Treating Macular Edema

Laser and intravitreal pharmacologic treatment of macular edema associated with diabetic retinopathy and retinal venous occlusive disease.

MICHAEL COLUCCIELLO, MD

Macular edema is a well-known cause of vision loss in patients presenting with diabetic retinopathy and retinal venous occlusive disease. Given the prevalence of diabetes and hypertensive vascular disease, retina specialists are frequently confronted with the issue of formulating a treatment plan for such patients. There is no absolute algorithm regarding the approach to patient care: the retinal physician takes into account the entire clinical picture, interacts with patients and their other physicians (eg, internist, endocrinologist, cardiologist, nephrologist), and can institute local treatment based on past and recent clinical studies regarding treatment of macular edema associated with retinal vascular disease.

When a patient presents with macular edema associated with retinal vascular disease, the patient is advised that optimization of blood pressure, blood sugar, lipid metabolism, and renal, cardiac and hematologic parameters is of utmost importance in the treatment of the edema. Consideration is also given to local treatment with focal macular laser photocoagulation and intravitreal antipermeability pharmacologic therapy with a steroid and/or an anti–vascular endothelial growth factor agent, and surgical delamination of macular epiretinal tissue (vitreous cortex or avascular cellular proliferation) to release mechanical traction.

This article will summarize major studies that have been conducted regarding laser and intravitreal pharmacologic approaches to aid retina specialists in our decisionmaking when the opportunity to treat these patients presents itself. Developments in these areas have been extensive; this article simply serves as a brief overview of the landscape of new and proposed therapeutic options. The reader may wish to investigate further the details behind each of these approaches to therapy, guided by the references.

DIABETIC MACULAR EDEMA
Laser Photocoagulation

Focal laser photocoagulation for treatment of "clinically significant" diabetic macular edema was studied in the Early Treatment Diabetic Retinopathy Study (ETDRS).¹ In this study, direct laser treatment of microaneurysms and "grid" treatment of microaneurysm clusters and areas of retinal capillary nonperfusion 500 to 3,000 μm from the foveal center was performed; this was repeated upon reevaluation every four months if the edema was persistent.

In the ETDRS, compared to the 1,490 eyes without treatment, the 754 eyes treated had an approximately 50% decrease in the risk of vision loss (defined as doubling of the initial visual angle or a loss of three or more lines). At three years of follow-up, 12% of treated eyes lost vision, compared to 24% of untreated eyes. Importantly, laser photocoagulation did not significantly improve vision in patients enrolled in the ETDRS.

In 2002, a collaborative network came into existence that was sponsored by the National Eye Institute and dedicated to facilitating multicenter clinical research of diabetic retinopathy: the Diabetic Retinopathy Clinical Research Network (DRCR.net). In their steroid vs laser study for DME (described further below), 26% of DME patients treated with laser did gain 15 or more letters of vision at three years.^2,3

Selective retina therapy (SRT) employs focal laser treatment using a Q-switched, frequency-doubled Nd:YLF (neodymium: yttrium lithium fluoride) laser, which selectively affects the retinal pigment epithelium while sparing the photoreceptor layer. SRT was recently studied for treatment of clinically significant DME.⁴ Overall, there was no change in retinal thickness, hard exudates, or leakage in fundus fluorescein angiography. However, there was moderate vision improvement: Average best corrected visual acuity did improve from 43.7 letters on the ETDRS chart (standard deviation, SD = 9.1) at baseline to 46.1 letters (SD = 10.5) at the six-month follow-up (P=.02). Vision improved (>5 letters) or remained stable (+/−5 letters) in 84% of eyes. The procedure was safe; there was no severe loss of vision (defined as loss of 15 letters or more).

Steroid

Triamcinolone. Small studies demonstrated efficacy of intravitreal preserved triamcinolone acetonide for treatment of DME.^5,6 However, another prospective randomized study of 88 eyes demonstrated no difference in visual acuity or central macular thickness with repeated intravitreal 4 mg triamcinolone compared with conventional laser therapy for persistent DME at one-year follow-up.⁷

The DRCR.net steroid vs laser study for DME^2,3 study compared 1 mg and 4 mg preservative-free triamcinolone intravitreal doses to macular laser photocoagulation, all repeated every four months as needed. Although the steroid groups fared better at the four-month follow-up, laser was superior at three years. Twenty-six percent of patients treated with laser photocoagulation gained 15 or more letters of vision at three years, vs 21% of patients treated with triamcinolone. Only 8% of patients treated with laser photocoagulation lost 15 or more letters of vision, compared to 16% of patients treated with triamcinolone. There was also a lower incidence of cataract and increased intraocular pressure with laser compared to triamcinolone.

The Verisome liquid triamcinolone delivery system (Icon Bioscience, Inc., Sunnyvale, CA) allows 13.8 mg of drug to be delivered to the vitreous cavity over a 12-month period (injected via a 30-gauge needle); phase 1 data presented at ARVO in 2010 showed promising one-year safety and efficacy results for its use in the treatment of DME.⁸

Figure 1. Clinicians must balance short-term and long-term outcomes when treating diabetic macular edema.

Dexamethasone. The 700 μg dexamethasone drug delivery system (Ozurdex, Allergan) implant, biodegradable in the vitreous cavity over six months, has been shown to significantly improve vision and reduce retinal thickness (by an average of 132 μm at 90 days) compared to observation in DME patients. The optimal effect of the implant occurs at three months. At day 90, a BCVA improvement of 10 letters or more was seen in more eyes in the 700-μg group (33.3%) than the observation group (12.3%; P=.007).⁹

Fluocinolone. The fluocinolone acetonide intravitreal implant (Iluvien, Alimera Pharmaceuticals) appears to be nearing FDA approval. This implant delivers drug for 24 to 36 months; it has been shown to be beneficial for DME in the FAME (Fluocinolone Acetonide in diabetic Macular Edema) study.¹⁰ In the FAME trial, 20% of the 0.5 g/day and 15% of the 0.2 g/day fluocinolone implant patients gained 15 letters vision at the 12-month follow-up. This improvement in vision was accompanied by a substantial reduction in excess foveal thickness. Recurrent edema occurred in some patients starting at the six-month visit.

There was a mild increase in IOP (mean 2.6 mm Hg increase at 12 months) with the 0.5 g/day implant; none of the patients receiving the 0.2 g/day implants had IOP >25 mm Hg at any time point.

Figure 2. Branch retinal vein occlusion with macular edema and exudative foveal detachment: clinical photograph and OCT images.

Anti-VEGF

A prospective study published in 2006 demonstrated a significant decrease in central foveal thickness and improved vision in DME patients treated with as-needed 1.25 mg intravitreal bevacizumab (Avastin, Genentech) over a 12-week follow-up.¹¹ Later, another small retrospective study demonstrated that intravitreal bevacizumab at doses of 1.25 mg or 2.5 mg seemed to provide stability and improvement in vision, foveal edema, and angiographic leakage in DME patients at six months.¹²

A prospective randomized trial completed in 2009 involving 126 patients showed that, during a span of six months, ranibizumab (Lucentis, Genentech) injections in months 1, 3 and 5 had a significantly better visual outcome than focal/grid laser treatment (with retreatment at three months if necessary) in patients with DME (the READ-2 trial).¹³

A two-year clinical trial (the BOLT study, reporting in 2010) demonstrated support for the use of intravitreal bevacizumab in patients with DME without advanced macular ischemia, compared to focal laser.¹⁴ The bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P=.0002). At 12 months, central macular thickness decreased from 507 �±145 μm at baseline to 378 ±134 μm (P<.001) in the bevacizumab group, whereas it decreased to a lesser extent in the laser group, from 481 ±121 μm to 413 ±135 μm (P=.02).

Ranibizumab, developed for intraocular use, is an antigenbinding fragment (Fab) derived from the same parent molecule as bevacizumab. A recently completed NIH study¹⁵ showed that nearly 50% of DME patients who received 0.5 mg intravitreal ranibizumab experienced substantial visual improvement after one year, compared with 28% who received standard laser treatment. Patients treated with intravitreal triamcinolone also gained, but not as frequently as ranibizumab (30%); they had a high frequency of increased IOP (30%) and cataracts requiring surgery (60%).

In this DRCR.net trial, intravitreal ranibizumab, either with prompt or deferred (24 weeks) focal/grid laser, resulted in superior visual acuity and optical coherence tomography outcomes compared with focal/grid laser treatment without ranibizumab at both one and two years of follow-up.

Optical coherence tomography may be used to predict response to intravitreal bevacizumab. Patients with diabetes showing cystoid macular edema upon OCT achieved greater improvements in visual acuity and macular thickness after intravitreal bevacizumab injection than patients with diffuse macular edema.¹⁶ Therefore, the type of macular edema shown by OCT may provide an objective guideline in predicting the response of DME to intravitreal bevacizumab injection: A 2007 DRCR.net study showed that OCT-measured center point thickness and visual acuity correlate, as do changes in retinal thickening and visual acuity after focal laser treatment for DME.¹⁷

VEGF Trap. VEGF Trap-Eye (Regeneron and BayerHealthcare AG), a fusion protein specifically designed to bind all forms of VEGF-A and placental growth factor (PLGF), has also been used to treat DME in an experimental protocol called DA VINCI (DME And VEGF Trap-Eye INvestigation of Clinical Impact). In the phase 2 study, at six months, vision and macular edema improved much more with VEGF Trap-Eye 0.5-2 mg administered every four to six weeks compared to laser.¹⁸

RETINAL VENOUS OCCLUSIVE DISEASE
Branch Retinal Vein Occlusion

Laser photocoagulation. The benefit of focal laser treatment of macular edema associated with branch retinal vein occlusion (BRVO) was confirmed with the Branch Retinal Vein Occlusion Study (BRVOS).¹⁹ The 71 treated eyes gained an average of 1.33 lines compared to a gain of 0.23 lines in the untreated 68 eyes (with a mean follow-up of 3.1 years). In the BRVOS, focal laser treatment was given if the retinal vein occlusion was associated with visual acuity of 20/40 or worse after three to 18 months duration, with sufficient clearing of intraretinal hemorrhage to allow adequate fluorescein angiography and laser. A spot size of 100 μm, duration 0.1 seconds, blue-green macular extrafoveal laser was used. Final visual acuity was at least 20/40 in 60% of treated eyes compared to 34% of untreated eyes.

Steroid. In the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE-BRVO) study, despite early benefits of steroid compared to laser, the final, longer-term results showed no significant difference between 1 mg and 4 mg intravitreal preservative-free triamcinolone and laser groups (26%, 27%, and 29%, respectively, gained three or more lines at three years). However, 49% of the 4 mg intravitreal triamcinolone group needed IOP-lowering medications and cataract progression was higher in the steroid group.²⁰

The 0.7 mg dexamethasone implant was approved by the FDA for treatment of RVO-related macular edema in June 2009. At the 90-day follow-up, 23.7% of the treated BRVO patients gained three lines, compared to 14.7% of the observed patients. The incidence of increased IOP seemed less than triamcinolone; it was 25% at six months.²¹

Anti-VEGF. Intravitreal ranibizumab demonstrated impressive efficacy in the BRAVO (Ranibizumab for the treatment of macular edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety) study. This phase 3 study showed brilliant results of treatment of BRVO with ranibizumab: 55.7% of patients treated with monthly 0.3 mg intravitreal ranibizumab injections and 61.1% of the 0.5 mg ranibizumab group improved three lines at six months, compared to 28.8% of the control group.²²

In a head-to-head study of intravitreal triamcinolone and bevacizumab for BRVO (10 patients in each group), both treatments decreased the central macular thickness, but only bevacizumab induced an improvement in visual acuity from baseline. This improvement was significant eight weeks after treatment, but no longer significant after 13 months.²³

Central Retinal Vein Occlusion

Laser photocoagulation. Focal macular photocoagulation is not recommended for macular edema associated with central retinal vein occlusion (CRVO): While angiographic macular edema was found to decrease with focal macular laser photocoagulation in the Central Retinal Vein Occlusion Study, such treatment did not affect visual prognosis.²⁴

Steroid. Intravitreal triamcinolone has shown promise for treatment of CRVO. A 2005 study demonstrated that intravitreal triamcinolone, reinjected with recurrent or persistent macular edema, was associated with a decrease of central foveal thickness from an average of 635 μm to 352 μm with an average visual gain of 1.3 Snellen lines over a mean follow-up of 10 months in a retrospective chart review of 24 eyes with central or hemicentral retinal vein occlusion.²⁵

In the SCORE-CRVO study, 26% and 27% of the 4 mg and 1 mg intravitreal triamcinolone groups (with reinjections every four months when needed for recurrent edema) respectively gained three lines at one year, compared to 7% in the control group. There were also far fewer three-line losers in the steroid group. The 1 mg dose was favored based on the side effect profile.²⁶

The dexamethasone implant also showed benefit in the CRVO patients: At the 60-day follow-up, 28.7% of treated subjects gained three lines vs 8.8% of the observed patients. At 90 days, the difference narrowed: 17.6% treated subjects and 10.2% of the observed had a three-line gain.²¹

Figure 3. The dexamethasone intravitreal implant (inferior) in place in a patient with CRVO.

Anti-VEGF. Ranibizumab has shown efficacy for treatment of CRVO/ME. The results of the CRUISE (Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety) study paralleled those of the BRAVO study.²⁷ In the CRUISE study, 46.2% of CRVO patients treated with monthly 0.3 mg intravitreal ranibizumab and 47.7% of the 0.5 mg ranibizumab group, compared with 16.9% of the sham group, improved three lines at six months. Visual improvement occurred in the first week in the anti-VEGF group.

VEGF Trap. Two major VEGF Trap CRVO trials are in progress. The COPERNICUS (COntrolled Phase III Evaluation of Repeated iNtravitreal administration of VEGF Trap-Eye In Central retinal vein occlusion: Utility and Safety) study is being led by Regeneron and the GALILEO (General Assessment Limiting Infiltration of Exudates in central retinal vein Occlusion with VEGF Trap-Eye) study is being led by Bayer HealthCare. The primary endpoint of both studies is improvement in visual acuity vs baseline after six months of treatment. Initial data are anticipated in early 2011.

SUMMARY

Retinal physicians have more options than ever before for treatment of macular edema due to hyperpermeable retinal vascular disease (Table 1).

Since there are many options, treatment can be individualized based on unique patient characteristics and the side effect profile of each treatment. The anti-VEGF agents have demonstrated impressive short-term results; there will be much interest going forward to see whether the results hold in the long term. The prospect of extended-release preparations, newer agents such as VEGF Trap-Eye, and combination therapy gives more hope that in the future vision gains can be achieved with greater frequency and will hopefully be sustained. RP

REFERENCES

1. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796-1806.
2. 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.
3. Diabetic Retinopathy Clinical Research Network, Beck RW, Edwards AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245-251.
4. Roider J, Liew SH, Klatt C, et al. Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2010 Apr 15. [Epub ahead of print]
5. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927.
6. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a doublemasked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113:1533-1538.
7. Ockrim ZK, Sivaprasad S, Falk S, et al. Intravitreal triamcinolone versus laser photocoagulation for persistent macular oedema. Br J Ophthalmol. 2008;92:795-799.
8. Lim JI, Hung D, Fung AE, Wieland M. Wong V. One-rear results of a phase 1 study evaluating the safety and evidence of efficacy of a single intravitreal injection of the Verisome™ liquid drug delivery system for sustained release of low-dose triamcinolone (IBI-20089) in eyes with cystoid macular edema. Paper presented at: 82nd Annual Meeting of the Association for Research in Vision and Ophthalmology; May 2-6, 2010; Fort Lauderdale, FL.
9. Haller, JA, Kuppermann BD, Blumenkranz MS, et al.; Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289-296.
10. Campochiaro PA, Hafiz G, Shah SM, et al.; Famous Study Group. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010 Mar 2. [Epub ahead of print]
11. Haritoglou, C, Kook, D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999-1005.
12. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al.; Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology. 2007;114:743-750.
13. Nguyen QD, Shah SM, Heier JS, et al.; READ-2 Study Group. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study. Ophthalmology. 2009;116:2175-2181.
14. 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 Apr 21. [Epub ahead of print]
15. 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 Apr 22. [Epub ahead of print]
16. Roh MI, Kim JH, Kwon OW. Features of optical coherence tomography are predictive of visual outcomes after intravitreal bevacizumab injection for diabetic macular edema. Ophthalmologica. 2010;224:374-380.
17. Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525-536.
18. Paper presented at: Angiogenesis 2010; February 10, 2010; Miami, FL.
19. Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271-282.
20. 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;127:1115-1128.
21. Haller JA, Bandello F, Belfort R, et al.; Ozurdex Geneva Study Group. Randomized, sham-controlled trial of dexamenthasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010 Apr 22. [Epub ahead of print]
22. Campochiaro PA, Heier JS, Feiner L, et al.; BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Apr 14. [Epub ahead of print]
23. Guthoff R, Meigen T, Hennemann K, et al. Comparison of bevacizumab and triamcinolone for treatment of macular edema secondary to branch retinal vein occlusion in a pair-matched analysis. Ophthalmologica. 2010;224:319-324.
24. Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology, 1995;102:1425-1433.
25. Cekic O, Chang S, Tseng JJ, et al. Intravitreal triamcinolone treatment for macular edema associated with central retinal vein occlusion and hemiretinal vein occlusion. Retina. 2005;25:846-850.
26. Ip MS, Scott IU, VanVeldhuisen PC, et al.; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127:1101-1114.
27. Brown DM, Campochiaro PA, Singh RP, et al.; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: sixmonth primary end point results of a phase III study. Ophthalmology. 2010 April 14. [Epub ahead of print]