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Retreatment with Ozurdex for macular edema secondary to retinal vein occlusion

Abstract

Purpose

To review the current practice of retreatment with Ozurdex injections in patients with macular edema (ME) secondary to retinal vein occlusion (RVO), and to recommend simple guidelines for Ozurdex reinjection in management of RVO.

Methods

This was a multicenter retrospective study of patients who received more than 2 Ozurdex injections for the treatment of ME in RVO. Recorded parameters included percent of patients with a 15-letter gain, visual acuity (VA) improvement from baseline, change in central macular thickness (CMT), time to reinjection, and occurrence of any complications.

Results

A total of 128 patients were included, 58 (45.3%) with central RVO (CRVO) and 70 (54.7%) with branch RVO (BRVO). Mean interval for Ozurdex reinjection was 5.9 months following the first injection and 8.7 months following the second. A >15-letter gain in VA was observed in 34 (48.8%) patients with CRVO and 16 (28%) patients with BRVO. Mean overall VA improvement at month 6 did not show significance (p>0.05); however, a significantly better mean VA improvement was seen in treatment-naïve eyes (p<0.03). The CMT was significantly reduced compared to baseline. The mean CMT decreased by 214.6 µm in eyes with BRVO (n = 53) and by 355.1 µm in eyes with CRVO (n = 63) (p = 0.002). Complication rates were very low.

Conclusions

Repeated injections of Ozurdex are effective and have a favorable safety profile. In current practice, the retreatment interval with Ozurdex injections might be too long, precluding the full therapeutic potential of this treatment modality. A strategy for managing RVO patients treated with Ozurdex on an as-needed basis is provided.

Eur J Ophthalmol 2014; 24(1): 1 - 9

Article Type: ORIGINAL RESEARCH ARTICLE

Article Subject: Retina MED

DOI:10.5301/ejo.5000376

Authors

Gabriel Coscas, Albert Augustin, Francesco Bandello, Marc D. de Smet, Paolo Lanzetta, Giovanni Staurenghi, Maria Cristina Parravano, Patricia Udaondo, Elad Moisseiev, Gisele Soubrane, Yossi Yatziv, Anat Loewenstein

Article History

Disclosures

Financial Support: No financial support was received for this submission.
Conflict of Interest Statement: None of the authors has conflict of interest with this submission.

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INTRODUCTION

Retinal vein occlusion (RVO) is a sight-threatening retinal vascular disorder associated with macular edema (ME) and neovascularization (1-2-3-4-5-6). The overall goal of RVO management is improvement of patients’ vision, which translates into improved quality of life. This is achieved by identifying modifiable risk factors and means of managing them, and by recognizing and managing sight-threatening complications. Close monitoring and early intervention has been shown to effectively reduce retinal complications and the rate of vision loss (3, 4, 6).

Until recently, the standard of care for branch RVO (BRVO)–associated ME was grid laser photocoagulation, and observation was suggested for central retinal vein occlusion (CRVO)–associated ME. Central RVO with neovascularization was treated with scatter laser photocoagulation (3-4-5-6).

Over the past decade, advances in retinal imaging technology and drug development have radically changed the standard of care (7-8-9-10-11-12-13-14-15-16). Two classes of drugs have emerged as alternative treatments for ME in RVO: corticosteroids and anti–vascular endothelial growth factor (VEGF) agents. Superiority of these treatments over the previous standard of care has been demonstrated in a number of randomized, controlled multicenter studies. Intravitreal injection of triamcinolone acetate was the first treatment shown to improve the visual prognosis in ME secondary to CRVO, and observation of these patients in no longer an acceptable option. It was also found to be approximately equal to laser treatment in ME secondary to BRVO (11, 12).

In 2009, a sustained-release intravitreal 0.7 mg dexamethasone delivery system, Ozurdex® (Allergan Inc., Irvine, California, USA), was approved for the treatment of ME secondary to RVO (9, 10). Ozurdex, which contains the corticosteroid dexamethasone, has demonstrated efficacy and safety for the treatment of BRVO and CRVO when delivered to the vitreous cavity by a sustained-release intravitreal implant (DEX implant; Ozurdex, Allergan, Inc.).

A single intravitreal treatment of 0.7 mg DEX implant was shown to produce improvements in visual acuity (VA) already at 30 days post-treatment, which persisted over 90 days, and in many eyes for as long as 6 months; good tolerance was also observed for a 12-month period, with significantly less adverse effects compared to triamcinolone (9, 10).

Studies of anti-VEGF agents for management of RVO have specifically used ranibizumab (Lucentis, Genentech Inc., South San Francisco, California, USA), which has been demonstrated to be a safe and effective therapy for ME associated with both BRVO and CRVO (14-15-16-17), and was subsequently approved for use in RVO in 2012 in Europe. Efficacy of bevacizumab (Avastin, Genentech Inc.) in the treatment of ME in RVO was also reported in several uncontrolled studies (18-19-20), but this anti-VEGF agent is currently not licensed for use in any ophthalmologic indications. Also, recent studies have shown positive results for aflibercept (VEGF Trap-Eye, Eylea, Regeneron, New York, USA) for the treatment of CRVO (21).

In light of the wide variety of treatment options available for the treatment of RVO associated with ME, the standard of care that was used until a few years ago is no longer valid. The new therapeutics have all been compared to the now obsolete standard of care that included laser treatment in BRVO patients with ME and observation alone in CRVO patients with ME.

However, direct comparisons between the new drugs are not yet available, and controversy exists regarding the current optimal long-term treatment scheme for ME in RVO. A guideline for first-line therapy of RVO has been proposed in a consensus paper published in 2011 (8) but did not address retreatment.

Today, studies and experience from clinical practice have shown that both corticosteroids and anti-VEGF agents usually require long-term repeated treatments in order to control the ME, prevent vision loss, and increase the chance of visual improvement.

Criteria for the retreatment of ME in RVO have yet to be defined, and there are currently no established protocols for long-term management of these patients.

Ozurdex is a promising treatment option for ME in RVO. Being a slow-release implant, its pharmacokinetics enable high concentrations of dexamethasone to be sustained in the retina and vitreous during the first 2-3 months after Ozurdex injection, and lower concentrations are sustained up to 6 months (22). Therefore, long-term therapy with Ozurdex will require significantly fewer injections compared with anti-VEGF agents, which need to be administered as frequently as once a month for an optimal VA outcome (14-15-16-17).

Existing Ozurdex studies have not directly addressed the question of the optimum retreatment interval for the Ozurdex® implant 0.7 mg or safety after long-term repeated injections. The time course and magnitude of the response to Ozurdex treatment suggests that some eyes are undertreated and that physicians may want to evaluate their patients for retreatment earlier (before 180 days) than the current pivotal studies indicate. Today, in clinical practice, many patients are being treated before month 6, at their physician’s discretion.

The purpose of this study was to demonstrate real-life data on repeated use of Ozurdex in patients with RVO, i.e., 2 or more injections during at least 1 year of follow-up, and evaluate its efficacy and safety. In addition, we suggest a simple algorithm for its repeated use. Efficacy outcomes were BCVA and central macular thickness (CMT), and safety outcomes were intraocular pressure (IOP) and cataract development.

METHODS

Patient selection

Patient data were collected from 9 participating retina clinics all over Europe. The study was approved by the institutional review boards of all institutions. Included patients had received at least 2 Ozurdex injections for the treatment of ME secondary to RVO between August 1, 2010, and July 31, 2012. All patients had at least 6 months of follow-up after the last injection. A minimal VA of 20/200 at baseline was required for inclusion in the study.

Eyes with documentation of severe macular ischemia on fluorescein angiography were excluded. Patients with additional ophthalmic comorbidity, which could have had a considerable influence on VA, were excluded from this analysis. Specifically, patients with any history of advanced age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), advanced glaucoma, optic neuropathy, or corneal opacity were not included. Also, patients with previous ocular trauma or vitrectomy were excluded. Patients who participated in other therapeutic studies during the time period of this study were also excluded.

Data collection

Data were retrieved by retrospective review of the patients’ medical charts. Collected parameters included demographic information, previous ocular history, type of RVO, number and dates of Ozurdex injections, additional treatments for RVO-associated ME (before and after Ozurdex administration), VA and IOP throughout the study period, and the occurrence of any complications. Data regarding CMT and presence of intraretinal fluid from OCT scans were also included when available.

Outcome measures

Primary outcome measures were VA improvement from baseline, the percentage of patients with a 15-letter gain, and change in CMT following at least 2 Ozurdex injections.

Secondary outcome measures included IOP measured 5-7 months after the last injection, the time to reinjection, and the incidence of any adverse effects following repeated injections. Recorded adverse events included IOP elevation, cataract progression, retinal detachment (RD), vitreous hemorrhage (VH), and endophthalmitis.

Statistical analysis

For statistical analysis, all visual acuity values were converted to the logMAR scale. According to Holladay (23) and the University of Freiburg study group results (24), blindness was set at 0.00125/2.9 (decimal/logMAR), light perception al 0.0025/2.6, hand movements at 0.005/2.3, and counting fingers at 0.014/1.85.

t Test was used to compare continuous variables between groups. Chi-square test was used to analyze associations between categorical parameters. A p value of 0.05 was used to declare statistically significant difference between groups for all analyses. Data were analyzed using SPSS for Windows version 15 (SPSS Inc., Chicago, Illinois, USA).

RESULTS

Included in the study were 128 eyes of 128 patients who fulfilled the inclusion criteria. Of the 128 eyes, 58 (45.3%) had ME secondary to BRVO and 70 (54.7%) had ME secondary to CRVO. Patients included 75 (58.6%) men and 53 (41.4%) women, with a mean age of 65.8 ± 12.9 years (range 27-101 years). The duration of ME was under 6 months in 62 (48.4%) patients. Previous treatment had been administered for 68 (53.1%) eyes. These included 39 (30.2%) eyes that were previously treated with anti-VEGF injections, 9 (7%) eyes with laser treatment, 8 (6.2%) eyes with both anti-VEGF and laser, and 10 (7.8%) eyes with other steroid treatment (Fig. 1).

Distribution of previous treatments for macular edema administered to the patients in this study. VEGF = vascular endothelial growth factor.

Effect of repeated injections on visual acuity

At baseline, mean VA of all patients was 0.42 ± 0.32. An improvement of 15 letters or more after the first 2 injections of Ozurdex was achieved in 50 (39%) patients. These included 34 (48.8%) patients with CRVO and 16 (28%) patients with BRVO. A loss of 15 letters or more was observed in 13 (10%) patients, which included 8 (12.2%) of the patients with CRVO and 5 (8%) of those with BRVO (Fig. 2).

Patients who gained or lost >15 letters in visual acuity following 2 Ozurdex injections. BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion.

Mean final VA, measured at the last follow-up visit between 5 and 7 months after the last injection, was 0.48 ± 0.38, with no significant difference (p = 0.13). In patients with BRVO, mean baseline VA was 0.44 ± 0.27 and final VA was 0.48 ± 0.27. In patients with CRVO, mean baseline VA was 0.41 ± 0.36 and final VA was 0.489 ± 0.46. The differences were not statistically significant (p = 0.24 and p = 0.14, respectively).

Repeated Ozurdex injections achieved a better mean final VA improvement in treatment-naive eyes when compared to eyes that were previously treated for ME. A trend towards better final VA in these eyes was noted (p = 0.06) (Tab. I). Although this parameter did not reach statistical significance, the change in VA compared to baseline was significantly greater in treatment-naive eyes (p = 0.03).

COMPARISON OF VISUAL ACUITY BETWEEN TREATMENT-NAIVE AND PREVIOUSLY TREATED EYES AT 5-7 MONTHS AFTER LAST INJECTION

Parameter Treatment-naive eyes Previously treated eyes p Value
VA = visual acuity.
Final VA 0.38 ± 0.28 0.54 ± 0.35 0.06
VA change 0.26 ± 0.36 0.04 ± 0.26 0.03

Effect of repeated injections on retinal thickness

Following repeated Ozurdex injections, CMT continued to decline significantly after the second injection, showing a positive response to retreatment.

At the final follow-up, for CRVO patients with a baseline CMT of 629.4 ± 191.2 µm, the mean change in CMT was −355.1 μm. For BRVO patients with a baseline CMT of 507.5 ± 158.0 µm, the mean change in CMT was −214.6 μm (p<0.002) (Fig. 3). These data represent a mean reduction of 56.4% and 42.3% in CMT for patients with CRVO and BRVO, respectively (p<0.002 for both).

Baseline and final central macular thickness (CMT) values of patients with central retinal vein occlusion branch (CRVO) and branch retinal vein occlusion branch (BRVO). A significant reduction was noted in both groups (p<0.002).

No significant difference in CMT reduction was noted between treatment-naive eyes and those that had undergone previous treatments.

Timing of reinjection

The mean time between the first and second Ozurdex injections was 175.7 days (approximately 5.9 months, range 3-23 months), and between the second and third injections, 261.7 days (approximately 8.7 months, range 3-16 months) (Fig. 4). The interval between the first and second Ozurdex injections was under 5 months in 71 (55.4%) patients, and 7 months or longer in 25 (19.5%) patients.

Mean intervals (in months) between the first and second Ozurdex injections and between the second and third Ozurdex injections.

Safety of repeated injections

No safety issues were observed following more than 2 injections of Ozurdex. The IOP increases were transient and easily handled with medications. Intraocular pressure increases of >10 mm Hg or >25 mm Hg were seen in 9 (7%) patients, and 21 patients (16.4%) required medical treatment during the study period. Cataract progression occurred in 3.9% of patients. No cases of RD, VH, or endophthalmitis were encountered in any of these patients.

DISCUSSION

The GENEVA study has demonstrated the safety of retreatment with Ozurdex for both BRVO and CRVO. Following 2 DEX implants, the incidence of adverse events was similar to that of those who received a single DEX implant, except for a greater number of patients with cataract progression, 29.8% compared to 10.5%, and IOP elevation of more than 10 mm Hg, 15.4% compared to 12.6% (9, 10). Cataract extraction was performed in only 1.3% of the patients who received 2 DEX implants; IOP increases were usually transient and controlled with medication or observation. Acute treatment-related serious adverse events, including VH, endophthalmitis, and RD, were extremely rare following both initial and second injections (9, 10).

Regarding efficacy, the beneficial effects of treatment on VA and macular thickening were similar after the first and second injections of DEX implants. However, the decline in benefit observed in some eyes before the 6-month assessment led the investigators to conclude that some eyes were undertreated and that evaluation for retreatment should occur earlier than 6 months (10).

A number of small, single-center retrospective series have recently documented the efficacy and safety of repeated treatments with Ozurdex on an as-needed basis (25-26-27-28-29-30). Improvements in VA measured at the time of peaking efficacy following the second implant were similar to those following the first implant, with no increase in serious adverse effects (25-26-27-28-29-30). It has also been shown that 1 or 2 injections of Ozurdex are not associated with any complications in the long term, and may have a beneficial effect on long-term visual prognosis (31).

Our study was designed to evaluate the results of current practice with repeated Ozurdex injections and analyze the long-term outcome of efficacy and safety after at least 2 or more injections. Based on these study results, evaluating patient data from clinical practice, Ozurdex is shown to be both effective and well-tolerated after multiple re-treatments.

A marked improvement of 15 letters or more was recorded after the first 2 injections of Ozurdex in 39% of patients. These included 34 (48.8%) patients with CRVO and 16 (28%) patients with BRVO. Mean initial VA was not significantly different between CRVO and BRVO patients, and a higher rate of VA improvement of 15 letters or more in CRVO patients repeatedly treated with Ozurdex has also been reported in another study (29).

Another finding of our study is that Ozurdex retreatment achieved a greater improvement in VA in treatment-naive eyes 5-7 months after last injection, compared to previously treated eyes (Tab. I), in which the overall improvement of VA at this time was not significant. This is not surprising, since previously treated eyes have had a longer duration and more aggressive disease. It also indicates that Ozurdex retreatment may be an effective first-line treatment regimen for eyes with ME secondary to RVO, and strengthens the need for establishing an optimal protocol for repeated injections.

Interestingly, the time to retreatment was approximately 5.5 months, which is a longer treatment interval than reported in previous studies, which ranged from 3.2 to 5.5 months (25-26-27-28-29-30). As mentioned, it has previously been suggested that the optimal interval for repeated Ozurdex injection can be less than 6 months. Our results of VA gain in general population of patients with ME due to RVO at 5-7 months after the last injection support this notion, as the long intervals achieved no significant change in mean VA at this time. The collected data in this retrospective multicenter study demonstrate that the absence of standardized criteria for retreatment with Ozurdex has a significant impact on the timing of the repeated injections, which is highly variable.

Following repeated Ozurdex injections, CMT showed a good response to treatment and continued to decline significantly after the second Ozurdex injection.

Overall, CMT was significantly reduced from a baseline mean of 568.45 ± 186.4 µm to 284.85 ± 174.6 µm, which represents a mean reduction of 50.1% (p<0.002), a clinically significant reduction of retinal thickness well within what has been shown in previous studies.

Our study also demonstrated that long-term treatment with multiple injections of Ozurdex is safe and well-tolerated. Complication rates were comparable with previously published data on Ozurdex retreatment (10, 25, 29). The positive safety profile observed in this study, with more than 2 injections of Ozurdex and a mean follow-up of over 6 months following last injection, suggests that retreatment is not associated with an increase in any adverse effects. The common side effects, mainly cataract progression and a transient increase in IOP, were not a major problem during the follow-up in our study. This has also been demonstrated in long-term follow-up in patients who were treated with Ozurdex for RVO (31).

These side effects should not cause a barrier to repeated Ozurdex use in RVO patients. The IOP elevation is usually mild and transient, easy to manage, and has not been shown to cause significant glaucomatous optic nerve damage or visual field loss. No surgery for uncontrolled IOP was needed.

Cataract progression was documented in 3.9% of patients, which is lower than reported in other studies. In the GENEVA study, cataract progression was demonstrated in approximately 30% of patients after 1 year with 2 Ozurdex injections, but cataract extraction was needed in only 1.3% of eyes (10). Although cataract progression may adversely affect VA, it should be noted that cataract extraction is a simple and safe procedure.

Macular edema in RVO is a condition that persists for a considerable time, and its treatment is also prolonged. Close monitoring for a long time is required in these patients, and as-needed in regimens enable tailoring of treatment to individual patients. In the continuing efforts to improve vision and quality of life, cataract progression and eventual extraction should be considered part of the treatment process in phakic patients, much like is commonly the case in patients who undergo vitrectomy for any indication.

Studies have yet to compare the long-term effectiveness and safety of repeated corticosteroid and anti-VEGF regimens for treatment of RVO. In patients with CRVO, monthly dosages during a second year of treatment with intravitreal ranibizumab were associated with sustained VA, as well as regained VA in patients who were on a quarterly regimen during the previous year, with no serious adverse events (32).

In another trial of patients with CRVO, improvements in VA and CMT were sustained for up to 2 years, during which time intravitreal ranibizumab was administered according to signs of macular edema, averaging 6.6 injections during the second year (33). However, rescue treatment was allowed in the treated arm, which might reflect the treatment outcome. In a second year extension of the BRAVO and CRUISE trials, patients were examined at least once in 3 months and were administered intraocular injections of ranibizumab on an as-needed basis. The resultant reductions in examinations and treatments, compared to the first year, were associated with a decline in vision in CRVO eyes, yet stable vision in BRVO eyes (34). In these studies, response to treatment varied considerably among patients with RVO. It appears that after the first year with monthly injections, one anti-VEGF injection every 3 months may be adequate to treat many patients with BRVO, but most patients with CRVO seem to require more frequent monitoring and treatment.

The continuous release of medication by the DEX implant maintains a consistent level of drug within the eye, precluding the need for multiple repeated injections of other medications. This is a significant advantage of Ozurdex over anti-VEGF agents, since as-needed treatment with Ozurdex would result in 2 or 3 injections per year, much less than that required with anti-VEGF injections (32-33-34).

Our study includes the largest series of patients treated with at least 2 Ozurdex injections. The information provided reflects the current practice patterns of retreatment with Ozurdex injections in Europe. It seems that repeated Ozurdex injection is a valid treatment option of ME in RVO, accepted by both clinicians and patients. However, indications and protocols for reinjections have not been clarified and marked variation exists in the timing of repeated injections. Although it is generally accepted that due to its pharmacokinetic and clinical profiles, Ozurdex should be reinjected within less than 6 months after the previous injection, our results indicate that in many cases it is reinjected after 6 months or more. The retreatment intervals in current practice may be too long, and a shorter treatment interval may allow Ozurdex to reach its full potential efficacy after multiple injections. As a general rule, the decision to retreat, with any drug, should be based on both functional (VA) and morphologic (OCT) criteria. As such, retreatment should be considered when VA deteriorates or if persistent ME is documented by OCT (and fluorescein angiography in case of doubt).

Therefore, we have established the following recommendations for the treatment of ME in RVO with Ozurdex. The suggested retreatment algorithm is based on the joint clinical experience of the authors, as well as on data from this and other recent studies on this issue. After baseline VA, complete examination, and imaging have been performed, an Ozurdex injection is administered. In patients with BRVO, but not CRVO, laser treatment can be considered in combination with the injections, at the physician’s discretion.

Following an Ozurdex injection, IOP should be monitored between 4 to 8 weeks, and this monitoring can be done by the local physician or a nurse at the closest clinic. If an IOP rise >10 mm Hg or ≤30 mm Hg occurs, treatment should be initiated with IOP-lowering agents and the patient followed monthly until IOP returns to normal. If a patient experiences blurred vision or pain, he or she should contact the clinic immediately.

A complete examination including VA and OCT imaging should be performed 3 months after an Ozurdex injection. According to the findings in the examination, a repeated Ozurdex injection should be performed if ME is still present or if VA has decreased. With this strategy (Fig. 5), repeated injection can be administered from 3 to 6 months (or more), according to the patient’s individual clinical course.

Ozurdex retreatment strategy. IOP = intraocular pressure; ME = macular edema; VA = visual acuity.

If there is ME and VA has improved 6 months after the injection, monitoring should be continued without reinjection. This protocol may allow for adequate monitoring of such patients, early recognition of sight-threatening complications, and timely reinjections tailored to each patient’s needs. If ME is present even without VA decrease, reinjection may be considered in order to achieve greater VA improvement.

Based on available data from this and other studies (25-26-27-28-29), reinjections generally will be performed after 4 to 5 months, with a mean of approximately 2-3 injections per year. We recommend applying this suggested protocol until large-scale, randomized, controlled trials addressing this issue are conducted.

Disclosures

Financial Support: No financial support was received for this submission.
Conflict of Interest Statement: None of the authors has conflict of interest with this submission.
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Authors

Affiliations

  • Centre Hospitalier Intercommunal de Créteil - France
  • Augenklinik, Städtisches Klinikum Karlsruhe - Germany
  • Eye Clinic, University Vita-Salute, Scientific Institute San Rafaele, Milan - Italy
  • Retina and Inflammation Unit, Clinique De Montchoisi, Lausanne - Switzerland
  • Department of Ophthalmology, University of Udine, and Istituto Europeo di Microchirurgia Oculare–IEMO, Udine - Italy
  • Department of Biomedical and Clinical Science “Luigi Sacco,” Sacco Hospital, University of Milan, Milan - Italy
  • Fondazione G.B. Bietti–IRCCS, Rome - Italy
  • Department of Ophthalmology, Nuevo Hospital Universitario y Politecnico La Fe, Valencia - Spain
  • Department of Ophthalmology, Tel Aviv Medical Centre, and the Sackler School of Medicine, Tel Aviv University - Israel
  • Department of Ophthalmology, Hotel Dieu, University Paris Centre, Paris - France

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