·Clinical Research·
Effect
of different lens status on intraocular pressure elevation in patients treated
with anti-vascular endothelial growth factor injections
Amir
Sternfeld1,2, Rita Ehrlich1,2, Dov Weinberger1,2,
Assaf Dotan1,2
1Department of Ophthalmology, Rabin
Medical Center Beilinson Hospital, Petach Tikva 4941402, Israel
2Sackler Faculty of Medicine, Tel
Aviv University, Ramat Aviv, Tel Aviv 6997801, Israel
Correspondence to: Assaf Dotan. Department of
Ophthalmology, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492,
Israel. docdotan@gmail.com
Received:
Abstract
AIM: To assess the effect
of lens status on sustained intraocular pressure (IOP) elevation in patients
treated intravitreally with anti-vascular endothelial growth factor (VEGF)
agents.
Methods: Data were
retrospectively collected for all patients treated with intravitreal injections
of anti-VEGF medication at a tertiary medical center in July 2015. Findings
were analyzed by lens status during 6 months’ follow-up. The main outcome
measure was a sustained increase in IOP (≥
Results: A total of 119 eyes of
100 patients met the study criteria: 40 phakic, 40 pseudophakic, and 39
pseudophakic after Nd:YAG capsulotomy. The rate of sustained IOP elevation was
significantly higher in the post-capsulotomy group (23.1%) than in the
phakic/pseudophakic groups (8.1%; p=0.032),
with no statistically significant differences among the 3 groups in mean number
of injections, either total (p=0.82)
or by type of anti-VEGF mediation (bevacizumab: p=0.19; ranibizumab: p=0.13),
or mean follow-up time (p=0.70).
Conclusion: Nd:YAG capsulotomy
appears to be a risk factor for sustained IOP elevation in patients receiving
intravitreal anti-VEGF injections. This finding has important implications
given the growing use of anti-VEGF treatment and the irreversible effects of
elevated IOP.
Keywords: anti-VEGF injections;
cataract surgery; intraocular pressure; Nd:YAG capsulotomy
DOI:10.18240/ijo.2020.01.12
Citation:
Sternfeld A, Ehrlich R, Weinberger D, Dotan A. Effect of different lens status
on intraocular pressure elevation in patients treated with anti-vascular
endothelial growth factor injections. Int J Ophthalmol 2020;13(1):79-84
Introduction
The overexpression of vascular
endothelial growth factor (VEGF) has been identified as a cornerstone of the
pathologic process leading to vascular leakage and neovascularization.
Accordingly, intravitreal injection of anti-VEGF inhibitors is the main mode of
treatment for exudative age-related macular degeneration and other retinal
vascular diseases characterized by macular edema and neovascularization
including diabetic macular edema and retinal vein occlusion[1-3]. Several anti-VEGF agents are currently available:
bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA), a
recombinant full-length humanized monoclonal antibody; ranibizumab (Lucentis;
Genentech), a humanized monoclonal antibody fragment; and aflibercept (Eylea;
Regeneron Pharmaceuticals, Tarrytown, NY, USA), a soluble decoy receptor fusion
protein[4-6]. The drugs have a
favorable safety profile, with only rare reports of adverse vision-threatening
events such as endophthalmitis, vitreous hemorrhage, retinal detachment, and
retinal tears, despite their widespread use[7].
A known immediate effect of any
intravitreal injection is a transient elevation of intraocular pressure (IOP).
In the majority of cases, the spikes normalize within 30min without further
intervention[8-9]. However, the
occurrence of sustained ocular hypertension in this setting is controversial,
with only sparse reports in the recent literature. Both the MARINA trial
(anti-VEGF antibody ranibizumab in the treatment of neovascular age-related
macular degeneration) and the ANCHOR Trial (ranibizumab versus verteporfin for
neovascular age-related macular degeneration), which investigated the effect of
ranibizumab treatment in patients with minimal classic or occult
neovascularization, reported an absence of long-term effects of monthly
injections on mean IOP[10]. Similar findings were
noted in a phase III study on the use of aflibercept for neovascular
age-related macular degeneration[6]. Wehrli et
al[11] conducted a large retrospective study
of 302 eyes treated with bevacizumab and/or ranibizumab, with 226 untreated
fellow eyes serving as the control group. No between-group difference was noted
in the rate of delayed ocular hypertension.
By contrast, several reports in
recent years have provided evidence that IOP elevation may be a long-term
adverse effect of anti-VEGF drugs[12-15].
Among them is a post-hoc data analysis of the MARINA and ANCHOR trials
comparing the anti-VEGF-treated eyes with eyes treated with sham injections or
photodynamic therapy. The authors found that the study group had a
statistically significant increase in the number of eyes with an elevation of
The risk factors contributing to the
sustained IOP elevation remain unclear owing to differences among the studies
in the number of injections[11,13-15] and type of anti-VEGF agent used[13-14], and the inclusion of patients with pre-existing
glaucoma[14-15,17]
or prior use of topical or intravitreal steroids[12,15,17].
Besides the medication, there is
evidence pointing to the contribution of the cataract extraction itself[18], alone or with the performance of neodymium doped
yttrium aluminum garnet (Nd:YAG) capsulotomy[19],
and Nd:YAG capsulotomy itself[20]. The present
study sought to shed further light on this issue. The aim of the study was to
assess the effect of lens status, in particular after Nd:YAG capsulotomy, on
sustained IOP elevation.
SUBJECTS AND Methods
Ethical Approval The study adhered to the tenets of
the Declaration of Helsinki and was approved by the institutional review board
of Rabin Medical Center. Informed consent was waived due to the retrospective
nature of the study.
The database of the Retina Clinic of
Rabin Medical Center, a tertiary university-affiliated hospital, was
retrospectively reviewed for all patients with retinal vascular disease who
were treated with an intravitreal injection of anti-VEGF agent in July 2015. It
is our departmental policy in these cases to start with bevacizumab (1.25
mg/0.05 mL) and switch to ranibizumab (0.5 mg/0.05 mL) on the basis of the
patient response. Therefore, none of the patients received only ranibizumab. We
included only patients for whom the pre-injection (baseline) IOP value and all
IOP values during a minimum of 6 months’ follow-up from the first injection
were available. Exclusion criteria were a change in lens status during
follow-up (cataract surgery or Nd:YAG capsulotomy), intraocular lens
implantation outside the bag, receipt of intravitreal corticosteroid treatment
during follow-up, and any intraocular surgery other than cataract surgery prior
to or during follow-up, with the exception of glaucoma surgery (trabeculectomy,
glaucoma drainage devices or laser trabeculoplasty) during follow-up.
The following data were collected
from the medical files: patient age and sex, reason for treatment, number of
anti-VEGF injections, type of injection, follow-up time (defined as the time
from the first injection until the last follow-up), lens status prior to and
throughout treatment, IOP prior to treatment and at every follow-up visit,
diagnosis of glaucoma, and medications for glaucoma before anti-VEGF injection
and throughout follow-up.
IOP was measured by Goldmann
applanation tonometry. Measurements were performed before every injection and
at every office visit.
The main outcome measure was a
sustained increase in IOP, defined as IOP≥
Continuous variables are presented
as means and standard deviation, and nominal variables, as number and
percentage. Continuous data were checked for normality (Shapiro-Wilk test).
One-way analysis of variance (ANOVA) with Bonferroni post hoc test or the
Kruskal-Wallis nonparametric test was used to compare variables by lens status.
Unpaired Student’s t-test or the nonparametric Mann-Whitney test was
used to compare variables by the presence or absence of sustained IOP
elevation. A p value of
<0.05 was considered statistically significant. All statistical analyses
were performed using the SPSS v. 3.
Results
A total of 119 eyes of 100 patients
met the study criteria. The patient characteristics and clinical data are shown
in Table 1.
Table 1 Baseline demographic and clinical characteristics of patients treated
with anti-VEGF agents, by lens status n (%)
|
Characteristics |
Phakic eyes |
Pseudophakic eyes |
Post-capsulotomy eyes |
P |
|
No. of eyes |
40 |
40 |
39 |
|
|
Males |
21 (52.5) |
8 (20) |
14 (35.9) |
|
|
Age (y) |
73.2±14.5 |
82.6±7.9 |
82.9±8.5 |
< |
|
Laterality (right eye) |
18 (45) |
15 (37.5) |
19 (48.7) |
0.59 |
|
Diagnosis |
|
|||
|
Exudative AMD |
25 (62.5) |
31 (77.5) |
27 (69.2) |
0.13 |
|
Diabetic macular edema |
13 (32.5) |
6 (15) |
5 (12.8) |
|
|
Othersb |
2 (5) |
3 (7.5) |
7 (18) |
|
|
Number of injections |
|
|||
|
Bevacizumab |
10.2±3.5 |
9.9±4.0 |
8.7±4.3 |
0.19 |
|
Ranibizumab |
2.0±3.1 |
1.8±3.1 |
3.3±4.3 |
0.13 |
|
Total |
12.2±3.2 |
11.7±3.7 |
11.9±4.5 |
0.82 |
|
Follow-up (d) |
701.3±80.1 |
710.4±100.0 |
735.7±301.9 |
0.70 |
|
Pretreatment glaucoma |
3 (7.5) |
1 (2.5) |
5 (12.8) |
0.22 |
AMD: Age-related macular
degeneration. aStatistically significant (post-capsulotomy vs
phakic/pseudophakic); bOthers indication for anti-VEGF treatment
included myopic choroidal neovascularization, peripapillary choroidal
neovascularization, central retinal vein occlusion and branch retinal vein
occlusion.
Division by lens status during
follow-up yielded 3 groups: 40 phakic eyes, 40 pseudophakic eyes, and 39
pseudophakic eyes following Nd:YAG capsulotomy. There was no significant
difference among the groups in the rate of pre-treatment glaucoma (phakic,
7.5%; pseudophakic, 2.5%; post-capsulotomy, 12.8%; p=0.22) or mean pre-treatment IOP [14.6±
The association of lens status with
IOP elevation is shown in Table 2.
Table 2 Sustained IOP elevation criteria by study groups
n
(%)
|
Criterion |
Phakic eyes |
Pseudophakic eyes |
Post-capsulotomy eyes |
p |
|
≥ |
3 (7.5) |
3 (7.5) |
5 (12.8) |
0.64 |
|
|
6 (7.5) |
5 (12.8) |
0.35 |
|
|
≥ |
0 |
0 |
0 |
|
|
New IOP lowering medication |
0 |
2 (5) |
4 (10.3) |
0.11 |
|
|
2 (2.5) |
4 (10.3) |
0.09 |
|
|
Total |
3 (7.5) |
4 (10) |
9 (23.1) |
0.09 |
|
|
7 (8.8) |
9 (23.1) |
|
|
IOP: Intraocular pressure. aP<0.05.
The overall rate of sustained IOP
elevation was 13.4%. The rate was significantly higher in the post-capsulotomy
group than in the phakic+pseudophakic groups (23.1% vs 8.8%; p=0.03). There were no
statistically significant differences among the 3 groups (Table 1) in mean
number of injections, either total (phakic: 12.2±3.2; pseudophakic: 11.7±3.7;
post-capsulotomy: 11.9±4.5; p=0.82)
or by type of anti-VEGF medication (bevacizumab, 10.2±3.5, 9.9±4.0 and 8.7±4.3,
respectively, p=0.19;
ranibizumab, 2.0±3.1, 1.8±3.1 and 3.3±4.3, respectively, p=0.13). Mean follow-up time was
similar in all 3 groups (701.3±80.1, 710.4±100.0, and 735.7±301.9d,
respectively; p=0.70) as
was the interval between the beginning of treatment and IOP elevation
(247.0±158.0, 251.0±11.7 and 445.1±259.1, P=0.23). IOP in the three
groups ranged between 8
Sustained IOP elevation rate
remained significantly higher in the post-capsulotomy group following further
analysis of the data using multivariable logistic regression that included
total number on injections and pre-existing glaucoma (P=0.047). When
separately analyzing bevacizumab and ranibizumab, significance remained with
the former while there was a trend toward significance with the latter (P=0.045
and 0.073, respectively).
Two patients with pre-treatment
glaucoma had sustained IOP elevation (12.5% of all patients with sustained IOP
elevation and 22.2% of patients with pre-treatment glaucoma), both were in the
post-capsulotomy group. Their initial IOP elevation occurred 10 and 13mo after
beginning treatments and after receiving 9 and 10 injections, respectively.
Their IOP was stable until that point and restabilized after adding topical
treatments (two and one IOP lowering drops, respectively).
Comparison of the patients with and
without a sustained IOP elevation (Table 3) revealed that the group with a
consistently high IOP had a significantly lower baseline IOP (
Table 3 Comparison between patients with sustained IOP elevation
and patients without sustained IOP elevation n (%)
|
Characteristics |
Sustained IOP elevation |
No IOP elevation |
p |
|
Eyes |
16 |
103 |
|
|
Males |
6 (37.5) |
37 (35.9) |
0.90 |
|
Age (y) |
81.3±7.6 |
79.3±12.1 |
0.53 |
|
No. of injections |
|
||
|
Bevacizumab |
9.1±4.1 |
9.7±4.0 |
0.56 |
|
Ranibizumab |
3.8±4.5 |
2.1±3.4 |
0.16 |
|
Total |
11.8±3.9 |
12.9±3.4 |
0.30 |
|
Baseline IOP (mm Hg) |
13.3±2.7 |
14.5±2.2 |
|
|
Diagnosis |
|
||
|
Exudative AMD |
10 (62.5) |
73 (70.9) |
0.46 |
|
Diabetic macular edema |
3 (18.8) |
21 (20.4) |
|
|
Others |
3 (18.8) |
9 (8.7) |
|
|
Follow-up (d) |
778.8±170.0 |
705.8±188.4 |
0.15 |
|
Pretreatment glaucoma |
2 (12.5) |
7 (6.8) |
0.42 |
AMD: Age-related macular
degeneration; IOP: Intraocular pressure. aP<0.05.
Discussion
The present study suggests that
Nd:YAG capsulotomy is a risk factor for sustained IOP elevation in patients
treated with anti-VEGF injections. This finding in important given the
increasing use of anti-VEGF injections and the potentially irreversible damage
caused by elevated IOP.
Several leading theories have been
proposed to explain the mechanism underlying long-term IOP elevation after
anti-VEGF injection. Some authors suggested that microparticles from the
medication’s packaging or delivery equipment may obstruct the trabecular
meshwork. This assumption is based on reports of a different aggregate
high-molecular-weight protein concentration in repackaged samples of
bevacizumab and a higher prevalence of sustained IOP elevations in patients
attending centers using repackaged bevacizumab than in patients treated in
centers receiving bevacizumab in its original package[14,19].
It is also possible that the
high-molecular-weight drugs themselves, especially bevacizumab (MW 150 kDa;
ranibizumab, 48 kDa), obstruct the outflow channels. Support for this
assumption was provided by findings of a higher prevalence of sustained
elevated IOP in studies of patients receiving bevacizumab[12].
Moreover, in a recent experimental study, bevacizumab was found in the
trabecular meshwork and Schlemm’s canal after injection into a rat model[21].
A third theory suggests that
recurrent episodes of transient post-injection IOP elevation chronically damage
the aqueous outflow channels, eventually causing sustained IOP elevation[22]. Alternatively, inflammation, whether recurrent inflammation,
post- injection subclinical inflammation, or chronic drug-induced trabeculitis
or uveitis, may induce scar formation and fibroblast proliferation which
gradually obstruct aqueous outflow[9,23].
Although cataract surgery is
generally thought to lower IOP to some degree[18],
in the setting of intraocular anti-VEGF injections, lens extraction and,
especially, opening of the posterior capsule during Nd:YAG capsulotomy, may
promote the introduction of the injected proteins and molecules into the trabecular
meshwork, thereby increasing IOP[19]. Supporting evidence to this theory could be drawn
from several animal studies showing increased clearance of bevacizumab and
ranibizumab after lensectomy, vitrectomy or both. The improved clearance is
attributed, at least in part and specifically in the aphakic eyes, to increased
role of the trabecular meshwork[24-26].
It is possible that posterior capsulotomy increases the evacuation through the
trabecular meshwork in a similar manner, which in turn increases the risk for
sustained elevated IOP. Our finding of higher prevalence of increased IOP in
patients after Nd:YAG capsulotomy supports this assumption. Interestingly, if
increased clearance does exist after posterior capsulotomy, this may be an
indication for more frequent anti-VEGF injections in these patients. Further
studies are needed to shed light on this matter. Two previous studies focused
on the effect of lens status on sustained IOP elevation. In the first, Hoang et
al[15] reported no association between these
factors. However, they included only the final lens status at the last
injection in the analysis. In a subsequent study, the same group found, in
accordance with our results, that phakic lenses are apparently protective
against sustained IOP elevation. Both of the earlier studies, however, by
contrast to ours, included only a minimal number of patients who had undergone
Nd:YAG capsulotomy (3.9% and 6%, respectively).
The 13.4% total incidence of a
sustained increase in IOP in the present study was higher than reported by
Bakri et al[16] on post hoc analysis of
the ANCHOR and MARINA trials (5.4% for 0.3 mg ranibizumab and 4.5% for 0.5 mg
ranibizumab), and higher than in the studies of Hoang et al[15,17] (7.2% and 11.6%), and Good et
al[14] (6%). The discrepancy may be
attributable to our high percentage of post-capsulotomy patients. The high
number of bevacizumab injections may also have played a role, as bevacizumab
has been found to be a risk factor for sustained IOP elevation[14]. Bevacizumab was not used at all in the ANCHOR and
MARINA trials, and was used in only a relatively low percentage of eyes in the
studies of Hoang et al[15,17]
(34.1% and 32.4%) and Good et al[14]
(55.3%). The incidence of increased IOP in the post-capsulotomy group in our
study is higher than attributed to the procedure in the literature (23.1% vs
1%-6%, respectively)[20,27-28], possibly related to the role of anti-VEGF injections
in this pathology.
The present study did not identify
other major risk factors for sustained IOP elevation. Hoang et al[15,17] found total number of anti-VEGF
injections to be a risk factor, but their patients received a much higher mean
number of injections (20.8 and 21.1, respectively) than ours (11.9). Good et
al[14] noted an association of pre-existing
glaucoma with a high frequency of sustained IOP elevation (33%). In our study,
the number of patients with pre-existing glaucoma (n=9) may have been
too small to achieve statistical significance, although a relatively high
percentage of the patients with sustained IOP elevation had a pretreatment
diagnosis of glaucoma (12.5%). This is certainly an important direction for
future research. The lack of a difference in the rate of IOP elevation by type
of anti-VEGF agent in our study may be explained by our departmental policy of
starting all patients on bevacizumab such that none received only ranibizumab,
making it difficult to differentiate the individual effect of the two drugs.
The fact that capsulotomy did not
remain a significant risk factor following multivariable analysis using number
of ranibizumab injections could result from the smaller size of the molecule.
Potentially this enables easier diffusion of the molecule to the anterior
chamber even without the opening in the posterior capsule and therefore
eliminates its effect.
The patients with a sustained IOP
elevation had a lower baseline IOP (
This study has several limitations.
Our sample size was limited, future prospective multi-center studies are needed
for the evaluation of this important subject.
Excluding patients whose baseline or
follow-up IOP measurements were not available could have created a selection
bias assuming these data would not be missing in patients at risk for increased
IOP. This may explain the relatively high percentage of patients with
pre-existing glaucoma found to have sustained IOP elevations. However, since it
is our policy to always measure and document the IOPs, this phenomenon is
probably marginal resulting from inattention and was spread evenly between the
groups.
As a result of the retrospective
nature of this study, the effect of the time frame between the cataract
surgery, Nd:YAG capsulotomy and IOP elevation, or Nd:YAG capsulotomy
specifications (energy, spot size, number of shots) and IOP elevation could not
be assessed. This information is not detailed in most patients’ charts.
Evaluating these data in future studies could add valuable information.
Another drawback was the higher
prevalence of pretreatment glaucoma in the post capsulotomy group. This could
have potentially confounded the outcomes of the study, especially since 12.5%
of the sustained IOP elevation group did have pre-existing glaucoma. However,
since these differences did not reach statistical significance, neither in the
3 study groups nor between the patients with and without sustained IOP
elevation, and since the absolute numbers and overall prevalence of
pretreatment glaucoma patients were not high, we believe their effect on the
results was minimal at most. The effect of pre-existing glaucoma combined with
lens status could also be an interesting direction for research.
In conclusion, this study suggests
that Nd:YAG capsulotomy is a risk factor for a sustained elevation in IOP in
patients treated with anti-VEGF injections. This finding may have clinical
implications when capsulotomy is being considered in patients under anti-VEGF
treatment. It supports the recommendation for routine monitoring of IOP levels
in all patients treated with anti-VEGF drugs, and particularly, patients after
capsulotomy.
ACKNOWLEDGEMENTS
Authors’ contributions: Sternfeld A, Dotan A: substantial
contributions to conception and design, acquisition of data, analysis and
interpretation of data. Drafting the article or revising it critically for
important intellectual content. Final approval of the version to be published.
Ehrlich R, Weinberger D: contributions to conception and design, acquisition of
data, analysis and interpretation of data. Drafting the article or revising it
critically for important intellectual content. Final approval of the version to
be published.
Conflicts of Interest: Sternfeld A, None; Ehrlich R, None;
Weinberger D, None; Dotan A, None.
References