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Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib, aflibercept) are being evaluated for the treatment of disorders of choroidal circulation. Ophthalmic disorders affecting the choroidal circulation include age-related macular degeneration (AMD), central serous chorioretinopathy (CSC), pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic choroidal neovascularization (CNV), uveitis, choroidal rupture or trauma, and chorioretinal scars.
Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by choroidal neovascularization (CNV) 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™), pegaptanib (Macugen®), and aflibercept (Eylea™) are approved to treat CNV associated with AMD and are being evaluated for the treatment of other disorders of choroidal circulation. Other therapeutic options may include photodynamic therapy (PDT), antioxidants, and thermal laser photocoagulation. The safety and efficacy of each treatment depends on the form and location of the neovascularization. Angiostatic agents block some stage in the pathway leading to new blood vessel formation (angiogenesis). In contrast to palliative treatments for CNV (e.g., thermal photocoagulation and PDT), they are potentially disease modifying by inhibiting the development of newly formed vessels.
The distinct pharmacologic properties of available VEGF inhibitors suggest that safety and efficacy data from one agent can not be extrapolated to another. These agents may vary by penetration, potency, half-life, localization to the retina, and initiation of the immune system. Pegaptanib is an oligonucleotide aptamer that binds to the VEGF-165 isomer of VEGF-A. Ranibizumab is an antibody fragment which does not possess the fragment crystallizable domain and is directed at all isoforms of VEGF-A receptors. Bevacizumab (Avastin®) is a full-length anti-VEGF antibody derived from the same murine monoclonal antibody precursor as ranibizumab and inhibits all isoforms of VEGF-A. VEGF Trap-Eye (Eylea) 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.
Age-Related Macular Degeneration (AMD)
Neovascular AMD is characterized by CNV, which is the growth of abnormal choroidal blood vessels beneath the macula, which causes severe loss of vision and is responsible for most of the loss of vision caused by AMD. In its earliest stages, AMD is characterized by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination. As AMD progresses, 2 distinctively different forms of degeneration may be observed. The first, called the atrophic or areolar or dry form, evolves slowly. Atrophic AMD is the most common form of degeneration and is often a precursor of the second form, the more devastating exudative neovascular form, also referred to as disciform or wet degeneration. The wet form is distinguished from the atrophic form by serous or hemorrhagic detachment of the retinal pigment epithelium and the development of CNV, sometimes called neovascular membranes. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV. The pattern of CNV, as revealed by fluorescein or indocyanine angiography, is further categorized as classic or occult. For example, classic CNV appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult CNV lacks the characteristic angiographic pattern, either due to the opacity of coexisting subretinal hemorrhage or, especially in CNV associated with AMD, by a tendency for epithelial cells to proliferate and partially or completely surround the new vessels. Interestingly, lesions consisting only of classic CNV carry a worse visual prognosis than those made up of only occult CNV, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of AMD.
Intravitreal triamcinolone acetonide is one of the first pharmacologic compounds evaluated for the treatment of CNV secondary to AMD. The most important effects of this treatment consist of the stabilization of the blood-retinal barrier and the down-regulation of inflammation. Triamcinolone acetonide also has anti-angiogenic and anti-fibrotic properties and remains active for months after intravitreal injection. However, cataracts are a common side effect, and steroid-related pressure elevation occurs in approximately one third of patients, with some requiring filtration surgery.
Photodynamic therapy is a treatment modality designed to selectively occlude ocular choroidal neovascular tissue. The therapy is a 2-step process, consisting initially of an injection of the photosensitizer verteporfin, followed 15 minutes later by laser treatment to the targeted sites of neovascularization in the retina. The laser treatment selectively damages the vascular endothelium. Patients may be re-treated if leakage from CNV persists. Combination therapy with PDT and VEGF antagonists is being investigated.
Prior to the availability of angiostatic agents and PDT, CNV was treated with photocoagulation using either argon, green, or infrared lasers. This conventional photocoagulation was limited to extrafoveal lesions due to the risk of retinal burns. Introduction of a scotoma or enlargement of a pre-existing scotoma, with or without visual acuity loss, is an immediate and permanent effect of photocoagulation surgery. Because of the loss of vision associated with laser photocoagulation, photocoagulation is no longer recommended as the initial treatment of subfoveal neovascularization.
Polypoidal Choroidal Vasculopathy
Polypoidal choroidal vasculopathy (PCV) is characterized by the presence of a branching vascular network with terminal, polyp-like aneurismal dilations. Some investigators consider PCV to be a subtype of AMD, while others suggest that the lesions, when submacular, can be mistaken for AMD. PCV is more common in Asian compared with Caucasian populations. Both PDT and ranibizumab have been used to treat PCV; although the optimal treatment for PCV may differ from that for AMD.
Central Serous Chorioretinopathy (CSC)
CSC is the fourth most common retinopathy after AMD, diabetic retinopathy, and branch retinal vein occlusion. CSC refers to an idiopathic disease in which there is a serous detachment of the macula due to leakage of fluid from the choriocapillaris through the retinal pigment epithelium. CSC can be divided into acute, recurrent, and chronic conditions. Usually, serous retinal detachments have spontaneous resolution with recovery of visual function; however, a subset of patients may experience permanent deterioration of visual function attributable to chronic CSC or multiple recurrences of CSC. The pathogenesis of CSC is believed to be ischemia and inflammation, which lead to abnormal permeability of the inner choroid and elevation of the retinal pigment epithelium, causing serous epithelial detachments. The separated retinal pigment epithelium can then undergo tiny rips (blowouts) with a break in continuity. The change in permeability of the retinal pigment epithelium results in focal leakage and retinal detachment. Neovascularization can occur as a secondary complication. In about 90% of cases, CSC resolves spontaneously with detachment resolution within 3 months. The traditional management of acute CSC is observation. Recurring or chronic CSC can be treated with focal laser photocoagulation if the leaks are extrafoveal. Although laser may shorten the duration of symptoms, it does not have any impact on the final vision or the recurrence rate of CSC. In addition, laser photocoagulation causes collateral damage creating symptomatic scotomas and a risk of triggering secondary CNV. Photodynamic therapy is not a standard treatment for CSC due to complications that may include CNV, although low-fluence PDT is being evaluated.
Other Causes of Choroidal Neovascularization (CNV)
Other causes of CNV include pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic CNV, uveitis, choroidal rupture or trauma, and chorioretinal scars. Treatments that have been evaluated for CNV not related to AMD include submacular surgery, laser photocoagulation, and PDT. Efficacy of these treatment modalities is limited.
Pegaptanib (Macugen®, Eyetech and Pfizer), ranibizumab (Lucentis™, Genentech) and aflibercept (Eylea™, Regeneron Pharmaceuticals), are approved by the U.S. Food and Drug Administration (FDA) for use in AMD. Pegaptanib was the first VEGF antagonist to be approved by the FDA for use in neovascular (wet) AMD. Ranibizumab is approved for the treatment of patients with neovascular (wet) 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.
Aflibercept (EYLEA™, previously called VEGF Trap-Eye) is a recombinant fusion protein consisting of the VEGF binding domains of human VEGF receptors R1 and R2 fused to the Fc domain of human immunoglobulin-G1. Aflibercept was approved by FDA in 2011 for the treatment of neovascular (wet) AMD. The recommended dose for EYLEA™ is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months).
Ranibizumab and aflibercept are also approved by FDA for retinal vascular conditions such as diabetic macular edema and macular edema following retinal vein occlusion.
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.
No VEGF inhibitors have been approved by the FDA for the treatment of central serous chorioretinopathy.
Related medical policies are as follows:
POLICYIntravitreal injection of bevacizumab (Avastin®) may be considered medically necessary as a treatment of neovascular (wet) age-related macular degeneration.
Anti-vascular endothelial growth factor therapies (anti-VEGF) may be considered medically necessary for the treatment of choroidal neovascularization due to angioid streaks, central serous chorioretinopathy, choroidal rupture or trauma, idiopathic choroidal neovascularization, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome, and uveitis.
Anti-vascular endothelial growth factor therapies (anti-VEGF) are considered investigational for the treatment of chorioretinal scars.
Macugen® (pegaptanib sodium injection), Lucentis® (ranibizumab injection), Eylea® (aflibercept injection) are addressed in a separate policy.
POLICY EXCEPTIONSFederal 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.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of 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. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY07/21/2011: Approved by Medical Policy Advisory Committee
01/17/2012: Added the following policy statement: Anti-vascular endothelial growth factor therapies (anti-VEGF) may be considered medically necessary for the treatment of choroidal neovascularization due to angioid streaks, central serous chorioretinopathy, choroidal rupture or trauma, idiopathic choroidal neovascularization, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome, and uveitis. Investigational policy statement revised to state that this therapy is considered investigational for the treatment of chorioretinal scars. Added ICD-9 code 362.16 to the Covered Codes table.
04/26/2012: Added aflibercept (Eylea™) to the medically necessary policy statement.
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 reviewed; no changes.
05/08/2014: Policy reviewed; description updated regarding polypoidal choroidal vasculopathy and aflibercept (Eylea™). Policy statement unchanged.
08/28/2015: Medical policy revised to add ICD-10 codes.
05/27/2016: Policy number added. Policy Guidelines updated to add medically necessary and investigative definitions.
09/30/2016: Code Reference section updated to add the following new ICD-10 diagnosis codes: H35.3110 - H35.3194 and H35.3210 - H35.3293.
SOURCE(S)Blue Cross Blue Shield Association policy # 9.03.24
CODE REFERENCEThis 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.Covered Codes