of medication may play a greater role in IOP elevation than the medication itself. Ten studies did not report the source of bevacizumab,21,23–27,29,31,32,35 three studies reported using repackaged or prefilled bevacizumab,22,28,33 one study reported that they did not use repackaged bevacizumab,34 and one study reported using silicone-free syringes and compounding bevacizumab at an onsite pharmacy.30 Although high-molecular-weight protein aggregates may contribute to sustained elevation of IOP, Tseng et al35 described 11 eyes with the sustained elevation of IOP that never received bevacizumab and the absence of silicone droplets in the AC. Although it has been reported that intravitreal bevacizumab has a toxic effect on trabecular meshwork cells in vitro,47 other studies in cultured human cells did not support this finding.48 Good et al22 reports an overall incidence of the sustained elevation of IOP postinjection of 6% with 9.9% in patients receiving bevacizumab only and 3.1% in patients receiving ranibizumab only (P = 0.049). Although this relationship has been suggested in other studies, many patients in these studies received previous or concurrent treatment with other intravitreal VEGF inhibitors. In nine studies, patients received multiple intravitreal medications, including ranibizumab, bevacizumab, pegaptanib, and/or corticosteroids either before or during the study.21–23,25,26,30,32,35 Theories supporting the higher incidence of sustained elevation of IOP in patients receiving bevacizumab partially arise from the thought that high-molecular-weight proteins, such as bevacizumab (150 kDa), may accumulate in the outflow

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channels, obstructing aqueous outflow. Because bevacizumab is approximately 3 times larger than ranibizumab (48 kDa), it seems that bevacizumab might be more likely to obstruct outflow channels.21,23 Role of Inflammation Many other theories have been developed to describe the pathogenesis of transient and the sustained elevation of IOP after intravitreal injection of VEGF inhibitor. For example, it has been hypothesized that subclinical inflammation immediately postinjection can incite scar formation and fibroblast proliferation in the trabecular meshwork, resulting in chronic obstruction of aqueous outflow.34 Another proposed mechanism implicates inflammation, such as drug-induced trabeculitis or uveitis.21,49 In this theory, bevacizumab would be more likely to incite inflammation and cause sustained elevation of IOP as it is a larger molecule, with an Fc portion and a longer serum and vitreous half-life.49,50 Six studies reported no AC inflammation,22–24,28,30,35 and one study excluded patients with clinical intraocular inflammation.34 Even in the absence of identifiable inflammation in the AC, it is important to consider that subclinical inflammation may contribute to the elevation of IOP.21 Role of Transient Elevations in Intraocular Pressure Other hypotheses suggest that the IOP rise after the intravitreal injection of VEGF inhibitors can be attributed to chronic changes from recurrent episodes of transient postinjection elevations in IOP. In consideration of the reports of transient rapid elevations in IOP, some have attempted to prevent these elevations with preinjection administration of IOP-lowering medications. In one study, brimonidine/timolol fixed combination (Combigan) was administered twice a day on the day of the injection and on the day before the intravitreal injection of ranibizumab and was found to reduce the rapid increase in postinjection IOP in a safe and effective manner.51 The sustained elevation of IOP was not evaluated in this study; therefore, it remains unclear whether or not the prevention of transient elevation of IOP has any effect on the sustained elevation of IOP. Despite this, if the immediate postinjection elevations in IOP are associated with sustained elevation of IOP and can be prevented with preinjection use of IOP-lowering medications, the sustained elevation of IOP could potentially be prevented as chronic damage to aqueous outflow channels can be reduced.

Discussion The lack of an effect of intravitreal VEGF inhibitor injections on long-term IOP in some studies may be due to a small cumulative number of injections and/or short follow-up periods. Other studies may not show an association between the sustained or delayed elevation of IOP after injection of intravitreal VEGF inhibitors, as this may be a rare event, and small study size may limit the ability to detect significant differences. Finally, although setting a higher threshold IOP when defining sustained elevation of IOP identifies eyes that definitely have a clinically significant increase, the threshold values may be too specific, missing many cases requiring therapy. Most of the reports described above represent retrospective cohort/chart reviews and case series without a control population. Although there may be insufficient data to conclusively determine that intravitreal injection of VEGF inhibitors results in sustained elevation of IOP, the current body of literature supports this theory. Large prospective studies with more frequent and standardized monitoring of IOP preinjection and postinjection over an extended period are ideal for examining this relationship. In the studies discussed above, there were intrastudy and interstudy variations in the method and timing of IOP measurement; therefore, absolute IOP values between studies may not be comparable and variations within studies may be confounded by method used for IOP measurement. The greater variability and decreased accuracy with Tono-Pen XL makes Goldmann applanation the ideal method for measurement of IOP. To more aptly compare IOP values across articles, the standardization of IOP measurement is necessary, as is predefining and standardizing IOP thresholds. Additionally, investigation into aqueous outflow facility and changes in the trabecular meshwork at a molecular level may reveal the pathogenesis of postinjection sustained elevation of IOP. It is important to quantitate reflux of medication/ vitreous at the time of injection, as studies have shown higher IOP transiently in eyes with decreased reflux.52– 54 The injection technique has been shown to affect medication reflux and postinjection IOP.54 Evaluation of different techniques, including needle size, may allow for the optimization of medication delivery. Furthermore, the level of intravitreal medication remaining in the eye after injection may affect drug efficacy and safety. Other factors to consider for future studies of sustained elevation of IOP after intravitreal injection of VEGF inhibitors include medication processing and storage time, refractive error, and use of preinjection IOP-lowering medications.

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