Reframing How We Think About Treatment for RVO
Changing therapy options require a change in our approach.
By Pravin U. Dugel, MD
The number of options retina specialists have for managing macular edema associated with retinal vein occlusion (RVO) has increased since observation was the prevailing approach and the only proven treatment, solely for branch occlusion, was laser photocoagulation. The increase in options has led to a focus on debating the question: Which treatment is best for RVO? I venture to say there is a better way to frame the issue.
First, we should understand that RVO, like any other chronic, complex disease, has a life cycle consisting of various stages. Oncologists, for example, have approached cancer this way for many years. Rather than simply diagnosing lung cancer or colon cancer, they delve deeper to categorize it at a specific stage, stage 1, stage 2, and so on, and use that insight to implement the appropriate treatment plan. Ideally, we would do the same with RVO. Clinically, we see the repercussions of RVO disease stages that follow the initial occlusive event — capillary permeability and leakage, edema, inflammation, vessel remodeling and recanalization, neovascularization if ischemia is present, and fibrosis. However, not all patients go through all the stages. Furthermore, although we know a multitude of chemical factors are involved, e.g., angiogenic and inflammatory cytokines,1-3 we’re still working to clearly define the stages at the cellular level and discern the relationships between them. Until we’re armed with that information, we aren’t able to predict, for instance, that a specific patient’s RVO is at the leakage stage and therefore an anti-VEGF agent alone will resolve his macular edema. In the meantime, what we can do is work with the life cycle of RVO in a roundabout way, by titrating our treatment options and perhaps combining* them until we arrive at what works for the individual patient. By doing this, we not only provide the best possible current care but also adopt the mindset that will be most helpful to us as our knowledge of RVO and associated macular edema expands.
Here, I summarize other key aspects of my approach to macular edema secondary to retinal vein occlusion.
The treatment criteria used in the early studies of laser for RVO and in subsequent anti-VEGF studies are outdated. Rather than observe patients for 3 months to see if macular edema spontaneously resolves and visual acuity improves to 20/40 or better, I treat all patients who have edema and a vision complaint, even if their Snellen visual acuity is 20/20. One reason is that the longer we wait to treat, the less vision we can expect the patient to recover. Another reason is that Snellen acuity is not a true assessment of visual function. It doesn’t take into account the real-world aspects of what constitutes clear, comfortable vision for patients, such as contrast sensitivity and color perception. I often see RVO patients with 20/20 Snellen acuity who say they’re having trouble seeing.
Gauging Response to Treatment
My most frequent first-line therapy for RVO-associated macular edema is an anti-VEGF agent, as it is for most retina specialists. I gauge whether it is adequate for a given patient based on a post hoc analysis from the BRAVO and CRUISE studies of ranibizumab4 (Lucentis, Genentech). The analysis showed that in patients with central retinal vein occlusion, 90% of the response to treatment occurred within the first three injections. Therefore, if I see no response after three injections, I’m confident that monotherapy will not be adequate, and I move to the next option. If I see robust improvement in macular thickness and visual acuity by the third injection, I’m inclined to continue with the injections until the response plateaus.
I use another subanalysis from BRAVO and CRUISE, the RETAIN study,5 as guidance. This analysis showed that despite a good visual response, approximately 50% of patients continue to need anti-VEGF injections for edema as much as 4 years later. This indicates that at least half of patients are likely better off if we use additional treatment to keep the retina dry, thus reducing the treatment burden.
Updated Approaches to Laser Treatment
The role of traditional laser treatment is becoming less and less relevant. It does produce benefits, but, as we know, it is also photodestructive, producing scarring and scotoma. Scars can expand slowly over time, which is especially troubling for young patients.
On the other hand, some recent developments in laser technology are encouraging. For example, Endpoint Management (Topcon Medical), for use with the PASCAL and Streamline lasers, is an innovative way to precisely control laser output. Through photostimulation, the retinal pigment epithelium cells can be selectively targeted with subthreshold treatment to prompt the necessary biologic response for decreasing edema, without collateral tissue damage. It will be interesting to see what further studies reveal about the safety and efficacy of these types of technology. In other words, although traditional laser photocoagulation may be less relevant in the treatment of RVO, selective laser photostimulation may have a role.
All steroids and steroid delivery devices are not the same. The pharmacokinetics (PK) of each is an important consideration in the treatment of macular edema. Injecting a bolus of steroid, such as intravitreal triamcinolone, results in a large increase of drug in the eye followed by a sudden decrease, which is not a favorable PK profile. Beneficial effects are minimized, and complications are maximized. In comparison, the dexamethasone intravitreal implant provides an initial burst of drug elution followed by a gradual decrease over time, a much more favorable profile. Complications are more predictable, and therefore more easily managed.
Thinking in terms of the life cycle of RVO-associated edema, we can see how using an anti-VEGF agent is a sensible option at the relatively early stage of capillary permeability. When inflammation becomes more of a factor, based on how the eye responds to anti-VEGF, the steroid implant makes sense. Studies have confirmed the safety of using it multiple times as well. Should the fluocinolone intravitreal insert (Alimera Sciences) receive FDA approval for RVO treatment, it could be a useful next step, in particular for eyes with very diffuse edema that could benefit from the device’s 3-year steady-state release of steroid.
Attention to Potential Complications
All of the available treatments for macular edema have side effects, which we must understand and manage. Anti-VEGF agents are certainly effective, yet they may increase the risk for systemic arteriothromboembolic events (ATEs). Even though there’s a lack of definitive data, we must be mindful of the trends. We do have to use caution in our patients who are at highest risk for ATEs, particularly patients 85 and older. Whether different anti-VEGF agents have different systemic safety profiles is not known. One theory that has been put forth suggests that the IgG1 protein could have an impact by allowing for greater systemic exposure. We are also learning that chronic anti-VEGF treatment may additionally have local side effects. This has been seen in neovascular AMD as geographic atrophy and fibrosis. The systemic and local side effects of chronic anti-VEGF treatment for RVO requires more study.
Our main concerns with steroid treatments are cataract formation and elevated IOP. As mentioned previously, using steroids with known favorable PK profiles improves our ability to predict and manage these side effects.
Whether we’re using monotherapy or combination therapies, we must use them in the context of the risk/benefit ratio for the individual patient. For example, in an 85-year-old patient with a history of heart attack or stroke, I prefer to use an anti-VEGF agent without the Fc fragment for a short period of time, and I’m more likely to switch to the dexamethasone implant quickly. I’m less likely to use the implant in steroid-responsive patients or patients with uncontrolled glaucoma, although several studies indicate the side effects are quite manageable in glaucoma patients with good IOP control.6 I do monitor such patients more closely than patients without these added risks. When deciding whether to use the dexamethasone implant in phakic patients, the risk/benefit equation is also an important consideration. For patients in danger of losing vision to fibrosis, for instance, the need for future cataract surgery becomes less of a concern. The clinical trials for both the dexamethasone and fluocinolone implants showed that eyes with these devices do very well with cataract surgery. As a final example, I’m more likely to use the dexamethasone implant rather than anti-VEGF therapy in a vitrectomized eye, because its sustained presence in the eye has been shown to be effective in this scenario.7
Further Progress to Come
As we learn more about the pathophysiology of RVO and its sequelae, we’ll be better able to select targeted treatment plans. We’ll also continue to benefit from the knowledge that most diseases of the retina share a final common pathway, leading to vision loss. Therefore, lessons learned from new therapies for age-related macular degeneration and diabetic macular edema will be applicable to vein occlusion. Anti-platelet-derived growth factor is an example of this potential cross-pollination of seemingly disparate diseases. Its potent anti-fibrotic effect is now being studied in AMD and may be applicable in RVO in the future.
In conclusion, we’ve made meaningful progress in RVO treatment in the past several years, and I believe additional treatment options are on the horizon. However, a better understanding of this and other chronic retinal diseases begins with an understanding of the life cycle of the disease.
1. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-1487.
2. Feng J, Zhao T, Zhang Y, Ma Y, Jiang Y. Differences in aqueous concentrations of cytokines in macular edema secondary to branch and central retinal vein occlusion. PLoS ONE. 2013;8(7):e68149.
3. Lee WJ, Kang MH, Seong M, Cho HY. Comparison of aqueous concentrations of angiogenic and inflammatory cytokines in diabetic macular oedema and macular oedema due to branch retinal vein occlusion. Br J Ophthalmol. 2012;96(11):1426-1430.
4. Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio RG. Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography. Ophthalmology. 2013;120(5):1057-1063.
5. Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN Study. Ophthalmology. 2014;121(1):209-219.
6. Capone A Jr, Singer MA, Dodwell DG, et al. Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (Shasta study). Retina. 2014;34(2):342-351.
7. Boyer DS, Faber D, Gupta S, et al.; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31(5):915-923.
* In my practice, more than 50 percent of patients have combination therapy.
Dr. Dugel is Managing Partner with Retinal Consultants of Arizona and a founding member of Spectra Eye Institute in Sun City. He is also a Clinical Associate Professor at the USC Department of Ophthalmology, Keck School of Medicine, University of Southern California.