Medical Policy

Policy Num:      M5.001.012
Policy Name:    Vascular Endothelial Growth Factor Inhibitors for the Treatment of Ophthalmological Diseases
Policy ID:          [M5.001.012]  [Ac / MA / M+/ P+]  [ 07.004.002 ]

Last Review:      May 10, 2024
Next Review:      May 20, 2025
 

Related Article: A56716

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.

Objective

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

coverage indications, limitations, and/or medical necessity

Pegaptanib sodium injection will be covered for Food and Drug Administration (FDA) approved labeled indications. See the FDA drug label for the FDA approved indications and dosages. https://labels.fda.gov/.

Pegaptanib sodium injection will be covered for the following off-label indication:

·          Diabetic macular edema (DME)

Physicians should provide appropriate informed consent with respect to the off-label use of this drug and maintain it in the patient chart.

Ranibizumab injection will be covered for Food and Drug Administration (FDA) approved labeled indications. See the FDA drug label for the FDA approved indications and dosages. https://labels.fda.gov/.

Bevacizumab is a monoclonal antibody that binds to VEGF and is covered for Food and Drug Administration (FDA) approved labeled indications. See the FDA drug label for the FDA approved indications and dosages. https://labels.fda.gov/.

Bevacizumab is covered for the following off-label indications:

·          Neovascular (wet) age-related macular degeneration (ARMD/AMD).

·          Macular edema following branch retinal vein occlusion (BRVO).

·          Macular edema following central retinal vein occlusion (CRVO).

·          Diabetic macular edema (DME).

·          Diabetic retinopathy (DR) in members with DME.

·          Proliferative diabetic retinopathy.

·         Secondary angle-closure glaucoma resulting from neovascularization (i.e., neovascular glaucoma).

·          Stage 3 retinopathy of prematurity (ROP).

·          Cystoid macular degeneration of retina

·          Retina edema

·          Rubeosis iridis

·          Retinal neovascularization

·          BRVO with retinal neovascularization

·          CRVO with retinal neovascularization

Physicians should provide appropriate informed consent with respect to the off-label use of bevacizumab.

Aflibercept will be covered for Food and Drug Administration (FDA) approved labeled indications. See the FDA drug label for the FDA approved indications and dosages. https://labels.fda.gov/.

Limitations

Though the optimal frequency of VEGF inhibitors is yet to be determined, the expectation is that the clinical assessment pre-treatment on date of service (DOS) (or close to it) should support decision making for treatment and subsequent follow-up treatment. Generally, a maximum of monthly intervals (q 4 weeks) should be assessed after the initial 3 months (12 weeks) of treatment for possible alternative frequency (such as q 8 weeks to quarterly etc.) based on the clinical assessment. The treatment frequency should be consistent with the clinical assessment (symptoms, exam, testing when indicated (OCT, FA, etc.) as documented in the medical record. Office based retina diagnostic tests are addressed in other polices. The diagnosis of AMD or other retinal diseases may require fluorescein dye retinal angiography (FA), optical coherence tomography (OCT), as well as other testing per standards of care. After establishment of a diagnosis and during treatment protocol for indicated VEGF Inhibitors OCT, Ultrasound, FA may be necessary to assess new symptoms and/or assess treatment progress for decisions on the subsequent frequency prescription. Documentation must support the need for testing and testing not used for decision making will be denied. Multiple testing modalities on a DOS may be subject to medical review and denial if testing exceeds the medical need. Injections of drugs that are administered at an excessive frequency are not medically necessary. Frequency is considered excessive when services are performed more frequently than listed in the package insert or generally accepted by peers and the reason for additional services is not justified by documentation. Dose and frequency should be in accordance with the FDA label or recognized compendia (for off-label uses). When services are performed in excess of established parameters, they may be subject to review for medical necessity.

The following are considered not reasonable and necessary and therefore may be denied:

1.    It is not reasonable and necessary to inject more than one anti-VEGF medication (pegaptanib sodium, ranibizumab, bevacizumab, aflibercept) in the same eye during the same treatment session.

2.    It is not expected to inject one anti-VEGF medication in one eye and another in the other eye. If different medications are injected into each eye during the same date of service, the rationale for this therapy must be documented in the medical record and the billing modifier (RT/LT) must be appended to the correct drug.

3.    VEGF inhibitors addressed in this LCD are contraindicated in patients with ocular or periocular infections and in patients with known hypersensitivity to the VEGF inhibitor or any of its inactive ingredients.

4.    Frequency is considered excessive when services are performed more frequently than listed in the package insert or generally accepted by peers and the reason for additional services is not justified by documentation. Dose and frequency should be in accordance with the FDA label or recognized compendia (for off-label uses). When services are performed in excess of established parameters, they may be subject to review for medical necessity.

5.    Multi-dosing from a single eye use vial or syringe or single-dose syringe is not medically reasonable and necessary, and is not a covered service.

As published in the CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13, Section 13.5.4, an item or service may be covered by a contractor LCD if it is reasonable and necessary under the Social Security Act Section 1862 (a)(1)(A). Contractors shall determine and describe the circumstances under which the item or service is considered reasonable and necessary.

Provider Qualifications

The following provider qualification requirements must be met for the service to be considered reasonable and necessary: 

·         Provider Specialties: Services rendered will be considered medically reasonable and necessary only when furnished by a qualified ophthalmologist.

population references 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 references 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 (ETDRSDRSS) 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

poPULATION REFERENCES 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 references no. 4

population references 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 references 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 references 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 references 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 references 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 forthe 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) 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 references 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 (ETDRSDRSS) compared with patients treated with laser photocoagulation. In 2015, theU.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) 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 references 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) 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 references no. 12

For individuals with neovascular (wet) age-related macular degeneration after retinal vein occlusion treated with intravitreal ranibizumab (Lucentis) 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 references no. 13

For individuals with choroidal neovascularization with intravitreal Intravitreal ranibizumab (Lucentis) 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 references no. 14

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 references no. 15

For the treatment of diabetic retinopathy, evidence is available for ranibizumab, bevacizumab, aflibercept, andpegaptanib. 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 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 (ETDRSDRSS) 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 references no. 16

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 references no. 17

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 references no. 18

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 references no. 19

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 pegaptanib sodium injection (Macugen) 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 

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 pegaptanib sodium injection (Macugen) 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 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. 22 

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. 23

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. 24 

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. 25 

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. 26 

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.

Benefit Application

Triple-S Salud Preferred Drugs Determination

Triple-S considers Bevacizumab as preferred agent. Aflibercept (Eylea) HD will be considered as branded agent of choice if there is a significant risk of a clinical adverse outcome of using Bevacizumab.  Other Vascular Endothelial Growth Factor (VEGF) Inhibitors  will be considered for payment when a contraindication, intolerance or ineffective response to Bevacizumab or Aflibercept HD or previous use of the requested agent within the last 365 days is documented.

regulatory Status

(IOM) Citations:

·         CMS IOM Publication 100-04, Medicare Claims Processing Manual,

o    Chapter 17, Section 40 Discarded Drugs and Biologicals

·         CMS IOM Publication 100-08, Medicare Program Integrity Manual,

o    Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

·         Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.

·         Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.

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.

This Billing and Coding Article provides billing and coding guidance for Local Coverage Determination (LCD) L36962 Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Ophthalmological Diseases. Please refer to the LCD for reasonable and necessary requirements.

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 the LCD are administered via intravitreal injection or through the devices that deliver anti-vascular endothelial growth factor medications.

 Services performed for any given diagnosis must meet all of the indications and limitations stated in the LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and   all Medicare payment rules.

 Documentation Requirements

1.   All documentation must be maintained in the patient's medical record and made available to the contractor upon request.

2.   Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service[s]). The documentation must include the legible signature of the physician or non-physician practitioner responsible for and providing the care to the patient.

3.   The submitted medical record must support the use of the selected ICD-10 code(s). The submitted CPT/HCPCS code must describe the service performed.

4.   Medical record documentation maintained by the performing physician must include the clinical indication for the VEGF inhibitor injection.

5.   Documentation maintained by the performing ophthalmologist must include the test results to firmly establish diagnosis by fluorescein angiogram or optical coherence tomography (OCT), for individuals with proliferative diabetic retinopathy, diabetic macular edema, retinal neovascularization, central retinal vein occlusion, venous tributary (branch) occlusion, exudative macular degeneration, and retinal edema. Tests to confirm the established diagnosis are not required for rubeosis iridis, or in the case of a vitreous hemorrhage in which the neovascularization cannot be visualized.

6.   Documentation must include the actual dosage of the VEGF inhibitor given, site of injection and route of administration.

7.   Documentation should support that the patient has been provided appropriate informed consent regarding the benefits and risks of the off-label use of bevacizumab or pegaptanib sodium injection when applicable.

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

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.

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for Vascular Endothelial Growth Factor Inhibitors for the Treatment of Ophthalmological Diseases. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for Vascular Endothelial Growth Factor Inhibitors for the Treatment of Ophthalmological Diseases and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site.

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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