Description
Vascular endothelial growth factor inhibitors (e.g., ranibizumab, bevacizumab, pegaptanib, aflibercept) can be given via intraocular injections as a treatment for disorders of retinal circulation. Ophthalmic disorders affecting the retinal circulation include diabetic macular edema (DME), diabetic retinopathy, macular edema following central or branch retinal vein occlusion and retinopathy of prematurity.

The evidence for intravitreal vascular endothelial growth factor (VEGF) inhibitors in individuals who have retinal vascular conditions (e.g., 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, evidence is available for ranibizumab, bevacizumab, aflibercept and pegaptanib. A large trial by the DRCRN found that intravitreal injection of ranibizumab is noninferior to photocoagulation in eyes with proliferative diabetic retinopathy at 2 years. Treatment with ranibizumab for DME may also reduce progression to proliferative diabetic retinopathy and need for vitrectomy. A number of smaller RCTs report superior outcomes for bevacizumab as a single agent or as an adjunct to photocoagulation or vitrectomy. A single small RCT reported that pegaptanib had similar efficacy to photocoagulation for patients with proliferative diabetic retinopathy. Analysis of data from the RISE and RIDE trials found that treatment with ranibizumab over 3 years led to improvement in proliferative diabetic retinopathy in a significantly greater proportion of eyes than those treated with sham injections for the first 2 years. Two-year data from the VIVID and VISTA trials showed a significantly greater percentage of patients in the aflibercept groups who gained at least 2 steps in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (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 diabetic retinopathy in patients with DME. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

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

Clinical input was requested on the treatment of less common indications. 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 syndrome and vitreous hemorrhage secondary to retinal neovascularization.

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 associated with age-related macular degeneration (AMD) and are being evaluated for the treatment of disorders of retinal circulation (e.g., diabetic macular edema [DME], diabetic retinopathy, macular edema following retinal vein occlusion, retinopathy of prematurity [ROP]).

For the treatment of ocular disorders, these agents are given by intravitreal injection every 1 to 2 months. 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. 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 and Diabetic Retinopathy
Diabetic retinopathy 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 diabetic retinopathy. 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 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 DME and 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 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 diabetic retinopathy. For DME, outcomes of interest include macular thickness and visual acuity. For proliferative and non-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 (CRVO) or branch retinal vein occlusion (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 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
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^®, EyeTech and Pfizer), ranibizumab (Lucentis^™) and aflibercept (EYLEA^™, Regeneron Pharmaceuticals) are presently the only angiostatic drugs approved by FDA for use in the eye. Macugen^® was the first VEGF antagonist to be approved by FDA for use in wet AMD.

Lucentis^™ (Genentech) was first approved for the treatment of patients with neovascular AMD. In 2010, Lucentis^™ was approved by 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 diabetic retinopathy in patients with DME.¹

EYLEA^® was approved by 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, FDA approved EYLEA^® for the treatment of diabetic retinopathy in patients with DME. 

Bevacizumab has been developed and approved for use in oncology but has not been licensed for use in the eye.

Related Policies
90308 Photodynamic Therapy for Choroidal Neovascularization
90313 Retinal Telescreening for Diabetic Retinopathy
90323 Intravitreal Corticosteroid Implants
90324 Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions

Policy
Intravitreal injection of ranibizumab, bevacizumab or aflibercept may be considered MEDICALLY NECESSARY for the treatment of the following retinal vascular conditions: 

• Diabetic macular edema* 
• Diabetic retinopathy* 
• Macular edema following retinal vein occlusion* 
• Retinopathy of prematurity 
• Neovascular glaucoma 
• Rubeosis (neovascularization of the iris)

Intravitreal injection of ranibizumab, bevacizumab or aflibercept is considered INVESTIGATIONAL for the treatment of all other retinal vascular disorders. 

Intravitreal injection of pegaptanib is considered INVESTIGATIONAL for treatment of retinal vascular disorders, including proliferative diabetic retinopathy, diabetic macular edema and central or branch retinal vein occlusion. 

* FDA approved indication (Lucentis and EYLEA).

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

Rationale
Diabetic Macular Edema
The available evidence on vascular endothelial growth factor (VEGF) inhibitors for the treatment of diabetic macular edema (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.^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 1,000 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.

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.^13,14,15 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 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,^18,19,20 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

Bevacizumab (Avastin)
Several smaller RCTs from outside of the United States 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).

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.  

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% vs. 10%) and 15 or more letters (18% vs. 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% vs. 19.7%, respectively), and fewer pegaptanib than sham-treated subjects received focal/grid laser treatment (23.3% vs. 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.  

Section Summary: Diabetic Macular Edema
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
In 2015, Simunovic and Maberley reported a meta-analysis of VEGF inhibitors in the management of proliferative diabetic retinopathy.³⁰ The review identified 22 RCTs (1,397 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.

Ranibizumab (Lucentis)
Intravitreal injection of ranibizumab has been compared with photocoagulation or sham injection for the treatment of proliferative and non-proliferative diabetic retinopathy.

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 diabetic retinopathy 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% vs. 4%, p<0.001) and DME was more frequent (28% vs. 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 diabetic retinopathy.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 diabetic retinopathy.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 diabetic retinopathy 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 diabetic retinopathy 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.

Bevacizumab (Avastin)
Multiple intravitreal injections of bevacizumab have been compared with laser photocoagulation for the treatment of diabetic retinopathy 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 diabetic retinopathy with DME.³⁴ Most patients had nonproliferative diabetic retinopathy, 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 diabetic retinopathy. 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 diabetic retinopathy, 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 diabetic retinopathy 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 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.

VEGF inhibitors are also being evaluated as adjunctive treatment to reduce bleeding, improve surgical outcomes visual acuity in patients with diabetic retinopathy 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 diabetic retinopathy 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 vs. 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 alone 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 diabetic retinopathy 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.

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 diabetic retinopathy 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.

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

Retinal Vein Occlusion
In 2015, the American Academy of Ophthalmology 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 vs. 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.

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 (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.

Bevacizumab (Avastin)
Three RCTs from outside of the United States have been published on the use of bevacizumab for macular edema following retinal vein occlusion. 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 Versus Ranibizumab
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% vs. 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 vs. 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 vs. 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. 

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.^45,46,47,48 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 vs. 128.0 μm, p<0.001).  

Pegaptanib (Macugen)
In 2009, the Central Retinal Vein Occlusion Study Group published results from its 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 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, 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: Retinal Vein Occlusion
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
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 retinopathy of prematurity (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.  

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

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 No.	Trial Name	Planed Enrollment	Completion Date
Ongoing
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
Unpublished
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)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial. 

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

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

For the treatment of retinopathy of prematurity, 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 retinopathy of prematurity 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. 

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

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

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

Practice Guidelines and Position Statements
American Academy of Ophthalmology
The 2016 preferred practice pattern for diabetic retinopathy from the American Academy of Ophthalmology (AAO) concludes that intravitreal injection of anti-VEGF agents is the initial treatment of choice for center-involving diabetic macular edema.⁶⁴ Laser photocoagulation remains the preferred treatment for non-center-involving diabetic macular edema. The panel concluded that VEGF antagonists are an alternative for proliferative diabetic retinopathy, and when it is at the high-risk stage (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 diabetic retinopathy and non-high-risk proliferative diabetic retinopathy is being evaluated.

The 2015 preferred practice pattern for retinal vein occlusions from AAO states that the safest treatment for macular edema associated with CRVOs and BRVOs is anti-VEGF treatment.⁶⁵ This is based on well conducted studies that have shown efficacy of anti-VEGF treatment for macular edema associated with CRVO and BRVO. The body of evidence was considered to be of good quality leading to a strong recommendation.

National Institute for Health and Clinical Excellence
In a final appraisal determination from July 15, 2011, the National Institute for Health and Clinical Excellence (NICE) does not recommend ranibizumab (Lucentis) for the treatment of DME.⁶⁶ The independent Appraisal Committee found that the manufacturer’s model underestimated the incremental cost-effectiveness ratio (ICER) for ranibizumab monotherapy compared with the current standard treatment for people with DME, laser photocoagulation. It concluded that a model that relied on a combined set of plausible assumptions would be certain to produce an ICER that substantially exceeded the range that NICE considers an effective use of National Health Service resources. Therefore, ranibizumab could not be recommended as a treatment for people with DME. In 2013 NICE issued Technology Assessment 274, which stated that ranibizumab is recommended as an option for the treatment of macular edema only if the eye to be treated has a central retinal thickness of 400 μm or more at the start of treatment and the agreed on manufacturer discount is in place.67

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

U.S. Preventive Services Task Force Recommendations
Not applicable

References 

1. Lucentis Prescribing Information. 2015; http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125156s106lbl.pdf. Accessed February 16, 2016.
2. Eylea Prescribing Information. 2014; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125387s043lbl.pdf. Accessed February 16, 2016.
3. 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. Apr 2008;246(4):483-489. PMID 17917738
4. O'Malley PG. Comparative effectiveness of anti-growth factor therapies for diabetic macular edema: summary of primary findings and conclusions. Arch Intern Med. Jul 9 2012;172(13):1014-1015. PMID 22688778
5. American Academy of Ophthalmology Retina Panel. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology [Review]. 2012; 2012/08/25:2179-2188. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22917890. Accessed January 7, 2015. 
6. Virgili G, Parravano M, Menchini F, et al. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema. Cochrane Database Syst Rev. 2012;12:CD007419. PMID 23235642
7. Virgili G, Parravano M, Menchini F, et al. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014;10:CD007419. PMID 25342124
8. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. Mar 26 2015;372(13):1193-1203. PMID 25692915
9. 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. Nov 2010;33(11):2399-2405. PMID 20980427
10. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. Apr 2012;119(4):789-801. PMID 22330964
11. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. Oct 2013;120(10):2013-2022. PMID 23706949
12. Boyer DS, Nguyen QD, Brown DM, et al. Outcomes with As-Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials. Ophthalmology. Dec 2015;122(12):2504-2513 e2501. PMID 26452713
13. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. Apr 2011;118(4):615-625. PMID 21459215
14. Lang GE, Berta A, Eldem BM, et al. Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study. Ophthalmology. Oct 2013;120(10):2004-2012. PMID 23725735
15. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-Year Outcomes of Individualized Ranibizumab Treatment in Patients with Diabetic Macular Edema: The RESTORE Extension Study. Ophthalmology. Feb 1 2014. PMID 24491642
16. 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. Jun 2010;117(6):1064-1077 e1035. PMID 20427088
17. 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. Apr 2011;118(4):609-614. PMID 21459214
18. 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. Nov 2009;116(11):2175-2181 e2171. PMID 19700194
19. 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. Nov 2010;117(11):2146-2151. PMID 20855114
20. Do DV, Nguyen QD, Khwaja AA, et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol. Feb 2013;131(2):139-145. PMID 23544200
21. Ishibashi T, Li X, Koh A, et al. The REVEAL Study: Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy in Asian Patients with Diabetic Macular Edema. Ophthalmology. Jul 2015;122(7):1402-1415. PMID 25983216
22. Berger A, Sheidow T, Cruess AF, et al. Efficacy/safety of ranibizumab monotherapy or with laser versus laser monotherapy in DME. Can J Ophthalmol. Jun 2015;50(3):209-216. PMID 26040221
23. 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. Jun 2009;116(6):1142-1150. PMID 19376585
24. Soheilian M, Garfami KH, Ramezani A, et al. Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. Retina. Feb 2012;32(2):314-321. PMID 22234244
25. 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. Jun 2010;117(6):1078-1086 e1072. PMID 20416952
26. 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. Sep 2011;118(9):1819-1826. PMID 21546089
27. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. Oct 2015;122(10):2044-2052. PMID 26198808
28. 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. Oct 2005;112(10):1747-1757. PMID 16154196 
29. 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. Apr 27 2011. PMID 21529957
30. Simunovic MP, Maberley DA. Anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy: A Systematic Review and Meta-Analysis. Retina. Oct 2015;35(10):1931-1942. PMID 26398553
31. Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. Nov 24 2015;314(20):2137-2146. PMID 26565927
32. Diabetic Retinopathy Clinical Research Network. Randomized clinical trial evaluating intravitreal ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy. JAMA Ophthalmol. Mar 2013;131(3):283-293. PMID 23370902
33. Ip MS, Domalpally A, Sun JK, et al. Long-term Effects of Therapy with Ranibizumab on Diabetic Retinopathy Severity and Baseline Risk Factors for Worsening Retinopathy. Ophthalmology. Feb 2015;122(2):367-374. PMID 25439595
34. Javanovic S, Canadanovic V, Sabo A, et al. Intravitreal bevacizumab injection alone or combined with macular photocoagulation compared to macular photocoagulation as primary treatment of diabetic macular edema. Vojnosanit Pregl. Oct 2015;72(10):876-882. PMID 26665553
35. Cho WB, Moon JW, Kim HC. Intravitreal triamcinolone and bevacizumab as adjunctive treatments to panretinal photocoagulation in diabetic retinopathy. Br J Ophthalmol. Jul 2010;94(7):858-863. PMID 20606024
36. 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. Mar-Apr 2008;18(2):263-269. PMID 18320520
37. 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. PMID 21563165
38. Ahmadieh H, Shoeibi N, Entezari M, et al. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients: a randomized clinical trial. Ophthalmology. Oct 2009;116(10):1943-1948. PMID 19699531
39. 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. Nov-Dec 2010;20(6):1047-1052. PMID 20491044
40. 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. Jun 2010;248(6):785-791. PMID 20135139
41. Gonzalez VH, Giuliari GP, Banda RM, et al. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol. Nov 2009;93(11):1474-1478. PMID 19692371
42. Yeh S, Kim SJ, Ho AC, et al. Therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology. Ophthalmology. Apr 2015;122(4):769-778. PMID 25576994
43. 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. Jun 2010;117(6):1124-1133 e1121. PMID 20381871
44. 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. Oct 2011;118(10):2041-2049. PMID 21715011
45. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. Mar 2013;97(3):278-284. PMID 23298885
46. Korobelnik JF, Holz FG, Roider J, et al. Intravitreal Aflibercept Injection for Macular Edema Resulting from Central Retinal Vein Occlusion: One-Year Results of the Phase 3 GALILEO Study. Ophthalmology. Jan 2014;121(1):202-208. PMID 24084497
47. Ogura Y, Roider J, Korobelnik JF, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol. Nov 2014;158(5):1032-1038. PMID 25068637
48. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. Jul 2014;121(7):1414-1420 e1411. PMID 24679444
49. Epstein DL, Algvere PV, von Wendt G, et al. Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study. Ophthalmology. Jun 2012;119(6):1184-1189. PMID 22424833
50. Mitry D, Bunce C, Charteris D. Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion. Cochrane Database Syst Rev. 2013;1:CD009510. PMID 23440840 
51. 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. Jun 2010;117(6):1102-1112 e1101. PMID 20398941
52. 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. Aug 2011;118(8):1594-1602. PMID 21684606
53. 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. Feb 2011;249(2):193-200. PMID 21337043
54. Varma R, Bressler NM, Suner I, et al. Improved Vision-Related Function after Ranibizumab for Macular Edema after Retinal Vein Occlusion: Results from the BRAVO and CRUISE Trials. Ophthalmology. Oct 2012;119(10):2108-2118. PMID 22817833
55. Epstein DL, Algvere PV, von Wendt G, et al. Benefit from Bevacizumab for Macular Edema in Central Retinal Vein Occlusion: Twelve-Month Results of a Prospective, Randomized Study. Ophthalmology. Aug 16 2012. PMID 22902212
56. 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. Oct 2010;35(10):925-929. PMID 20858114
57. Narayanan R, Panchal B, Das T, et al. A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J Ophthalmol. Jul 2015;99(7):954-959. PMID 25631483
58. Rajagopal R, Shah GK, Blinder KJ, et al. Bevacizumab Versus Ranibizumab in the Treatment of Macular Edema Due to Retinal Vein Occlusion: 6-Month Results of the CRAVE Study. Ophthalmic Surg Lasers Imaging Retina. Sep 2015;46(8):844-850. PMID 26431300
59. Campochiaro PA, Clark WL, Boyer DS, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. Ophthalmology. Mar 2015;122(3):538-544. PMID 25315663
60. Wroblewski JJ, Wells JA, 3rd, Adamis AP, et al. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. Arch Ophthalmol. Apr 2009;127(4):374-380. PMID 19365011
61. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. Feb 17 2011;364(7):603-615. PMID 21323540
62. Autrata R, Krejcirova I, Senkova K, et al. Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. Eur J Ophthalmol. Sep-Oct 2012;22(5):687-694. PMID 22669848
63. Simha A, Braganza A, Abraham L, et al. Anti-vascular endothelial growth factor for neovascular glaucoma. Cochrane Database Syst Rev. 2013;10:CD007920. PMID 24089293
64. American Academy of Ophthalmology Retina/Vitreous Panel. Diabetic Retinopathy Preferred Practice Pattern. 2016; http://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2016. Accessed February 25, 2016.
65. American Academy of Ophthalmology Retina/Vitreous Panel. Retinal Vein Occlusions Preferred Practice Pattern Guidelines. 2015; http://www.aaojournal.org/content/preferred-practice-pattern. Accessed February 25, 2016.
66. National Institute for Health and Clinical Excellence (NICE). Final appraisal determination: Ranibizumab for the treatment of diabetic macular oedema TA274. 2013; http://www.nice.org.uk/guidance/TA274. Accessed January 7, 2015.
67. National Institute for Health and Clinical Excellence (NICE). TA 274 Ranibizumab for treating diabetic macular oedema. 2013; http://publications.nice.org.uk/ranibizumab-for-treating-diabetic-macular-oedema-rapid-review-of-technology-appraisal-guidance-ta274/about-this-guidance. Accessed January 7, 2015.
68. National Institute for Health and Clinical Excellence (NICE). TA 283 Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. 2013; http://publications.nice.org.uk/ranibizumab-for-treating-visual-impairment-caused-by-macular-oedema-secondary-to-retinal-vein-ta283. Accessed January 7, 2015.

Coding Section

Codes	Number	Description
CPT	67028	Intravitreal injection of a pharmacologic agent (separate procedure)
ICD-9 Procedure
ICD-9 Diagnosis	250.50-250.53	Diabetes with ophthalmic manifestations, code range
	362.02	Proliferative diabetic retinopathy
	362.07	Diabetic macular edema
	362.83	Retinal edema
HCPCS	C9257	Injection, bevacizumab, 0.25 mg
	C9291	Injection, aflibercept, 2 mg vial (code deleted 6/30/12)
	J0179	Injection, alibercept, 1 mg (new code 1/1/13)
	J2503	Injection, pegaptanib sodium, 0.3 mg
	J2778	Injection, ranibizumab, 0.1 mg
	Q2046	Injection, alibercept, 1 mg (code deleted 12/31/12)
ICD-10-CM (effective 10/01/15)	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 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
	3E0C3GC	Administration, physiological systems and anatomical regions, introduction, eye, percutaneous, therapeutic substance

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

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

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

History From 2014 Forward     

02/09/2023	Annual review. No changes to policy intent.
02/01/2022	Annual review. No changes to policy intent.
02/02/2021	Annual review. No changes to policy intent.
02/19/2020	Annual review. No change to policy intent.
02/21/2019	Annual review, no change to policy intent.
02/28/2018	Annual review, no change to policy intent.
02/02/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
02/18/2016	Annual review, policy verbiage updated to take FDA recommendations into account. Updating background, description, regulatory status, rationale and references.
02/11/2015	Annual review, no change to policy intent. Updating rationale and references. Adding benefit application and coding.
02/17/2014	Changed annual review date to include changes in policy language related to neovascular glaucoma and rubeosis stage 3+, treatment of retinopathy of prematurity and macular edema. Updated description, policy verbiage, rationale, references and regulatory status.