ORIGINAL ARTICLE
Bevacizumab and Panretinal
photocoagulation protect against ocular
hypertension after posterior subtenon
injection of triamcinolone acetonide for
diabetic macular edema
Yi-Ting Hsieh
a,b,c, Chung-May Yang
a, Shu-Hui Chang
b,*
a
Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
b
Division of Biostatistics, Graduate Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
c
Department of Ophthalmology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
Received 10 July 2016; received in revised form 26 September 2016; accepted 29 September 2016
KEYWORDS anti-vascular endothelial growth factor; diabetic macular edema; ocular hypertension; panretinal photocoagulation; steroids
Background/Purpose: To analyze the prognostic factors for ocular hypertension after posterior subtenon injection of triamcinolone acetonide (PSTA) for the treatment of diabetic macular edema (DME).
Methods: Patients who received PSTA for DME from January 2006 to December 2011 were enrolled retrospectively and were followed until December 2012 in one hospital. Modified Cox regression models were used to analyze the factors associated with ocular hypertension, which was defined as an intraocular pressure> 21 mmHg after PSTA.
Results: A total of 180 PSTA injections were given to 114 eyes from 73 adults with DME. During a mean follow-up of 50.4 weeks after each injection, ocular hypertension occurred in 20.6% of injections (28.1% of eyes). Treatment-naı¨ve patients with proliferative diabetic retinopathy (PDR) had a higher risk of ocular hypertension after PSTA than those with nonproliferative dia-betic retinopathy (NPDR) [hazard ratio (HR)Z 3.255, p Z 0.030]. Intravitreal injection of bev-acizumab (IVB) before PSTA had a significant effect in lowering the risk of ocular hypertension after PSTA in patients with PDR who had received panretinal photocoagulation (PRP) (HRZ 0.107, p Z 0.035). Both prompt PRP and IVB following PSTA had a protective effect against ocular hypertension in treatment-naı¨ve patients with PDR (HRZ 0.086, p Z 0.0002 and HRZ 0.155, p Z 0.049, respectively).
Conflicts of interest: The authors have no conflicts of interest relevant to this article.
* Corresponding author. Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 538, 17 Xu-Zhao Road, Taipei 10055, Taiwan.
E-mail address:shuhui@ntu.edu.tw(S.-H. Chang).
http://dx.doi.org/10.1016/j.jfma.2016.09.014
0929-6646/Copyrightª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online atwww.sciencedirect.com
ScienceDirect
Conclusion: Treatment-naı¨ve patients with PDR had a higher risk of ocular hypertension after PSTA than those with NPDR. Bevacizumab and prompt PRP both had a protective effect against ocular hypertension after PSTA in patients with PDR.
Copyrightª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Diabetic retinopathy (DR) is one of the leading causes of visual loss worldwide,1and diabetic macular edema (DME)
is the most common cause of visual loss in patients with DR.2The breakdown of the blooderetinal barrier, increased
permeability of macular retinal vessels, and exudation of serous fluid and lipids into the macula lead to visual dete-rioration in patients with DME.3Treatments for DME include laser photocoagulation, corticosteroids, anti-vascular endothelial growth factor (VEGF) administration, and pars plana vitrectomy.2,3Triamcinolone acetonide is a minimally soluble repository steroid that can slowly release its con-tents. Posterior subtenon injections of triamcinolone ace-tonide (PSTA) and intravitreal injections of triamcinolone acetonide (IVTA) both have been shown to decrease mac-ular thickness and improve vision in patients with DME.4e8 Combined treatment with triamcinolone acetonide and anti-VEGF has also been advocated to treat DME.9e11 In addition, for patients with proliferative diabetic retinop-athy (PDR) and concomitant DME, PSTA has been proved to be effective in preventing panretinal photocoagulation (PRP)-induced macular edema.12
One of the most important side effects of PSTA is ocular hypertension after injections; some patients even require surgical intervention to control their intraocular pressure (IOP).13e22 Persistent ocular hypertension may also rarely
occur after intravitreal administration of anti-VEGF.23 To the best of our knowledge, the role of anti-VEGF in ocular hypertension after PSTA for DME has not been investigated. In this study, we retrospectively collected data from pa-tients who received PSTA for DME in order to investigate the risk and protective factors regarding ocular hypertension after PSTA; in particular, we examined the effect of anti-VEGF as well as the severity of DR on IOP after PSTA. We also evaluated the timing of PRP with respect to ocular hypertension after PSTA in patients with PDR and DME.
Materials and Methods
Study sampleWe retrospectively collected data from patients who received PSTA for DME in Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, between January 2006 and December 2011. The follow-up period ended in December 2012. The exclusion criteria for this study were as follows: (1) a history of glaucoma or an IOP> 21 mmHg at the time of PSTA; (2) concurrent antiglaucoma medication at the time of PSTA; (3) iris or angle rubeosis; (4) simultaneous
systemic or intravitreal steroid treatment during the follow-up period; (5) systemic connective tissue disease; (6) scleral buckle or intravitreal silicone oil; (7) retinal vascular occlusive diseases; and (8) follow-up time< 2 months. After exclusion, a total of 114 eyes from 73 pa-tients were included in this study. The mean age at the time of the first PSTA was 63.4 10.1 years (range, 42e89 years), and 44.7% patients were females. This research adhered to the tenets of the Declaration of Helsinki, and Institutional Review Board (IRB) approval was obtained from the IRB of Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. Waiver of informed consent was approved by the IRB due to the retrospective nature of this study. Power analysis was performed to justify the number of patients enrolled in the study.
Procedure for PSTA
The procedure for PSTA was modified according to the method described by Nozik.24 The patient was asked to
direct his or her gaze superonasally, and an injection of 40 mg/mL of triamcinolone acetonide was administered inferotemporally into the posterior subtenon space with a 27-gauge needle.
IOP and clinical characteristics
The IOP was measured with a noncontact tonometer (CT-80; Topcon Corporation, Tokyo, Japan). Baseline IOP was measured in each eye just before PSTA. Thereafter, the IOPs were monitored at least monthly for the first 3 months. Patients’ age, sex, and severity of DR at baseline were recorded. The severity of DR at baseline was classified into nonproliferative diabetic retinopathy (NPDR) or PDR, ac-cording to the criteria proposed by the Global Diabetic Retinopathy Project Group25; for eyes with PDR, they were further classified according to the presence of PRP. In this study, all the eyes with PDR without previous PRP were treatment-naı¨ve at baseline, which means that no retinal laser or anti-VEGF agents had been given to these patients before PSTA. The use of anti-VEGF therapy was also recorded. In this study, bevacizumab was the only anti-VEGF agent used for all patients.
Outcomes and follow-up events
In this study, we defined ocular hypertension as an IOP> 21 mmHg. The primary endpoint was defined as the first IOP> 21 mmHg after PSTA for a single eye. More than one PSTA treatment was performed in some eyes during the
study period due to recurrent macular edema, and the in-formation obtained from the course of one PSTA treatment in one eye was considered to be a single record. Other possible endpoints included a subsequent PSTA treatment, any intraocular surgery other than cataract surgery or intravitreal injection of anti-VEGF, loss to follow-up, or end of study.
Statistical analysis
For eyes that received multiple PSTA treatments, each PSTA was treated as a single record. Multiple PSTA in one eye led to multiple gap times (time period between suc-cessive PSTAs) within the same eye, and these gap times were correlated. The ordered nature of serial PSTA in-jections in one eye allowed us to apply conditional regression analysis for repeated gap times.26,27Therefore, stratified Cox proportional hazards (PH) models were used to analyze the factors for ocular hypertension after PSTA, and a robust sandwich varianceecovariance estimation method was adopted to correct the correlation between fellow eyes from the same patient. Paired t tests were used to compare baseline and posttreatment IOPs. A p val-ue< 0.05 was considered statistically significant. SAS 9.4 (SAS Institute Inc., Cary, NC, USA) software was used for all statistical analyses.
Results
A total of 180 PSTA injections were administered to the 114 eyes: 31 eyes had NPDR, 53 eyes had PDR with PRP, and 30 eyes had PDR with no previous PRP or anti-VEGF at baseline. The mean number of PSTA injections was 1.6 (range, 1e8) for each eye. During the study period, 29 eyes received multiple PSTA during the study period. The minimal gap time or interval between two successive in-jections in the same eye was 8 weeks. For each injection, the mean follow-up time was 50.4 51.6 weeks (range, 8e280 weeks), and the mean baseline IOP was 14.0 3.2 mmHg (range, 6e21 mmHg). Among the 114 eyes, 12 eyes had received intravitreal injections of
bevacizumab (IVB) at the time of the first PSTA. During the follow-up period, 22 additional eyes received initial IVB injections. Additional baseline data are shown in
Table 1.
Figure 1 shows the IOP changes after PSTA. The mean IOP increased to 15.1 3.6 mmHg at the 1stmonth, formed
a plateau from the 2nd to the 5th month (range, 16.0e16.2 mmHg), and then decreased gradually after the 6thmonth (15.5 4.8 mmHg). The IOP values measured 1e6 months after PSTA were all significantly higher than the baseline value (p< 0.001 for the 1stto the 5thmonth and pZ 0.002 for the 6thmonth). Ocular hypertension occurred in 20.6% of injections (28.1% of eyes) after PSTA. The mean event time for ocular hypertension after each injection was 16.1 14.7 weeks (range, 2e77 weeks, median Z 11 weeks). Among the 114 eyes in this study, 21 eyes (18.4%) received antiglaucoma agents during the study period, 3 eyes (2.6%) received surgical removal of subtenon triam-cinolone acetonide particles, and 2 eyes (1.8%) received filtering surgery for IOP control.
Factors associated with ocular hypertension after PSTA
Baseline characteristics
Table 2shows the unadjusted and adjusted hazard ratios (HRs) of baseline characteristics for ocular hypertension after PSTA determined by stratified Cox PH models. Eyes with a baseline IOP> 15 mmHg had a higher risk of ocular hypertension after PSTA than did those with a baseline IOP 15 mmHg (adjusted HR Z 4.003, p < 0.001). For treatment-naı¨ve eyes with PDR, the risk of ocular hyper-tension after PSTA was 3.255 times that for eyes with NPDR after adjustment for the remaining risk factors (pZ 0.030). IVB before and after PSTA
The effects of IVB in patients with different degrees of severity of DR are shown inTable 3. In the NPDR group, neither IVB before nor after PSTA had a significant effect on ocular hypertension following PSTA (p> 0.05 for both comparisons). For eyes with PDR and complete PRP, IVB before PSTA provided a protective effect against ocular hypertension after PSTA (HRZ 0.107, p Z 0.035); however, IVB after PSTA was not protective (HRZ 0.919, p Z 0.88). For treatment-naı¨ve eyes with PDR, IVB after PSTA also provided a protective effect against ocular hypertension following PSTA (HRZ 0.155, p Z 0.049).
Prompt vs. deferred PRP
For treatment-naı¨ve eyes with PDR, prompt PRP following PSTA was shown to have a protective effect against ocular hypertension after PSTA compared with deferred PRP (HRZ 0.086, p Z 0.0002) after adjustments for age, sex, and baseline IOP (Table 3).
Combined effect of prompt PRP and IVB after PSTA For treatment-naı¨ve eyes with PDR, prompt PRP plus IVB after PSTA provided a protective effect against ocular hy-pertension after PSTA compared with deferred PRP only (HRZ 0.050, p Z 0.0007) after adjustments for age, sex, and baseline IOP (Table 3).
Table 1 Baseline data for 114 eyes in this study. Age (years), mean (SD) 63.2 (10.4)
Sex (female), n (%) 51 (44.7)
Hypertension, n (%) 57 (50.0)
Intraocular pressure (mmHg), mean (SD) 14.0 (3.3) Severity of diabetic retinopathy, n (%)
NPDR 22 (19.3) PDR with PRP 62 (54.4) Treatment-naı¨ve PDR 30 (26.3) Intravitreal bevacizumab, n (%) Before PSTA 12 (10.5) After PSTA 22 (19.3)
NPDRZ nonproliferative retinopathy, PDR Z proliferative reti-nopathy, PRPZ panretinal photocoagulation, PSTA Z posterior subtenon injection of triamcinolone acetonide.
Serial PSTA
In this study, 29 eyes received multiple PSTA, and the number of previous PSTA was evaluated as an explanatory variable in the Cox regression model with adjustment for age, sex, and other clinical variables. The results showed that the number of previous injections was not associated with the risk of ocular hypertension (HRZ 1.171, pZ 0.78).
Discussion
Glucocorticoids have been proved to be effective in treat-ing DR and DME by means of their antiinflammatory action and direct inhibition of VEGF expression. They also have neuroprotective properties, in contrast to the possible neurotoxic effects of VEGF inhibitors.28Although anti-VEGF
therapy has become the mainstream treatment of DME, triamcinolone acetonide is still indispensable due to its cost effectiveness.29IVTA or PSTA in combination with an
anti-VEGF agent has also been shown to be equally or even more effective than anti-VEGF agents alone in treating DME.9e11A common side effect of intraocular steroid use is ocular hypertension, which may result in glaucomatous optic nerve atrophy if uncontrolled. Therefore, it is important to monitor IOP and to consider the risk factors for ocular hypertension after PSTA. Because patients with DME may receive repeated PSTA treatments, it is even more clinically necessary to monitor IOP and to investigate the factors associated with the risk of developing ocular hy-pertension following each PSTA injection. Therefore, in this study, we calculated the time interval from each PSTA to the occurrence of ocular hypertension and defined the latter as the major event time per injection in one eye. Figure 1 Intraocular pressure at baseline and after posterior subtenon injection of triamcinolone acetonide.
Table 2 Factors associated with ocular hypertension after posterior subtenon injection of triamcinolone acetonide by stratified Cox regression analysis.
Simple regression Multiple regression
Hazard ratio 95% CI p Hazard ratio 95% CI p
Age 0.988 0.955e1.023 0.50 0.984 0.940e1.031 0.50
Sex
Female 1 (reference) 1 (reference)
Male 1.601 0.792e3.238 0.19 1.947 0.952e3.982 0.068
Baseline IOP
15 mmHg 1 (reference) 1 (reference)
> 15 mmHg 3.096 1.645e5.828 < 0.001 4.003 1.975e8.112 < 0.001 Severity of diabetic retinopathy
NPDR 1 (reference) 1 (reference)
PDR with PRP 1.862 0.790e4.389 0.16 1.970 0.786e4.938 0.15
Treatment-naı¨ve PDR 2.468 0.860e7.087 0.093 3.255 1.124e9.426 0.030 IOPZ intraocular pressure, NPDR Z nonproliferative retinopathy, PDR Z proliferative retinopathy, PRP Z panretinal photocoagulation.
Previous studies demonstrated that the proportion of patients who developed secondary glaucoma or ocular hypertension after PSTA ranged from 11.4% to 46%.13e22
The criteria for glaucoma or ocular hypertension, how-ever, varied among these studies. An IOP normally ranges from 10 to 21 mmHg, and an absolute IOP> 21 mmHg is usually considered suspicious for glaucoma. In this study, we defined an IOP> 21 mmHg as the criterion for ocular hypertension; the results showed that ocular hypertension occurred in 20.6% of injections and 28.1% of eyes after PSTA during the follow-up period. The mean follow-up time for each injection in this study was 50.4 weeks, which was longer than the follow-up time in most previous studies. The mean and median event times for ocular hypertension were 16.1 and 11 weeks, respectively, which indicates that careful IOP monitoring during the first 3e4 months after PSTA was mandatory. However, it is worth noting that two patients in this study first experienced ocular hypertension at 77 and 46 weeks after PSTA although it cannot be confirmed if the ocular hypertension was caused by PSTA in these two cases.
In this study, treatment-naı¨ve eyes with PDR were found to have a significantly higher risk of ocular hypertension after PSTA than did those with NPDR. According to the study design, cases with a history of glaucoma, including neo-vascular glaucoma, and cases with iris rubeosis were excluded at enrollment. However, some of the PDR patients may develop subclinical angle rubeosis with partially occluded anterior chamber angles during the follow-up periods. Such patients may have presented with normal
baseline IOPs, but may have been prone to ocular hyper-tension after PSTA. As to eyes with PDR and prior PRP, the risk for ocular hypertension after PSTA was not significantly different from that of patients with NPDR. These results are reasonable because angiogenetic activity should have decreased after PRP, and the possibility of angle rubeosis may also have decreased.
For eyes with PDR and PRP, IVB before PSTA significantly reduced the risk of ocular hypertension after PSTA. For treatment-naı¨ve patients with PDR, IVB after PSTA also significantly reduced the risk of ocular hypertension after PSTA. As mentioned above, some patients with PDR, even with complete PRP, might develop subclinical angle rubeosis with partially occluded anterior chamber angles and, thus, were prone to ocular hypertension after PSTA. Furthermore, the ocular hypertension after PSTA in some PDR patients possibly was due to the later onset of neovascular glaucoma rather than steroid-induced ocular hypertension. Anti-VEGF agents have shown promising effects for the treatment of patients with neovascular glaucoma.30 Therefore, IVB in these cases may suppress the angle rubeosis in the injected eyes, thus allowing better aqueous outflow to protect against the steroid-induced ocular hypertension or control the neovascular glaucoma itself. According to such results, we suggest anti-VEGF therapy should be considered in combination with PSTA for the treatment of DME in patients with PDR in order to decrease the incidence of ocular hy-pertension after PSTA. Further investigations should enroll patients prospectively to confirm the role of anti-VEGF in steroid-induced ocular hypertension.
Table 3 Effects of bevacizumab and panretinal photocoagulation on ocular hypertension after posterior subtenon injection of triamcinolone acetonide in patients with different degrees of severity of diabetic retinopathy by stratified Cox regression analysis.
Simple regression Multiple regression
Hazard ratio 95% CI p Hazard ratio 95% CI p
NPDR group: IVB effect:
No IVB 1 (reference) 1 (reference)
IVB before PSTA 2.951 0.129e67.273 0.50 3.531 0.148e84.250 0.44
IVB after PSTA 3.727 0.657e21.157 0.14 4.346 0.743e25.427 0.10
PDR with PRP group: IVB effect:
No IVB 1 (reference) 1 (reference)
IVB before PSTA 0.118 0.016e0.876 0.037 0.107 0.013e0.855 0.035
IVB after PSTA 0.834 0.234e2.973 0.78 0.919 0.304e2.775 0.88
Treatment-naı¨ve PDR group: IVB effect:
Prompt PRP 1 (reference) 1 (reference)
Prompt PRP plus IVB after PSTA 0.474 0.065e3.443 0.46 0.155 0.024e0.999 0.049 Prompt vs. deferred PRP:
Deferred PRP 1 (reference) 1 (reference)
Prompt PRP 0.159 0.053e0.477 0.001 0.086 0.023e0.313 0.0002
Combined effect of prompt PRP plus IVB:
Deferred PRP 1 (reference) 1 (reference)
Prompt PRP plus IVB after PSTA 0.163 0.019e1.433 0.10 0.050 0.009e0.282 0.0007 IVBZ intravitreal injection of bevacizumab, NPDR Z nonproliferative retinopathy, PDR Z proliferative retinopathy, PRP Z panretinal photocoagulation.
PRP has been a well-established treatment for PDR for decades. However, PRP may result in macular edema and visual deterioration in PDR patients who previously had good vision.31 Proinflammatory cytokines, such as interleukin-6 and regulated on activation normal T cell expressed and secreted (RANTES), but not VEGF, were found to be related to PRP-induced macular edema.32PSTA has been shown to effectively suppress leukocyte dynamics and to prevent PRP-induced macular edema and visual impairment.12,33However, for patients with persistent
se-vere DME, the timing of PRP is still controversial. In this study, we found that prompt PRP following PSTA had a protective effect against ocular hypertension after PSTA compared with deferred PRP for treatment-naı¨ve eyes with concomitant PDR and DME. Besides, we also found that prompt PRP plus IVB had additive effects in protecting against ocular hypertension after PSTA. This result is compatible with our suggestion above that ocular hyper-tension may be related to the extent of angiogenetic ac-tivity. Regarding concerns about the progression of PRP-induced macular edema, both triamcinolone acetonide and anti-VEGF agents have been proved to be effective in suppressing PRP-related macular edema and promoting short-term visual improvement after PRP.34 Accordingly,
PRP should be performed promptly following PSTA or intravitreal anti-VEGF in treatment-naı¨ve patients with PDR with concomitant DME; deferred PRP after resolution of macular edema is not necessary and may be harmful due to persistent secretion of VEGF from the ischemic retina and increased risk of ocular hypertension.
Inatani et al19 and Hirano et al21 found that a higher
baseline IOP was associated with a higher incidence of ocular hypertension. The present study also showed that for eyes with a baseline IOP> 15 mmHg, the risk of ocular hypertension was 4.003 times the risk of eyes with a baseline IOP 15 mmHg. These results suggest that in pa-tients with high baseline IOPs who undergo PSTA, post-operative IOPs should be carefully monitored.
To evaluate the cumulative effect of serial PSTA on ocular hypertension, we used stratified Cox PH models to allow that eyes with different numbers of injections had different risks of ocular hypertension for the same eye; if the number of injections has a significant correlation with ocular hypertension after PSTA, it might suggest the un-derlying cumulative effects of serial PSTA. In the present study, it is found that the number of previous injections was not associated with ocular hypertension after adjustment for the baseline IOP for each injection and other factors. On the other hand, Iwao et al18 reported that the difference
between peak and baseline IOPs significantly increased as the number of injections increased; however, we think it would be arbitrary to conclude a cumulative effect of serial PSTA on IOP elevation because the IOP at enrollment, instead of the pretreatment IOP before each injection, was used as the baseline IOP for analysis in the study by Iwao et al. Regarding the possible side effects of ocular hyper-tension following PSTA, we propose that ophthalmologists should consider the patient’s pretreatment IOP before each injection, instead of the number of injections she or he has previously received.
Several previous studies showed that younger age was associated with a higher risk of post-PTSA ocular
hypertension.17e22 Yamamoto et al20 found that the
inci-dence of ocular hypertension was relatively higher in fe-males; however, other studies found that the patient’s sex was not related to ocular hypertension.18,22 The age and sex distributions of the participants in the present study were similar to those in previous studies. We found that neither age nor sex was related to ocular hypertension following PSTA.
The major limitation of this study is its retrospective design. There were no consistent treatment protocols for the study cases. The selection and timing for PSTA or IVB were based on not only the severity of DME but also on the patients’ economic burdens and personal choices. Howev-er, we excluded cases with pre-existing glaucoma and angle rubeosis. Therefore, patients’ subjective selection for IVB was more of a noninformative bias, and the significant re-sults regarding the protective effect of IVB against ocular hypertension following PSTA in PDR patients should be robust. On the other hand, the tonometer used in this study was a noncontact one instead of a standard Goldmann applanation apparatus. However, the accuracy and reli-ability of the tonometer used in this study (Topcon CT-80) have been documented.35 Therefore, bias from the tonometer should be limited and noninformative.
In conclusion, we found that IOP significantly increased from 1 to 6 months after PSTA for DME and that post-operative ocular hypertension can occur as soon as 2 weeks or as late as more than 1 year after PSTA. After a mean follow-up of 50.4 weeks for each injection, ocular hyper-tension occurred in 20.6% of injections and 28.1% of eyes. Treatment-naı¨ve patients with PDR had a higher risk of ocular hypertension after PSTA than those with NPDR. For patients of PDR with previous PRP, IVB before PSTA had a protective effect against ocular hypertension following PSTA. Compared with deferred PRP, prompt PRP and IVB both had a protective effect against ocular hypertension following PSTA for treatment-naı¨ve patients with PDR.
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