Medical Policy

 

Subject: Intravitreal Treatment for Retinal Vascular Conditions
Document #: DRUG.00028 Publish Date:    10/01/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the following medications used to treat retinal vascular conditions of the eye:

  1. Pegaptanib (Macugen® , Bausch & Lomb, Bridgewater, NJ)
  2. Bevacizumab (Avastin® , Genentech, Inc., San Francisco, CA)
  3. Ranibizumab (Lucentis® , Genentech, Inc., San Francisco, CA)
  4. Aflibercept (Eylea® , Regeneron, Tarrytown, NY)

Note: Please see the following related documents for additional information:

Position Statement

I.  Pegaptanib (Macugen)

Medically Necessary:

A series of intravitreal injections with pegaptanib is considered medically necessary as a treatment of:

  1. Established neovascular "wet" age-related macular degeneration.

Investigational and Not Medically Necessary:

The use of intravitreal pegaptanib is considered investigational and not medically necessary for all other conditions including, but not limited to:

  1. Diabetic eye disease
  2. As a treatment of other forms of age-related macular degeneration to prevent progression to neovascular "wet" age-related macular degeneration.

II. Bevacizumab (Avastin)

Medically Necessary: 

A series of intravitreal injections with bevacizumab is considered medically necessary as a treatment for any of the following:

  1. Diabetic macular edema; or
  2. Proliferative diabetic retinopathy with or without diabetic macular edema; or
  3. Established neovascular "wet" age-related macular degeneration; or
  4. Macular edema from branch retinal vein occlusion; or
  5. Macular edema from central retinal vein occlusion; or
  6. Neovascular glaucoma; or
  7. Other rare causes of choroidal neovascularization for one or more of the following conditions:
    1. angioid streaks; or
    2. choroiditis (including, but not limited to histoplasmosis induced choroiditis); or
    3. degenerative myopia (idiopathic); or
    4. retinal dystrophies; or
    5. trauma; or
  8. Pseudoxanthoma elasticum; or
  9. Radiation retinopathy; or
  10. Retinopathy of prematurity.

Investigational and Not Medically Necessary:

The use of intravitreal bevacizumab is considered investigational and not medically necessary for any other condition not listed above as medically necessary.

III. Ranibizumab (Lucentis)

Medically Necessary:

A series of intravitreal injections with ranibizumab is considered medically necessary as a treatment for any of the following:

  1. Choroidal neovascularization associated with myopic degeneration; or
  2. Diabetic macular edema; or
  3. Proliferative diabetic retinopathy with or without diabetic macular edema; or
  4. Established neovascular "wet" age-related macular degeneration; or
  5. Macular edema from branch retinal vein occlusion; or
  6. Macular edema from central retinal vein occlusion; or
  7. Radiation retinopathy.

Investigational and Not Medically Necessary:

The use of intravitreal ranibizumab is considered investigational and not medically necessary for any other condition not listed above as medically necessary.

IV. Aflibercept (Eylea)

Medically Necessary:

A series of intravitreal injections with aflibercept is considered medically necessary as a treatment for any of the following:

  1. Diabetic macular edema; or
  2. Proliferative diabetic retinopathy with or without diabetic macular edema; or
  3. Established neovascular "wet" age-related macular degeneration; or
  4. Macular edema from branch retinal vein occlusion; or
  5. Macular edema from central retinal vein occlusion; or
  6. Radiation retinopathy.

Investigational and Not Medically Necessary:

The use of intravitreal aflibercept is considered investigational and not medically necessary for any other condition not listed above as medically necessary.

Clinically Equivalent Cost Effective Agents

Note:  When anti-vascular endothelial growth factor is determined to be medically necessary based on the clinical criteria above, the benefit plan may have in addition a medically necessary criterion that the treatment be cost effective.

A benefit plan may select any one or more of the following as clinically equivalent cost effective anti-vascular endothelial growth factor agents: Pegaptanib (Macugen), Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (Eylea). A list of one or more cost effective anti-vascular endothelial growth factor agents for each plan is available here.

In benefit plans where there is a requirement to use a cost effective anti-vascular endothelial growth factor agent, requests for an anti-vascular endothelial growth factor agent that is not cost effective may be approved when the following criteria are met:

  1. The individual has had a trial of and is intolerant to one cost effective agent; or
  2. For the prescribed indication, the cost effective agent(s) is/are not FDA-approved or does not meet the off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use (see below) or
  3. The prescribed indication is neovascular age-related macular degeneration and Pegaptanib (Macugen) is the sole cost effective anti-vascular endothelial growth factor agent selected by a benefit plan.

FDA-approved Indications or Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use

 

Pegaptanib (Macugen)

Bevacizumab (Avastin)

Ranibizumab (Lucentis)

Aflibercept (Eylea)

Diabetic macular edema

Y

Y

X

X

Diabetic retinopathy in patients with diabetic macular edema

 

Y

X

X

Macular edema following retinal vein occlusion

 

Y

X

X

Myopic choroidal neovascularization

 

Y

X

 

Neovascular age-related macular degeneration

X

Y

X

X

Neovascular glaucoma

 

Y

 

 

Retinopathy of prematurity

 

Y

 

 

X = FDA-approved Indications (excluding cosmetic indications)
Y = Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use

Rationale

I. Pegaptanib (Macugen)

Neovascular (wet) Age-Related Macular Degeneration (AMD)
In 2004, the United States Food and Drug Administration (FDA) approved pegaptanib for the treatment of neovascular (wet) AMD. Two concurrent, prospective randomized, double blind controlled clinical trials were used as the basis of approval from the FDA (VEGF [vascular endothelial growth factor] Inhibition Study in Ocular Neovascularization [VISION] Clinical Trial Group, 2006a, VISION Clinical Trial Group, 2006b). The populations of these studies included all forms of wet AMD. While on average, both treated and control groups continued to experience vision loss, the rate of vision decline in the treated group was slower than that in the control group.

Since that time, research has continued to be reported on the use of pegaptanib for neovascular AMD. Friberg and colleagues (2010) reported on a prospective, phase IV, open-label, uncontrolled study for the use of pegaptanib as maintenance therapy for neovascular AMD after induction therapy. Pegaptanib was given every 6 weeks for 48 weeks with follow-up to week 54. A total of 568 participants were enrolled and 487 participants completed the 54-week study. Mean visual acuity improved during the induction from 49.6 letters to 65.5 letters and was 61.8 letters at week 54. Pegaptanib was well tolerated with a total of 468 participants reporting one or more adverse events, 350 participants experienced an ocular adverse event and 112 participants had one or more serious adverse events. The authors conclude that this maintenance therapy may be a viable option for those individuals who respond initially to induction therapy.

There is little published data about the long-term use of intravitreal pegaptanib. In a 2015 study by Inoue and colleagues, the authors reported on the results of a 3-year follow-up of pegaptanib given as maintenance treatment for neovascular AMD. Sixteen of 20 eyes were available for follow-up after 3 years. Best corrected visual acuity improved from 0.56 ± 0.31 before treatment to 0.24 ± 0.25 at baseline and was 0.25 ± 0.28 at 156 weeks. Central foveal thickness was also assessed and found to have decreased. No severe side effects were reported during follow-up. Studies with larger group sizes are necessary to continue to assess long-term use.

Diabetic Macular Edema (DME)
In 2011, Sultan and colleagues reported on a randomized, double-masked, 2-year trial of pegaptanib, as an off-label use, for DME. A total of 288 participants were enrolled to receive intravitreal pegaptanib (n=145) or sham injections (n=143). Sham injections weren't injections but rather a dynamic minimization procedure of an empty barrel of a needleless syringe designed to mimic the intravitreal injection. A total of 230 participants completed 54 weeks of treatment and 207 participants completed 2 years of treatment. During year 1, injections were administered every 6 weeks for a total of nine injections. Treatment effect was assessed 6 weeks after each injection. After 18 weeks, participants could receive laser photocoagulation (of which 84 participants did). Participants were still evaluated every 6 weeks during year 2 to determine if a medication injection was required. Forty-nine (49) participants in the pegaptanib group and 25 participants in the sham group reported a visual acuity improvement of greater than 10 letters at week 54. While this study does suggest the potential benefit of pegaptanib for DME, the study did not compare pegaptanib to other available VEGF inhibitors or support the conclusion that pegaptanib is as good as or better than the current standard of care for DME.

Other literature for Macugen for DME includes retrospective analyses (Querques, 2009a; Querques, 2009b) and small group sizes (Rinaldi, 2013). Insufficient data is available for the use in other ophthalmologic processes such as diabetic retinopathy (Dahr, 2007; Krzystolik, 2006; Gonzalez, 2009).

II. Bevacizumab (Avastin)

Neovascular (wet) AMD
Bevacizumab, which was initially approved by the FDA in 2004 for the treatment of metastatic colon cancer, is a monoclonal antibody that binds to VEGF. Intravitreal usage of bevacizumab is a non-FDA approved use which has been widely reported by practicing ophthalmologists to be beneficial in select individuals with neovascular AMD.

Arevalo and colleagues (2010) report the results of a 24-month study in which 180 subjects received at least one injection of intravitreal bevacizumab for subfoveal choroidal neovascularization (CNV) secondary to AMD. Individuals received best-corrected visual acuity testing, ophthalmoscopic exam, optical coherence tomography and fluorescein angiography at baseline and at 1, 3, 6, 12, and 24 months thereafter. Systemic adverse events included elevated blood pressure, cerebrovascular accidents, myocardial infarctions, iliac artery aneurysms, toe amputations and death. Ocular complaints included bacterial endophthalmitis, tractional retinal detachments, uveitis and rhegmatogenous retinal detachment and vitreous hemorrhage. At 24 months, all individuals showed stability or improvement in best-corrected visual acuity, optical coherence tomography and fluorescein angiography.

Tufail et al (2010) randomized 131 subjects to either intervention with intravitreal bevacizumab or standard treatment of photodynamic treatment with verteporfin, pegaptanib or sham control for AMD with 54-week follow-up. In the bevacizumab group, more letters were gained from baseline when compared to the standard treatment group.

Diabetic Retinopathy
In a 2015 study by Manabe and colleagues, the authors investigated the use of bevacizumab for proliferative diabetic retinopathy prior to surgery. A total of 66 eyes of 62 participants were randomized to etiher intravitreal bevacizumab (n=34 eyes) or sham control group (n=32). Following surgery (within 4 weeks), the frequency of reoperation was 20.6% (7/24 eyes) in the sham group and 3.1% (1/32 eyes) in the bevacizumab group; recurrent vitreous hemorrhage occurred in 23.5% (8/34 eyes) in the sham group and 3.1% (1/32 eyes) in the bevacizumab group. At 1 month following surgery, best-corrected visual acuity improved in both the bevacizumab and sham groups, however the visual improvement did not differ significantly between the two groups. While this study has limitations including a short observation period and multiple surgeons performing the surgery, injection of bevacizumab for proliferative diabetic retinopathy decreased the incidence of reoperation due to early postoperative vitreous hemorrhage.

In an updated Cochrane review (Smith, 2015) the authors reported on the use of bevacizumab prior to having vitrectomy for proliferative diabetic retinopathy to avoid postoperative vitrectomy cavity hemorrhage. After review of 12 randomized controlled trials with a total of 654 eyes, the authors concluded that the participants who received bevacizumab in addition to pars plana vitrectomy were less likely to have postoperative vitrectomy cavity hemorrhage when compared to pars plana vitrectomy alone. However, the effect of pre- or intraoperative bevacizumab on the incidence of late postoperative hemorrhage was uncertain. Several of the included studies were unclear when describing the randomization methods. Due to significant study heterogeneity, the authors were unable to give an estimate of the effect of bevacizumab on postoperative visual acuity.

DME and Retinal Vein Occlusion
Since ranibizumab is derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab, specialty consensus suggests that bevacizumab may be appropriate for the same disorders as ranibizumab including branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO) and DME. Intravitreal bevacizumab has also been suggested for CRVO (Costa, 2007; Mohamed, 2007; Moschos, 2008; Rosenfeld, 2005), BRVO (Ahmadi, 2009; Gunduz, 2008; Kreutzer, 2008; Rensch, 2009) and DME (Arevalo, 2007; Arevalo, 2009; Haritoglou, 2006).

Soheilian (2012) reported on the 24-month findings of a trial comparing bevacizumab monotherapy to bevacizumab with intravitreal triamcinolone acetonide versus photocoagulation as a treatment for DME. A total of 150 eyes were included in the study. The eyes were randomly assigned to 1 of 3 study arms: the bevacizuamb group, the bevacizumab/triamcinolone acetonide group, or the photocoagulation group. At the end of the 24-month study period, 39 eyes remained in the bevacizumab group, 36 eyes remained in the bevacizumab/ triamcinolone acetonide group, and 38 eyes remained in the photocoagulation group. Whenever indicated, retreatment was performed at 3-month intervals. The bevacizumab group had 39 eyes which required retreatment, 27 eyes in the bevacizumab/triamcinolone acetonide group required retreatment, and 31 eyes in the photocoagulation group required retreatment. The visual acuity improved the most in the bevacizumab group at month 6, but did not sustain up to 24 months and the difference between the groups was not significant at all visits. But the mean visual acuity was greater in the bevacizumab group compared to the other groups and in the bevacizumab/triamcinolone acetonide group compared to the photocoagulation group.

Neovascular Glaucoma
Neovascular glaucoma is a severe form of glaucoma caused by the growth of new blood vessels which obstruct aqueous humor outflow. This causes an increase in intraocular pressure (IOP). In a study by Costagliola (2008), 23 individuals were scheduled to receive intravitreal injections of bevacizumab at 4 week intervals. At the end of the scheduled protocol (three injections of intravitreal bevacizumab), IOP was reduced, and visual acuity, pain and edema were significantly improved.

CNV
There are rare causes of CNV (degenerative myopia [idiopathic], angioid streaks, trauma, choroiditis, retinal dystrophies, and ocular histoplasmosis) for which there are no approved therapies. There is an unmet medical need for treatment and the extremely low incidence of disease will make comparative treatment trials challenging. There is strong biologic plausibility from small case series that intravitreal bevacizumab may be of benefit (Chan, 2007b; 2008b). Specialty consensus opinion also suggests that the drug may be used for these rare disorders due to the lack of other available treatment. A retrospective case series by Cionni and colleagues (2012) reported on the long-term outcomes of intravitreal bevacizumab for the treatment of CNV due to presumed ocular histoplasmosis. A total of 117 eyes received intravitreal bevacizumab and 34 eyes received a combination of intravitreal bevacizumab and photodynamic therapy. The mean follow-up was 21.1 months. Visual acuity was measured at baseline, 12 months and 24 months. There was no significant difference in the number of eyes with a 3-line gain between the bevacizumab group and the bevacizumab and photodynamic therapy groups. The number of participants with a gain of 3 or more lines of vision was 39/104 eyes. At 1 year, 84/104 eyes showed maintained or improved visual acuity. At 2 years, 17/57 eyes continued to maintain a 3-line gain in visual acuity.

Radiation Retinopathy
Radiation retinopathy occurs following irradiation for tumors or inflammation of the choroid, retina, orbit, and paranasal sinuses. It is a rare and progressive disease resulting in loss of vision. It has been treated with laser photocoagulation. The anti-VEGF drugs have been studied to treat this condition. In a study by Finger and colleagues (2008a), 21 participants with radiation retinopathy received intravitreal bevacizumab every 6-12 weeks. In 18 of the participants, visual acuity was stable or improved. Three participants regained two or more lines of visual acuity. No adverse effects were reported. Although this is a small group size with a short-term follow-up, the condition is rare enough that no real case-control or randomized studies can be effectively carried out and no other effective therapy can be used.

A study by Finger (2016) reviewed the charts of 120 individuals who received intravitreal anti-VEGF therapy for radiation maculopathy. A total of 99 participants were available for analysis for measuring visual acuity and central foveal thickness. There was a mean treatment interval of 38 months with a mean observation period of 6.75 years. A total of 20 participants lost three or more lines of visual acuity (measured by Early Treatment Diabetic Retinopathy Study [ETDRS] Charts). Before beginning anti-VEGF treatment, 69 participants had visual acuity better than or equal to 20/40 and 99 participants had visual acuity better than or equal to 20/200. Following the last treatment, 65 participants had visual acuity better than or equal to 20/40 and 96 participants had acuity better than or equal to 20/200. Central foveal thickness was measured using optical coherence tomography. There were 63 participants with initial central foveal thickness values available. At the 3-month interval, 15/63 had thickness which was within 10 μm of baseline, 39 participants had improved thickness. There were no treatment-related retinal detachments or vitreous hemorrhages reported. The study limitations include increasing technology/techniques over the 10-year time span and the retrospective, uncontrolled study design.

Retinopathy of Prematurity
Retinopathy of prematurity is a leading cause of childhood blindness throughout the world. For neonates, it is believed that exposure to high levels of oxygen obliterate the vessels in the retina. Current treatment is peripheral retinal ablation with laser therapy which is destructive (that is, the laser destroys the majority of cells that produce VEGF in the retina), has complications and does not prevent all vision loss. Bevacizumab is an emerging treatment for retinopathy of prematurity. There have been several small case series studies which have shown improvement in retinopathy of prematurity after use of intravitreal bevacizumab (Ahmed, 2010; Erol, 2010; Wu, 2011). Mintz-Hittner and colleagues (2011) reported on a controlled (but not masked) study of 150 infants with retinopathy of prematurity who were randomized to receive either intravitreal bevacizumab or conventional laser therapy. The primary outcome was whether retinopathy of prematurity recurred in the eyes and required re-treatment using bevacizumab before 54 weeks postmenstrual age. In infants with zone I retinopathy of prematurity, 94% had no evidence of recurrence compared to 58% of the infants treated with conventional laser therapy. In addition, there were more structural complications (need for vitrectomy, detachment, macular dragging) in the infants treated with laser therapy. The authors concluded that:

Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina.

The limited number of infants studied makes it difficult to draw conclusions regarding the safety of this treatment. The authors noted that the "study was too small to address the question of whether intravitreal bevacizumab is safe" and that additional research is necessary. However, the primary alternative treatment is also not without risk. Laser photocoagulation requires intubating, sedating, and immobilizing the child and may permanently destroy the peripheral retina. The available scientific literature suggests that intravitreal bevacizumab for retinopathy of prematurity improves net health outcomes and is at least as beneficial as the established alternatives at this time. Martínez-Castellanos and colleagues (2013) reported on 18 eyes of 13 children with retinopathy of prematurity who received intravitreal bevacizumab. Follow-up was 5 years. During that time, all of the children showed initial regression of neovascularization and visual acuity was preserved. Although 1 child showed delay in growth and neurodevelopment, the others were all within the normal range. The results are suggestive that intravitreal bevacizumab for retinopathy of prematurity preserves ocular function and development.

Other Retinal Conditions
There are other rare eye disorders in which bevacizumab is being used. Coats' disease is a very rare disorder in which there is an abnormal development of blood vessels behind the retina. The retinal capillaries break open, leaking the serum portion of blood into the back of the eye. This causes the retina to swell and can cause retinal detachment. The most common treatments for Coats' disease are laser photocoagulation and cryotherapy. Wang and colleagues (2011) reported on 3 individuals with Coats' disease who received a treatment of bevacizumab combined with laser photocoagulation. Fundus photography and fluorescein angiography showed regression of the vascular dilatation and the aneurismal appearance of the telangiectasia areas. Optical coherence tomography showed a decrease of the macular edema and fluid. Visual improvement was noted. Ramasubramanian and colleagues (2012) reported a retrospective analysis of 8 individuals with Coats' disease who had received laser photocoagulation and/or cryotherapy and bevacizumab injections. After a mean follow-up of 8.5 months, retinopathy resolved in all 8 individuals, Coats'-related subretinal fluid resolved in all 8 individuals and retinal exudation resolved in 6 individuals. This was not without side effects. Four individuals developed vitreous fibrosis following the bevacizumab injections and 3 individuals then progressed on to traction retinal detachment. The authors concluded that "Caution is advised in the use of bevacizumab for patients with Coats' disease." A retrospective review by Ray and colleagues (2013) reported on the use of bevacizumab plus ablative therapy versus the use of ablative therapy alone. Ten children with Coats' disease received intravitreal bevacizumab and were compared to 10 children who received ablative therapy. In the bevacizumab group, the eyes required more treatments over a longer period of time compared to the ablative group, but all the children were successfully treated. In the ablative group, 2 of the children failed ablative therapy. The authors state that while bevacizumab may play a role in the treatment of Coats' disease, there is no decrease in the time it takes to reach full treatment.

III. Ranibizumab (Lucentis)

Neovascular (wet) AMD
On June 30, 2006, the FDA approved ranibizumab for the treatment of individuals with neovascular "wet" AMD. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) study was a 2-year, double-blind, sham-controlled study in which 716 randomly assigned individuals with AMD received either monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections for 24 months (Boyer, 2007; Rosenfeld, 2006). Results were reported at 12 months and 24 months. At 12 months, 94.5% of the 0.3 mg dose group and 94.6% of the 0.5 mg dose group lost fewer than 15 letters, as compared with 62.2% of individuals receiving sham injections. Visual acuity improved by 15 or more letters in 24.8% of the 0.3 mg dose group and 33.8% of the 0.5 mg dose group, as compared with 5.0% of the sham-injection group. Mean increases in visual acuity were 6.5 letters in the 0.3 mg group and 7.2 letters in the 0.5 mg group, as compared with a decrease of 10.4 letters in the sham-injection group. The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in 5 individuals (1.0%) and serious uveitis in 6 individuals (1.3%) given ranibizumab. A subgroup analysis compared efficacy outcomes across subgroups based on individuals' gender, age, baseline visual acuity score, baseline CNV lesion size, CNV lesion type, and duration of neovascular AMD (Boyer, 2007). Ranibizumab treatment was associated with an average increase from baseline visual acuity in all subgroups evaluated and was superior to sham treatment across all subgroups. Predictors of visual acuity outcomes were, in decreasing order of importance, baseline visual acuity score, CNV lesion size, and age.

The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) Study is a 2-year, multicenter, double-blind study, in which 423 individuals with AMD were randomly assigned to monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy (Brown, 2006). The primary end point was the proportion of individuals losing fewer than 15 letters from baseline visual acuity at 12 months. Of the 423 individuals enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (p<0.001 for each comparison). Follow-up is continued through 2 years of treatment (Brown, 2009). Of the 423 individuals who started the study, at least 77% in each group have completed the 2-year study. Consistent with the results measured at month 12, at month 24 the visual acuity benefit from ranibizumab therapy showed 89.9% to 90% had lost less than 15 letters from baseline versus 65.7% of individuals treated with verteporfin therapy.

In 2011, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group reported on a comparison between ranibizumab and bevacizumab for the treatment of neovascular AMD. Using a single-blind, noninferiority study, 1208 individuals were randomized to receive either intravitreal injections of ranibizumab or bevacizumab monthly or as needed. The primary outcome was the change in mean visual acuity at 1 year when compared to baseline. Visual acuity improved from baseline to 1 year when the drugs were given monthly and when the drugs were given as needed. The results were inconclusive when bevacizumab was given as needed when compared to bevacizumab given monthly. Results were also inconclusive when bevacizumab was given as needed when compared to ranibizumab given monthly.

The CATT Research Group (2012) has published their 2-year results for ranibizumab and bevacizumab for treatment of neovascular AMD. The year 2 of CATT was done to describe the longer-term effects of the original four treatment groups and to describe the impact of switching from monthly to as-needed treatment after a year of monthly treatment. Primary outcome measure was mean change in visual acuity. After 2 years, there were 1030 individuals still available for visual acuity score assessment. Most of the mean visual acuity changes occurred during year 1 with little change during year 2. At 2 years, the mean increase in letters of visual acuity was 8.8 in the group who received ranibizumab monthly, 7.8 in the group who received bevacizumab monthly, 6.7 in the group who received ranibizumab as-needed, and 5.0 in the group who received bevacizumab as-needed. For both ranibizumab and bevacizumab, the mean change in visual acuity at 2 years was similar in the as-needed group to the group which switched from monthly to as-needed treatment.

CNV
CNV is a complication of different diseases which affect the posterior segment of the eye. It has the potential to cause blindness. This loss of vision is usually caused by hemorrhage, leakage and fibrosis. Other than AMD, pathological myopia is the most common condition associated with CNV. In a 2014 randomized study by Wolf and colleagues, the authors reported on 277 participants with myopic CNV who received ranibizumab or photodynamic therapy. There were three treatment arms; group I included 106 participants who received ranibizumab once and then thereafter as needed based on visual acuity, group II included 116 participants who received ranibizumab once and then as needed based on disease activity criteria, group III included 55 participants who received photodynamic therapy once and disease activity treated with ranibizumab or photodynamic therapy only at investigators' discretion from month 3. From baseline to month 12, the mean best-corrected visual acuity was +13.8 in group I, +14.4 in group II, and +9.3 ETDRS letters in group III. A total of 63.8%-65.7% of participants showed resolution of myopic CNV leakage at month 12.

DME and Diabetic Retinopathy
In August 2012, the FDA approved ranibizumab for DME. Current treatment for DME includes laser photocoagulation, intravitreal triamcinolone acetonide and pars plana vitrectomy. Triamcinolone acetonide and pars plana vitrectomy have limited efficacy and significant side effects. A 2012 article by Nguyen and colleagues reports on the safety and efficacy of intravitreal ranibizumab in individuals with DME. The article discussed two parallel, phase III, double-masked, sham-injection-controlled, randomized design studies. The primary outcome was the proportion of individuals who gained greater than or equal to 15 letters of visual acuity from baseline at 24 months. In the Ranibizumab Injection in Subjects with clinically significant macular edema with center involvement Secondary to diabetes mellitus (RISE) portion of the study, 377 participants were randomized to one of three arms; 127 to sham injections, 125 to 0.3 mg injection of ranibizumab, and 125 to 0.5 mg injection of ranibizumab. The second study was Ranibizumab Injection in subjects with clinically significant macular edema with center involvement secondary to Diabetes mellitus (RIDE) and consisted of 382 participants who were randomized to sham injection (n=130), 0.3 mg ranibizumab injection (n=125) and 0.5 mg ranibizumab injection (n=127). For the RISE portion, at 24 months, 44.8% of participants who received 0.3 mg injection of ranibizumab and 39.2% of participants who received 0.5 mg injection of ranibizumab gained greater than or equal to 15 letters compared to 18.1% of individuals who received sham injections. In the RIDE portion, corresponding proportions were 33.6%, 45.7% and 12.3%, respectively. Vision changes were observed as early as 7 days after the first injection of ranibizumab. All of the 759 participants from both trials had diabetic retinopathy with DME.

In a phase IIIb prospective study by Pearce and colleagues (2015), the authors evaluated the use of ranibizumab in 109 participants with DME. In this study, the participants received an initial three monthly injections of ranibizumab and then had subsequent bi-monthly follow-up from months 6-18 based on the results of best-corrected visual acuity and optical coherence tomography. A total of 100 participants completed the 12-month portion of the study and 99 participants completed 18 months. At baseline, the best-corrected visual acuity was 62.9 letters. The mean change in best-corrected visual acuity from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3). The mean change in best-corrected visual acuity at 12 months following bi-monthly treatment of ranibizumab was +4.8 letters (95% CI, 2.9-6.7; p<0.001). At 18 months, best-corrected visual acuitywas +6.5 letters (95% CI, 4.2-8.8). At month 12, 24.8% of participants gained ≥ 10 letters and 13.8% of participants gained ≥ 15 letters. At month 18, 34.9% gained ≥ 10 letters and 19.3% gained ≥ 15 letters.

In February 2015, the FDA expanded their indications for ranibizumab to include diabetic retinopathy in individuals with DME. According to the FDA labeling, the safety and efficacy of the expanded indication was supported by the RISE and RIDE trials.

Diabetic Retinopathy and Radiation Retinopathy
As noted above, ranibizumab is derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab which suggests that bevacizumab may be appropriate for the same disorders as ranibizumab. The studies by Finger, 2008 and Finger, 2016 are summarized above. The Manabe, 2015 study is summarized above.

In a study published by the Writing Committee for the Diabetic Retinopathy Clinical Research Network in 2015, the authors reported on a randomized trial comparing ranibizumab to panretinal photocoagulation in 305 participants with proliferative diabetic retinopathy. A total of 203 eyes received panretinal photocoagulation and 191 eyes received intravitreal ranibizumab. Panretinal photocoagulation was completed in one to three visits. Participants received ranibizumab at baseline and every 4 weeks through 12 weeks. After 12 weeks re-treatment was determined based on investigator assessment of neovascularization. Of the participants in the panretinal photocoagulation group, there were 72 eyes that received ranibizumab at baseline and an additional 36 eyes that received ranibizumab during the subsequent 2 years. At the 2-year follow-up, the mean visual acuity letter score improvement in the ranibizumab group was +2.8 and +0.2 in the panretinal photocoagulation group. There were no significant differences in adverse events reported between the two groups.

Retinal Vein Occlusion
The use of ranibizumab has been suggested for the treatment of retinal vein occlusion and in June 2010, the FDA approved ranibizumab for macular edema following retinal vein occlusion. The Diabetic Retinopathy Clinical Research Network (Elman, 2010) reports on 1-year and 2-year data for ranibizumab for DME. In this phase III study, a total of 854 study eyes were randomized to one of four treatment arms: sham injection plus prompt laser, ranibizumab plus prompt laser, ranibizumab plus deferred laser, or triamcinolone plus prompt laser. Approximately half of the eyes treated with ranibizumab had a greater than 10-letter gain from baseline and approximately 30% gained greater than 15 letters (equivalent to three lines on the eye chart). For the eyes treated with ranibizumab plus laser, the results were similar whether the laser was prompt or delayed. Additional studies are reporting outcomes data on the use of ranibizumab for DME (Nguyen, 2010).

In 2010, Massin et al, reports the Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study). Individuals (n=151) with DME were randomized to receive intravitreal ranibizumab or sham. At 12 months, the ranibizumab group had an improvement of 7.8 letters compared with -0.1 letters in the sham group. Best-corrected visual acuity in the ranibizumab group improved by 10.3 letters from baseline compared to a decline of 1.4 letters from baseline in the sham group. While this study suggests ranibizumab is effective in improving best-corrected visual acuity for those with DME, further clinical trials are necessary to confirm long-term safety and efficacy.

Campochiaro and colleagues (2010) reported on the 6-month results of a phase III study assessing the safety and efficacy of intraocular injections of ranibizumab for those with BRVO. A total of 397 individuals were randomized to receive either intraocular injection of ranibizumab or sham injections. There was a mean improvement of 7.5 letters 1 week after the first treatment with the ranibizumab injections. After 6 months of treatment with ranibizumab there was a mean improvement of between 3 and 4 lines of vision compared to 1.5 lines in the sham group. At 6-month follow-up there was a 65% improvement for those treated with ranibizumab versus 42% for those in the sham group.

IV. Aflibercept (Eylea)

Neovascular (wet) AMD
On November 18, 2011 the FDA approved aflibercept for the treatment of individuals with neovascular "wet" AMD. Heier and colleagues (2012) reported on two phase-III studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) in which participants were treated and evaluated for efficacy of aflibercept versus ranibizumab. A total of 2419 participants were enrolled in the two studies and were randomly assigned to one of four treatment arms with three of the treatment arms receiving varying doses of aflibercept and one treatment arm receiving ranibizumab. The primary endpoint was visual acuity at 1 year (losing less than 15 letters of visual acuity at week 52 compared to baseline). Intravitreal aflibercept was dosed monthly or every 2 months after three initial monthly doses showed similar efficacy and safety outcomes as the monthly doses of ranibizumab. The groups who received intravitreal aflibercept had best corrected visual acuity within 0.5 letters of the ranibizumab group. Side effects were similar among the treatment groups.

Macular Edema and CRVO
The FDA approved aflibercept for the treatment of macular edema following CRVO in September 2012. The approval was based on two randomized, multi-center, double-masked, sham-controlled studies in individuals with macular edema following CRVO. The published study, Boyer and colleagues (2012), reported on the 6-month results of the phase III Vascular Endothelial Growth Factor [VEGF] Trap-Eye: Investigation of Efficacy and Safety in Central Retinal Vein Occlusion [CRVO] (COPERNICUS). This study enrolled 189 eyes with macular edema secondary to CRVO. The primary endpoint was the number of eyes with a gain of 15 letters or more in best corrected visual acuity from baseline to week 24. Participants were randomly assigned in a 3:2 ratio to receive either receive aflibercept (n=115 eyes) or sham injections (n=74 eyes) every 4 weeks for 24 weeks. Assessments were performed on day 1, at week 4, and every 4 weeks thereafter to week 24. Assessments included a full ocular exam, visual acuity testing, slit-lamp biomicroscopy, indirect ophthalmoscopy, intraocular pressure measurement and optical coherence tomography. Examiners were masked to treatment assignment. The National Eye Institute 25-item Visual Function Questionnaire was administered at baseline and at week 24. At the 24-week assessment, 110 participants in the aflibercept group remained and 60 participants in the sham group remained. The aflibercept group had a mean gain of 17.3 ± 12.8 letters at 24 weeks compared with a mean loss of 4.0 ± 18.0 letters in the sham group. At week 24, the aflibercept group showed an improvement of 7.2 points in the National Eye Institute 25-item Visual Function Questionnaire total score compared to an improvement of 0.8 points in the sham group. Visual acuity maintained throughout the course of the 24-week study.

DME and Diabetic Retinopathy
In July 2014, the FDA approved aflibercept for the treatment of diabetic macular edema. In a 2014 article by Korobelnik and colleagues, the authors reported the outcome results of two parallel, phase III DME studies (the VISTA and VIVID). A head-to-head comparison was made between intravitreal aflibercept and macular laser photocoagulation for individuals with diabetic macular edema. Using the results of the two similarly designed, double-masked, randomized, phase III trials, a total of 872 eyes were included. Participants who received aflibercept received injections every 4 weeks or every 8 weeks after 5 monthly doses. The primary endpoint was the change from baseline in best-corrected visual acuity in ETDRS letters at week 52. For those who received the intravitreal aflibercept, the mean best-corrected visual acuity gains from baseline to week 52 were 12.5 (in the every 4 week group) and 10.7 (in the every 8 week group) compared to 0.2 letters in the laser group in one trial and 10.5 and 10.7 versus 1.2 letters in the other trial. Secondary endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (p<0.0001) in one trial, and 32.4% and 33.3% versus 9.1% (p<0.0001) in the second trial. Mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (p<0.0001) in one trial, and 195.0 and 192.4 versus 66.2 μm (p<0.0001) in the second trial. At week 52, those in the group who received intravitreal aflibercept showed superiority in functional and anatomic endpoints when compared to the laser group. All of the participants from both trials had diabetic retinopathy with DME at baseline.

In 2015, Brown and colleagues reported on the 100-week results from the VISTA and VIVID trials. The participants received aflibercept every 4 weeks, every 8 weeks, or laser treatment. The best-corrected visual acuity at 100 weeks in the every 4 week group of aflibercept was 11.5 letters, 11.1 letters in the every 8 week group, and 0.9 letters in the laser group in the VIVID study. In the VISTA study, the every 4 week group gained 11.4 letters, 9.4 letters in the every 8 week group, and 0.7 letters in the laser group. In the VISTA study, a total of 3.2% of participants lost ≥ 15 letters in the every 4 week group, 0.7% of participants lost ≥ 15 letters in the every 8 week group and 9.7% of participants lost ≥ 15 letters in the laser group.In the VIVID study, 2.2% of participants lost ≥ 15 of letters in the every 4 week group, 1.5% of participants lost ≥ 15 letters in the every 8 week group and 12.9% of participants lost ≥ 15 letters in the laser group.

In March 2015, the FDA expanded the indication for aflibercept to include diabetic retinopathy with DME based on the VIVID and VISTA studies.

In a 2015 study by the Diabetic Retinopathy Clinical Research Network, the authors reported on the 1-year outcome of safety and efficacy of a head-to-head comparison of aflibercept, bevacizumab and ranibizumab in the treatment of DME. Individuals were randomized to receive either aflibercept (n=224), bevacizumab (n=218) or ranibizumab (n=218). During the first year, visits occurred every 4 weeks. Each visit involved best-corrected visual acuity (as measured by ETDRS) and optical coherence tomography to measure central subfield thickness. In the aflibercept group, the mean improvement in the visual acuity letter score was 13.3 and the central subfield thickness decreased by 169 ± 138 μm. In the bevacizumab group the mean improvement in visual acuity letter score was 9.7 with a central subfield thickness decrease of 101 ± 121 μm. In the ranibizumab group the mean improvement in visual acuity letter score was 11.2 with a decreased central subfield thickness of 147 ± 134 μm. Although the participants who received aflibercept showed a greater improvement in visual acuity, the difference was driven by the eyes with the worse visual acuity at baseline. For the participants with an initial visual-acuity letter score of 78 to 69, 20 participants had a mean improvement of 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab. For the participants with an initial letter score less than 69, the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab. Adverse events included 2 participants who received aflibercept and ranibizumab with injection-related infectious endophthalmitis (both nonstudy eyes). While the injections improved vision, there were no differences among the groups if the initial visual acuity loss was mild; aflibercept was more effective at improving vision if the initial visual acuity levels were worse.

Diabetic Retinopathy and Radiation Retinopathy
As noted above, the anti-VEGF agents are derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab which suggests that aflibercept may be appropriate for the same disorders as other anti-VEGF agents. The studies by Finger, 2008; Finger, 2016; and Manabe, 2015 are summarized above.

Background/Overview

AMD is an eye disease characterized by progressive degeneration of the macula, the central part of the retina at the back of the eye. When this is caused by the development of abnormal blood vessels develop behind the retina, the condition is commonly referred to as "wet" or neovascular AMD. These new blood vessels tend to be fragile and leak blood and fluid. The blood and fluid raise the macula from its normal position at the back of the eye. With wet AMD, loss of central vision can occur quickly. AMD is the leading cause of severe vision loss in people over 55 years of age in the developed world. The neovascular "wet" form of this disease represents 10% of the overall disease prevalence but is responsible for roughly 90% of the vision loss due to AMD. It is more common in Caucasians and its incidence increases with age as it is estimated that 10 to 15% of individuals older than 80 years have some form of AMD.

VEGF, a cytokine, appears to have a key role in the angiogenesis and vascular permeability associated with wet AMD. Overexpression of VEGF is also thought to contribute to diabetic retinopathy, and other retinal disorders associated with neovascularization. Research focused on development of compounds designed to bind to and inhibit VEGF can be an effective treatment for AMD.

Retinal vein occlusion occurs when there is a blockage of the blood supply from the retina. Depending on where the blockage occurs, the condition can be characterized as CRVO or BRVO. This condition most often affects older individuals and can be caused by a blood clot, diabetes, glaucoma, atherosclerosis or hypertension. Symptoms include sudden blurred vision or loss of vision. Retinal vein occlusion is the second most common type of retinal vascular disease and is estimated to involve 180,000 eyes per year.

The macula is the part of the eye where sharp, straight-ahead vision occurs. Fluid can leak into the center of the macula, causing the macula to swell, resulting in blurred vision. Common in diabetics, this is known as DME.

Infants born before 31 weeks gestation are at risk for retinopathy of prematurity, the development of abnormal retinal fibrovascular tissue and blindness. With appropriate screening and treatment, the incidence of blindness in infants due to retinopathy of prematurity is relatively low (approximately 1 case in 820 infants).

Intraocular injections pose a risk for infection, retinal detachment and traumatic lens injury. These injections require the treating physician to adhere to appropriate aseptic technique, educate individuals regarding worrisome symptoms and monitor individuals after each injection as increases in intraocular pressure have been seen.

I. Pegaptanib (Macugen)

Pegaptanib, a selective VEGF antagonist, is an oligonucleotide, twenty-nucleotides in length, to which two polyethylene glycol (PEG) units are attached. This oligonucleotide (aptamer) has a complex 3-dimensional structure that binds to upregulated VEGF, preventing it from binding to its receptors. It is administered by a series of intravitreous injections (into the interior space of the eye). The proposed benefit of pegaptanib is slowed progression of wet AMD. Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post-marketing. Medical history for hypersensitivity reaction should be evaluated prior to the procedure.

II. Bevacizumab (Avastin)   

Bevacizumab works by binding to VEGF and inhibiting the interaction of VEGF to Flt1 and kinase insert domain receptors (KDR) on the surface of endothelial cells. As a result of the binding process, the increase of endothelial cells and formation of new blood vessels is prevented.

III. Ranibizumab (Lucentis)

Derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab, ranibizumab is an anti-VEGF antibody fragment that competitively binds VEGF and inhibits its activity. Ranibizumab was specifically developed for intraocular use. As a smaller molecule, ranibizumab may have better penetration through all the layers of the retina. Ranibizumab is administered by intravitreal injection.

IV. Aflibercept (Eylea)

Aflibercept binds to the angiogenic VEGF, VEGF-A, and placental growth factor (PIGF), to inhibit their binding to receptor tyrosine kinases and activation of VEGF-A.  Aflibercept is administered by intravitreal injections.

Definitions

Age-related macular degeneration (AMD): A slowly progressive, painless disease affecting the macula that blurs the sharp, central vision needed for "straight-ahead" activities such as reading, sewing, and driving.

Branch retinal vein occlusion: An occlusion near the retina in a branch retinal vein.

Central retinal vein occlusion: An occlusion of the central retinal vein where it enters the eye.

Choroid: Sponge like membrane in the eye located between the sclera and the retina.

Diabetic macular edema: The leakage of fluid from retinal blood vessels which in turn causes the macula to swell.

Diabetic retinopathy: The progressive damage to the blood vessels in the back of the eye.

Neovascular (wet) AMD: A subset of AMD representing approximately 10% of all cases but accounting for 90% of the severe vision loss. AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid which thickens the macula and damages the photoreceptors. Damage to the macula can occur rapidly, resulting in sudden loss of central vision. Wet AMD is considered to be advanced AMD and more severe than the dry form.

Neovascular glaucoma: A severe form of glaucoma with devastating visual outcome caused by the growth of new blood vessels which obstruct aqueous humor outflow.

Neovascularization: The formation of abnormal new blood vessels.

Pseudoxanthoma elasticum: An inherited disorder of the connective tissue in the skin, eyes, gastrointestinal and cardiovascular system.

Retinal vein occlusion: A blockage in the blood supply from the retina.

Retinopathy: Damage to the retina.

Vascular endothelial growth factor: A chemical signal produced by the body's cells that stimulates growth of new blood vessels.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

I. Intravitreal injections of pegaptanib [Macugen] 

When services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as intravitreal injection of pegaptanib, in conjunction with the HCPCS code listed below]
   
HCPCS  
J2503 Injection, pegaptanib sodium, 0.3 mg [Macugen]
   
ICD-10 Diagnosis  
H35.3210-H35.3293 Exudative age-related macular degeneration

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of pegaptanib for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

II. Intravitreal injections of bevacizumab [Avastin] 

When services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as intravitreal injection of bevacizumab, in conjunction with the HCPCS code(s) listed below]
   
HCPCS  
C9257 Injection, bevacizumab, 0.25 mg [Avastin]
J3590 Unclassified biologics [when specified as Avastin intravitreal or biosimilar bevacizumab-awwb (Mvasi) intravitreal)]
J9035 Injection, bevacizumab, 10 mg [when specified as Avastin intravitreal]
   
ICD-10 Diagnosis  
B39.0-B39.9 Histoplasmosis
E08.311-E08.3519 Diabetes mellitus due to underlying condition with diabetic retinopathy with macular edema [includes only codes E08.311 and ranges E08.3211-E08.3219, E08.3311-E08.3319, E08.3411-E08.3419, E08.3511-E08.3519]
E08.3521-E08.3599 Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy [without macular edema]
E09.311-E09.3519 Drug or chemical induced diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E09.311 and ranges E09.3211-E09.3219, E09.3311-E09.3319, E09.3411-E09.3419, E09.3511-E09.3519]
E09.3521-E09.3599 Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E10.311-E10.3519 Type 1 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E10.311 and ranges E10.3211-E10.3219, E10.3311-E10.3319, E10.3411-E10.3419, E10.3511-E10.3519]
E10.3521-E10.3599 Type 1 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E11.311-E11.3519 Type 2 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E11.311 and ranges E11.3211-E11.3219, E11.3311-E11.3319, E11.3411-E11.3419, E11.3511-E11.3519]
E11.3521-E11.3599 Type 2 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E13.311-E13.3519 Other specified diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E13.311 and ranges E13.3211-E13.3219, E13.3311-E13.3319, E13.3411-E13.3419, E13.3511-E13.3519]
E13.3521-E13.3599 Other specified diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
H21.1X1-H21.1X9 Other vascular disorders of iris and ciliary body (neovascularization)
H30.001-H30.049 Focal chorioretinal inflammation
H30.101-H30.149 Disseminated chorioretinal inflammation
H30.891-H30.899 Other chorioretinal inflammations
H30.90-H30.93 Unspecified chorioretinal inflammation
H32 Chorioretinal disorders in diseases classified elsewhere
H34.8110 Central retinal vein occlusion, right eye, with macular edema
H34.8120 Central retinal vein occlusion, left eye, with macular edema
H34.8130 Central retinal vein occlusion, bilateral, with macular edema
H34.8190 Central retinal vein occlusion, unspecified eye, with macular edema
H34.8310 Tributary (branch) retinal vein occlusion, right eye, with macular edema
H34.8320 Tributary (branch) retinal vein occlusion, left eye, with macular edema
H34.8330 Tributary (branch) retinal vein occlusion, bilateral, with macular edema
H34.8390 Tributary (branch) retinal vein occlusion, unspecified eye, with macular edema
H35.00-H35.09 Background retinopathy and retinal vascular changes
H35.101-H35.179 Retinopathy of prematurity
H35.3210-H35.3293 Exudative age-related macular degeneration
H35.33 Angioid streaks of macula
H35.50-H35.54 Hereditary retinal dystrophy
H35.9 Unspecified retinal disorder [specified as radiation retinopathy]
H40.50X0-H40.53X4 Glaucoma secondary to other eye disorders [neovascular glaucoma]
H40.89 Other specified glaucoma [neovascular glaucoma]
H44.20-H44.23 Degenerative myopia
H44.2A1-H44.2A9 Degenerative myopia with choroidal neovascularization
Q82.8 Other specified congenital malformations of skin [pseudoxanthoma elasticum]
T66.XXXA-T66.XXXS Radiation sickness, unspecified [specified as radiation retinopathy]

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for the following diagnosis codes

ICD-10 Diagnosis  
E08.319 Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E09.319 Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E10.319 Type 1 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E11.319 Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if proliferative diabetic retinopathy]
E13.319 Other specified diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of bevacizumab for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

III. Intravitreal injections of ranibizumab [Lucentis] 

When services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as intravitreal injection of ranibizumab, in conjunction with the HCPCS code listed below]
   
HCPCS  
J2778 Injection, ranibizumab; 0.1 mg [Lucentis]
   
ICD-10 Diagnosis  
E08.311-E08.3519 Diabetes mellitus due to underlying condition with diabetic retinopathy with macular edema [includes only codes E08.311 and ranges E08.3211-E08.3219, E08.3311-E08.3319, E08.3411-E08.3419, E08.3511-E08.3519]
E08.3521-E08.3599 Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy [without macular edema]
E09.311-E09.3519 Drug or chemical induced diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E09.311 and ranges E09.3211-E09.3219, E09.3311-E09.3319, E09.3411-E09.3419, E09.3511-E09.3519]
E09.3521-E09.3599 Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E10.311-E10.3519 Type 1 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E10.311 and ranges E10.3211-E10.3219, E10.3311-E10.3319, E10.3411-E10.3419, E10.3511-E10.3519]
E10.3521-E10.3599 Type 1 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E11.311-E11.3519 Type 2 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E11.311 and ranges E11.3211-E11.3219, E11.3311-E11.3319, E11.3411-E11.3419, E11.3511-E11.3519]
E11.3521-E11.3599 Type 2 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E13.311-E13.3519 Other specified diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E13.311 and ranges E13.3211-E13.3219, E13.3311-E13.3319, E13.3411-E13.3419, E13.3511-E13.3519]
E13.3521-E13.3599 Other specified diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
H21.1X1-H21.1X9 Other vascular disorders of iris and ciliary body (neovascularization)
H34.8110 Central retinal vein occlusion, right eye, with macular edema
H34.8120 Central retinal vein occlusion, left eye, with macular edema
H34.8130 Central retinal vein occlusion, bilateral, with macular edema
H34.8190 Central retinal vein occlusion, unspecified eye, with macular edema
H34.8310 Tributary (branch) retinal vein occlusion, right eye, with macular edema
H34.8320 Tributary (branch) retinal vein occlusion, left eye, with macular edema
H34.8330 Tributary (branch) retinal vein occlusion, bilateral, with macular edema
H34.8390 Tributary (branch) retinal vein occlusion, unspecified eye, with macular edema
H35.3210-H35.3293 Exudative age-related macular degeneration
H35.9 Unspecified retinal disorder [specified as radiation retinopathy]
H44.20-H44.23 Degenerative myopia
H44.2A1-H44.2A9 Degenerative myopia with choroidal neovascularization
T66.XXXA-T66.XXXS Radiation sickness, unspecified [specified as radiation retinopathy]

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for the following diagnosis codes

ICD-10 Diagnosis  
E08.319 Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E09.319 Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E10.319 Type 1 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E11.319 Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if proliferative diabetic retinopathy]
E13.319 Other specified diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of ranibizumab for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

IV. Intravitreal injection of aflibercept [Eylea]  

When Services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as intravitreal injection of aflibercept]
   
HCPCS  
J0178 Injection, aflibercept, 1 mg [Eylea]
   
ICD-10 Diagnosis  
E08.311-E08.3519 Diabetes mellitus due to underlying condition with diabetic retinopathy with macular edema [includes only codes E08.311 and ranges E08.3211-E08.3219, E08.3311-E08.3319, E08.3411-E08.3419, E08.3511-E08.3519]
E08.3521-E08.3599 Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy [without macular edema]
E09.311-E09.3519 Drug or chemical induced diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E09.311 and ranges E09.3211-E09.3219, E09.3311-E09.3319, E09.3411-E09.3419, E09.3511-E09.3519]
E09.3521-E09.3599 Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E10.311-E10.3519 Type 1 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E10.311 and ranges E10.3211-E10.3219, E10.3311-E10.3319, E10.3411-E10.3419, E10.3511-E10.3519]
E10.3521-E10.3599 Type 1 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E11.311-E11.3519 Type 2 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E11.311 and ranges E11.3211-E11.3219, E11.3311-E11.3319, E11.3411-E11.3419, E11.3511-E11.3519]
E11.3521-E11.3599 Type 2 diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
E13.311-E13.3519 Other specified diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E13.311 and ranges E13.3211-E13.3219, E13.3311-E13.3319, E13.3411-E13.3419, E13.3511-E13.3519]
E13.3521-E13.3599 Other specified diabetes mellitus with proliferative diabetic retinopathy [without macular edema]
H34.8110 Central retinal vein occlusion, right eye, with macular edema
H34.8120 Central retinal vein occlusion, left eye, with macular edema
H34.8130 Central retinal vein occlusion, bilateral, with macular edema
H34.8190 Central retinal vein occlusion, unspecified eye, with macular edema
H34.8310 Tributary (branch) retinal vein occlusion, right eye, with macular edema
H34.8320 Tributary (branch) retinal vein occlusion, left eye, with macular edema
H34.8330 Tributary (branch) retinal vein occlusion, bilateral, with macular edema
H34.8390 Tributary (branch) retinal vein occlusion, unspecified eye, with macular edema
H35.3210-H35.3293 Exudative age-related macular degeneration
H35.9 Unspecified retinal disorder [specified as radiation retinopathy]
T66.XXXA-T66.XXXS Radiation sickness, unspecified [specified as radiation retinopathy]

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for the following diagnosis codes

ICD-10 Diagnosis  
E08.319 Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E09.319 Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E10.319 Type 1 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]
E11.319 Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema [if proliferative diabetic retinopathy]
E13.319 Other specified diabetes mellitus with unspecified diabetic retinopathy without macular edema [if described as proliferative diabetic retinopathy]

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of aflibercept for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Adamis AP, Altaweel M, Bressler NM, et al. Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. 2006; 113(1):23-28.
  2. Adán A, Navarro M, Casaroli-Marano RP, et al. Intravitreal bevacizumab as initial treatment for choroidal neovascularization associated with presumed ocular histoplasmosis syndrome. Graefes Arch Clin Exp Ophthalmol. 2007; 245(12):1873-1875.
  3. Ahmadi AA, Chuo JY, Banashkevich A, et al. The effects of intravitreal bevacizumab on patients with macular edema secondary to branch retinal vein occlusion. Can J Ophthalmol. 2009; 44(2):154-159.
  4. Ahmed AE, Channa R, Durrani J, et al. Early experience with intravitreal bevacizumab combined with laser treatment for retinopathy of prematurity. Middle East Afr J Ophthalmol. 2010; 17(3):264-267.
  5. Antoszyk AN, Tuomi L, Chung CY, Singh A. FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol. 2008; 145(5):862-874.
  6. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology. 2007; 114(4):743-750.
  7. Arevalo JF, Sánchez JG, Wu L, et al. Intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration at twenty-four months: the Pan-American Collaborative Retina Study. Ophthalmology. 2010; 117(10):1974-1981.
  8. Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology. 2009; 116(8):1488-1497.
  9. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006b; 113(3):363-372.
  10. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol. 2006; 142(1):1-9.
  11. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol. 2008; 145(2):249-256.
  12. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012; 119(5):1024-1032.
  13. Boyer DS, Antoszyk AN, Awh CC, et al. MARINA Study Group. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007; 114(2):246-252.
  14. Brown DM, Kaiser PK, Michels M, et al. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1432-1444.
  15. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009; 116(1):57-65.
  16. 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. 2015; 122(10):2044-2052.
  17. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010; 117(6):1102-1112.
  18. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364(20):1897-1908.
  19. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012; 119(7):1388-1398.
  20. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, secondary to punctate inner choroidopathy, or of idiopathic origin. Am J Ophthalmol. 2007a; 143(6):977-983.
  21. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (Avastin) for myopic choroidal neovascularization: six-month results of a prospective pilot study. Ophthalmology. 2007b; 114(12):2190-2196.
  22. Chang LK, Spaide RF, Brue C, et al. Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration. Arch Ophthalmol. 2008; 126(7):941-945.
  23. Cionni DA, Lewis SA, Petersen MR, et al. Analysis of outcomes for intravitreal bevacizumab in the treatment of choroidal neovascularization secondary to ocular histoplasmosis. Ophthalmology. 2012; 119(2):327-332.
  24. Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab (avastin) for central and hemicentral retinal vein occlusions: IBeVO study. Retina. 2007; 27(2):141-149.
  25. Costagliola C, Cipollone U, Rinaldi M, et al. Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 cases throughout 12-month follow-up. Br J Clin Pharmacol. 2008; 66(5):667-673.
  26. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007; 27(2):150-158.
  27. Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009; 18(10):1573-1580.
  28. Erol N, Gürsoy H, Sahin A, Basmak H. Intravitreal bevacizumab following laser therapy for severe retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2010; 47:e1-4.
  29. Ferenchak K, Duval R, Cohen JA, MacCumber MW. Intravitreal bevacizumab for postoperative recurrent vitreous hemorrhage after vitrectomy for proliferative diabetic retinopathy. Retina. 2014; 34(6):1177-1181.
  30. Finger PT, Mukkamala SK. Intravitreal anti-VEGF bevacizumab (Avastin) for external beam related radiation retinopathy. Eur J Ophthalmol. 2011; 21(4)446-451.
  31. Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin). Int J Radiat Oncol Biol Phys. 2008a; 70(4):974-977.
  32. Finger RP, Charbel Issa P, Ladewig M, et al. Intravitreal bevacizumab for choroidal neovascularisation associated with pseudoxanthoma elasticum. Br J Ophthalmol. 2008b; 92(4):483-487.
  33. Finger PT, Chin KJ, Semenova EA. Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study. Eur J Ophthalmol. 2016; 26(1):60-66.
  34. Friberg TR, Tolentino M; LEVEL Study Group, et al. Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study. Br J Ophthalmol. 2010; 94(12):1611-1617.
  35. Göncü T1, Özdek S, Ünlü M. The role of intraoperative bevacizumab for prevention of postoperative vitreous hemorrhage in diabetic vitreous hemorrhage. Eur J Ophthalmol. 2014; 24(1):88-93.
  36. González VH, Giuliari GP, Banda RM, Guel DA. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol. 2009; 93(11):1474-1478.
  37. Gündüz K, Bakri SJ. Intravitreal bevacizumab for macular oedema secondary to branch retinal vein occlusion. Eye. 2008; 22(9):1168-1171.
  38. Han XX, Guo CM, Li Y, Hui YN. Effects of bevacizumab on the neovascular membrane of proliferative diabetic retinopathy: reduction of endothelial cells and expressions of VEGF and HIF-1α. Mol Vis. 2012; 18:1-9.
  39. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006; 26(9):999-1005.
  40. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006; 113(4):633-642.
  41. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012; 119(12):2537-2548.
  42. Inoue M, Kadonosono K, Arakawa A, et al. Long-term outcome of intravitreal pegaptanib sodium as maintenance therapy in Japanese patients with neovascular age-related macular degeneration. Jpn J Ophthalmol. 2015; 59(3):173-178.
  43. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal Aflibercept for Diabetic Macular Edema. Ophthalmology. 2014; 121(11):2247-2254.
  44. Kreutzer TC, Alge CS, Wolf AH, et al. Intravitreal bevacizumab for the treatment of macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol. 2008; 92(3):351-355.
  45. Kriechbaum K, Michels S, Prager F, et al. Intravitreal Avastin for macular oedema secondary to retinal vein occlusion: a prospective study. Br J Ophthalmol. 2008; 92(4):518-522.
  46. Krzystolik MG, Filippopoulos T, Ducharme JF, Loewenstein JI. Pegaptanib as an adjunctive treatment for complicated neovascular diabetic retinopathy. Arch Ophthalmol. 2006; 124(6):920-921.
  47. Manabe A, Shimada H, Hattori T, et al. Randomized controlled study of intravitreal bevacizumab 0.16 mg injected one day before surgery for proliferative diabetic retinopathy. Retina. 2015; 35(9):1800-1807.
  48. Martínez-Castellanos MA, Schwartz S, Hernández-Rojas ML, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina. 2013; 33(2):329-338.
  49. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010; 33(11):2399-2405.
  50. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011; 364(7):603-615.
  51. Mirshahi A, Roohipoor R, Lashay A, et al. Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol. 2008; 18(2):263-269.
  52. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007; 114(3):507-519, 524.
  53. Moschos MM, Moschos M. Intraocular bevacizumab for macular edema due to CRVO. A multifocal-ERG and OCT study. Doc Ophthalmol. 2008; 116(2):147-152.
  54. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012; 119(4):789-801.
  55. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study. Ophthalmology. 2010; 117(11):2146-2151.
  56. Pearce I, Banerjee S, Burton BJ, et al. Ranibizumab 0.5 mg for diabetic macular edema with bimonthly monitoring after a phase of initial treatment: 18-month, multicenter, phase IIIB RELIGHT study. Ophthalmology. 2015; 122(9):1811-1819.
  57. Querques G, Bux AV, Fusco AR, et al. Pegaptanib sodium versus pegaptanib sodium combined with macular laser photocoagulation or laser alone for diabetic macular edema. J Ophthalmol. 2009a;2009: 1-6.
  58. Querques G, Bux AV, Martinelli D, et al. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol. 2009b; 87(6):623-630.
  59. Ramasubramanian A, Shields CL. Bevacizumab for Coats' disease with exudative retinal detachment and risk of vitreoretinal traction. Br J Ophthalmol. 2012; 96(3):356-359.
  60. Ray R, Barañano DE, Hubbard GB. Treatment of Coats' disease with intravitreal bevacizumab. Br J Ophthalmol. 2013; 97(3):272-277.
  61. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008; 145(2):239-248.
  62. Rensch F, Jonas JB, Spandau UH. Early intravitreal bevacizumab for non-ischaemic branch retinal vein occlusion. Ophthalmologica. 2009; 223(2):124-127.
  63. Rinaldi M, Chiosi F, dell'Omo R, et al. Intravitreal pegaptanib sodium (Macugen®) for treatment of diabetic macular oedema: a morphologic and functional study. Br J Clin Pharmacol. 2012; 74(6):940-946.
  64. Rosenfeld PJ, Brown DM, Heier JS, et al.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1419-1431.
  65. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005; 36(4):336-339.
  66. Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularisation associated with pathological myopia. Br J Ophthalmol. 2007; 91(2):161-165.
  67. Schadlu R, Blinder KJ, Shah GK, et al. Intravitreal bevacizumab for choroidal neovascularization in ocular histoplasmosis. Am J Ophthalmol. 2008; 145(5):875-878.
  68. 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. 2012; 32(2):314-321.
  69. Steinbrook R. The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006; 355(14):1409-1412.
  70. Stewart MW. Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug. Inflamm Allergy Drug Targets. 2011; 10(6):497-508.
  71. Sultan MB, Zhou D, Loftus J, et al. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology. 2011; 118(6):1107-1118.
  72. The Diabetic Retinopathy Clinical Research Network, Elman M, Aiello L, Beck R, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010; 117(6):1064-1077.
  73. The Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372(13):1193-1203.
  74. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010; 340:c2459.
  75. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr., et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006b; 113(9):1508-1521.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Aflibercept. In DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated March 2, 2017. Available at: http://www.micromedexsolutions.com. Accessed on April 07, 2017.
  2. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2016® . Bethesda, MD. American Society of Health-System Pharmacists® ; 2016.
  3. Avastin® [Product Information]. San Francisco, CA. Genentech, Inc. December 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125085s317lbl.pdf . Accessed on April 07, 2017.
  4. Bevacizumab. In DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated March 6, 2017. Available at http://www.micromedexsolutions.com. Accessed on April 07, 2017.
  5. Eylea [Product Information]. Tarrytown, NY. Regeneron. October 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125387s052lbl.pdf . Accessed on April 07, 2017.
  6. Lucentis® [Product Information]. San Francisco, CA. Genentech, Inc., January 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125156s111lbl.pdf . Accessed on April 07, 2017.
  7. Macugen® [Product Information]. Bridgewater, NJ. Bausch & Lomb. July 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021756s018lbl.pdf. Accessed on April 07, 2017.
  8. Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, et al. Anti-vascular endothelial growth factor for proliferative diabetic retinopathy. Cochrane Database Syst Rev. 2014;(11):CD008721.
  9. Pegaptanib. In DrugPoints® System (electronic version). Truven Health Analytics, Greenwood, CO. Updated March 22, 2017. Available at http://www.micromedexsolutions.com. Accessed on April 07, 2017.
  10. Ranibizumab. In DrugPoints® System (electronic version). Truven Health Analytics, Greenwood, CO. Updated September 12, 2014. Available at http://www.micromedexsolutions.com. Accessed on April 07, 2017.
  11. 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. 2015;(8):CD008214.
  12. Solomon SD, Lindsley K, Vedula SS, et al. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;(8):CD005139.
Index

Aflibercept
Age-Related Macular Degeneration
AMD
Avastin
Bevacizumab
Branch retinal vein occlusion
Central retinal vein occlusion
Choroidal Neovascularization
Diabetic macular edema
Diabetic retinopathy
Eylea
Lucentis
Macugen
Macular degeneration
Neovascular glaucoma
Pegaptanib
Ranibizumab
Retinopathy of prematurity

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.  Added biosimilar bevacizumab-awwb (Mvasi) for intravitreal use.
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated formatting in Position Statement section. Updated Rationale and References sections. Added new section addressing Clinically Equivalent Cost Effective Agents.
  10/01/2016 Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.
Revised 05/20/2016 MPTAC review. Clarification of MN statement for bevacizumab, ranibizumab, and aflibercept to proliferative diabetic retinopathy with or without diabetic macular edema. Updated Coding section.
Revised 05/05/2016 MPTAC review. Added radiation retinopathy to bevacizumab, ranibizumab, and aflibercept MN statements. Added CNV associated with myopic degeneration to ranibizumab MN statement. Added diabetic retinopathy with or without diabetic macular edema to MN statements for bevacizumab, ranibizumab, and aflibercept. Updated Rationale, Coding and Reference sections.
  04/01/2016 Updated Coding section regarding acceptable coding for bevacizumab to coincide with local plan billing instructions; removed ICD-9 codes.
Revised 05/07/2015 MPTAC review. Reformatted pegaptanib medically necessary and investigational and not medically necessary criteria. Added medically necessary indications for ranibizumab and aflibercept for diabetic retinopathy for those with diabetic macular edema. Updated Rationale, Definitions, Background/Overview, Coding, References and Index.
Revised 11/13/2014 MPTAC review. Addition of medically necessary for aflibercept for diabetic macular edema. Updated Coding, Rationale, Background/Overview and References sections.
Reviewed 11/14/2013 MPTAC review. Updated Rationale, References and Index.
Revised 11/08/2012 MPTAC review. Updated Description/Scope, Rationale, and References. Added the indication of macular edema following central retinal vein occlusion or branch retinal vein occlusion to the aflibercept Position Statement. Clarification to bevacizumab and ranibizumab Position Statements. Updated Coding section to include 01/01/2013 HCPCS changes; removed Q2046 deleted 12/31/2012.
  07/01/2012 Updated Coding section with 07/01/2012 HCPCS updates; removed HCPCS C9291 deleted 06/30/2012.
Revised 02/16/2012 MPTAC review. Updated Description/Scope to include aflibercept. Added aflibercept to Position Statement. Update Rationale, Background/Overview, Definitions, References, and Index. Removed Web Sites for Additional Information. Removed anecortave acetate from scope of document. Updated Coding section with 04/01/2012 HCPCS changes; removed CPT code 0124T no longer addressed.
Revised 05/19/2011 MPTAC review. Added retinopathy of prematurity to medically necessary Position Statement. Updated Rationale, Background/Overview, Definitions, References and Index.
  10/20/2010 Rationale and References updated.
Revised 05/13/2010 MPTAC review. Addition to medically necessary statements for bevacizumab and ranibizumab the use for branch retinal vein occlusion, central retinal vein occlusion and diabetic macular edema. Clarified not medically necessary statement for ranibizumab. Updated Description/Scope, Rationale, Background/Overview, Coding, Definitions and References.
Revised 02/25/2010 MPTAC review. Re-formatting of rare causes of choroidal neovascularization, addition of "including but not limited to histoplasmosis induced choroiditis" to choroiditis. Removal from bevacizumab criteria requirement of "Patient has failed U.S. Food and Drug Administration (FDA)-approved therapies; or Patient is likely to have a therapeutic response with the use of intravitreal bevacizumab, which is comparable to results from other approved treatments." Updated Description/Scope, Rationale, References, and Web Sites.
  01/01/2010 Updated Coding section with 01/01/2010 HCPCS changes; removed HCPCS Q2024 deleted 12/31/2009.
  10/01/2009 Updated Coding section with 10/01/2009 HCPCS changes; removed HCPCS code J9035 (no longer applicable).
Revised 05/21/2009 MPTAC review. Updated Rationale, Definitions, Coding, References, and Web Sites. Title changed to Intravitreal and Periocular Injection Treatment for Retinal Vascular Conditions. Added medically necessary statement for pseudoxanthoma elasticum, rare causes of choroidal neovascularization to include degenerative myopia, idiopathic, angioid streaks, trauma, choroiditis, retinal dystrophies, and neovascular glaucoma.
Reviewed 11/20/2008 MPTAC review. Additional documents added for cross reference in Description/Scope section. Updated Coding section to include 01/01/2009 CPT changes.
Reviewed 08/28/2008 MPTAC review. Updated References, Rationale, Web Sites and Coding.
  01/28/2008 Updated cross-reference in Description/Scope section from CG-DRUG-23 Bevacizumab (Avastin) for Oncologic Indications to DRUG.00038 Bevacizumab (Avastin) for Oncologic Indications.
  01/01/2008 Updated Coding section to include 01/01/2008 HCPCS changes; removed HCPCS C9233 deleted 12/31/2007. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 08/23/2007 MPTAC review. Rationale and References updated.
  01/01/2007 Updated Coding section with 01/01/2007 CPT/HCPCS changes; removed HCPCS S0116, S0198 deleted 06/30/2006.
Revised 09/14/2006 MPTAC review. Macugen criteria updated. Lucentis added to document.
Revised 06/08/2006 MPTAC review. Information on bevacizumab (Avastin) added to Position Statement and Rationale. Added new anaphylaxis warning for Macugen.
Revised 03/23/2006 MPTAC review. Document title changed. Additional information added to rationale regarding off label use. Added conjunctival incision with posterior juxtascleral placement of anecortave acetate (Retaane) depot suspension as a new treatment.
  01/01/2006 Updated Coding section with 01/01/2006 CPT/HCPCS changes.
New 04/28/2005 MPTAC initial document development.