BlueCross and BlueShield of Montana Medical Policy/Codes
Anti-Vascular Endothelial Growth Factor (VEGF) Inhibitors for use in the Eye
Chapter: Vision
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

1.  Age-related macular degeneration (ARMD or AMD) is a painless, insidious disease process of vision loss that is characterized by progressive degeneration of the macula, the central part of the retina at the back of the eye.  ARMD, also known as the neovascular (wet) form of the disease, is the leading cause of irreversible, severe vision loss in people 55 years or older.  This neovascular (wet) form of the disease represents approximately 10 percent of the overall disease prevalence, but is responsible for 90 percent of the severe vision loss.  Though the cause of ARMD is not known, several risk factors have been identified: advanced age, hypertension, tobacco exposure, and/or history of vascular disease.

2.  Neovascular ARMD is characterized by CNV that invades the subretinal space, often leading to exudation and hemorrhage.  If the condition is left untreated, damage to photoreceptors and loss of central vision usually result, and after several months to years, the vessels are largely replaced by a fibrovascular scar.  Patients in whom a central scotoma (vascular scar) develops have difficulty performing critical tasks that are typically associated with central vision, such as reading, driving, walking and recognizing faces. 

3.  Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of blindness in the working-age population of most developed countries.  The increasing number of individuals with diabetes worldwide suggests that DR and DME will continue to be major contributors to vision loss and associated functional impairment for years to come.  Early detection of retinopathy in individuals with diabetes is critical in preventing visual loss, but current methods of screening fail to identify a sizable number of high-risk patients.  The control of diabetes-associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is also important in preserving visual function because these conditions have been identified as risk factors for both the development and progression of DR or DME.  The currently available interventions for DR or DME, laser photocoagulation and vitrectomy, only target advanced stages of disease.  Several biochemical mechanisms, including protein kinase C–β activation, increased vascular endothelial growth factor production, oxidative stress, and accumulation of intracellular sorbitol and advanced glycosylation end products, may contribute to the vascular disruptions that characterize DR or DME.  The inhibition of these pathways holds the promise of intervention for DR at earlier non–sight-threatening stages.  To implement new therapies effectively, more individuals will need to be screened for DR or DME at earlier stages—a process requiring both improved technology and interdisciplinary cooperation among physicians caring for patients with diabetes.

Stages of Diabetic Retinopathy

  • Mild Nonproliferative Retinopathy:  At this earliest stage, microaneurysms occur.  These are small areas of balloon-like swelling in the retina’s tiny blood vessels.
  • Moderate Nonproliferative Retinopathy:  As the disease progresses, some blood vessels that nourish the retina are blocked.
  • Severe Nonproliferative Retinopathy:  Many more blood vessels are blocked, depriving several areas of the retina with their blood supply.  These areas of the retina send signals to the body to grow new blood vessels for nourishment.
  • Proliferative Retinopathy:  At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels.  This condition is called proliferative retinopathy.  These new blood vessels are abnormal and fragile.  They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye.  By themselves, these blood vessels do not cause symptoms or vision loss.  However, they have thin, fragile walls.  If they leak blood, severe vision loss and even blindness can result.

4.  Macular Edema occurs when fluid and protein deposits collect on or under the macula of the eye, a yellow central area of the retina, causing it to thicken and swell.  The swelling may distort a person’s central vision, as the macula is near the center of the retina at the back of the eyeball.  This area holds tightly packed cones that provide sharp, clear central vision to enable a person to see form, color, and detail that is directly in the line of sight.

5.  Cystoid macular edema (CME) is a painless disorder that affects the central retina or macula.  When this condition is present, multiple cyst-like (cystoid) areas of fluid appear in the macula and cause retinal swelling or edema.

Although the exact cause of CME is not known, it may accompany a variety of diseases such as retinal vein occlusion, uveitis, or diabetes.  It most commonly occurs after cataract surgery. About 1-3 % of those who have cataract extractions will experience decreased vision due to CME during the first post-operative year, usually from two to four months after surgery.  If the disorder appears in one eye, there is an increased risk (possibly as high as 50%) that it will also affect the second eye.  Fortunately, however, most patients recover their vision with treatment.

6.  Central Retinal Vein Occlusion (CRVO) & Branch Retinal Vein Occlusion (BRVO) are common retinal vascular disorders.  Clinically, CRVO presents with variable visual loss; the fundus may show retinal hemorrhages, dilated tortuous retinal veins, cotton-wool spots, macular edema, and optic disc edema.  In view of the devastating complications associated with the severe form of CRVO, a number of classifications were described in the literature.  All of these classifications take into account the area of retinal capillary non-perfusion and the development of neovascular complications.  The signs of a BRAO are similar, but present in just one quadrant.

7.   Myopic degeneration is a hereditary deformation of the eye that causes dramatically blurred vision or complete blindness.  It is a severe form of simple myopia, which describes the common near-sightedness present in many people.  Myopic degeneration is caused by the thinning, stretching and deformation of the sclera.  When the sclera weakens due to inherited degenerative myopia, structures such as the macula and retina become damaged.

8.   Angioid Streaks (idiopathic, secondary to toxoplasmosis, trauma).  Angioid streaks are linear gray, brown, or red-brown lines that extend radially from the optic disc and are located at the level of Bruch's membrane.  These streaks usually are associated with peripapillary atrophic retinal pigment epithelium (RPE) changes surrounding the optic disc.   Angioid streaks may not be readily visible or may be more extensive than apparent by ophthalmoscopic examination alone.  Patients may present with vision loss when a streak extends into the fovea or when choroidal neovascularization develops in the macula, most commonly at the distal tip of an angioid streak.  Angioid streaks may be idiopathic or may be associated with systemic disorders such as pseudoxanthoma elasticum, Paget's disease, Ehlers-Danlos syndrome, or sickle cell disease.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Verteporfin (Visudyne™)

Visudyne may be considered medically necessary as a Food and Drug Administration (FDA) off-label indication for:

  • Neovascular (wet) age-related macular degeneration (ARMD or AMD); or
  • Choroidal neo- revascularization (CNV) secondary to pathologic myopia and presumed ocular histoplasmosis. 

Visudyne is considered experimental, investigational and unproven for all other indications.

Pegaptanib sodium injection (Macugen®)

Macugen may be considered medically necessary as an FDA labeled indication for the treatment of neovascular (wet) ARMD.  

Macugen may be considered medically necessary as an FDA off-label indication for the treatment of diabetic macular edema and diabetic retinopathy.  

Macugen is considered experimental, investigational and unproven for all other indications. 

Ranibizumab injection (Lucentis™)

Lucentis may be considered medically necessary as an FDA labeled indication for the treatment of:

  • Neovascular (wet) ARMD; 
  • Macular retinal edema due to retinal vein occlusion;
  • Diabetic macular edema.

Lucentis is considered experimental, investigational and unproven as a treatment for all other indications.

Aflibercept injection (Eylea™)

Eylea may be considered medically necessary for treatment of the following FDA labeled indications:

  • “Wet” age-related macular degeneration (ARMD),
  • Macular edema following central retinal vein occlusion (CRVO)

Eylea is considered experimental, investigational and unproven for all other ophthalmologic indications. 

Bevacizumab (Avastin™)

Avastin may be considered medically necessary as an FDA off-label indication for the treatment of:

  • Age related macular degeneration (ARMD);
  • Diabetic macular edema;
  • Diabetic retinopathy;
  • Choroidal (subretinal) neovascularization (i.e., secondary to neovascular (wet) age-related macular degeneration, myopic degeneration, angioid streaks, idiopathic, secondary to toxoplasmosis, trauma, etc.);
  • Retinal neovascularization (i.e., secondary to diabetes, secondary to central retinal vein occlusion (CRVO), etc.);
  • Macular retinal edema due to diabetes mellitus, central retinal vein occlusion (CRVO) and/or branch retinal vein occlusion (BRVO);
  • Other neovascular conditions of the eye (e.g., rubeosis iridis, trabecular angle neovascularization, etc.).

Avastin is considered experimental, investigational and unproven for all other ophthalmologic indications. 

Other

Conjunctival incision with posterior juxtascleral placement of Anecortave Acetate (Retaane™) is considered experimental, investigational and unproven as a treatment of neovascular (wet) ARMD or AMD.

Delivery of pharmacologic agents into the suprachoroidal space of the eye by injection or microcannulation is considered experimental, investigational and unproven.

Rationale

Verteporfin photodynamic therapy received FDA approval in 2000 for the treatment of “predominantly classic subfoveal choroidal neovascularization associated with ARMD.”  Therefore, the labeled indications for Visudyne and Macugen overlap, although Macugen includes a broader range of patients with ARMD.

While there is no direct comparison with Visudyne therapy, the randomized studies used for both Visudyne and Macugen therapy incorporated the same primary outcome.  After one year of follow-up in the randomized study of Visudyne, 61 percent of the treated patients lost less than 15 letters of acuity, versus 46 percent in the placebo group.  After two years, 53 percent of the treatment group versus 38 percent of the placebo group lost fewer than 15 letters.

It is not clear how providers may choose to offer either Macugen or Visudyne.  One major difference between the two is that Macugen requires intravitreal injections while Visudyne requires intravenous injection followed by laser therapy.  In the randomized trials, Macugen was administered every six weeks, in contrast to Visudyne which is administered once, with follow-up every three months, with additional treatment if neovascularization recurs.  Many ophthalmologists are now familiar with administering Visudyne therapy, and given the apparently equivalent results of the two drugs, many may continue to preferentially offer Visudyne.  Patient preference will also play a role.  In the randomized studies of Macugen, patients were allowed to undergo concomitant Visudyne therapy, so it is likely that some patients will continue to receive both therapies. 

FDA approval of Macugen was based in part on the results of two similarly designed randomized trials.  The results of these studies were published in the New England Journal of Medicine in 2004.  Patients were randomized to receive control (placebo treatment) or one of three different doses of Macugen administered as intravitreous injections every six weeks for 48 weeks.  Patients were re-randomized between treatment and no-treatment groups during the second year of the trial.  The primary outcome was the proportion of patients losing less than 15 letters of visual acuity, from baseline up to 54 week assessment.  After the first year in one study, 73 percent of patients in the treatment group lost less than 15 letters of acuity versus 60 percent sham, and 67 percent versus 53 percent in the second randomized trial, both statistically significant results.  Macugen was less effective during the second year of the trial, with 57 percent of the treatment group losing less than 15 letters of vision, compared to 56 percent in the sham group in one trial, and 61 percent versus 34 percent in the second trial.

The study entry criteria for Macugen trials were quite broad including patients whose vision ranged from 20/40 to 20/320.  While 20/40 vision is required for such routine activities as reading or driving, 20/320 vision represents legal blindness.  Therefore, the functional impact of preservation of visual acuity will be quite different at different ends of the spectrum.  For example, preservation of vision to a level of 20/100 suggests that with optical assistance, a patient could perform reasonably well.  However, preservation of 20/400 vision would provide only very limited function.  While patients with greater vision impairment at initiation of therapy also appeared to benefit from Macugen therapy (in terms of visual acuity as measured by number of letters lost), there was no discussion of functional outcomes.

Macugen is a selective RNA aptamer that inhibits vascular endothelial growth factor (VEGF) 165, the VEGF isoform primarily responsible for pathologic ocular neovascularization and vascular permeability, while sparing the physiological isoform VEGF 121.  After more than 10 years in development and preclinical study, pegaptanib was shown in clinical trials to be effective in treating CNV associated with ARMD.  Its excellent ocular and systemic safety profile has also been confirmed in patients receiving up to three years of therapy.  Early, well-controlled studies further suggest that pegaptanib may provide therapeutic benefit for patients with DME, proliferative DR and retinal vein occlusion.  Notably, pegaptanib was the first available aptamer approved for therapeutic use in humans and the first VEGF inhibitor for the treatment of ocular vascular diseases.

Administration of intravitreal pegaptanib (Cunningham et al.) led to an improvement in visual acuity and a reduction in central retinal thickness in some patients with early stage DME in a randomized, double-blind, dose-finding, phase II trial.  Pegaptanib-treated patients received an average of five injections, with 49% (83/172) receiving the maximum of six injections.  Of the patients receiving the active study regimen, the patients allocated to the 0.3 mg dose had greater improvement in vision acuity, greater decrease in retinal thickness, and lesser need for focal or grid laser intervention.

FDA approval of Lucentis for ARMD was based on three, double-masked sham or active-controlled clinical trials in patients with neovascular AMD (combined n=1323).  In the first study, patients with minimally classic or occult CNV lesions received monthly intravitreal injections of Lucentis (0.3mg or 0.5mg) or monthly sham injections over a 24-month period.  In a second study, patients with predominantly classic CNV lesions received one of the following:

  • Monthly intravitreal injections of Lucentis (0.3mg) and sham photodynamic therapy (PDT),
  • Monthly intravitreal injections of Lucentis (0.5mg) and sham PDT,
  • Sham intravitreal injections and active verteporfin PDT over a twelve month period.

The primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline.  Almost all Lucentis-treated patients (approximately 95%) maintained their visual acuity.  Thirty-four percent to 40% of Lucentis-treated patients experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months.  The size of the lesion did not significantly affect the results.  In the third study (n=184), patients with neovascular AMD (with or without a classic CNV component) received Lucentis 0.3mg (n=60) or 0.5 mg (n=61) intravitreal injections or sham (n=63) injections once a month for three consecutive doses, followed by a dose administered every 12 months.  The primary efficacy endpoint was mean change in visual acuity (following monthly dosing), on average, patients dosed once every three months with Lucentis lost visual acuity, returning to baseline at month 12.  Ninety percent of Lucentis-treated patients maintained their visual acuity at month 12. 

On June 22, 2010 the FDA approved Lucentis® for the treatment of macular edema following retinal vein occlusion (RVO).  RVO is the second most common retinal vascular disease after diabetic retinopathy.  RVO affects as many as 180,000 people in the United States and macular edema leads to vision loss in many patients with either central or branch retinal vein occlusion (CRVO or BRVO).  Accounting for approximately 80% of RVO, BRVO is the more common of the two presentations.

Two phase III clinical trials (BRAVO and CRUISE) studied the effects of intravitreal Lucentis measured over a period of six months.  In the BRAVO study 61% of the patients in the Lucentis study arm gained 15 or more letters in BCVA from baseline at six months compared with only 29% in the sham injection arm.  In the CRUISE study 48% of the patients in the Lucentis study arm gained 15 or more letters in BCVA from baseline at six months compared to only 17% in the sham injection arm.  These results demonstrated that in macular edema due to RVO, patients who were treated with Lucentis made significant improvement in best-corrected visual acuity (BCVA).

On August 10, 2012 the Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection) for the treatment of diabetic macular edema (DME), a sight-threatening eye disease that occurs in people with diabetes.

The safety and efficacy of Lucentis were assessed in two randomized, double-masked, 3-year studies in patients with DME. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (Lucentis 0.3 mg, 250 patients; Lucentis 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36. In Studies DME-1 and DME-2, patients received monthly Lucentis 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly Lucentis 0.5 mg and patients originally randomized to monthly Lucentis 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with Lucentis 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with Lucentis 0.3 mg and 30 of 257 (12%) patients treated with sham. Compared to monthly Lucentis 0.3 mg, no additional benefit was observed with monthly treatment with Lucentis 0.5 mg.

Visual acuity (VA) outcomes observed at Month 24 in patients treated with Lucentis 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received Lucentis 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with Lucentis at the beginning of the studies.

On November 18, 2011, the Food and Drug Administration (FDA) approved Eylea™ (aflibercept) previously called VEGF Trap-Eye for the treatment of “wet” (neovascular) age-related macular degeneration (ARMD, AMD), a leading cause of vision loss and blindness in Americans ages 60 and older.  The safety and effectiveness of Eylea was evaluated in two clinical trials involving 2,412 adult patients.  Patients in the study received either Eylea or Lucentis (ranibizumab injection).  The primary endpoint in each study was a patient’s clearness of vision (visual acuity) after one year of treatment.

A total of 2,457 patients were randomized in the two clinical trials of Eylea, with more than 90% completing the year-long study.  Maintenance of visual acuity was similar between aflibercept and ranibizumab in the multicenter, randomized, double-masked, active-controlled VIEW1 and VIEW2 studies for the treatment of neovascular (wet) age-related macular degeneration (n=2412; mean age, 76 years; range, 49 to 99 years).  Patients were randomized to receive intravitreal injections of aflibercept 2 mg every eight weeks following three initial monthly doses (n=301), 2 mg every four weeks (n=304), 0.5 mg every four weeks, or ranibizumab 0.5 mg every four weeks (n=304) in VIEW1 and VIEW2 (n=306, n=309, and n=291, respectively).  Data from the aflibercept 0.5 mg every four weeks treatment arm was not reported.  Of evaluable patients in VIEW1 at 52 weeks, the proportion of patients who maintained visual acuity (less than 15 letter loss of best corrected visual acuity (BCVA) from baseline; primary outcome) was 94%, 95%, and 94% in the aflibercept eight-week arm, four-week arm, and ranibizumab four-week arm, respectively.  In VIEW1, the treatment difference at 52 weeks between aflibercept every eight weeks and ranibizumab was 0.6 letters (95.1% confidence interval (CI), -3.2 to 4.4 letters), and the difference between aflibercept every four weeks and ranibizumab was 1.3 letters (95%.1 CI, -2.4 to 5 letters).  Similarly, in VIEW2 at 52 weeks, the proportion of patients who maintained visual acuity was 95% among all treatment arms.  In VIEW2, the treatment difference at 52 weeks between aflibercept every eight weeks and ranibizumab was 0.6 (95.1% CI, -2.9 to 4 letters), and the difference between aflibercept every four weeks and ranibizumab was -0.3 (95.1% CI, -4 to 3.3 letters).  The proportion of patients who gained at least 15 letters of vision from baseline was similar for aflibercept eight-week and four-week arms and ranibizumab in VIEW1 (31%, 38%, and 31%, respectively) and in VIEW2 (31%, 29%, and 34%, respectively). The mean change in BCVA (Early Treatment Diabetic Retinopathy Study) was also similar among all arms in VIEW1 and VIEW2.

Ophthalmologists are using Avastin off-label to treat AMD and similar conditions since research indicates that VEGF is one of the causes for the growth of the abnormal vessels that cause these conditions.  Some patients treated with Avastin had less fluid and more normal-appearing maculas, and their vision improved.  Avastin is also used to treat macular edema or swelling of the macula.

Intravitreal use of Avastin involves both an off-label application of the drug and an alternative route of drug delivery.  Positive presentations at retinal meetings and the two published case reports of visual acuity improvement and decreased retinal thickness have led the retinal community to embrace this new treatment.  As a result, the use of intravitreal Avastin has increased exponentially.  The main force driving intravitreal Avastin usage is the high percentage of patients who experience symptomatic relief from active subfoveal CNV.

Because Avastin was not created to be given as an intraocular injection, there have been no published animal or human safety data on retinal toxicity.  The intraocular safety profile of Avastin is unknown in contrast to that of Macugen or even Lucentis.  Avastin is also a full-sized antibody, unlike the Lucentis fragment, which means there is more potential for inflammation and immune reactions to this larger molecule over time.  The longer half-life (up to 20 days) of Avastin is useful for systemic cancer but may cause safety concerns in the eye.  (In contrast, the half-life of Lucentis was targeted for four hours.)  Whether systemic absorption is more likely with a longer half-life drug is unknown.  Although an intravitreal injection uses minute fractions of the drug and the systemic absorption is unlikely to be significant, measurement of systemic levels after intravitreal injection has not been done.  The clearance of Avastin is 100-fold slower than Lucentis, and the affinity of Avastin for VEGF is less than that of Lucentis.  Reasons to use Avastin center on fast onset of improved retinal morphology and visual acuity.  The anecdotal report showed dramatic improvement in optical coherence tomography appearance and corresponding improvement in visual acuity.  Other reasons to use it include its low cost and wide availability, with no unexpected toxicity shown to date.  Applications of its use include:

  • Salvage therapy (after lack of efficacy of FDA approved drugs);
  • Lesions that fall outside the indications for approved drugs;
  • Patient refusal to use other drugs; and
  • Lower cost in uninsured patients.

For patients who have failed therapy with approved drugs and have not yet evolved to disciform scars, off-label Avastin could be recommended as a salvage therapy.  Of all of these reasons, the overwhelming reason to use it is, of course, efficacy.

Considerations surrounding the use of anti-VEGF agents for neovascular glaucoma include safety, the most effective dose, the best route of administration, and utility as adjuvant therapy to panretinal photocoagulation (PRP), surgical filtration, or cyclodestructive procedures.  Studies suggest that the risk of endophthalmitis is extremely small; reported rates include 0.1% and 0.019%.  The preferred route of administration currently is intravitreal, and the recommended dose of Avastin for neovascular glaucoma is 1.25 mg.

The Retaane clinical study was a blinded, randomized controlled trial, with an enrollment of 128 patients with subfoveal CNV at 18 clinical sites, followed up patients for two years, and was completed in June 2003.  The study eye was randomized to 30 mg, 15 mg, 3 mg, or placebo from a central coordinating center.  Retaane or placebo was administered at baseline; retreatment at the six month visit occurred at the discretion of an unmasked ophthalmologist based on perceived benefit.  Compared to placebo, 15 mg (the most efficacious dose) was accompanied by a 25.5% absolute risk benefit for losing fewer than 15 letters of visual acuity.  No serious clinically relevant-treatment-related safety issues were reported from either the study medication Retaane or the procedure for administration.  Adverse ocular events seen in excess in patients treated with Retaane versus placebo were 15.3% excess of vision abnormalities and 7.1% excess of ocular foreign body sensation.  Cataracts were found in 27% and 30% and decreased visual acuity was noted in 25% and 30% in the treatment and placebo groups, respectively.  These occurrences included only study eyes, untreated eyes, or both eyes and are commonly experienced in patients with AMD.  Other adverse events that were reported as mild and transient included ptosis, ocular pain, visual abnormalities (e.g. hazy vision, black spots, light flashes), subconjunctival hemorrhage, and ocular pruritus.

A phase III randomized control trial compared the one-year safety and efficacy of Retaane 15 mg with photodynamic therapy (PDT) with Visudyne in 530 patients with predominantly classic CNV.  Retaane 15 mg was comparable to PDT for maintaining vision, with no statistical difference in the responder rates between the two groups.  Percent responders, defined as patients losing less than three lines of vision at month 12, in the Retaane 15 mg and PDT groups were 45% and 49% respectively.  The month 12 outcome of Retaane was improved in patients for whom reflux was controlled and who were treated within the six month window.  The most frequently reported adverse event in both treatment groups was decreased visual acuity, defined as a loss of vision of plus or minus four lines from the previous visit, occurring at an incidence of 31.9% and 30.3%, respectively.      

Traditional methods of ocular drug delivery include topical application, intraocular injection and systemic administration however these methods have difficulty effectively delivering drugs to the back (posterior portion) of the eye.  Current animal studies show promise of a drug delivery system using the suprachoroidal space of the eye that may avoid the complications associated with intraocular injection and systemic administration.

Clinical trials are currently investigating the potential use of suprachoroidal drug delivery to the posterior pole (macula and optic nerve) using an advanced microcannula system and demonstrated relative safety by studying the choroidal and retinal blood flow with high-speed confocal Scanning Laser Ophthalmoscope (cSLO) video angiography, fundus exam by cSLO imaging and wide-field fundus photography, and short- and long-term histopathology in the pig model.  These data have been used to justify the safety of this methodology for use in humans.  Clinical trials are currently investigating the potential use of this technology for treatment of macular disease.

A study by Einmahl et al. investigated the feasibility and tolerance of suprachoroidal delivery of poly ortho ester (POE), a bioerodible and biocompatible polymer, as a biomaterial potentially useful for development of sustained drug delivery systems.  The authors concluded that POE suprachoroidal injections, an easy, controllable, and reproducible procedure, were well tolerated in the rabbit eye.  POE appears to be a promising biomaterial to deliver drugs focally to the choroid and the retina.

Another study by Olsen et al. in 2006 evaluated the pharmacokinetics of a posterior drug delivery system (PDS) by means of microcannulation of the suprachoroidal space in both the primate and pig animal model.  Cannulation was performed in 93 of 94 animals.  Complications included: endophthalmitis (1/94), choroidal tear (1/94), choroidal blood flow irregularities (4/94), postoperative inflammation (6/94), scleral ectasia (4/94), wound abscess (1/94), and others. Histopathology demonstrated normal anatomy in uncomplicated cases.  Triamcinolone remains in the local ocular tissue for at least 120 days, and measurable at very low levels in the systemic circulation.  The authors concluded accessing the suprachoroidal space by the microcannulation system can be performed in a safe and reproducible manner by using careful surgical technique. Forceful PDS tip impact into connective tissues in the macular and optic nerve regions should be avoided.  Triamcinolone pharmacokinetics is unique and suggests long-term local tissue levels with low systemic levels.  PDS access to the suprachoroidal space represents a novel drug delivery method; applicable to a wide variety of pharmacotherapy’s to the macula, optic nerve, and posterior pole.

The published literature to date does not permit scientific conclusions concerning the effects of suprachoroidal delivery of pharmacologic agents on health outcomes in humans.

On September 21, 2012, the FDA granted approval of Aflibercept injection (Eylea®) for the treatment of macular edema following central retinal vein occlusion (CRVO).

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

14.29, 14.75, 14.9, 360.21, 362.0-362.07, 362.50, 362.51, 362.52, 364.42

ICD-10 Codes

H35.051, H35.052, H35.053, H35.059, H35.32, E08.311, E08.319, E08.321, E08.329, E08.331, E08.339, E08.341, E08.349, E08.351, E08.359, E09.311, E09.319, E09.321, E09.329, E09.331, E09.339, E09.341, E09.349, E09.351, E09.359, E10.311, E10.319, E10.321, E10.329, E10.331 E10.339, E10.341   E10.351, E10.359, E11.311, E11.319, E11.321,E11.329, E11.331, E11.339, E11.341, E11.351, E11.359, E13.311, E13.319, E13.321, E13.331, E13.339, E13.351, E13.359, H21.1X1, H21.1X2, H21.1X3, H21.1X9, H35.32

Procedural Codes: 0124T, 0186T, 67028, J0178, J2503, J2778, J3396, J3490, J9035
References
  1. Hayes Alert Technology Assessment brief.  Photodynamic therapy with verteporfin (Visudyne™) for neovascular age related macular degeneration.  Hayes Alert® critical development in medical technology assessment.  Volume III numbers 9 (2000 September).
  2. Rubin, G.S., and N.M. Bressler.  The treatment of age-related macular degeneration with photodynamic therapy (TAP) study group.  Retina (2003 October) 22(5):536-44.
  3. D`Amico, D.J., Goldberg, M.F., et al.  Anecortave acetate as monotherapy for treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD):  interim (month 6) analysis of clinical safety and efficacy.  Retina (2003) 23(1):14-23.
  4. Ciulla, T.A., Amador, A.G., et al.  Diabetic retinopathy and diabetic macular edema, pathophysiology, screening, and novel therapies.  Diabetes Care (2003 May 11). http://care.diabetesjournals.org (accessed - 2009 June 8).
  5. Gragoudas, E.S., Adamis, A.P., et al.  Pegaptanib (Macugen therapy in diabetic individuals). New England Journal of Medicine (2004) 351(27):2805-16.
  6. Azab, M., Benchaboune, M., et al.  Verteporfin therapy of subfoveal choroidal neovascularization in age related macular degeneration:  meta-analysis of 2-year safety results in three randomized clinical trials:  Treatment of age-related macular degeneration with photodynamic therapy and Verteporfin in photodynamic therapy study report number 4.  Retina (2004) 24(1):1-12.
  7. Nimjee, S.M., Rusconi, C.P., et al.  Aptamers: an emerging class of therapeutics.  Annual Review of Medicine (2005) 56:555-83.
  8. Schmidt-Erfurth, U., Michels, S., et al.  Pegaptanib for neovascular age-related macular degeneration.  European Journal of Ophthalmology (2005) 15(4):482-5.
  9. Augustin, A.J., D`Amico, D.J., et al.  Safety of posterior juxtascleral depot administration of the angiostatic cortisone anecortave acetate treatment of subfoveal choroidal neovascularization in patients with age-related macular degeneration.  Graefes Archives of Clinical and Experimental Ophthalmology (2005) 15(4): 243(1):9-12.
  10. Michels, S., and Rosenfeld, P.J.  Treatment of neovascular age-related macular degeneration with Ranibizumab (Lucentis).   Klinische Monatsblatter Fur Augenheilkunde (2005 June) 222(10):480-4.
  11. Cunningham, E.T., Adams, A.P., et al.  A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factoraptamer, for diabetic macular edema.  Ophthalmology (2005 October 12) 112(10):1747-57.
  12. Medscape.com—the pros and cons of bevacizumab therapy:  Exploring off-label treatment Options.  http://cme.medscape.com (2005) 6(2) Medscape (accessed – 06/10/2009).
  13. Bressler, N.M., and M. Altaweed.  Macugen retinopathy study group.  Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.  Ophthalmology (2005 December 9).
  14. Adamis, A.P., Altaweel, M., et al.  Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.  Ophthalmology (2006 January) 113(1):23-8.
  15. Slakter, J.S., Bochow, T.W., et al.  Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration.  Ophthalmology (2006) 113(1):3-13.      
  16. Avery, R.I., Pieramici, D.J., et al.  Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.  Ophthalmology (2006) 113(3):363-72.
  17. Spaide, R.F., Land, K., et al.  Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration.  Retina (2006) 26(4):383-90.
  18. Tobin, K.A., Macugen treatment for wet age-related macular degeneration.  Insight (2006 January-March) 31(1):11-4.
  19. Avery, R.L., Pieramici, D.J., et al.  Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.  Ophthalmology (2006 March) 113(3):363-72. e5.
  20. Rosenfeld, P.J., and J.S. Heier.  Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration.  Ophthalmology (2006 April) 113(4):632.el.
  21. Gonzales, R.M., Rosenfeld, P.J., et al.  Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.  Retina (2006 May-June) 26(5):495-511.
  22. Bartz-Schmidt, K.U., and F.G. Holz.  Introduction to the topic:  Off-label use of bevacizumab in the treatment of neovascular age-related macular degeneration.  Ophthalmologe (2006 June) 103(6):461-2.
  23. Rosenfeld, P.J.  Intravitreal Avastin:  the low cost alternative to Lucentis?  American Journal of Ophthalmology (2006 July) 142(1):141-3.
  24. Bashshur, Z.F., and A.Bazarbachi.  Intravitreal bevacizumab for the management of choroidal neovascularization in age related macular degeneration.  American Journal of Ophthalmology (2006 July) 142(1):1-9.
  25. Vavvas, D., and D.J. D`Amico.  Pegaptanib, (Macugen): treating neovascular age-related macular degeneration and current role in clinical practice.  Ophthalmology Clinics of North America (2006 September) 19(3):353-60.
  26. Williams, A.J., and S. Fekrat.  Progression of choroidal neovascularization following injection of pegaptanib sodium (macugen) in two eyes with neovascular age related macular degeneration.  American Journal of Ophthalmology (2006 October) 142(4):683-4.
  27. Moshfeghi, A.A., Rosenfeld, P.J., et al.  Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration:  twenty-four-week results of an uncontrolled open-label clinical study.  Ophthalmology (2006 November) 113(11):2002.el-12.
  28. Olsen, T.W., Feng, X., et al.  Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment.  American Journal of Ophthalmology (2006 November) 142(5):777-87. 
  29. Shukla, D., Namperumalsamy, P., et al.  Pepaptanib sodium for ocular vascular disease.  Indian Journal of Ophthalmology (2007 November/December) 55(6):427-30.
  30. Suprachoroidal Delivery of Pharmacological Agents.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2007 December) Vision 9.03.19.
  31. Chan, W., Lai, TY., et al.  Intravitreal bevacizumab (Avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, Secondary to Punctate inner choroidopathy, or of idiopathic origin (2007 June) 143(6):977-83.
  32. Haritoglou, C.  Intravitreal bevacizumab in diabetic macular edema improved visual acuity, retinal thickness.  Retina Today (2007 January/February) www.cmetoday.net (accessed – 2009 June 8).
  33. Joussen, A., Smyth, N., et al.  Diabetic Retinopathy.  Pathophysiology of Diabetic Macular Edema http://content.karger.com (2007) 39:1-12 (accessed 06/09/2009).
  34. Andrijevic-Derk, B., Vatavuk, Z., et al.  Intravitreal bevacizumab for neovascular glaucoma.  Acta. Clin. Croat. (2008 September) 47(3):175-9.
  35. MedScape – Avastin IV:  Uses and Warnings.  http://www.medscape.com (2008 February 25). (accessed – 2009 June 9).
  36. Conjunctival Incision with Posterior Juxtascleral Placement of Anecortave Acetate Depot Suspension.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 May) 9.03.16.
  37. Photodynamic Therapy for Subfoveal Choroidal Neovascularization.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 June) Vision 9.03.08.
  38. Wakabayashi, T., Oshima, Y., et al.  Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal disease in 41 consecutive cases.  American Academy of Ophthalmology (2008) 2(26):1571-8.
  39. NIH – Diabetic Retinopathy.  Facts about diabetic eye disease.  National Institute of Health. National Eye Institute www.nei.nih.gov (accessed – 2009 June 8).
  40. Micromedex® Healthcare Series:  DRUGDEX® Drug Point.  Thompson Micromedex http://www.thomsonhc.com (accessed – 2009, June 8-10).
  41. Brown, D.M.  Safety and efficacy of intravitreal ranibizumab (Lucentis) in patients with macular edema secondary to central retinal vein occlusion: The CRUISE Study. Paper presented at: Retina Congress (2009 October 4) New York, NY.
  42. Ho,A.C., Gray, S., et al.   BRAVO and CRUISE Investigators. Ranibizumab in patients with macular edema following retinal vein occlusion: 12-month outcomes of BRAVE and CRUISE.  Poster presented at: Association for Research in Vision and Ophthalmology. (2010 May 6) Fort Lauderdale, FL.
  43. Rouvas, A., Petrou, P., et al.  Intravitreal ranibizumab (Lucentis) for branch retinal vein occlusion- induced macular edema: nine-month results of a prospective study.  Retina (2010 June) 30(6):893-902.
  44. FDA—Center for Drug Evaluation and Research.  Lucentis®.  Food and Drug Administration.  Available at http://www.fda.gov .  (accessed – 2010 September 20).
  45. Genzyme Corporation.  (2010 July 22).  FDA – Approval Letter and Label for Lucentis®.  Food and Drug Administration – Center for Devices and Radiologic Health, Medical Devices (2010 July 22).  Available at http://www.accessdata.fda.gov (accessed – 2010 September 20).
  46. Micromedex® Healthcare Series:  DRUGDEX® Drug Point.  Thompson Micromedex <http://www.thomsonhc.com> (accessed – 2010, September 20).
  47. Campochiaro, P.A., Hafiz, G., et al.  Antagonism of Vascular Endothelial Growth Factor for Macular Edema Caused by Retinal Vein Occlusions: Two-Year Outcomes. Ophthalmology (2010 Jul 12) [Epub ahead of print].
  48. Campochiaro, P.A., Heier, J.S., et al.  BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology (2010 Jun) 117(6):1102-1112.e1. [Epub 2010 Apr 15].
  49. Product Information: Eylea™ intravitreal injection, aflibercept intravitreal injection.  Regeneron Pharmaceuticals, Inc (per manufacturer), Tarrytown, NY, (2011).
  50. Clinical trials.gov.  Safety and Efficacy of Repeated Intravitreal Administration of VEGF-Trap in Patients With Wet AMD (NCT00320788) 2011 April 20.  www.clinicaltrial.gov  accessed 2011, December 8.
  51. Clinical trials.gov.  Safety and Tolerability Study of Intravitreal VEGF-Trap Administration in Patients With Neovascular AMD (NCT00320775) 2011 June 8. accessed 2011, December 8.
  52. FDA –News Release.  FDA approves Eylea for eye disorder in older people.  Maintains clearness of vision in those with wet age-related macular degeneration (2011, November 18). 
  53. Clinical Trials.gov.  Safety and Efficacy of Ranibizumab in Diabetic Macular Edema.  (NCT00284050) 2011, February 22.  (accessed 2012, September 12).
  54. Clinical trials. gov. Efficacy Study of Lucentis in the treatment of diabetic macular edema. (NCT00387582) 2012, May 23. (accessed 2012 September 12).
  55. FDA-News Release.  FDA approves Lucentis™ intravitreal injection for the treatment of diabetic macular edema, a sight-threatening eye disease that occurs in people with diabetes. (2012, August 10).    
  56. Product Information Lucentis™ intravitreal injection. Genentech manufacturer South San Franscisco, Calif. (2012).
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Anti-Vascular Endothelial Growth Factor (VEGF) Inhibitors for use in the Eye