Medical Policy

Policy Num:       07.004.002
Policy Name:     Vascular Endothelial Growth Factor Inhibitors for the Treatment of Ophthalmological Diseases
Policy ID:          [07.004.002]  [Ac / L / M+ / P+]  [0.00.00]

Last Review:       October 24, 2024
Next Review:      October 20, 2025
 

Related Policies:  

08.001.005 Photodynamic Therapy for Choroid Neovascularization

09.003.005 Intravitreal and Punctum Corticosteroid Implants 

09.003.004 - Intraocular Radiotherapy for Age-Related Macular Degeneration

Vascular Endothelial Growth Factor Inhibitors for the Treatment of Ophthalmological Diseases

Summary

Vascular endothelial growth factor has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by choroidal neovascularization (CNV) and macular edema. 

Neovascular age related macular degeneration (AMD) is characterized by CNV which is the growth of abnormal choroidal blood vessels beneath the macula. This abnormal vascular growth causes severe loss of vision and is responsible for most of the loss of vision caused by AMD. Angiostatic agents block a stage in the vascular growth pathway leading to new blood vessel formation (angiogenesis) and therefore are disease modifying by inhibiting the development of newly formed vessels. Angiogenesis inhibitors are also being evaluated for the treatment of other disorders of choroidal circulation, including central serous chorioretinopathy pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic CNV, uveitis, choroidal rupture or trauma, and chorioretinal scars

Examples of angiogenesis inhibiting drugs for treating choroidal vascular conditions are Ranibizumab (Lucentis™), and Bevacizumab (Avastin®) from Genentech. 

Objective

The objective of this local policy is to determine medical necessity for the use of  Vascular Endothelial Growth Factor (VEGF) Inhibitors for the treatment of ophthalmological diseases.

Policy Statements

Intravitreal bevacizumab (Avastin)

Intravitreal bevacizumab (Avastin) injections is considered medically necessary for the treatment of the following indications:

• Diabetic macular edema
• Proliferative diabetic retinopathy
• Macular edema following retinal vein occlusion (BRVO)
• Neovascular (wet) AMD
• Neovascular glaucoma
• Polypoidal choroidal vasculopathy
• Choroidal neovascularization, (including myopic choroidal neovascularization (mCNV), angioid streaks, choroiditis [including choroiditis secondary to ocular histoplasmosis], idiopathic degenerative myopia, retinal dystrophies, rubeosis iridis, pseudoxanthoma elasticum, and trauma)
• Retinopathy of prematurity

Intravitreal bevacizumab (Avastin)  injections is considered investigational for any other ophthalmological indications not mentioned above.

Ranibizumab (Lucentis)/Ranibizumab-eqrn (Cimerli)

Intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) is considered  medically necessary  for the treatment of the following indications:

• Diabetic macular edema
• Diabetic retinopathy
• Macular edema following retinal vein occlusion (BRVO)
• Myopic choroidal neovascularization
• Neovascular (wet) AMD

Ranibizumab-eqrn (Cimerli)  is interchangeable with ranibizumab (Lucentis). 

Intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) is considered investigational for any other ophthalmological indications not mentioned above.

Ranibizumab (Susvimo)

Intravitreal ranibizumab (Susvismo) is considered  medically necessary  for the treatment of the following indications:

• Neovascular (wet) AMD who have previously responded to at least two intravitreal injections of a VEGF inhibitor.

Intravitreal ranibizumab (Susvismo) is considered investigational for any other ophthalmological indications not mentioned above.

Intravitreal aflibercept (Eylea)

Intravitreal aflibercept (Eylea) is considered medically necessary for the treatment of the following indications:

• Diabetic macular edema
• Diabetic retinopathy
• Macular edema following retinal vein occlusion (including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO)
• Neovascular (wet) AMD.
• Retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+)
  or AP-ROP (aggressive posterior ROP) disease. 

Intravitreal aflibercept (Eylea) is considered investigational for any other ophthalmological indications not mentioned above.

Intravitreal brolucizumab-dbll (Beovu)

Brolucizumab-dbll intravitreal injection (Beovu) is considered medically necessary for the treatment of neovascular (wet) age-related macular degeneration.

Brolucizumab-dbll intravitreal injection (Beovu) is considered investigational for any other ophthalmological indications not mentioned above.

Ranibizumab-nuna (Byooviz)

Intravitreal ranibizumab-nuna (Byooviz) is considered medically necessary for the treatment of the following indications:

• Macular edema following retinal vein occlusion (RVO)
• Neovascular (Wet) Age-Related Macular Degeneration (AMD).
• Myopic Choroidal Neovascularization (mCNV)

Intravitreal ranibizumab-nuna (Byooviz) is considered investigational for any other ophthalmological indications not mentioned above.

Faricimab-svoa (Vabysmo)

Intravitreal Faricimab-svoa (Vabysmo) is considered medically necessary for the treatment of the following indications:

• Diabetic macular edema (DME)
• Neovascular (Wet) Age-Related Macular Degeneration (AMD).

Intravitreal Faricimab-svoa (Vabysmo) is considered investigational for any other ophthalmological indications not mentioned above.

Policy Guidelines

Coding

Please see the Codes table for details.

Benefit Application

Preferred drug statement:

Triple-S considers Bevacizumab as preferred agent with no preauthrization requried. Other Vascular Endothelial Growth Factor (VEGF) Inhibitors will require preauthorization.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Vascular endothelial growth factor (VEGF) plays an important role in both physiologic and pathologic angiogenesis and contributes to increased permeability across both the blood-retinal and blood-brain barriers.¹ VEGF is a protein that stimulates the growth, proliferation, and survival of vascular endothelial cells. After two decades of extensive research into the VEGF families and receptors, specific molecules have been targeted for drug development, and several medications have received US Food and Drug Administration (FDA) approval.¹

VEGF, through its promotion of angiogenesis and vascular permeability, is a central component of the pathologic process driving wet age-related macular degeneration (AMD), as well as other choroidal and retinal vascular disorders. The VEGF inhibitors referenced within this LCD are administered via intravitreal injection.

Pegaptanib sodium injection is a sterile, aqueous solution containing pegaptanib sodium. Pegaptanib is a selective VEGF antagonist. Pegaptanib binds to VEGF and inhibits its binding to cellular receptors. Pegaptanib sodium’s anti- VEGF activity is expected to inhibit abnormal blood vessel proliferation and, therefore, decrease the vision loss associated with the proliferation of abnormal blood vessels.

Ranibizumab injection is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Bevacizumab which was initially approved by the FDA in 2004 for the treatment of metastatic colon cancer, is a monoclonal antibody that binds to VEGF. Non-FDA approved intravitreal use of bevacizumab has been widely reported by practicing ophthalmologists to be beneficial in select individuals with neovascular AMD. Consistent with the statement by the American Academy of Ophthalmology (AAO) in support of intravitreal use of bevacizumab, physicians should provide appropriate informed consent with respect to the off-label use of this drug and maintain it in the patient’s chart.

Based on published reports and widespread clinical use, there is compelling evidence of bevacizumab’s safety and efficacy for choroidal neovascularization in AMD and also in proliferative diabetic retinopathy, neovascular glaucoma, DME, retinal and iris neovascularizations and macular edema following branch and central retinal vein occlusions.

Aflibercept is a VEGF inhibitor administered as an intravitreal injection. Aflibercept is a fully human recombinant fusion protein that binds all isoforms of VEGFA, and prevents their binding to VEGFR-1 and VEGFR-2. Aflibercept also binds to Placental Growth Factor (PlGF) inhibiting binding to VEGFR-1. Inhibiting the binding to these receptors decreases inflammation and vascular permeability, prevents the progression of neovascular AMD, and prevents further loss of vision.

Regulatory Status

Rationale

Population Reference No. 1 

For the treatment of DME, there is substantial evidence that VEGF inhibitors (ranibizumab, bevacizumab, aflibercept) are efficacious agents when given by the intravitreal route. Ranibizumab has been studied in large sham-controlled trials and both ranibizumab and aflibercept have been studied in comparison with laser photocoagulation. A large high-quality head-to-head comparison of aflibercept, bevacizumab, and ranibizumab by the Diabetic Retinopathy Clinical Research Network (DRCRN) demonstrated generally similar outcomes for the 3 agents, with some advantage of aflibercept in patients with worse visual acuity at baseline. Although for bevacizumab the quality of the other RCTs is less, the evidence from the DRCRN trial is sufficient to conclude that bevacizumab is at least as effective as ranibizumab or aflibercept for the treatment of DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. . Evidence remains insufficient to determine if pegaptanib is as effective as an alternative treatment.

For individuals with diabetic macular edema treated with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 2 

For the treatment of diabetic retinopathy, evidence is available for ranibizumab, bevacizumab, aflibercept, and pegaptanib. A large trial by the DRCRN found that intravitreal injection of ranibizumab is noninferior to photocoagulation in eyes with proliferative diabetic retinopathy at 2 years. Treatment with ranibizumab for DME may also reduce progression to proliferative diabetic retinopathy and need for vitrectomy. A number of smaller RCTs report superior outcomes for bevacizumab as a single agent or as an adjunct to photocoagulation or vitrectomy. A single small RCT reported that pegaptanib had similar efficacy to photocoagulation for patients with proliferative diabetic retinopathy. Analysis of data from the RISE and RIDE trials found that treatment with ranibizumab over 3 years led to improvement in proliferative diabetic retinopathy in a significantly greater proportion of eyes than those treated with sham injections for the first 2 years. Two-year data from the VIVID and VISTA trials showed a significantly greater percentage of patients in the aflibercept groups who gained at least 2 steps in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) compared with patients treated with laser photocoagulation. In 2015, the U.S. Food and Drug Administration (FDA) approved Lucentis and EYLEA to treat diabetic retinopathy in patients with DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals with proliferative diabetic retinopathy treated with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 3 

For the treatment of retinal vein occlusion, RCTs are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with central branch retinal vein occlusion (CRVO), that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome

For individuals with macular edema after retinal vein occlusion treated with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 4 

Section Summary: Retinal Vein Occlusion RCTs on the treatment of retinal vein occlusion are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with CRVO, that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes.

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 5 

For the treatment of retinal vein occlusion, RCTs are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with central branch retinal vein occlusion (CRVO), that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome

For individuals with neovascular glaucoma after retinal vein occlusion treated with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 6 

For individuals with polypoidal choroidal vasculopathy with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7 

For individuals with choroidal neovascularization with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 8

Section Summary: Retinopathy of Prematurity The evidence on the benefit of VEGF treatment for retinopathy of prematurity includes at least 2 RCTs, 1 high-quality trial using bevacizumab and a more problematic study using pegaptanib, reporting that recurrence of retinopathy is reduced compared with laser treatment alone. This evidence suggests that bevacizumab improves outcomes for infants with retinopathy of prematurity when given by the intravitreal route.

For individuals with retinopathy of prematurity with intravitreal bevacizumab compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 9 

For the treatment of DME, there is substantial evidence that VEGF inhibitors (ranibizumab, bevacizumab, aflibercept) are efficacious agents when given by the intravitreal route. Ranibizumab has been studied in large sham-controlled trials and both ranibizumab and aflibercept have been studied in comparison with laser photocoagulation. A large high-quality head-to-head comparison of aflibercept, bevacizumab, and ranibizumab by the Diabetic Retinopathy Clinical Research Network (DRCRN) demonstrated generally similar outcomes for the 3 agents, with some advantage of aflibercept in patients with worse visual acuity at baseline. Although for bevacizumab the quality of the other RCTs is less, the evidence from the DRCRN trial is sufficient to conclude that bevacizumab is at least as effective as ranibizumab or aflibercept for the treatment of DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. . Evidence remains insufficient to determine if pegaptanib is as effective as an alternative treatment.

For individuals with diabetic macular edema treated with intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 10 

For the treatment of diabetic retinopathy, evidence is available for ranibizumab, bevacizumab, aflibercept, and pegaptanib. A large trial by the DRCRN found that intravitreal injection of ranibizumab is noninferior to photocoagulation in eyes with proliferative diabetic retinopathy at 2 years. Treatment with ranibizumab for DME may also reduce progression to proliferative diabetic retinopathy and need for vitrectomy. A number of smaller RCTs report superior outcomes for bevacizumab as a single agent or as an adjunct to photocoagulation or vitrectomy. A single small RCT reported that pegaptanib had similar efficacy to photocoagulation for patients with proliferative diabetic retinopathy. Analysis of data from the RISE and RIDE trials found that treatment with ranibizumab over 3 years led to improvement in proliferative diabetic retinopathy in a significantly greater proportion of eyes than those treated with sham injections for the first 2 years. Two-year data from the VIVID and VISTA trials showed a significantly greater percentage of patients in the aflibercept groups who gained at least 2 steps in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) compared with patients treated with laser photocoagulation. In 2015, the U.S. Food and Drug Administration (FDA) approved Lucentis and EYLEA to treat diabetic retinopathy in patients with DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals with proliferative diabetic retinopathy treated with intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 11 

For the treatment of retinal vein occlusion, RCTs are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with central branch retinal vein occlusion (CRVO), that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome

For individuals with macular edema after retinal vein occlusion treated with intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 12 

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 13 

For individuals with choroidal neovascularization with intravitreal ranibizumab (Lucentis) or Ranibizumab-eqrn (Cimerli) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No.14 

EYLEA is indicated in preterm infants for the treatment of • retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or AP-ROP (aggressive posterior ROP) disease

Population Reference No.15 

For the treatment of retinal vein occlusion, RCTs are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with central branch retinal vein occlusion (CRVO), that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome

For individuals with diabetic macular edema treated with intravitreal aflibercept (Eylea) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 16 

For the treatment of diabetic retinopathy, evidence is available for ranibizumab, bevacizumab, aflibercept, and pegaptanib. A large trial by the DRCRN found that intravitreal injection of ranibizumab is noninferior to photocoagulation in eyes with proliferative diabetic retinopathy at 2 years. Treatment with ranibizumab for DME may also reduce progression to proliferative diabetic retinopathy and need for vitrectomy. A number of smaller RCTs report superior outcomes for bevacizumab as a single agent or as an adjunct to photocoagulation or vitrectomy. A single small RCT reported that pegaptanib had similar efficacy to photocoagulation for patients with proliferative diabetic retinopathy. Analysis of data from the RISE and RIDE trials found that treatment with ranibizumab over 3 years led to improvement in proliferative diabetic retinopathy in a significantly greater proportion of eyes than those treated with sham injections for the first 2 years. Two-year data from the VIVID and VISTA trials showed a significantly greater percentage of patients in the aflibercept groups who gained at least 2 steps in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) compared with patients treated with laser photocoagulation. In 2015, the U.S. Food and Drug Administration (FDA) approved Lucentis and EYLEA to treat diabetic retinopathy in patients with DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals with proliferative diabetic retinopathy treated with intravitreal aflibercept (Eylea) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 17 

For the treatment of retinal vein occlusion, RCTs are available for all 4 agents (ranibizumab, bevacizumab, aflibercept, pegaptanib). These trials are consistent in reporting that ranibizumab, bevacizumab, and aflibercept are efficacious agents in preserving visual acuity and reducing retinal thickness. The largest amount of evidence is available for ranibizumab and bevacizumab, and direct comparative trials indicate that the 2 VEGF antagonists have similar efficacy. A 2015 Ophthalmic Technology Assessment by the American Academy of Ophthalmology concluded that there is level I evidence supporting the use of VEGF inhibitors for macular edema associated with central branch retinal vein occlusion (CRVO), that they are safe and effective over 2 years for macular edema associated with CRVO, and that delay in treatment is associated with worse visual outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome

For individuals with macular edema after retinal vein occlusion treated with intravitreal aflibercept (Eylea) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 18 

Section Summary There is RCT evidence supporting the efficacy of all 4 agents (bevacizumab, ranibizumab, pegaptanib, aflibercept) for preserving visual acuity in patients with AMD. These trials report that VEGF inhibitors are superior to placebo and superior to PDT. A preliminary report of increased stroke rates in patients treated with ranibizumab was published in 2012.

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal aflibercept (Eylea) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 19 

The FDA approval of Beovu was based on the results from two-phase three clinical studies named HAWK and HARRIER. The randomised, multi-centre, double-masked and active-controlled trials were conducted on patients with wet AMD.

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal brolucizumab-dbll (Beovu)) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 20

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with ranibizumab-nuna (Byooviz) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 21

For individuals with macular edema after retinal vein occlusion treated with intravitreal ranibizumab-nuna (Byooviz) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 22

For individuals with choroidal neovascularization with intravitreal Intravitreal ranibizumab-nuna (Byooviz) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 23

For individuals with neovascular (wet) age-related macular degeneration  who have previously responded to at least two intravitreal injections of a VEGF inhibitor with Intravitreal ranibizumab (Susvismo) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 24

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal Faricimab-svoa (Vabysmo) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 25 

For individuals with diabetic macular edema treated with intravitreal Faricimab-svoa (Vabysmo) compared with the standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Supplemental Information

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2013 Input In response to requests, input was received from 2 physician specialty societies and 1 academic medical center while this policy was under review in 2013. Input agreed with the medically necessary indications, but also recommended use of bevacizumab for earlier stages of retinopathy of prematurity. Input supported use of intravitreal VEGF inhibitors for neovascular glaucoma and rubeosis (neovascularization of the iris). Input was mixed on the medical necessity of VEGF inhibitors for cystoid macular edema resulting from vasculitis, Coats disease, Eales disease, idiopathic macular telangiectasia type II, neovascularization of the angle, pseudoxanthoma elasticum, radiation retinopathy, retinal neovascularization, von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.

2011 Input In response to requests, input was received from 1 physician specialty society and 3 academic medical centers while this policy was under review in 2011. The input supported the use of ranibizumab and bevacizumab for diabetic retinopathy (DME and proliferative diabetic retinopathy) and for CRVO or branch retinal vein occlusion (BRVO). Reviewers suggested additional indications for VEGF inhibitors including 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, retinopathy of prematurity, rubeosis, von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.

Practice Guidelines and Position Statements

American Academy of Ophthalmology The 2016 preferred practice pattern for diabetic retinopathy from the American Academy of Ophthalmology (AAO) concludes that intravitreal injection of anti-VEGF agents is the initial treatment of choice for center-involving diabetic macular edema.64 Laser photocoagulation remains the preferred treatment for non-center-involving diabetic macular edema. The panel concluded that VEGF antagonists are an alternative for proliferative diabetic retinopathy, and when it is at the high-risk stage (ie, if new vessels at the optic disc is extensive or vitreous/preretinal hemorrhage has occurred recently), anti-VEGF therapy and panretinal photocoagulation may be performed concomitantly. The practice pattern indicates that anti-VEGF therapy for the management of severe nonproliferative diabetic retinopathy and non-highrisk proliferative diabetic retinopathy is being evaluated.

The 2015 preferred practice pattern for retinal vein occlusions from AAO states that the safest treatment for macular edema associated with CRVOs and BRVOs is anti-VEGF treatment.65 This is based on well conducted studies that have shown efficacy of anti-VEGF treatment for macular edema associated with CRVO and BRVO. The body of evidence was considered to be of good quality leading to a strong recommendation.

National Institute for Health and Clinical Excellence In a final appraisal determination from July 15, 2011, the National Institute for Health and Clinical Excellence (NICE) does not recommend ranibizumab (Lucentis) for the treatment of DME.66 The independent Appraisal Committee found that the manufacturer’s model underestimated the incremental cost-effectiveness ratio (ICER) for ranibizumab monotherapy compared with the current standard treatment for people with DME, laser photocoagulation. It concluded that a model that relied on a combined set of plausible assumptions would be certain to produce an ICER that substantially exceeded the range that NICE considers an effective use of National Health Service resources. Therefore, ranibizumab could not be recommended as a treatment for people with DME. In 2013 NICE issued Technology Assessment 274, which stated that ranibizumab is recommended as an option for the treatment of macular edema only if the eye to be treated has a central retinal thickness of 400 μm or more at the start of treatment and the agreed on manufacturer discount is in place.67

In 2013 NICE issued Technology Assessment 283, which recommended the use of ranibizumab as a treatment option for macular edema following CRVO or BRVO only if treatment with laser photocoagulation has not been beneficial or is not possible due to macular hemorrhage. It is also only recommended if the agreed-upon manufacturer discount is in place.68

Medicare National Coverage

No medicare national coverage determination.  PR MAC FCSO have LCD  L36962.

In March 2012, Centers for Medicare and Medicaid Services (CMS) held a Medicare Evidence Development and Coverage Advisory Committee meeting on use of anti-VEGF agents for the treatment of DME. The panel voted that they had moderately high confidence that there is adequate evidence to evaluate whether DME management using intravitreal targeted anti-VEGF treatment improves patient health outcomes compared with DME management without targeted anti-VEGF treatment. CMS concluded that repeated eye injections of anti-VEGF medications may help to manage DME, preventing visual loss and promoting recovery. CMS does not have a national coverage determination for the use of anti-VEGF treatments in DME.

References

1. Stewart MW. The Expanding Role of Vascular Endothelial Growth Factor Inhibitors. Mayo Clin Proc. 2012; 87(1): 77- 88.
2. American Academy of Ophthalmology (AAO) Retina Panel. Preferred Practice Pattern® Age-Related Macular Degeneration. San Francisco, CA: AAO. 2015.
3. American Academy of Ophthalmology (AAO) Retina Panel. Preferred Practice Pattern® Diabetic Retinopathy. San Francisco, CA: AAO. 2017.
4. American Academy of Ophthalmology (AAO) Retina Panel. Preferred Practice Pattern® Retinal Vein Occlusion. San Francisco, CA: AAO. 2015.
5. Genentech, Inc. Avastin® (bevacizumab). Avastin® (2016). Accessed September 09, 2016.
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