ORIGINAL STUDY
Ocular Hypertension Following Intravitreal Antivascular Endothelial Growth Factor Therapy: Review of the Literature and Possible Role of Nitric Oxide R. Grant Morshedi, MD,* Aaron M. Ricca, BS,* and Barbara M. Wirostko, MDw
Purpose: To review the literature regarding ocular hypertension following intravitreal antivascular endothelial growth factor therapy, and to propose a novel mechanism for the development of ocular hypertension as a result of such therapy. Methods: The PubMed database was used to identify publications by using combinations of the search terms, “glaucoma,” “ocular hypertension,” “pegaptanib,” “bevacizumab,” “ranibizumab,” “aflibercept,” “anti-vascular endothelial growth factor,” intraocular pressure,” and “intravitreal.” The reference lists of these publications were also reviewed for relevant articles. Results: Numerous articles have been published describing ocular hypertension, either immediate-term/short-term or delayed/sustained, following intravitreal antivascular endothelial growth factor therapy. Ocular hypertension has been reported following intravitreal pegaptanib, bevacizumab, and ranibizumab, and aflibercept. On the basis of the fact that vascular endothelial growth factor, normally present as a vascular modulating and reparative growth factor, is known to upregulate endothelial nitric oxide (NO) synthase, and that NO has been shown to decrease intraocular pressure in both normal and glaucomatous human and animal eyes, we propose a novel mechanism for sustained ocular hypertension following intravitreal antivascular endothelial growth factor therapy. We propose that such intravitreal therapy may lead to decreased NO in the anterior segment, which then leads to trabecular meshwork constriction, decreased outflow facility, and increased intraocular pressure. Conclusions: Sustained ocular hypertension following the intravitreal administration of antivascular endothelial growth factor agents is a potentially serious side effect that has not been adequately explained. Further investigation is necessary to determine the role of NO in the mediation of this adverse effect. Key Words: anti-VEGF, ocular hypertension, nitric oxide, intraocular pressure, glaucoma, intravitreal
(J Glaucoma 2016;25:291–300)
T
he intravitreal administration of antivascular endothelial growth factor (VEGF) agents has become the standard of care for wet age-related macular degeneration,
Received for publication February 1, 2014; accepted September 1, 2014. From the *Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and wJohn A. Moran Eye Center, University of Utah, Salt Lake City, UT. Supported in part by an unrestricted grant from Research to Prevent Blindness Inc., New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. Disclosure: The authors declare no conflict of interest. Reprints: R. Grant Morshedi, MD, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301W. Markham St., Slot 523, Little Rock, AR 72205 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000173
J Glaucoma
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and an important tool in the treatment of other conditions such as diabetic macular edema, retinal vein occlusionassociated macular edema, and neovascular glaucoma. Ocular hypertension (elevated intraocular pressure [IOP]) following the administration of these agents has been increasingly reported as a potential side effect. The incidence in the reported literature is variable, but is estimated between 66% and 100% for immediate ocular hypertension1–4 and between 3.45% and 11.6% for sustained ocular hypertension.5–9 All currently available intravitreal anti-VEGF agents, including pegaptanib, bevacizumab, ranibizumab, and aflibercept, have had ocular hypertension reported as a side effect.10,11 The reports of anti-VEGF-related ocular hypertension have described both an immediate-term or short-term IOP elevation as well as a delayed and/or sustained IOP elevation. The definition of “short-term” versus “sustained” is somewhat heterogenous and arbitrary among publications, but in general we will refer to short-term IOP elevation as occurring immediately postinjection, with a return to normal within 60 minutes of the injection, whereas sustained IOP elevation is most frequently defined as IOP > 21 mm Hg on 2 visits, along with an increase of 5 mm Hg from baseline preinjection IOP. Although immediate IOP elevation might be expected based purely on volumetric considerations, the precise mechanism underlying sustained IOP elevation has yet to be elucidated. Several potential causes have been hypothesized, including a direct mechanical effect; protein, silicone oil, or other high–molecular weight aggregates clogging the trabecular meshwork; direct trabecular toxicity; and inflammation/trabeculitis.7,8,12,13 It is well accepted and understood that VEGF upregulates endothelial nitric oxide synthase (eNOS) systemically, which in turn synthesizes nitric oxide (NO).14 NO has been extensively studied for its role on endothelial cell function, permeability, and smooth muscle vasodilation.15–22 The fact that systemic anti-VEGF agents lead to systemic hypertension as an adverse event is, in fact, attributed to the downregulation of eNOS and NO, thereby increasing systemic vascular bed constriction.23 In addition, within ocular tissue, there is ample evidence that NO improves aqueous outflow facility, most likely by regulating trabecular meshwork and/or Schlemm’s canal cell volume.16–18 Novel antihypertensive NO-donating therapies have recently been investigated for their ability to decrease IOP, theoretically by causing trabecular meshwork vasodilation and decreased outflow resistance.24,25 On the basis of this knowledge, we propose that repeated and long-term VEGF antagonism may lead to a deficiency of intraocular NO, which in turn adversely affects outflow facility and leads to a sustained rise in IOP. The aim of this paper is to review the existing reports of intravitreal anti-VEGF-induced ocular hypertension, and to provide evidence from the existing www.glaucomajournal.com |
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291
References
N
Design
Agent
45 eyes
Prospective cohort
Sharei et al28
45 eyes
Prospective cohort
Ranibizumab
Theoulakis et al4
88 eyes
Prospective doubleblind placebocontrolled
Ranibizumab
Bakri et al29
161 patients
Gismondi et al2
54 eyes
Retrospective chart review July 2005December 2005 Prospective cohort
Pegaptanib, Bevacizumab, Triamcinolone Ranibizumab
Kim et al1
120 eyes
Retrospective chart review
Ranibizumab (12%), Bevacizumab (67%), Pegaptanib (14%), Triamcinolone (8%)
Postinjection: 37.0 11-12 min: 23.25
IOP reduced to 40 and 19 eyes (42.2%) >50. T3: 22 eyes (48.4%) >40 and 10 eyes (22.6%) >50. T10: 5 eyes (11.1%) > 40 and 1 eye (2.2%) >50 IOP > 30: 9%, 8/44 eyes, in Combigan group at 5 min. IOP > 30: 91%, 40/44 eyes, in control group at 5 min
100% >30 between 1 and 10 min and 0% at 30 min NA
IOP > 30: 79% at T0, 30% at 5 min, 4% at 15 min, 1% at 25 min, 0% at 30 min 36% IOP at T0 reachedZ50 mm Hg
Conclusions No benefit to prophylactic meds No difference with preexisting glaucoma IOP back to normal in 1 wk IOP increase significantly higher if a tunneled scleral injection was performed
Less IOP increase if subconjunctival backflow after injection
Combigan prophylaxis is safe and effective to prevent immediate IOP spikes after ranibizumab
Few patients required postinjection IOP meds None required paracentesis Significant IOP rise at 5 s, 5, 10, 15, and 30 min Not significant after 1 h or 1 d
Higher incidence of IOP spikes with small-bore needles, hx of glaucoma, and lack of postinjection subconjunctival reflux
Volume 25, Number 3, March 2016
Hohn and Mirshahi27
Pegaptanib (n = 30), Bevacizumab (n = 47), Ranibizumab (n = 42) Ranibizumab
Retrospective chart review
Incidence of Significant IOP (mm Hg) Increases
J Glaucoma
71 eyes
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Frenkel et al26
Average Pressures at Different Time Points (mm Hg)
Morshedi et al
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TABLE 1. Summary of Studies Describing Immediate or Short-term IOP Elevation
Significant spike from baseline at 2, 5, and 30 min Phakic patients have higher IOP at 30 min Mean change of IOP from baseline at 30 min was 8.74 ± 7.23 IOP > 30: 67.4% at 2 min, 28.9% at 5 min, 1% at 30 min
METHODS The PubMed database was searched using combinations of the search terms, “glaucoma,” “ocular hypertension,” “pegaptanib,” “bevacizumab,” “ranibizumab,” “aflibercept,” “anti-vascular endothelial growth factor,” intraocular pressure,” and “intravitreal.” The reference lists of these publications were also reviewed for relevant articles. All published papers were reviewed, but the search was limited to the English literature.
RESULTS Thirty-four relevant articles were identified. Twelve described immediate or short-term IOP elevation, and 22 described long-term or sustained IOP elevation. Pertinent details of these publications are summarized in Tables 1 and 2. For the purpose of these tables, we excluded studies in which meaningful statistical analyses were not performed due to small sample size (small case series).
Pre: 15.73 ± 3.14 30 min: 24.47 ± 6.29 5-7 d f/u: 15.81 ± 4.02
DISCUSSION Intravitreal injections of anti-VEGF agents have become an important tool in the management of some of the most common retinal and choroidal neovascular diseases. Adverse effects are uncommon, but one of the more commonly reported and unexplained adverse events is IOP elevation. IOP elevation following intravitreal anti-VEGF injection has been cited in the literature as early as 2006.32 Published studies on this subject vary in design and sample size. The mechanism of IOP elevation as a result of intravitreal anti-VEGF agents is unclear. It is likely that shortterm IOP elevation represents a different adverse event, with a distinct mechanism, than sustained IOP elevation. Furthermore, there may not be a singular unifying mechanism for either of these 2 adverse events, but rather several mechanisms that, depending on the individual’s underlying pathophysiology and/or comorbid ocular conditions, interact to cause IOP elevation.
Short-term IOP Elevation
f/u indicates follow-up; IOP, intraocular pressure.
Pegaptanib Retrospective chart review 122 injections in 79 patients Hariprasad et al32
Bevacizumab 104 eyes
Prospective Cohort
r
Hollands et al3
Pegaptanib Retrospective chart review 75 eyes Frenkel et al31
Bevacizumab Prospective cohort 70 eyes (29 with repeated injections) Falkenstein et al30
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Ocular Hypertension After Intravitreal Anti-VEGF
literature regarding the plausibility of NO deficiency-mediated sustained IOP elevation.
IOP > 30: 13% at 30 min
5.3% had transient NLP vision immediately postinjection with IOP > 55 mm Hg and underwent paracentesis
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NA
Pre: 15.7 ± 3.42 3 min: 36.27 ± 5.1 10 min: 24.56 ± 5.9 Pre: 14 ± 3 1 min: 38 ± 14 3-10 min: 34 ± 9 11-20 min: 26 ± 10 21-30 min: 24 ± 11 31-50 min: 22 ± 3 f/u: 13 ± 3 Pre: 14 2 min: 36.1 5 min: 25.7 30 min: 15.5
IOP > 30: 14% at 10 min, 0% at 15 min
Significant spike from baseline at 3 min and 10 min
J Glaucoma
Short-term IOP elevation, defined as within 60 minutes from the injection, is a more common event than sustained IOP elevation. Although estimating a true incidence from the existing literature is difficult given the prevalence of retrospective studies and inconsistent definitions, existing studies have described between 66% and 100% of patients having an immediate postinjection IOP spike.1–4 Studies that have evaluated IOP in the immediate postinjection period have consistently found a high rate of ocular hypertension that generally returns to 29 unilateral injections had sustained IOP elevation 0/46 control eyes had sustained IOP elevation 0% experienced sustained IOP elevation
Significant effect of number of injections on IOP elevation
7 eyes developed final IOP 21-25 mm Hg with previous baseline 14-18 mm Hg NA
Ranibizumab (97.1%) and/or Bevacizumab (34.1%)
150.1 wk
Kim et al33
83 eyes
Propsective interventional case series
Bevacizumab
2y
Menke et al34
320 eyes
Retrospective chart review
Ranibizumab
22.7 ± 14.1 mo
Mean injections for all eyes: 13.0 ± 8.0
Pershing et al35
21 eyes
Retrospective chart review
Ranibizumab and Bevacizumab
At least 1 y
Average months until delayed OHT: 15.5 ± 16.1 Average injections until delayed OHT: 9.7 ± 11.2
Segal et al36
528 treated eyes and 328 control eyes
Retrospective case series
Bevacizumab
NA
Mean injections: 7.8 (range, 3-13)
Sobaci et al37
65 eyes
Retrospective cohort
Bevacizumab (54%) or Ranibizumab (46%)
14.05 ± 2.6 mo for bevacizumab 13.6 ± 2.1 mo for ranibizumab
Hoang et al5
207 eyes
Retrospective case control
Ranibizumab (96.6%) and/or Bevacizumab (32.4%), or both
148.6 wk
Mean number of bevacizumab injections 5.1 ± 1.3 Mean number of ranibizumab injections 6.3 ± 1.9 Mean total injections 20.8 (3-48) Mean for sustained IOP: 24.4 (9-39) Mean for those without sustained IOP: 20.4 (3-48)
Mathalone et al9
201 eyes
Retrospective cohort
Bevacizumab
15.7 ± 11.5 mo
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Sustained IOP elevation: median 5 (3-18) No IOP elevation: median 4 (3-22)
24/528 (4.5%) had sustained IOP > 24 19/528 (3.6%) had IOP 3070 mm Hg 3-30 d after injection, compared with 1/328 (0.3%) control eyes 0% experienced sustained IOP elevation
IOP elevation was not observed during the longterm follow-up period The numbers of injection and preexisting glaucoma did not affect IOP changes Signficant IOP increase after ranibizumab, but no patients required treatment Elevated IOP may occur after ranibizumab or bevacizumab injections Significant IOP asymmetry and unilateral glaucoma after unilateral injections Bevacizumab may be associated with persistent IOP elevation
Repeated ranibizumab or bevacizumab does not seem to have adverse effects on RNFL or IOP
Patients receiving Z29 injections more likely to have IOP elevation >5 mm Hg above baseline on Z2 consecutive visits than pt receiving r12 injections (20% vs. 4.2%) 22/201 (11%) had sustained IOP elevation
Total number of injections showed an association with IOP elevation
Prevalence of IOP elevation was significantly higher when the interval between injections was 5 mm Hg) 1 h following the injection was 1/49 (0.4%) 3.4% (19/555) of total treated over preceding 62 mo
5/302 (1.7%) injected eyes, compared with 7/226 (3.1%) control eyes developed delayed OHT
5.8% (9/155) developed sustained elevated IOP 3.2% (5/155) developed transient elevated IOP
13/215 (6%) had sustained IOP elevation requiring intervention 18/215 (8.4%) had transient IOP elevation which resolved w/in 30 d without intervention No cases of bilateral IOP elevation in the 20 patients who received bilateral intravitreal injections 4/116 (3.45%) developed sustained elevated IOP after multiple injections
0% experienced sustained IOP elevation
Ranibizumab injections caused a significant decrease in RNFL thickness after 12 mo of follow-up
Serial injections may lead to persistent IOP elevations requiring therapy At time of IOP elevation 15 eyes (60%) were phakic and 10 eyes (40%) were pseudophakic No difference between injected group and control group, with or without glaucoma, of developing delayed OHT No difference in rate of delayed OHT between medications injected Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon No association with patient demographics or injection history was identified Incidence of sustained elevated IOP is significant Preexisting glaucoma may be risk factor for elevated IOP after injections
Persistent OHT may occur after intravitreal antiVEGF injection in patients with no previous diagnosis of glaucoma or OHT OHT may persist across several visits and require therapy Sustained IOP usually occurs after multiple injections No change in RNFL after long-term injections
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1y
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Ranibizumab
Prospective cohort
r
49 eyes
J Glaucoma
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Martinez-de-la-Casa et al38
Morshedi et al
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References
N
Design
Agent
Average Time or Injections (N) Until OHT Onset
Median Length of Follow-up
Incidence of OHT
Ranibizumab (32%), Bevacizumab (39%), and Pegaptanib (4%), or multiple agents (26%)
928 ± 489 d for sustained elevated IOP cohort 417 ± 388 d for entire cohort
Good et al7
215 eyes
Retrospective chart review
Bevacizumab (47%), Ranibizumab (45%), or both
3y
Adelman et al8
116 patients
Retrospective chart review
Bevacizumab (34%), Ranibizumab (49%), or both (16%)
3-36 mo
Mean injections: 13.3 (range, 3-19)
Horsley et al41
41 eyes
Ranibizumab, Bevacizumab, and/or Pegaptanib
27 ± 9.7 mo
All patients: 16.0 ± 5.5 intravitreal injections
0% experienced sustained IOP elevation
Lee et al42
185 eyes
Retrospective observational consecutive case series Propsective interventional case series
Bevacizumab
6 mo
All patients received either 1 or 2 injections during this study
0% experienced sustained IOP elevation
Seth et al43
23 eyes
Retrospective case series
Pegaptanib (91%) or both Pegaptanib and Ranibizumab (9%)
9 mo
Average injections received: 6.7
0% experienced sustained IOP elevation.
All injected eyes: average injections: 7 ± 7 (range, 1-39) Sustained OHT: average injections: 9.6 ± 7.7 (range, 1-24), average frequency was 6.9 ± 2.1 per year (range, 3.4-9.7) Median number of total injections: 9 (range, 1-30), average interval between injections 70.2 d (SD = 54.6) Median injections before peak IOP: 5
5.8% (9/155) developed sustained elevated IOP 3.2% (5/155) developed transient elevated IOP
13/215 (6%) had sustained IOP elevation requiring intervention 18/215 (8.4%) had transient IOP elevation which resolved w/in 30 d without intervention No cases of bilateral IOP elevation in the 20 patients who received bilateral intravitreal injections 4/116 (3.45%) developed sustained elevated IOP after multiple injections
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c/d indicates cup to disc ratio; IOP, intraocular pressure; OHT, ocular hypertension; RNFL, retinal nerve fiber layer.
Conclusions Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon No association with patient demographics or injection history was identified Incidence of sustained elevated IOP is significant Preexisting glaucoma may be risk factor for elevated IOP after injections
Persistent OHT may occur after intravitreal antiVEGF injection in patients with no previous diagnosis of glaucoma or OHT OHT may persist across several visits and require therapy Sustained IOP usually occurs after multiple injections No change in RNFL after long-term injections
Intravitreal bevacizumab injection is safe in terms of blood pressure and IOP in both hypertensive and nonhypertensive patients No statistically significant change in c/d in pts receiving multiple injections
Volume 25, Number 3, March 2016
Retrospective chart review
155 eyes
J Glaucoma
Choi et al11
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TABLE 2. (Continued)
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Volume 25, Number 3, March 2016
The increased IOP is likely rapidly equilibrated by an increase in aqueous outflow from the anterior chamber to compensate for the increased vitreous volume, with further equilibration occurring later by a reduction in vitreous volume to its preinjection level. Patients who have a higher immediate postinjection IOP or who have a longer postinjection IOP spike may have compromised aqueous outflow facility, or a compromised ability to equilibrate the volume of vitreous with surrounding structures.12,13 Some authors have investigated the role of preventive measures to mitigate the immediate postinjection IOP spike. For instance, preinjection ocular massage with a cotton swab,46 prophylactic medications,4,33,44,47 and preinjection anterior chamber paracentesis48 have all been found to decrease the likelihood and/or duration of immediate postinjection IOP spike.
Sustained IOP Elevation Sustained IOP elevation has been estimated to be less common than immediate postinjection IOP elevation. The definition of sustained IOP elevation varies, but most authors referenced in this paper considered it to be IOP > 21 mm Hg on 2 visits, along with an increase from baseline IOP of at least 5 mm Hg. Using that definition, the incidence of sustained IOP elevation has been estimated between 3.45% and 11.6%.5–9 In what represents perhaps the most robust data set to date, Bakri et al49 recently published a post hoc analysis of IOP data from 2 pivotal ranibizumab clinical trials and found that 9.3% to 13.1% of patients receiving serial injections had a sustained IOPZ21 mm Hg on 2 consecutive visits, when the IOP was measured just before the next injection. Table 2 lists the characteristics of the articles that described sustained IOP
Ocular Hypertension After Intravitreal Anti-VEGF
elevation. Of note, several articles were not listed in this table due to small sample size.12,50–53 The mechanism underlying sustained IOP elevation has not been clearly elucidated, although several potential etiologies have been proposed. Direct blockage of trabecular meshwork outflow has been proposed as an etiologic factor, either from the anti-VEGF molecules themselves,8 or other high–molecular weight aggregates13 such as silicone oil microdroplets that may leach into the injected solution from the syringe or plunger.7 Drug-induced trabeculitis has also been proposed as a mechanism.12 Several authors have proposed that anti-VEGF agents may directly physiologically decrease aqueous outflow,8,50,51 and some have proposed that this may be due to direct anti-VEGF toxicity to anterior segment cells. However, in vitro toxicity studies have yielded conflicting results.54,55 On the basis of the well-understood mechanism of action of VEGF antagonism on systemic smooth muscle and vascular endothelial cells, we propose that another possible mechanism be entertained perhaps in a subset of patients.
Potential Role of NO VEGF upregulates the expression of eNOS, which increases the production of NO.14 Therefore, VEGF blockade decreases the production of NO.56,57 One well-described and well-accepted adverse effect of this decreased NO is systemic arterial hypertension seen as a result of systemic anti-VEGF therapy in oncology patients.58 Interestingly, this anti-VEGFinduced systemic hypertension has been effectively treated with systemic NO donor therapy.59 Similar to systemic endothelial and vascular relaxation, NO has been extensively studied as a mediator of IOP in animal and human eyes. Figures 1 and 2 illustrate the putative
FIGURE 1. A, Illustration of the mechanism of action of vascular endothelial growth factor (VEGF) and nitric oxide on trabecular meshwork cell volume. B, The trabecular meshwork pore size is increased by the decrease in trabecular cell volume.
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FIGURE 2. A, Illustration of the effect of vascular endothelial growth factor (VEGF) inhibition on the pathway seen in Figure 1. There is less potassium efflux, and therefore enlarged trabecular meshwork cell volume. B, Because of increased trabecular cell volume, the trabecular meshwork pore size is decreased.
mechanism. NO acts by activating soluble guanyl cyclase (sGC), which in turn synthesizes cyclic guanosine monophosphate (cGMP). cGMP then activates protein kinase G, which phosphorylates the large-conductance calcium-activated potassium channel (BKCa) and allows potassium efflux. The potassium efflux and resultant osmotic shift is thought to lead to decreased cell volume in the trabecular meshwork and/or Schlemm’s canal cells, which leads to enlargement of trabecular pore size, increased aqueous outflow facility, and decreased IOP.16 Another potential explanation for the NO-mediated increase in aqueous outflow is reduction in trabecular meshwork cell contractility.17,60 Although Figure 1 demonstrates the increased aqueous outflow as a result of NO-mediated reduction in cell volume, it is not known whether the NO-mediated reduction in cell volume or reduction in cell contractility is a more important factor in NO-mediated IOP reduction. The role of NO in the maintenance of aqueous outflow facility has been studied in both human and animal eyes, and in fact, topical NO-donating medications have been studied clinically as IOP-lowering agents.24,25 One such compound, latanoprostene bunod (previously known as BOL-303259-X and NCX 116) is a NO-donating prostaglandin F2-a analog licensed by Nicox to Bausch + Lomb. This agent is currently being investigated in phase 3 clinical trials for lowering IOP.61 Various components of the NO signaling pathway (eNOS, NO, guanyl cyclase) have been demonstrated histologically and/or physiologically in human, porcine, and murine anterior segments.15–22 Buys et al15 recently described a novel murine model for primary open-angle glaucoma in which the gene for one of the subunits of sGC was knocked out. These mice developed an age-related optic
neuropathy characterized by modestly increased IOP, thinning of the retinal nerve fiber layer (RNFL), and loss of optic nerve axons in the setting of an open angle. Furthermore, they histologically identified the sGC a1 and b1 subunits in not only the anterior segment (ciliary muscle) of human and mouse eyes, but also the smooth muscle layer of retinal blood vessels and in retinal ganglion cells themselves. Taken together with their finding that the knockout mice had smaller decrease in retinal vascular diameter in response to pharmacologically induced systemic hypotension than their wild-type counterparts, the expression of sGC subunits in retinal blood vessels may indicate that NO signaling is important for normal vascular autoregulation as well.15 It is unknown whether this finding can be extrapolated to the microvascular network supplying the optic nerve, but these results suggest that impaired NO signaling may also be able to cause optic neuropathy by vascular as well as mechanical (ie, increased IOP) means. However, given the clinical finding that patients with intravitreal anti-VEGF-related glaucoma tend to have high IOP, the increased IOP likely plays more of a role in the resultant optic neuropathy than does the potential vascular dysregulation. If VEGF antagonism were able to cause progressive optic neuropathy via an IOP-independent pathway, then one would expect to find progressive RNFL loss in serially treated patients, independent of IOP level. However, studies looking at this metric have yielded conflicting results, with Horsley et al41 reporting no change in RNFL thickness among patients receiving serial anti-VEGF injections with 27 months of follow-up, utilizing a retrospective study design and time-domain optical coherence tomography. In
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contrast, Martinez-de-la-Casa et al38 reported significant RNFL loss among patients being treated with ranibizumab, when measured prospectively over 12 months using spectral-domain optical coherence tomography. It is our hypothesis that the intravitreal administration of anti-VEGF agents leads to a relative deficiency of NO in the anterior segment through downregulation of the eNOS pathway. This inhibits the normal physiological role that NO plays in maintaining aqueous outflow facility and leads to increased IOP. This effect is a relative rather than absolute phenomenon, which explains why sustained IOP elevation may be more likely to occur in patients with preexisting decreased aqueous outflow facility (glaucoma).7 Further investigation is necessary to examine the role of NO signaling in anti-VEGF-mediated ocular hypertension. The sGCa1 knockout mouse15 may be a particularly useful model in which to perform these studies. Further study is also necessary to determine the optimal treatment paradigm for this type of glaucoma. NO-donating medications may be an interesting treatment to study in the setting of a putative NO deficiency-mediated glaucoma.
REFERENCES 1. Kim JE, Mantravadi AV, Hur EY, et al. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol. 2008;146:930–934, e931. 2. 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. 3. Hollands H, Wong J, Bruen R, et al. Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol [Journal canadien d’ophtalmologie]. 2007;42:807–811. 4. Theoulakis PE, Lepidas J, Petropoulos IK, et al. Effect of brimonidine/timolol fixed combination on preventing the short-term intraocular pressure increase after intravitreal injection of ranibizumab. Klin Monbl Augenheilkd. 2010; 227:280–284. 5. 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. 6. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013;33:179–187. 7. Good TJ, Kimura AE, Mandava N, et al. Sustained elevation of intraocular pressure after intravitreal injections of antiVEGF agents. Br J Ophthalmol. 2011;95:1111–1114. 8. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocular Pharmaco Ther. 2010;26:105–110. 9. 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. 10. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119:1658–1665. 11. Choi DY, Ortube MC, McCannel CA, et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib. Retina. 2011;31: 1028–1035. 12. 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.
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13. Kahook MY, Liu L, Ruzycki P, et al. High-molecular-weight aggregates in repackaged bevacizumab. Retina. 2010;30: 887–892. 14. Hood JD, Meininger CJ, Ziche M, et al. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998;274(3 pt 2):H1054–H1058. 15. Buys ES, Ko YC, Alt C, et al. Soluble guanylate cyclase alpha1-deficient mice: a novel murine model for primary open angle glaucoma. PloS One. 2013;8:e60156. 16. Dismuke WM, Mbadugha CC, Ellis DZ. NO-induced regulation of human trabecular meshwork cell volume and aqueous humor outflow facility involve the BKCa ion channel. Am J Physiol Cell Physiol. 2008;294:C1378–C1386. 17. Ellis DZ, Dismuke WM, Chokshi BM. Characterization of soluble guanylate cyclase in NO-induced increases in aqueous humor outflow facility and in the trabecular meshwork. Investig Ophthalmol Vis Sci. 2009;50:1808–1813. 18. Ellis DZ, Sharif NA, Dismuke WM. Endogenous regulation of human Schlemm’s canal cell volume by nitric oxide signaling. Investig Ophthalmol Vis Sci. 2010;51:5817–5824. 19. Meyer P, Champion C, Schlotzer-Schrehardt U, et al. Localization of nitric oxide synthase isoforms in porcine ocular tissues. Cur Eye Res. 1999;18:375–380. 20. Nathanson JA, McKee M. Alterations of ocular nitric oxide synthase in human glaucoma. Investig Ophthalmol Vis Sci. 1995;36:1774–1784. 21. Nathanson JA, McKee M. Identification of an extensive system of nitric oxide-producing cells in the ciliary muscle and outflow pathway of the human eye. Investig Ophthalmol Vis Sci. 1995;36:1765–1773. 22. Wiederholt M, Sturm A, Lepple-Wienhues A. Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide. Investig Ophthalmol Vis Sci. 1994;35:2515–2520. 23. Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis. 2007;50:203–218. 24. Mincione F, Benedini F, Biondi S, et al. Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action. Bioorg Med Chem Lett. 2011;21:3216–3221. 25. Krauss AH, Impagnatiello F, Toris CB, et al. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2alpha agonist, in preclinical models. Exp Eye Res. 2011;93:250–255. 26. Frenkel MP, Haji SA, Frenkel RE. Effect of prophylactic intraocular pressure-lowering medication on intraocular pressure spikes after intravitreal injections. Archiv Ophthalmol. 2010;128:1523–1527. 27. Hohn F, Mirshahi A. Impact of injection techniques on intraocular pressure (IOP) increase after intravitreal ranibizumab application. Graefes Arch Clin Exp Ophthalmol. 2010;248:1371–1375. 28. Sharei V, Hohn F, Kohler T, et al. Course of intraocular pressure after intravitreal injection of 0.05 mL ranibizumab (Lucentis). Eur J Ophthalmol. 2010;20:174–179. 29. Bakri SJ, Pulido JS, McCannel CA, et al. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye. 2009; 23:181–185. 30. Falkenstein IA, Cheng L, Freeman WR. Changes of intraocular pressure after intravitreal injection of bevacizumab (avastin). Retina. 2007;27:1044–1047. 31. Frenkel RE, Mani L, Toler AR, et al. Intraocular pressure effects of pegaptanib (Macugen) injections in patients with and without glaucoma. Am J Ophthalmol. 2007;143:1034–1035. 32. Hariprasad SM, Shah GK, Blinder KJ. Short-term intraocular pressure trends following intravitreal pegaptanib (Macugen) injection. Am J Ophthalmol. 2006;141:200–201. 33. 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.
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34. Menke MN, Salam A, Framme C, et al. Long-term intraocular pressure changes in patients with neovascular age-related macular degeneration treated with ranibizumab. Ophthalmologica. 2013;229:168–172. 35. Pershing S, Bakri SJ, Moshfeghi DM. Ocular hypertension and intraocular pressure asymmetry after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2013;44:460–464. 36. Segal O, Ferencz JR, Cohen P, et al. Persistent elevation of intraocular pressure following intravitreal injection of bevacizumab. Isr Med Assoc J. 2013;15:352–355. 37. Sobacı G, Gu¨ngo¨r R, Ozge G. Effects of multiple intravitreal anti-VEGF injections on retinal nerve fiber layer and intraocular pressure: a comparative clinical study. Int J Ophthalmol. 2013;6:211–215. 38. Martinez-de-la-Casa JM, Ruiz-Calvo A, Saenz-Frances F, et al. Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab. Investig Ophthalmol Vis Sci. 2012;53:6214–6218. 39. Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma.. 2012;21:241–247. 40. Wehrli SJ, Tawse K, Levin MH, et al. A lack of delayed intraocular pressure elevation in patients treated with intravitreal injection of bevacizumab and ranibizumab. Retina. 2012;32:1295–1301. 41. Horsley MB, Mandava N, Maycotte MA, et al. Retinal nerve fiber layer thickness in patients receiving chronic anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2010;150 :558–561, e551. 42. Lee K, Yang H, Lim H, et al. A prospective study of blood pressure and intraocular pressure changes in hypertensive and nonhypertensive patients after intravitreal bevacizumab injection. Retina. 2009;29:1409–1417. 43. Seth RK, Salim S, Shields MB, et al. Assessment of optic nerve cup-to-disk ratio changes in patients receiving multiple intravitreal injections of antivascular endothelial growth factor agents. Retina. 2009;29:956–959. 44. El Chehab H, Le Corre A, Giraud JM, et al. Efficacy of prophylactic treatment of intraocular pressure spikes due to intravitreal injections. J Fr Ophtalmol. 2012;35:614–621. 45. Kotliar K, Maier M, Bauer S, et al. Effect of intravitreal injections and volume changes on intraocular pressure: clinical results and biomechanical model. Acta Ophthalmol Scand. 2007;85:777–781. 46. Gregori NZ, Weiss MJ, Goldhardt R, et al. Ocular decompression with cotton swabs lowers intraocular pressure elevation after intravitreal injection. J Glaucoma. 2013, Apr 29, 2013. [Epub ahead of print]. 47. Katayama BY, Bonini-Filho MA, Messias AM, et al. Comparison of acetazolamide, brimonidine, and anterior chamber
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paracentesis for ocular hypertension control after initial intravitreal bevacizumab injection: a randomized clinical trial. J Glaucoma. 2014;23:461–463. Knip MM, Valimaki J. Effects of pegaptanib injections on intraocular pressure with and without anterior chamber paracentesis: a prospective study. Acta Ophthalmol. 2012;90:254–258. Bakri SJ, Moshfeghi DM, Francom S, et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials. Ophthalmology. 2014;121:1102–1108. 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. Bakri SJ, McCannel CA, Edwards AO, et al. Persisent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol. 2008;246:955–958. 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. Skalicky SE, Ho I, Agar A, et al. Glaucoma filtration surgery following sustained elevation of intraocular pressure secondary to intravitreal anti-VEGF injections. Ophthalmic Surg Lasers Imaging. 2012;43:328–334. Kernt M, Welge-Lussen U, Yu A, et al. Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells. Ophthalmologe. 2007;104:965–971. Kahook MY, Ammar DA. In vitro effects of antivascular endothelial growth factors on cultured human trabecular meshwork cells. J Glaucoma. 2010;19:437–441. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788– 1795. Robinson ES, Khankin EV, Choueiri TK, et al. Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. Hypertension. 2010;56:1131–1136. Dai F, Shu L, Bian Y, et al. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and metaanalysis of all randomized clinical trials. Clin Drug Investig. 2013;33:779–788. Kruzliak P, Kovacova G, Pechanova O. Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension. Angiogenesis. 2013;16:289–295. Stumpff F, Wiederholt M. Regulation of trabecular meshwork contractility. Ophthalmologica. 2000;214:33–53. Bausch + Lomb Initiates Phase 3 Program for Glaucoma Drug Candidate Licensed from Nicox. 2013. Available at: http://www.bausch.com/our-company/recent-news/2013archive/bausch-lomb-phase-3-program-for-glaucoma-drugcandidate-nicox/. Accessed January 12, 2013.
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Ocular Hypertension Following Intravitreal Antivascular Endothelial Growth Factor Therapy: Review of the Literature and Possible Role of Nitric Oxide R. Grant Morshedi, MD,* Aaron M. Ricca, BS,* and Barbara M. Wirostko, MDw
Purpose: To review the literature regarding ocular hypertension following intravitreal antivascular endothelial growth factor therapy, and to propose a novel mechanism for the development of ocular hypertension as a result of such therapy. Methods: The PubMed database was used to identify publications by using combinations of the search terms, “glaucoma,” “ocular hypertension,” “pegaptanib,” “bevacizumab,” “ranibizumab,” “aflibercept,” “anti-vascular endothelial growth factor,” intraocular pressure,” and “intravitreal.” The reference lists of these publications were also reviewed for relevant articles. Results: Numerous articles have been published describing ocular hypertension, either immediate-term/short-term or delayed/sustained, following intravitreal antivascular endothelial growth factor therapy. Ocular hypertension has been reported following intravitreal pegaptanib, bevacizumab, and ranibizumab, and aflibercept. On the basis of the fact that vascular endothelial growth factor, normally present as a vascular modulating and reparative growth factor, is known to upregulate endothelial nitric oxide (NO) synthase, and that NO has been shown to decrease intraocular pressure in both normal and glaucomatous human and animal eyes, we propose a novel mechanism for sustained ocular hypertension following intravitreal antivascular endothelial growth factor therapy. We propose that such intravitreal therapy may lead to decreased NO in the anterior segment, which then leads to trabecular meshwork constriction, decreased outflow facility, and increased intraocular pressure. Conclusions: Sustained ocular hypertension following the intravitreal administration of antivascular endothelial growth factor agents is a potentially serious side effect that has not been adequately explained. Further investigation is necessary to determine the role of NO in the mediation of this adverse effect. Key Words: anti-VEGF, ocular hypertension, nitric oxide, intraocular pressure, glaucoma, intravitreal
(J Glaucoma 2016;25:291–300)
T
he intravitreal administration of antivascular endothelial growth factor (VEGF) agents has become the standard of care for wet age-related macular degeneration,
Received for publication February 1, 2014; accepted September 1, 2014. From the *Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and wJohn A. Moran Eye Center, University of Utah, Salt Lake City, UT. Supported in part by an unrestricted grant from Research to Prevent Blindness Inc., New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. Disclosure: The authors declare no conflict of interest. Reprints: R. Grant Morshedi, MD, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301W. Markham St., Slot 523, Little Rock, AR 72205 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000173
J Glaucoma
Volume 25, Number 3, March 2016
and an important tool in the treatment of other conditions such as diabetic macular edema, retinal vein occlusionassociated macular edema, and neovascular glaucoma. Ocular hypertension (elevated intraocular pressure [IOP]) following the administration of these agents has been increasingly reported as a potential side effect. The incidence in the reported literature is variable, but is estimated between 66% and 100% for immediate ocular hypertension1–4 and between 3.45% and 11.6% for sustained ocular hypertension.5–9 All currently available intravitreal anti-VEGF agents, including pegaptanib, bevacizumab, ranibizumab, and aflibercept, have had ocular hypertension reported as a side effect.10,11 The reports of anti-VEGF-related ocular hypertension have described both an immediate-term or short-term IOP elevation as well as a delayed and/or sustained IOP elevation. The definition of “short-term” versus “sustained” is somewhat heterogenous and arbitrary among publications, but in general we will refer to short-term IOP elevation as occurring immediately postinjection, with a return to normal within 60 minutes of the injection, whereas sustained IOP elevation is most frequently defined as IOP > 21 mm Hg on 2 visits, along with an increase of 5 mm Hg from baseline preinjection IOP. Although immediate IOP elevation might be expected based purely on volumetric considerations, the precise mechanism underlying sustained IOP elevation has yet to be elucidated. Several potential causes have been hypothesized, including a direct mechanical effect; protein, silicone oil, or other high–molecular weight aggregates clogging the trabecular meshwork; direct trabecular toxicity; and inflammation/trabeculitis.7,8,12,13 It is well accepted and understood that VEGF upregulates endothelial nitric oxide synthase (eNOS) systemically, which in turn synthesizes nitric oxide (NO).14 NO has been extensively studied for its role on endothelial cell function, permeability, and smooth muscle vasodilation.15–22 The fact that systemic anti-VEGF agents lead to systemic hypertension as an adverse event is, in fact, attributed to the downregulation of eNOS and NO, thereby increasing systemic vascular bed constriction.23 In addition, within ocular tissue, there is ample evidence that NO improves aqueous outflow facility, most likely by regulating trabecular meshwork and/or Schlemm’s canal cell volume.16–18 Novel antihypertensive NO-donating therapies have recently been investigated for their ability to decrease IOP, theoretically by causing trabecular meshwork vasodilation and decreased outflow resistance.24,25 On the basis of this knowledge, we propose that repeated and long-term VEGF antagonism may lead to a deficiency of intraocular NO, which in turn adversely affects outflow facility and leads to a sustained rise in IOP. The aim of this paper is to review the existing reports of intravitreal anti-VEGF-induced ocular hypertension, and to provide evidence from the existing www.glaucomajournal.com |
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291
References
N
Design
Agent
45 eyes
Prospective cohort
Sharei et al28
45 eyes
Prospective cohort
Ranibizumab
Theoulakis et al4
88 eyes
Prospective doubleblind placebocontrolled
Ranibizumab
Bakri et al29
161 patients
Gismondi et al2
54 eyes
Retrospective chart review July 2005December 2005 Prospective cohort
Pegaptanib, Bevacizumab, Triamcinolone Ranibizumab
Kim et al1
120 eyes
Retrospective chart review
Ranibizumab (12%), Bevacizumab (67%), Pegaptanib (14%), Triamcinolone (8%)
Postinjection: 37.0 11-12 min: 23.25
IOP reduced to 40 and 19 eyes (42.2%) >50. T3: 22 eyes (48.4%) >40 and 10 eyes (22.6%) >50. T10: 5 eyes (11.1%) > 40 and 1 eye (2.2%) >50 IOP > 30: 9%, 8/44 eyes, in Combigan group at 5 min. IOP > 30: 91%, 40/44 eyes, in control group at 5 min
100% >30 between 1 and 10 min and 0% at 30 min NA
IOP > 30: 79% at T0, 30% at 5 min, 4% at 15 min, 1% at 25 min, 0% at 30 min 36% IOP at T0 reachedZ50 mm Hg
Conclusions No benefit to prophylactic meds No difference with preexisting glaucoma IOP back to normal in 1 wk IOP increase significantly higher if a tunneled scleral injection was performed
Less IOP increase if subconjunctival backflow after injection
Combigan prophylaxis is safe and effective to prevent immediate IOP spikes after ranibizumab
Few patients required postinjection IOP meds None required paracentesis Significant IOP rise at 5 s, 5, 10, 15, and 30 min Not significant after 1 h or 1 d
Higher incidence of IOP spikes with small-bore needles, hx of glaucoma, and lack of postinjection subconjunctival reflux
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Hohn and Mirshahi27
Pegaptanib (n = 30), Bevacizumab (n = 47), Ranibizumab (n = 42) Ranibizumab
Retrospective chart review
Incidence of Significant IOP (mm Hg) Increases
J Glaucoma
71 eyes
r
Frenkel et al26
Average Pressures at Different Time Points (mm Hg)
Morshedi et al
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TABLE 1. Summary of Studies Describing Immediate or Short-term IOP Elevation
Significant spike from baseline at 2, 5, and 30 min Phakic patients have higher IOP at 30 min Mean change of IOP from baseline at 30 min was 8.74 ± 7.23 IOP > 30: 67.4% at 2 min, 28.9% at 5 min, 1% at 30 min
METHODS The PubMed database was searched using combinations of the search terms, “glaucoma,” “ocular hypertension,” “pegaptanib,” “bevacizumab,” “ranibizumab,” “aflibercept,” “anti-vascular endothelial growth factor,” intraocular pressure,” and “intravitreal.” The reference lists of these publications were also reviewed for relevant articles. All published papers were reviewed, but the search was limited to the English literature.
RESULTS Thirty-four relevant articles were identified. Twelve described immediate or short-term IOP elevation, and 22 described long-term or sustained IOP elevation. Pertinent details of these publications are summarized in Tables 1 and 2. For the purpose of these tables, we excluded studies in which meaningful statistical analyses were not performed due to small sample size (small case series).
Pre: 15.73 ± 3.14 30 min: 24.47 ± 6.29 5-7 d f/u: 15.81 ± 4.02
DISCUSSION Intravitreal injections of anti-VEGF agents have become an important tool in the management of some of the most common retinal and choroidal neovascular diseases. Adverse effects are uncommon, but one of the more commonly reported and unexplained adverse events is IOP elevation. IOP elevation following intravitreal anti-VEGF injection has been cited in the literature as early as 2006.32 Published studies on this subject vary in design and sample size. The mechanism of IOP elevation as a result of intravitreal anti-VEGF agents is unclear. It is likely that shortterm IOP elevation represents a different adverse event, with a distinct mechanism, than sustained IOP elevation. Furthermore, there may not be a singular unifying mechanism for either of these 2 adverse events, but rather several mechanisms that, depending on the individual’s underlying pathophysiology and/or comorbid ocular conditions, interact to cause IOP elevation.
Short-term IOP Elevation
f/u indicates follow-up; IOP, intraocular pressure.
Pegaptanib Retrospective chart review 122 injections in 79 patients Hariprasad et al32
Bevacizumab 104 eyes
Prospective Cohort
r
Hollands et al3
Pegaptanib Retrospective chart review 75 eyes Frenkel et al31
Bevacizumab Prospective cohort 70 eyes (29 with repeated injections) Falkenstein et al30
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Ocular Hypertension After Intravitreal Anti-VEGF
literature regarding the plausibility of NO deficiency-mediated sustained IOP elevation.
IOP > 30: 13% at 30 min
5.3% had transient NLP vision immediately postinjection with IOP > 55 mm Hg and underwent paracentesis
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NA
Pre: 15.7 ± 3.42 3 min: 36.27 ± 5.1 10 min: 24.56 ± 5.9 Pre: 14 ± 3 1 min: 38 ± 14 3-10 min: 34 ± 9 11-20 min: 26 ± 10 21-30 min: 24 ± 11 31-50 min: 22 ± 3 f/u: 13 ± 3 Pre: 14 2 min: 36.1 5 min: 25.7 30 min: 15.5
IOP > 30: 14% at 10 min, 0% at 15 min
Significant spike from baseline at 3 min and 10 min
J Glaucoma
Short-term IOP elevation, defined as within 60 minutes from the injection, is a more common event than sustained IOP elevation. Although estimating a true incidence from the existing literature is difficult given the prevalence of retrospective studies and inconsistent definitions, existing studies have described between 66% and 100% of patients having an immediate postinjection IOP spike.1–4 Studies that have evaluated IOP in the immediate postinjection period have consistently found a high rate of ocular hypertension that generally returns to 29 unilateral injections had sustained IOP elevation 0/46 control eyes had sustained IOP elevation 0% experienced sustained IOP elevation
Significant effect of number of injections on IOP elevation
7 eyes developed final IOP 21-25 mm Hg with previous baseline 14-18 mm Hg NA
Ranibizumab (97.1%) and/or Bevacizumab (34.1%)
150.1 wk
Kim et al33
83 eyes
Propsective interventional case series
Bevacizumab
2y
Menke et al34
320 eyes
Retrospective chart review
Ranibizumab
22.7 ± 14.1 mo
Mean injections for all eyes: 13.0 ± 8.0
Pershing et al35
21 eyes
Retrospective chart review
Ranibizumab and Bevacizumab
At least 1 y
Average months until delayed OHT: 15.5 ± 16.1 Average injections until delayed OHT: 9.7 ± 11.2
Segal et al36
528 treated eyes and 328 control eyes
Retrospective case series
Bevacizumab
NA
Mean injections: 7.8 (range, 3-13)
Sobaci et al37
65 eyes
Retrospective cohort
Bevacizumab (54%) or Ranibizumab (46%)
14.05 ± 2.6 mo for bevacizumab 13.6 ± 2.1 mo for ranibizumab
Hoang et al5
207 eyes
Retrospective case control
Ranibizumab (96.6%) and/or Bevacizumab (32.4%), or both
148.6 wk
Mean number of bevacizumab injections 5.1 ± 1.3 Mean number of ranibizumab injections 6.3 ± 1.9 Mean total injections 20.8 (3-48) Mean for sustained IOP: 24.4 (9-39) Mean for those without sustained IOP: 20.4 (3-48)
Mathalone et al9
201 eyes
Retrospective cohort
Bevacizumab
15.7 ± 11.5 mo
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Sustained IOP elevation: median 5 (3-18) No IOP elevation: median 4 (3-22)
24/528 (4.5%) had sustained IOP > 24 19/528 (3.6%) had IOP 3070 mm Hg 3-30 d after injection, compared with 1/328 (0.3%) control eyes 0% experienced sustained IOP elevation
IOP elevation was not observed during the longterm follow-up period The numbers of injection and preexisting glaucoma did not affect IOP changes Signficant IOP increase after ranibizumab, but no patients required treatment Elevated IOP may occur after ranibizumab or bevacizumab injections Significant IOP asymmetry and unilateral glaucoma after unilateral injections Bevacizumab may be associated with persistent IOP elevation
Repeated ranibizumab or bevacizumab does not seem to have adverse effects on RNFL or IOP
Patients receiving Z29 injections more likely to have IOP elevation >5 mm Hg above baseline on Z2 consecutive visits than pt receiving r12 injections (20% vs. 4.2%) 22/201 (11%) had sustained IOP elevation
Total number of injections showed an association with IOP elevation
Prevalence of IOP elevation was significantly higher when the interval between injections was 5 mm Hg) 1 h following the injection was 1/49 (0.4%) 3.4% (19/555) of total treated over preceding 62 mo
5/302 (1.7%) injected eyes, compared with 7/226 (3.1%) control eyes developed delayed OHT
5.8% (9/155) developed sustained elevated IOP 3.2% (5/155) developed transient elevated IOP
13/215 (6%) had sustained IOP elevation requiring intervention 18/215 (8.4%) had transient IOP elevation which resolved w/in 30 d without intervention No cases of bilateral IOP elevation in the 20 patients who received bilateral intravitreal injections 4/116 (3.45%) developed sustained elevated IOP after multiple injections
0% experienced sustained IOP elevation
Ranibizumab injections caused a significant decrease in RNFL thickness after 12 mo of follow-up
Serial injections may lead to persistent IOP elevations requiring therapy At time of IOP elevation 15 eyes (60%) were phakic and 10 eyes (40%) were pseudophakic No difference between injected group and control group, with or without glaucoma, of developing delayed OHT No difference in rate of delayed OHT between medications injected Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon No association with patient demographics or injection history was identified Incidence of sustained elevated IOP is significant Preexisting glaucoma may be risk factor for elevated IOP after injections
Persistent OHT may occur after intravitreal antiVEGF injection in patients with no previous diagnosis of glaucoma or OHT OHT may persist across several visits and require therapy Sustained IOP usually occurs after multiple injections No change in RNFL after long-term injections
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1y
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Ranibizumab
Prospective cohort
r
49 eyes
J Glaucoma
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Martinez-de-la-Casa et al38
Morshedi et al
Copyright
References
N
Design
Agent
Average Time or Injections (N) Until OHT Onset
Median Length of Follow-up
Incidence of OHT
Ranibizumab (32%), Bevacizumab (39%), and Pegaptanib (4%), or multiple agents (26%)
928 ± 489 d for sustained elevated IOP cohort 417 ± 388 d for entire cohort
Good et al7
215 eyes
Retrospective chart review
Bevacizumab (47%), Ranibizumab (45%), or both
3y
Adelman et al8
116 patients
Retrospective chart review
Bevacizumab (34%), Ranibizumab (49%), or both (16%)
3-36 mo
Mean injections: 13.3 (range, 3-19)
Horsley et al41
41 eyes
Ranibizumab, Bevacizumab, and/or Pegaptanib
27 ± 9.7 mo
All patients: 16.0 ± 5.5 intravitreal injections
0% experienced sustained IOP elevation
Lee et al42
185 eyes
Retrospective observational consecutive case series Propsective interventional case series
Bevacizumab
6 mo
All patients received either 1 or 2 injections during this study
0% experienced sustained IOP elevation
Seth et al43
23 eyes
Retrospective case series
Pegaptanib (91%) or both Pegaptanib and Ranibizumab (9%)
9 mo
Average injections received: 6.7
0% experienced sustained IOP elevation.
All injected eyes: average injections: 7 ± 7 (range, 1-39) Sustained OHT: average injections: 9.6 ± 7.7 (range, 1-24), average frequency was 6.9 ± 2.1 per year (range, 3.4-9.7) Median number of total injections: 9 (range, 1-30), average interval between injections 70.2 d (SD = 54.6) Median injections before peak IOP: 5
5.8% (9/155) developed sustained elevated IOP 3.2% (5/155) developed transient elevated IOP
13/215 (6%) had sustained IOP elevation requiring intervention 18/215 (8.4%) had transient IOP elevation which resolved w/in 30 d without intervention No cases of bilateral IOP elevation in the 20 patients who received bilateral intravitreal injections 4/116 (3.45%) developed sustained elevated IOP after multiple injections
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c/d indicates cup to disc ratio; IOP, intraocular pressure; OHT, ocular hypertension; RNFL, retinal nerve fiber layer.
Conclusions Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon No association with patient demographics or injection history was identified Incidence of sustained elevated IOP is significant Preexisting glaucoma may be risk factor for elevated IOP after injections
Persistent OHT may occur after intravitreal antiVEGF injection in patients with no previous diagnosis of glaucoma or OHT OHT may persist across several visits and require therapy Sustained IOP usually occurs after multiple injections No change in RNFL after long-term injections
Intravitreal bevacizumab injection is safe in terms of blood pressure and IOP in both hypertensive and nonhypertensive patients No statistically significant change in c/d in pts receiving multiple injections
Volume 25, Number 3, March 2016
Retrospective chart review
155 eyes
J Glaucoma
Choi et al11
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TABLE 2. (Continued)
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Volume 25, Number 3, March 2016
The increased IOP is likely rapidly equilibrated by an increase in aqueous outflow from the anterior chamber to compensate for the increased vitreous volume, with further equilibration occurring later by a reduction in vitreous volume to its preinjection level. Patients who have a higher immediate postinjection IOP or who have a longer postinjection IOP spike may have compromised aqueous outflow facility, or a compromised ability to equilibrate the volume of vitreous with surrounding structures.12,13 Some authors have investigated the role of preventive measures to mitigate the immediate postinjection IOP spike. For instance, preinjection ocular massage with a cotton swab,46 prophylactic medications,4,33,44,47 and preinjection anterior chamber paracentesis48 have all been found to decrease the likelihood and/or duration of immediate postinjection IOP spike.
Sustained IOP Elevation Sustained IOP elevation has been estimated to be less common than immediate postinjection IOP elevation. The definition of sustained IOP elevation varies, but most authors referenced in this paper considered it to be IOP > 21 mm Hg on 2 visits, along with an increase from baseline IOP of at least 5 mm Hg. Using that definition, the incidence of sustained IOP elevation has been estimated between 3.45% and 11.6%.5–9 In what represents perhaps the most robust data set to date, Bakri et al49 recently published a post hoc analysis of IOP data from 2 pivotal ranibizumab clinical trials and found that 9.3% to 13.1% of patients receiving serial injections had a sustained IOPZ21 mm Hg on 2 consecutive visits, when the IOP was measured just before the next injection. Table 2 lists the characteristics of the articles that described sustained IOP
Ocular Hypertension After Intravitreal Anti-VEGF
elevation. Of note, several articles were not listed in this table due to small sample size.12,50–53 The mechanism underlying sustained IOP elevation has not been clearly elucidated, although several potential etiologies have been proposed. Direct blockage of trabecular meshwork outflow has been proposed as an etiologic factor, either from the anti-VEGF molecules themselves,8 or other high–molecular weight aggregates13 such as silicone oil microdroplets that may leach into the injected solution from the syringe or plunger.7 Drug-induced trabeculitis has also been proposed as a mechanism.12 Several authors have proposed that anti-VEGF agents may directly physiologically decrease aqueous outflow,8,50,51 and some have proposed that this may be due to direct anti-VEGF toxicity to anterior segment cells. However, in vitro toxicity studies have yielded conflicting results.54,55 On the basis of the well-understood mechanism of action of VEGF antagonism on systemic smooth muscle and vascular endothelial cells, we propose that another possible mechanism be entertained perhaps in a subset of patients.
Potential Role of NO VEGF upregulates the expression of eNOS, which increases the production of NO.14 Therefore, VEGF blockade decreases the production of NO.56,57 One well-described and well-accepted adverse effect of this decreased NO is systemic arterial hypertension seen as a result of systemic anti-VEGF therapy in oncology patients.58 Interestingly, this anti-VEGFinduced systemic hypertension has been effectively treated with systemic NO donor therapy.59 Similar to systemic endothelial and vascular relaxation, NO has been extensively studied as a mediator of IOP in animal and human eyes. Figures 1 and 2 illustrate the putative
FIGURE 1. A, Illustration of the mechanism of action of vascular endothelial growth factor (VEGF) and nitric oxide on trabecular meshwork cell volume. B, The trabecular meshwork pore size is increased by the decrease in trabecular cell volume.
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FIGURE 2. A, Illustration of the effect of vascular endothelial growth factor (VEGF) inhibition on the pathway seen in Figure 1. There is less potassium efflux, and therefore enlarged trabecular meshwork cell volume. B, Because of increased trabecular cell volume, the trabecular meshwork pore size is decreased.
mechanism. NO acts by activating soluble guanyl cyclase (sGC), which in turn synthesizes cyclic guanosine monophosphate (cGMP). cGMP then activates protein kinase G, which phosphorylates the large-conductance calcium-activated potassium channel (BKCa) and allows potassium efflux. The potassium efflux and resultant osmotic shift is thought to lead to decreased cell volume in the trabecular meshwork and/or Schlemm’s canal cells, which leads to enlargement of trabecular pore size, increased aqueous outflow facility, and decreased IOP.16 Another potential explanation for the NO-mediated increase in aqueous outflow is reduction in trabecular meshwork cell contractility.17,60 Although Figure 1 demonstrates the increased aqueous outflow as a result of NO-mediated reduction in cell volume, it is not known whether the NO-mediated reduction in cell volume or reduction in cell contractility is a more important factor in NO-mediated IOP reduction. The role of NO in the maintenance of aqueous outflow facility has been studied in both human and animal eyes, and in fact, topical NO-donating medications have been studied clinically as IOP-lowering agents.24,25 One such compound, latanoprostene bunod (previously known as BOL-303259-X and NCX 116) is a NO-donating prostaglandin F2-a analog licensed by Nicox to Bausch + Lomb. This agent is currently being investigated in phase 3 clinical trials for lowering IOP.61 Various components of the NO signaling pathway (eNOS, NO, guanyl cyclase) have been demonstrated histologically and/or physiologically in human, porcine, and murine anterior segments.15–22 Buys et al15 recently described a novel murine model for primary open-angle glaucoma in which the gene for one of the subunits of sGC was knocked out. These mice developed an age-related optic
neuropathy characterized by modestly increased IOP, thinning of the retinal nerve fiber layer (RNFL), and loss of optic nerve axons in the setting of an open angle. Furthermore, they histologically identified the sGC a1 and b1 subunits in not only the anterior segment (ciliary muscle) of human and mouse eyes, but also the smooth muscle layer of retinal blood vessels and in retinal ganglion cells themselves. Taken together with their finding that the knockout mice had smaller decrease in retinal vascular diameter in response to pharmacologically induced systemic hypotension than their wild-type counterparts, the expression of sGC subunits in retinal blood vessels may indicate that NO signaling is important for normal vascular autoregulation as well.15 It is unknown whether this finding can be extrapolated to the microvascular network supplying the optic nerve, but these results suggest that impaired NO signaling may also be able to cause optic neuropathy by vascular as well as mechanical (ie, increased IOP) means. However, given the clinical finding that patients with intravitreal anti-VEGF-related glaucoma tend to have high IOP, the increased IOP likely plays more of a role in the resultant optic neuropathy than does the potential vascular dysregulation. If VEGF antagonism were able to cause progressive optic neuropathy via an IOP-independent pathway, then one would expect to find progressive RNFL loss in serially treated patients, independent of IOP level. However, studies looking at this metric have yielded conflicting results, with Horsley et al41 reporting no change in RNFL thickness among patients receiving serial anti-VEGF injections with 27 months of follow-up, utilizing a retrospective study design and time-domain optical coherence tomography. In
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contrast, Martinez-de-la-Casa et al38 reported significant RNFL loss among patients being treated with ranibizumab, when measured prospectively over 12 months using spectral-domain optical coherence tomography. It is our hypothesis that the intravitreal administration of anti-VEGF agents leads to a relative deficiency of NO in the anterior segment through downregulation of the eNOS pathway. This inhibits the normal physiological role that NO plays in maintaining aqueous outflow facility and leads to increased IOP. This effect is a relative rather than absolute phenomenon, which explains why sustained IOP elevation may be more likely to occur in patients with preexisting decreased aqueous outflow facility (glaucoma).7 Further investigation is necessary to examine the role of NO signaling in anti-VEGF-mediated ocular hypertension. The sGCa1 knockout mouse15 may be a particularly useful model in which to perform these studies. Further study is also necessary to determine the optimal treatment paradigm for this type of glaucoma. NO-donating medications may be an interesting treatment to study in the setting of a putative NO deficiency-mediated glaucoma.
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