Steroids are becoming an integral part of the management of retinal vein occlusion (RVO). And as a result, new parameters have been reviewed regarding which steroid(s) to use and when to use them.
At the recently held 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) which took place in Shanghai, China, a panel of experts and specialists revealed their thoughts and conclusions on steroids in ophthalmology. In this article, we’ll go over the nuances of steroid use in RVO and what, if any, place they have in practice.
Not all steroids are the same
Potency and overall utility differs across the many steroids available. For instance, triamcinolone is five times more potent than cortisol, whereas dexamethasone is 25 times more potent. But there are more differences to note.
What actually distinguishes one steroid from another? According to Dr. Barry Kupperman from University of California-Irvine, USA, every steroid has their own mechanism of suppressing cytokines. Due in part to their unique structures, steroids can also up-regulate and alter the expression of thousands of genes.
From his own laboratory, Dr. Kupperman found that steroids exhibit their own toxicities that can often be masked by apparent benefits. He explained that, “while triamcinolone causes some toxicity to retinal cells in cultures, dexamethasone and fluocinolone do not appear to”.
All steroids, to varying degrees, can cause cataracts and intraocular pressure (IOP) issues. From cell culture work, Dr. Kupperman described how the affinity of dexamethasone to the human trabecular meshwork is much less than that of triamcinolone and fluocinolone. “This may explain the slightly lower rate of cataracts from dexamethasone, as well as the easier management of IOP issues associated with it compared to triamcinolone and/or fluocinolone,” he said.
Water solubility also differs within each steroid, with dexamethasone having the highest solubility. Dr. Kupperman explained that this can be a double-edged sword. Because solubility indicates a shorter half-life in the eye, the drug can leave the eye faster without inducing lingering effects. However, it may have a shorter active effect.
He also stated that, despite their differing efficacies, the risk for intraocular hypertension is still associated with the use of steroids. The incidence of intraocular hypertension was 15% in dexamethasone versus 30 to 40% in triamcinolone and 60% in fluocinolone. Clinical applications of steroids therefore have their own caveats.
Regardless of treatment used, Dr. Kupperman advised to treat early for RVO. The dexamethasone implant can work rather quickly with initial effects seen within 24 hours and dramatic effects apparent within 1 week. Because IOP and cataracts can be easily managed with dexamethasone implants, it may be the more preferred steroid from a pressure elevation standpoint.
Outcomes in clinical trials
As exemplified in the GENEVA study, dexamethasone intravitreal implants exhibited improvements in mean visual acuity compared with sham treatment (P≤0.006). The percentage of eyes with a ≥15-letter improvement in visual acuity was higher in the implant groups although there was no significant difference in the occurrence of cataracts or cataract surgery compared to sham groups.
In regards to the RVO natural course, the initial visual acuity is closely related to the final prognosis of the patient. As presented by Dr. Sun Xiaodong from China, 87% of patients with ischemic CRVO have a final visual acuity of less than 0.05. This is distinguishable from the fact that half of those patients with BRVO can maintain visual acuity above 0.5.
Dr. Xiaodong explained that RVO treatment mainly lies in the treatment of complications. Visual impairment in patients with RVO is typically caused by macular edema (ME) which is the most common complication, among others such as retinal neovascularization and neovascular glaucoma. Fortunately, there are currently approved RVO-ME treatments such as laser photocoagulation, ranibizumab, aflibercept and dexamethasone implants.
Further results were emphasized by Dr. Xiaodong where he compared the GENEVA study with an identical phase 3 study based in China. This trial evaluated the safety and efficacy of dexamethasone intravitreal implant compared with sham treatment in Chinese patients with ME due to BRVO or CRVO.
While mean IOP peaked at 2 months, Dr. Xiaodong mentioned that no accumulated effect was observed after retreatment. The results of the China registration study showed that dexamethasone improved visual acuity in both BRVO and CRVO during the first 3 months where similar improvements were also seen with CRT in both BRVO and CRVO. Dexamethasone implants overall provided long-lasting and significant anatomical and functional improvements in Chinese patient populations with RVO.
Dr. Xiaodong also reviewed another study based in China comparing intravitreal dexamethasone with intravitreal ranibizumab for ME. Both dexamethasone and ranibizumab reduced CMT while also improving visual acuity at each follow-up. Although dexamethasone was accompanied with more side effects such as IOP, it required a lesser mean number of injections due to its sustained release.
How real-world data in RVO can affect actual practice
While clinical results may prove to be informative, there is still something to be said for ophthalmologists who practice and report real-world data. This data often begs questions like, “what is going to provide sustained visual improvement for my patient in the long run?” and “what are my options for patients who are non-responsive to particular treatments?”
As a supplement to the discussion, Dr. Marc De Smet from Canada, went over current practices in ophthalmology regarding RVO treatment. He stated that anti-VEGF treatment is certainly effective based on clinical trials with 40 to 50% of patients achieving a 20/40 vision or better. However, he also stated that “there is a drop-off over time” with those who require sustained injections becoming a problem in the long run.
In contrast with anti-VEGF treatment, Dr. De Smet noted that dexamethasone (Ozurdex, Allergan, Dublin, Ireland) is released over a long period of time, with maximized release at 1 month followed by stabilized release for 2 months. Depending on how severe the occlusion might be in an RVO patient, low drug release after this period may be sufficient enough for those who do not have severe ME or ischemia. Otherwise, for severely affected patients, Dr. De Smet recommends retreating due to the need for more steroids.
It is also important to consider patients who have had a vitrectomy as the release of Ozurdex will be sustained over a prolonged period of time. Dr. De Smet clarified that those who had a delay in treatment never reach the sort of recovery seen in those patients who were initially treated with a steroid. “With each month of delay, there is less chance of improved vision and recovery,” he said.
Dr. De Smet also explained that 15 to 20% of patients with less severe BRVO will respond with one or two injections and be fine. “Although age is not much of a predicting factor of resolution, naive and early treatment can determine the number of injections needed,” he added. Some patients will require more injections depending on the degree of ischemia present or whether the patient is tackling a more severe situation.
When asked about treatment parameters in the conversion to ischemic RVO, Dr. De Smet affirmed the use of steroids to prevent inflammation. Thus, while the prognosis may be altered, he did not indicate a change in treatment in these cases.
He concluded that anti-VEGF response is limited in many patients. A less than 25% decrease in CMT on anti-VEGF with the first injection can often elicit a poor response long term. Therefore, Ozurdex can be considered for both early and late treatment as well as a first line therapy, he said.
Defining early use in RVO
Results from the pivotal GENEVA study can at times obscure the shortcomings of the study, such as longer duration of ME and less optimal injection frequency. Patients were retreated at 6 months, although real-world data often indicates use of injections as early as 3 to 4 months as needed. In highlighting results from the COBALT study, Dr. Young Hee Yoon, a clinician from South Korea, answered the question of early use in RVO.
The COBALT study modified the GENEVA study design and implemented an early treatment strategy in naive patients of less than 3 months duration. It also modified the treatment interval to every 4 months. Consequently, these changes resulted in 65% of participants achieving a ≥15 letter gain at month 6, as well as a mean gain of 18.6 letters in BCVA at month 6.
Overall, Dr. Yoon expressed that early treatment of BRVO-associated ME with dexamethasone implant significantly and safely provides BCVA and CRT improvements. As early as 1 week, treatment with dexamethasone implant can show a 12.6 letter improvement.
Although an IOP of ≥25 mmHG was experienced by 18% of patients, all were managed with IOP-lowering medications. In total, 36% of patients showed progression of lens opacity. Dr. Yoon noted an optimal retreatment interval of 5 months according to the study. Re-treatment with 4 month intervals was required in eyes with high CRT and a large area of macular non-perfusion at baseline.
Editor’s Note: Reporting for this story took place at the 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) in Shanghai, China.
