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Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by neovascularization and macular edema. The macula, with the fovea at its center, has the highest photoreceptor concentration and is where visual detail is discerned. The anti-VEGF agents ranibizumab (Lucentis™), bevacizumab (Avastin®), and pegaptanib (Macugen®) are used to treat choroidal neovascularization associated with age-related macular degeneration (AMD) and are being evaluated for the treatment of disorders of retinal circulation (e.g., diabetic retinopathy and retinal vein occlusion).

Diabetic Retinopathy

Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness in adults. The two most serious complications for vision are diabetic macular edema and proliferative diabetic retinopathy. At its earliest stage (nonproliferative retinopathy), microaneurysms occur. With disruption of the blood-retinal barrier, macular retinal vessels become permeable, leading to exudation of serous fluid and lipids into the macula (macular edema). As the disease progresses, blood vessels that provide nourishment to the retina are blocked, triggering the growth of new and fragile blood vessels (proliferative retinopathy). Severe vision loss with proliferative retinopathy arises from vitreous hemorrhage. Moderate vision loss can also arise from macular edema (fluid accumulating in the center of the macula) during the proliferative or nonproliferative stages of the disease. Although proliferative disease is the main blinding complication of diabetic retinopathy, macular edema is more frequent and is the leading cause of moderate vision loss in people with diabetes.

Tight glycemic and blood pressure control is the first line of treatment to control diabetic retinopathy, followed by laser photocoagulation for patients whose retinopathy is approaching the high-risk stage. Although laser photocoagulation is effective at slowing the progression of retinopathy and reducing visual loss, it results in collateral damage to the retina and does not restore lost vision. Focal macular edema (characterized by leakage from discrete microaneurysms on fluorescein angiography) may be treated with focal laser photocoagulation, while diffuse macular edema (characterized by generalized macular edema on fluorescein angiography) may be treated with grid laser photocoagulation. Corticosteroids may reduce vascular permeability and inhibit vascular endothelial growth factor (VEGF) production but are associated with serious adverse effects including cataracts and glaucoma with damage to the optic nerve. Corticosteroids can also worsen diabetes control. VEGF inhibitors (e.g., ranibizumab, bevacizumab, and pegaptanib), which reduce permeability and block the pathway leading to new blood vessel formation (angiogenesis) are being evaluated for the treatment of diabetic macular edema and proliferative diabetic retinopathy. For diabetic macular edema, outcomes of interest are macular thickness and visual acuity. For proliferative diabetic retinopathy, outcomes of interest are operative and perioperative outcomes and visual acuity.

Central and Branch Retinal Vein Occlusions

Retinal vein occlusions are classified by whether there is a central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). CRVO is also categorized as ischemic or non-ischemic. Ischemic CRVO is associated with a poor visual prognosis, with macular edema and permanent macular dysfunction occurring in virtually all patients. Non-ischemic CRVO has a better visual prognosis, but many patients will have macular edema, and it may convert to the ischemic type within 3 years. Most of the vision loss associated with CRVO results from the main complications, macular edema and intraocular neovascularization. BRVO is a common retinal vascular disorder in adults between 60 and 70 years of age and occurs approximately 3 times more commonly than CRVOs. Macular edema is the most significant cause of central visual loss in BRVO.

Retinal vein occlusions are associated with increased venous and capillary pressure and diminished blood flow in the affected area, with a reduced supply of oxygen and nutrients. The increased pressure causes water flux into the tissue while the hypoxia stimulates the production of inflammatory mediators such as VEGF, which increases vessel permeability and induces new vessel growth. Intravitreal corticosteroid injections or implants have been used to treat the macular edema associated with retinal vein occlusions, with a modest beneficial effect on visual acuity. However, cataracts are a common side effect, and steroid-related pressure elevation occurs in about one-third of patients, with some requiring filtration surgery. Macular grid photocoagulation has also been used to improve vision in BRVO but is not recommended for CRVO. The serious adverse effects of available treatments have stimulated the evaluation of new treatments, including intravitreal injection of VEGF inhibitors. Outcomes of interest for retinal vein occlusions are macular thickness and visual acuity.

Use of any VEGF inhibitors for diabetic retinopathy would be considered off-label.

In 2010, Ranibizumab (Lucentis™, Genentech, 0.5 mg) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of macular edema following retinal vein occlusion. Labeling indicates that patients should be treated monthly. The FDA has required a postmarketing safety and efficacy study on at least 150 patients who have received at least 7 doses of Lucentis™ and have been followed for at least 15 months.

Pegaptanib (Macugen®, Eyetech and Pfizer) and ranibizumab (Lucentis™) are presently the only angiostatic drugs approved by the FDA for use in the eye. Pegaptanib was the first VEGF antagonist to be approved by the FDA for use in wet AMD. Ranibizumab is approved for the treatment of patients with neovascular AMD. Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway and are administered by intravitreous injections every 4–6 weeks. Pegaptanib binds to the VEGF-165 isomer of VEGF-A while ranibizumab is an antibody fragment directed at all isoforms of VEGF-A. Bevacizumab (Avastin®) is derived from the same murine monoclonal antibody precursor as ranibizumab, which binds to all isoforms of VEGF-A. Bevacizumab has been developed and approved for use in oncology but has not been licensed for use in the eye.

Aflibercept (previously called VEGF Trap-Eye) is a recombinant fusion protein consisting of the VEGF binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin-G1. Aflibercept was approved by the FDA in 2011 for the treatment of wet (neovascular) age-related macular degeneration and is administered by intravitreous injections every 4 or 8 weeks. As of February 2012, a supplemental Biologics License Application (sBLA) was under review by the FDA for the treatment of patients with diabetic macular edema (DME).

Related medical policies are as follows:

• Macugen® (pegaptanib sodium injection), Lucentis® (ranibizumab injection), Eylea® (aflibercept injection)
• Photodynamic Therapy for Choroidal Neovascularization                                
• Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions

• Diabetic macular edema
• Proliferative diabetic retinopathy as an adjunctive treatment to vitrectomy or photocoagulation
• Macular edema following central retinal vein occlusion*
• Macular edema following branch retinal vein occlusion*

Intravitreal injection of bevacizumab (Avastin®) may be considered medically necessary for the treatment of stage 3+ retinopathy of prematurity.

Macugen® (pegaptanib sodium injection), Lucentis® (ranibizumab injection), Eylea® (aflibercept injection) are addressed in a separate policy.  

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

04/26/2012: Policy description updated regarding FDA status of the drugs. Added the following policy statements:  1) Intravitreal injection of bevacizumab may be considered medically necessary for the treatment of stage 3+ retinopathy of prematurity. 2) Intravitreal injection of aflibercept may be considered medically necessary for treatment of diabetic macular edema.

08/03/2012:  Revised policy statement to note that Macugen® (pegaptanib sodium injection), Lucentis® (ranibizumab injection), Eylea® (aflibercept injection) are addressed in a separate policy. 

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document. 

Covered Codes

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