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Treatment for Age Related Macular Degeneration (AMD), Diabetic Retinopathy and Retinal Vein Occlusion

Number 9.03.504

Effective Date December 9, 2013

Revision Date(s) 12/09/13; 12/11/12; 04/10/12; 11/08/11; 07/12/11; 02/08/11; 05/11/10; 05/13/08; 01/08/08; 10/10/06

Replaces 9.03.08, 9.03.10, 9.03.11, 9.03.16 and 9.03.27

Policy

Intravitreal injection of ranibizumab, bevacizumab or aflibercept may be considered medically necessary for the treatment of the following retinal vascular conditions:

  • Neovascular “wet” macular degeneration
  • Diabetic macular edema
  • Proliferative diabetic retinopathy as an adjunctive treatment to vitrectomy or photocoagulation
  • Macular edema following central retinal vein occlusion*
  • Macular edema following branch retinal vein occlusion*
  • Choroidal neovascularization in patients with ocular histoplasmosis syndrome

Intravitreal injection of pegaptanib may be considered medically necessary for treatment of the following retinal vascular conditions:

  • Neovascular “wet” macular degeneration

*FDA approved indication (Lucentis)

Related Policies

2.01.514

Dermatologic Applications of Photodynamic Therapy

5.01.517

Use of Vascular Endothelial Growth Factor Receptor (VEGF) Inhibitors and Other Arigiogenesis Inhibitors in Oncology Patients

5.01.603

Epidermal Growth Factor Receptor (EGFR) Inhibitors

9.03.20

Epiretinal Radiation Therapy for Age-Related Macular Degeneration

9.03.23

Intravitreal Corticosteriod Implants

Policy Guidelines

Note: The use of bevacizumab (Avastin) for treating oncologic conditions is addressed in a separate medical policy. (See Related Policies)

Effective in 1/1/13, there is a specific HCPCS code for Eylea:

J0178 Injection, aflibercept, 1 mg

Effective 12/31/12, the following HCPCS codes for Eylea is deleted:

Q2046 Injection, abfilibercept (Eylea), 1mg

Effective 7/1/12, the following HCPCS code for Eylea is deleted:

C9291 Injection, Abfilibercept (Eylea), 2mg vial

Description

Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib) are being evaluated for the treatment of disorders of retinal circulation. Ophthalmic disorders affecting the retinal circulation include proliferative diabetic retinopathy, diabetic macular edema, and central or branch retinal vein occlusion.

Background

Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by neovascularization 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™), bevacizumab (Avastin®), and pegaptanib (Macugen®) are used to treat choroidal neovascularization associated with age-related macular degeneration (AMD) and are being evaluated for the treatment of disorders of retinal circulation (e.g., diabetic retinopathy and retinal vein occlusion).

Diabetic Retinopathy

Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness in adults. The two most serious complications for vision are diabetic macular edema and proliferative diabetic retinopathy. At its earliest stage (nonproliferative retinopathy), microaneurysms occur. With disruption of the blood-retinal barrier, macular retinal vessels become permeable, leading to exudation of serous fluid and lipids into the macula (macular edema). As the disease progresses, blood vessels that provide nourishment to the retina are blocked, triggering the growth of new and fragile blood vessels (proliferative retinopathy). Severe vision loss with proliferative retinopathy arises from vitreous hemorrhage. Moderate vision loss can also arise from macular edema (fluid accumulating in the center of the macula) during the proliferative or nonproliferative stages of the disease. Although proliferative disease is the main blinding complication of diabetic retinopathy, macular edema is more frequent and is the leading cause of moderate vision loss in people with diabetes.

Tight glycemic and blood pressure control is the first line of treatment to control diabetic retinopathy, followed by laser photocoagulation for patients whose retinopathy is approaching the high-risk stage. Although laser photocoagulation is effective at slowing the progression of retinopathy and reducing visual loss, it results in collateral damage to the retina and does not restore lost vision. Focal macular edema (characterized by leakage from discrete microaneurysms on fluorescein angiography) may be treated with focal laser photocoagulation, while diffuse macular edema (characterized by generalized macular edema on fluorescein angiography) may be treated with grid laser photocoagulation. Corticosteroids may reduce vascular permeability and inhibit vascular endothelial growth factor (VEGF) production but are associated with serious adverse effects including cataracts and glaucoma with damage to the optic nerve. Corticosteroids can also worsen diabetes control. VEGF inhibitors (e.g., ranibizumab, bevacizumab, and pegaptanib), which reduce permeability and block the pathway leading to new blood vessel formation (angiogenesis) are being evaluated for the treatment of diabetic macular edema and proliferative diabetic retinopathy. For diabetic macular edema, outcomes of interest are macular thickness and visual acuity. For proliferative diabetic retinopathy, outcomes of interest are operative and perioperative outcomes and visual acuity.

Central and Branch Retinal Vein Occlusions

Retinal vein occlusions are classified by whether there is a central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). CRVO is also categorized as ischemic or non-ischemic. Ischemic CRVO is associated with a poor visual prognosis, with macular edema and permanent macular dysfunction occurring in virtually all patients. Non-ischemic CRVO has a better visual prognosis, but many patients will have macular edema, and it may convert to the ischemic type within 3 years. Most of the vision loss associated with CRVO results from the main complications, macular edema and intraocular neovascularization. BRVO is a common retinal vascular disorder in adults between 60 and 70 years of age and occurs approximately 3 times more commonly than CRVOs. Macular edema is the most significant cause of central visual loss in BRVO.

Retinal vein occlusions are associated with increased venous and capillary pressure and diminished blood flow in the affected area, with a reduced supply of oxygen and nutrients. The increased pressure causes water flux into the tissue while the hypoxia stimulates the production of inflammatory mediators such as VEGF, which increases vessel permeability and induces new vessel growth. Intravitreal corticosteroid injections or implants have been used to treat the macular edema associated with retinal vein occlusions, with a modest beneficial effect on visual acuity. However, cataracts are a common side effect, and steroid-related pressure elevation occurs in about one-third of patients, with some requiring filtration surgery. Macular grid photocoagulation has also been used to improve vision in BRVO but is not recommended for CRVO. The serious adverse effects of available treatments have stimulated the evaluation of new treatments, including intravitreal injection of VEGF inhibitors. Outcomes of interest for retinal vein occlusions are macular thickness and visual acuity.

Regulatory Status

Use of any VEGF inhibitors for diabetic retinopathy would be considered off-label.

In 2010, ranibizumab (Lucentis™, Genentech, 0.5 mg) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of macular edema following retinal vein occlusion. Labeling indicates that patients should be treated monthly. (1) The FDA has required a postmarketing safety and efficacy study on at least 150 patients who have received at least 7 doses of Lucentis™ and have been followed for at least 15 months.

Pegaptanib (Macugen®, Eyetech and Pfizer) and ranibizumab (Lucentis™) are presently the only angiostatic drugs approved by the FDA for use in the eye. Pegaptanib was the first VEGF antagonist to be approved by the FDA for use in wet AMD. Ranibizumab is approved for the treatment of patients with neovascular AMD. Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway and are administered by intravitreous injections every 4–6 weeks. Pegaptanib binds to the VEGF-165 isomer of VEGF-A while ranibizumab is an antibody fragment directed at all isoforms of VEGF-A. 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.

Aflibercept (Eylea, Regeneron Pharmaceuticals and Bayer Healthcare Pharmaceuticals) was recently FDA-approved for the treatment of wet AMD. Aflibercept (previously called VEGF Trap-Eye) 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.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

N/A

Rationale

Diabetic Macular Edema

Ranibizumab (Lucentis™)

The RESOLVE study is a 12-month multicenter randomized controlled trial (RCT) from Europe that compared ranibizumab (0.3 or 0.5 mg) with sham injection. (2) Included in the study were 151 eyes with type 1 or 2 diabetes, central retinal thickness >300 microns, and best corrected visual acuity (BCVA) of 73-39 letters (20/40 to 20/160) with the decrease in vision attributed to foveal thickening from diabetic macular edema. The treatment schedule comprised 3 monthly injections, after which treatment could be stopped or reinitiated, with an opportunity for rescue laser photocoagulation according to protocol-defined criteria. There were more discontinuations in the sham arm than the ranibizumab arm (18.4% vs. 9.8%). Dose doubling was allowed after the first month, and a total of 86% of patients in the pooled ranibizumab arm received a dose of 0.5 mg or higher. At 12 months, BCVA improved 10.3 letters in the pooled ranibizumab group and declined by 1.4 letters in the sham group. A gain of >10 letters BCVA occurred in 60.8% of ranibizumab and 18.4% of sham treated eyes. Mean central retinal thickness was reduced by 194 microns with ranibizumab (from 455 to 261) and 48 microns (from 448 to 400) with sham treatment.

Six month and 2-year outcomes from the North American READ-2 study were reported in 2009 and 2010. (3, 4) READ-2 was a randomized multicenter trial comparing ranibizumab (0.5 mg at baseline and months 1, 3, and 5) versus focal or grid laser photocoagulation (baseline and month 3 if needed), or combined ranibizumab and photocoagulation (baseline and month 3), with 42 patients per group. After the primary endpoint was reached at month 6, all subjects could be treated with ranibizumab. For the primary endpoint at month 6, the mean gain in BCVA was significantly greater for 3 injections of ranibizumab (+7.2 letters) compared to photocoagulation (-0.4 letters), or the combined photocoagulation plus 2 injection treatment (+3.8 letters). Improvement of 3 lines or more occurred in 8 of 37 (22%) of the ranibizumab group, 0 of 38 (0%) of the photocoagulation group, and 3 of 40 (8%) of the combined group (91% follow-up out of 126). Excess foveal thickness (>212 microns) at baseline was 199 microns, 228 microns, and 262 microns for the 3 groups. Foveal thickness was reduced by 50%, 33%, and 45%, respectively. After the primary endpoint, most patients in all groups were treated with ranibizumab; the mean number of injections during the 18 months’ follow-up period was 5.3, 4.4, and 2.9, respectively. With approximately 80% follow-up for the 3 groups, the mean improvement in BCVA at 24 months was 7.7, 5.1, and 6.8 letters. Mean foveal thickness at 24-months was 340 microns, 286 microns, and 258 microns for the 3 groups. The percentage of patients with a center subfield thickness of 250 microns or less was 36%, 47%, and 68% - both respectively.

The Diabetic Retinopathy Clinical Research Network published 1 and 2-year results of a sham controlled multicenter RCT that evaluated ranibizumab (with prompt or deferred laser) or triamcinolone plus prompt laser. (5, 6) A total of 854 eyes (691 participants) with visual acuity of 20/32 to 20/320 and diabetic macular edema involving the fovea were randomized to sham injection + prompt laser (n=293), ranibizumab + prompt laser (n=187), ranibizumab + deferred laser (n=188) or triamcinolone + prompt laser (n=186). The study drug or sham injection treatments were performed every 4 weeks through 12 weeks. Beginning at week 16, study drug or sham injections were performed according to a retreatment algorithm. Participants in the 3 prompt laser groups were masked through the 1-year primary outcome evaluation, with planned 5-years of follow-up. Analysis was based on intention-to-treat, with the last observation carried forward for missing data at 1 year. At 1-year follow-up, the sham + prompt laser group showed a 3 letter gain in BCVA. BCVA for both ranibizumab groups was significantly greater than sham (+9 letters for either the prompt or deferred laser), but the triamcinolone plus laser group was not significantly different from sham (+4 letters). The percentage of eyes meeting criteria for success (visual acuity letter score >84 [approx 20/20) or central subfield <250 microns) at 1 year was 32% for the sham + prompt laser, 64% for the ranibizumab + prompt laser, 52% for the ranibizumab + deferred laser, and 56% for the triamcinolone + prompt laser group. The reduction in macular thickness was similar in all 3 injection groups (median of 241, 256, and 247 microns) and was greater than the laser only group (307 microns).

Two-year data were available for 642 eyes of 526 patients and were not available for 212 eyes (25%) of 165 participants. (6) The major reason that patients were not available for follow-up (n=99) was a protocol change in which participants not originally assigned to ranibizumab could choose to receive ranibizumab. Most eyes assigned to ranibizumab received at least 1 additional injection because of recurrence of diabetic macular edema between the 1- and 2-year visits. Patients in the sham plus laser group gained an average of 3 letters, while patients in the ranibizumab + prompt laser group gained an average of 7 letters, and patients in the ranibizumab + deferred laser group gained an average of 9 letters. The percentage of patients who gained >15 letters was 29% and 28% in the ranibizumab groups compared with 18% in the laser group. The percentage of patients who lost >15 letters was 4% and 2% in the ranibizumab groups and 10% in the laser group. There was a greater proportion of patients who had retinal thickness less than 250 microns (54% and 56% vs. 39%) but no significant difference between groups in the mean change in retinal thickness from baseline.

Bevacizumab (Avastin®)

A number of RCTs from Asia have been published that assessed the efficacy of bevacizumab for diabetic macular edema. In 2008, Ahmadieh et al. reported the efficacy of 3 injections of bevacizumab (1.25 mg every 6 weeks) either alone or in combination with triamcinolone in 115 eyes (101 patients) with macular edema that was unresponsive to macular laser photocoagulation. (7) Patients were randomized to 1 of 3 study arms (3 injections of bevacizumab, combined triamcinolone and bevacizumab, or sham injection). Improvement in BCVA was observed earlier in the combined group (6 weeks) than the bevacizumab only group (12 weeks). At 24 weeks, BCVA was similar in the 2 treatment groups, (-0.18 and -0.21 logMAR [logarithm of the minimum angle of resolution]), vs. -0.3 logMAR for the sham group. The change in central macular thickness was -95.7 microns in the bevacizumab arm, -92.1 microns in the combined group, and +34.9 microns in the control group. Elevation of intraocular pressure occurred in 3 eyes (8.1%) of the combined treatment group.

In 2009, Soheilian et al. reported an RCT of intravitreal bevacizumab (1.25 mg alone or combined with triamcinolone) versus macular photocoagulation in 150 treatment-naïve eyes (129 patients). (8) Sham laser and sham injections were performed, and evaluators were blinded to the treatment condition. Follow-up evaluations were performed at 6, 12, 24, and 36 weeks. Retreatment was required for 14 eyes in the bevacizumab alone group, 10 in the bevacizumab and triamcinolone group, and 3 in the photocoagulation group. At 36 weeks, BCVA changes were -0.28 for bevacizumab alone, -0.04 for bevacizumab and triamcinolone, and +0.01 logMAR for photocoagulation. BCVA improvement greater than 2 Snellen lines was detected in 37%, 25%, and 14.8% of patients in the bevacizumab alone, bevacizumab and triamcinolone, and photocoagulation groups, respectively. Central macular thickness changes were not different between the groups.

In 2010, Michaelides and colleagues reported 12-month results from the BOLT study, an RCT that compared multiple intravitreal injections of bevacizumab (1.25 mg) with photocoagulation. (9) A total of 80 eyes of 80 patients who had diabetic macular edema and at least 1 prior macular laser therapy were randomized to bevacizumab every 6 weeks as needed (minimum of 3 and maximum of 9) or macular laser therapy (minimum of 1 and maximum of 4). The baseline BCVA was 55.7 in the bevacizumab group and 54.6 in the laser arm. With a median of 9 injections over the 12-month study, the bevacizumab group had gained a median of 8 letters while the laser group lost a median of 0.5 letters (61.3 vs. 50.1). The odds of gaining >10 letters was 5.1 times greater with bevacizumab. There was a trend toward a greater decrease in central macular thickness (from 507 to 378 microns in the bevacizumab group and from 481 to 413 microns in the laser group, p=0.06).

Pegaptanib (Macugen®)

A Phase II randomized double masked trial of pegaptanib patients (n=172) with diabetic macular edema was reported by the Macugen Diabetic Retinopathy Study Group in 2005. (10) Intravitreous pegaptanib (0.3, 1, or 3 mg) or sham injections were given at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments, conducted at week 36, showed BCVA improvement of >10 letters in 34% of the 0.3-mg group, 30% of the 1-mg group, 14% of the 3-mg group, and 10% of the sham group. Median BCVA was significantly better at week 36 only with the 0.3-mg dose (20/50), as compared to sham (20/63), with a larger proportion of those receiving 0.3 mg gaining >10 letters (34% vs. 10%) and >15 letters (18% vs. 7%). Mean changes in retinal thickness decreased were -68, -23, -5, and +4 microns, respectively. The reason for the greater efficacy of the lowest dose is not clear.

One-year and 2-year results from a Phase II/III multi-center RCT of pegaptanib for the treatment of diabetic macular edema were reported by the Macugen 1,013 study group in 2011. (11) In year 1, a total of 288 patients were randomized to pegaptanib 0.3 mg or sham injections every 6 weeks, with supplemental focal or grid photocoagulation as needed. (The original protocol had included treatment groups of 0.003, 0.03, and 0.3 mg pegaptanib, but the 2 lower doses were eliminated from the study due to drug product instability issues.) In the second year, injections were provided as needed per prespecified criteria at up to 6 week intervals. At 1-year follow-up (n=230), more patients in the pegaptanib group had an increase >10 letters (36.8% vs.19.7%), and fewer pegaptanib than sham-treated subjects received focal/grid laser treatment (23.3% vs. 41.7%). At 2-year follow-up (n=132), pegaptanib patients gained an average of 6.1 letters versus 1.3 letters for the sham group. The proportion of subjects with an improvement >10 letters was 38.3% for pegaptanib and 30.0% for sham (not significantly different). Eighty-three patients (29%) discontinued the study, and 53 patients (18%) had not yet reached the 2-year endpoint at the time of data analysis. In addition to the marginal efficacy of pegaptanib over sham observed at 2 years, these results are potentially biased by the high loss to follow-up and use of the last-observation-carried-forward method. Evidence remains insufficient to determine if pegaptanib is as effective as alternative treatments. Therefore, it is considered investigational.

Aflibercept (Eyelea)

In 2011, Do et al. reported 6-month results from the Phase II double-masked randomized, controlled multicenter (39 sites) DA VINCI trial of aflibercept (called “VEGF Trap-Eye” in the study). (12) A total of 221 patients with diabetic macular edema were randomized to 1 of 5 treatment regimens: 0.5 mg aflibercept every 4 weeks; 2 mg aflibercept every 4 weeks; 2 mg aflibercept for 3 initial monthly doses and then every 8 weeks; 2 mg aflibercept for 3 initial monthly doses and then on an as-needed (PRM) basis; or macular laser photocoagulation. Patients in the laser arm received sham injections at each visit, and patients in the aflibercept arms received sham injections during visits in which an active dose was not given. Sham laser was given to the aflibercept groups at week 1. Patients in the laser arm could be retreated no more often than every 16 weeks. A total of 200 patients (90%) completed the study, with a similar proportion of discontinuations among the treatment groups. The gain in BCVA from baseline to week 24 was significantly greater in each aflibercept group (ranging from 8.5 to 11. Gains from baseline of >0, >10 and >15 letters were seen in 68%, 32%, and 21%, respectively, in the laser group. In the aflibercept group, gains from baseline >0 letters ranged from 77% to 91%; >10 letters ranged from 43% to 64%, and >15 letters ranged from 17% to 34%. Outcomes tended to be worse for the 0.5 mg and the 8-week interval groups. No patients in the 2-mg aflibercept groups lost >15 letters compared with 9.1% of the laser group. 4 letters) compared with the laser group (2.5 letters). Mean reductions in central retinal thickness were significantly greater in the 4 aflibercept groups (ranging from -127.3 to -194.5 microns vs. -67.9 microns in the laser group). There was a 1-2% incidence of myocardial infarction, cerebrovascular accident, and death in patients who were treated with aflibercept compared with 0% in the laser group, but a history of cardiac disease was twice as common in the aflibercept groups compared with the laser group.

Proliferative Diabetic Retinopathy

VEGF inhibitors are being evaluated as adjunctive treatment to reduce bleeding, improve surgical outcomes, reduce edema, and improve visual acuity in patients with proliferative diabetic retinopathy. Typically, a single injection of a VEGF inhibitor is administered several days before photocoagulation or vitrectomy. In a 2011 Cochrane review, 4 RCTs of anti-VEGF for the prevention of postoperative vitreous cavity hemorrhage after vitrectomy were included, but due to methodologic issues, they were unable to conduct a meta-analysis. (13) Participants in the trials had to have proliferative diabetic retinopathy undergoing vitrectomy for the first time. Trials were excluded if participants had silicone oil used as a tamponade agent postoperatively. The authors concluded that results from one of the studies (14) supported the use of preoperative intravitreal bevacizumab to reduce the incidence of early vitreous cavity hemorrhage after vitrectomy, but due to methodologic issues in the remaining studies, definitive conclusions could not be reached.

Ranibizumab (Lucentis™)

No RCTs were identified that evaluated intravitreal ranibizumab for the treatment of proliferative diabetic retinopathy.

Bevacizumab (Avastin®)

A search of the MEDLINE database through February 2011 identified a number of smaller RCTs (<100 patients) that examined a single injection of bevacizumab as an adjunct to laser photocoagulation or vitrectomy. Following is a summary of the key literature to date.

One double-masked trial from 2010 (included in the Cochrane review above) randomized 68 eyes of 68 patients to a single injection of bevacizumab or sham injection 1 week before vitrectomy. (14) Eyes were included if indications for vitrectomy for complications of proliferative diabetic retinopathy existed such as nonclearing vitreous hemorrhage, tractional retinal detachment, and active progressive proliferative diabetic retinopathy. The primary outcome measure was the incidence of early postvitrectomy hemorrhage. Secondary outcome measures included changes in BCVA and adverse events. Nineteen eyes were omitted from the study because exclusion criteria were met during surgery (intraoperative use of long-acting gas or silicone oil). Resolution of vitreous hemorrhage was observed in 9 eyes (25.7%) after bevacizumab injection and 2 eyes (6.1%) in the control group, obviating the need for vitrectomy. Sixteen patients in the bevacizumab group and 18 patients in the control group completed the study according to the protocol. Intraoperative bleeding occurred in 63% of the bevacizumab group and 94% of the control group. Intraoperative endodiathermy for controlling the hemorrhage was reduced (mean of 1.90 vs. 2.47 times). Iatrogenic retinal breaks occurred in 2 eyes in the bevacizumab group and 1 eye in the control group. In both the intention-to-treat and per protocol analysis, the incidence of postvitrectomy hemorrhage 1 week and 1 month after surgery was significantly lower in the bevacizumab group compared with the control group. Mean BCVA (per protocol) improved from 1.88 to 0.91 logMAR in the bevacizumab group and from 1.88 to 1.46 logMAR in the control group. No bevacizumab-related complication was observed.

Another 2010 study randomized 40 eyes (40 patients) to a single1.25 mg injection of bevacizumab 48 hours before vitrectomy or vitrectomy alone. (15) Inclusion criteria were presence of advanced proliferative diabetic retinopathy, presence of tractional retinal detachment threatening the macula area, and HbA1c <7. The effective vitrectomy time was significantly shorter in the bevacizumab group, taking 8.05 minutes versus 16.8 minutes for the control group. Mean total vitrectomy time was 62 minutes for the bevacizumab group and 98 minutes for the control group. There was also less intraoperative bleeding with bevacizumab. During 6 months of follow-up, the vitrectomy alone group showed no improvement in visual acuity, with values close to 2.0 logMAR. Visual acuity significantly improved in the bevacizumab group at follow-up of 1 week and 3 and 6 months. The mean final visual acuity at 6-month follow-up was 0.82 logMAR in the bevacizumab group versus 2.01 logMAR in the non-bevacizumab group. Persistent hemorrhage was observed in 4 eyes in the bevacizumab-treated group and 8 eyes in the control group. Transient ocular hypertension was observed in 3 eyes of the bevacizumab group compared to none in the control group. There were no significant differences in the incidence of complications between the 2 groups in this small study.

In 2010, Di Lauro and colleagues reported a block randomized study on 72 eyes of 68 patients with severe proliferative diabetic retinopathy who were affected by vitreous hemorrhage and tractional retinal detachment. (16) The patient groups were matched by vitreous hemorrhage, prior retinal laser-photocoagulation, and morphologic type of retinal detachment. Outcome measures were the intraoperative management, safety, and efficacy of bevacizumab at 7 or 20 days before vitrectomy. An additional 3 patients were excluded from the study due to significant regression of the retinal neovascularization and the complete clearing of vitreous hemorrhage after injection of bevacizumab. In the group receiving sham injections, the mean surgical time was 84 minutes. Intraoperative bleeding occurred in 79% of cases, use of endodiathermy in 54%, relaxing retinotomy in 4%, and iatrogenic retinal breaks occurred in 17% of patients. In the group that received bevacizumab 7 days before vitrectomy, the mean surgical time was 65 minutes. Intraoperative bleeding occurred in 8%, and the use of endodiathery was necessary in 8%. No iatrogenic breaks occurred during the surgery. In the group receiving bevacizumab 20 days before vitrectomy, the mean surgical time was 69 minutes. Intraoperative bleeding occurred in 13%, use of endodiathermy in 13%, and an iatrogenic break in 4%. The best surgical results were achieved with bevacizumab administered 7 days preoperatively. At 6-month follow-up, the mean BCVA had increased from 1.6 to 1.2 logMAR in the sham-treated group, from 1.4 to 0.78 logMAR in the 7-day group, and from 1.6 to 0.9 logMAR in the 20-day bevacizumab group.

In a 2010 randomized study, a single injection of bevacizumab or triamcinolone were administered as an adjunct to panretinal (scatter) photocoagulation to reduce the macular edema that can develop/increase with this treatment. (17) Of 91 eyes (76 patients) with severe diabetic retinopathy, 46 eyes had clinically significant macular edema and 45 did not. Triamcinolone was administered 1 day after the first session of photocoagulation while bevacizumab was given about 1 week before photocoagulation. BCVA and central macular thickness at 1 and 3 months (after the final session of photocoagulation) were compared with eyes that had been randomized to photocoagulation alone. At baseline, the mean BCVA (logMAR) was 0.27 in the triamcinolone group, 0.28 in the bevacizumab group, and 0.26 in the control group. The mean macular thickness was 344 microns in the triamcinolone group, 328 microns in the bevacizumab group, and 326 microns in the control (photocoagulation alone) group. In the photocoagulation alone group, there was significant worsening of BCVA from 0.26 logMAR to 0.29 logMAR at both 1 and 3 months’ follow-up. In the triamcinolone and bevacizumab groups, there were no significant changes in BCVA from baseline. In eyes without macular edema at baseline, there was significant worsening of BCVA only in the control group (photocoagulation alone). In eyes with macular edema at baseline, only the triamcinolone group had an improvement in BCVA, and the proportion of eyes with a decrease in macular thickness was greater with triamcinolone than with bevacizumab or photocoagulation alone. Triamcinolone resulted in increased intraocular pressure in 4 eyes.

One double-masked trial with 40 patients used a single injection of bevacizumab on the first day of laser treatment with a sham control procedure in the other (fellow) eye in patients with high-risk diabetic retinopathy characteristics (identified by the area and location of neovascularization and/or presence of hemorrhage). (18) All cases received standard laser treatment and focal or grid macular photocoagulation for clinically significant macular edema. Panretinal laser photocoagulation was completed in 3 sessions, 1 week apart. Follow-up was performed on the first day, at weeks 1, 2, 3, and 6 and then monthly thereafter to monitor safety and efficacy. The primary outcome measure was regression, and the secondary outcome measure was recurrence from week 6 to week 16 of follow-up. A total of 87.5% of bevacizumab-treated eyes and 25% of control eyes showed complete regression at week 6. However, at week 16, proliferative diabetic retinopathy recurred in many of the bevacizumab-treated eyes, and the complete regression rate in the 2 groups was the same (25%). Partial regression rates were 70% versus 65%. The study concluded that repeat injections of bevacizumab may be needed.

In 2011, Schmidinger et al. reported the use of repeated intravitreal bevacizumab for the treatment of persistent new vessels after complete panretinal photocoagulation in a series of 10 patients (11 eyes). (19) Patients received bevacizumab at baseline and at each of the monthly follow-up visits when reappearance of retinal new vessels was documented. At the 1-week follow-up visit, 8 eyes (73%) showed complete regression of retinal neovascularizations. These 8 eyes had stable retinal findings until the 3-month follow-up visit. At the 3-month follow-up, 8 eyes (73%) were retreated with bevacizumab because of the reappearance of new vessels. At 6 months, 36% of the eyes were found to have reperfusion of retinal new vessels and were retreated. Over the course of the 6-month study, the mean retreatment rate was 1.9, with a mean interval to retreatment of 2.9 months. The mean leakage area decreased from 7.2 mm2 at baseline to 1.2 mm2 at the final follow-up. BCVA increased from 59.2 to 70.7 at the final visit.

Pegaptanib (Macugen®)

Gonzalez et al. compared intravitreal pegaptanib versus panretinal photocoagulation in a randomized open-label study of 20 patients with active proliferative diabetic retinopathy. (20) Pegaptanib-treated eyes were scheduled to receive a total of 6 intravitreal injections at 6-week intervals, while photocoagulation was administered in 1 or 2 sessions. Two patients from each arm were discontinued from the study due to non-compliance. In 90% of the eyes randomized to pegaptanib, retinal neovascularization showed regression by week 3. By week 12, all pegaptanib-treated eyes showed complete regression of neovascularization, and this was maintained through week 36. In the laser-treated group, 2 eyes showed complete regression, 2 showed partial regression, and 4 showed active proliferative retinopathy. The mean change in visual acuity at 36 weeks was +5.8 letters in pegaptanib-treated eyes and -6.0 letters in laser-treated eyes (not statistically significant). Additional controlled studies with a larger number of subjects and longer follow-up are needed to evaluate the safety and efficacy of pegaptanib for this condition.

Retinal Vein Occlusion

A 2010 Cochrane review assessed the evidence on the use of anti-VEGF treatments for macular edema secondary to central retinal vein occlusion. (21) Included in the review were the CRUISE (ranibizumab) and CRVOSC (pegaptanib) studies, which are described in more detail below. (22, 23) Participants with ischemic central retinal vein occlusion (CRVO) were excluded in these trials. The primary outcome for the systematic review was BCVA of >15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (EDTRS) Chart with at least 6 months of follow-up. Secondary outcomes were the proportion of patients with a loss of 15 or more letters compared to baseline and objective assessment of macular edema regression, measured by mean change in central retinal thickness on ocular coherence tomography (OCT). In the study with ranibizumab, outcomes were significantly improved in both treatment groups compared to sham. (22) In the smaller Phase II study with pegaptanib, efficacy was demonstrated for some but not all outcomes. (23) The authors noted that numerous RCTs investigating anti-VEGF for the treatment of CRVO were in progress, and that, while anti-VEGF may improve outcomes at 6 months, effectiveness and safety over longer periods of follow-up had yet to be determined. In addition, there were no RCT data on their use in the treatment of ischemic CRVO, and the optimal timing of treatment had not yet been determined.

Ranibizumab (Lucentis™)

Ranibizumab has been evaluated for macular edema following central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), with 6- and 12-month results available from 2 double-masked multicenter trials. A Phase III trial of ranibizumab for macular edema following CRVO was reported by the CRUISE investigators in 2010 and 2011. (22, 24) A total of 392 patients with macular edema after CRVO were randomized to monthly injections of 0.3 or 0.5 mg ranibizumab or sham. Inclusion criteria were BCVA <20/40 or mean central subfield thickness >250 microns. Randomization was stratified by baseline BCVA letter score and study center. One eye was chosen as the study eye for each patient. The intent-to-treat approach was used for efficacy analysis and included all patients as randomized; missing values were imputed using the last observation carried forward. The approximate BCVA at baseline was 20/100, and the central foveal thickness was more than 650 microns. The improvement in BCVA following ranibizumab treatment was rapid, with patients gaining an average of 9 letters 7 days after the first injection. Following treatment for 6 months, the mean change from baseline BCVA score was 12.7 and 14.9 letters in the 0.3-mg and 0.5-mg groups compared with 0.8 letters in the sham group. The percentage of patients who gained >15 letters was 46.2% (0.3 mg) and 47.7% (0.5 mg) in the ranibizumab groups and 16.9% in the sham group. The percentage of patients who achieved BCV>20/40 was 43.9% (0.3 mg) and 46.9% (0.5 mg) compared with 20.8% in the sham group. Central foveal thickness decreased by a mean of 434 microns (0.3 mg) and 452 microns (0.5 mg) in the ranibizumab groups and 168 microns in the sham group. At month 6, the mean increase from baseline National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score was 7.1 points (0.3 mg) and 6.2 points (0.5 mg) in the ranibizumab-treatment groups compared with 2.8 points in the sham group.

After 6 months, all patients with BCVA <20/40 or mean central subfield thickness >250 microns could receive ranibizumab. Between months 6 and 12, the mean number of as-needed ranibizumab injections was 3.8, 3.3, and 3.7 in the 0.3-mg, 0.5-mg, and sham/0.5-mg groups, respectively. At 12-month follow-up, the mean change from baseline BCVA was maintained at 13.9 letters in both ranibizumab groups and improved to 7.3 letters in the sham/0.5 mg group. The percentage of patients who gained >15 letters was 47% and 50.8% for 0.3 mg and 0.5 mg ranibizumab and 33.2% for sham/0.5 mg. The reduction in central foveal thickness in the ranibizumab groups was maintained at 453 (0.3 mg) and 462 (0.5 mg) microns at month 12. There was a rapid reduction in average central foveal thickness in the sham/0.5-mg group after the first as-needed injection of ranibizumab; this was sustained through month 12 (427 micron reduction). The reduction in central foveal thickness did not differ significantly between the 3 groups. Treatment with ranibizumab as needed from months 6-11 maintained, on average, the increases in the NEI VFQ-25 (7.1 and 6.6 points) and resulted in an increase of 5 points from baseline in the sham/0.5-mg group. There was an increase in the incidence of cataract in the ranibizumab groups at 12 months (3.8% for 0.3 mg and 7.0% for 0.5 mg) compared with 0% for sham at 6-months.

Also published in 2010 and 2011 by the BRAVO investigators were results from a Phase III trial of ranibizumab for macular edema following BRVO. (25, 26) The study design was similar to the study on CRVO (above) and included 397 patients with macular edema who received monthly intraocular injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. Rescue laser treatment was allowed for eyes meeting prespecified criteria. The approximate BCVA at baseline was 20/80, and the central foveal thickness was greater than 475 microns. At 7 days after the first treatment, the ranibizumab groups had gained an average of 7.5 letters. After 6 months of treatment, the mean BCVA improvement was 16.6 and 18.3 letters for the 0.3-mg and 0.5-mg ranibizumab groups and 7.3 letters for the sham group. The percentage of patients who gained >15 letters was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups compared with 28.8% in the sham group. The percentage of patients who achieved BCVA >20/40 was 67.9% (0.3 mg) and 64.9% (0.5 mg) compared with 41.7% in the sham group. Central foveal thickness decreased by a mean of 337 microns (0.3 mg) and 345 microns (0.5 mg) in the ranibizumab groups and 158 microns in the sham group. More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3-mg (18.7%) and 0.5-mg (19.8%) ranibizumab groups. No new safety events were identified in patients with BRVO.

After 6 months, all patients with BCVA <20/40 or mean central subfield thickness >250 microns could receive ranibizumab. Patients could also receive rescue laser treatment once during the observation period if criteria were met. The percentage of patients who received rescue laser treatment during the 6-month observation period was 30.6% (0.3 mg), 23.7% (0.5 mg, and 23.5% (sham/0.5 mg). Between months 6 and 12, the mean number of as-needed ranibizumab injections was 2.8, 2.7, and 3.6 in the 0.3-mg, 0.5-mg, and sham/0.5-mg groups, respectively. The percentage of patients who did not receive any injections during the observation period was 20.9%, 23.7%, and 12.9%, respectively. There was a decrease in BCVA in eyes that did not receive ranibizumab from month 6 to 7, but the mean change from baseline BCVA letter score at month 12 was maintained at 16.4 (0.3 mg) and 18.3 (0.5 mg) letters. Eyes in the sham/0.5-mg group gained 12.1 letters from baseline; this was significantly lower than both ranibizumab groups. The percentage of patients who gained >15 letters from baseline at month 12 was 56.0%, and 60.3% in the 0.3-mg and 0.5-mg groups and 43.9% in the sham/0.5-mg group. On average, the reduction in central foveal thickness was maintained in the ranibizumab groups (314 and 347 microns). There was a rapid reduction in central foveal thickness after the first as-needed injection in the sham/0.5-mg group, which was sustained through month 12 (273.7 microns); this was significantly less than both ranibizumab groups. No new ocular or nonocular safety events were identified, although the cataract rate was reported to be 4.5% and 6.2% in the 0.3-mg and 0.5-mg ranibizumab groups compared with 3.1% for sham at 6 months.

Bevacizumab (Avastin®)

Two small RCTs from Europe and Asia were published in 2010 and 2011. One study with 52 patients compared triamcinolone (4 mg) or bevacizumab (1.25 mg) monotherapy versus combined therapy (2 mg triamcinolone and 1.25 mg bevacizumab) for macular edema due to BRVO. (27) Fifty-two eyes with BRVO, visual acuity of 20/40 or worse, and central macular thickness of 250 microns or greater were enrolled in the study. Nearly 90% of eyes received intravitreal injections as the primary treatment, the remainder had received grid laser photocoagulation at least 4 months before enrollment. Re-injections of triamcinolone or bevacizumab were done when macular edema recurred that was at least 1 month apart for bevacizumab monotherapy, 2 months for bevacizumab plus triamcinolone, and 3 months for triamcinolone monotherapy, and the mean number of injections within 6 months ranged from 1.4 to 1.6. Otherwise, grid laser photocoagulation was performed. Macular grid laser photocoagulation was applied within 3 months of injections in 47% of the triamcinolone monotherapy group, 50% of bevacizumab monotherapy, and 43% of the combined treatment group. All 3 groups showed significant reductions of central macular thickness and improvement in visual acuity 1 month after injection, but by 6 months, only the bevacizumab monotherapy group demonstrated significant improvement in visual acuity (from 0.9 to 0.4 logMAR). At 6 months, there was a significant reduction in central macular thickness for all 3 groups (follow-up was completed in 86-88% of patients in the monotherapy groups, but only 48% of the combined therapy group). The average intraocular pressure change from baseline (+1.4) was significantly higher in the triamcinolone monotherapy group. Cataract progression was noted in 36% of phakic eyes in the triamcinolone monotherapy group, 8% of the bevacizumab monotherapy group, and 10% of eyes in the combined treatment group.

A 2011 publication reported a double-masked sham-controlled RCT in 81 eyes (81 patients) with branch retinal vein occlusion (BRVO). (28) Bevacizumab or sham injection was administered after baseline and week 6. The mean duration of symptoms was 7.5 weeks in the bevacizumab group and 4.9 weeks in the sham group. In the sham group, BCVA was 0.8 logMAR at baseline, 0.75 logMAR at week 6, and 0.66 logMAR at week 12. In the bevacizumab group, BCVA improved from 0.74 logMAR at baseline to 0.49 logMAR at week 6 and 0.42 logMAR at week 12. The difference between groups was statistically significant at week 6 and approached significance (p=0.064) at week 12. Central macular thickness at baseline was 471 microns for the control group and 575 microns for the bevacizumab group. At week 6, the central macular thickness was 462 microns for sham and 325 microns for bevacizumab. Central macular thickness at week 12 was 393 microns for sham versus 309 microns for bevacizumab. The difference in macular thickness was statistically different at both 6 and 12 weeks’ follow-up.

Yasuda et al. reported rebound of macular edema (> 110% of baseline thickness) in 7 of 65 eyes (10.8%) after treatment of BRVO with bevacizumab. (29) This retrospective study examined the records of all patients who had received an intravitreal injection of bevacizumab, had received no other treatment for BRVO, and had at least 6 months of follow-up. Patients were evaluated monthly for BCVA and foveal thickness by OCT. The mean interval between the onset of symptoms and intravitreal bevacizumab was 10 weeks (range, 2 to 52 weeks). Bevacizumab was found to be not effective in 3 eyes (4.6%), effective without recurrence in 21 eyes (32.3%), effective with a recurrence <110% of baseline thickness in 34 eyes (52.3%), and effective with a recurrence >110% of baseline thickness in 7 eyes (10.8%). Retreatment was performed as needed. Multivariate logistic regression and subgroup analyses showed that a thinner pretreatment fovea and a shorter interval between symptom onset to the initiation of the intravitreal bevacizumab were significantly associated with a rebound of macular edema. The interval from symptom onset to the initiation of treatment was less than 8 weeks in all 7 eyes with a rebound macular edema.

Another retrospective study from 2011 evaluated factors predictive for improvement of visual acuity and central retinal thickness following treatment with bevacizumab. (30) A total of 205 eyes (204 patients) with macular edema secondary to BRVO from 6 sites were included. Measurement of BCVA and retinal thickness was measured every 12 weeks with results at 24 weeks used for analysis of predictive factors. The mean follow-up was 36.8 weeks (range, 18 to 54 weeks). During the follow-up period, retreatments were performed in 85% of eyes, with a median of 3 injections (range, 1 to 10). Although both non-ischemic and ischemic eyes showed a median 2-line improvement of BCVA, the final median BCVA was significantly worse in eyes with ischemic macular edema compared to non-ischemic macular edema (0.6 logMAR vs. 0.3 logMAR). Eyes with a duration of macular edema less than 3 months had a median 2.5-line increase of BCVA, while eyes with a duration of macular edema between 3 and 12 months had a median 2-line increase in BCVA, and eyes with a duration >12 months had a 0.5-line increase in median BCVA. Other factors identified were absence of previous treatments of macular edema, age younger than 60 years, and low baseline BCVA.

Additional studies are needed to determine the appropriate candidates and timing of anti-VEGF treatment and to evaluate durability of treatment over longer periods of follow-up. Comparison with grid photocoagulation for BRVO is also needed.

Pegaptanib (Macugen®)

In 2009, the Central Retinal Vein Occlusion Study Group published results from their Phase II multicenter double-masked randomized trial (CRVOSC). (23) Ninety-eight subjects were randomized to receive 0.3 mg or 1 mg pegaptanib or sham injections every 6 weeks for 24 weeks. For the primary outcome measure (the percentage of subjects showing a gain of 15 or more letters at week 30), there was no significant difference between the groups treated with pegaptanib 0.3 mg and 1 mg (36% and 39%, respectively) and the control group (28%). For the secondary outcome measures, fewer subjects treated with pegaptanib lost 15 or more letters (9% and 6%) compared with sham-treated eyes (31%) and showed greater improvement in mean visual acuity (+7.1 and +9.9 vs. -3.2 letters with sham). However, there was no difference in the percentage of subjects with visual acuity of 20/50 or better at week 30 (33% for both pegaptanib doses and 34% for sham). By week 30, the difference in mean reduction in retinal thickness between the 0.3-mg dose and sham was 95 microns, while the difference between the 1-mg group and sham was 31 microns.

Ongoing Clinical Trials

A search of online site ClinicalTrials.gov in April 2011 identified a number of clinical trials with anti-VEGF therapy for retinal vascular conditions. Of particular note are the following:

  • Ranibizumab for ischemic retinal vein occlusions is currently in Phase I trials. (Available online at: http://www.clinicaltrials.gov/ct2/results?term=retinal+vein+occlusion+VEGF)
  • An industry-sponsored Phase III study of monthly injection of aflibercept (VEGF Trap-Eye) vs. sham injection in subjects with macular edema secondary to CRVO (GALILEO; NCT00943072). A total of 189 subjects are expected to be enrolled, and the study completion date is listed as April 2012.
  • An industry-sponsored Phase III study of aflibercept (VEGF Trap-Eye) vs. laser photocoagulation in subjects with diabetic macular edema (VIVID-DME; NCT01331681). The primary outcome is the change from baseline of BCVA ETDRS (early treatment diabetic retinopathy) letter score at 52 weeks. A total of 375 subjects are expected to be enrolled, with the primary outcome measure completed by May 2013 and a study completion date of March 2015.

Clinical Input Received through 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 3 academic medical centers while this policy was under review in 2011. The input supported the use of ranibizumab and bevacizumab for diabetic retinopathy (diabetic macular edema and proliferative diabetic retinopathy) and for central or branch retinal vein occlusions. Reviewers suggested additional indications for VEGF inhibitors including cystoid macular edema resulting from vasculitis, Coats disease, Eales disease, idiopathic macular telangiectasia type II, neovascularization of the iris/neovascularization of the angle/neovascular glaucoma, pseudoxanthoma elasticum, radiation retinopathy, retinal neovascularization, retinopathy of prematurity, rubeosis, Von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.

Summary

Evidence from randomized controlled trials is sufficient to conclude that ranibizumab and bevacizumab may be considered medically necessary for the following conditions:

  • Diabetic macular edema
  • Proliferative diabetic retinopathy as an adjunctive treatment to vitrectomy or photocoagulation
  • Macular edema secondary to central retinal vein occlusion
  • Macular edema secondary to branch retinal vein occlusion

Ranibizumab and bevacizumab have been shown to lead to improved visual acuity for the above conditions, compared to standard treatment without these agents. For diabetic proliferative retinopathy, these drugs also lead to reduced vitreous hemorrhage, and for macular edema, reduced macular thickness.

Trials with pegaptanib for diabetic macular edema and retinal vein occlusion do not conclusively demonstrate a gain in visual acuity with this treatment; therefore, intravitreal injection of pegaptanib for retinal vascular conditions is considered investigational.

Practice Guidelines and Position Statements

In a final appraisal determination from July 15, 2011, the National Institute for Health and Clinical Excellence (NICE) does not recommend ranibizumab (Lucentis) for the treatment of diabetic macular edema. (31) The independent Appraisal Committee found that the manufacturer's model underestimated the incremental cost-effectiveness ratio (ICER) for ranibizumab monotherapy compared with the current standard treatment for people with diabetic macular edema, laser photocoagulation. It concluded that a model that relied on a combined set of plausible assumptions would be certain to produce an ICER that substantially exceeded the range that NICE considers represents an effective use of National Health Service (NHS)resources. Therefore, ranibizumab could not be recommended as a treatment for people with diabetic macular edema.

2012 Update

Added update to labeled indications for aflibercept (Eylea).

2013 Update

Literature search and added off-label indication of anti-VEGFtherapy to treat ocular histoplasmosis syndrome.

References

  1. Lucentis Prescribing Information. 2010. Available online at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125156s053lbl.pdf . Accessed November 6, 2013.
  2. Massin P, Bandello F, Garweg JG et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010; 33(11):2399-405.
  3. Nguyen QD, Shah SM, Heier JS et al. Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2009; 116(11):2175-81 e1.
  4. Nguyen QD, Shah SM, Khwaja AA et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2010; 117(11):2146-51.
  5. Elman MJ, Aiello LP, Beck RW et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117(6):1064-77 e35.
  6. Elman MJ, Bressler NM, Qin H et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011; 118(4):609-14.
  7. Ahmadieh H, Ramezani A, Shoeibi N et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2008; 246(4):483-9.
  8. Soheilian M, Ramezani A, Obudi A et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 2009; 116(6):1142-50.
  9. Michaelides M, Kaines A, Hamilton RD et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010; 117(6):1078-86 e2.
  10. Cunningham ET, Jr., Adamis AP, Altaweel M et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005; 112(10):1747-57.
  11. Sultan MB, Zhou D, Loftus J et al. A Phase 2/3, Multicenter, Randomized, Double-Masked, 2-Year Trial of Pegaptanib Sodium for the Treatment of Diabetic Macular Edema. Ophthalmology 2011.
  12. Do DV, Schmidt-Erfurth U, Gonzalez VH et al. The DA VINCI Study: Phase 2 Primary Results of VEGF Trap-Eye in Patients with Diabetic Macular Edema. Ophthalmology 2011.
  13. Smith JM, Steel DH. Anti-vascular endothelial growth factor for prevention of postoperative vitreous cavity haemorrhage after vitrectomy for proliferative diabetic retinopathy. Cochrane Database Syst Rev 2011; 5:CD008214.
  14. Ahmadieh H, Shoeibi N, Entezari M et al. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients: a randomized clinical trial. Ophthalmology 2009; 116(10):1943-8.
  15. Hernandez-Da Mota SE, Nunez-Solorio SM. Experience with intravitreal bevacizumab as a preoperative adjunct in 23-G vitrectomy for advanced proliferative diabetic retinopathy. Eur J Ophthalmol 2010; 20(6):1047-52.
  16. di Lauro R, De Ruggiero P, di Lauro MT et al. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248(6):785-91.
  17. Cho WB, Moon JW, Kim HC. Intravitreal triamcinolone and bevacizumab as adjunctive treatments to panretinal photocoagulation in diabetic retinopathy. Br J Ophthalmol 2010; 94(7):858-63.
  18. Mirshahi A, Roohipoor R, Lashay A et al. Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol 2008; 18(2):263-9.
  19. Schmidinger G, Maar N, Bolz M et al. Repeated intravitreal bevacizumab (Avastin((R))) treatment of persistent new vessels in proliferative diabetic retinopathy after complete panretinal photocoagulation. Acta Ophthalmol 2011; 89(1):76-81.
  20. Gonzalez VH, Giuliari GP, Banda RM et al. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol 2009; 93(11):1474-8.
  21. Braithwaite T, Nanji AA, Greenberg PB. Anti-vascular endothelial growth factor for macular edema secondary to central retinal vein occlusion. Cochrane Database Syst Rev 2010; (10):CD007325.
  22. Brown DM, Campochiaro PA, Singh RP et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010; 117(6):1124-33 e1.
  23. Wroblewski JJ, Wells JA, 3rd, Adamis AP et al. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. Arch Ophthalmol 2009; 127(4):374-80.
  24. Campochiaro PA, Brown DM, Awh CC et al. Sustained Benefits from Ranibizumab for Macular Edema following Central Retinal Vein Occlusion: Twelve-Month Outcomes of a Phase III Study. Ophthalmology 2011.
  25. Brown DM, Campochiaro PA, Bhisitkul RB et al. Sustained Benefits from Ranibizumab for Macular Edema Following Branch Retinal Vein Occlusion: 12-Month Outcomes of a Phase III Study. Ophthalmology 2011; 118(8):1594-602.
  26. Campochiaro PA, Heier JS, Feiner L et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010; 117(6):1102-12 e1.
  27. Cekic O, Cakir M, Yazici AT et al. A comparison of three different intravitreal treatment modalities of macular edema due to branch retinal vein occlusion. Curr Eye Res 2010; 35(10):925-9.
  28. Moradian S, Faghihi H, Sadeghi B et al. Intravitreal bevacizumab vs. sham treatment in acute branch retinal vein occlusion with macular edema: results at 3 months (Report 1). Graefes Arch Clin Exp Ophthalmol 2011; 249(2):193-200.
  29. Yasuda S, Kondo M, Kachi S et al. Rebound of macular edema after intravitreal bevacizumab therapy in eyes with macular edema secondary to branch retinal vein occlusion. Retina 2011.
  30. Jaissle GB, Szurman P, Feltgen N et al. Predictive factors for functional improvement after intravitreal bevacizumab therapy for macular edema due to branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011; 249(2):183-92.
  31. National Institute for Health and Clinical Excellence (NICE). Final appraisal determination: Ranibizumab for the treatment of diabetic macular oedema. 2011. Available online at: http://www.nice.org.uk/nicemedia/live/13125/55324/55324.pdf. Accessed November 6, 2013.
  32. Blue Cross and Blue Shield Association. Photodynamic Therapy for Choroidal Neovascularization. Medical Policy Reference Manual, Policy 9.03.08, 2012.
  33. Blue Cross and Blue Shield Association. Transpupillary Thermotherapy for Treatment of Choroidal Neovascularization. Medical Policy Reference Manual, Policy 9.03.10, 2012.
  34. Blue Cross and Blue Shield Association. Photocoagulation of Macular Drusen – Archived. Medical Policy Reference Manual, Policy 9.03.11, 2011.
  35. Blue Cross and Blue Shield Association. Conjunctival Incision with Posterior Juxtascleral Placement of Anecortave Acetate Depot Suspension – Archived. Medical Policy Reference Manual, Policy 9.03.16, 2009.
  36. Blue Cross and Blue Shield Association. Intravitreal Angiogenesis Inhibitors for Retinal Vascular Conditions. Medical Policy Reference Manual, Policy 9.03.27, 2012.
  37. Eylea Prescribing Information. 2012, Available online at: http://www.eylea.com/index.php?id=13. Last accessed November 6, 2013.
  38. Nielsen JS, Fick TA, Saggau DD, et al. Intravitrial antivascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome. Retina 2012;32(3):468-472.

Coding

Codes

Number

Description

CPT

0124T

Conjunctival incision with posterior extrascleral placement of a pharmacological agent (does not include supply of medication) (deleted effective 12/31/13)

 

67028

Intravitreal injection of a pharmacologic agent (separate procedure)

 

67220

Destruction of localized lesions of choroids (e.g., choroidal neovascularization); photocoagulation (e.g., laser) one or more sessions

 

67221

photodynamic therapy (includes intravenous infusion)

 

67225

photodynamic therapy, second eye, at single session (list separately in addition to code for primary eye treatment)

 

67299

Unlisted procedure, posterior segment

ICD-9 Procedure

   

ICD-9 Diagnosis

250.50 – 250.53

Diabetes with ophthalmic manifestations, code range

 

362.01

Background diabetic retinopathy

 

362.02

Proliferative diabetic retinopathy

 

362.03

Nonproliferative diabetic retinopathy NOS

 

362.04

Mild nonproliferative diabetic retinopathy

 

362.05

Moderate nonproliferative diabetic retinopathy

 

362.06

Severe nonproliferative diabetic retinopathy

 

362.07

Diabetic macular edema (Diabetic retinal edema)

 

362.35

Central retinal vein occlusion

 

362.36

Venous tributary (branch) occlusion

 

362.50

Macular degeneration (senile), unspecified

 

362.51

Nonexudative senile macular degeneration

 

362.52

Exudative senile, macular degeneration (includes wet)

 

377.21

Drusen of optic disk

 

362.83

Retinal edema

ICD-10-CM
(effective 10/01/14)

E10.311, E10.321, E10.331, E10.341, E10.351

Type 1 diabetes mellitus with ophthalmic complications, codes for macular edema

 

E10.359

Type 1 diabetes mellitus with ophthalmic complications, proliferative diabetic retinopathy without macular edema

 

E11.311, E11,321, E11.331, E11.341, E11.351

Type 2 diabetes mellitus with ophthalmic complications, codes for macular edema

 

E11.359

Type 2 diabetes mellitus with ophthalmic complications, proliferative diabetic retinopathy without macular edema

 

H35.81

Retinal edema

ICD-10-PCS
(effective 10/01/14)

3E0C3GC

Administration, physiological systems and anatomical regions, introduction, eye, percutaneous, therapeutic substance

HCPCS

C9257

Injection, bevacizumab (Avastin), 0.25 mg

 

C9291

Injection, Abfilibercept (Eylea), 2 MG vial (deleted 7/1/2012)

 

J0178

Injection, aflibercept, 1 mg (effective 1/1/13)

 

J2503

Injection, pegaptanib sodium (Macugen), 0.3 mg

 

J2778

Injection, ranibizumab (Lucentis), 0.1 mg

 

J3590

Unclassified biologics (Eylea)

 

J7312

Injection, dexamethasone intravitreal implant, 0.1mg

 

J9035

Injection, bevacizumab (Avastin), 10 mg

 

Q2046

Injection, Abfilibercept (Eylea), 1 mg (deleted 12/31/12)

Type of Service

Vision

 

Place of Service

Outpatient

 

Appendix

N/A

History

Date

Reason

10/10/06

Add to Vision Section - New policy combining policies BC.9.03.08, BC.9.03.10, BC.9.03.11 and BC.9.03.18. Added Lucentis as medically necessary.

12/11/07

Cross Reference Updated - No other changes.

01/08/08

Replace Policy - Policy updated with literature search; no change to policy statement. References added.

05/13/08

Replace Policy - Policy updated with literature search. Policy statement updated to include a series of intravitreal injections with bevacizumab (Avastin) may be considered medically necessary as a treatment of diabetic retinopathy and other diseases involving choroidal neovascularization. Title expanded to include Diabetic Retinopathy. References and codes added. Reviewed by P&T committee on March 25, 2008.

07/08/08

Code Updated - 362.36 added to policy, no other changes.

07/14/09

Replace Policy - Policy updated with literature search. No change to policy statement. References added.

09/15/09

Code Updated - Q2024 added.

05/11/10

Replace Policy - Policy updated with literature search. Policy statement updated to include Avastin injections for “branch” vein occlusion, in addition to “central” vein occlusion, as medically necessary. References added. Reviewed by P&T committee on March 2010.

08/19/10

Code Updated - C9257 added; replaces Q2024 – no other changes.

02/08/11

Replace Policy - Policy updated with literature review; title changed to include “Retinal Vein Occlusion.” Description and Rationale sections updated to include retinal vein occlusion; references added. A new policy statement has been added to indicate dexamethasone intravitreal implant as medically necessary as treatment to reduce macular edema following central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). Reviewed by P&T in November 2010. Codes updated; 67299 added and deleted code Q2024 removed.

05/16/11

Code Update - J7312 was added to the policy Codes section.

07/12/11

Replace Policy - Policy statement updated to reflect the treatment of non-infectious uveitis affecting the posterior segment of the eye with Ozurdex may be a medically necessary indication; and intravitreal injections with ranibizumab (Lucentis®) may be considered medically necessary as a treatment of Macular Edema following Retinal Vein Occlusion (RVO).

11/08/11

Replace Policy - Ozurdex removed from policy; this is now covered in a separate medical policy. References removed and renumbered. Related Policy 9.03.23 added.

01/03/12

Deleted codes 0016T and 0017T removed.

04/10/12

Replace Policy – Policy updated with additional policy statements for Intravitreal injection of ranibizumab or bevacizumab and Intravitreal injection of aflibercept or pegaptanib for the treatment of neovascular wet macular degeneration, both as medically necessary. Rational and Reference sections updated. This updated incorporates policy statements with 9.03.27, which has not been adopted. Codes updated. Reviewed by P&T March 27th, 2012.

05/08/12

HCPCS code descriptors corrected. Codes C9291 and Q2046 added to the policy.

09/21/12

Update Related Policy – Add 5.01.517; ICD-10 codes are now effective 10/01/2014.

12/11/12

Replace policy. Afilbercept added to the list of drugs considered medically necessary for the treatment of the indicated retinal vascular conditions. Reviewed by P&T, 11/27/12. Codes updated: HCPCS code J0178 added effective 1/1/13; C9291 deleted effective 7/1/12.

12/09/13

Replace policy. Policy section updated with an additional medically necessary indication: choroidal neovascularization in patients with ocular histoplasmosis syndrome.

12/23/13

Coding Update. CPT code 0124T discontinued effective 12/31/13.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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