Controversies in Care

Treating Macular Edema Associated With Retinal Venous Occlusive Disease

Michael Colucciello, MD

Retinal vein occlusions (central and branch) are the second most common retinal vascular diseases after diabetic retinopathy. The 15-year cumulative incidence of BRVO in the Beaver Dam Eye Study was 1.8%; the 15-year cumulative incidence of CRVO in that study was 0.5%.¹ We can expect an increase in incidence of these diseases with the increasing prevalence of diabetes mellitus and increased longevity in the population.

Macular edema is a well-known cause of vision loss in patients presenting with retinal venous occlusive disease. In addition to supporting and promoting cardiovascular and metabolic care for their patients, retina specialists have an ever-expanding array of local treatment options in their armamentarium.

Decades have passed since the retinal vein occlusion studies defined our current standard of care for treatment of patients with retinal venous occlusive disease and macular edema associated with vision loss. In 1984, the Branch Retinal Vein Occlusion Study demonstrated that focal laser treatment of macular edema in patients with branch retinal vein occlusions present for three months or longer and vision equal to or worse than 20/40 was beneficial.² In 1995, the Central Retinal Vein Occlusion study showed that, while focal macular laser treatment of these patients could reduce macular edema, there was no benefit regarding visual acuity.³

Recently new data have become available that substantiate treatment choices that may now be considered.

Increasingly, inflammation has been considered to play an important role in the pathophysiology and complications of vascular disease. It has been demonstrated that the risk of first myocardial infarction and stroke in men may be predicted by the level of systemic inflammation assessed by the plasma concentration of C-reactive protein, independent of the classic risk factors (hypertension, hyperlipidemia, diabetes mellitus, exposure to tobacco).⁴ In addition, an association between venous thromboembolism and the inflammatory markers interleukin 6 and 8 and tumor necrosis factor has been demonstrated.⁵

A clear association exists between inflammation, cytokines involved in the inflammatory process, vascular endothelial growth factor (VEGF), intravascular hydrostatic ("blood") pressure and increasing vascular permeability, which leads to edema.

Based on these principles, investigations regarding efficacy of intravitreal injections of anti-inflammatory steroid agents and inhibitors of VEGF activity have been undertaken.

The results of the CRUISE and BRAVO studies of anti-VEGF/dexamethasone implant and SCORE study of (BRVO and CRVO) triamcinolone have influenced our treatment selections in these patients. In addition, VEGF Trap-Eye, a VEGF receptor blocker that also has anti-placental growth factor properties, has shown promise in treating macular edema associated with retinal venous occlusive disease in early studies. Fluocinolone, a potent steroid, is being evaluated in an extended-release implant formulation for treatment in these circumstances.

The CRUISE study (Central Retinal vein OcclUsIon Study: Efficacy and safety) demonstrated that monthly intravitreal injections of 0.5 mg ranibizumab for six months in patients with CRVO with macular edema, vision greater than 20/320 Snellen equivalent and no "brisk" afferent pupil defect had a highly statistically significant mean gain of 14.9 ETDRS letters vision (three Snellen lines) associated with a dramatic reduction in edema compared to sham controls. Rapid gains were the rule: patients averaged a nine-letter gain in the first seven days after the initial ranibizumab injection. Following the initial six months, intravitreal ranibizumab, given when vision was worse than 20/40 or when central foveal thickness was >250 µm, maintained the gains noted in the first six months (an average of four injections over the next six months were needed).⁶

The BRAVO study (BRAnch Retinal Vein Occlusion) evaluated efficacy of six consecutive monthly intravitreal ranibizumab treatments in BRVO patients with macular edema, in a similar fashion to the CRUISE trial. Patients in the 0.5 mg ranibizumab group improved by 18.3 ETDRS letters (vs 7.3 letters in the sham group); 61.1% (vs 28.8% in the sham group) improved 15 or more letters. These results were again associated with a highly statistically significant edema reduction in the study group.⁷

The dexamethasone (Ozurdex) trial studied responses to the intravitreal biodegradable dexamethasone implant in patients with retinal vein occlusion complicated by macular edema. The peak effect of the implant is seen at 60 days. At day 60, evaluation of the 0.7 mg dexamethasone implant group showed that 38% of eyes with macular edema duration of <90 days and 27% of eyes with macular edema present for >90 days improved >15 letters, compared to 11% in the standard treatment group.⁸

The SCORE (Standard Care versus COrticosteroid for REtinal vein occlusion study)-CRVO trial demonstrated that 27% of CRVO patients with macular edema injected PRN (average 2.2 over 12 months) with 1 mg intravitreal preservative-free triamcinolone acetonide (vs 7% of observation group) achieved 15-letter ETDRS gains over 12 months. The vision benefit was demonstrated as early as four months and persisted at 24 months. Since the vision gain was no different in the 4 mg triamcinolone group, but the incidence of cataract and increased intraocular pressure was greater, the 1 mg dose has been recommended when considering this treatment.⁹

The SCORE-BRVO trial studied patients with macular edema due to BRVO; 1 mg and 4 mg intravitreal preservative-free triamcinolone treatments were evaluated against "standard of care." Beginning with the 12-month visit, and extending to the final analysis at month 36, the greatest improvement in vision occurred in the standard-care arm (29% gained at least 15 letters on the ETDRS chart).¹⁰

Retinal physicians have the anti-VEGF agents ranibizumab (Lucentis) and bevacizumab (Avastin), as well as preservative-free triamcinolone and the dexamethasone implant (Ozurdex) available for patients now; other therapeutic agents are being evaluated at this time that may be available in the future: VEGF Trap and the fluocinolone implant. Two Phase 3 studies (COPERNICUS [COntrolled Phase III Evaluation of Repeated iNtravitreal administration of VEGF Trap-Eye In Central retinal vein occlusion: Utility and Safety] and GALILEO [General Assessment Limiting InfiLtration of Exudates in central retinal vein Occlusion with VEGF Trap-Eye]) of VEGF Trap-Eye in central retinal vein occlusion (CRVO) are fully enrolled; initial data from these studies are anticipated in the first half of 2011. The FAVOR (Fluocinolone Acetonide intravitreal inserts for Vein Occlusion in Retina) study, utilizing the Iluvien intravitreal implant, is anticipated to report results in 2011.

UNANSWERED QUESTIONS

Many controversies now exist. What should be the preferred treatment in a given scenario? Should combinations be considered initially, later, or at all? Which anti-VEGF agent should be preferred, if any (a question with both medical and financial implications, due to the vast difference in the cost of the two agents)? What is the role of laser treatment in this "pharmacologic" era?

I will now consider some common clinical scenarios for consideration. I will assume that the retinal physician will work with the primary care physician to optimize metabolic and blood pressure care, and emphasize salt restriction to patients as a baseline in each — and discuss local treatment options.

In a patient with an acute branch or central retinal vein occlusion without macular edema, I advocate observation with monthly photographic evaluation until signs of resolution occur, or until macular edema occurs.

Figure 1. Branch retinal vein occlusion with macular edema and a significant hemorrhagic component, right eye, before (left) and after (right) five consecutive monthly bevacizumab injections.

In a patient with an acute branch or central retinal vein occlusion of less than three months' duration with macular edema and visual acuity better than 20/40, I advocate early treatment rather than waiting three months for spontaneous resolution. Advocates of waiting point out that one-third of patients in the Branch Retinal Vein Occlusion Study had spontaneous resolution. However, many had poor outcomes with observation, and current options are quite efficacious, so I advocate early treatment. My preference for these early cases is monthly intravitreal anti-VEGF injections, at least for three months (Figure 1). I would consider early laser treatment of a branch retinal vein occlusion complicated by macular edema without a significant hemorrhagic component, even with good visual acuity.

If there is a significant hemorrhagic component associated with macular edema in a branch retinal vein occlusion, or if there is macular edema associated with a central retinal vein occlusion, I will opt for beginning monthly treatment with an anti-VEGF agent, possibly for six consecutive months. Now, since bevacizumab is larger than ranibizumab and has more binding sites (perhaps improving half-life), I prefer bevacizumab. I plan on monthly injections for at least three months, and follow the patient with a combination of fundus photography and optical coherence tomography.

I will strongly consider adding the dexamethasone implant to the anti-VEGF treatment regimen in pseudophakic individuals, especially if they have a low cup-to-disc ratio and no evidence of glaucoma, when there is evidence of ischemia or in the presence of diffuse hemorrhage in the macula (Figure 2). I will also consider addition of the dexamethasone implant to help prevent rebound edema with an anti-VEGF regimen if I am planning panretinal photo-coagulation in a patient with an ischemic central retinal vein occlusion.

Figure 2. Nonischemic CRVO with macular edema and significant hemorrhagic component, right eye, before (left), and after (right) six consecutive monthly bevacizumab intravitreal injections and dexamethasone intravitreal implant. Note disc edema with Patton lines on the left; note resolution of disc and macular edema on the right, with decompression of veins and dexamethasone implant inferiorly.

I will utilize the dexamethasone implant as a primary treatment if there is anticipated an issue with monthly follow-up for several months, provided that the patient assures me that they will return for a one-month post-implant visit to check for an increased IOP response.

With additional treatment options, we have more controversy. What are your opinions? Send your feedback to michael@macula.us. RP

REFERENCES

1. Klein R, Moss SE, Meuer SM, et al. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008; 126:513-518.
2. 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.
3. 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.
4. Ridker, PM, Cushman, M, Stampfer, MJ, et al. Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men. N Engl J Med. 1997;336:973-979.
5. Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol. 2007; 264:306-311.
6. Brown DM. Safety and efficacy of intravitreal ranibizumab in patients with macular edema secondary to central retinal vein occlusion. The CRUISE study. Ophthalmology. 2010;117:1124-1133.
7. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion. Ophthalmology. 2010; 117:1102-1112.
8. Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117:1134-1146.
9. 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.
10. 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.