January 2013




Retinal pharmacotherapy for the anterior segment surgeon

Anti-VEGF agents changing diabetic retinopathy treatment paradigm

by Erin L. Boyle EyeWorld Senior Staff Writer

Carl Baker, M.D.

Tamer H. Mahmoud, M.D.

Dante J. Pieramici, M.D.

Sharon D. Solomon, M.D.

Thomas W. Stone, M.D.


Drugs are increasingly becoming first-line treatment option

The traditional first-line treatment paradigm for proliferative retinopathy and clinically significant diabetic macular edema has been laser treatment followed by surgery in advanced cases, but that is shifting with the approval of an anti-VEGF agent.

"Only in recent years with the advent of anti-vascular endothelial growth factor (VEGF) therapy has there been a paradigm shift in the treatment of diabetic macular edema (DME)," said Sharon D. Solomon, M.D., Katharine M. Graham Professorship, associate professor of ophthalmology, Wilmer Eye Institute, and Johns Hopkins University, School of Medicine, Baltimore. "Several randomized, multicenter clinical trials have demonstrated that intravitreal anti-VEGF therapy alone or in combination with focal or grid laser is more efficacious with respect to increasing visual acuity from baseline and reducing central retinal thickness compared to laser therapy alone in patients with DME," she said.

Thomas W. Stone, M.D., partner, vice-president, Retina Associates of Kentucky, Lexington, Ky., said the treatment paradigm for diabetic retinopathy is in a "state of transition."

"For many years we've had excellent data on the use of macular photocoagulation in this disease, but over the past few years, the use of injectable medication has been shown to be as good, if not better, than laser," he said. "In many cases, the first-line treatment is to initiate anti-IOL in proper position post-opVEGF medication and determine how the patient responds before deciding on laser or other treatments."

Innovations in treatment

Diabetic retinopathy is usually treated when it is in the proliferative stage, unless patients have retinal swelling, or DME, which is often more commonly treated first. In August 2012, the U.S. FDA approved the anti-VEGF agent Lucentis (ranibizumab, Genentech, San Francisco) for the treatment of DME. It was previously approved for the treatment of wet age-related macular degeneration and macular edema following retinal vein occlusion. Another anti-VEGF agent, Avastin (bevacizumab, Genentech), has not been approved for the treatment of proliferative diabetic retinopathy or DME, but can be used off-label. Most recently, EYLEA (aflibercept, Regeneron Pharmaceuticals, Tarrytown, N.Y.), also known as VEGF Trap-Eye, was approved by the FDA for wet AMD and macular edema following central retinal vein occlusion, but could be used off-label for DME and proliferative retinopathy as well.

"There is a growing consensus that anti-VEGF treatment plays an important role in the management of diabetic macular edema, and there is quite a lot of interest in the role that anti-VEGF injections may play in proliferative diabetic retinopathy as well," said Carl Baker, M.D., Paducah Retinal Center, Paducah, Ky., and vice-chair, Diabetic Retinopathy Clinical Research Network. "Overall, the management of diabetic retinopathy is improving. Better screening is yielding earlier detection and better visual outcomes. Better medical management of systemic hypertension and hyperglycemia is delaying the progression of ophthalmic disease."

Surgical techniques have also evolved for proliferative retinopathy cases warranting surgery, said Tamer H. Mahmoud, M.D., associate professor, vitreoretinal surgery, Duke University Eye Center, Durham, N.C. Advancements have been allowing for smaller gauge surgery of 23-, 25-, and 27-gauge vitrectomy. "It is possible nowadays to do complex cases with smaller gauges, and the new vitrectomy probes have ports, or the opening of the vitrectomy probe, very close to the end, making it much easier and safer to get closer to the areas of traction and be able to dissect those from the surface of the retina," he said. In complex surgical cases that need bimanual technique, multiple possibilities are also available, Dr. Mahmoud said.

"Options include using a lighted pick, together with forceps or scissors or a soft tip to detach the adherent hyaloid, or insert a chandelier to be able to have access with forceps and scissors. In very complex cases, use the tissue manipulator and membrane peeler cutter scissors with light supplied by the three-way tissue manipulator as well as diathermy at the tip," he said.

Role of laser

Thermal laser photocoagulation was the treatment of choice in DME cases since the 1990s, when the landmark Early Treatment Diabetic Retinopathy Study (ETDRS) found that focal photocoagulation reduced risk of moderate visual loss in DME patients, Dr. Solomon said. Then, the more recent Diabetic Retinopathy Clinical Research Network (DRCR.NET) Protocol I showed that intravitreal ranibizumab with laser was more effective than laser only in DME with foveal center involvement at one year. Recent three-year results confirm the effectiveness of injections, Dr. Solomon said.

Additional studies with similar findings include the READ-2 Study, the RESOLVE Study, the RESTORE Study, and the RISE and RIDE Studies.

However, those studies have largely examined central-involved DME, so in threatening but non-central macular edema cases, treatment with laser is still often the best solution, said Dante J. Pieramici, M.D., California Retina Consultants, Santa Barbara, Calif.

"If the edema does not involve the center of the retina, and is threatening the center of the retina, then either we can do traditional laser therapy or we might consider just watching that patient and when it does involve the center of the retina, then consider using anti-VEGF therapy," Dr. Pieramici said.

Dr. Baker said there are limited data treating patients with excellent vision with anti-VEGF treatment alone in studies on the subject.

"In my practice, I am more likely to use macular laser to treat truly focal areas of exudation, i.e., circinate lipid rings within 500 μm of the macular center, and in patients with better vision where DME is related to leaking microaneurysms not in the macular center," he said. "For most other cases of DME treatment, I prefer to start treatment with intravitreal anti-VEGF agents. I will certainly consider adding macular laser in cases where the response to anti-VEGF is suboptimal."

An important question to consider would be the current role of laser, Dr. Mahmoud said. He said that most current anti-VEGF trials included patients with subfoveal DME of a specific thickness. Those trials emphasize the better outcome with injections alone. However, for patients with macular edema that does not involve the center but is clinically significant with micro-aneurysms seen as the source of leakage outside the fovea, laser photocoagulation would be the treatment of choice because it typically resolves the edema, he said.

Dr. Stone also uses laser in those cases where the focal edema is outside the macula but threatening it. Additional factors for laser are good vision and asymptomatic cases, he said. He said such cases often do not need the repetitive nature of the intravitreal injection treatment regime. "And with their good vision, I have the time for the laser to work. I've found it [to be] very successful," he said.

Future of treatment

The future of treatment for proliferative retinopathy and DME will most likely include a combination of the current treatments with new delivery methods or products, Dr. Pieramici said. He emphasized that physicians need to remember that diabetic retinopathy patients have a systemic disease that also needs to be controlled and should be monitored by a team of physicians. It is important that the team communicates on the status of the patient.

"We can have a big effect on the disease and the progression of the disease by controlling the systemic health, so it's important to counsel our patients to be following up with their medical doctor and encouraging them to do better with their systemic control because that will help," he said.

Advances in lasers could also enhance their use, with such technology as IRIDEX's (Mountain View, Calif.) TxCell Scanning Laser Delivery System, which uses a multi-spot scanning that appears more efficient than the traditional single-spot mode, in the approval pipeline.

Dr. Mahmoud said the future of diabetic retinopathy treatment could be a combined approach that employs injections, steroids, laser, and small gauge vitrectomy on a case-by-case basis. "I don't think we can take the information from clinical trials and all the evidence-based medicine that we have and apply it to every patient in our clinic," he said. "It has to be a custom approach. What's the status of diabetes, are they insulin dependent or non-insulin dependent? Do they have concomitant high blood pressure? Do they have high cholesterol? Do they have neuropathy, kidney disease, have had strokes or heart problems? What's their age? What's the hemoglobin A1c? Every one of us is genetically different, and it may be that our response to injections will differ."

In the future, a slow-release method of administering anti-VEGF drugs could enhance patient quality of life by reducing office visits, Dr. Solomon said. She called the potential of such drug delivery methods a "great leap forward" that could help enhance the treatment of DME. Dr. Stone said the future would most likely also yield results of anti-VEGF agents for proliferative retinopathy. "It's encouraging that we can offer our patients a wider array of treatment options going forward for this potentially blinding disease," he said. "While most of the therapy has centered on DME, there's certainly a role for anti-VEGF agents in proliferative disease as well. It will be interesting to see the results of the ongoing studies on this condition."

Editors' note: Dr. Pieramici has financial interests with Genentech, ThromboGenics (Brussels), Allergan (Irvine, Calif.), and Regeneron. The other physicians have no financial interests related to this article.

Contact information

Baker: 270-442-1671, eyedude3@paducaheyes.com
Mahmoud: 888-275-3853, tamer.mahmoud@duke.edu
Pieramici: 805-963-1648, dpieramici@yahoo.com
Solomon: 410-955-3518, ssolomon1@jhmi.edu
Stone: 800-627-2020, drstone@retinaky.com

Anti-VEGF agents changing diabetic retinopathy treatment paradigm Anti-VEGF agents changing diabetic retinopathy treatment paradigm
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