Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Secondary Ocular Hypertension and the Risk of Glaucoma Surgery After Dexamethasone Intravitreal Implant in Routine Clinical Practice

Kornwipa Hemarat, MD; Jacquelyn D. Kemmer, BA; Travis C. Porco, PhD; Alexander M. Eaton, MD; Rahul N. Khurana, MD; Jay M. Stewart, MD

Abstract

BACKGROUND AND OBJECTIVES:

To determine the rate of ocular hypertension (OHT) after dexamethasone intravitreal implant in routine clinical practice and identify patient characteristics associated with a risk for glaucoma surgery.

PATIENTS AND METHODS:

The charts of 260 eyes from 221 patients with diabetic macular edema, retinal vein occlusion, uveitis, and macular edema secondary to various causes treated with one or more dexamethasone implants were reviewed. Intraocular pressure (IOP), medications, and glaucoma interventions were collected before and after implantation.

RESULTS:

The mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg, and after receiving dexamethasone implant(s), 26.2% and 7.7% of patients had IOP greater than 25 mm Hg and 35 mm Hg, respectively. There was evidence (P < .001) of an association between preexisting glaucoma or glaucoma suspect status (103 eyes) and need for glaucoma surgery, and 4.62% (12 eyes) required glaucoma surgery.

CONCLUSIONS:

Secondary OHT induced by the dexamethasone implant can usually be controlled by medications, but the incidence of OHT requiring glaucoma surgery was high (4.62%) in our study relative to rates previously reported in the literature. All patients, especially those with preexisting glaucoma, should be advised of the possible need for glaucoma surgery prior to undergoing treatment with the dexamethasone implant.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:680–685.]

Abstract

BACKGROUND AND OBJECTIVES:

To determine the rate of ocular hypertension (OHT) after dexamethasone intravitreal implant in routine clinical practice and identify patient characteristics associated with a risk for glaucoma surgery.

PATIENTS AND METHODS:

The charts of 260 eyes from 221 patients with diabetic macular edema, retinal vein occlusion, uveitis, and macular edema secondary to various causes treated with one or more dexamethasone implants were reviewed. Intraocular pressure (IOP), medications, and glaucoma interventions were collected before and after implantation.

RESULTS:

The mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg, and after receiving dexamethasone implant(s), 26.2% and 7.7% of patients had IOP greater than 25 mm Hg and 35 mm Hg, respectively. There was evidence (P < .001) of an association between preexisting glaucoma or glaucoma suspect status (103 eyes) and need for glaucoma surgery, and 4.62% (12 eyes) required glaucoma surgery.

CONCLUSIONS:

Secondary OHT induced by the dexamethasone implant can usually be controlled by medications, but the incidence of OHT requiring glaucoma surgery was high (4.62%) in our study relative to rates previously reported in the literature. All patients, especially those with preexisting glaucoma, should be advised of the possible need for glaucoma surgery prior to undergoing treatment with the dexamethasone implant.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:680–685.]

Introduction

The dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) has recently gained widespread appeal as a treatment option for various ocular conditions. Currently the device is approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of diabetic macular edema (DME), macular edema (ME) associated with retinal vein occlusion (RVO), and posterior noninfectious uveitis. One of its side effects is the risk of elevated intraocular pressure (IOP) (ocular hypertension), a feature common to corticosteroid use in the eye. If uncontrolled, ocular hypertension can lead to glaucomatous optic nerve damage and vision loss. As a result, it is clinically important to determine the likelihood of developing significant ocular hypertension when using treatments such as the dexamethasone intravitreal implant.

In the randomized clinical trials that were conducted prior to the dexamethasone intravitreal implant gaining approval for the indications described above, the incidence of significant ocular hypertension (OHT) was relatively low, with most patients being able to be managed with topical treatment. In the GENEVA study, in which one or two implants were administered during a 12-month period to eyes with RVO, no increase in the number of patients with elevated IOP was observed after a second injection was given, and very few patients required laser or surgical treatment for OHT.1 In the HURON study, a single implant was injected for the treatment of noninfectious posterior uveitis; during a 26-week period, less than a quarter of eyes required treatment with IOP-lowering drops, and no eyes required laser or incisional glaucoma surgery.2 The MEAD study evaluated the use of the dexamethasone implant no more frequently than every 6 months for the treatment of DME. In that study, 41.5% of patients treated with the 0.7 mg implant required topical IOP-lowering drops, and only one patient (0.3%) needed incisional glaucoma surgery to control IOP.3 These findings are reassuring regarding the risk of OHT and glaucoma with the dexamethasone implant.

However, in practice, the use of the dexamethasone intravitreal implant has differed from the clinical guidelines followed in the randomized trials, chiefly in that the implant has been administered more frequently and in greater sequential numbers of injections per patient than had been described in the trial protocols. As a result, some clinicians have anecdotally observed higher rates of OHT requiring treatment than had been observed in the randomized trials, including a greater need for incisional glaucoma surgery in some instances, whereas other investigators have not reported increased rates of glaucoma.4–8 This is of significance when considering the informed consent discussion that a clinician conducts with a patient upon commencing a treatment regimen that includes the dexamethasone intravitreal implant. We conducted this retrospective review of dexamethasone intravitreal implant use in patients with a variety of ocular conditions to determine the risk of developing OHT requiring treatment and, in particular, the need for glaucoma surgery in routine clinical practice with this therapeutic modality.

Patients and Methods

The charts of 260 eyes from 221 patients with DME, RVO, posterior noninfectious uveitis, and ME secondary to many causes (off-label, in some cases) treated with one or repeated dexamethasone implant at three clinical sites, one academic practice (University of California, San Francisco) and two private practices (Northern California Retina Vitreous Associates, Mountain View, CA, and Retina Health Center, Fort Myers, FL), were retrospectively reviewed. Human Research Protection Program approval was obtained for the study. Cases were included in the series if patients received any dexamethasone implant treatment between January 2009 and December 2015. Patients with follow-up of less than 3 months after the first implant were excluded, as were minors. Clinical data included the indication for treatment, the dates of all administrations of the dexamethasone intravitreal implant, baseline ocular findings, and clinical findings at all subsequent visits. Of particular relevance to the aims of this study, parameters related to IOP were collected, including IOP at all visits, pre-existing glaucoma or glaucoma-suspect conditions, the use of any IOP-lowering medication at each visit, and any other glaucoma-related interventions taken subsequent to dexamethasone implant injection. The main outcome measures of the study were the incidence of any IOP reading greater than 25 mm Hg, the incidence of any IOP reading greater than 35 mm Hg, a rise in IOP 10 mm Hg or more from baseline, and severe OHT needing glaucoma surgical intervention in the judgement of the treating physician (and not attributable to neovascular glaucoma). Statistical analyses were performed using Fisher's Exact Test and Wilcoxon ranked-sum test.

Results

Study Population

Patient characteristics at the time of the first dexamethasone intravitreal implant administration are listed in Table 1. The patients' mean age was 66.97 years ± 16.02 years. One hundred twenty-two eyes had RVO; 73 eyes had posterior noninfectious uveitis including intermediate uveitis, birdshot retinochoroiditis, multifocal choroiditis and panuveitis, serpiginous choroiditis, retinal vasculitis, and Vogt-Koyanagi-Harada syndrome; 52 eyes had DME; and 13 eyes had ME secondary to miscellaneous causes, including three with epiretinal membrane, one with choroidal neovascularization, and nine with idiopathic cystoid macular edema. One hundred three eyes had preexisting glaucoma or glaucoma-suspect status. The mean number of injections was three; the median was two injections (range: one to 23 injections). At the time of the first injection, the mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg. The mean follow-up time after the first injection was 15.4 months (range: 2.2 months to 74.2 months).

Patient Demographics and Indication for Treatment at the Time of Initial Dexamethasone Intravitreal Implant Administration

Table 1:

Patient Demographics and Indication for Treatment at the Time of Initial Dexamethasone Intravitreal Implant Administration

Incidence of OHT After Injection

An IOP measurement greater than 25 mm Hg at any visit following implantation occurred in 26.2% of eyes (68 of 260). By subgroup, it occurred in 26.2% (32 of 122), 24.7% (18 of 73), 25% (13 of 52), and 46.2% (six of 13) of eyes with diagnosis of RVO, uveitis, DME, and miscellaneous CME, respectively. IOP greater than 35 mm Hg occurred in 7.3% of patient eyes. This affected 9.8% (12 of 122), 1.4% (one of 73), 7.5% (four of 53), and 15.4% (two of 13) of the RVO group, uveitis group, DME group, and CME group, respectively.

Patients with a baseline IOP of 15 mm Hg or greater had a higher risk of developing secondary OHT defined as IOP greater than 25 mm Hg (P = .0415).

Risk of IOP Rise by Diagnosis

RVO and uveitis have previously been associated with glaucoma or glaucoma-suspect conditions. In our study, the RVO group was no more likely than other groups to develop an IOP rise of 10 mm Hg or more from baseline (P = .144), nor did they show an increased risk of developing IOP greater than 35 mm Hg (P = .158). Similarly, patients with uveitis did not show a statistically significantly increased risk of an IOP rise of 10 mm Hg or more from baseline (P = .656), but with one patient in this subgroup developing IOP greater than 35 mm Hg, the risk of this outcome reached statistical significance (P = .0179). No other subgroups showed an association with developing IOP greater than 35 mm Hg, IOP greater than 25 mm Hg, or a rise in IOP greater than or equal to 10 mm Hg from baseline (Table 2).

IOP Elevation Associated With Dexamethasone Intravitreal Implant for Varying Indications

Table 2:

IOP Elevation Associated With Dexamethasone Intravitreal Implant for Varying Indications

Role of Injection Frequency in the Development of OHT

Eyes that developed IOP greater than 25 mm Hg at any point during the follow-up period were more likely to have had a greater number of injections than those eyes that did not develop IOP greater than 25 mm Hg (P = .00273). Specifically, patients whose maximal IOP was 25 mm Hg or less had a mean of 2.6 injections, whereas those patients with IOP recorded at greater than 25 mm Hg had a mean of 4.06 injections. The subgroup of patients who received more than three injections within 1 year were more likely to develop IOP greater than 35 mm Hg than those who did not (P = .0227). On the other hand, in a proportional hazards model, we found no evidence that the hazard of a glaucoma outcome as defined by either requiring glaucoma surgery or experiencing an ocular hypertension event of IOP greater than 25 mm Hg or greater than 35 mm Hg depends on the number of injections a person has had (P > .05), possibly because of the confounding effect of changes in proactive IOP management throughout the treatment course and because of selection tendency in this group favoring patients deemed clinically suitable for repeated treatment, perhaps at least in part based on IOP response patterns following initial injections.

Use of IOP-Lowering Medication

Seventy-two of 260 eyes (27.7%) were newly prescribed IOP-lowering drops after dexamethasone intravitreal injection. In a regression evaluation of the IOP according to elapsed days since first injection of dexmethasone, we found that as the number of elapsed days increases, the IOP is lower by about 2 mm Hg per year (P< .001), perhaps because of various factors such as patient selection for those receiving repeated injections, favoring patients without IOP rise after early injections or those with more successful IOP management. This relationship holds true even when adjusting for the number of medications used by each patient at each visit (P < .001).

Timing of Increased IOP

Because of confounding factors such as intermittent use of topical IOP-lowering drops and physician and patient discretion in determining the timing of repeat dexamethasone administration, particularly taking IOP into account at a given visit, it was not possible to calculate with certainty a threshold level at which a given number of dexamethasone injections would likely lead to OHT. We also did not find a certain point or number of injections after which a patient was no longer at risk of developing ocular hypertension.

Severe OHT Requiring Incisional Glaucoma Surgery

Twelve eyes (4.62%) developed severe OHT requiring incisional glaucoma surgery; five of these eyes were in the RVO subgroup, and seven were in the uveitis subgroup. Two patients underwent selective laser trabeculoplasty and one had laser peripheral iridotomy before undergoing incisional surgery. A Kaplan-Meier curve demonstrates the time course to the development of a glaucoma/OHT event as defined by either the need for incisional surgery or occurrence of IOP greater than 25 mm Hg or greater than 35 mm Hg (Figure 1). We found evidence of an increased hazard of undergoing glaucoma surgery after dexamethasone implant injection in patients with preexisting glaucoma or glaucoma-suspect status (odds ratio: 20.6; 95% CI, 2.97–892; P < .001). In all, 103 of the 260 eyes in the study (39.6%) had a preexisting diagnosis of either glaucoma or glaucoma-suspect status.

Kaplan-Meier curve demonstrating time to occurrence of a first glaucoma / ocular hypertension event. Solid red line: time to either glaucoma surgery or an instance of intraocular pressure (IOP) greater than 25 mm Hg. Solid blue line: time to either glaucoma surgery or an instance of IOP greater than 35 mm Hg. Dashed lines: 95% confidence intervals.

Figure.

Kaplan-Meier curve demonstrating time to occurrence of a first glaucoma / ocular hypertension event. Solid red line: time to either glaucoma surgery or an instance of intraocular pressure (IOP) greater than 25 mm Hg. Solid blue line: time to either glaucoma surgery or an instance of IOP greater than 35 mm Hg. Dashed lines: 95% confidence intervals.

Discussion

In this study we found that the rate of OHT associated with routine clinical practice of the dexamethasone implant was higher than had been reported in the randomized clinical trials that led to FDA approval of the treatment for various indications. The key findings of the study were that 26% of eyes had any occurrence of IOP greater than 25 mm Hg, and 4.6% of eyes required incisional glaucoma surgery to control their pressure.

Several investigators have described retrospective studies of dexamethasone implant use outside of clinical trials supporting the association of this therapy with OHT. Our findings of an increased association in the setting of preexisting glaucoma or suspected glaucoma support those of Chin et al. and Mazarella et al. but demonstrate a more definitive link between baseline conditions and the ultimate risk of incisional surgery, given that 100% of patients in our study who needed incisional surgery had either glaucoma or glaucoma-suspect status at the time of initial treatment with the implant.9,10 This information can be highly useful for clinicians in advising prospective patients who are considering the dexamethasone implant as a treatment modality, since the possible risk of needing incisional surgery in the future is by far the most concerning implication of the decision to proceed with a therapy that involves intraocular corticosteroids.

It is helpful for clinicians to know whether particular indications for treatment with the dexamethasone intravitreal implant are more likely than others to result in OHT. Compared to the results of previous studies such as those reported by Malcles et al., which showed a statistically significant difference in incidence of OHT in patients with RVO and uveitis as compared to those with DME, we did not find a significantly increased risk of IOP elevation in patients with RVO (although there was a trend); however, we did see an increased risk of OHT in implanted patients with uveitis (with seven requiring incisional surgery and one developing IOP greater than 35 mm Hg). This variance could be accounted for by the higher proportion of uveitic patients in our study population (28% percent as compared to 17% percent in SAFODEX).11 Overall, this IOP elevation seen in the uveitic subgroup of our study is in line with prior studies. In a clinical trial of dexamethasone implant treatment for patients with uveitis by Lowder et al. (HURON trial), 23% of the subjects required IOP-lowering medications, versus 27% (20 of 73) of the uveitic subjects in our study.2 This difference is relative to the fact that the mean number of dexamethasone implants patients received in our study was three versus one implant given in HURON. Thus, patients with uveitis may have an increased risk of developing post-dexamethasone implant OHT, and it is possible that multiple treatments could increase this risk, contributing to the slightly higher rate of OHT in uveitics seen in our study.

Our results showed a greater incidence of eyes requiring incisional glaucoma surgery post-implant compared to previous retrospective studies, which reported rates of glaucoma surgery ranging from 0% to 3.2% versus the nearly 5% of eyes we observed in our study.3,10,11–13 This result is likely related to the higher incidence of eyes classified as preexisting glaucoma or suspected glaucoma status in our study (39.6%), as our data, consistent with previous studies, demonstrated a significantly increased risk of post-dexamethasone treatment glaucoma surgery in this subgroup.

The results also showed that the incidence of OHT and glaucoma increased with the number of treatments received. Glaucoma surgery was required throughout patients' treatment regimens and occurred after anywhere from one to 10 injections. This suggests that it is important to monitor patients receiving ongoing therapy for OHT and not assume that because they did not have a pressure elevation after their first few injections that they are not likely to develop one in the future.

Several studies, including our own, noted that OHT associated with dexamethasone implantation is clinically managed with IOP-lowering drops, and these drops are often effective at mitigating the IOP increases. Though the prescription of new IOP-lowering drops is a confounding variable within our study, this variable would trend the data toward less of an association between OHT and dexamethasone administration. Another potential confounder toward the null is that physicians could be less likely to proceed with additional dexamethasone implants in a patient with poorly controlled OHT, despite the potential for this treatment having clinical benefit otherwise.

An advantage of our study is that, because we collected data from real-world use of this drug in a clinical setting, we were able to analyze the potential effects of dexamethasone as it is administered during a relatively long follow-up period (average: 15.4 months ± 12.8 months). Due to the inconsistent intervals between follow-up appointments because of the retrospective nature of this study, a limitation is that IOP spikes during the follow-up period could have been missed. It has become clear from clinical practice and this study that these implants are often given much more frequently and within shorter interval time periods than the initial clinical trials in which the dexamethasone intravitreal implant was tested. This study supports the theory that higher frequency of injections is associated with an increased risk of ocular hypertension (IOP > 25 mm Hg). Because OHT can be of serious consequence, this finding, along with that of the potential for increased risk of glaucoma surgery, should be discussed in conversations with patients prior to obtaining clinical consent to receive the dexamethasone intravitreal implant.

References

  1. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12):2453–2460. doi:10.1016/j.ophtha.2011.05.014 [CrossRef]
  2. Lowder C, Belfort R Jr., Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129(5):545–553. doi:10.1001/archophthalmol.2010.339 [CrossRef]
  3. Maturi RK, Pollack A, Uy HS, et al. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year MEAD study. Retina. 2016;36(6):1143–1152. doi:10.1097/IAE.0000000000001004 [CrossRef]
  4. Matonti F, Pommier S, Meyer F, et al. Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur J Ophthalmol. 2016;26(5):454–459. doi:10.5301/ejo.5000787 [CrossRef]
  5. Meyer LM, Schonfeld CL. Secondary glaucoma after intravitreal dexamethasone 0.7 mg implant in patients with retinal vein occlusion: A one-year follow-up. J Ocul Pharmacol Ther. 2013;29(6):560–565. doi:10.1089/jop.2012.0253 [CrossRef]
  6. Jimenez-Gomez B, Gonzalez-Montpetit M, Fonollosa Calduch A, Orive Banuelos A, Valsero Franco S. [Effects of ozurdex on intraocular pressure. A real life clinical practice study]. Arch Soc Esp Oftalmol. 2015;90(9):421–425.
  7. Guigou S, Hajjar C, Parrat E, et al. . [Multicenter Ozurdex(R) assessment for diabetic macular edema: MOZART study]. J Fr Ophtalmol. 2014;37(6):480–485. doi:10.1016/j.jfo.2014.03.001 [CrossRef]
  8. Schmitz K, Maier M, Clemens CR, et al. [Reliability and safety of intravitreal Ozurdex injections. The ZERO study]. Ophthalmologe. 2014;111(1):44–52. doi:10.1007/s00347-012-2737-2 [CrossRef]
  9. Mazzarella S, Mateo C, Freixes S, et al. Effect of intravitreal injection of dexamethasone 0.7 mg (Ozurdex(R)) on intraocular pressure in patients with macular edema. Ophthalmic Res. 2015;54(3):143–149. doi:10.1159/000438759 [CrossRef]
  10. Chin EK, Almeida DRP, Velez G, et al. Ocular hypertension after intravitreal dexamethasone (Ozurdex) sustained-release implant. Retina. 2017;37(7):1345–1351. doi:10.1097/IAE.0000000000001364 [CrossRef]
  11. Malcles A, Dot C, Voirin N, et al. Safety of intravitreal dexamethasone implant (Ozurdex): The SAFODEX study. Incidence and risk factors of ocular hypertension. Retina. 2017;37(7):1352–1359. doi:10.1097/IAE.0000000000001369 [CrossRef]
  12. Dugel PU, Capone A Jr, Singer MA, et al. Two or more dexamethasone intravitreal implants in treatment-naive patients with macular edema due to retinal vein occlusion: Subgroup analysis of a retrospective chart review study. BMC Ophthalmol. 2015;15:118. doi:10.1186/s12886-015-0106-z [CrossRef]
  13. Lam WC, Albiani DA, Yoganathan P, et al. Real-world assessment of intravitreal dexamethasone implant (0.7 mg) in patients with macular edema: The CHROME study. Clin Ophthalmol. 2015;9:1255–1268.

Patient Demographics and Indication for Treatment at the Time of Initial Dexamethasone Intravitreal Implant Administration

n (%)
Number of Patients221
Age in Years, Mean (Range)68.04 (22–94)
Female Gender107 (48.42)
Number of Eyes260
Indication for DEX Treatment by Eye
  RVO122 (46.92)
  Uveitis73 (28.08)
  DME52 (20)
  Other Causes of ME13 (5)

IOP Elevation Associated With Dexamethasone Intravitreal Implant for Varying Indications

SubgroupTotalAssociation With IOP > 35 mm Hg?P ValueOR; 95% CIAssociation with IOP > 25 mm Hg?P ValueOR; 95% CIAssociation With IOP Increase > 10 mm Hg From baseline?P ValueOR; 95% CI
RVO122No.1582.04; 0.71–6.33No.8911.06; 0.60–1.88No.1441.48; 0.85–2.60
Uveitis73Yes.0187.63; 0.0031–0.86No.6481.21; 0.42–1.57No.6561.20; 0.44–1.56
DME52No11.14; 0.21–2.84No.6081.27; 0.36–1.63No.0950.52; 0.23–1.12
Misc. CME13No.2440.41; 0.24–12.67No.0570.33; 0.85–11.43No.3570.52; 0.52–6.93
Authors

From University of California, San Francisco, Department of Ophthalmology, San Francisco (KH, JDK, TCP, JMS); University of California, San Francisco, Francis I. Proctor Foundation, San Francisco (TCP); Retina Health Center, Fort Meyers, FL (AME); and Northern California Retina Vitreous Associates, Mountain View, CA (RNK).

Presented at the annual meeting of the Association for Research in Vision and Ophthalmology in Seattle, WA, in 2016 and at the annual meeting of the American Academy of Ophthalmology in Chicago, IL, in 2016.

This study received support from That Man May See and Research to Prevent Blindness. The supporting sources had no role in the design or conduct of the study.

Dr. Eaton is a stockholder for Alimera outside the submitted work. Dr. Khurana has received grant money from and is a consultant for Allergan and Santen; has received grant money from and is a consultant and on the speakers bureau for Genentech and Regeneron; and has received grant money from Clearside Biomedical outside the submitted work. Dr. Stewart is a consultant for Genentech, Merck, and Achaogen outside the submitted work. The remaining authors report no relevant financial disclosures.

Address correspondence to Jay M. Stewart, MD, University of California, San Francisco, Department of Ophthalmology, 10 Koret Way, K301, San Francisco, CA 94143-0730; email: jay.stewart@ucsf.edu.

Received: December 04, 2017
Accepted: August 03, 2018

10.3928/23258160-20180831-05

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