Medical Policies - Other


Intravitreal Angiogenesis Inhibitors for Retinal Vascular Disorders

Number:OTH903.027

Effective Date:10-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

NOTE 1: Information on intravitreal angiogenesis inhibitors (anti-vascular endothelial growth factor [VEGF or anti-VEGF]) for choroidal vascular conditions may be found on OTH903.020.

NOTE 2: Bevacizumab (Avastin™) is a recognized, viable, cost-effective anti-VEGF (vascular endothelial growth factor) alternative treatment.

Intravitreal injection of ranibizumab (Lucentis™) may be considered medically necessary for the treatment of the following retinal vascular conditions:

Diabetic macular edema (DME);

Diabetic retinopathy (DR);

Macular edema following central retinal vein occlusion (CRVO);

Macular edema following branch retinal vein occlusion (BRVO);

Neovascular glaucoma; or

Rubeosis (neovascularization of the iris).

Intravitreal injection of bevacizumab (Avastin™) may be considered medically necessary for the treatment of the following conditions:

Choroidal (subretinal) neovascularization (i.e., secondary to neovascular age-related macular degeneration (AMD), myopic degeneration, angioid streaks, idiopathic, secondary to toxoplasmosis, trauma, etc.);

Diabetic macular edema (DME);

Diabetic retinopathy (DR);

Retinal neovascularization (i.e., secondary to diabetes, secondary to central retinal vein occlusion, etc.);

Macular retinal edema due to diabetes mellitus, central retinal vein occlusion and/or branch retinal vein occlusion;

Neovascular glaucoma;

Proliferative diabetic retinopathy as an adjunctive treatment to vitrectomy or photocoagulation;

Other neovascular conditions of the eye (e.g., rubeosis iridis, trabecular angle neovascularization, etc.);

Retinopathy of prematurity (ROP); or

Rubeosis (neovascularization of the iris).

NOTE 3: For information on all non-ophthalmologic related indications for Bevacizumab (Avastin™), refer to OTH903.020.

Intravitreal injection of pegaptanib (Macugen®) may be considered medically necessary for the treatment of the following conditions:

Diabetic macular edema (DME), or

Diabetic retinopathy (DR).

Intravitreal injection of aflibercept (EYLEA™) may be considered medically necessary for the treatment of the following conditions:

Macular edema following retinal vein occlusion (RVO), inclusive of central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO);

Diabetic macular edema (DME); or

Diabetic retinopathy (DR) in patients with diabetic macular edema (DME).

Intravitreal injection of ranibizumab (Lucentis™), bevacizumab (Avastin™), pegaptanib (Macugen®) or aflibercept (EYLEA™) is considered experimental, investigational and/or unproven for the treatment of all other retinal vascular disorders.

NOTE 4: For coverage information on verteporfin (Visudyne™), refer to policy OTH903.015, Photodynamic Therapy for Choroidal Neovascularization.

NOTE 5: For conditions resulting from wet age-related macular degeneration, (e.g., retinal detachment, refer to medical policy OTH903.020, Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions, for the appropriate U.S. Food and Drug Administration approved drug for coverage information.

Description:

Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib, aflibercept) are being evaluated for the treatment of disorders of choroidal circulation. Angiogenesis inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib, aflibercept) can be given via intraocular injections as a treatment for disorders of choroidal and retinal 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. Ophthalmic disorders affecting the retinal circulation include proliferative diabetic macular edema (DME), diabetic retinopathy (DR), central (CRVO) or branch retinal vein occlusion (BRVO), and retinopathy of prematurity (ROP).

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®), pegaptanib (Macugen®), and aflibercept (EYLEA™) are used to treat choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) and are being evaluated for the treatment of disorders of retinal circulation (e.g., DME, DR, macular edema following retinal vein occlusion, ROP).

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 and PDT), they are potentially disease modifying by inhibiting the development of newly formed vessels.

For the treatment of ocular disorders, these agents are given by intravitreal injection every 1 to 2 months. 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, half-life, localization to the retina, and initiation of the immune system.

Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway. Pegaptanib binds to the VEGF-165 isomer of VEGF-A, while ranibizumab is an antibody fragment directed at all isoforms 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 is derived from the same murine monoclonal antibody precursor as ranibizumab, which binds to all isoforms of VEGF-A. 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. Aflibercept binds VEGF-A and placental growth factor, another angiogenic growth factor.

Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)

DR is a common microvascular complication of diabetes and a leading cause of blindness in adults. The 2 most serious complications for vision in patients with diabetes are DME and DR. At its earliest stage, 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 DR, 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 DME and DR, 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 vision 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 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, aflibercept, pegaptanib), which reduce permeability and block the pathway leading to new blood vessel formation (angiogenesis) are being evaluated for the treatment of DME and proliferative DR. For DME, outcomes of interest include macular thickness and visual acuity. For proliferative and non-proliferative DR, outcomes of interest are operative and perioperative outcomes and visual acuity.

Central (CRVO) and Branch Retinal Vein Occlusions (BRVO)

Retinal vein occlusions are classified by whether there is a CRVO or BRVO. CRVO is also categorized as ischemic or nonischemic. Ischemic CRVO is associated with a poor visual prognosis, with macular edema and permanent macular dysfunction occurring in virtually all patients. Nonischemic 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 vision 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 adverse 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.

Retinopathy of Prematurity (ROP)

ROP is a neovascular retinal disorder that primarily affects premature infants of low birth weight. It is one of the most common causes of childhood blindness in the United States. Typically, retinal vascularization begins at the optic nerve when the eye begins to develop (16 weeks of gestation) and reaches the edge of the retina at 40 weeks of gestation. If an infant is born prematurely, normal vessel growth may stop, followed by neovascularization at the interface between the vascular and avascular retinal areas. Stages of ROP are defined by vessel appearance and the level of retinal detachment, ranging from mild (stage I) to severe (stage V). Stage I or stage II ROP may resolve on its own. The optimal time for treatment is stage III, when a ridge with neovascularization extends into the vitreous gel. The neovascularization may progress and form fibrous scar tissue that causes partial (stage IV) or total retinal detachment (stage V), accompanied by loss of vision. Both cryotherapy and laser therapy have been used to slow or reverse the abnormal growth of blood vessels in the peripheral areas of the retina. While successful in about 50% of cases, these treatments can cause myopia and permanent loss of the peripheral field of vision. Vitrectomy may be needed when cryotherapy or laser therapy fails to induce regression.

Other Retinal Vascular Conditions

Other retinal vascular conditions that are being evaluated for treatment with VEGF inhibitors are 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, rubeosis, von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.

Regulatory Status

Pegaptanib (Macugen®), ranibizumab (Lucentis™), and aflibercept (EYLEA™) are presently the only angiostatic drugs approved by the U.S. Food Drug and Administration (FDA) for use in the eye.

Macugen® (Eyetech) was the first VEGF antagonist to be approved by the FDA for use in wet AMD in 2004.

Lucentis™ (Genentech) was first approved for the treatment of patients with neovascular AMD. In 2010, Lucentis™ was approved by the FDA for the treatment of macular edema following retinal vein occlusion. In 2012, Lucentis™ was approved for the treatment of DME and in 2015 it was approved for the treatment of proliferative DR in patients with DME. In 2017, the FDA approved a label change for DR to not include any limitations for that that diagnosis. Therefore, Lucentis™ is approved for DR in patients. (1)

EYLEA® (Regeneron) was approved by the FDA in 2011 for the treatment of wet (neovascular) AMD and is administered by intravitreous injections every 4 or 8 weeks. In 2012, EYLEA® was approved for the treatment of macular edema following CRVO. In 2014, EYLEA® was approved for the treatment of patients with retinal vein occlusion (BRVO and CRVO) and DME. (2) In 2015, the FDA approved EYLEA® for the treatment of DR in patients with DME.

Avastin® (bevacizumab) (Genentech) has been developed and FDA approved for use in oncology but has not been licensed for use in the eye.

Rationale:

This policy was originally created in 2014; however, conditions related to retinal vascular disorders had been located on OTH903.020 since 2009. The most recent scientific literature search was performed through June 1, 2017. The following is a summary of key literature to date.

Diabetic Macular Edema (DME)

The available evidence on vascular endothelial growth factor (VEGF) inhibitors for the treatment of DME consists of numerous randomized controlled trials (RCTs), some of which are large, and systematic reviews of the published trials.

In 2012, 3 technology assessments were published that evaluated the efficacy of antigrowth factors as a group. In the first of these reports, the Institute for Clinical and Economic Review published a technology assessment on the comparative effectiveness of antigrowth factor therapies for DME for the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC). (3, 4) The assessment evaluated data from 15 RCTs and 8 observational studies of anti-VEGF drugs. Improvement in visual acuity was consistently seen for all anti-VEGF agents, ranging from 6 to 9 letters greater than controls (laser or sham injection) for ranibizumab, bevacizumab, and aflibercept, and 4 to 5 letters greater than controls for pegaptanib. Meta-analysis of data on the mean change in best-corrected visual acuity (BCVA) and percentage of patients gaining 10 or more letters indicated no significant differences in clinical performance between anti-VEGF agents. Serious adverse events were rare, and there was no conclusive evidence that rates of systemic events differed substantially between treatment and control arms. The greatest area of uncertainty was the systemic adverse effect profile of bevacizumab relative to other anti-VEGF agents because the quality of the evidence on adverse events for bevacizumab was lower than for other agents. The assessment concluded that anti-VEGF therapy improves vision (»2-3 times more than laser photocoagulation or sham injection) and provides other clinical benefits in patients with DME.

Another technology assessment, published in 2012, was from the American Academy of Ophthalmology (AAO). This report found 5 studies that provided level I evidence for the efficacy of intravitreal ranibizumab, alone or in combination with other treatments, as a treatment for DME. (5) AAO also identified a level I study on pegaptanib for DME. Nine additional studies were rated as level II evidence. Evidence was limited for long-term results (i.e., >2 years of follow-up) or for the comparative efficacy of different anti-VEGF agents.

Also, published in 2012 was a Cochrane review of VEGF inhibitors for DME. (6) This review was updated in 2014, and included 18 studies with a total of over 1000 patients for the 4 comparisons of interest. (7) Meta-analysis found that patients treated with ranibizumab, bevacizumab, or aflibercept were more likely to gain 3 or more lines of vision (risk ratio [RR], 3.6; 95% confidence interval [CI], 2.7 to 4.8) and less likely to lose 3 or more lines of vision (RR=0.11; 95% CI, 0.05 to 0.24) than patients treated with grid laser photocoagulation. The overall quality of the body of evidence was considered to be high. It was estimated that 28 of 100 patients treated with VEGF inhibitors would gain 3 or more lines of visual acuity compared with 8 of 100 using photocoagulation. No significant differences were found between ranibizumab, bevacizumab, and aflibercept, although it was noted that this subanalysis was underpowered.

In 2015, the Diabetic Retinopathy Clinical Research Network (DRCRN) published results from a National Institutes of Health?sponsored double-masked RCT with head-to-head comparison of aflibercept, bevacizumab, and ranibizumab. (8) A total of 660 patients with vision loss from DME were randomized to 1 of the 3 agents. The study drugs were administered at an interval as frequent as every 4 weeks, based on a prespecified algorithm. The median number of intravitreal injections was 9 in the aflibercept group, 10 in the bevacizumab group, and 10 in the ranibizumab group (p=0.045). At 1 year, visual acuity had improved significantly more with aflibercept (13.3 letters) compared with either bevacizumab (9.7 letters, p<0.001) or ranibizumab (11.2 letters, p=0.03), although this difference was not considered to be clinically meaningful. The advantage with aflibercept was driven primarily by patients with worse vision (20/50 or worse), where the mean improvement was 18.9 letters with aflibercept, compared to 11.8 with bevacizumab (p<0.001), and 14.2 with ranibizumab (p=0.003). This is a high-quality trial with low risk of bias. There were no significant differences among the groups in the rates of serious adverse events.

The clinical trial evidence for individual agents is discussed next.

DME: Ranibizumab (Lucentis™)

A number of large RCTs have evaluated ranibizumab for the treatment of DME. Evidence includes 3 sham-controlled trials with rescue laser photocoagulation as needed that evaluated efficacy of ranibizumab compared with sham injection.

The RESOLVE study is a 12-month multicenter RCT from Europe (151 eyes) that compared ranibizumab (0.3 or 0.5 mg) with sham injection. (9) At 12 months, BCVA improved 10.3 letters in the pooled ranibizumab group and declined by 1.4 letters in the sham group, and a gain of 10 or more letters BCVA occurred in 60.8% of ranibizumab- versus 18.4% of sham-treated eyes.

RISE and RIDE were 2 identical U.S. Food and Drug Administration (FDA)?regulated phase 3 multicenter, double-masked, randomized sham-controlled trials, reported in 2012. (10) An additional publication in 2013 reported follow-up to 36 months.11 A total of 759 patients with DME were randomized to ranibizumab 0.3-mg or 0.5-mg or sham injections. Both trials found that significantly more ranibizumab-treated patients gained 15 or more letters. In RISE, 18.1% of sham patients gained 15 or more letters compared with 44.8% of 0.3-mg and 39.2% of 0.5-mg treated patients. In RIDE, 12.3% of sham-treated patients gained 15 or more letters compared with 33.6% of the 0.3-mg and 45.7% of the 0.5-mg group. An open-label extension with 500 patients from the 36-month RISE and RIDE trials was reported in 2015. (12) The mean number of injections was 4.5 (range, 0-24) over a mean 14-month follow-up (range, 1-27 months). About 25% of patients did not require any additional treatment during the open-label period.

Evidence in support of ranibizumab for DME also includes a number of studies that evaluated the efficacy of ranibizumab compared to laser photocoagulation.

RESTORE was an industry-sponsored randomized double-masked comparative trial with 345 patients that was conducted at 73 centers outside of the United States. (13-15) Mean changes in BCVA were 6.1 for the ranibizumab group, 5.9 for the ranibizumab plus laser group, and 0.8 for laser alone. The proportion of patients who had a BCVA gain of 5 letters or more was 65.2% for ranibizumab, 63.6% for ranibizumab and laser, and 33.6% for laser alone. Quality of life, measured with the National Eye Institute Visual Functioning Questionnaire?25 (VFQ-25), showed significantly greater improvements for the ranibizumab groups. Two hundred eight patients (86.7%) of 240 enrolled completed the 2-year extension study. (14, 15) The improvements in visual acuity and central retinal thickness achieved during the initial 12 months of ranibizumab therapy were maintained at 36 months and the prior laser group achieved a progressive improvement in visual acuity over the 2-year extension period.

A large multicenter RCT from the DRCRN compared the efficacy of ranibizumab versus triamcinolone and/or laser for DME. (16, 17) A total of 854 eyes (691 participants) were randomized to sham injection plus prompt laser (n=293), ranibizumab plus prompt laser (n=187), ranibizumab plus deferred laser (n=188), or triamcinolone plus prompt laser (n=186). Strengths of this study include the use of a sham control, masking through the first year of the study, and intention-to-treat (ITT) analysis. At 1-year follow-up, the sham plus 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 group), but the triamcinolone plus prompt laser group was not significantly different from sham (+4 letters). Among the groups examined, the percentage of eyes meeting criteria for success at 1 year was 32% for sham plus prompt laser, 64% for ranibizumab plus prompt laser, 52% for ranibizumab plus deferred laser, and 56% for triamcinolone plus prompt laser.

Two-year data from the DRCRN trial were available for 642 eyes (526 patients). (17) The major reason that some 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 DME between the 1- and 2-year visits. The percentage of patients who gained 15 or more letters was 29% and 28% in the ranibizumab groups compared with 18% in the laser group. The percentage of patients who lost 15 or more letters was 4% and 2% in the ranibizumab groups and 10% in the laser group.

Additional RCTs supporting the efficacy of ranibizumab for DME include READ-2 with 126 eyes and 6-month, 2-year, and 3-year outcomes, (18-20) and the 2015 REVEAL study with 396 Asian patients. (21) In 2015, Berger et al. published an industry-sponsored open-label study that included 220 patients. (22)

DME: Bevacizumab (Avastin®)

Several smaller RCTs from outside of the U.S. have been published comparing bevacizumab to photocoagulation for DME. The results from these RCTs indicate that bevacizumab is effective for the treatment of DME, similar to results found for ranibizumab.

In 2009 and 2012, Soheilian et al. reported an RCT of intravitreal bevacizumab (1.25 mg alone or combined with triamcinolone) versus macular photocoagulation in 150 treatment-naive eyes (129 patients). (23, 24) Sham laser and sham injections were performed, and evaluators were blinded to the treatment condition. Evaluations were performed through 9 months in the 2009 report and through 24 months in the follow-up study. At 9 months, 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. Throughout the follow-up, eyes with significant macular edema were retreated with the assigned intervention at 12-week intervals. At 24-month follow-up, there was no significant difference in visual or anatomic outcomes between the 3 groups, suggesting that the superiority of bevacizumab may diminish over time when administered at this interval.

The BOLT study was a 2010 RCT that compared bevacizumab (1.25 mg) to photocoagulation. (25) A total of 80 eyes of 80 patients who had DME and at least 1 prior macular laser therapy were randomized to bevacizumab every 6 weeks as needed or macular laser therapy. 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. The odds of gaining more than 10 letters were 5.1 times greater with bevacizumab.

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. (3) Patients were randomized to 1 of 3 study arms (3 injections of bevacizumab, combined triamcinolone and bevacizumab, or sham injection). At 24 weeks, BCVA was similar in the 2 treatment groups, (-0.18 and -0.21 logMAR, [logarithm of the minimum angle of resolution] versus -0.3 logMAR for the sham group).

The results from these lower quality RCTs suggest that bevacizumab is effective for the treatment of DME, similar to results found for ranibizumab. Additionally, DrugDex Compendia supported the off-FDA-labeled indication of DME using bevacizumab. (72)

DME: Aflibercept (EYLEA®)

The evidence on treatment of DME with aflibercept includes a double-masked multicenter phase 2 RCT and 2 double-masked multicenter phase 3 RCTs. The control in all 3 trials was laser photocoagulation.

DA VINCI was a phase 2 multicenter (39 sites) trial of aflibercept (called VEGF Trap-Eye in the study) compared with laser photocoagulation. (26) A total of 221 patients with DME were randomized to 1 of 5 treatment regimens: aflibercept 0.5 mg every 4 weeks; aflibercept 2 mg aflibercept every 4 weeks; aflibercept 2 mg for 3 initial monthly doses and then every 8 weeks; aflibercept 2 mg for 3 initial monthly doses and then on an as-needed basis; or macular laser photocoagulation. Gains from baseline of 15 letters or more were seen in 21% of the laser group. In the aflibercept groups, gains from baseline of 15 letters or more 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 aflibercept 2-mg groups lost 15 or more letters compared with 9.1% of the laser group. Mean gains in visual acuity were significantly greater in the aflibercept groups (from 8.5 to 11.4 letters) compared with the laser group (2.5 letters).

Two-year results from the pivotal phase 3 trials (VIVID-DME, VISTA-DME) were published in 2015. (27) A total of 872 eyes from 127 sites worldwide were randomized to 1 of 2 dosing regimens (2 mg every 4 weeks or 2 mg every 8 weeks) or to laser photocoagulation. Rescue treatment with aflibercept or laser was allowed after 24 weeks. At 1 year, eyes treated with aflibercept (4 groups) gained a mean of 10.5 to 12.5 letters, compared with 0.2 and 1.2 letters for the 2 laser groups. At 2 years, eyes treated with aflibercept gained a mean of 9.4 to 11.5 letters compared to 0.8 letters with laser. About one-third of patients in the aflibercept groups gained at least 15 letters, compared with about 12.5% of the photocoagulation group.

DME: Pegaptanib (Macugen®)

A phase 2 randomized double-masked trial of patients with DME (n=172) treated with pegaptanib was reported by the Macugen Diabetic Retinopathy Study Group in 2005. (28) 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 or more 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), compared with sham (20/63), with a larger proportion of those receiving 0.3 mg gaining 10 or more letters (34% versus 10%) and 15 or more letters (18% versus 7%). Mean changes in retinal thickness were -68, -23, -5, and +4 μm, respectively. The reason for the greater efficacy of the lowest dose is not clear.

One-year and 2-year results from a phase 2/3 multicenter RCT of pegaptanib for the treatment of DME were reported by the Macugen 1013 study group in 2011. (29) 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 than the sham group had an increase of 10 or more letters (36.8% versus 19.7%, respectively), and fewer pegaptanib than sham-treated subjects received focal/grid laser treatment (23.3% versus 41.7%, respectively). 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 of 10 or more 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 end point 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 (LOCF) method.

The off-FDA-label indication of DME is supported by the DrugDex Compendia using pegaptanib. (73)

Section Summary: DME

There is substantial evidence that VEGF inhibitors (ranibizumab, bevacizumab, aflibercept) are efficacious agents for the treatment of DME when given by the intravitreal route. A large high-quality head-to-head comparison of aflibercept, bevacizumab, and ranibizumab by DRCRN demonstrated generally similar outcomes for the 3 agents, with some advantage of aflibercept in patients with worse visual acuity at baseline. Although for bevacizumab the quality of the other RCTs is less, the evidence from the DRCRN trial is sufficient to conclude that bevacizumab is at least as effective as ranibizumab or aflibercept for the treatment of DME. Evidence remains insufficient to determine if pegaptanib is as effective as an alternative treatment.

Diabetic Retinopathy (DR)

In 2015, Simunovic and Maberley reported a meta-analysis of VEGF inhibitors in the management of proliferative DR. (30) The review identified 22 RCTs (1397 patients) that met the criteria for inclusion. The review found that use of VEGF inhibitors prior to photocoagulation results in superior functional and structural outcomes at 3 to 4 months and that the use of VEGF antagonists before vitrectomy results in a decreased duration of surgery, fewer breaks, and less intraoperative bleeding. Following is a description of key trials and those trials published after the August 2014 literature search for this meta-analysis.

DR: Ranibizumab (Lucentis™)

Intravitreal injection of ranibizumab has been compared with photocoagulation or sham injection for the treatment of proliferative and non-proliferative DR.

In 2015, results were published from a 2-year multicenter noninferiority trial by the DRCRN that compared ranibizumab to photocoagulation for the treatment of proliferative DR in 305 patients (394 eyes). (31) About half the patients in the photocoagulation group also received ranibizumab for DME. At 2 years, the proportion of patients who had gained 15 letters and the proportion of patients who lost 10 letters were similar in the 2 groups. In the photocoagulation group, peripheral visual field loss was worse, vitrectomy was more frequent (15% versus 4%, p<0.001), and DME was more frequent (28% versus 9%, p<0.001). There was no significant difference between the groups in the proportion of eyes with neovascularization.

In 2013, DRCRN reported a 16-week double-masked, randomized, 61-center phase 3 trial with 261 patients that compared multiple intravitreal injections of ranibizumab or saline for the treatment of vitreous hemorrhage associated with proliferative DR. (32) The cumulative probability of vitrectomy within 16 weeks was 12% with ranibizumab and 17% with saline, suggesting little likelihood of a clinically important difference in the short term. Secondary outcomes (complete panretinal photocoagulation, improvement in visual acuity, recurrent vitreous hemorrhage) showed a modest improvement with ranibizumab.

In 2015, Ip et al. published results of a study that examined the effect of long-term use of ranibizumab on the development of proliferative DR. (33) This was an analysis of data from the RISE and RIDE trials previously described, and included 759 patients with DME, randomized to monthly ranibizumab 0.3 or 0.5 mg or sham injections for 2 years. (10) During the third year, patients in the sham arm could be treated with ranibizumab 0.5 mg. The primary outcome for this analysis was a composite measure of progression to proliferative DR based on photographic changes and clinical events. At the 36-month follow-up, a 3-step or greater improvement in the Early Treatment Diabetic Retinopathy Study severity scale was achieved by 3.3% of eyes in the sham/0.5-mg crossover arm, compared with 15.0% of eyes in the 0.3-mg arm and 13.2% of eyes in the ranibizumab 0.5-mg arm (p<0.0001). By 36 months, proliferative DR had developed in 39.1% of patients in the sham/0.5-mg group compared with 18.3% and 17.1% of eyes treated with ranibizumab 0.3 mg or 0.5 mg, respectively.

DR: Bevacizumab (Avastin®)

Multiple intravitreal injections of bevacizumab have been compared with laser photocoagulation for the treatment of DR and DME.

A 2015 study with 72 patients (120 eyes) compared the effect of bevacizumab with or without photocoagulation to photocoagulation alone for the treatment of DR with DME. (34) Most patients had nonproliferative DR, categorized as mild (3%), moderate (46%), or severe (44%). BCVA improved by 0.161 logMAR in eyes treated with bevacizumab alone and by 0.093 logMAR in the combined treatment group (p<0.05). Photocoagulation alone did not have a significant effect on macular thickness or visual acuity.

Intravitreal administration of bevacizumab has been evaluated in several trials as an adjunct to photocoagulation in patients with DR. The objective of this treatment is to reduce the macular edema that can develop or increase with photocoagulation.

In a 2010 randomized study, a single injection of bevacizumab or triamcinolone was administered as an adjunct to panretinal (scatter) photocoagulation. (35) Of 91 eyes (76 patients) with severe DR, 46 eyes had clinically significant macular edema and 45 did not. 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 of follow-up. In the triamcinolone and bevacizumab groups, there were no significant changes in BCVA from baseline.

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 DR characteristics (identified by the area and location of neovascularization and/or presence of hemorrhage). (36) 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 DR 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.

VEGF inhibitors are also being evaluated as adjunctive treatment to reduce bleeding, improve surgical outcomes visual acuity in patients with DR who are treated with vitrectomy. Typically, a single injection of a VEGF inhibitor is administered several days before 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. (37) Participants in the trials had to have been undergoing vitrectomy for proliferative DR for the first time. The authors concluded that results from one of the studies (38) 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. A number of smaller RCTs (<100 patients) have subsequently been identified that examined a single injection of bevacizumab as an adjunct to laser photocoagulation or vitrectomy.

One double-masked trial from 2009 (included in the Cochrane review discussed above) randomized 68 eyes of 68 patients to a single injection of bevacizumab or sham injection 1 week before vitrectomy. (38) Resolution of vitreous hemorrhage was observed in 9 (25.7%) eyes after bevacizumab injection and 2 (6.1%) eyes 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 with bevacizumab versus sham (mean, 1.90 times versus 2.47 times). In both the ITT and per-protocol analysis, the incidence of after vitrectomy 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 (p=0.001). No bevacizumab-related complication was observed.

Another 2010 study randomized 40 eyes (40 patients) to a single 1.25-mg injection of bevacizumab 48 hours before vitrectomy or to vitrectomy alone. (39) 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 compared with vitrectomy along at follow-up of 1 week and 3 and 6 months (p<0.05 for each visit). The mean final visual acuity at 6-month follow-up was 0.82 logMAR in the bevacizumab group versus 2.01 logMAR in the vitrectomy-alone group. Persistent hemorrhage was observed in 4 eyes in the bevacizumab-treated group and 8 eyes in the control group.

In 2010, Di Lauro et al. reported a block randomized study on 72 eyes of 68 patients with severe proliferative DR who were affected by vitreous hemorrhage and tractional retinal detachment. (40) 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 endodiathermy 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 was required in 13%, and iatrogenic break occurred 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.

DR: Aflibercept (EYLEA®)

As summarized in FDA-approved prescribing information, the pivotal phase 3 trials (VIVID, VISTA, described above) evaluated the change in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS). (2) All 862 patients who were evaluated had DR and macular edema at baseline. At 100 weeks, about one-third of patients in the aflibercept groups gained at least 2 steps in the ETDRS-DRSS compared with 7% of controls in VIVID and 16% of controls in VISTA.

DR: Pegaptanib (Macugen®)

Gonzalez et al. compared intravitreal pegaptanib versus panretinal photocoagulation in a randomized open-label study of 20 patients with active proliferative DR. (41) 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 noncompliance. 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.

Section Summary: DR

For the treatment of DR, evidence is available for ranibizumab, bevacizumab, aflibercept, and pegaptanib. A large trial by the DRCRN found that intravitreal injection of ranibizumab is noninferior to photocoagulation in eyes with proliferative DR at 2 years. Treatment with ranibizumab for DME may also reduce progression to proliferative DR and need for vitrectomy. A number of smaller RCTs report superior outcomes for bevacizumab as a single agent or as an adjunct to photocoagulation or vitrectomy. A single small RCT reported that efficacy of pegaptanib was similar to photocoagulation for patients with proliferative DR. Analysis of data from the RISE and RIDE trials found that treatment with ranibizumab over 3 years led to improvement in proliferative DR in a significantly greater proportion of eyes than those treated with sham injections for the first 2 years. Two-year data from the VIVID and VISTA trials showed a significantly greater percentage of patients in the aflibercept groups who gained at least 2 steps in the ETDRS-DRSS compared with patients treated with laser photocoagulation. In 2015, the FDA approved Lucentis™ and EYLEA® to treat DR in patients with DME.

Retinal Vein Occlusion (RVO)

In 2015, the American Academy of Ophthalmology (AAO) published a technology assessment on therapies for macular edema associated with central retinal vein occlusion (CRVO). (42) The review identified 4 clinical trials that provided level I evidence supporting the use of VEGF inhibitors for macular edema associated with CRVO. These include the CRUISE trial with ranibizumab, (43, 44) COPERNICUS and GALILEO trials with aflibercept (VEGF Trap-Eye), (45-48) and a 2012 trial by Epstein et al. with bevacizumab. (49) These are described in greater detail in the text that follows. The review concluded that there is level I evidence that intravitreal anti-VEGF pharmacotherapy is safe and effective over 2 years for macular edema associated with CRVO and that delay in treatment is associated with worse visual outcomes.

A 2013 Cochrane review assessed the evidence on the use of anti-VEGF treatments for macular edema secondary to branch retinal vein occlusion (BRVO). (50) Included in the review was the BRAVO trial (RCT of ranibizumab versus placebo, described in more detail next) and a small quasi-randomized study of bevacizumab with 30 patients. (51, 52) A larger study with bevacizumab was excluded because it had follow-up only to 3 months. (53) The Cochrane review concluded that ranibizumab may improve clinical and visual outcomes at 6 and 12 months, but questions remain concerning the frequency of retreatment, the effect of prior or combined laser photocoagulation on outcomes, and long-term efficacy and safety.

RVO: Ranibizumab (Lucentis™)

Ranibizumab has been evaluated for macular edema following CRVO and BRVO, with 6- and 12-month results available from 2 double-masked multicenter trials.

A phase 3 trial of ranibizumab for macular edema following CRVO was reported by the CRUISE investigators in 2010 and 2011. (43, 44) A total of 392 patients with macular edema after CRVO were randomized to monthly injections of ranibizumab 0.3 or 0.5 mg or sham. Inclusion criteria were BCVA of 20/40 or lower or mean central subfield thickness 250 μm or more. Randomization was stratified by baseline BCVA letter score and study center. One eye was chosen as the study eye for each patient. The ITT approach was used for efficacy analysis and included all patients as randomized; missing values were imputed using the LOCF method. The approximate BCVA at baseline was 20/100, and the central foveal thickness was more than 650 μm. 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 or more 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 BCVA of 20/40 or higher was 43.9% (0.3 mg) and 46.9% (0.5 mg) for the active treatment groups compared with 20.8% in the sham group. Central foveal thickness decreased by a mean of 434 μm (microns; 0.3 mg) and 452 μm (0.5 mg) in the ranibizumab groups and 168 μm in the sham group. At month 6, the mean increase from baseline 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 of 20/40 or lower or mean central subfield thickness of 250 μm or more 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 or more letters was 47% and 50.8% for ranibizumab 0.3 mg and 0.5 mg and 33.2% for sham/0.5 mg. The reduction in central foveal thickness in the ranibizumab groups was maintained at 453 μm (0.3 mg) and 462 μm (0.5 mg) 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-μm reduction). The reduction in central foveal thickness did not differ significantly between the 3 groups. Treatment with ranibizumab as needed from months 6 to 11 maintained, on average, the increases in the 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 3 trial of ranibizumab for macular edema following BRVO. (51, 52) The study design was similar to the study on CRVO (previous) 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 μm. 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 ranibizumab 0.3-mg and 0.5-mg groups and 7.3 letters for the sham group. The percentage of patients who gained 15 or more 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 of 20/40 or higher 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 μm (0.3 mg) and 345 μm (0.5 mg) in the ranibizumab groups and 158 μm in the sham group. More patients in the sham group (54.5%) received rescue grid laser treatment compared with the ranibizumab 0.3-mg (18.7%) and 0.5-mg (19.8%) groups. No new safety events were identified in patients with BRVO.

After 6 months, all patients with BCVA of less than 20/40 or mean central subfield thickness of 250 μm or more 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 or more 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 μm and 347 μm). 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 μm); 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 ranibizumab 0.3-mg and 0.5-mg groups compared with 3.1% for sham at 6 months.

Vision-related function in the BRAVO and CRUISE trials was reported by Varma et al. in 2012. (54) Baseline scores on the VFQ-25 were comparable between groups. Through the 6-month follow-up, visual function on the VFQ-25 was statistically greater in the ranibizumab groups compared with sham. In BRAVO, the sham group improved by 5.4 points, the ranibizumab 0.3-mg group improved by 9.3 points, and the 0.5-mg group improved by 10.4 points. In CRUISE, the sham group improved by 2.8 points, the 0.3-mg group improved by 7.1 points, and the 0.5-mg group improved by 6.2 points. The proportion of patients who improved by a clinically meaningful amount (≥5 points on the VFQ-25) was reported to be greater for ranibizumab than sham.

RVO: Bevacizumab (Avastin®)

Three RCTs from outside of the U.S. have been published on the use of bevacizumab for macular edema following RVO. Two of the trials were sham-controlled (1 CRVO, 1 BRVO); the third compared bevacizumab with triamcinolone in patients with BRVO.

In 2012, Epstein et al. reported a randomized, sham-controlled, double-masked trial in 60 patients with CRVO. (49, 55) Intraocular bevacizumab or sham injections were administered every 6 weeks for 6 months. For the next 6 months, all patients received bevacizumab every 6 weeks. At 6-month follow-up, mean BCVA improved by 14.1 letters in the bevacizumab group compared with a decrease of 2.0 letters in the control group. Sixty percent of patients in the bevacizumab group had gained 15 letters or more compared with 20% in the control group. The mean decrease in central retinal thickness was greater in the bevacizumab group (426 μm) compared with controls (102 μm), and 86.7% of patients in the bevacizumab group had no residual edema compared with 20% in the control group. At 12-month follow-up, the percentage of patients who had gained 15 letters or more remained at 60% in the bevacizumab/bevacizumab group, while 33% of patients who received sham/bevacizumab gained 15 letters or more, suggesting that patients receiving delayed treatment may have limited visual improvement.

A 2011 publication reported a double-masked sham-controlled RCT in 81 eyes (81 patients) with BRVO. (53) 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. Central macular thickness at baseline was 471 μm for the control group and 575 μm for the bevacizumab group. At week 6, the central macular thickness was 462 μm for sham and had decreased to 325 μm for bevacizumab. Central macular thickness at week 12 was 393 μm for sham versus 309 μm for bevacizumab. The difference in macular thickness was statistically different at both 6 and 12 weeks of follow-up.

Another study with 52 patients compared triamcinolone (4 mg) to bevacizumab (1.25 mg) monotherapy or combined therapy (triamcinolone 2 mg and bevacizumab 1.25 mg) for macular edema due to BRVO. (56) Reinjections 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. Otherwise, macular grid laser photocoagulation was performed. Macular grid laser photocoagulation was applied in a similar proportion across the 3 groups. 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% to 88% of patients in the monotherapy groups but only 48% of the combined-therapy 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.

Bevacizumab (Avastin®) versus Ranibizumab (Lucentis™)

Evidence on the comparative effectiveness of bevacizumab versus ranibizumab includes 2 RCTs, both of which showed similar efficacy of the 2 agents.

In 2015, Narayanan et al. reported results of the MARVEL study. (57) This double-masked RCT included 75 patients with macular edema due to BRVO. An intravitreal injection of ranibizumab or bevacizumab was given at baseline and then pro re nata, with a mean number of injections of 3.2 for ranibizumab and 3.0 for bevacizumab over 6 months. The study had a follow-up rate of close to 90%, and used ITT analysis with the LOCF. At 6 months, the mean gain in BCVA was similar in the 2 groups, with a gain of 18.1 letters in the ranibizumab group and 15.6 letters in the bevacizumab group. The percentage of patients who gained at least 15 letters (ranibizumab, 59.4% versus bevacizumab, 57.8%) and the reduction in central retinal thickness (ranibizumab 177.1-μm reduction, bevacizumab 201.68-μm reduction) were also similar for the 2 groups.

Six-month results from the CRAVE study were reported in 2015. (58) The study included 93 patients with BRVO or CRVO who were randomized to 6 monthly injections with either bevacizumab or ranibizumab followed by pro re nata treatment. An additional 9 patients were assigned to bevacizumab due to financial hardship. Patients and physicians were not masked to treatment. There was a high loss to follow-up (23% the bevacizumab arm versus 21.3% in the ranibizumab arm), although the study used ITT analysis. At 6 months, there was no significant difference between the 2 treatment arms in the primary outcome of decrease in central foveal thickness (bevacizumab 212.6 μm versus ranibizumab 243.8 μm). Gains in function were also similar in the 2 groups, with 71.4% of the bevacizumab group and 70.6% of the ranibizumab group showing a 3-line or greater improvement in vision.

RVO: Aflibercept (EYLEA®)

Safety and efficacy of aflibercept were assessed in 2 pivotal randomized, multicenter, double-masked, sham-controlled studies (COPERNICUS, GALILEO) in patients with macular edema following CRVO. (2) A total of 358 patients were randomized 3:2 to aflibercept 2 mg or to sham administered every 4 weeks. Between 24 and 48 weeks, patients were treated as needed. At 24 weeks, the proportion of patients who gained at least 15 letters in BCVA following treatment with aflibercept was 56% and 60% (COPERNICUS and GALILEO, respectively). For the 2 control groups, 12% and 22% of patients gained at least 15 letters. The mean change in BCVA was 17.3 and 18.0 letters for aflibercept compared with -4.0 and +3.3 for controls (all respectively). After week 52, both groups received aflibercept.

The 6-, 18-, and 24-month results of the COPERNICUS and GALILEO trials were published in 2013 and 2014. (45-48) At 52 weeks in the GALILEO trial, the percentage of patients gaining 15 or more letters was 60.2% in the aflibercept group and 32.4% in the sham group, and at 76 weeks, the proportion of patients gaining at least 15 letters was 57.3% and 29.4%, respectively. At 100 weeks in the COPERNICUS trial, the proportion of patients who gained at least 15 letters was 49.1% in the aflibercept groups and 23.3% with sham. All differences were statistically significant. Treatment with aflibercept also led to a greater reduction in central retinal thickness compared with sham treatment.

In 2015, Campochiaro et al. published the 6-month results of the multicenter sham-controlled phase 3 VIBRANT study that compared aflibercept to laser photocoagulation for the treatment of macular edema after BRVO. (59) The 91 patients in the aflibercept group also received sham laser photocoagulation and the 92 patients in the photocoagulation group also received sham intravitreal injections. The proportion of eyes that gained at least 15 letters from baseline was 52.7% in the aflibercept group compared with 26.7% in the laser group (p<0.001). The decrease in central retinal thickness, measured by an independent central reading center, was also greater in the aflibercept group (280.5 μm versus 128.0 μm, p<0.001).

RVO: Pegaptanib (Macugen®)

In 2009, the Central Retinal Vein Occlusion Study Group published results from their phase 2 multicenter double-masked randomized trial. (60) Ninety-eight subjects were randomized to receive pegaptanib 0.3-mg or 1-mg or sham injections every 6 weeks for 24 weeks. For the primary outcome measure (percentage of subjects showing a gain of »15 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 those treated with pegaptanib showed greater improvement in mean visual acuity (+7.1 and +9.9 versus. -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, 34% for sham). By week 30, the difference in mean reduction in retinal thickness between the 0.3-mg dose and sham was 95 μm, while the difference between the 1-mg group and sham was 31 μm.

Section Summary: RVO

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

Retinopathy of Prematurity (ROP)

ROP: Bevacizumab (Avastin®)

The BEAT-ROP cooperative study group reported a multicenter randomized trial of a single injection of bevacizumab versus conventional laser therapy in 2011. (61) Included in the study were 150 infants (300 eyes with stage III+ disease in zone I or zone II) who were randomized to receive intravitreal bevacizumab or conventional laser therapy. (Zone I is a circle whose radius extends from the optic disk and is twice the distance between the center of the disk and the center of the macula, while zone II encircles zone I with a radius that is 3 times the distance between the center of the disk and the center of the macula.) The study was not masked, due to the marks made by laser therapy. However, photographs taken at 54 weeks were assessed post hoc by 6 independent experts at the reading center who were masked to treatment by cropping the photographs. The primary outcome was recurrence of ROP in 1 or both eyes requiring retreatment before 54 weeks of postmenstrual age. ROP was found to recur in 4 infants (4%) in the bevacizumab group compared with 19 infants (22%) in the laser-therapy group. The mean time for recurrence was 16.0 weeks for 6 eyes after bevacizumab compared with 6.2 weeks for 32 eyes after laser therapy. When divided by zone, a significant treatment effect was found for zone I disease but not for zone II. For zone I disease, recurrences were observed in 6% of infants treated with bevacizumab compared with 42% of infants treated with laser therapy. For zone II disease, the rate of recurrence was 5% in infants treated with bevacizumab and 12% in infants treated with laser therapy. The study appears to have been underpowered to detect the smaller difference between the groups in zone II, because there is less recurrence following laser therapy in zone II (12%) than zone I (42%), and the study did not achieve the target enrollment of 50 infants per group with zone II disease. Notably, intravitreal bevacizumab was found to allow vessel growth into the peripheral retina while conventional laser therapy resulted in permanent destruction of vessels in the peripheral retina. Thus, bevacizumab was more effective than laser for zone I disease and at least as effective as laser for zone II disease without the ocular adverse effects of laser therapy, which can include significant loss of visual field.

ROP: Pegaptanib (Macugen®)

In 2012, Autrata et al. reported a randomized study of intravitreal pegaptanib combined with laser therapy in 152 eyes (76 premature babies) with stage III+ ROP in zone I and posterior zone II. (62) Controls were treated with laser alone or laser plus cryotherapy. The authors did not report the method of randomization or whether the treatment condition was masked. The rationale for using pegaptanib was that the more selective VEGF-165 inhibitor might be a safer option for ROP treatment than bevacizumab. The primary outcome of treatment success was defined as absence of recurrence of stage III+ ROP in 1 or both eyes by 55 weeks postmenstrual age. This outcome was observed in 85.4% of eyes in the pegaptanib group and 50% of eyes in the control group. Treatment failure, defined as the recurrence of neovascularization, was observed in 11.7% of infants in the pegaptanib groups and 38% of infants in the laser control group. At about 20-month follow-up, 89.7% of eyes in the pegaptanib group and 60.8% of eyes in the laser control group had a favorable anatomic outcome and stable regression of ROP.

Section Summary: ROP

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

Neovascular Glaucoma

A 2013 Cochrane review found no RCTs that met the review’s inclusion criteria; 2 RCTs of anti-VEGF agents for treating neovascular glaucoma were not included in the review due to heterogeneity and uncontrolled adjunct treatments. (63)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Unpublished

NCT01908816a

An Open-label Extended Clinical Protocol of Ranibizumab to Evaluate Safety and Efficacy in Rare VEGF Driven Ocular Diseases

260

Mar 2016

NCT01635790

Comparing the Effectiveness and Costs of Bevacizumab to Ranibizumab in Patients with Diabetic Macular Edema (The BRDME Study)

246

Jun 2016

NCT01969708

Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2)

362

Mar 2017

NCT01783886a

A Randomized, Double Masked, Active Controlled, Phase III Study of the Efficacy and Safety of Repeated Doses of Intravitreal VEGF Trap Eye in Subjects with Diabetic Macular Edema

378

Mar 2015 (completed)

Table Key:

NCT: national clinical trial.

a: Denotes industry-sponsored or cosponsored trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

Blue Cross Blue Shield Association (BCBSA) received input from physician specialty societies and academic medical centers in 2011 and then again in 2013. 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.

2011: In response to requests, input was received from 1 physician specialty society and 3 academic medical centers in 2011. The input supported the use of ranibizumab and bevacizumab for DR (DME and proliferative DR) and for central or BRVO. Reviewers suggested additional indications for VEGF inhibitors including cystoid macular edema resulting from vasculitis, Coats disease, Eales disease, idiopathic macular telangiectasia type II, neovascularization of the iris/neovascularization of the angle/neovascular glaucoma, pseudoxanthoma elasticum, radiation retinopathy, retinal neovascularization, retinopathy of prematurity, rubeosis, Von Hippel-Lindau, and vitreous hemorrhage secondary to retinal neovascularization.

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

Practice Guidelines and Position Statements

American Academy of Ophthalmology (AAO)

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

The 2015 Preferred Practice Pattern for Retinal Vein Occlusions from the AAO states that the safest treatment for macular edema associated with CRVOs and BRVOs is anti-VEGF treatment. (65) This is based on well conducted studies that have shown efficacy of anti-VEGF treatment for macular edema associated with CRVO and BRVO. The body of evidence was considered to be of good quality leading to a strong recommendation.

National Institute for Health and Clinical Excellence (NICE)

In a final appraisal determination from July 15, 2011, the NICE does not recommend ranibizumab (Lucentis™) for the treatment of DME. (66) The independent Appraisal Committee found that the manufacturer’s model underestimated the incremental cost-effectiveness ratio (ICER) for ranibizumab monotherapy compared with the current standard treatment for people with DME, laser photocoagulation. It concluded that a model that relied on a combined set of plausible assumptions would be certain to produce an ICER that substantially exceeded the range that NICE considers an effective use of National Health Service resources. Therefore, ranibizumab could not be recommended as a treatment for people with DME.

In 2013 NICE issued Technology Assessment 274, which stated that ranibizumab is recommended as an option for the treatment of macular edema only if the eye to be treated has a central retinal thickness of 400 μm or more at the start of treatment and the agreed-on manufacturer discount is in place. (67)

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

Summary of Evidence

The evidence for intravitreal vascular endothelial growth factor (VEGF) inhibitors in individuals who have retinal vascular conditions (e.g., diabetic macular edema [DME], diabetic retinopathy, macular edema following retinal vein occlusion, retinopathy of prematurity) includes numerous randomized controlled trials (RCTs). Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. Evidence for the most common retinal vascular conditions follows.

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

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

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

For the treatment of retinopathy of prematurity (ROP), the evidence includes 2 RCTs, 1 high-quality trial using bevacizumab and a more problematic study using pegaptanib, reporting that recurrence of retinopathy is reduced compared with laser treatment alone. This evidence suggests that VEGF inhibitors improve outcomes for infants with ROP when given by the intravitreal route. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Given the similarity in efficacy of aflibercept, bevacizumab, and ranibizumab, these 3 VEGF inhibitors may be considered medically necessary for the treatment of DME and proliferative DR, RVO, and ROP. Based on the clinical input to BCBSA in 2011 and 2013, aflibercept, bevacizumab, and ranibizumab may be considered medically necessary for the treatment of neovascular glaucoma and rubeosis (neovascularization of the iris).

Contract:

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

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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

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

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

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

67028

HCPCS Codes

C9257, J0178, J2503, J2778, J3490, J9035

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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70. FDA–Macugen Prescribing Information. 2012. U.S. Food and Drug Administration. Available at <http://www.accessdata.fda.gov> (accessed May 25, 2017).

71. Intravitreal Angiogenesis Inhibitors for Retinal Vascular Conditions (Archived). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 March) Other 9.03.27.

72. DrugPoint®Summary—Bevacizumab. Microdex® (DrugDex Compendia). Available at <http://www.micromedexsolutions.com> (accessed June 1, 2017).

73. DrugPoint®Summary—Pegaptanib. Microdex® (DrugDex Compendia). Available at <http://www.micromedexsolutions.com> (accessed June 1, 2017).

74. DrugPoint®Summary—Ranibizumab. Microdex® (DrugDex Compendia). Available at <http://www.micromedexsolutions.com> (accessed June 1, 2017).

75. DrugPoint®Summary—Aflibercept. Microdex® (DrugDex Compendia). Available at <http://www.micromedexsolutions.com> (accessed June 1, 2017).

Policy History:

DateReason
10/15/2018 Reviewed. No changes.
11/1/2017 Document updated with literature review. The following wording was removed from the Lucentis™ medically necessary coverage statement “proliferative” and “as an adjunctive treatment to vitrectomy or photocoagulation” following the U.S. Food and Drug Administration-approved labeling. The following NOTEs were added in the Coverage section: “NOTE 2: Bevacizumab (Avastin™) is a recognized, viable, cost-effective anti-VEGF (vascular endothelial growth factor) alternative treatment”; and “NOTE 5: For conditions resulting from wet age-related macular degeneration, (e.g., retinal detachment, refer to medical policy OTH903.020, Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions, for the appropriate U.S. Food and Drug Administration approved drug for coverage information.”
7/15/2016 Reviewed. No changes.
12/1/2015 Document updated with literature review. The following indication was added to the medically necessary coverage statement intravitreal injection of aflibercept (EYLEA™): “Diabetic retinopathy in patients with diabetic macular edema.” Otherwise, coverage unchanged.
11/15/2014 Document updated with literature review. The following was added as an approved U.S. Food and Drug Administration labeled indication for aflibercept (EYLEA™): Intravitreal injection of aflibercept (EYLEA™) may be considered medically necessary for the treatment of macular edema following retinal vein occlusion, inclusive of branch retinal vein occlusion. The Rationale and References were revised.
10/1/2014 New medical document. Intravitreal injection of ranibizumab (Lucentis™) or bevacizumab (Avastin™) may be considered medically necessary for the treatment of specifically listed retinal vascular conditions. Intravitreal injection of pegaptanib (Macugen®) may be considered medically necessary for the treatment of diabetic macular edema and diabetic retinopathy. Intravitreal injection of aflibercept (EYLEA™) may be considered medically necessary for the treatment of macular edema following central retinal vein occlusion and for diabetic macular edema. Intravitreal injection of bevacizumab (Avastin™) may be considered medically necessary for the treatment of specific retinal or macular conditions. Intravitreal injection of ranibizumab (Lucentis™) or bevacizumab (Avastin™) is considered experimental, investigational and/or unproven for the treatment of all other retinal vascular disorders. Intravitreal injection of aflibercept (EYLEA™) is considered experimental, investigational and/or unproven for all other ophthalmologic indications listed in the coverage. CPT/HCPCS code(s) updated. Significant revisions were made to entire medical policy document. This topic was previously addressed on OTH903.020, Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions.

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