Not so long ago, the only real treatment we had to offer patients with diabetic macular edema (DME) and branch retinal vein occlusion (BRVO) was thermal laser photocoagulation. Two landmark trials, the Early Treatment Diabetic Retinopathy Study1 and the Branch Vein Occlusion Study,2 established the respective benchmark treatments for these conditions in the 1980s.

Lately, however, treatment paradigms have been changing in both DME and BRVO. The availability of pharmacologic interventions, including intravitreal injection of anti-VEGF agents, steroids, and long-lasting steroid implants, has broadened our horizons and shown that other approaches to treatment can play a role in management of DME and BRVO. This article reviews some of what we have learned, and explores the new role of laser as 1 weapon in our armamentarium, rather than our sole therapeutic option for treatment of these conditions.

DME

The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I provided a lot of answers about primary management of patients with DME. These are questions we all had as the newer pharmacologic therapies began to appear. What do we do when we first see a patient: Should we laser first, then inject anti-VEGF? Inject first, then laser? When do we give steroids?

From that study it clearly emerged, at both the 1- and 2-year timepoints,3,4 that anti-VEGF injections are an integral part of treating DME. Intravitreal ranibizumab with prompt or deferred laser was more effective, compared with prompt laser alone, in the treatment of DME involving the central macula.

Note, in this trial there was no difference in ultimate outcome between the prompt and deferred laser groups— but some patients never needed the laser. This was a small percentage of patients, less than 10%, but clearly there were patients in the study who received 1 or 2 anti-VEGF injections and needed no more treatment. So this brings us to a paradigm shift; for patients with DME with center involvement, treatment can start with a series of injections, and in some patients laser may never be needed.

It must be recognized that laser as a first-line therapy will still have a role in some patients. If a small area of focal swelling, or a circinate exudate from a microaneurysm, can be readily identified on clinical exam, color photograph, or optical coherence tomography (OCT), grid laser may be a very effective first-line treatment in that case. But when the swelling under the fovea is more diffuse, laser is no longer the gold standard approach in DME.

Another reason to be more reserved in our use of laser in DME is that laser may limit the patient's visual potential. It is not that lasering decreases the effectiveness of subsequent anti-VEGF injections; however, after aggressive laser, the patient's chances of getting back to 20/20 visual acuity can be somewhat decreased.

Laser therapy can provide vision stabilization for many patients with DME, but generally it does not improve vision. Anti-VEGF therapy, by contrast, has been shown to improve visual acuity in patients with DME. The series of phase 3 clinical trials sponsored by Genentech—RISE, RIDE, RESOLVE, RESTORE5-8—all point to the fact that anti-VEGF injections are an important part of therapy for DME. In those trials, the agent used was ranibizumab (Lucentis, Genentech), but other anti-VEGF agents may prove equally effective. Aflibercept (Eylea, Regeneron, Inc.) is currently being evaluated in phase 3 studies for treatment of DME.

There also appears to be a role for steroids in management of DME. Emerging evidence suggests that, in chronic edema, in both DME and BRVO, there is an inflammatory cascade that is not necessarily addressed by anti-VEGF therapy. This is where steroids may play a role.

In a subgroup analysis of DRCR.net Protocol I,3 among patients who were pseudophakic at baseline, those who received intravitreal triamcinolone acetonide had results comparable to those in the two ranibizumab groups. Also, in the FAME trials9 comparing the fluocinolone implant (Iluvien fluocinolone acetonide intravitreal implant, Alimera Sciences) with placebo, patients with DME of greater than 3 years duration fared better with the Iluvien implant. Remember, even though the implant did not receive US Food and Drug Administration (FDA) approval for treatment of DME, it did meet its clinical endpoint in these 2 parallel clinical trials. The dexamethasone implant (Ozurdex dexamethasone intravitreal implant, Allergan, Inc.) is also currently undergoing phase 3 clinical trials in the setting of DME. It remains to be seen how and in what form extended-duration steroid therapy for DME will be available to US physicians.

Surgery will continue to have a role in DME, although in general it will be reserved for use in patients who have not responded to other therapeutic attempts, usually including laser, steroids, and anti-VEGF treatments. In the DRCR.net vitrectomy study in patients with DME and vitreomacular traction (VMT),10 results were mixed; vision improved after vitrectomy in about one-third of patients, stayed the same in about a third, and worsened in a third. In the era of pharmacotherapy, therefore, the role of vitrectomy is going to be limited, and almost always secondary.

Previously, when all we had in our armamentarium for DME was laser, our approach was relatively simplistic: Is there edema or not? With more therapeutic options recently available, our view of DME has become more nuanced. Now we can ask more questions. Is the edema diffuse or focal? Is it chronic or acute? The future of treatment for DME in most cases will probably be some kind of combination: steroid and laser, steroid and anti-VEGF.

Although anti-VEGF treatment of DME has shown outstanding results in clinical trials, it must be noted that these trials mandated monthly treatment—36 injections over a period of 3 years. For patients in their 40s and 50s, as many of our diabetic patients are, monthly injections are a considerable burden. Therefore, as we come to understand our therapeutic options better, we may employ those with a longer period of action—both laser and steroid implants would fit in this category—to attempt to extend the duration of therapy and give patients good vision with longer intervals between treatments.

BRVO

Paradigms are also changing in the treatment of BRVO. Large-scale clinical studies such as BRAVO,11 GENEVA,12 and others have taught us that the observation period that we typically used to recommend in patients with BRVO is no longer valid. Patients in these trials who were treated earlier—whether with steroid implant in GENEVA or anti-VEGF in BRAVO—had a greater potential to gain vision; that is, those who were crossed over to the treatment arm at 6 months experienced improvements in vision, but not as great as those who received the treatment starting at baseline.

In addition, in subgroup analysis of data from the GENEVA trial,13 patients who had macular edema for a shorter period of time had a greater chance of gaining vision.

Nowadays, therefore, we are treating patients with BRVO earlier. If a patient comes in with decreased vision secondary to a robust BRVO, I offer treatment immediately, most often anti-VEGF.

I said above that the role of laser in management of DME is decreasing. The question in management of BRVO is becoming: When do we use laser at all? Rarely will I use laser first today in a BRVO, certainly not on the macula. Giving a series of anti-VEGF injections is relatively benign, compared with thermal laser, so we might as well start with that.

The next question, however, is what do we do next? For many patients with BRVO, 2 or 3 anti-VEGF injections are all they need. When BRVO-related edema persists and patients require chronic therapy, treatment choices require more subtlety.

I obtain wide-field fluorescein angiography (FA) for all vein occlusions, including BRVO, in order to better understand the level of ischemia. For patients in whom FA shows extensive peripheral retinal ischemia, I am more prone to be aggressive in treatment with laser— but in the periphery, not in the macula.

For many patients with chronic edema from BRVO, the best choice may be the dexamethasone implant (Figure 1). As with patients with DME, those with BRVO are often young and still working, and frequent visits for intravitreal injections are a burden.

Earlier today I saw a patient I would consider a typical candidate for the dexamethasone implant. He has persistent edema from a BRVO. With treatment his visual acuity is 20/20, but it worsens to about 20/40 when edema returns. He initially responded well to bevacizumab (Avastin, Genentech) injections, but he became tired of seeing me every 4 weeks. He is in his 50s and cannot put his professional life on hold to spend 2 hours in my office once a month. So a year ago we had a conversation. I told him we could continue anti-VEGF injections, or I could perform macular laser (he did not have a lot of peripheral ischemia) or insert a dexamethasone implant. The effect of the latter 2 options would last longer, perhaps 4 to 5 months. Macular laser may leave a scotoma. With the dexamethasone implant there is an elevated chance of cataracts. Or with anti-VEGF injection I will see you again in 4 weeks. Today I put in his third dexamethasone implant.

We are learning that all steroids are not the same. The SCORE study14 showed that intravitreal triamcinolone injection resulted in no better outcomes than grid laser in BRVO but elevated levels of adverse events (glaucoma and cataract). The fluocinolone implant has been shown to have a higher level of adverse events than the dexamethasone implant; in a trial in patients with DME,15 nearly 5% of patients with the fluocinolone implant required glaucoma surgery. By contrast, the effect of the dexamethasone implant is not as long.

Overall, there is definitely a trend to treat patients with BRVO earlier. In earlier trials in BRVO, there were requirements for a duration of macular edema of 90 days, or in some cases there were observation periods built into the protocol. In more recent trials, such as BRAVO, CRUISE, and GENEVA, the trend is in the opposite direction; patients with macular edema of less than 90 days duration were treated in the active study arms.

Our treatment decisions today are based on much more information than in previous decades. Believe it or not, the landmark BVOS study, which guided our treatment of BRVO—the second most common retinal vascular disease— for more than 20 years, enrolled only a grand total of 139 eyes. Now we have evidence from treatments in thousands of patients with anti-VEGF agents, steroids, and steroid implants. When you add up all the experience in these studies, we have a better understanding of the natural history of BRVO. And we have new treatment options that are improving outcomes.

The next step will be to use this information and these new treatment options to devise an algorithm that maximizes visual potential while minimizing the treatment burden and side effect profile. In both DME and BRVO, we have not set aside the use of thermal laser, but it will have a more limited role alongside the new pharmacologic options for treatment of these conditions.

Szilárd Kiss, MD, is an Assistant Professor of Ophthalmology and Director of Clinical Research at Weill Cornell Medical College and an Assistant Attending Physician at the New York Presbyterian Hospital. He is a member of the Retina Today Editorial Board. Dr. Kiss states that he is on the speakers' bureau, is a consultant for, and/or has had research sponsored by Genentech, Allergan, Inc., and Optos; that he is a consultant for and has had research sponsored by Regeneron, Inc.; and he is a consultant for Alimera Sciences. He can be reached via e-mail at szk7001@med.cornell.edu.

  1. [No authors listed] Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987;94(7):761-774.
  2. [No authors listed] Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104(1):34-41.
  3. Elman MJ, Aiello, LP, Beck RW, et al; The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6): 1064-1077.e35
  4. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.
  5. Two pivotal Phase III Lucentis studies showed patients with diabetic macular edema experienced significant improvements in vision and fewer developed more advanced retinopathy [press release]. South San Francisco, CA; Genentech. http://www.gene. com. Accessed July 27, 2011.
  6. Wolf S, Massin P, Bandello F, et al; RESOLVE Study Group. Safety and efficacy of ranibizumab treatment in patients with diabetic macular edema: 12-month results of the RESOLVE Study. Paper presented at: Association for Research in Vision and Ophthalmology annual meeting; May 3–7, 2009; Fort Lauderdale, FL.
  7. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): A 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399-2405.
  8. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.
  9. Antoszyk A, for the FAME Study Group. Efficacy and safety of Iluvien (fluocinolone acetonide [FAC] intravitreal insert) for the treatment of diabetic macular edema. Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2011; Fort Lauderdale, FL. Abstract #6645.
  10. Diabetic Retinopathy Clinical Research Network Writing Committee on behalf of the DRCR.net, Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;117:1087-1093.e3
  11. Campochiaro PA, Hafiz G, Channa R, et al. Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: two-year outcomes. Ophthalmology. 2010;117(12):2387-2394.e1-5.
  12. Haller JA, Bandello F, Belfort R Jr, et al; for Ozurdex GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.
  13. Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmology. 2012;119(6):1190-1198. Epub 2012 Feb 22.
  14. Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128.
  15. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118(8):1580-1587.