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Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib) are being evaluated for the treatment of disorders of retinal circulation. Ophthalmic disorders affecting the retinal circulation include diabetic macular edema (DME), diabetic retinopathy, macular edema following central or branch retinal vein occlusion, and retinopathy of prematurity (ROP).
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®), pegaptanib (Macugen®), and aflibercept (EYLEA) 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 macular edema [DME], diabetic retinopathy, macular edema following retinal vein occlusion, retinopathy of prematurity [ROP]).
Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway. Pegaptanib binds to the VEGF-165 isomer of VEGF-A while ranibizumab is an antibody fragment directed at all isoforms of VEGF-A. Bevacizumab is derived from the same murine monoclonal antibody precursor as ranibizumab, which binds to all isoforms of VEGF-A. 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.
Diabetic Macular Edema and 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 in patients with diabetes are diabetic macular edema and diabetic retinopathy. At its earliest stage, 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 macular edema and 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 vision 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 include macular thickness and visual acuity. For proliferative and non-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 adverse 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.
Retinopathy of Prematurity
ROP is a neovascular retinal disorder that primarily affects premature infants of low birth weight. It is one of the most common causes of childhood blindness in the United States. Typically, retinal vascularization begins at the optic nerve when the eye begins to develop (16 weeks of gestation) and reaches the edge of the retina at 40 weeks of gestation. If an infant is born prematurely, normal vessel growth may stop, followed by neovascularization at the interface between the vascular and avascular retinal areas. Stages of ROP are defined by vessel appearance and the level of retinal detachment, ranging from mild (stage I) to severe (stage V). Stage I or stage II ROP may resolve on its own. The optimal time for treatment is stage III, when a ridge with neovascularization extends into the vitreous gel. The neovascularization may progress and form fibrous scar tissue that causes partial (stage IV) or total retinal detachment (stage V), accompanied by loss of vision. Both cryotherapy and laser therapy have been used to slow or reverse the abnormal growth of blood vessels in the peripheral areas of the retina. While successful in about 50% of cases, these treatments can cause myopia and permanent loss of the peripheral visual field. Vitrectomy may be needed when cryotherapy or laser therapy fail to induce regression.
Other retinal vascular conditions that are being evaluated for treatment with VEGF inhibitors are cystoid macular edema resulting from vasculitis, Coats disease, Eales disease, idiopathic macular telangiectasia type II, neovascularization of the iris/neovascularization of the angle/neovascular glaucoma, pseudoxanthoma elasticum, radiation retinopathy, retinal neovascularization, rubeosis, von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.
The angiostatic drugs pegaptanib (Macugen®, Eyetech and Pfizer), ranibizumab (Lucentis™, Genentech), and aflibercept (EYLEA™, Regeneron Pharmaceuticals) are presently approved by the FDA for use in the eye.
Lucentis™ was first approved for the treatment of patients with neovascular age-related macular degeneration (AMD). In 2010, Lucentis™ was approved by the U.S. Food and Drug Administration (FDA) for the treatment of macular edema following retinal vein occlusion. In 2012, Lucentis™ was approved for the treatment of diabetic macular edema (DME).
EYLEA™ 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. In 2012, EYLEA was approved for the treatment of macular edema following central retinal vein occlusion (CRVO).
Bevacizumab has been developed and approved for use in oncology but has not been licensed for use in the eye.
Related medical policies -
Intravitreal injection of bevacizumab (Avastin®) may be considered medically necessary for the treatment of the following retinal vascular conditions:
Macugen® (pegaptanib sodium injection), Lucentis® (ranibizumab injection), Eylea® (aflibercept injection) are addressed in a separate policy.
Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
03/22/2012: Approved by Medical Policy Advisory Committee.
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.
08/07/2013: Policy updated to remove "stage 3+" from the policy statement regarding retinopathy of prematurity.
08/28/2015: Medical policy revised to add ICD-10 codes.
06/09/2016: Policy number added. Policy Guidelines updated to add medically necessary definition.
07/06/2016: Policy description updated regarding retinopathy of prematurity, other retinal vascular conditions, and FDA drug status. Medically necessary policy statements combined and updated to make the following changes: "proliferative diabetic retinopathy as an adjunctive treatment to vitrectomy or photocoagulation" changed to "diabetic retinopathy."
Blue Cross Blue Shield Association policy # 9.03.27
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.