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A New Treatment for Ocular Neovascularization
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     Neovascularization leads to blindness in a large number of ocular disorders, most notably age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and other vascular occlusive diseases. Various versions of scatter-photocoagulation (laser) treatment in the peripheral retina have been shown to reduce the loss of vision that results from retinal vascular diseases but not from age-related macular degeneration.1,2,3 For example, scatter photocoagulation, along with vitrectomy when necessary, can reduce the risk of blindness in eyes with retinal neovascularization from diabetic retinopathy by 90 percent.4 Current treatments for the neovascular complications of age-related macular degeneration are nowhere near this effective, with the result that age-related macular degeneration is the leading cause of blindness in the United States.5

    Twenty years ago, ophthalmologists were hopeful that direct photocoagulation of the neovascularization associated with age-related macular degeneration would prove to be very effective. The short-term results of a clinical trial of this direct ablative treatment showed a reduction by 50 percent in the risk of severe loss of vision.6 Unfortunately, there were two drawbacks. First, because photocoagulation damages the retina, the treatment was limited largely to areas of neovascularization that did not involve the center of the macula, and thus only about 15 percent of the neovascularization resulting from age-related macular degeneration could be treated. Second, the follow-up data from this five-year trial were much less impressive than the initial results, largely owing to the recurrence of neovascularization, with extension beneath the fovea.7

    A major advance in our ability to treat the neovascularization associated with age-related macular degeneration occurred a decade ago, with the development of an ingenious technique that allows the treatment of neovascularization beneath the retina without serious damage to the retina itself. This approach, termed photodynamic therapy, relies on a photosensitive drug that has an affinity for neovascular tissue. The drug is delivered by means of an intravenous infusion, and several minutes later, photocoagulation of the choroidal neovascular lesion is performed with the use of an infrared laser. The infrared light passes through the retina, and the drug is photoactivated in the neovascular tissue, resulting in the closing of the neovascularization. Repeated treatments may be necessary, because these lesions often reperfuse. However, the treatment is generally successful in finally closing the neovascular lesions, and several clinical trials have shown that it can reduce the risk of severe visual loss by 30 to 50 percent, depending on the characteristics of the neovascular lesions.8,9 However, the treatment is far from optimal. At the time of treatment, most patients already have decreased visual acuity, and they continue to lose vision, despite the treatment. Only about 10 percent of patients have a substantial improvement in vision, and many are disappointed with their visual acuity after they have undergone multiple expensive treatments.

    More than 50 years ago, Michaelson suggested that an unknown factor was released by ischemic tissue in the eye and that this factor could be responsible for the development of neovascularization.10 After decades of searching by many investigators, Aiello and colleagues showed that the level of vascular endothelial growth factor (VEGF) was markedly elevated in the vitreous of patients with ischemic retinal diseases.11 The release of VEGF, induced by ischemia, can stimulate neovascularization and increase capillary permeability. Both of these effects are associated with a loss of vision in retinal vascular disease, and an intense search was initiated for a drug that could block VEGF in eyes at risk. The aptamer injected into eyes with age-related macular degeneration in the clinical trial described by Gragoudas and colleagues in this issue of the Journal12 is just such a compound. The high degree of compliance with multiple injections into the eye among the patients in this study is remarkable, and the side-effect profile of the injections seems tolerable. The trial showed a statistically significant reduction in the loss of visual acuity with this treatment as compared with sham injection, although it remains unclear to what extent this effect is due to a decrease in capillary permeability and to what extent it is due to an actual reduction in neovascularization.

    Unfortunately, the magnitude of the treatment effect in reducing the risk of visual loss is similar to that seen with photodynamic therapy and, as with photodynamic therapy, only about 10 percent of patients can anticipate improvement in their vision. If this new treatment is not dramatically better than photodynamic therapy, why is there such general enthusiasm for it? It is because we now have more than one way of attacking neovascularization, and thus may have the opportunity to test combinations of treatments, similar to the successful approaches used for various cancers.

    Although this treatment is not all that we would wish for, and although the mechanism of the treatment benefit remains unclear, the study by Gragoudas and colleagues marks the start of a new era in the treatment of age-related macular degeneration and other causes of ocular neovascularization. Their work shows that the intravitreal delivery of a drug is a viable approach. This treatment is one of many antiangiogenic and anti-VEGF therapies currently under study. It is hoped that one of these alternative treatments will have an even more impressive effect, or that perhaps these new treatments, in combination with each other or with photodynamic therapy, will result in the improvement in visual acuity and the destruction of the neovascularization that we and our patients desire. It is the efficacy of a new medical approach that makes this a landmark study. The hope is that it is the first step in the development of multiple effective treatments for neovascularization, especially for treatments that can be used to prevent the occurrence of neovascularization and its devastating complications.

    Source Information

    From the National Institutes of Health, Bethesda, Md.

    References

    Ferris FL III, Davis MD, Aiello LM. Treatment of diabetic retinopathy. N Engl J Med 1999;341:667-678.

    Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity randomized trial. Arch Ophthalmol 2003;121:1684-1694.

    Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol 1986;104:34-41.

    Ferris FL III. How effective are treatments for diabetic retinopathy? Commentary. JAMA 1993;269:1290-1291.

    Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-572.

    Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three-year results from randomized clinical trials. Arch Ophthalmol 1986;104:694-701.

    Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch Ophthalmol 1991;109:1109-1114.

    Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials -- TAP report. Arch Ophthalmol 1999;117:1329-1345.

    Blinder KJ, Bradley S, Bressler NM, et al. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003;136:407-418.

    Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc U K 1948;68:137-190.

    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;331:1480-1487.

    Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805-2816.(Frederick L. Ferris, III,)