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About 33% of patients with diabetes have some level of diabetic retinopathy (DR), and, of those, 7% will progress to diabetic macular edema (DME).1 Medical therapies have decreased the severity of DME and DR in recent years, and timely treatment can reduce severe vision loss by 90%. Even with these advances, DME remains a leading cause of blindness in developed countries.2,3
To treat DME and preserve vision, retina specialists need to keep the macula fluid-free. Panretinal photocoagulation endured as the gold standard DME treatment for decades,4,5 but after 2 years, 20% of patients experience worsening vision.6
The advent of anti-vascular endothelial growth factor (VEGF) therapy in the early 2000s transformed the field because of their safety and effectiveness;7 DME patients receiving anti-VEGF injections with agents such as bevacizumab, ranibizumab, and aflibercept experience greater improvements in vision than with laser alone.8,9
Despite these advantages, anti-VEGF treatments are heavily reliant on patient compliance and buy-in, because treatment requires long-term commitment and monthly visits for monitoring/treatment in the first few years.
Some studies have indicated that greater injection frequency leads to improved outcomes10,11 and recommend a fixed 4-week follow-up interval. This treatment frequency has led to a number of challenges for physicians and patients, including overtaxing ophthalmology clinics and increased financial burden and time constraints for patients and their caregivers.
One single-center study showed a 3-fold increase in clinic visits, from 3 to 9 per year, over a decade due to the exponential growth and use of anti-VEGF injections.12
Treatment burden relief, however, is gaining interest in the retinal community as studies are now showing alternative dosing regimens may be equally effective.
There are emerging data showing that fixed monthly injections may not be needed to properly control DME after all.
Treat-and-extend and/or as-needed (PRN) approaches may be the treatment “sweet spot” for patients and providers by providing disease control with fewer clinic visits and greater compliance. It’s important to note that both treat-and-extend and PRN dosing require patients to have 6 monthly injections upon presentation. The differences lie in the frequency of treatment needed for appropriate long-term disease management over time.
Physicians using a PRN approach treat patients based on their discretion, using visual acuity and the presence of fluid on imaging such as optical coherence tomography (OCT) to inform their decision.
PRN was assessed in Protocol I from the Diabetic Retinopathy Clinical Research Network, which compared the visual acuity of patients treated with intravitreal ranibizumab with either prompt or deferred laser, intravitreal triamcinolone with prompt laser, or sham injection with prompt laser.8
Patients were initially treated with monthly ranibizumab for 6 months, and treatment continued until their vision reached 20/20 and macular thickness was less than 250 µm, among other factors. Treatment stopped until the patient’s vision dropped 10 or more letters from baseline.
The PRN approach in Protocol I successfully decreased the appointment burden through year 3.Patients had an average of 13 clinic visits in year 1, 8 visits in year 2, and 7 visits in year 3. Visual acuity was maintained through 5 years.13
Treat and extend
With treat-and-extend, the dosing interval depends on disease activity as assessed through OCT and visual acuity. Initially, like PRN, the patient is treated monthly until the macula dries and vision and macular thickness stabilizes.
Once stabilization occurs, a baseline is established through OCT, and the treatment interval is extended 1 to 2 weeks at a time until fluid returns or vision worsens. The interval is then shortened by 1 to 2 weeks at a time until the fluid resolves and the eye stabilizes.
The TREX-DME trial was specifically designed to evaluate the effectives of less-frequent anti-VEGF dosing by comparing monthly ranibizumab, treat-and-extend ranibizumab with laser, and treat-and-extend ranibizumab without laser.14 Researchers found no statistically significant differences in visual acuity between the three arms at 1 year, but the treat-and-extend regimen greatly reduced the number of clinic visits.
David M. Brown, MD, presented year 2 TREX-DME results during the 2017 Retina Subspecialty Day at the American Academy of Ophthalmology meeting, and found that year 1 data endured; the visual acuity among the three groups remained simliar.15
Treat-and-extend, PRN, and monthly fixed-dosing are all appropriate management strategies in the treatment of DME. Based on available data, treat-and-extend may provide similar visual outcomes and disease control with less frequent visits to clinic, saving patients and physicians valuable time and resources and increasing patient compliance.
1. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35(3):556-64.
2. Romero-Aroca P. Current status in diabetic macular edema treatments. World J Diabetes. 2013;4(5):165-9.
3. Calvo P, Abadia B, Ferreras A, et al. Diabetic macular edema: options for adjunct therapy. Drugs. 2015;75(13):1461-9.
4. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-806.
5. Relhan N, Flynn HW, Jr. The Early Treatment Diabetic Retinopathy Study historical review and relevance to today's management of diabetic macular edema. Curr Opin Ophthalmol. 2017;28(3):205-12.
6. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-9, 9 e1-10.
7. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-203.
8. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-77 e35.
9. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972-9.
10. Hussain RM, Hariprasad SM, Ciulla TA. Treatment Burden in Neovascular AMD:Visual Acuity Outcomes are Associated With Anti-VEGF Injection Frequency. Ophthalmic Surg Lasers Imaging Retina. 2017;48(10):780-4.
11. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
12. Jusufbegovic D, Mugavin MO, Schaal S. Evolution of controlling diabetic retinopathy: Changing Trends in the Management of Diabetic Macular Edema at a Single Institution Over the Past Decade. Retina. 2015;35(5):929-34.
13. Bressler SB, Glassman AR, Almukhtar T, et al. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016;164:57-68.
14. Payne JF, Wykoff CC, Clark WL, et al. Randomized Trial of Treat and Extend Ranibizumab with and without Navigated Laser for Diabetic Macular Edema: TREX-DME 1 Year Outcomes. Ophthalmology. 2017;124(1):74-81.
15. Brown DM. TREX-DME Trial: two year outcomes. American Academy of Ophthalmology Annual Meeting Retina Subspecialty Day. New Orleans: 2017.
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