Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema Due to Retinal Vein Occlusion

doi:10.1016/j.ophtha.2010.03.032

Ophthalmology

Volume 117, Issue 6, June 2010, Pages 1134-1146.e3

A preliminary report of this study was presented at: Retina Congress 2009, September 30 to October 4, 2009, New York.

https://doi.org/10.1016/j.ophtha.2010.03.032 Get rights and content

Objective

To evaluate the safety and efficacy of dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc., Irvine, CA) compared with sham in eyes with vision loss due to macular edema (ME) associated with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

Design

Two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials (each of which included patients with BRVO and patients with CRVO).

Participants

A total of 1267 patients with vision loss due to ME associated with BRVO or CRVO.

Intervention

A single treatment with DEX implant 0.7 mg (n = 427), DEX implant 0.35 mg (n = 414), or sham (n = 426).

Main Outcome Measures

The primary outcome measure for the pooled data from the 2 studies was time to achieve a ≥15-letter improvement in best-corrected visual acuity (BCVA). Secondary end points included BCVA, central retinal thickness, and safety.

Results

After a single administration, the time to achieve a ≥15-letter improvement in BCVA was significantly less in both DEX implant groups compared with sham (P<0.001). The percentage of eyes with a ≥15-letter improvement in BCVA was significantly higher in both DEX implant groups compared with sham at days 30 to 90 (P<0.001). The percentage of eyes with a ≥15-letter loss in BCVA was significantly lower in the DEX implant 0.7-mg group compared with sham at all follow-up visits (P≤0.036). Improvement in mean BCVA was greater in both DEX implant groups compared with sham at all follow-up visits (P≤0.006). Improvements in BCVA with DEX implant were seen in patients with BRVO and patients with CRVO, although the patterns of response differed. The percentage of DEX implant-treated eyes with intraocular pressure (IOP) of ≥25 mmHg peaked at 16% at day 60 (both doses) and was not different from sham by day 180. There was no significant between-group difference in the occurrence of cataract or cataract surgery.

Conclusions

Dexamethasone intravitreal implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with ME secondary to BRVO or CRVO and may be a useful therapeutic option for eyes with these conditions.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Design

Two randomized, prospective, multicenter, masked, sham-controlled, parallel-group clinical trials were conducted in compliance with regulatory obligations, the Declaration of Helsinki, and the institutional review board and informed consent regulations at each investigational site. These trials are registered at clinicaltrials.gov as NCT00168324 and NCT00168298. Two separate phase III clinical trials (each of which included patients with BRVO and patients with CRVO) were conducted for

Results

Patients were recruited into this study between November 2004 and March 2008. A total of 1267 patients (DEX implant 0.7 mg: n = 427; DEX implant 0.35 mg: n = 414; sham: n = 426) were enrolled, and the majority of patients (1196/1267; 94%) completed day 180 (Fig 1). There was no statistically significant between-group difference with regard to the number of patients who completed or withdrew from the study before day 180. Fifteen of 1267 patients (1.2%) withdrew from the study because of ocular

Discussion

A single treatment with DEX implant 0.7 or 0.35 mg produced significantly greater improvements in visual acuity than did a sham procedure in eyes with vision loss due to ME associated with BRVO or CRVO. This was evident in the results for several efficacy measures, including the time to achieve a 15-letter improvement from baseline BCVA (primary outcome measure for the 2 pooled studies), the proportion of eyes achieving at least a 15-letter improvement, the proportion of eyes with BCVA

Acknowledgments

The writing assistance and manuscript preparation services of Amy Lindsay, PhD (Lindsay Biomedical Communications, Inc.), were retained by Allergan, Inc., for the writing committee. Dr. Lindsay, who did not meet authorship criteria, attended all meetings and conference calls of the writing committee; collated committee drafts, comments, and references; compiled an outline for discussion and review; drafted a first manuscript iteration on the basis of committee discussion and reworking of the

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Cited by (882)

Real-world effectiveness of intravitreal dexamethasone implants - Comparison between eyes eligible and ineligible for clinical trials and their associated outcomes
2024, Biomedical Journal
Concerns about the generalizability of pivotal randomized controlled trials (pRCTs) findings have been raised. We aimed to compare intravitreal dexamethasone implants’ (IDIs) effectiveness for diabetic macular edema (DME) and central retinal vein occlusion (CRVO), between eyes eligible and ineligible for pRCTs.
This retrospective cohort study analyzed Taiwan's Chang Gung Research Database, including DME or CRVO eyes initiating IDIs during 2015–2020. We classified all treated eyes as eligible or ineligible for pRCTs following major selection criteria of the MEAD and GENEVA trials, and evaluated three-, six-, and twelve-month changes in central retinal thickness (CRT) and visual acuity (VA) after initiating IDIs.
We included 177 IDI-treated eyes (DME: 72.3%; CRVO: 27.7%), of which 39.8% and 55.1% were ineligible for DME and CRVO pRCTs, respectively. LogMAR-VA and CRT changes at different times were comparable in DME eyes eligible (LogMAR-VA difference: 0.11 to 0.16; CRT difference: −32.7 to −96.9 μm) and ineligible (LogMAR-VA difference: −0.01 to 0.15; CRT difference: −54.5 to −109.3 μm) for the MEAD trial. By contrast, CRVO eyes ineligible for the GENEVA trial had greater LogMAR-VA changes (0.37 ~ 0.50) than those eligible (0.05 ~ 0.13), with comparable CRT reductions (eligible eyes: −72.3 to −106.4 μm; ineligible eyes: −61.8 to −110.7 μm) (all p-values <0.05 of the mean differences between eligible and ineligible CRVO eyes for all follow-ups).
IDIs had similar VA and CRT outcomes among DME eyes, regardless of pRCT-eligibility. However, among CRVO eyes, those ineligible for pRCTs showed greater deterioration in VA than those eligible.
SCORE2 Report 24: Nonlinear Relationship of Retinal Thickness and Visual Acuity in Central Retinal and Hemiretinal Vein Occlusion
2023, Ophthalmology
To investigate whether a nonlinear association between central subfield thickness (CST) on spectral-domain OCT and concurrent visual acuity letter score (VALS) exists in eyes treated initially with aflibercept or bevacizumab for macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2).
Long-term follow-up after a randomized clinical trial from 64 centers in the United States.
Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol.
Two-segment linear regression models were compared with simple linear regression models of VALS on CST. Pearson correlation coefficients were calculated to assess strength of CST and VALS associations.
Central subfield thickness was measured by OCT and VALS by the electronic Early Treatment Diabetic Retinopathy Study methodology.
Estimated inflection points, reflecting turning points at which the CST and VALS association changes from positive to negative, calculated at 7 postbaseline visits, range from 217 to 256 μm. A strongly positive correlation exists to the left of each estimated inflection point, ranging from 0.29 (P < 0.01 at month 60) to 0.50 (P < 0.01 at month 12), and a strongly negative correlation exists to the right of each estimated inflection point, ranging from −0.43 (P < 0.01 at month 1) to −0.74 (P < 0.01 at month 24). Randomization statistical tests showed that 2-segment models are favored over 1-segment models for all postbaseline months (P < 0.001 for all tests performed).
The relationship between CST and VALS in eyes with CRVO or HRVO after treatment with anti–vascular endothelial growth factor (VEGF) therapy is not simply linear. The usually modest correlations between OCT-measured CST and visual acuity belie strong left and right correlations present in 2-segment models. Post-treatment CST close to the estimated inflection points showed the best expected VALS. The SCORE2 participants with a post-treatment CST after treatment close to the estimated inflection points of 217 to 256 μm showed the best VALS. In patients treated with anti-VEGF for macular edema associated with CRVO or HRVO, a thinner retina is not always associated with better VALS.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Mathematical modeling for drug delivery and inflammation process: An application in macular edema
2023, Applied Mathematical Modelling
In this paper, we introduce a mathematical model for the drug release from an intravitreal implant and the subsequent effect of the drug on the inflammation process of macular edema. Coupling the drug transport problem with the growth of the edema, we compare the numerical simulations with patient-specific medical images. We fit the model with respect to one parameter and match the retinal thickness observed in the patient. After the validation of the proposed model, we perform numerical experiments regarding patient-specific treatments. In particular, we analyze the drug concentration in the different sub-domains (e.g., the implant and the retina) and simulate the scenario of edema recurrence and implant re-injection. The proposed mathematical model has the potential to provide important insights into the use of intravitreal dexamethasone implants and the treatment of macular edema.
Predictive impact of optical coherence tomography biomarkers in anti-vascular endothelial growth factor resistant macular edema treated with dexamethasone implant
2023, Photodiagnosis and Photodynamic Therapy
To perform a longitudinal analysis of the effect of optic coherence tomography (OCT) biomarkers on macular thickness in patients with persistent macular edema secondary to diabetes mellitus and retinal vein occlusion who recieved intravitreal dexamethasone (DEX) implant.
Eighty-nine patients were included in the retrospective study. Patients with anti-VEGF-resistant macular edema were included in the study. The effect of the presence or absence of OCT biomarkers before intravitreal DEX implant therapy on central foveal thickness (CFT) was evaluated. In addition, the change in biomarkers from the baseline visit to the final visit was evaluated. The evaluated OCT biomarkers were as follows: ellipsoid zone and external limiting membrane (ELM) integrity, hyperreflective foci (HRF), disorganization of inner retinal layers (DRIL), hard exudates, serous macular detachment (SMD), pearl necklace, posterior vitreous detachment and the epiretinal membrane (ERM).
The mean age of the overall sample in the study was 64.4 ± 9.6. CFT decreased significantly from 625.3 ± 22.3 μm at baseline to 365.0 ± 21.7 μm in the 1st month but increased significantly to 430.2 ± 22.6 μm in the 3rd month. In the presence of HRF and SMD, recurrence of macular edema was significant in the 3rd month. The percentage of ELM disruption, DRIL, and ERM deteriorated significantly and the percentage of SMD improved significantly at the final visit.
DEX implant therapy resulted in a satisfactory reduction in CFT in patients with DME and RVO. The presence of HRF and SMD is a negative predictor of recurrence in CFT in short term. DEX implant therapy resulted in satisfactory improvement in SMD.
A Comparison of Ocular Complications after 0.7 mg Dexamethasone Implant versus 2 mg of Intravitreal Triamcinolone in Vitrectomized Eyes
2023, Ophthalmology Retina
To compare the rates of complications in eyes that received a dexamethasone (DEX) implant (0.7 mg) or intravitreal triamcinolone (IVT) (2 mg) to treat postvitrectomy macular edema (ME).
Retrospective, comparative, case series.
A total of 148 eyes (147 patients); 75 eyes (75 patients) in the DEX group and 73 eyes (72 patients) in the IVT group.
The medical records of patients who received an intravitreal DEX 0.7 mg (Ozurdex) or triamcinolone (2 mg) (Triesence) for postvitrectomy ME between July 2014 and December 2021 with a minimum follow-up of 3 months were reviewed. Ocular hypotony and ocular hypertension were defined as intraocular pressure of < 6 mmHg and > 24 mmHg, respectively.
The rates of complications.
The follow-up duration was 2.5 ± 1.6 years, with no significant difference between the groups (P = 0.398). The rate of transient ocular hypotony per eye and per injection was significantly higher in the DEX group (10 eyes [13%], 30 of 443 injections [7%]) compared with the IVT group (2 eyes [3%], 2 of 262 injections [0.8%]) (P = 0.039 and < 0.001, respectively). Mean visual acuity significantly decreased at the time of ocular hypotony (P = 0.031), but returned to preinjection level after resolution of the hypotony after a median of 12 days. The incidence of ocular hypertension was higher in the DEX group (23 eyes [31%]) than the IVT group (16 eyes [22%]), but this was not statistically significant (P = 0.307). Ocular hypertension was controlled with observation or topical medication. There were no between-group differences in the incidence of vitreous hemorrhage (DEX, 3 eyes [4%]; IVT, 1 eye [1%]; P = 0.632) or rhegmatogenous retinal detachment (DEX, 3 eyes [4%]; IVT, 0 eyes [0%]; P = 0.253). Four eyes (5%) experienced migration of the DEX implant into the anterior chamber. No eye developed endophthalmitis.
The incidence of ocular hypotony, which causes transient visual impairment, was significantly higher in vitrectomized eyes treated with DEX compared with eyes treated with IVT. Injections other than the inferotemporal quadrant or rotating injection sites may be recommended.
Proprietary or commercial disclosure may be found after the references.
Acetazolamide and bevacizumab combination therapy versus bevacizumab monotherapy in macular edema secondary to retinal vein occlusion
2023, Journal Francais d'Ophtalmologie
To determine and compare the efficacy of intravitreal bevacizumab (IVB) and oral acetazolamide (OA) combination therapy versus IVB monotherapy in patients with macular edema secondary to retinal vein occlusion (RVO).
This randomized clinical trial included 54 eyes of 52 patients with RVO central macular thickness (CMT) of more than 300 μm, and best corrected visual acuity (BCVA) between 20/400 and 20/40. Eligible patients were randomly assigned to two groups: (I) IVB and OA (250 mg twice daily) combination therapy or (II) IVB monotherapy. Ocular injections were repeated monthly for up to three months; BCVA and CMT were measured monthly.
Both regimens resulted in significant reduction in CMT (534 ± 150 μm to 352 ± 90 μm in the IVB + OA group, P < 0.001; and 580 ± 175 μm to 362 ± 90 μm in the IVB group, P < 0.001); neither showed superiority in this regard. Likewise, BCVA showed significant improvement in both groups (0.87 ± 0.56 to 0.53 ± 0.28 LogMAR in the IVB + OA group, P = 0.001; and 0.85 ± 0.62 to 0.46 ± 0.4 LogMAR in the IVB group, P < 0.001), with no intergroup difference.
Addition of oral acetazolamide to IVB in eyes with macular edema secondary to RVO may not result in additional short-term benefits regarding functional and anatomical outcomes. Trial registration: ClinicalTrials.gov, NCT05290948, registered on March 22, 2022. https://clinicaltrials.gov/ct2/show/NCT05290948
L’objectif était de déterminer et de comparer l’efficacité du traitement combiné intravitréen bevacizumab (IVB) et acétazolamide (OA) par rapport à la monothérapie IVB chez les patients présentant un œdème maculaire secondaire à une occlusion veineuse rétinienne (RVO).
Cet essai clinique randomisé a inclus 54 yeux de 52 patients avec une OVR et une épaisseur maculaire centrale (CMT) de plus de 300 μm et une meilleure acuité visuelle corrigée (MAVC) entre 20/400 et 20/40. Les patients éligibles ont été répartis au hasard en deux groupes : (I) thérapie combinée IVB et OA (250 mg, deux fois par jour) ou (II) monothérapie IVB. Les injections oculaires ont été répétées tous les mois pendant jusqu’à trois mois ; BCVA et CMT ont été mesurés mensuellement.
Les deux traitements ont entraîné une réduction significative de la CMT (534 ± 150 μm à 352 ± 90 μm dans le groupe IVB + OA, p < 0,001 ; et 580 ± 175 μm à 362 ± 90 μm dans le groupe IVB, p < 0,001) ; aucun n’a montré de supériorité à cet égard. De même, la BCVA a montré une amélioration significative dans les deux groupes (0,87 ± 0,56 à 0,53 ± 0,28 LogMAR dans le groupe IVB + OA, p = 0,001 ; et 0,85 ± 0,62 à 0,46 ± 0,4 LogMAR dans le groupe IVB, p < 0,001), et aucune différence intergroupe n'a été notée.
L’association de l’acétazolamide par voie orale à l’IVB dans les yeux présentant un œdème maculaire secondaire à l’OVR peut n’entraîner aucun avantage supplémentaire à court terme en ce qui concerne les résultats fonctionnels et anatomiques. Inscription à l’essai ClinicalTrials.gov, NCT05290948, enregistré le 22 mars 2022. https://clinicaltrials.gov/ct2/show/NCT05290948

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: Manuscript no. 2009-1609.

: *GENEVA: Global Evaluation of implaNtable dExamethasone in retinal Vein occlusion with macular edemA. A list of the members of the GENEVA study group is available at http://aaojournal.org.

: This article contains online-only material. The following should appear online only: Figure 3 and The GENEVA Study Group.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): Dr. Haller is a consultant with Genentech and Allergan and an equity owner with Macusight and OptiMedica. Dr. Bandello is a consultant and lecturer with Allergan and Novartis. Dr. Belfort is a consultant and lecturer with Allergan and Alcon. Dr. Blumenkranz is a consultant with Allergan, Macusight, and Genentech, an equity owner with Macusight and Optimedica, a lecturer with Allergan, and a patent holder with Optimedica. Dr. Gillies is a consultant with Allergan, Novartis, and Pfizer. Dr. Heier is a consultant for and received financial support from Alimera, Allergan, Genetech, and Regeneron, and is a lecturer for Regeneron. Dr. Lowenstein is a consultant for Allergan and Notal Vision and a lecturer for Novartis and Alcon. Dr. Yoon is a consultant for Allergan and a lecturer for Alcon. Drs. Jacques, Jiao, Li, and Whitcup are employees of Allergan, Inc.

: Sponsored by Allergan, Inc., which participated in the design of the study, data analysis, and interpretation, and supervised the preparation of the manuscript and approved the final version.

^⁎: Group members listed online in Appendix 1 (available at http://aaojournal.org).

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Original articleRandomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema Due to Retinal Vein Occlusion

Objective

Design

Participants

Intervention

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Study Design

Results

Discussion

Acknowledgments

Mol Ther

Eur J Pharmacol

Am J Ophthalmol

Kaohsiung J Med Sci

Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management

Intern Med J

Prevalence and associations of retinal vein occlusion in Australia: the Blue Mountains Eye Study

Arch Ophthalmol

Retinal vein occlusion (RVO) interim guidelines

The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study

Trans Am Ophthalmol Soc

Natural history and clinical management of central retinal vein occlusion

Arch Ophthalmol

Retinal vein occlusionEmedicine

Central retinal vein occlusion

Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities

Curr Eye Res

Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells

Diabetes

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 6

Arch Ophthalmol

Two phase III studies of Lucentis show early and sustained improvement in vision in patients with retinal vein occlusion

Medical News Today

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 5

Arch Ophthalmol

Intravitreal triamcinolone for acute central retinal vein occlusion: a randomized clinical trial

Graefes Arch Clin Exp Ophthalmol

Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema

Arch Ophthalmol

Original article
Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema Due to Retinal Vein Occlusion