Age-related macular degeneration (AMD) is the leading cause of blindness in elderly individuals. Treatments for the condition vary, but all options thus far have been limited to exudative (wet) AMD, which accounts for 10% of all cases of macular degeneration.1 Wet AMD is associated with choroidal neovascularization (CNV) formation that results in abnormal vascular growth and leakage within the macula. If left untreated, irreversible vision loss will ensue.
Until recently, there were but a few effective management options for patients with wet AMD. Treatments, such as laser photocoagulation and photodynamic therapy (PDT), simply decrease disease progression. However, antiangiogenic medications (anti-VEGF drugs) promise to treat AMD more effectively than laser correction, and may actually restore associated vision loss.
Laser Treatments
For years, laser photocoagulation was the standard treatment for wet AMD.2,3 This procedure uses a thermal laser to cauterize CNV. The Macular Photocoagulation Study demonstrated that laser photocoagulation was beneficial in reducing the risk of severe vision loss in patients with CNV.2,3 But, numerous complications have been reported in association with this procedure, including permanent retinal scars, scotomas and re-growth of neovascularization.2,3
In 2000, we witnessed a major breakthrough: PDT with Visudyne (verteporfin, QLT PhotoTherapeutics and Novartis Ophthalmics), an intravenously infused, photosensitive drug. Visudyne preferentially binds to CNV and is activated by a low-intensity laser, which induces a photochemical reaction. Platelet activation and thrombosis yields both occlusion of CNV and cessation of leakage.
Unlike laser photocoagulation, PDT spares destruction of normal retinal tissue, which makes the procedure a suitable treatment for selected subfoveal CNV.4-6 Benefits vary depending on the size and type of CNV.5,6 Although PDT successfully reduces AMD progression, re-treatment is often necessary.4,5
This patient with active CNV received two IV anti-VEGF treatments. Note the improvement between initial presentation (top) and one-month follow up (bottom).
Nevertheless, laser treatments for AMD have concentrated on either the destruction or closure of CNV. These options only slow disease progression and are primarily effective at treating classic, well-delineated CNV.3-5
Anti-VEGF Treatments
During the last few years, our understanding of the role of vascular endothelial growth factor (VEGF) in the pathogenesis of wet AMD has resulted in new pharmacological treatments: antiangiogenic drugs. By blocking vascular infiltration and permeability, anti-VEGF drugs have revolutionized the way we manage wet AMD.
The most widely recognized and readily available anti-VEGF drugs are Macugen (pegaptanib sodium, EyeTech Pharmaceuticals and Pfizer), Lucentis (ranibizumab, Genentech) and Avastin (bevacizumab, Genentech).
In 2004, Macugen became the first FDA-approved anti-VEGF treatment for wet AMD. Macugen targets a specific VEGF isomer (VEGF-165) that is believed to play a critical role in CNV development. The VEGF Inhibition Study in Ocular Neovascularization (VISION) demonstrated stabilization of vision in approximately 70% of patients with wet AMD who received Macugen.7 This finding was independent of the type of CNV. However, most of the results simply demonstrated a marginal visual gain at best.7
Lucentis is a recombinant humanized antibody derived from bevacizumab, a larger monoclonal antibody. Unlike Macugen, Lucentis has an affinity for all VEGF-A isomers, which contributes to its a potent pharmacokinetic property. Clinical trials have shown that Lucentis not only slows the progression of vision loss, but also improves vision in up to 40% of cases.8,9 Lucentis was approved by the FDA in 2006 and became the new gold standard treatment for wet AMD.
The following year, Philip J. Rosenfeld, M.D., Ph.D., presented evidence that Avastin was an effective treatment for wet AMD.10 Avastin has the same binding properties as Lucentis, but demonstrates a longer half-life. Currently, Avastin is FDA approved as a cancer treatment only, but it is used off-label to treat wet AMD.11
Small-scale studies and case reports have demonstrated that Avastin is well tolerated and is an effective and inexpensive treatment for wet AMD.10,12,13 Yet, to date, there are no rigorous randomized controlled trials that have reported on its safety profile or efficacy. The Comparison of AMD Treatments Trials (CATT) is a large-scale study funded by the National Institutes of Health, which is scheduled to start soon.14 It will compare the efficacy and safety of Lucentis and Avastin in the treatment of AMD.14
Which Treatment is Best?
Although landmark trials using anti-VEGF treatments have enhanced the way we manage wet AMD, the optimal induction-maintenance interval remains unknown. Pivotal studies have indicated that empirical quarterly treatments were not as favorable as monthly treatments.8,9,15 These findings suggest that some form of sustained anti-VEGF treatment interval is required.
Does this finding obligate the retinal specialist to administer monthly injections? Some patients require only a minimal series of injections for quiescent CNV.16 For them, an increased number of treatment intervals may result in additional cost and a cumulative risk of complications.
Many retinal specialists adhere to a treat-and-watch approach, in which patient symptoms, funduscopic findings and diagnostic tools (such as optical coherence tomography and fluorescein angiography) dictate retreatment frequency.16 This strategy includes three initial monthly injections, followed by re-injections on an as-needed basis.15 One drawback of this model is that it may allow for potential fluid accumulation between injections.
Another treatment model involves a treat-and-extend paradigm. In this scenario, a patient receives monthly treatments until the leakage is arrested. Then, he or she receives continuous maintenance treatments, as long as deterioration is not noted.17
So, the question remains: What is the best treatment plan for our AMD patients? There is no right or wrong answer. The bottom line is that we need to become familiar with the treatment protocols of retinal specialists in our communities to provide the most adequate comanagement approach.
Clearly, some patients may need more treatments, while others need fewer ones. Current monotherapy treatment options have certainly altered how we manage wet AMD. However, we need stronger and longer-lasting therapeutic modalities.
Age-related macular degeneration is a multifactorial disease, so new treatment modalities may need to address various pathways of the angiogenic cascade. As we look ahead, emerging research will focus on the advantages of combination therapies and sustained-release devices, which will set new expectations for future trials.18,19
1. The Eye Disease Prevalence Research Group. Cause and prevalence of visual impairment among adults in US. Arch Ophthlamol 2004 Apr;122:477-85.
2. Macular Photocoagulation Study Group: Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol 1994 Apr;112(4):500-9.
3. National Eye Institute. Macular Photocoagulation Study. Available at: www.nei.nih.gov/neitrials/viewStudyWeb.aspx?id=60 (Accessed May 6, 2008).
4. Barbazetto I, Burdan A,
5. 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 trialsTAP report. Arch Ophthalmol 1999 Oct;11710): 1329-45.
6. Verteporfin In Photodynamic Therapy Study Group 1. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularizationverteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001 May;131(5):541-60.
7. Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration.
8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration.
9. Brown DM,
10. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005 Jul-Aug;36(4):331-5.
11. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005 Jul 29;333(2):328-35.
12. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005 Jun;112(6):1035-47.
13. Rosenfeld PJ. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration (
15. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008 Feb;145(2):239-48.
16. Fung AE,
17. Brown D. Regillo C. Anti-VEGF agents in the treatment of neovascular age-related macular degeneration: applying clinical trial results to the treatment of everyday patients. Am J Ophthalmol 2007 Oct;144(4):627-37.
18. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003 Aug;110(8):1517-25.
19. Brown DM, Schmitz NT. Lucentis Utilizing Visudyne (LUV Trial) Combination Therapy in the Treatment of Age-Related Macular Degeneration. Available at: http://clinicaltrials.gov/ct2/show/NCT00423189?intr=%22Verteporfin%22&rank=16 (Accessed May 6, 2008).
