eMedicine Specialties > Ophthalmology > Retina
ARMD, Exudative: Treatment & Medication
Updated: Jun 25, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Laser treatments
Thermal laser photocoagulation
Ophthalmologists have traditionally used thermal laser destruction of CNV as the primary treatment of exudative AMD based on the results of the Macular Photocoagulation Study (MPS). This study, which was initiated in the 1980s and supported by the National Institutes of Health, demonstrated that laser photocoagulation of extrafoveal, juxtafoveal, and subfoveal CNV limited the risk of severe reductions in visual acuity compared with observation alone.
Patients were eligible for laser photocoagulation if they had classic CNV, as determined by FA. However, only 13-26% of all patients with exudative AMD presented with this inclusion pattern. Therefore, it was unclear whether laser photocoagulation was beneficial to a majority of patients with exudative AMD.41,42,43,44,45,46 Moreover, at least one half of the enrolled subjects had persistent or recurrent CNV within 2 years of treatment.42,43
Today, thermal laser photocoagulation is usually reserved for CNV outside the fovea and for treatment of the variants of exudative AMD, including retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy.14,47 Although data from the subfoveal CNV arm of the MPS suggested that laser photocoagulation was better than observation, most clinicians do not treat subfoveal CNV with thermal photocoagulation because of the induction of an immediate, iatrogenic, central scotoma.43,44 Researchers have searched for alternative methods of treating subfoveal CNV with laser, including feeder-vessel photocoagulation48 and transpupillary thermotherapy49 ; however, these methods are not widely used clinically.
Photodynamic therapy
To avoid creating a central blinding scotoma when treating subfoveal CNV with thermal laser, clinicians turned to PDT. After intravenous infusion of a photosensitizing dye and a sufficient delay to concentrate it into pathologic choroidal neovascular tissue, the photosensitizer is stimulated with a specific wavelength of light focused through the pupil to it within the CNV. The dye reacts with water to create oxygen and hydroxyl free radicals, which, in turn, induce occlusion of the pathologic vasculature by means of massive platelet activation and thrombosis while preserving the normal choroidal vasculature and nonvascular tissue.50,51,52
Verteporfin therapy
In April 2000, the US Food and Drug Administration (FDA) approved PDT with verteporfin (Visudyne; QLT Therapeutics, Inc, Vancouver, British Columbia, Canada, and Novartis Ophthalmics, Bulach, Switzerland) for use in patients with predominantly classic, subfoveal CNV caused by AMD. Marketing approval was granted in Europe in July 2000, and the drug is currently commercially available in more than 70 countries for the treatment of predominantly classic CNV.53
Verteporfin is a modified porphyrin with an absorption peak near 689 nm that is delivered intravenously for 10 minutes. After a 5-minute delay, the CNV complex is irradiated through the pupil with a large-spot diode laser at 689 nm for 83 seconds. The laser energy activates the intravascular photosensitizer and stimulates the photodynamic action within the pathologic CNV. Verteporfin is cleared rapidly from the body, resulting in minimal skin sensitivity by 5 days.
In 2001, the 2-year results of the Treatment of AMD with PDT (TAP) trial were published. TAP consisted of 2 randomized, prospective, double-blind, placebo-controlled phase III trials with 609 subjects. Second-year data showed that 59% of treated eyes lost less than 15 letters on a standardized eye chart compared to 31% in the control group when the lesion was predominantly classic.19 The TAP trial was unmasked after 2 years of follow-up, and investigators continued with an open-label extension (to 36 mo) in 124 of the 159 original TAP participants with predominantly classic CNV. The data revealed that visual acuity remained nearly constant and the number of required repeat treatments decreased.54
Although standard PDT with verteporfin has shown promise in treating some forms of CNV, it is expensive, typically slows vision loss rather than improves it, and requires numerous repeat treatments. Therefore, other interventions to treat subfoveal CNV membranes were developed.
Antiangiogenic agents
VEGF inhibitors
Animal and clinical studies have established VEGF as a key mediator in ocular angiogenesis.55,56 In clinical trials, particular attention has focused on the development of pharmaceutical agents to block or neutralize VEGF expression.
Pegaptanib sodium
Pegaptanib sodium (Macugen; OSI Pharmaceuticals, Inc, Melville, NY and Pfizer, Inc, New York, NY) is an anti-VEGF pegylated aptamer that demonstrated both safety and efficacy in clinical trials compared to placebo. This intravitreally administered polyethylene glycol (PEG)–conjugated oligonucleotide was specifically designed to bind and neutralize VEGF165, hypothesized to be the predominant VEGF isomer associated with CNV in humans.
The VEGF Inhibition Study in Ocular Neovascularization (VISION) Study was comprised of 2 phase II-III multicenter, randomized, placebo-controlled trials. Enrollment of 1186 subjects was completed in July 2002. The 12-month data for all types of CNV showed that 70% of subjects receiving a 0.3-mg intravitreous injection every 6 weeks lost less than 3 lines of vision versus 55% of control subjects receiving sham injection (P <0.001),57 which is a similar efficacy to PDT.
The FDA accepted a new drug application (NDA) for wet AMD in August 2004, as did the European Medicines Agency (EMEA) in September 2004.58 On December 17, 2004, the FDA approved the drug, which became available for consumer use in the United States in January 2005.59
Ranibizumab
Ranibizumab (Lucentis; Genentech Inc, South San Francisco, CA, and Novartis Ophthalmics, Basel, Switzerland), an intravitreally injected, recombinant, humanized, monoclonal antibody fragment designed to actively bind and inhibit all isoforms of VEGF, has become a common treatment for exudative AMD.
The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (formerly, RhuFab) in the Treatment of Neovascular AMD (MARINA) was a phase III randomized, prospective, double-blind, placebo-controlled comparison of ranibizumab against sham controls. Investigators enrolled 716 patients to receive 24 monthly intravitreal injections (0.3 mg or 0.5 mg) or sham injections. At 12-month follow-up, 95% of those treated with monthly ranibizumab injections had improved or stable vision versus 62% of control subjects receiving sham treatment (P <0.001). More importantly, 34% of participants receiving the 0.5-mg dose experienced at least a 15-letter improvement that was maintained over 2 years (P <0.001).40
The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial was another prospective, randomized, multicenter, double-blind phase III trial designed to compare ranibizumab versus verteporfin in 423 subjects with predominantly classic exudative AMD. Similar to MARINA, 96% of subjects receiving 0.5 mg of ranibizumab had improved or stable vision versus 64% receiving verteporfin (P <0.001). Visual acuity improved in 40% of subjects receiving the 0.5-mg dose versus 6% in the verteporfin group (P <0.001).60
These trials altered the treatment paradigm of exudative AMD from a condition in which vision loss could only be slowed or stabilized to one in which visual acuity improvement was a real possibility. Clinicians are now attempting to maximize visual acuity while minimizing the number of retreatments to eyes with exudative AMD. The PIER trial gave 3 monthly injections of ranibizumab followed by quarterly injections over a 24-month interval. The 3-month results mirrored MARINA and ANCHOR; however, visual acuity gains declined once quarterly dosing began. The PIER data suggest that quarterly injections are less effective than monthly dosing.61
A newer approach is based on the Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Lucentis (PrONTO) Study, a small, uncontrolled open-label study, that treated patients with 3 monthly ranibizumab injections followed by monthly follow-up and redosing on an as-needed basis. The visual acuity improvements remained near the level of MARINA and ANCHOR, but the average number of retreatments dropped to 5.6 over 12 months.62 Other clinicians are adopting the "treat and extend" approach, where patients are treated with 3 serial monthly ranibizumab injections followed by gradually extending the interval between subsequent injections until fluid reaccumulates. If a time pattern of recurrence develops, tailored treatments can be adopted.
Bevacizumab
Prior to the commercial availability of ranibizumab, bevacizumab (Avastin, Genentech Inc, South San Francisco, CA) was attempted as an off-label VEGF inhibitor to control exudative AMD. Bevacizumab is a full-length humanized monoclonal antibody against human VEGF, whereas ranibizumab is a fragmented humanized monoclonal antibody against human VEGF. The FDA approved bevacizumab for the treatment of metastatic colorectal cancer on February 26, 2004.63
Researchers initiated the Systemic Avastin for Neovascular ARMD (SANA) Study, an open-label uncontrolled pilot study of 9 subjects with subfoveal CNV, to evaluate the efficacy of systemic intravenous bevacizumab. Patients were infused with 5 mg/kg bevacizumab every 2 weeks for 2-3 treatments. Follow-up through 12 weeks revealed significant improvements in mean visual acuity (P = 0.008) and central retinal thickness (P = 0.001) over baseline with a marked reduction in leakage on FA.64
To allay concerns about systemic morbidity, an intravitreal injection route was detailed in a case report in 2005 that demonstrated marked reduction of subretinal fluid and stable visual acuity.65 Numerous small studies have subsequently supported the use of intravitreal bevacizumab by demonstrating decreased retinal thickness and improved visual acuity over baseline.66,67,68,69,70
Because ranibizumab ($1950/dose) and bevacizumab ($50-75/dose) have an enormous price differential, yet, as many retina physicians feel, comparable effectiveness, a great deal of interest exists in comparing the 2 medications directly. The National Eye Institute has recently funded a large randomized controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) that is expected to begin enrollment in early 2008 and be completed by 2011 (www.clinicaltrials.gov, CATT study).
Combination therapies
Several clinical researchers have performed a variety of treatment combinations in attempting to maximize visual acuity recovery while minimizing the number of retreatments in exudative AMD.71,72 Larger randomized clinical trials are currently underway, including trials combining Visudyne PDT/VEGF inhibitor (LUV Trial, DENALI, MONT BLANC), Visudyne PDT/VEGF inhibitor/corticosteroid (RADICAL, TAPER), and Visudyne PDT/corticosteroid (VERITAS).
Surgical Care
Vitreoretinal surgeons have attempted to remove CNVM with direct surgical excision of the CNV complex. In 1998, the National Eye Institute of the National Institutes of Health awarded funding to the Submacular Surgery Trial (SST).
This study was a large randomized clinical trial comparing submacular CNVM removal versus observation. Patients were followed for 2 years and assessed for stabilization or deterioration of their visual acuity, a change in contrast sensitivity, cataract development, surgical complications, and quality of life. The trials did not demonstrate significant benefit of submacular surgery over observation.73,74
Medication
Visudyne for PDT of subfoveal, predominantly classic CNVM was approved in 2000, as outlined Medical Care.
Ranibizumab (Lucentis) was approved by the FDA in 2006.
In addition, various experimental protocols (eg, antiangiogenic agents) are currently under investigation; some of these are outlined in Medical Care.
Phototherapy agents
These agents are used for PDT in cases of subfoveal, predominantly classic CNV membranes.
Verteporfin (Visudyne)
Benzoporphyrin derivative monoacid (BPD-MA), consisting of equally active isomers BPD-MAC and BPD-MAD, which can be activated by low-intensity, nonthermal light of 689-nm wavelength. After activation and with oxygen, forms cytotoxic oxygen free radicals and singlet oxygen, which damages biologic structures in range of diffusion, leading to local vascular occlusion, cell damage and cell death.
Phase III data from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group showed that 61% of 402 eyes treated lost <15 letters of visual acuity at 12 mo vs 46% of 207 eyes receiving placebo (P <.001). In subgroup analysis, visual-acuity benefit persisted (67% vs 37%, P <.001) when CNV membrane was predominantly classic (50% or more of area of entire complex). Visual acuity not significantly different when the area of classic CNV membranes <50% entire complex. Patients needed mean of about 3 treatments in first y. At most recent follow-up, patients needed mean of 5 treatments in first 2 y.
Adult
Administered IV with dose based on body mass index (BMI)
Pediatric
Not applicable; AMD cannot be diagnosed in patients <50 y
None reported; many drugs can influence effect; theoretic examples include concomitant use of other photosensitizer (eg, tetracycline, sulfonamide, phenothiazine, sulfonylurea, hypoglycemic substances, thiazide diuretics, griseofulvin) can increase photosensitivity; compounds that scavenge active oxygen species or radicals (eg, dimethylsulphoxide, beta beta-carotene, ethanol, formate, mannitol) can reduce activity; calcium channel blockers, polymyxin B, or radiation therapy can increase rate of uptake by vascular endothelium; anticoagulants, vasoconstrictors, or platelet-aggregation inhibitors (eg, thromboxane-A2 inhibitors) can reduce effectiveness
Documented hypersensitivity; patients with porphyria
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients photosensitive to sunlight and strong artificial light for >48 h after infusion; wearing sunglasses and long-sleeved clothing highly recommended to avoid serious skin and eye burns; indoor lighting generally safe and recommended over complete darkness because accelerates breakdown of active drug; caution in advanced liver disease; extravasation can cause severe pain, inflammation, swelling, and discoloration at the injection site; cold compresses and analgesia helpful to reduce pain and complications of extravasation
Anti-VEGF therapy
This treatment reduces the risk of visual loss similar to that seen with PDT.
Pegaptanib (Macugen)
Selective VEGF antagonist that promotes vision stability and reduces visual acuity loss and progression to legal blindness. VEGF causes angiogenesis and increases vascular permeability and inflammation, all of which contribute to neovascularization in wet AMD
Adult
0.3 mg injected intravitreally into affected eye q6wk
Pediatric
Not established
None reported
Ocular or periocular infections
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Intravitreous injections associated with endophthalmitis; use proper aseptic technique; may increase intraocular pressure; most frequent adverse effects (10-40% patients over 24 mo) include anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities
Ranibizumab (Lucentis)
Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) AMD. In clinical trials, about one third of patients had improved vision at 12 mo that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to AMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.
Adult
0.5 mg (0.05 mL) intravitreal injection every month; administer under controlled, aseptic conditions
Pediatric
Not indicated
Data limited; none reported
Documented hypersensitivity; ocular or periocular infection
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include conjunctival hemorrhage, eye pain, floaters, increased eye pressure, and inflammation; serious adverse events were rare in clinical trials and were often related to injection procedures (eg, endophthalmitis, intraocular inflammation, retinal detachment, retinal tear, increased ocular pressure, traumatic cataract); may cause arterial thromboembolic events; administer anesthesia and antibiotic prophylaxis prior to procedure; prepare dose as directed using 5-micrometer filter
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Further Reading
Keywords
exudative ARMD, age-related macular degeneration, AMD, age-related maculopathy, ARM, macular degeneration, choroidal neovascularization, choroidal neovascular membrane, CNVM, CNV, vision loss
