Description    
Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib, aflibercept) are being evaluated for the treatment of disorders of choroidal circulation. Ophthalmic disorders affecting the choroidal circulation include age-related macular degeneration (AMD), central serous chorioretinopathy (CSC), pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic choroidal neovascularization (CNV), uveitis, choroidal rupture or trauma and chorioretinal scars.

The available literature from randomized controlled trials supports the use of antivascular endothelial growth factor (anti-VEGF) therapies (ranibizumab, bevacizumab, pegaptanib, aflibercept) as monotherapy for the treatment of CNV associated with AMD. The use of anti-VEGF therapies for CNV secondary to other relatively rare disorders of choroidal circulation (angioid streaks, CSC, choroidal rupture or trauma, idiopathic CNV, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome and uveitis) is supported by a few small randomized trials, numerous case series and clinical input. Therefore, anti-VEGF therapies (ranibizumab, bevacizumab, pegaptanib, aflibercept) may be considered medically necessary for CNV associated with these conditions. Anti-VEGF therapies are considered investigational for the treatment of chorioretinal scars.

Background
VEGF has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by CNV and macular edema. The macula, with the fovea at its center, has the highest photoreceptor concentration and is where visual detail is discerned. The anti-VEGF agents ranibizumab (Lucentis^™), pegaptanib (Macugen^®) and aflibercept (Eylea^™) are approved to treat CNV associated with AMD and are being evaluated for the treatment of other disorders of choroidal circulation. Other therapeutic options may include photodynamic therapy (PDT), antioxidants and thermal laser photocoagulation. The safety and efficacy of each treatment depends on the form and location of the neovascularization. Angiostatic agents block some stage in the pathway leading to new blood vessel formation (angiogenesis). In contrast to palliative treatments for CNV (e.g., thermal photocoagulation, PDT), they are potentially disease modifying by inhibiting the development of newly formed vessels.

The distinct pharmacologic properties of available VEGF inhibitors suggest that safety and efficacy data from one agent cannot be extrapolated to another. These agents may vary by penetration, potency, halflife, localization to the retina and initiation of the immune system. Pegaptanib is an oligonucleotide aptamer that binds to the VEGF-165 isomer of VEGF-A. Ranibizumab is an antibody fragment that does not possess the fragment crystallizable domain and is directed at all isoforms of VEGF-A receptors. Bevacizumab (Avastin^®) is a full-length anti-VEGF antibody derived from the same murine monoclonal antibody precursor as ranibizumab and inhibits all isoforms of VEGF-A. VEGF Trap-Eye (Eylea) is a recombinant fusion protein consisting of the VEGF-binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin-G1.

Age-Related Macular Degeneration
Neovascular AMD is characterized by CNV, which is the growth of abnormal choroidal blood vessels beneath the macula, which causes severe loss of vision and is responsible for most of the loss of vision caused by AMD. In its earliest stages, AMD is characterized by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination. As AMD progresses, 2 distinctively different forms of degeneration may be observed. The first, called the atrophic, or areolar or dry form, evolves slowly. Atrophic AMD is the most common form of degeneration and is often a precursor of the second form, the more devastating exudative neovascular form, also referred to as disciform or wet degeneration. The wet form is distinguished from the atrophic form by serous or hemorrhagic detachment of the retinal pigment epithelium and the development of CNV, sometimes called neovascular membranes. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV. The pattern of CNV, as revealed by fluorescein or indocyanine angiography, is further categorized as classic or occult. For example, classic CNV appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult CNV lacks the characteristic angiographic pattern, either due to the opacity of coexisting subretinal hemorrhage or, especially in CNV associated with AMD, by a tendency for epithelial cells to proliferate and partially or completely surround the new vessels. Interestingly, lesions consisting only of classic CNV carry a worse visual prognosis than those made up of only occult CNV, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of AMD.

Intravitreal triamcinolone acetonide is one of the first pharmacologic compounds evaluated for the treatment of CNV secondary to AMD. The most important effects of this treatment consist of the stabilization of the blood-retinal barrier and the down-regulation of inflammation. Triamcinolone acetonide also has antiangiogenic and antifibrotic properties and remains active for months after intravitreal injection. However, cataracts are a common adverse effect, and steroid-related pressure elevation occurs in approximately one-third of patients, with some requiring filtration surgery.

PDT is a treatment modality designed to selectively occlude ocular choroidal neovascular tissue. The therapy is a 2-step process, consisting initially of an injection of the photosensitizer verteporfin, followed 15 minutes later by laser treatment to the targeted sites of neovascularization in the retina. The laser treatment selectively damages the vascular endothelium. Patients may be retreated if leakage from CNV persists. Combination therapy with PDT and VEGF antagonists is being investigated (see Policy No. 90308).

Before the availability of angiostatic agents and PDT, CNV was treated with photocoagulation using either argon, green or infrared lasers. This conventional photocoagulation was limited to extrafoveal lesions due to the risk of retinal burns. Introduction of a scotoma or enlargement of a pre-existing scotoma, with or without visual acuity loss, is an immediate and permanent effect of photocoagulation surgery. Because of the loss of vision associated with laser photocoagulation, photocoagulation is no longer recommended as the initial treatment of subfoveal neovascularization.

Polypoidal Choroidal Vasculopathy
Polypoidal choroidal vasculopathy (PCV) is characterized by the presence of a branching vascular network with terminal, polyp-like aneurismal dilations. Some investigators consider PCV to be a subtype of AMD, while others suggest that the lesions, when submacular, can be mistaken for AMD. PCV is more common in Asian compared with white populations. Both PDT and ranibizumab have been used to treat PCV, although the optimal treatment for PCV may differ from that for AMD.

Central Serous Chorioretinopathy
CSC is the fourth most common retinopathy after AMD, diabetic retinopathy and branch retinal vein occlusion. CSC refers to an idiopathic disease in which there is a serous detachment of the macula due to leakage of fluid from the choriocapillaris through the retinal pigment epithelium. CSC can be divided into acute, recurrent and chronic conditions. Usually, serous retinal detachments have spontaneous resolution with recovery of visual function; however, a subset of patients may experience permanent deterioration of visual function attributable to chronic CSC or multiple recurrences of CSC. The pathogenesis of CSC is believed to be ischemia and inflammation, which lead to abnormal permeability of the inner choroid and elevation of the retinal pigment epithelium, causing serous epithelial detachments. The separated retinal pigment epithelium can then undergo tiny rips (blowouts) with a break in continuity. The change in permeability of the retinal pigment epithelium results in focal leakage and retinal detachment. Neovascularization can occur as a secondary complication. In about 90% of cases, CSC resolves spontaneously with detachment resolution within 3 months. The traditional management of acute CSC is observation. Recurring or chronic CSC can be treated with focal laser photocoagulation if the leaks are extrafoveal. Although laser may shorten the duration of symptoms, it does not have any impact on the final vision or the recurrence rate of CSC. In addition, laser photocoagulation causes collateral damage, creating symptomatic scotomas and a risk of triggering secondary CNV. PDT is not a standard treatment for CSC due to complications that may include CNV, although low-fluence PDT is being evaluated.

Other Causes of CNV
Other causes of CNV include pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic CNV, uveitis, choroidal rupture or trauma and chorioretinal scars. Treatments that have been evaluated for CNV not related to AMD include submacular surgery, laser photocoagulation and PDT. Efficacy of these treatment modalities is limited.

Regulatory Status
Pegaptanib (Macugen^®, Eyetech and Pfizer), ranibizumab (Lucentis^™, Genentech) and aflibercept (Eylea^™, Regeneron Pharmaceuticals), are approved by FDA for use in AMD. Pegaptanib was the first VEGF antagonist to be approved by FDA for use in neovascular (wet) AMD in 2004. Ranibizumab was approved for the treatment of patients with neovascular (wet) AMD in 2006. Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway and are administered by intravitreous injections every 4 to 6 weeks. Pegaptanib binds to the VEGF-165 isomer of VEGF-A, while ranibizumab is an antibody fragment directed at all isoforms of VEGF-A

Aflibercept (EYLEA^™, previously called VEGF Trap-Eye) is a recombinant fusion protein consisting of the VEGF binding domains of human VEGF receptors R1 and R2 fused to the Fc domain of human immunoglobulin-G1. Aflibercept was approved by FDA in 2011 for the treatment of neovascular (wet) AMD. The recommended dose for EYLEA^™ is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months).

Ranibizumab and aflibercept are also approved by FDA for retinal vascular conditions such as diabetic macular edema and macular edema following retinal vein occlusion (see Policy No. 90327).

Bevacizumab (Avastin^®) is derived from the same murine monoclonal antibody precursor as ranibizumab, which binds to all isoforms of VEGF-A. Bevacizumab has been developed and approved for use in oncology but has not been licensed for use in the eye.

Related Policies
90308 Photodynamic Therapy for Choroidal Neovascularization
90310 Transpupillary Thermotherapy for Treatment of Choroidal Neovascular Conditions
90320 Intraocular Radiation Therapy for Age-Related Macular Degeneration
90327 Intravitreal Angiogenesis Inhibitors for Retinal Vascular Conditions

Policy
Anti-vascular endothelial growth factor therapies (anti-VEGF), i.e., pegaptanib (Macugen^®*), ranibizumab (Lucentis^™*), bevacizumab (Avastin^™), and aflibercept (Eylea^™*), may be considered MEDICALLY NECESSARY as a treatment of neovascular (wet) age-related macular degeneration.

Anti-vascular endothelial growth factor therapies (anti-VEGF) may be considered MEDICALLY NECESSARY for the treatment of choroidal neovascularization due to angioid streaks, central serous chorioretinopathy, choroidal rupture or trauma, idiopathic choroidal neovascularization, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome and uveitis.

Anti-vascular endothelial growth factor therapies (anti-VEGF) are considered INVESTIGATIONAL for the treatment of chorioretinal scars.

*FDA-approved indication

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs, biologics and imaging may not be considered investigational and, thus, may only be assessed on their basis of their medical necessity. 

Rationale
Age-Related Macular Degeneration
A 2014 Cochrane review evaluated antivascular endothelial growth factor (anti-VEGF) therapies (pegaptanib, ranibizumab, bevacizumab) for neovascular age-related macular degeneration (AMD).¹ This systematic review included 12 randomized controlled trials (RCTs) with a total of 5,496 patients. There were 5 trials of pegaptanib, ranibizumab or bevacizumab compared with controls and 6 trials that compared bevacizumab with ranibizumab. The number of participants per trial ranged from 28 to 1,208. There was a low risk of bias in the included trials, and the overall quality of the evidence was considered to be very good. Patients treated with any of the anti-VEGF treatments were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity and have vision 20/200 or better compared with controls. Improvements in vision were found to be similar for ranibizumab and bevacizumab, while both of these agents resulted in greater improvements in visual outcomes compared with pegaptanib. Trials with aflibercept were not included in the review. Details of relevant trials are described next.  

Pegaptanib
Pegaptanib was compared with sham in 2 concurrent multicenter double-masked studies by the VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group in 2004.² Patients with all angiographic subtypes of lesions were enrolled if they had subfoveal sites of choroidal neovascularization (CNV) secondary to AMD. A total of 1,208 patients were randomized to a dose of 0.3, 1.0 or 3.0 mg pegaptanib or sham injections, administered every 6 weeks over a period of 48 weeks. The use of PDT was permitted only in the treatment of patients with predominantly classic lesions by an ophthalmologist who was masked to the treatment assignment. A total of 1,186 patients received at least 1 study treatment, had visual acuity assessments at baseline and were included in efficacy analyses. Approximately 90% of the patients in each treatment group completed the study, and an average of 8.5 injections was administered per patient. In the combined analysis, there was a significant improvement in the primary end point of the proportion of patients who had lost fewer than 15 letters of visual acuity for all 3 doses of pegaptanib. In the sham group, 55% of patients lost fewer than 15 letters at 54 weeks. In the 0.3-, 1.0- and 3.0-mg groups, the percentage of patients who lost fewer than 15 letters was 70%, 71% and 65%, respectively. The risk of severe loss of visual acuity (≥ 30 letters) was reduced from 22% in the sham injection group to 8% to14% in the pegaptanib groups. More patients receiving pegaptanib maintained their visual acuity or gained acuity (31% – 37% vs. 23%, respectively). Use of PDT after baseline was similar in the 4 groups, ranging from 17% to 21% of patients. Adverse events (AEs) associated with a severe loss of visual acuity occurred in 0.1% of patients. Discontinuation of therapy due to AEs was 1% in the pegaptanib and sham groups. 

No RCTs with pegaptanib were identified after 2004. 

Ranibizumab
ANCHOR
Ranibizumab was compared with photodynamic therapy (PDT) in a multicenter, manufacturer-funded double-blind study (423 patients) designated Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) in 2006.³ Patients with subfoveal CNV and a predominantly classic lesion (n = 423) were randomized in a 1:1:1 ratio to receive 0.3 mg (n = 137) or 0.5 mg (n = 139) of intravitreal ranibizumab plus sham verteporfin or sham injections plus active verteporfin (n = 142) monthly. Patients were to receive monthly injections for 2 years in the study eye. Only 1 eye per patient was chosen as the study eye, and only the study eye received ranibizumab with sham PDT or sham injection with active PDT. The primary, intention-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the following: the percentage losing fewer than 15 letters from baseline visual acuity score (month 12 primary efficacy outcome measure); percentage gaining more than 15 letters from baseline; and mean change over time in visual acuity score and fluorescein angiography-assessed lesion characteristics. AEs were monitored. Following 12 monthly treatments, patient groups treated with ranibizumab (0.3 or 0.5 mg) and sham verteporfin had 94% to 96% of subjects lose fewer than 15 letters. The patient group treated with monthly sham injection and active verteporfin therapy (average, 2.8 times over the year) had 64% of subjects lose fewer than 15 letters. Visual acuity improved by more than 15 letters in 36% and 40% of the ranibizumab groups (average dose-dependent gain, 8.5 and 11.3 letters), in comparison with 5.6% of subjects in the verteporfin group (average loss, 9.5 letters). Intraocular inflammation occurred in 10.2% and 15% of ranibizumab-treated patients, with presumed endophthalmitis in 1.4% and serious uveitis in 0.7% of patients treated with the highest dose. 

Brown et al. reported the 2-year results of the trial by the ANCHOR study group in 2009.⁴ Of 423 patients, at least 77% in each group completed the 2-year study. Consistent with results at month 12, at month 24, the visual acuity benefit from ranibizumab was statistically significant and felt to be clinically meaningful; 89.9% to 90.0% of ranibizumab-treated patients had lost fewer than 15 letters from baseline versus 65.7% of PDT patients; and 34% to 41.0% had gained 15 or more letters versus 6.3% of the PDT group. Changes in lesion anatomic characteristics on fluorescein angiography also favored ranibizumab. There was a trend for an increased incidence of cataract in the ranibizumab groups compared with the PDT group, which was statistically significant at the 0.5-mg dose. There were no statistically significant differences among the 3 treatment groups in the rates of serious nonocular AEs. In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with AMD with new-onset, predominantly classic CNV.  

Bressler et al. reported a subanalysis of the patient-reported outcomes from the ANCHOR trial.⁵ The National Eye Institute Visual Functioning Questionnaire‒25 (VFQ-25) was administered at baseline and at 1, 2, 3, 6, 9, 12, 18 and 24 months. The primary outcome measure was mean change from baseline in VFQ-25 scores at 12 months. At 12 months, patients treated with ranibizumab had mean improvements in VFQ-25 composite scores of 5.9 (range, 3.6 – 8.3) for 0.3-mg dose group and 8.1 (range, 5.3 – 10.8) points for the 0.5-mg dose group; patients treated with PDT had a mean improvement of 2.2 points (range, -0.3 to 4.7). At each dose through 24 months, patients treated with ranibizumab were more likely to improve in most subscales, including the prespecified subscales (near vision activities, distance vision activities, vision-specific dependency).  

HORIZON
In 2012, Singer et al. reported a 2-year open-label extension trial of ranibizumab for CNV secondary to AMD in patients who had completed 1 of 3 randomized 2-year clinical trials (ANCHOR, FOCUS, MARINA; see Policy No. 90308).⁶ There were 600 patients treated with ranibizumab in the initial studies, 190 patients who were initially in the control arm and crossed over to ranibizumab for the extension study, and 63 patients who remained ranibizumab-naive. Ranibizumab was administered at the investigator's discretion (no prespecified retreatment criteria). Follow-up was scheduled quarterly for 24 to 40 months, although investigators could see patients more frequently. On average, patients were seen about every 2 months, and the average number of injections was 2.1 for year 1, 4.4 for year 2 and 4.7 for year 3. The primary outcome, ocular safety, did not identify any serious AEs with intravitreal ranibizumab. While retinal hemorrhage was increased, cataracts were decreased. There was also a decline in visual acuity in the open-label phase with the less frequent treatment. At 24 months from the baseline of the open-label phase, best-corrected visual acuity (BCVA) decreased from +9.0 to +2.0 in the ranibizumab-treated group and from -9.6 to -11.8 in the 2 control groups. 

In 2012, Bressler et al. conducted an exploratory analysis of the rate of cerebrovascular accidents (CVA) with ranibizumab.⁷ With data pooled from 5 trials (FOCUS, MARINA, ANCHOR, PIER, SAILOR), CVA rates were less than 3%. The odds ratios for CVA risk were 1.2 for 0.3 mg ranibizumab versus control, 2.2 for 0.5 mg versus control and 1.5 for 0.5 mg versus 0.3 mg ranibizumab. These results are considered preliminary, but do suggest the need for continued monitoring for CVA with anti-VEGF agents.  

Bevacizumab
ABC Trial
In 2010, Tufail et al. reported a randomized multicenter study (ABC Trial) of bevacizumab for neovascular AMD in 131 patients (eyes), 65 of whom received bevacizumab.⁸ Outcomes at 54 weeks were compared with patients who had received standard care from the U.K.'s National Health Service (NHS), which was considered on a case-by-case basis. Patients with classic or predominantly classic CNV were randomized to PDT or bevacizumab with sham PDT. Patients with minimally classic or occult CNV were randomized to bevacizumab or (depending on NHS funding) pegaptanib or placebo. The standard care group included 38 patients treated with pegaptanib, 16 treated with verteporfin and 12 treated with a sham intravitreal injection. Bevacizumab (1.25 mg in 0.05 mL) was prepared in single-use sterile plastic syringes in sealed plastic pouches (shelf life of 6 weeks) and administered once every 6 weeks for the first 18 weeks; further injections were provided based on standardized criteria. Patients received a mean of 7.1 (range, 3 – 9) injections of bevacizumab or 7.3 (range, 3 – 9) sham injections. Active verteporfin PDT was administered at a mean of 3.2 times (range, 2 – 5). Independent assessment of outcomes found that 21 patients (32%) in the bevacizumab group gained 15 or more letters compared with 2 (3%) in the standard care group. More patients receiving bevacizumab lost fewer than 15 letters (91% vs. 67%, respectively). The mean change in visual acuity at 54 weeks increased by +7.0 letters in the bevacizumab group and decreased by -9.4 letters in the standard care group.  

Aflibercept
VIEW1 and VIEW 2
Data submitted to the U.S. Food and Drug Administration and published in 2012 included 52-week results from 2 multicenter double-masked, randomized trials (VIEW1, VIEW2) that compared 3 doses of aflibercept (VEGF Trap-Eye) with ranibizumab (0.5 mg).^9,10 A total of 2,457 patients with all 3 subtypes of AMD (occult, minimally classic, predominantly classic) were enrolled in the 2 studies. VIEW1 was conducted primarily in North America and VIEW2 was conducted primarily in Europe, Asia, Australia and Latin America. Both trials used a noninferiority design with a 10% margin and tested doses of aflibercept at 0.5 mg every 4 weeks, 2.0 mg every 4 weeks and 2.0 mg every 8 weeks after 3 initial monthly doses. Ranibizumab (0.5 mg) was administered every 4 weeks. Between 52 and 96 weeks, patients received the assigned study drug as needed (PRN) based on standardized criteria.¹¹ All doses of aflibercept met noninferiority compared with 0.5 mg ranibizumab, with about 94% of patients maintaining vision (losing < 15 letters) at week 52. At week 96, about 92% of patients in all groups had maintained stable vision. Post hoc analysis found that the number of injections in the 2-mg aflibercept groups (4.1 and 4.2) was statistically lower than in the ranibizumab group (4.7). 

In addition to VIEW1 and VIEW2, safety and tolerability of aflibercept was evaluated in a 3-year extension study with 157 patients. Intravitreal injections of aflibercept were given as needed, not more frequently than every 4 weeks. The most common adverse reactions (≥ 5%) reported in patients receiving aflibercept injection were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters and increased intraocular pressure (IOP). The data provided from these 3 trials were found to support the safety of aflibercept injection in the treatment of patients with neovascular (wet) AMD. The dose of 2 mg every 8 weeks was recommended for the labeling of aflibercept, because it has fewer injections than the other two doses studied and has the theoretical benefit of less injection-related risks (i.e., endophthalmitis).  

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.  

On-Label Versus Off-Label Use of VEGF Inhibitors 
Comparison of AMD Treatment Trials 
There has been considerable interest in determining whether efficacy of bevacizumab used off-label is similar to ranibizumab, which is specifically approved for use in the eye. In 2011, the 1-year results of the National Eye Institute-sponsored multicenter (44 sites) Comparison of AMD Treatment Trials (CATT) were published.¹² CATT was a randomized single-blind head-to-head comparison of the safety and effectiveness of ranibizumab and bevacizumab in treating wet AMD. A total of 1,208 patients with previously untreated active CNV due to AMD (neovascularization, fluid or hemorrhage under the fovea) and visual acuity between 20/25 and 20/320 were enrolled in the study. Patients were randomly assigned to receive intravitreal injections of ranibizumab (0.5 mg) or bevacizumab (1.25 mg) on either a monthly schedule or as needed with monthly evaluation. The mean number of injections on the as-needed schedule was 6.9 for ranibizumab and 7.7 for bevacizumab over the first year of the study (significantly different). The primary outcome measure was a change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.  

When administered according to the same schedule, bevacizumab and ranibizumab had equivalent (not inferior) effects on visual acuity. With bevacizumab and ranibizumab administered monthly, patients gained an average of 8.0 and 8.5 letters, respectively. When administered as needed, the number of letters gained with bevacizumab was similar to that of ranibizumab, with 5.9 and 6.8 letters gained, respectively. At 1 year, there were no significant differences in the proportion of patients who lost or gained 15 or more letters. There were significant differences in the anatomy of the retina with the different treatments. At 1 year, monthly ranibizumab decreased central retinal thickness to a greater extent (196m) than the other 3 groups (152 to 168m). The absolute between-drug difference in the amount of residual fluid was small; at 1 year, total thickness at the fovea was 266m for the ranibizumab monthly group and close to 300m for the other 3 groups. In comparison, the retinal thickness of healthy eyes measured by optical coherence tomography (OCT) at the fovea averages 212m.¹³ Rates of death, myocardial infarction (MI) and stroke were similar for patients receiving either bevacizumab or ranibizumab. The proportion of patients with serious systemic AEs (primarily hospitalizations) was higher with bevacizumab than with ranibizumab, although these events were broadly distributed in disease categories not considered to be areas of concern for use of bevacizumab and were not dose-dependent.  

An accompanying editorial noted that although the OCT retinal thickness measurements favor ranibizumab, this difference was not reflected in any of the visual-acuity or angiographic outcomes; whether this difference was associated with changes in vision would become clearer during the second year of follow-up.¹⁴ In 2012, the CATT Research Group reported the 2-year follow-up on 1,107 of the 1,185 patients enrolled in the trial.¹⁵ Visual acuity gains at 2 years were similar to those obtained at 1 year, ranging from 5.0 to 8.8 letters, and when following the same treatment regimen, the mean gain in visual acuity was similar for ranibizumab and bevacizumab. The proportion of patients with 1 or more systemic serious AEs was higher with bevacizumab (39.9% vs. 31.7%), although most of the excess events were not previously associated with systemic VEGF inhibitors.   

Several research groups from Europe also found no evidence of inferiority in visual outcomes with off-label use of bevacizumab. The IVAN study was a multicenter double-masked noninferiority trial from the United Kingdom that randomized 610 patients to ranibizumab or bevacizumab given monthly, or ranibizumab or bevacizumab given PRN.¹⁶ Results at 1 and 2 years were inconclusive (bevacizumab was neither inferior nor equivalent, with a mean difference of -1.37 letters).¹⁷ The GEFAL study was a randomized double-masked noninferiority trial from France with 501 patients.18 In both per protocol and intention-to-treat analysis, bevacizumab was noninferior to ranibizumab (mean difference, +1.89 letters). The multicenter MANTA research group from Austria reported a double-masked randomized noninferiority trial comparing ranibizumab and bevacizumab in 317 patients with AMD.¹⁹ At 12 months, there was a similar increase in visual acuity for the 2 groups (4.9 letters in the bevacizumab group, 4.1 letters in the ranibizumab group).  

The potential for an increased risk of AEs with bevacizumab remains controversial. A randomized study from 2013 found that a single intravitreal injection of bevacizumab led to significantly reduced levels of VEGF in plasma (from 89.7 pg/mL to 22.8 pg/mL) for up to 1 month after intravitreal injection.²⁰ However, this large reduction appears to be driven largely by 1 outlier with plasma VEGF levels of close to 400 pg/mL. VEGF levels in plasma were not affected by ranibizumab or pegaptanib. In 2012, Schmucker et al. reported a meta-analysis of the safety of bevacizumab compared with ranibizumab.²¹ Direct comparison (3 trials, 1,333 patients) found a significantly higher rate of ocular and systemic AEs with bevacizumab compared with ranibizumab. Arterial thromboembolic events were similar between the 2 conditions.  

A retrospective analysis of claims from 146,942 Medicare beneficiaries compared treatment with PDT, pegaptanib, bevacizumab or ranibizumab.²² After adjustment for baseline characteristics and comorbid conditions, there were no significant differences in the hazard of mortality or MI between bevacizumab use and the other therapies. There was no statistically significant relationship between treatment group and bleeding events or stroke. In contrast, a 2011 preliminary report of 77,886 Medicare beneficiaries found an 11% higher risk in overall mortality and a 57% higher risk of hemorrhagic cerebrovascular accident following treatment with bevacizumab in comparison with ranibizumab.²³ The authors note that the study is limited by incomplete information on some important confounding factors, e.g., smoking, lipid and blood pressure levels, which would further clarify the relative safety of these treatments in wet AMD.  

Section Summary
Evidence on comparative effectiveness indicates there are no substantial differences in efficacy between bevacizumab and ranibizumab for the treatment of AMD. The evidence on AEs is not conclusive on whether bevacizumab is associated with a higher rate of AEs compared with ranibizumab. 

Other Causes of CNV
The literature on angiogenesis inhibitors for the treatment of other causes of CNV consists of cases series and small controlled trials. Following is a summary of the key literature to date, focusing on controlled trials. 

A 2011 U.S. multicenter phase 1 trial examined the efficacy of ranibizumab for CNV secondary to causes other than AMD.²⁴ Thirty patients with pathologic myopia (n = 14), ocular histoplasmosis (n = 9), angioid streaks (n = 3), idiopathic telangiectasia (n = 1), idiopathic chorioretinal scar (n = 1), choroidal ruptures (n = 1) or central serous retinopathy (n = 1) were randomly assigned to monthly intravitreal injections of 0.5 mg ranibizumab or 3 monthly injections followed by PRN at monthly follow-up visits. In the PRN group, retreatment was performed at follow-up visits if the study eye met prespecified criteria. A mean of 5.93 injections (range, 3 – 11) were administered to evaluable patients (n = 14) in the PRN treatment arm compared with 11.17 injections among evaluable patients (n = 12) in the monthly treatment arm. The mean BCVA at baseline was 53.5 and 48 letters in the monthly and PRN treatment arms, respectively. At 12 months (87% follow-up), mean visual acuity had improved by 26.9 and 19.2 letters in the 2 groups, respectively. Eight of 12 (66.7%) patients who received monthly injections gained 15 or more letters, compared with 8 of 14 (57.1%) on the PRN schedule. No patient in the study lost 15 or more letters. The mean baseline central retinal thickness was 345m and 383m in patients in the monthly and PRN treatment arms, respectively. Central retinal thickness decreased by 109.3m in the monthly group and 166.6m in the PRN treatment group. No statistically significant differences were observed between treatment groups. The most common ocular AEs included 5 cases of subconjunctival hemorrhage, 4 cases of ocular pain or soreness, 2 cases of vitreous floaters, 1 case of retinal hemorrhage and 2 cases of transiently elevated IOP. The study concluded that intravitreal ranibizumab has a promising safety and efficacy profile in the treatment of CNV unrelated to AMD and that larger, randomized studies are warranted to confirm these findings and to determine the optimal dosing regimen for ranibizumab. 

Chen et al. assessed visual outcomes and retreatment rates in a retrospective comparison of bevacizumab alone or bevacizumab combined with PDT.²⁵ Included were 23 patients with subfoveal CNV due to causes other than AMD (myopia, presumed ocular histoplasmosis, angioid streaks, choroiditis, idiopathic, central serous chorioretinopathy). At 12-month follow-up, the mean change in visual acuity was a gain of 1.7 lines in the monotherapy group (n = 17) compared with 2.8 lines in the combination therapy group (n = 6; p = 0.45). At 12 months, 36% in the bevacizumab monotherapy group gained more than 3 lines of vision compared with 60% in the combination group (p = 0.60). The monotherapy group received a mean of 4.8 reinjections, while the combination group received 2.6 injections over 12 months (p = 0.11).  

Angoid Streaks
A 2013 meta-analysis identified 54 small series (≥ 3 cases) on the treatment of angoid streaks; no RCTs were identified.²⁶ While PDT (11 studies) was found to slow down disease progression, VEGF inhibitors (16 studies) stabilized or improved vision. Pooled analysis showed superior results for VEGF inhibitors, with a mean difference between the treatments of approximately 6 lines.  

Central Serous Chorioretinopathy
In 2014, Bae et al. reported 1-year results from a small randomized trial that compared low-fluence PDT versus ranibizumab in 34 eyes (32 patients) with chronic (≥ 6 months) or recurrent central serous chorioretinopathy.²⁷ Rescue with the other treatment was available after 3 months if subretinal fluid persisted or recurred. Masked evaluation at 1 year found complete resolution of subretinal fluid without rescue treatment in 16 eyes (88.9%) of the PDT group compared with 2 eyes (12.5%) in the ranibizumab group. The improvement in BCVA at 3 months was significantly greater in the PDT group compared with the ranibizumab-treated eyes (.25 vs. .12 logMAR). At 1 year (after rescue treatment), there was no significant difference in BCVA between the 2 groups.  

Literature searches also identified 2 small controlled studies from Asia that assessed the efficacy of bevacizumab for central serous chorioretinopathy (CSC) compared with no treatment. In a 2010 report, 32 eyes with acute CSC ( < 3 months in duration) were randomized to a single intravitreal injection of bevacizumab or to observation.²⁸ During the 6-month follow-up, there were no significant differences in visual acuity, central retinal thickness or remission duration between the bevacizumab and control group. All patients had complete resolution of their macular subretinal fluid during the 6-month follow-up. In another prospective study, 15 eyes of 15 patients with persistent CSC (> 3 months) treated with a single intravitreal injection of bevacizumab were compared with 15 eyes with the same characteristics from patients who declined treatment.²⁹ At 6-month follow-up, the mean logMAR BCVA was significantly better in the treatment group (0.03) compared with the control group (0.14), and all 15 (100%) treated eyes had stable or improved vision, compared with 10 (66%) eyes in the control group.  

Multifocal Choroiditis
In 2010, Parodi et al. reported a pilot RCT that compared intravitreal bevacizumab and PDT in 27 patients with CNV associated with multifocal choroiditis.³⁰ Retreatments (2.8 for bevacizumab, 0.7 for PDT) were performed if any leakage from CNV was noted on fluorescein angiography. At the 12-month follow-up, 5 of 14 eyes (36%) in the bevacizumab group and 0 of 13 eyes (0%) in the PDT group had a gain of 3 or more lines of vision. Twelve eyes (86%) in the bevacizumab group and 6 eyes (46%) in the PDT group gained more than 1 line. There was a significant difference in BCVA favoring the bevacizumab group at the end of follow-up. The 2 groups showed a similar improvement in central macular thickness.  

Pathologic Myopia
RADIANCE was a 12-month, phase 3, multicenter, double-masked randomized trial that compared ranibizumab with PDT in 277 patients with myopic CNV.³¹ Treatment with ranibizumab continued on a monthly basis until BCVA stabilized (group I) or there was no disease activity (group II). Patients in the PDT group (group III) could be treated with ranibizumab from months 3 to 11 if disease activity was observed. All patients were treated with sham injection or PDT sham together with the study treatment to maintain masking, and evaluations were performed by an investigator not involved in the treatment. Patients who were initially treated with ranibizumab followed by PRN ranibizumab had superior visual acuity outcomes compared with PDT from month 1 through month 3. Group I gained 10.5 letters, group II gained 10.6 letters, compared with a gain of 2.2 letters following treatment with PDT (p < 0.000). Groups I and II continued to improve in BCVA up to month 12. Ranibizumab was allowed after month 3 in group III, at which time BCVA steadily improved. 

Parodi et al. compared intravitreal bevacizumab with laser photocoagulation and PDT in a randomized trial of 54 patients with juxtafoveal CNV secondary to pathologic myopia in 2010.³² Additional intravitreal bevacizumab injections were administered when OCT revealed persistent or recurrent fluid, or when the fluorescein angiography examination revealed CNV activity or progression. Eyes in the laser therapy or PDT groups that developed recurrent CNV with subfoveal location during follow-up could be retreated using PDT. At 24 months, the bevacizumab group had gained 1.8 lines from baseline with a mean of 3.8 intravitreal bevacizumab injections; 4 of 19 eyes (21%) required intravitreal bevacizumab injections during the second year. The laser photocoagulation group lost 1.1 lines with a mean of 1.17 PDT treatments and the PDT group lost 2 lines with 2.55 retreatments.  

A 2012 study from the same group of investigators compared ranibizumab PRN versus bevacizumab PRN in 48 eyes with neovascularization secondary to pathologic myopia.³³ Although this randomized study does not appear to be double-masked, the authors reported that visual acuity was assessed by an examiner who was unaware of the purpose of the study. At 18-month follow-up, there was no significant difference in mean BCVA between the 2 groups (0.42 logMAR for ranibizumab vs. 0.53 logMAR for bevacizumab). A 3-line or higher gain was reported for 30% of eyes in the ranibizumab group and 44% of eyes in the bevacizumab group. Stabilization of CNV was observed in 100% of ranibizumab-treated eyes and 84% of bevacizumab-treated eyes. Fewer injections were administered in the ranibizumab group (2.5) compared with the bevacizumab group (4.7).  

Another small randomized trial from 2010 compared ranibizumab and bevacizumab in 32 eyes (32 patients) with pathologic myopia.³⁴ Follow-up was performed at 1, 3 and 6 months. BCVA at baseline was 26.44 letters in the ranibizumab group and 29.50 letters in the bevacizumab group. At 6 months, ranibizumab-treated eyes had gained 17.31 letters and bevacizumab-treated eyes had gained 15.87 letters. Twelve eyes in the ranibizumab group (75%) and 13 in the bevacizumab group (81.2%) gained 10 or more letters. Foveal center thickness improved from 251 to 206m with ranibizumab and from 237 to 185m with bevacizumab. No significant differences in BCVA improvement or foveal center thickness reduction were found between the groups. Complete resolution of fluorescein leakage was observed in all 16 bevacizumab-treated eyes and in 15 of 16 (93.7%) of ranibizumab-treated eyes.  

• NCT01249664 is a study with 122 patients with myopic CNV randomized to aflibercept or sham injection. Results have been posted, but no published results have been identified as of Feb. 19, 2015.  

Polypoidal Choroidal Vasculopathy
LAPTOP was a multicenter randomized study that compared ranibizumab with PDT in 93 patients with PCV.³⁵ Although both treatments improved central retinal thickness, intention-to-treat analysis at 12 months found ranibizumab to be superior to PDT for changes in visual acuity. Mean logMAR improved in the ranibizumab arm (from .48 to .39, gain of .9 lines), but remained unchanged in eyes treated with PDT (from .57 to .62, loss of .5 lines). In the ranibizumab arm, 30.4% of patients achieved visual acuity gain (≥ .2 logMAR) compared with 17.0% of patients treated with PDT. 

EVEREST was a multicenter, double-masked comparison of PDT, ranibizumab or both in 61 patients with PCV.³⁶ At 6 months, PDT alone or combined with ranibizumab was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8%, 71.4%, 28.6%, respectively). In comparison, the proportion of patients gaining at least 15 letters was 21% for PDT plus ranibizumab, 19% for PDT alone and 33.3% for ranibizumab monotherapy. The study was not powered to demonstrate statistically significant differences in BCVA between groups.  

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. 

In response to requests, input was received from 1 physician specialty society and 2 academic medical centers while this policy was under review in 2011. The input supported the use of anti-VEGF therapies (ranibizumab, bevacizumab, pegaptanib) for CNV due to AMD, angioid streaks, central serous chorioretinopathy, choroidal rupture or trauma, idiopathic CNV, pathologic myopia, presumed ocular histoplasmosis syndrome and uveitis; clinical input did not uniformly support the use of anti-VEGF therapies for chorioretinal scars. The evidence provided in support of the medical necessity of anti-VEGF therapy for these conditions consisted of some small controlled trials and numerous case series. 

Summary of Evidence
The available literature from randomized controlled trials (RCTs) supports the use of antivascular endothelial growth factor (anti-VEGF) therapies (ranibizumab, bevacizumab, pegaptanib, aflibercept) as monotherapy for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). The use of anti-VEGF therapies for CNV secondary to other relatively rare disorders of choroidal circulation (angioid streaks, central serous chorioretinopathy, choroidal rupture or trauma, idiopathic CNV, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome and uveitis) is supported by a few small randomized trials, numerous case series and clinical input. Therefore, anti-VEGF therapies (ranibizumab, bevacizumab, pegaptanib, aflibercept) may be considered medically necessary for CNV associated with these conditions. Anti-VEGF therapies are considered investigational for the treatment of chorioretinal scars. 

Practice Guidelines and Position Statements
In 2014, the American Academy of Ophthalmology issued Age-Related Macular Degeneration Preferred Practice Patterns.³⁷ The recommendations for the care of AMD include the following:  

• Intravitreal injection therapy using anti-vascular endothelial growth factor (VEGF) agents (e.g., aflibercept, bevacizumab and ranibizumab) is the most effective way to manage neovascular AMD and represents the first line of treatment.  
• Intravitreal anti-VEGF therapy is generally well-tolerated and rarely associated with serious adverse events such as infectious endophthalmitis or retinal detachment. Symptoms suggestive of postinjection endophthalmitis or retinal detachment require prompt evaluation.  

In April 2008, the Canadian Agency for Drugs and Technologies in Health, released a health technology assessment titled Management of Neovascular Age-related Macular Degeneration: Systematic Drug Class Review and Economic Evaluation. The review of clinical evidence found that, with the exception of trials comparing ranibizumab with photodynamic therapy (PDT), there was a significant lack of trials comparing the other anti-VEGF agents in general. The authors concluded that “... overall, the efficacy of anti-vascular endothelial growth factor (anti-VEGF) therapies over verteporfin (V-PDT) is well supported by RCTs. What remains unclear is whether combination therapy (and which combinations) are superior or equal to monotherapy. Furthermore, the efficacy of one anti-VEGF agent compared with another is also unclear and this has very important practical and economic implications.”³⁸  

In 2012, the U.K.'s National Institute for Health and Care Excellence (NICE) modified their 2008 technology appraisal 155, which now recommends the use of ranibizumab for the treatment of wet AMD if all of the following conditions apply to the eye being treated: the BCVA is between 6/12 and 6/96, there is no permanent structural damage to the central fovea, the lesion size is less than or equal to the 12 disc areas in greatest linear dimension, there is evidence of recent presumed disease progression (blood vessel growth as indicated by fluorescein angiography) or recent visual acuity changes. Specified financial agreements with the manufacturer must also be in place.³⁹  

NICE issued TA 294 in 2013 recommending the use of aflibercept only if it is used in accordance with their technology appraisal 155 (see previous criteria TA155) for ranibizumab; specified financial agreements with the manufacturer must be in place.⁴⁰ 

NICE issued TA 298 in 2013 that states that ranibizumab is recommended as a treatment option for visual impairment due to CNV secondary to pathologic myopia when the manufacturer provides ranibizumab at the agreed-on discount.⁴¹  

U.S. Preventive Services Task Force Recommendations
Not applicable

References 

1. Solomon SD, Lindsley K, Vedula SS, et al. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;8:CD005139. PMID 25170575
2. Gragoudas ES, Adamis AP, Cunningham ET, Jr., et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. Dec 30 2004;351(27):2805-2816. PMID 15625332
3. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. Oct 5 2006;355(14):1432-1444. PMID 17021319
4. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. Jan 2009;116(1):57-65 e55. PMID 19118696
5. Bressler NM, Chang TS, Fine JT, et al. Improved vision-related function after ranibizumab vs photodynamic therapy: a randomized clinical trial. Arch Ophthalmol. Jan 2009;127(1):13-21. PMID 19139332
6. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. Jun 2012;119(6):1175-1183. PMID 22306121
7. Bressler NM, Boyer DS, Williams DF, et al. Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials. Retina. Oct 2012;32(9):1821-1828. PMID 23011184
8. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010;340:c2459. PMID 20538634
9. U.S. Food and Drug Administration. Drug approval package for Eylea (aflibercept) injection. 2011; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387s0000TOC.cfm. Accessed January 5, 2015.
10. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. Dec 2012;119(12):2537-2548. PMID 23084240
11. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal Aflibercept Injection for Neovascular Age-related Macular Degeneration: Ninety-Six-Week Results of the VIEW Studies. Ophthalmology. Jan 2014;121(1):193-201. PMID 24084500
12. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular agerelated macular degeneration. N Engl J Med. 2011;364(20):1897-1908. PMID
13. Chan A, Duker JS, Ko TH, et al. Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. Arch Ophthalmol. Feb 2006;124(2):193-198. PMID 16476888
14. Rosenfeld PJ. Bevacizumab versus Ranibizumab - The Verdict. N Engl J Med. Apr 28 2011;364(20):1966-1967. PMID 21526924
15. Comparison of Age-related Macular Degeneration Treatments Trials Research G, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. Jul 2012;119(7):1388-1398. PMID 22555112
16. Investigators IS, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular agerelated macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. Jul 2012;119(7):1399-1411. PMID 22578446
17. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. Oct 12 2013;382(9900):1258-1267. PMID 23870813
18. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. Ophthalmology. Nov 2013;120(11):2300-2309. PMID 23916488
19. Krebs I, Schmetterer L, Boltz A, et al. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol. Mar 2013;97(3):266-271. PMID 23292928
20. Zehetner C, Kirchmair R, Huber S, et al. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol. Feb 5 2013. PMID 23385630
21. Schmucker C, Ehlken C, Agostini HT, et al. A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard. PLoS One. 2012;7(8):e42701. PMID 22880086
22. Curtis LH, Hammill BG, Schulman KA, et al. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. Oct 2010;128(10):1273-1279. PMID 20937996
23. Gower EW, Cassard S, Shu L, et al. Adverse event rates following intravitreal injection of Avastin or Lucentis for treating age-related macular degeneration. The Association for Research in Vision and Ophthalmology (ARVO), May 1-5 2011; http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=3a667d20-f42d-421e-a859-e1b680de80ed&cKey=4e534aee-b678-4b9d-91dc-20a9d6ae0c56&mKey=%7B6F224A2D-AF6A-4533-8BBB-6A8D7B26EDB3%7D. Accessed January 5, 2015.
24. Heier JS, Brown D, Ciulla T, et al. Ranibizumab for choroidal neovascularization secondary to causes other than age-related macular degeneration: a phase I clinical trial. Ophthalmology. Jan 2011;118(1):111-118. PMID 20678799
25. Chen L, Miller JW, Vavvas D, et al. Anti-vascular endothelial growth factor monotherapy versus combination treatment with photodynamic therapy for subfoveal choroidal neovascularization secondary to causes other than age-related macular degeneration. Retina. Nov 2011;31(10):2078-2083. PMID 21691258
26. Gliem M, Finger RP, Fimmers R, et al. Treatment of choroidal neovascularization due to angioid streaks: a comprehensive review. Retina. Jul-Aug 2013;33(7):1300-1314. PMID 23719398
27. Bae SH, Heo J, Kim C, et al. Low-Fluence Photodynamic Therapy versus Ranibizumab for Chronic Central Serous Chorioretinopathy: One-Year Results of a Randomized Trial. Ophthalmology. Feb 2014;121(2):558-565. PMID 24268858
28. Lim JW, Ryu SJ, Shin MC. The effect of intravitreal bevacizumab in patients with acute central serous chorioretinopathy. Korean J Ophthalmol. Jun 2010;24(3):155-158. PMID 20532141
29. Artunay O, Yuzbasioglu E, Rasier R, et al. Intravitreal bevacizumab in treatment of idiopathic persistent central serous chorioretinopathy: a prospective, controlled clinical study. Curr Eye Res. Feb 2010;35(2):91-98. PMID 20136418
30. Parodi MB, Iacono P, Kontadakis DS, et al. Bevacizumab vs photodynamic therapy for choroidal neovascularization in multifocal choroiditis. Arch Ophthalmol. Sep 2010;128(9):1100-1103. PMID 20837791
31. Wolf S, Balciuniene VJ, Laganovska G, et al. RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia. Ophthalmology. Mar 2014;121(3):682-692 e682. PMID 24326106
32. Parodi MB, Iacono P, Papayannis A, et al. Laser photocoagulation, photodynamic therapy, and intravitreal bevacizumab for the treatment of juxtafoveal choroidal neovascularization secondary to pathologic myopia. Arch Ophthalmol. Apr 2010;128(4):437-442. PMID 20142520
33. Iacono P, Parodi MB, Papayannis A, et al. Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization. Retina. Sep 2012;32(8):1539-1546. PMID 22922846
34. Gharbiya M, Giustolisi R, Allievi F, et al. Choroidal neovascularization in pathologic myopia: intravitreal ranibizumab versus bevacizumab--a randomized controlled trial. Am J Ophthalmol. Mar 2010;149(3):458-464 e451. PMID 20172072
35. Oishi A, Kojima H, Mandai M, et al. Comparison of the effect of ranibizumab and verteporfin for polypoidal choroidal vasculopathy: 12-month LAPTOP study results. Am J Ophthalmol. Oct 2013;156(4):644-651. PMID 23876867
36. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. Sep 2012;32(8):1453-1464. PMID 22426346
37. American Academy of Ophthalmology. Preferred Practice Pattern Guidelines. Age-related macular degeneration 2014; www.aao.org/ppp. Accessed January 5, 2015.
38. Canadian Agency for Drugs and Technologies in Health (CADTH). Technology Overview. Management of Neovascular Age-related Macular Degeneration: Systematic Drug Class Review and Economic Evaluation. 2008; http://www.cadth.ca/index.php/en/publication/813. Accessed January, 2015.
39. National Institute for Health and Care Excellence (NICE). TA155 Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. 2012; http://publications.nice.org.uk/ranibizumab-and-pegaptanib-for-thetreatment-of-age-related-macular-degeneration-ta155. Accessed January, 2015.
40. National Institute for Health and Care Excellence (NICE). TA 294 Aflibercept solution for injection treating wet age-related macular degeneration. 2013; http://publications.nice.org.uk/aflibercept-solution-for-injection-fortreating-wet-agerelated-macular-degeneration-ta294. Accessed January, 2015.
41. National Institute for Health and Care Excellence (NICE). TA 298 Ranibizumab for treating choroidal neovascularization associated with pathological myopia 2013; http://publications.nice.org.uk/ranibizumab-fortreating-choroidal-neovascularisation-associated-with-pathological-myopia-ta298. Accessed January 5, 2015.  

Coding Section

Codes	Number	Description
CPT	67028	Intravitreal injection of a pharmacologic agent (separate procedure)
ICD-9  Procedure
ICD-9 Diagnosis	115.02; 115.92	Histoplasmosis; retinitis (infection by Histoplasma capsulatum and Histoplasmosis unspecified)
	360.21	Progressive high (degenerative) myopia (includes malignant/pathologic myopia)
	362.16	Retinal neovascularization NOS
	362.41	Central serous retinopathy
	362.50-362.52	Senile macular degeneration code range
	363.20	Chorioretinitis, unspecified (includes choroiditis NOS)
	363.43	Angioid streaks of choroid
	363.63	Choroidal rupture
	364.3	Unspecified iridocyclitis (uveitis NOS)
	921.3	Contusion of eyeball (includes choroid trauma)
HCPCS	C9257	Injection, bevacizumab, 0.25 mg
	J0178	Injection, aflibercept, 1 mg
	J2503	Injection, pegaptanib sodium, 0.3 mg
	J2778	Injection, ranibizumab, 0.1 mg
ICD-10-CM (effective 10/01/15)	H20.00-H20.9	Acute and subacute iridocyclitis (includes uveitis)
	H30.90-H30.93	Unspecified chorioretinal inflammation (includes choroiditis NOS)
	H31.321-H31.329	Choroidal rupture code range
	H32	Chorioretinal disorders in diseases classified elsewhere (used with other B39xx code for Histoplasmosis)
	H35.051-H35059	Retinal neovascularization, unspecified, code range
	H35.30-H35.32	Degeneration of macula and posterior pole, age-related macular degeneration code range
	H35.33	Angioid streaks of macula
	H35.711-H35.719	Central serous chorioretinopathy, code range
	H44.20-H4423	Degenerative myopia, code range
	S05.10xA-S0512xA	Contusion of eyeball and orbital issues, code range
ICD-10-PCS (effective 10/01/15)	3E0C3GC	ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure. Administration, physiological systems and anatomical regions, introduction, eye, percutaneous, therapeutic substance
Type of Service	Vision
Place of Service	Physician's Office

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines. 

"Current Procedural Terminology ^© American Medical Association. All Rights Reserved"  

History From 2014 Forward     

02/08/2024	Annual review, no change made to policy.
02/01/2023	Annual review, no changes made to policy.
02/01/2022	Annual review. No changes made to policy.
02/02/2021	Annual review. No changes made to policy
02/19/2020	Annual review. No change to policy intent.
02/21/2019	Annual review, no change to policy intent.
02/28/2018	Annual review, no change to policy intent.
02/09/2017	Annual review, no change to policy intent.
02/29/2016	Annual review, no change to policy intent. Updated background, description, rationale, references and regulatory status.
11/04/2015	Change category from Medicine to Prescription Drug
02/12/2015	Annual review, no change to policy intent. Updated background, regulatory status, rationale and references. Added coding.
02/10/2014	Annual review. Added related policies. Updated rationale and references. No change to policy intent.