RVO diagnosis and treatment

While the traditional approach to treating patients with retinal vein occlusion (RVO) involved watchful waiting, with laser treatment considered when vision worsened, the development of new imaging techniques and novel intravitreal treatment approaches is ushering in a new era in patient management. “When I was in training, if a person came in with a RVO, and that person had 20/20 vision, you would just watch and wait. If the person was 20/40 or worse, you watch and wait, and some would get better by themselves and some would not. If not, we might do laser. That is where we were not long ago. But now we understand that there are patients who might come in with 20/20 visual acuity (VA), but they complain bitterly about bad vision. A few years ago we didn't understand what was going on,” Pravin Dugel MD told EuroTimes in an interview. This is an example of where structural optical coherence tomography (OCT) imaging has advanced the understanding of RVO, said Dr Dugel, Managing Partner of Retinal Consultants of Arizona, Phoenix, and Clinical Professor at the University of Southern California Keck School of Medicine, Los Angeles, USA. Imaging studies revealed that such a patient might have an abnormal fovea, which would account for the vision complaint. Standard VA exams do not provide the information necessary to make that determination. “We understand that VA is not an adequate proxy or representation of visual function. Rarely are we in a dark room tunnel with a bright light at the end. Life has different lighting conditions - contrast, shade, glare and so on. Structural OCT gives information on what may affect visual function by causing subtle anatomical changes. In those patients we may choose to treat even though the vision is 20/20, because we understand that there is oedema there that is affecting visual function,” explained Dr Dugel. Indeed, OCT imaging studies have shown that there can be a price to be paid for delaying treatment in patients with good VA. While those patients who are treated after vision begins to deteriorate may get better following treatment, it has become clear that their vision will never be as good as it would have been had they been treated earlier, he added. Many clinicians, but not all, will still do routine fluorescein angiogram as part of the initial work-up of a patient with RVO. Fluorescein angiography is starting to fall out of favour in the management of age-related macular degeneration (AMD). What role does it have in RVO? “Fluorescein angiography is not crucial for the diagnosis and management of RVO disease, unless you suspect the existence of neovascularisation, and are not sure. However, I still tend to do fluorescein angiography at baseline mainly for assessing non-perfusion of the macula which has an impact on the prognosis for VA,” notes Anat Loewenstein MD, Chairman of the Division of Ophthalmology, Tel Aviv Medical Center, Israel.

Now we understand that there are patients who might come in with 20/20 visual acuity (VA), but they complain bitterly about bad vision

OCT ANGIOGRAPHY – 
A STRANGE SITUATION OCT-angiography (OCT-A) is one of the most exciting areas of retinal ophthalmic research today. Recent developments in hardware and software allow non-invasive three-dimensional vascular mapping of retinal and choroidal layers, showing structural and flow information. It is quickly finding a place in the diagnosis and management of neovascular AMD. However, its role in RVO is still in the developmental stage. “We are in a strange situation with OCT-A in general and as it pertains to vein occlusion. We know it is here to stay, we understand that it will be a paradigm we will be using for many diseases including RVO. We have a lot of studies that have shown very interesting findings, but we haven’t crossed the threshold where we have enough data to say OCT-A should be done. The biomarker data is simply not there yet. I have no doubt that it will be a diagnostic standard in the near future,” commented Dr Dugel. Indeed, an increasing amount of research appearing in the journals suggests that OCT-A will have an important role in the management of RVO. For example, researchers at the Karolinska Institute in Stockholm used OCT-A to evaluate factors associated with poor visual outcome in central RVO patients without macular oedema treated with anti-vascular endothelial growth factor (anti-VEGF) agents (Epstein et al, IOVS, 2016;57). They observed an association between an enlarged foveal avascular zone and poor VA. Another study, reported at ARVO 2016, compared OCT-A and fluorescein angiography for evaluating collateralisation in acute and chronic RVO. The researchers reported ‘perfect agreement’ between the two imaging systems in all patients (BP Jones et al. IOVS Vol.57, 5473). ARRAY OF OPTIONS FOR TREATMENT Laser photocoagulation has been a mainstay of therapy for RVO, specifically for macular oedema and for ischemia and neovascularisation. However, the success of anti-VEGF therapy for these indications, and, on the negative side, the destructive nature of the laser has led to much less use of the once traditional approach. “I only do pan-retinal photocoagulation in the rare cases of neovascularisation or neovascular glaucoma. I don’t think we have enough evidence for doing peripheral laser with the aim of controlling the macular oedema. If I treated the patient pharmacologically either with an anti-VEGF or steroid and there is no response, then I sometimes consider grid laser,” Dr Lowenstein told EuroTimes. A series of large clinical studies conducted in recent years confirm the value of anti-VEGF agents for RVO. Ranibizumab (Lucentis, Roche/Genentech) and aflibercept (Eyelea, Regeneron/Bayer) are both approved in the EU and the USA for the treatment of macular oedema following branch and central RVO. Both proved safe and effective in treating the oedema and in maintaining or improving VA. Bevacizumab (Avastin, Roche/Genentech) has shown similar effects in clinical studies and is used off-label. Which agent works best, and which regimen provides the best results with the least treatment burden? This is a focus of many clinical trials now under way. The large-scale LEAVO study aims to provide randomised clinical trial evidence on the comparative effectiveness of ranibizumab and aflibercept in central RVO patients. The results of another comparison study, the SCORE2 study, are expected soon. This was a non-inferiority study comparing aflibercept and bevacizumab in patients with macular oedema associated with central RVO. The primary outcome measure at six months was the mean change from baseline in VA letter score. Steroids, alone and in conjunctions with anti-VEGF agents also continue to have a role in RVO treatment. The dexamethasone intravitreal implant (Ozurdex, Allergan) is often used to provide an anti-inflammatory component to treatment. “I usually start with anti-VEGF treatment, Lucentis or Eylea. If there is a situation where the patient cannot tolerate the treatment burden and there is constant recurrence, or if there is a situation where the patient has reached a plateau and there is still oedema, I consider using Ozurdex. This does happen in approximately half of patients that I treat. In some cases Ozurdex decreases the treatment burden, and also addresses patients that may have a primarily inflammatory component causing resistance to anti-VEGF monotherapy,” notes Dr Dugel. It has become clear that, as good as they are, anti-VEGF treatments reach a physiological ceiling effect in the treatment of retinal vascular disease. There are no studies in neovascular AMD where treatment beyond four years maintains visions better than original baseline levels. Rather, there is a gradual deterioration associated with atrophy. There are also a small percentage of patients who do not respond well to anti-VEGF therapy. There is also a logistical ceiling effect where endless intravitreal injections are not feasible. This has driven the search for supportive therapeutic agents that could improve clinical outcomes while reducing the treatment burden of current monotherapy approaches. “We know we have to have a multimodal approach. We know that suppression of one chemical factor alone is not going to be sufficient. Neovascularisation and macular oedema are complex biological processes. VEGF is an important component, but it not the only component. Combination treatment is clearly the future,” said Dr Dugel. FULL PIPELINE Researchers had high hopes that blocking the activity of platelet-derived growth factor (PDGF), which plays a separate role in neovascularisation, could play a supportive role in combination treatment. This led to the development of the PDGF inhibitor Fovista (Ophthotech). However, the results of two international phase 3 studies caused considerable disappointment in the clinical research community. Those trials compared Fovista plus ranibizumab to ranibizumab alone in patients with neovascular AMD. The bottom line was that the combination did not provide additional benefit compared with ranibizumab alone. The angiopoietin pathway represents another potential front in the battle against retinal neovascularisation. A co-formulation developed by Regeneron (REGN910-3), combines aflibercept with nesvacumab, a novel anti-Ang2 monoclonal antibody. Early clinical research suggested the formulation was safe, with some evidence of benefit. A phase 2 clinical trial is under way in patients with neovascular AMD. Researchers at Roche Genentech have developed another approach seeking to exploit the angiopoietin pathway. The agent RG7716 is a unique bi-specific molecule with two different arms. One of these arms inhibits angiopoeitin2 while the other targets VEGF-A. The compound is held together with an Fc component engineered specifically for the retina. The Fc component includes one mutation that specifically decreases systemic absorption of the compound, while a second mutation decreases inflammation and effector cell function. Preliminary results from ongoing clinical studies with RG7716 indicating potential efficacy were presented at the 2016 AAO Annual Meeting in Chicago. Two phase 2 trials are under way, the AVENUE study for AMD and the BOULEVARD study for diabetic macular oedema (DME). “There are a lot of drugs in the pipeline. I think the most exciting are those that target the angiopoietin pathway. Clinical studies are under way with these agents, both for neovascular AMD as well as for DME. It would seem logical that if these agents prove efficacious, then treating vein occlusion would be the next step. This is the sequence we’ve seen with the anti-VEGF agents,” noted Dr Dugel. Anat Loewenstein: anatl@tlvmc.gov.il Pravin Dugel: pdugel@gmail.com   OCT-ANGIOGRAPHY: THE GAME CHANGER Optical coherence tomography (OCT) has proven to be an invaluable tool for retina specialists. More recently, OCT-angiography (OCT-A) has widened the scope of this imaging technology even further. EuroTimes asked Marco Lupidi MD, of University of Perugia, Italy, to provide some context for the rapidly evolving role of OCT in ophthalmology. The development of algorithms to analyse the contrast generated between static and non-static tissue in repeated consecutive B-scans was the basis for OCT-A. This “dramatic” change allows visualisation of retinal and choroidal perfusion in a depth-resolved approach, clearly distinguishing the superficial from the deep retinal capillary plexus, he noted. He explained that, with the development of OCT-A, it became possible to identify the exact morphology of a type I or II choroidal neovascularisation (CNV) and their anatomical and topographical relationship with outer retinal layers. “When considering retinal vein occlusion, OCT-A allows a precise assessment of the macular perfusion impairment. Not only the superficial capillary plexus, but also, and for the first time, we are able to analyse and quantify the deep capillary plexus and the potential damages induced by the occlusive process,” said Dr Lupidi. Marco Lupidi: dr.marco.lupidi@gmail.com

Tags: retina, retinal vein occlusion