Experts consider new solutions to an old problem.
With the diabetic population growing, retina specialists are eager to adopt new therapies that improve patient care. Can pharmaceutical options, such as anti-VEGF treatments and corticosteroids, replace or minimize laser surgery and vitrectomy? Read on for some of the latest thinking.
WAITING FOR MORE EVIDENCE
“The gold standard in managing diabetic macular edema therapy has historically been laser photocoagulation and, in patients with significant epiretinal proliferation and traction, vitrectomy has been shown to be therapeutic,” says Dr. Antoszyk.1 “Laser is a destructive procedure and vitreous surgery is expensive and requires an operating room. The future of diabetic macular edema (DME) therapy lies with pharmacotherapy. Recently, intravitreal triamcinolone acetonide has been used in patients who have diffuse diabetic macular edema that is unresponsive to laser photocoagulation and also in conjunction with laser photocoagulation.2 Significant reductions in retinal thickening clinically and on OCT with a concomitant improvement in visual acuity are achievable, but the effects are short-lived and associated with significant side effects, including cataract formation and increased intraocular pressure. One group that seems to do particularly well is pseudopakic patients.”
The most exciting development in the management of diabetic patients with diffuse diabetic macular edema is the use of anti-VEGF agents such as bevacizumab, ranibizumab and the VEGF Trap-Eye drug aflibercept injection, according to Dr. Antoszyk.3 A randomized controlled trial by the Diabetic Retinopathy Clinical Research Network showed that ranibizumab plus prompt or deferred laser was associated with more visual acuity improvement than treatment with either intravitreal triamcinolone acetonide plus laser or with only the laser alone.4
“The DRCR.net has demonstrated significant results with intravitreal ranibizumab, including improved visual acuity and reduced OCT thickness in patients for up to 2 years,” says Dr. Antoszyk. “These results also demonstrated that the severity of retinopathy can be reduced with anti-VEGF therapy. But how often should you administer it? Which drug is best? Is the economic burden cost effective? These are just a few unanswered questions.”
Several recent studies support the use of bevicizumab and ranibizumab for DME treatment.5-7 But Dr. Antoszyk notes that a head-to-head comparison, indicating which anti-VEGF agent might be best, has been limited.8
Most physicians are treating diffuse macular edema with anti-VEGF therapy and the laser, which can be administered during the same day or on separate visits. “I expect this trend to continue for now,” he says.
REMEMBER THE BURDEN
Dr. Pieramici is also encouraged by the potential benefit of combination therapy. “We have to remember that DME presents a significant burden,” he says. “The disease is typically bilateral and many patients develop it at a young age. Using current anti-VEGF regimens will mean many bilateral injections over the course of many years for some patients. We'll have to identify ways to maximize the benefits of therapy while minimizing the need for retreatment and complications. I believe the fluocinolone acetonide implant, Iluvien (Alimera Sciences), may be a helpful adjunct because its effects may last for years in some cases.”9
Dr. Pieramici says despite good phase 3 clinical trial data, physicians should continue to evaluate today's new treatments to determine the best strategy for each patient. DME will require customized therapies and “trial-and-error approaches” to achieve the best results, he notes.
“For proliferative disease, laser is still the standard of care,” says Dr. Pieramici. Anti-VEGF therapy and corticosteroid therapy can help reduce macular edema after laser treatment, he adds, but whether it's an effective therapy to address the long-term management of proliferative disease will require further investigation.4
“Anti-VEGF also can be a helpful adjunct to vitrectomy, administered days before surgery, particularly in cases of severe fibrovascular proliferation, when extensive dissection is necessary,” he adds.
INJECTIONS AND LASERS
Dr. Boyer believes pharmacological treatment will reduce the need for laser therapy and improve visual results in DME over laser treatment alone.
“We've never observed such outstanding visual results as seen with anti-VEGF pharmacotherapy or with anti-VEGF therapy and laser combined,” he says. “The protocols for when to use the laser in these situations must be determined in the future. Treatment with the laser, for example, may work very well in areas of non-central foveal edema. Pharmacotherapy may be best in diffuse center-involving edema. Patients treated with the constant-release fluocinolone acetonide implant may also experience long-term visual improvement from a different long-term pharmacologic therapy.
“Although the patients studied in the FAME trials were not treatment naïve — they had to have undergone one previous laser treatment — the visual success with these implants alone shows we can achieve substantial visual improvement without the need for laser in the future. We'll have to figure out the paradigm of when to use each therapy. Combination treatment using anti-VEGF, steroids and laser will become the norm.”
Dr. Boyer says future treatment directions will be driven by data, including results from DaVinci and READ 2.10,11
“Drug-only therapy has given us the best visual results,” says Dr. Boyer. “The ongoing DRCR.net I and J studies will hopefully help answer these questions for us.”
LIMITATIONS OF COMBINATIONS
The practice of combining focal-grid laser photocoagulation with ranizibumab to treat DME was well supported in a 2010 study that was based on the DRCR.net I protocol.12 The study also considered corticosteroid treatment.
“A goal of the study was to explore how to minimize the number of injections,” notes Dr. Dugel. “Subjects could receive a maximum of 13 injections during the first year and a maximum of 13 additional injections in the second year. In the first year, the median number of injections was eight in the ranibizumab plus prompt laser group and nine in the ranibizumab plus deferred laser group. In the second year, the median number of injections was two and three, respectively. Even with these results, the treatment burden associated with returning to the office monthly for such a long time was enormous. Consider that the very first opportunity to reduce treatment burden by seeing the patient less than on a monthly basis was only at week 60 in this study.”
He adds that even under an ideal scenario, in which patients achieved 20/20 vision and normalized OCT findings at week 16, they still needed to be seen monthly. In this better-performing group, 25% avoided injections, but 90% of these patients required injections later.
“What that shows you is that if you treat DME as per the DRCR.net protocol I, the treatment burden is simply not sustainable,” says Dr. Dugel. “Patients must take off work, sit in your office, wait to be seen, undergo diagnostic tests, and so on. As good as the results were in this study, following the protocol exactly isn't sustainable in practice.”
Dr. Dugel says it's also important to remember that pseudophakic patients receiving a corticosteroid injection did just as well as with multiple injections of ranibizumab, suggesting that vision gains in the triamcinolone plus prompt laser group may have been masked by the development of cataract among patients who remained phakic for the duration of the study. The intraocular pressure in the corticosteroid group was significantly higher.
“Corticosteroids definitely have a role, but the adverse effects must be controlled,” he says. “We need a suitable drug-delivery device. Currently, we administer an enormous bolus dose and it goes away. It makes much more sense to have a continuous delivery of a smaller dose.”
The Alimera Iluvien implant, for instance, may have an important role in the treatment of DME, according to Dr. Dugel.
“I believe that many types of drug-delivery devices will play a major role,” says Dr. Dugel. “ I also believe we'll learn that DME is a disease requiring different treatments in different stages of disease progression. Treating all patients the same way doesn't make sense and monotherapy doesn't make sense. We'll need to customize combination treatments for each patient.”
FULL CONFIDENCE IN ALTERNATIVES
Dr. Colucciello firmly believes anti-VEGF therapy and corticosteroids can replace or minimize laser surgery and vitrectomy in some cases.
“There's still a place for the laser, however,” he adds. “The BOLT, RISE and RIDE studies have shown that anti-VEGF is better than the laser in terms of achieving visual acuity. I've been using them more frequently — in combinations as well — and it has reduced the amount of laser treatments we've been doing.”12,13
As laser treatments decrease and injections increase, Dr. Colucciello says new treatment paradigms are developing.
“The frequency with which we're going to have to treat these patients with anti-VEGF intravitreal injections hasn't been answered,” he notes. “We have to be mindful of practice efficiencies and multiple injections until we come up with the holy grail — a long-acting anti-VEGF.”
Dr. Colucciello says he uses treat-and-extend, achieving therapeutic windows of up to eight weeks after a three straight months of loading doses in some patients. “I'll continue with that approach. I'm also using dexthamethasone,” he says. “I find for occlusive disease and DME, it can be effective for 3 to 4 months. It costs more than triamcinolone, but it's much gentler to the eye in terms of IOP response.” ■
1. Diabetic Retinopathy Clinical Research Network; Beck RW, Edwards AR, Aiello LP, et al. Three-year follow up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251.
2. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-1449.
3. 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.
4. Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.
5. Kim M, Lee P, Kim Y, Yu SY, Kwak HW. Effect of intravitreal bevacizumab based on optical coherence tomography patterns of diabetic macular edema. Ophthalmologica. 2011;226(3):138-144.
6. Marey HM, Ellakwa AF. Intravitreal bevacizumab alone or combined with triamcinolone acetonide as the primary treatment for diabetic macular edema. Clin Ophthalmol. 2011;5:1011-1016.
7. Keane PA, Sadda SR. Retinal vein occlusion and macular edema — critical evaluation of the clinical value of ranibizumab. Clin Ophthalmol. 2011;5:771-781.
8. Ozturk BT, Kerimoglu H, Bozkurt B, Okudan S. Comparison of intravitreal bevacizumab and ranibizumab treatment for diabetic macular edema. J Ocul Pharmacol Ther. 2011;27(4):373-377.
9. Campochiaro PA, Hafiz G, Shah SM, et al; Famous Study Group. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010;117(7):1393-1399.
10. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: Phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118(9):1819-1826.
11. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117(11):2146-2151.
12. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-Month data: report 2. Ophthalmology 2010;117(6):1078-1086.
13. Colucciello M. Unpublished ongoing studies.
Retinal Physician, Issue: November 2011