Discussion
Until recently, treatment strategy for patients with BRVO and CRVO was mainly based on the results of the BRVO and CRVO clinical trials, suggesting deferred focal laser for macular edema in BRVO patients with BCVA <20/40. Peripheral laser was advocated in cases with severe ischemia in BRVO and CRVO in order to treat or prevent vitreous hemorrhage and neovascular glaucoma, especially in CRVO. Laser photocoagulation of the macular region provided no functional benefit in eyes with CRVO.
Today, under the light of new treatment options, including intravitreal application of corticosteroids and VEGF inhibitors, patients with RVO, both CRVO and BRVO, have a better perspective of visual recovery. The rationale for both pharmacological approaches is based on pathogenetic factors that have been identified to have a key role in the development of macular edema associated with retinal vascular occlusion, such as the expression of VEGFand a cascade of inflammatory processes.
In clinical trials, VEGF inhibitors such as ranibizumab revealed a beneficial effect on visual function and reduced central macular thickness in eyes with BRVO and CRVO. However, with respect to the shorter half-life of ranibizumab, numerous injections are required to achieve and maintain this therapeutic effect. This is also valid for bevacizumab as shown by Epstein et al, who performed injections every 6 weeks for 12 months with a significant improvement of visual acuity (VA) and reduction of macular edema. Compared with the present study, the VA outcome as achieved by the strict treatment regime appeared better, although one needs to consider different study settings. Patients receiving delayed treatment have a limited visual improvement. Of note, ranibizumab was not approved for the treatment of RVO at the beginning of this study. Therefore, based on published clinical data, bevacizumab was used for treatment in an off-label setting after IRB approval.
Corticosteroids not only have an anti-inflammatory effect (eg, inhibition of fibrin deposition, leukocyte movement, suppression of homing, and migration of inflammatory cells) but also interfere with the synthesis of VEGF and other cytokines. Studies concerning intravitreal triamcinolone acetonide or intravitreal bevazicumab treatment showed mainly similar effects on macular edema reduction and VA improvement. However, a higher rate of side effects was reported using intravitreal triamcinolone acetonide.
Dexamethasone is a potent, water-soluble corticosteroid that can be delivered into the vitreous cavity either by injection of a dexamethasone solution with a very short half-life or by the implantation of an approved dexamethasone intravitreal implant using a customized applicator system (Ozurdex) releasing dexamethasone over a prolonged period until complete resolution of the matrix as shown in the GENEVA trial. Using this approach, a beneficial effect on VA and retinal thickness in patients with macular edema associated with BRVO and CRVO has been reported. However, a retreatment was not allowed before 6 months after the initial implantation according to the protocol of this trial.
The aim of the present study was to evaluate the efficacy and safety of Ozurdex in a clinical setting where reinjections were performed according to defined criteria, including a decrease of BCVA and an increase in retinal thickness. In addition, we wanted to see whether an upload therapy of three consecutive injections with an anti-VEGF drug provides any advantage or disadvantage when the treatment is continued with Ozurdex.
Comparing both treatment strategies 1 year after initiation of treatment, we observed a significant difference of gain in letters only for patients with CRVO, favouring eyes that were initially treated with bevacizumab (increase of 9.8 letters at 12 months). This may in part be explained by the fact that patients in this group had a lower BCVA (15.5 vs 22.4 ETDRS letters) at study entry, indicating that there was a greater window for improvement. However, even in CRVO eyes with an initial mean BCVA of 22.4 letters, an improvement of 6.6 letters was seen after 12 months. In BRVO patients, no significant difference between both groups was seen (7.8 vs 9.4 letters improvement at 12 months), and it seems noteworthy that there was no significant difference of initial BCVA (26.3 vs 28.5 letters) comparing both groups.
We hypothesized that a pre-treatment with a VEGF inhibitor may have an impact on the time until a recurrence of macular edema following the first Ozurdex implantation is seen. However, it appeared that the time to recurrence could not be prolonged, which is in contrast to a recent study of Singer et al, using a single bevacizumab injection followed by an Ozurdex implantation. Recurrences occurred after a period of 3.2 and 3.8 months and were in line with the known pharmacokinetics of the Ozurdex implant and the results of the GENEVA trial, which revealed a decrease of the treatment effect at about 3–4 months after implantation. Interestingly, the number of recurrences (and subsequent retreatments) in patients receiving a monotherapy with the dexamethasone implant was lower in BRVO compared with CRVO patients, which may be well explained by the more favorable natural course of macular edema associated with BRVO. Therefore, considering the potential adverse effect of a corticosteroidal implant, BRVO patients seem better candidates for this treatment as a first-line option compared with CRVO patients, as the latter require more retreatments as described in other trials too.
As to be expected for a corticosteroid, we observed an elevation of intraocular pressure of >5 mm Hg compared with baseline in approximately 40% of patients, irrespective of the treatment regime. One patient required cyclo-photocoagulation following the second steroid implant. In all other cases, the intraocular pressure was well controlled using topical medications. Interestingly, we observed no additive effect on intraocular pressure, although one might hypothesize that subsequent implantations after 3–4 months may increase the risk for an elevation of intraocular pressure, as the partially degraded first implant still releases dexamethasone into the vitreous cavity, though on a lower lever. In the GENEVA trial, no such additional effect had to be expected, as reinjections were not permitted within 6 months. Although we had no uncontrolled case with elevated intraocular pressure, based on our 12-month experience using Ozurdex, we suggest excluding patients with a known history of glaucoma and steroid response from this treatment.
Similar thoughts may theoretically apply for the formation or progression of cataracts in phacic eyes. In our series, it became apparent that lens opacities interfering with VA and requiring cataract extraction occurred after the second and finally after the third Ozurdex implantation in about 50% of treated eyes, and this is in line with previous reports in the literature. This observation should be considered when choosing a treatment option for the individual RVO patient. From our perspective, young phacic patients should be treated with a VEGF inhibitor in order to preserve a clear lens. In addition, a combination of Ozurdex with an anti-VEGF drug or a switch from a Ozurdex monotherapy to an anti-VEGF strategy may be an option in selected cases, for example, especially in CRVO patients, where the natural history is quite poor compared with patients with BRVO, and more treatments seem to be required to maintain function.
The limitation of the present study is the small number of patients included. We are also aware that the results seen for bevacizumab may not necessarily be transferred to the results one may obtain using ranibizumab in a similar setting. Of note, ranibizumab was not approved for the treatment of RVO at the initiation of our trial. A longer period of review will be needed to document whether the re-treatment effect observed in our study can be maintained. In addition, especially the safety issues such as secondary glaucoma and cataract progression need to be investigated in a prolonged period or review. However, we believe that the present investigation contributes interesting and helpful information on the use of Ozurdex in a setting that reflects its use in clinical practice.
In conclusion, combined treatment using Avastin and Ozurdex showed slightly better functional outcome for CRVO patients. Increased intraocular pressure and cataract progression was frequent and should be considered when an individual treatment is planned.