Outcomes of Combination Therapy using Aflibercept and Dexamethasone Intravitreal Implant versus Dexamethasone Monotherapy for Macular Edema Secondary to Retinal Vein Occlusion.

PURPOSE: The purpose of this study was to evaluate the efficacy of the combination therapy of intravitreal aflibercept 2 mg (Eylea®) and a sustained-release dexamethasone 0.7 mg intravitreal implant (Ozurdex®) versus dexamethasone alone in providing better visual acuity in eyes with macular edema (ME) secondary to retinal vein occlusion (RVO).
METHODS: Seventy-four eyes of 74 patients with treatment-naïve ME secondary to RVO were included in this prospective nonrandomized case series and were studied over a 12-month follow-up period. Patients in the dexamethasone monotherapy group were treated with an initial Ozurdex® injection while patients in the combination therapy group were treated with an Eylea® injection followed 2 weeks later by an Ozurdex® injection. The treatment was repeated as needed. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure were evaluated periodically. The primary outcome measure was the BCVA. The secondary outcome measures included CMT, number of retreatments, and safety parameters.
RESULTS: At 1 year, the primary endpoint was met. Patients receiving combined therapy had better mean visual acuity changes from baseline compared to those receiving monotherapy (0.369 ± 0.221 logarithm of the minimum angle of resolution [logMAR] vs. 0.218 ± 0.171 logMAR; P = 0.002). The secondary endpoints were not met since there were no significant differences in mean reductions in CMT (272.67 ± 82.35 vs. 248.11 ± 159.73; P = 0.412) and the mean number of retreatments was similar in the two groups (1.75 ± 1.13 vs. 1.42 ± 0.64; P = 0.126).
CONCLUSION: Aflibercept with dexamethasone implants achieved better visual outcomes compared to dexamethasone monotherapy with no significant differences in intravitreal retreatment rates at the 1st year in eyes with ME secondary to RVO. Copyright:

Introduction

Retinal vein occlusion (RVO) is the second leading cause of visual loss from retinal vascular disease after diabetic retinopathy,[1] and loss of vision is mainly secondary to macular edema (ME). The mechanisms underlying the formation of ME involve multiple factors. Increased intraluminal venous pressure behind the occlusion leads to an increased hydrostatic pressure, which can cause plasma transudation. In addition, decreased blood flow through the retinal vasculature after RVO results in ischemic injury to the capillaries, upregulation of vascular endothelial growth factor (VEGF), and overexpression of inflammatory mediators, leading to a breakdown of the blood–retinal barrier and an increased retinal vasculature permeability.[2] These factors that play a role in the ME pathogenesis are behind its pharmacological treatment that include both intravitreal injections of anti-VEGF or intravitreal injections of corticosteroids. However, both treatments have their limitations. The drawbacks of anti-VEGF therapy include the burdensome need for multiple injections,[3456] whereas intravitreal corticosteroid implants are associated with higher risks of elevated intraocular pressure (IOP) and cataract formation.

The purpose of this study was to determine if the combination of intravitreal aflibercept and a sustained-release dexamethasone intravitreal implant can be synergistic, thereby providing a better visual acuity and minimizing intravitreal retreatment rates.

Methods

In this multicenter, prospective, nonrandomized case series, 74 eyes of 74 patients with treatment-naïve ME secondary to either central RVO (CRVO) or branch RVO (BRVO) were recruited between December 2016 and September 2017 and were studied over a 12-month follow-up period. The diagnosis of CRVO and BRVO was carried out by performing fluorescein angiogram (Topcon TRC-50EX retinal camera) [Table 1].

Table 1

Baseline characteristics

Variables	Ozurdex group (n=38)	Combination therapy group (n=36)	P
Gender (male:female)	18:20	12:24	0.245
Age (years)	71.16±14.30	70.19±14.86	0.777
RVO (central:branch)	13:25	11:25	0.807
BCVA (logMAR)	0.737±0.214	0.706±0.233	0.552
CMT (µm)	527.03±127.09	482.44±80.92	0.078

BCVA: Best-corrected visual acuity, CMT: Central macular thickness, logMAR: Logarithm of minimum angle of resolution, RVO: Retinal vein occlusion

Patients were eligible for enrollment if they were at least 18 years old with baseline central macular thickness (CMT) >300 μm on the ZEISS Stratus optical coherence tomography (OCT), best-corrected visual acuity (BCVA) of 20/40 or worse, and a maximum duration of symptoms of 3 months. Exclusion criteria were as follows: ischemic CRVO/BRVO, or evidence of neovascularization in the anterior or posterior segment, or a history of vitrectomy, elevated IOP, glaucoma, or diabetes mellitus [Table 2].

Table 2

Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Adults ≥18 years of age	Ischemic CRVO/BRVO
CMT >300 µm	Glaucoma
BCVA of 20/40 or worse	Diabetes mellitus
Duration of symptoms ≤3 months	History of elevated IOP
Patients are treatment-naïve	Previous vitrectomy
Patients were available for a follow-up of at least 1 year	Neovascularization at the posterior or anterior segment of the eye

BCVA: Best-corrected visual acuity, BRVO: Branch retinal vein occlusion, CMT: Central macular thickness, CRVO: Central retinal vein occlusion, IOP: Intraocular pressure

Patients were recruited in a consecutive manner starting with the dexamethasone monotherapy group. The dexamethasone monotherapy group (38 eyes) received a dexamethasone (Ozurdex®; Allergan Inc., Irvine, CA, USA) intravitreal injection initially. The combination therapy group (36 eyes) received an aflibercept (Eylea®; Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA) injection followed 2 weeks later with an Ozurdex® injection. Then, the same treatment was repeated if patients were eligible for retreatment. Criteria for a retreatment were as follows: loss of BCVA by six or more Snellen letters from the best measurement and/or an increase in CMT by >50 μm from the lowest measurement. IOP was evaluated 2 and 4 weeks after the first injection. CMT, BCVA, and IOP were measured 6 weeks after the beginning of each cycle and subsequently every 4 weeks until retreatment is needed [Figure 1].

Figure 1

Treatment and retreatment protocol flowchart

The primary outcome measure was the BCVA. The secondary outcome measures included the peak changes in CMT, the number of retreatments, and the safety of the procedure.

The purpose of this study was to determine if the combination of intravitreal aflibercept 2 mg (Eylea®) and a sustained-release dexamethasone 0.7 mg intravitreal implant (Ozurdex®) can be synergistic, thereby providing a better visual acuity and minimizing intravitreal retreatment rates.

Ethical considerations

All patients included in the study gave their written informed consent. The study was approved by the ethics committee of our institution.

Statistical analysis

The BCVA fractions were converted into logarithm of the minimum angle of resolution (logMAR) units. Categorical data were analyzed using Fisher's exact test. Analysis of variance (ANOVA) and two-tailed t-tests were used to evaluate intertreatment interval and changes in BCVA and CMT, respectively. Continuous variables were noted by means and their corresponding standard deviations. P < 0.05 was considered as statistically significant. All data were analyzed using the Statistical Package for the Social Sciences (SPSS, version 24) (SPSS Inc., Chicago, IL, USA).

Results

In the dexamethasone monotherapy group, the mean BCVA was 0.737 ± 0.214 logMAR units at baseline. BCVA improved to a maximum of 0.518 ± 0.196 logMAR units across all treatment cycles. The mean peak improvement in BCVA was 0.218 ± 0.171 logMAR units, and 13 patients (34.21%) gained three or more lines of BCVA. In the combination therapy group, the mean BCVA was 0.706 ± 0.233 logMAR units at baseline. BCVA improved to a maximum of 0.336 ± 0.093 logMAR units across all treatment cycles. The mean peak improvement in BCVA was 0.369 ± 0.221 logMAR units, and 24 patients (66.67%) gained three or more lines of BCVA.

The mean CMT was 527.03 ± 127.09 μm at baseline in the dexamethasone alone group. CMT decreased to a minimum of 278.92 ± 88.87 μm across all treatment cycles, and the mean peak decrease was 248.11 ± 159.73 μm. The mean CMT was 482.44 ± 80.92 μm at baseline in the combination therapy group. CMT decreased to a minimum of 209.78 ± 13.33 μm across all treatment cycles, and the mean peak decrease was 272.67 ± 82.35 μm.

All patients in the monotherapy group needed at least one retreatment after 1-year follow-up. Twenty-five patients (65.79%) needed only one retreatment. Ten patients (26.32%) needed only two retreatments and three patients (7.89%) needed three additional injections. Each patient needed an average of 1.42 ± 0.64 retreatments. The first retreatment was at 139.55 ± 48.01 days. The second retreatment was 135.85 ± 37.23 days after the first retreatment. The third retreatment was 91.00 ± 1.73 days after the second retreatment. In the combination therapy group, seven patients (19.44%) needed no retreatment after 1-year follow-up. Twelve (33.33%) patients needed no retreatment for 6 months. Seven patients (19.44%) needed only one retreatment over 1 year of follow-up. Ten (27.78%) needed only two retreatments and twelve (33.33%) needed three additional injections. The first retreatment was at 142.17 ± 39.83 days. The second retreatment was 139.64 ± 35.78 days after the first retreatment. The third retreatment was 131.17 ± 33.66 days after the second retreatment. Each patient needed an average of 1.75 ± 1.13 retreatments. There was no statistically significant difference in mean intertreatment interval for up to four treatment cycles, and the mean intertreatment interval across all eyes was 135.96 ± 45.24 days in the monotherapy group and 139.19 ± 36.98 days in the combination therapy group [Table 3].

Table 3

Number of retreatments in participants who completed the study

Number of retreatments	Number of eyes, n (%)
	Ozurdex group	Combination therapy group
0	0 (0)	7 (19.44)
1	25 (65.79)	7 (19.44)
2	10 (26.32)	10 (27.78)
3	3 (7.89)	12 (33.33)

Before initiation of treatment, IOP was within normal ranges in all patients. A relevant increase of IOP was defined as an increase of >5 mmHg compared with baseline. During the 12-month follow-up, an increase of IOP was seen in 8 patients out of 38 (21.05%) in the monotherapy group. The IOP increased above 35 mmHg in one patient and above 25 mmHg in seven patients. In the combination group, IOP increased in 7 patients out of 36 (19.44%). The IOP increased above 35 mmHg in one patient and above 25 mmHg in six patients. IOP exceeding normal range was controlled by topical IOP-lowering medication.

No adverse events such as intravitreal hemorrhage, endophthalmitis, and retinal detachment were noted during this study.

Discussion

Lately, the idea of associating both treatment modalities for RVO-related ME is being promoted by clinicians. However, studies concerning this matter are scant and additional trials are needed for definitive results.

In a prospective nonrandomized case series, Mayer et al. compared three intravitreal bevacizumab injections followed by a dexamethasone implant versus dexamethasone implant monotherapy in eyes with ME secondary to RVO. This study found that dexamethasone implant monotherapy was associated with a better functional outcome in BRVO patients, whereas both treatment modalities showed no functional differences in CRVO patients. The initial treatment with an anti-VEGF drug was not effective in increasing the interval until the ME recurrence.[7]

Likewise, Maturi et al. reported that the addition of a dexamethasone implant 1 week following intravitreal bevacizumab increased the mean time to the first additional bevacizumab injection to 3 months versus 1 month in the bevacizumab monotherapy group, but the level of functional improvement was similar in both the groups. However, the relatively short period of follow-up (6 months) constitutes one of the study's limitations.[8]

Furthermore, Singer et al. conducted two studies, both lacking a control group, in which patients receiving dexamethasone implants 2 weeks after anti-VEGF injections had a mean re-injection interval of 135 ± 36.4[9] days and 129[10] days as well as improvements in visual acuity and central foveal thickness.

Hence, combination protocols used in these studies whether three bevacizumab injections followed by a dexamethasone implant, or an anti-VEGF injection followed by a dexamethasone injection 1 or 2 weeks later, showed no superiority to the dexamethasone monotherapy in terms of recurrence intervals. Results were in line with the 3–4 months obtained in the GENEVA trial.[1112] However, the first protocol did not provide more visual acuity improvements compared to dexamethasone monotherapy, and a control group was needed in Singer's study to evaluate visual acuity in a more accurate way. In addition, using one anti-VEGF, instead of a randomly chosen one, will allow to better study its efficacy.

Moreover, Lip et al., through a retrospective analysis, suggested the RandOL protocol (Ranibizumab and Ozurdex with Laser photocoagulation) as an individualized alternative for patients with ME due to RVO, in order to improve the short-term efficacy of intravitreal monotherapy and minimize the drug-related side effects. The protocol achieved visual and anatomical results similar to those obtained with a single-agent therapy, and with less retreatment rates at 1 year. Despite these findings, randomized controlled studies are needed, especially to evaluate the role of laser in ischemic RVO.[13]

In the TANZANITE study,[14] Clearside Biomedical Inc. (Alpharetta, GA, USA) compared suprachoroidal triamcinolone acetonide plus intravitreal aflibercept versus aflibercept alone in patients with RVO. At 3 months, the combination arm showed an increase in visual acuity and improved OCT compared with the aflibercept-alone cohort. Concerning safety findings, the study suggests that the suprachoroidal injection is well tolerated. However, solid conclusions cannot be made since this study is a phase 2 trial. In addition, cataract and increase in IOP need a chronic exposure to intraocular steroids in order to occur; therefore, studies with larger samples and a longer follow-up period are needed.

In the present study, patients were initially treated with either dexamethasone injection alone or intravitreal aflibercept injection associated with dexamethasone implant. They were followed monthly and retreated based on their BCVA and CMT scores. The study yielded considerable findings. At 1 year, the primary endpoint was met and crucial functional improvements were recorded. Patients receiving combined therapy had better mean visual acuity changes from baseline compared to those receiving monotherapy (0.369 ± 0.221 logMAR vs. 0.218 ± 0.171 logMAR; P = 0.002) and 34.21% of eyes gained at least three lines of BCVA in the monotherapy group versus 66.67% in the combination group. This percentage is similar to those seen in phase 3 trials for aflibercept (between 50 and 60%).[151617]

On the other hand, the secondary endpoints were not met since there were no significant differences in mean reductions in CMT (272.67 ± 82.35 vs. 248.11 ± 159.73; P = 0.412) and the mean number of retreatments was similar in the two groups (1.75 ± 1.13 vs. 1.42 ± 0.64; P = 0.126).

However, a relatively fixed and long intertreatment interval of 4–5 months was obtained in both the groups. Having a constant intertreatment interval of 4–5 months implies that patients' BCVA and CMT values are slightly changing during this period. This may be helpful in reducing the frequency of the follow-up visits. Patients would then be more compliant and the treatment more cost-effective.

Concerning the safety profile, rates of IOP increases (19.44% and 21.05%) in the current study were similar to those seen in the GENEVA trial[12] (12.6 and 15.4% after the first and second treatments, respectively). IOP exceeding normal range was controlled by topical IOP-lowering medication.

Conclusion

According to our study, associating anti-VEGF with dexamethasone implants showed encouraging results. Efficacy outcomes are better than those obtained with dexamethasone monotherapy while the need to retreat patients by anti-VEGF injections still meets that obtained with dexamethasone monotherapy. However, additional studies must be performed to find the best treatment regimen that will reduce the number of injections of both the anti-VEGF and the dexamethasone while providing a better visual acuity than anti-VEGF monotherapy alone. Despite being among the few trials to have investigated the efficacy of combining aflibercept and dexamethasone implants, this study has several limitations worth mentioning. In fact, having a small sample size, the relatively short duration of follow-up, and the absence of an anti-VEGF monotherapy control group are the major weaknesses. Therefore, the need of a large and comparative randomized clinical trial between combination and anti-VEGF monotherapy is of great value in order to be able to draw clear-cut conclusions. That being said, by achieving better visual outcomes compared to dexamethasone monotherapy with no significant differences in intravitreal retreatment rates at 1st year, combination therapy can provide better functional results and alleviate the treatment burden of ME secondary to RVO. Everything considered, this treatment modality provided imperative results that meet the study's primary endpoint, making it a practical substitute that warrants a starting point for further research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.