From the Early Treatment Diabetic Retinopathy Study (ETDRS), we know laser treatment is the primary and only proven therapy for clinically significant macular edema.1 Laser therapy, performed according to the ETDRS protocol, basically doubled the chances that a patient would not experience significant vision loss compared to observation. Less than 3% of eyes in the ETDRS gained 15 letters at 3 years, and many eyes started the study with excellent visual acuity.
The Diabetic Retinopathy Clinical Research Network (DRCR.net) compared the modified ETDRS laser technique and the mild macular grid technique for diabetic macular edema (DME).2 That trial found that when patients with 20/40 or worse vision received modified ETDRS focal laser, they had a 29% chance of a three-line gain and a 49% chance of a two-line gain. Many researchers in pharmaceutical trials had no idea laser was this good because they were comparing their results with historical ETDRS data in which most patients had visual acuity better than 20/40 and, thus, were unlikely to be able to improve. Two illustrative cases follow.
CASE EXAMPLES
Figures 1 and 2 show a patient before and after focal laser.
I have always said that for small areas of edema, focal/grid
laser works great. For large diffuse edema, laser has been
suggested as not being as effective, but there is no uniform
definition of diffuse edema.3 In the DRCR.net study, patients
with very thickened DME were more likely to have resolution
of edema with laser than with intravitreal triamcinolone.
In addition, visual acuity outcomes were not superior
with triamcinolone compared with focal/grid laser.
Figures 3 and 4 show a macula with a great deal of edema.
I might have suspected that laser would not have helped,
but this patient responded nicely to macular laser therapy.
What other treatment options do we have? Researchers
also have explored the potential of pharmacologic agents.
STEROIDS AND ANTI-VEGF AGENTS
The short-term benefit of intravitreal steroids is obvious,
but we often see problems, such as cataract; and endophthalmitis
and glaucoma can develop over time. As the
DRCR.net study showed, steroids win at month 4. By month
12, they are equal to laser, and by month 16 and beyond,
laser wins.4
We also have explored the use of anti-VEGF agents, such as ranibizumab (Lucentis, Genentech, Inc.) and bevacizumab (Avastin, Genentech, Inc.). In the phase 2 Ranibizumab for Edema of the Macula in Diabetes (READ) study, Nguyen and colleagues showed a gain of one to two lines over 6 to 12 months with continued ranibizumab injections.5 Is there a problem with attacking DME with a relatively short-acting anti-VEGF agent? The difference between the use of these agents in age-related macular degeneration (AMD) is that in AMD, there is only minimal VEGF. In diabetes, VEGF is present in high concentrations and is produced continuously. You cannot keep using sponges to try to dry up a waterfall. So short-acting anti-VEGF agents may not be the answer for long-term diabetes care.
NEXT STEP: COMBINING THERAPIES?
We know that laser therapy works fairly well, and we see
short-term benefits from steroids or anti-VEGF agents, so
why not combine them? The DRCR.net is studying those
options in the Laser-Ranibizumab-Triamcinolone for DME
Study. Patients with clinically significant DME are randomized
to four groups:
2. Focal/grid laser plus ranibizumab.
3. Ranibizumab alone, and then focal/grid laser if needed.
4. Focal/grid laser plus triamcinolone.
The primary efficacy outcome is visual acuity. The secondary efficacy outcomes are the number of injections in the first year and the change in retinal thickening of central subfield and retinal volume measured on optical coherence tomography (OCT).
The main safety outcomes are: injection-related (endophthalmitis, retinal detachment); ocular drug-related (inflammation, cataract, cataract surgery, increased IOP, glaucoma medications, glaucoma surgery); and systemic drug-related (cardiovascular events). Hopefully, this and other well-designed studies will uncover additional options.
EARLY EXPERIENCE: LASER WITH ANTI-VEGF
Anti-VEGF therapy stops macular edema, but our current
agents provide only short-term VEGF blockade, thus limiting
the utility of anti-VEGF therapy. What is the answer to
this dilemma?
If you want to stop your bathtub from overflowing, you turn off the spigot. Should we, in effect, turn off VEGF? I believe we soon will determine the source of the VEGF, which will help us understand how to control it. I am not necessarily advocating that we ablate it, but I would like to find out what it is and either kill it pharmacologically or make it healthier. Although it is not proven, I postulate that it is possible that most of the VEGF that is causing macular edema could be coming from ischemia in the peripheral retina.
Figure 5 shows an early phase angiogram (left) with large areas of capillary nonperfusion; the late phase is on the right. Figure 6 shows diffuse central macular edema on Figure 3. Before grid laser treatment. Figure 4. After grid laser treatment. OCT. Figure 7 shows the laser treatment directed at the most ischemic areas. This patient also has proliferative disease, but we are performing some panretinal (scatter) photocoagulation (PRP) to treat macular edema only.
This approach was proven to not work in the original ETDRS, but at that time, anti-VEGF agents were not available, and we were unable to target our PRP to areas that looked angiographically compromised. So if we can decrease the VEGF drive, we hypothesize that we may be able to decrease the need for monthly or every 6-week anti- VEGF therapy. I think this needs further study.
We discovered early on that even with micropulsed pattern scan laser therapy delivered to targeted ischemic areas, we saw rebound edema. So we began to use targeted PRP for areas of nonperfusion in combination with intravitreal bevacizumab and then ranibizumab. We often saw significant rebound edema, probably an inflammatory response to the laser burns. In the end, we had to treat patients concomitantly with a steroid.
Figure 8 shows the 6-month results with this patient after we treated the areas that looked the most ischemic with targeted PRP and a concomitant triamcinolone injection. This case appears to be a success, but this technique needs to be validated before we can recommend it.
FURTHER STUDY NEEDED
Treatment of DME requires ongoing management of
patients' underlying systemic conditions, and it begins with
focal/grid laser as applied in the DRCR Network studies. It is
yet to be determined if combining some type of laser treatment
with an intravitreal agent will be superior to ETDRS
laser alone. I encourage everyone who treats DME to consider
supporting one or more of the DRCR.net trials to help
advance the treatment of this common problem. ■
2. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.
3. Browning DJ, Altaweel MM, Bressler NM, Bressler SB, Scott IU; Diabetic Retinopathy Clinical Research Network. Diabetic macular edema: What is focal and what is diffuse? Am J Ophthalmol. 2008;146:649-655.
4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1459.
5. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema.Am J Ophthalmol. 2006;142:961-969.
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