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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Treatment
Policy Number:080
Effective Date: 08/21/2020
Original Policy Date:03/21/2005
Last Review Date:07/14/2020
Date Published to Web: 05/23/2012
Subject:
Angiogenic Inhibitors for the Treatment of Ophthalmic Macular Conditions

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Age-related macular degeneration (AMD), a major cause of blindness in people over age 60, is a painless, insidious process. AMD can be classified as “dry” (nonexudative) or “wet” (neo-vascular). The dry form is the most common form and is characterized by yellow deposits on the retina called “drusen”. It can progress to the wet form, which is more aggressive and severe. The wet form is caused by growth of abnormal leaky blood vessels (choroidal neovascularization) which eventually damage the macula (the area in the retina responsible for central vision which is essential for most visual activities).

While the central field of vision is affected in varying degrees, the peripheral or side vision remains intact. Although the wet form accounts for only 10% of all cases of AMD, it leads to 90% of the severe vision loss associated with the disease. If left untreated, the majority of patients with wet AMD will become functionally blind within two years. It is estimated that 500,000 new cases of wet AMD occur each year worldwide (about 200,000 in the U.S.).

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular (wet) age-related macular degeneration (AMD), abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but vascular endothelial growth factor (VEGF) has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD). VEGF has been implicated in blood retinal barrier breakdown and pathological neovascularization.

On December 14, 2004, Macugen (pegaptanib), an antagonist of vascular endothelial growth factor (VEGF), was the first angiogenic inhibitor drug to receive FDA approval for the treatment of neovascular (wet) age-related macular degeneration. On June 30, 2006, Lucentis (ranibizumab), another angiogenic inhibitor drug and also an antagonist of VEGF, received FDA approval for the treatment of neovascular (wet) age-related macular degeneration. On June 23, 2010, Lucentis (ranibizumab) received FDA approval for the treatment of macular edema following retinal vein occlusion. On November 18, 2011, the FDA approved Eylea (aflibercept) to treat patients with wet (neovascular) age-related macular degeneration (AMD). On September 9, 2012, the FDA approved Eylea (aflibercept) to treat patients with macular edema following central retinal vein occlusion (CRVO). On October 6, 2014, the FDA approved Eylea (aflibercept) for the treatment of patients with macular edema following retinal vein occlusion (RVO), expanding the previous CRVO indication to be inclusive of both macular edema following CRVO and macular edema following branch retinal vein occlusion (BRVO).

Other angiogenic inhibitor drugs that are currently being studied for the treatment of age-related macular degeneration but have not received FDA approval include, but are not limited to, bevacizumab (Avastin), triamcinolone acetonide, sirolimus (Rapamycin), squalamine lactate (Evizon) and combrestatine A-4 phosphate (the last two drugs are administered systemically).

In July 2008, Alcon Pharmaceuticals announced that it terminated the development program designed to evaluate the benefit of anecortave acetate (Retaane) in reducing the risk for developing sight-threatening choroidal neovascularization, secondary to age-related macular degeneration. The decision followed a planned interim analysis of two studies that was performed after 2,546 patients had completed the 24-month time point. In this analysis, anecortave acetate showed no effect on the primary or secondary endpoints. In addition to terminating these studies, the company also terminated two smaller studies with an identical design, which were being conducted in Asia. The company will no longer pursue studies in age-related macular degeneration, however, it will continue to study anecortave acetate administered as an anterior juxtascleral depot to reduce intraocular pressure in patients with open-angle glaucoma. Other angiogenic inhibitor drugs that are currently being studied for the treatment of macular edema following central retinal vein occlusion (CRVO) include, but are not limited to, bevacizumab (Avastin).

In 2015, the New England Journal of Medicine published a study that compared the effectiveness of Eylea (aflibercept), Avastin (bevacizumab), and Lucentis (ranibizumab) in the treatment of diabetic macular edema. The study indicated that Eylea is more effective at improving vision at worse levels of initial visual acuity compared to the other two agents (P<0.001 for aflibercept vs. bevacizumab, P = 0.003 for aflibercept vs. ranibizumab, and P = 0.21 for ranibizumab vs. bevacizumab). From baseline to 1 year, the mean visual-acuity letter score improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. However, the clinical meaningfulness of this measurement is uncertain because the high improvement associated with Eylea (aflibercept) was mainly driven by eyes with worse visual acuity at baseline.

In May 2019, Regeneron Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved EYLEA® (aflibercept) Injection 2 mg (0.05 mL) with an expanded indication in the treatment of Diabetic Retinopathy (DR). Based on its expanded indication for DR, EYLEA is now available for members with DR, without Diabetic Macular Edema (DME).

In October 2019, Novartis Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has approved Beovu® (brolucizumab) injection for the treatment of wet age-related macular degeneration (AMD). Beovu® is a human vascular endothelial factor (VEGF) inhibitor. Beovu® (brolucizumab) is administered by intravitreal injection. The recommended dose is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately every 25-31 days) for the first three doses, followed by one dose of 6 mg (0.05 mL) every 8-12 weeks.


[INFORMATIONAL NOTE: The FDA-approved Avastin (bevacizumab) package insert has the following BLACK BOX WARNINGS:

GASTROINTESTINAL PERFORATIONS: Avastin administration can result in the development of gastrointestinal perforation, in some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin (i.e., was not correlated to duration of exposure). The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving Avastin was 2.4% and 0.9%, respectively. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting. Gastrointestinal perforation should be included in the differential diagnosis of patients presenting with abdominal pain on Avastin. Avastin therapy should be permanently discontinued in patients with gastrointestinal perforation.

WOUND HEALING COMPLICATIONS: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. Avastin therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined.

HEMORRHAGE: Fatal pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 2.3% in patients with NSCLC excluding predominant squamous histology. Patients with recent hemoptysis (≥1/2 tsp of red blood) should not receive Avastin.]

Policy:
[INFORMATIONAL NOTE: Please refer to a separate policy on Photodynamic Therapy for Subfoveal Choroidal Neovascularization/Verteporfin (Visudyne) Therapy in the Treatment section (#027) of this database.

The requirements of the Horizon BCBSNJ Angiogenic Inhibitors for the Treatment of Ophthalmic Macular Conditions (except Avastin) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.]

I. Pegaptanib (Macugen):

    A. The intravitreal injection of pegaptanib (Macugen) is considered medically necessary for
      • neovascular (wet) age-related macular degeneration (AMD)
      • diabetic retinopathy
      • diabetic macular edema
      [INFORMATIONAL NOTE: AMD is the FDA-approved indication. Pegaptanib (Macugen) 0.3 mg is administered once every six weeks by intravitreal injection into the eye to be treated (up to 9 injections/eye/year). As stated in the FDA-approved package insert, the safety or efficacy of Macugen therapy beyond 2 years has not been demonstrated.]

    B. Macugen (pegaptanib sodium) should not be administered in patients with ocular or periocular infections as per the FDA approved package insert.

    C. The concomitant use of pegaptanib (Macugen) therapy and photodynamic therapy with verteporfin (Visudyne) or other angiogenic inhibitor agents (e.g., Lucentis) as a combination treatment of neovascular (wet) age-related macular degeneration is considered investigational.
        [INFORMATIONAL NOTE: There is insufficient evidence in the published medical literature documenting the safety and efficacy of combination treatment ( e.g., Macugen and photodynamic therapy with Visudyne) for neovascular (wet) AMD.]

      D. The intravitreal injection of pegaptanib is considered investigational for the treatment of all other retinal vascular disorders

        [INFORMATIONAL NOTE: Cunningham, et al. conducted a randomized, placebo controlled, dose ranging phase II trial to observe the efficacy of intravitreal pegaptanib injection for improvement in visual acuity and central retinal thickness in patients with diabetic macular edema. A total of 172 patients with early stages of diabetic macular edema were studied. Patients were randomized to pegaptanib 0.3 mg, 1 mg or 3 mg, or placebo injection. The mean change in visual acuity from baseline to 36 weeks were +4.7, +4.7, and +1.1 for pegaptanib 0.3 mg (p=0.04), 1 mg (p=0.05), and 3 mg (p=0.55), respectively, compared to -0.4 in the placebo group. The mean change in central retinal thickness from baseline to week 36 was -68 micrometers (range, -118.9 to -9.88) in the pegaptanib 0.3-mg group versus +3.7 micrometers in the placebo group (p=0.02). In this phase II trial, subjects assigned to pegaptanib had better visual acuity outcomes, were more likely to show reduction in central retinal thickness. Evaluation in a multicenter, randomized, controlled clinical trial with longer follow-up is needed.]
    II. Ranibizumab (Lucentis):
      A. The intravitreal injection of ranibizumab (Lucentis) is considered medically necessary for:
        • Neovascular (wet) age-related macular degeneration (AMD);
        • Macular edema following retinal vein occlusion (RVO)
        • Diabetic macular edema (DME)
        • Diabetic retinopathy(DR)
        • Myopic choroidal neovascularization (mCNV)
          [INFORMATIONAL NOTE: AMD, RVO, DME, and diabetic retinopathy DR, and mCNV are the FDA-approved indications. Ranibizumab (Lucentis) is administered once a month (approximately 28 days) at doses of either 0.5mg (AMD RVO, mCNV) or 0.3mg (DME and DR
          The READ-2 study was a randomized, multicenter study exploring the safety and tolerability of multiple intravitreal injections of Lucentis alone compared with focal laser and Lucentis plus focal laser. Patients were randomized 1:1:1 to one of three groups: Lucentis, focal laser or Lucentis plus focal laser. The primary endpoint is the proportion of patients that gain ≥ 15 letters, or achieve a final vision of ≥ 50 letters (20/25) at 6 months. The primary endpoint data at 6 months have been reported. It was reported that the mean gain in BCVA letter score from baseline at 3 and 6 months was significantly higher in the Lucentis treatment group compared with the focal laser group (p = 0.01 and 0.0001, respectively). Data at month 12 was analyzed using the last observation carried forward method. Patients treated with focal laser experienced improvements in visual acuity and excess foveal thickness between months 6 and 12 vs. no additional improvements in the Lucentis treatment group between months 6 and 12.

          The Diabetic Retinopathy Clinical Research Network published 1 and 2-year results of a sham controlled multicenter RCT that evaluated ranibizumab (with prompt or deferred laser) or triamcinolone plus prompt laser.

          The RESOLVE study is a 12-month multicenter randomized controlled trial (RCT) from Europe that compared ranibizumab (0.3 or 0.5 mg) with sham injection. The treatment schedule comprised 3 monthly injections, after which treatment could be stopped or reinitiated, with an opportunity for rescue laser photocoagulation according to protocol-defined criteria.

          Wet AMD and macular edema following retinal vein occlusion are the FDA-approved indications. Ranibizumab 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month. Patients should be evaluated regularly and treated monthly. Compared to continued monthly injection dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months.

          Proper aseptic injection technique should always be utilized when administering Lucentis. In addition, patients should be monitored for elevation in intraocular pressure, retinal detachment, and for endophthalmitis during the week following the injection, in order to permit early treatment..

          The RISE(NCT00473330) and RIDE(NCT00473382) trials were two identically designed phase III double-masked, multicenter, randomized sham injection-controlled studies of the efficacy and safety of ranibizumab injection 759 patients were enrolled and received either shame injection, Lucentis 0.3mg or Lucentis 0.5mg once a month. At the end of the studies (34 and 24 months respectively) patients receiving Lucentis 0.3mg showed DR improvement by 3 or more steps compared to baseline Early Treatment Diabetic Retinopathy Study Retinopathy Severity Scores (ETDRS-RSS). Differences in proportion of patients who showed DR improvement based on ETDRS-RSS in the Lucentis 0.3mg arm compared to the sham arm was observed as early as month 3 (2 or more step improvement) and month 12 (3 or more step improvement)

          Protocol S (NCT01489189), a funded by the NIH, compared treatment with Lucentis with panretinal or scatter photocoagulation laser therapy (considered the gold standard for proliferative diabetic retinopathy). 305 participants (394 eyes) with proliferative diabetic retinopathy in one or both eyes were enrolled in the study. Lucentis was permitted to be used in the laser group for treatment of diabetic macular edema as needed (in approximately 53% of the laser group eyes). Laser therapy was performed in approximately 6% of the Lucentis group eyes primarily for treatment of retinal detachment or bleeding. At two years, statistically significant improvement in visual acuity was seen in the Lucentis group (P<0.001). In addition, the Lucentis group showed little change in side vision (23 decibels worse on average) compared with substantial loss of side vision in with laser (average worsening of 422 decibels). Vitrectomy rate and development of DME was also lower in the Lucentis group (4% and 9%) compared to the laser group (15% and 28%). ]

      B. Lucentis (ranibizumab) should not be administered in patients with ocular or periocular infections as per the FDA approved package insert.
        C. The concomitant use of ranibizumab (Lucentis) therapy and photodynamic therapy with verteporfin (Visudyne) or other angiogenic inhibitor agents (e.g., Macugen) as a combination treatment of neovascular (wet) age-related macular degeneration is considered investigational.
          [INFORMATIONAL NOTE: Ranibizumab may be used as an adjunctive treatment to vitrectomy or photocoagulation f or proliferative diabetic retinopathy. There is insufficient evidence in the published medical literature documenting the safety and efficacy of combination treatment ( e.g., Lucentis and photodynamic therapy with Visudyne) for neovascular (wet) AMD.]
        D. The intravitreal injection of ranibizumab is considered investigational for the treatment of all other retinal vascular disorders
          [INFORMATIONAL NOTE: Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LUCENTIS clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).]
      III. Aflibercept (Eylea):
        A. The intravitreal injection of aflibercept (Eylea) is considered medically necessary for:
          • Neovascular (wet) age-related macular degeneration (AMD)
          • Macular edema following retinal vein occlusion (RVO)
          • Diabetic Macular Edema (DME)
          • Diabetic retinopathy (DR) in patients with or without DME
          • Proliferative diabetic retinopathy
            [INFORMATIONAL NOTE: AMD, RVO, DME, and DR with or without DME are the FDA-approved indication.

            Aflibercept was studied in two 52-week phase III randomized, double-masked, active-controlled trials in over 2,412 patients with wet AMD. These studies compared aflibercept 2 mg given every 4 or 8 weeks, 0.5 mg aflibercept given every 4 weeks, and ranibizumab 0.5 mg given every 4 weeks.

            Primary endpoints was the proportion of patients who maintained vision at week 52 (with <15 ETDRS letters lost). Both trials found all aflibercept groups to have comparable efficacy (95 to 96%) to ranibizumab (94.4%).

            Macular edema following RVO is inclusive of macular edema following CRVO or BRVO.

            For macular edema following CRVO, aflibercept was studied in two randomized, multi-center, double-masked, sham-controlled Phase III studies, titled COPERNICUS and GALILEO, with a total of 358 patients with macular edema following CRVO for a total of 24 weeks. These studies compared aflibercept 2 mg given every 4 weeks and sham injections (control group) given every 4 weeks for a total of 6 injections in each arm. For the COPERNICUS study, if sham-controlled patients met retreatment criteria after 24 months of treatment, they were given aflibercept as needed until week 52; the aflibercept arm also received as needed treatments in addition to the injections given every 4 weeks until week 52.

            The primary efficacy endpoint in both studies was the proportion of patients who gained at least 15 letters in best corrected visual acuity or compared to baseline. Both studies found aflibercept groups to have superior efficacy (56% to 60%) to the control group (12% to 22%) at week 24.

            For macular edema following BRVO, aflibercept was studied in a 24-week, randomized, multi-center, double-masked, controlled study titled VIBRANT and it included a total of 181 patients treated and evaluated for efficacy with aflibercept (91 with Eylea). In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg Eylea administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in at week 24 compared to baseline. At week 24, the Eylea 2 mg Q4 group was superior to the control group for the primary endpoint.

            Aflibercept was studied in two randomized, multi-center, double-masked, sham-controlled Phase III studies, titled VIVID and VISTA. with a total of 862 patients with diabetic macular edema for a total of 52 weeks. These studies compared aflibercept 2 mg given every 4 or 8 weeks and sham injections (control group) given every 4 weeks. Primary endpoint was change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Both trials found all aflibercept groups(2q4 and 2q8) to have comparable efficacy [12.5 and 10.7 vs. 1.2 in VISTA,P<0.001; 10.5 and 10.7 vs. 1.2 in VIVID, P<0.0001].

            The VIVID and VISTA studies were also utilized to get approval for diabetic retinopathy in patients with DME. At week 100, the proportion of patients improving
            by at least 2 steps on the ETDRS-DRSS was significantly greater in both EYLEA treatment groups (2Q4 and 2Q8) when compared to the control group [56 and 58 vs. 24 in VISTA, P<0.01; 32 and 27 vs 7 in VIVID, P<0.01].
      Efficacy and safety data for EYLEA in DR, with or without DME, are derived from 3 pivotal trials: PANORAMA, VISTA and VIVID. PANORAMA was the first anti-VEGF Phase 3 trial specifically designed to study patients with moderately severe to severe nonproliferative DR (NPDR) without DME. EYLEA significantly improved DR severity scores at 24 and 52 weeks in patients with moderately severe to severe NPDR.

            For AMD, Eylea is dosed as 2mg (0.05mL) by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2mg (0.05mL) by intravitreal injection once every 8 weeks (2months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 weeks (monthly) dosing after the first 12 weeks (3 months).

            For DME and diabetic retinopathy in patients with or without DME, Eylea is dosed as 2 mg (0.05 mL) by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 weeks (monthly) dosing after the first 20 weeks (5 months).

      For macular edema following RVO, Eylea is dosed as 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly).]

        B. Aflibercept (Eylea) should not be administered in patients with ocular or periocular infections or with active intraocular inflammation as per the FDA approved package insert.

        C. The concomitant use of aflibercept (Eylea) therapy and photodynamic therapy with verteporfin (Vysudine) or other angiogenic inhibitor agents (e.g., Macugen, Lucentis, or Avastin) as a combination treatment
        of neovascular (wet) age-related macular degeneration is considered investigational.
        D. The intravitreal injection of aflibercept is considered investigational for the treatment of all other retinal vascular disorders.
          [INFORMATIONAL NOTE: Per the package insert for Eylea, there is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause)]
      IV. Bevacizumab (Avastin):
        A. The intravitreal injection of bevacizumab (Avastin) is considered a medically necessary for:
        • Neovascular (wet) age-related macular degeneration (AMD),
        • Diabetic macular edema (DME)
        • Macular edema following retinal vein occlusion (RVO),
        • Diabetic retinopathy
        • Myopic choroidal neovascularization (mCNV)
            [INFORMATIONAL NOTE: Bevacizumab may be used as an adjunctive treatment to vitrectomy or photocoagulation for proliferative diabetic retinopathy. Timing of bevacizumab therapy in regards to vitrectomy or photocoagulation is at the discretion of the administering physician.
              • One double-masked trial in 2010 by Ahmadieh et al., randomized 68 eyes of 68 patients to a single injection of bevacizumab or sham injection 1 week before vitrectomy. Eyes were included if indications for vitrectomy for complications of proliferative diabetic retinopathy existed such as nonclearing vitreous hemorrhage, tractional retinal detachment, and active progressive proliferative diabetic retinopathy.
              • Another 2010 study by Hernandez et al. randomized 40 eyes (40 patients) to a single 1.25 mg injection of bevacizumab 48 hours before vitrectomy or vitrectomy alone.
              • In 2010, Di Lauro and colleagues reported a block randomized study on 72 eyes of 68 patients with severe proliferative diabetic retinopathy who were affected by vitreous hemorrhage and tractional retinal detachment.The patient groups were matched by vitreous hemorrhage, prior retinal laser-photocoagulation, and morphologic type of retinal detachment. Outcome measures were the intraoperative management, safety, and efficacy of bevacizumab at 7 or 20 days before vitrectomy.
              • In a 2010 randomized study by Cho et al., a single injection of bevacizumab or triamcinolone were administered as an adjunct to panretinal (scatter) photocoagulation to reduce the macular edema that can develop/increase with this treatment. Of 91 eyes (76 patients) with severe diabetic retinopathy, 46 eyes had clinically significant macular edema and 45 did not. Triamcinolone was administered 1 day after the first session of photocoagulation while bevacizumab was given about 1 week before photocoagulation.]

            The FDA is alerting health care professionals that repackaged intravitreal injection of bevacizumab have caused a cluster of serious eye infection.

            The following clinical studies have investigated the use of bevacizumab:

            A retrospective study between ranibizumab and bevacizumab in 452 patients (324 receiving bevacizumab, 128 receiving ranibizumab), found that both treatments were effective in stabilizing visual acuity (VA) loss. At one year, no difference in VA outcome was seen between treatment groups receiving monthly injections. When comparing as needed ranibizumab with as needed bevacizumab, study results were inconclusive.

            Soheilan M, et al. conducted a randomized 3-arm clinical trial to observe the efficacy of intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular laser photocoagulation for the treatment of diabetic macular edema. A total of 129 treatment naïve patients with clinically significant diabetic macular edema were studied. The change in visual acuity was statistically significant in the intravitreal bevacizumab group at the follow-up visits up to 36 weeks (p< 0.001). Significant central macular thickness reduction was observed in all groups up to 6 weeks.

            Takamura Y, et al. Conducted a prospective, randomized, masked cohort study in 42 patients with diabetic macular edema to receive either cataract surgery or cataract surgery combined with intravitreal injection of 1.25 mg bevacizumab. Mean central thickness was measured as the primary endpoint. Patients who underwent cataract surgery without bevacizumab had a mean central thickness of 351.6 micrometer at baseline vs. 389 at month 1 and 379.9 at month 3 (p = 0.0013 and 0.0068, respectively). The mean central thickness of eyes in the bevacizumab treatment group decreased from 355 micrometer at baseline vs. 327 at month 1 and 330 at month 3 (p = 0.0087 and p = 0.0217, respectively).

            Arevalo et. Al. conducted a retrospective, multicenter, interventional, comparative case series in 115 patients (139 eyes) with diffuse diabetic macular edema. Patients were treated with at least 1 intravitreal injection of 1.25 or 2.5 mg of bevacizumab. The primary endpoint measure was change in best corrected visual acuity (BCVA). The mean BCVA was 20/114. There were no statistically significant differences reported in the change of BCVA and in macular thickeness with OCT in the doses between 1.25 and 2.5 mg of intravitreal bevacizumab.

            Astam et al. evaluated short-term efficacy of intra-vitreal bevacizumab injection for macular edema due to diabetic retinopathy and retinal vein occlusion. Ophthalmic evaluation, visual acuity measurement, and central macular thickness (CMT) were performed at baseline and 1 month intervals after injection. Twenty-one patients with macular edema due to diabetic retinopathy (n=12) and retinal vein occlusion (n=9) were included. There was no statistically significant difference between logMAR visual acuity (p = 0.22) and CMT (p = 0.16) measurements at baseline and 3 months follow-up for diabetic retinopathy. However, there was a statistically significant difference seen at baseline and 3 months follow-up (p < 0.01) with retinal vein occlusion. Almost all of the eyes (88.8 %) regained normal foveal configuration. The authors concluded that although the follow-up period was short and the number of patients were limited to provide specific treatment recommendations, intra-vitreal bevacizumab appears more effective for macular edema due to retinal vein occlusion vs. diabetic macular edema.The favorable short-term findings suggested that further study is needed.

            Kook et al. evaluated the long-term efficacy of bevacizumab for the treatment of chronic diffuse diabetic macular edema after various previous treatments. 126 patients were consecutively incorporated in this prospective, non-comparative case series. All patients were treated with repeated intravitreal injections of bevacizumab (1.25 mg). All patients had received various previous treatments such as laser treatment (focal laser treatment, panretinal laser treatment, vitrectomy) or intravitreal injection of triamcinolone. Throughout follow-up, VA changes were not significant after 6 months, but were significant after 12 months. Even in cases with chronic diffuse ischemic diabetic macular edema, a long-term decrease of central retinal thickness can be observed following repeated intravitreal injections of bevacizumab.

            A Phase III study evaluating the effect of intravitreal bevacizumab alone or in combination with triamcinolone acetonide with laser photocoagulation on clinically significant macular edema is currently recruiting patients. Another Phase III study evaluating the effect of intravitreal bevacizumab vs. intravitreal ranibizumab on visual acuity and neovascularization in patients with macular edema is also currently recruiting patients.

            Evaluation of preoperative intravitreal bevacizumab (IVB) injection in 40 diabetic patients who were candidates for vitrectomy. Patients were assigned to receive 2.5 mg IVB 3-5 days before operation (injected group) or no injection before operation (noninjected group). IVB injection may decrease the rate of postoperative vitreous hemorrhage.

            Thirty-nine patients who have undergone primary vitrectomy with silicone oil tamponade for severe diabetic retinopathy were enrolled in a prospective, case control, study. Patients were given either intravitreal bevacizumab 1 week before study or no bevacizumab injection. Patients experienced regression of neovascularization after one week. Bevacizumab reduced intra- and postoperative bleeding.

            Ozturk and colleagues compared the effects of bevacizumab and ranibizumab in 29 eyes of 29 patients with DME. Patients receiving one injection of intravitreal bevacizumab and ranibizumab with at least 6-month interval were included (mean interval: 9.54±2.64 months). Bevacizumab increased the best-corrected visual acuity (BCVA) assessment from a median of 59 to 61.50 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (0.029), and it decreased the central subfield macular thickness (CSMT) from 411µm to 373 µm (p=0.011). Ranibizumab increased median BCVA from 53 to 66 EDTRS letters (p<0.001) and decreased median CSMT from 428 µm to 279 µm (p<0.001).

            Sonoda and colleagues conducted a nonrandomized study designed to examine the early change of central macular thickness (CMT) in 22 eyes with DME treated with intravenous triamcinolone and 18 eyes with DME treated with bevacizumab. Compared to baseline, CMT decreased significantly one hour after intravitreous triamcinolone (p<0.05) while it did not decrease significantly until 24 hours in the bevacizumab-treated group. In retinal vein occlusion, bevacizumab decreased CMT from 3 hours after injection (p<0.05) and CMT decrease was more evident in these patients after receiving bevacizumab compared to triamcinolone. At one month, visual acuity improved significantly in DME with either intravitreous triamcinolone (p<0.01) or intravitreous bevacizumab (p<0.05). Immediate decrease in CMT suggests the possible nongenomic pathway of triamcinolone action, but further studies are needed to confirm this.

        B. The concomitant use of bevacizumab (Avastin) therapy and photodynamic therapy with verteporfin (Vysudine) or other angiogenic inhibitor agents (e.g., Macugen or Lucentis) as a combination treatment of neovascular (wet) age-related macular degeneration is considered investigational.

        C. Intravitreal injection of bevacizumab is considered investigational for the treatment of all other retinal vascular disorders.
          [INFORMATIONAL NOTE: As mentioned in the Avastin prescribing information, there have been serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Venous Thromboembolic Events: Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE).]
      V. Brolucizumab-dbll (Beovu):
        A. The intravitreal injection of brolucizumab-dbll (Beovu) is considered a medically necessary for:
          • Neovascular (wet) age-related macular degeneration (AMD)

          • [INFORMATIONAL NOTE: As per the FDA aprpoved package insert: The recommended dose for brolucizumab-dbll (Beovu) is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately every 25-31 days) for the first three doses, followed by one dose of 6 mg (0.05 mL) every 8-12 weeks.

            The safety and efficacy of brolucizumab-dbll (Beovu) were assessed in two randomized, multi-center, double-masked, active-controlled studies (HAWK and HARRIER) in patients with neovascular AMD. A total of 1817 patients were treated in these studies for two years (1088 on brolucizumab-dbll and 729 on control). Patient ages ranged from 50 to 97 years with a mean of 76 years. In HAWK, patients were randomized in a 1:1:1 ratio to the following dosing regimens: brolucizumab-dbll 3 mg administered every 8 or 12 weeks after the first 3 monthly doses, brolucizumab 6 mg administered every 8 or 12 weeks after the first 3 monthly doses, or aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses. In HARRIER, patients were randomized in a 1:1 ratio to the following dosing regimens: brolucizumab-dbll 6 mg administered every 8 or 12 weeks after the first 3 monthly doses or aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses. The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes. At Week 48, each brolucizumab-dbll arm demonstrated noninferiority to aflibercept in BCVA change from baseline (p <0.001 for each comparison). Greather than 50% of brolucizumab-dbll 6 mg – treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51 [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab-dbll 6 mg – treated eyes had disease activity versus aflibercept in HAWK (24% vs 34.5%; P=0.001) and HARRIER (22.7% vs 32.2%; P=0.002). Anatomic retinal fluid outcomes favored brolucizuma-dbll over aflibercept. Overall, adverse event rates were generally similar with brolucizumab-dbll and aflibercept.]
        B. Brolucizumab-dbll (Beovu) should not be administered in patients with ocular or periocular infections or with active intraocular inflammation as per the FDA approved package insert.
            [INFORMATIONAL NOTE: Per the FDA approved package insert, there is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause)]
        C. The concomitant use of brolucizumab-dbll (Beovu) therapy and photodynamic therapy with verteporfin (Visudyne) or other angiogenic inhibitor agents (e.g., Macugen, Lucentis, Eylea, Avastin) as a combination treatment of neovascular (wet) age-related macular degeneration is considered investigational.
            [INFORMATIONAL NOTE: There is insufficient evidence in the published medical literature documenting the safety and efficacy of combination treatment ( e.g., Beovu and photodynamic therapy with Visudyne) for neovascular (wet) AMD.]

        D. The intravitreal injection of Brolucizumab-dbll (Beovu) is considered investigational for the treatment of all other retinal vascular disorders.

      VI. When treatment with Macugen (pegaptanib), Lucentis (ranibizumab), Eylea (afilbercept), Avastin (bevacizumab), or Beovu (brolucizumab-dbll), is considered medically necessary, initial treatment will be authorized for 6 months.

      VII. When treatment with Macugen (pegaptanib), Lucentis (ranibizumab), Eylea (afilbercept), Avastin (bevacizumab), or Beovu (brolucizumab-dbll), is considered medically necessary, continued therapy will be authorized annually as follows:


        A. Member continues to meet initial review criteria; AND

        B. There is an absence of unacceptable toxicity from the drug (e.g. endophthalmitis and retinal detachments, increase in intraocular pressure, arterial thromboembolic events, etc.); AND

        C. Continued administration is necessary for the maintenance treatment of the condition and member has had a beneficial response to therapy.


      [INFORMATIONAL NOTE: Please refer to a separate policy on Angiogenesis-Inhibiting Drugs [Avastin (bevacizumab) and Erbitux (cetuximab)] - Policy #036 under the Drugs Section of this database for all other FDA-approved and medically necessary off -label uses of Avastin.]


      Medicare Coverage:
      Per Novitas Article A53121, Bevacizumab (e.g., Avastin™), Ranibizumab (e.g., Lucentis™), and Aflibercept (e.g., Eylea™), used on or off-label, may be considered eligible for coverage when provided in keeping with the “Community Standard of Practice” for the treatment of retinal disease, for example: age-related macular degeneration (AMD), ischemic retinal vein occlusions, and decreasing the vascularity of proliferative diabetic retinopathy prior to vitreous surgery.

      Billing
      Providers should bill CPT code 67028 for the intravitreal injections, in addition to the drug(s) utilized. The appropriate site modifier (RT, LT, or 50) must be appended to CPT code 67028 to indicate if the service was performed unilaterally (RT or LT) or bilaterally (50).

      For additional information and eligibility, refer to Local Coverage Article: Billing and Coding Information Regarding Uses, Including Off-Label Uses, of Anti-Vascular Endothelial Growth Factor (anti-VEGF), for The Treatment of Ophthalmological Diseases (A53121). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46
      ________________________________________________________________________________________

      Horizon BCBSNJ Medical Policy Development Process:

      This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

      ___________________________________________________________________________________________________________________________

      Index:
      Angiogenic Inhibitors for the Treatment of Neovascular (Wet) Age-Related Macular Degeneration
      Pegaptanib (Macugen) for the Treatment of Neovascular (Wet) Age-Related Macular Degeneration
      Macugen
      Ranibizumab
      Lucentis
      Avastin
      Bevacizumab
      Triamcinolone Acetonide
      Anecortave Acetate
      Retaane
      Squalamine Lactate
      Evizone
      Neovascular (Wet) Age- Related Macular Degeneration
      Ophthalmic Macular Conditions
      Angiogenic Inhibitors for the Treatment of Ophthalmic Macular Conditions
      Eylea
      Aflibercept
      Brolucizumab-dbll
      Beovu

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        139. Liu YC, Yang CS, Shyong MP, et al. Intravitreal injection of bevacizumab for the treatment of choroidal neovascularization in a patient with angioid streaks. J Chin Med Assoc. 2009 Feb;72(2):98-102.

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        156. Weiss K, Steinbrugger I, Weger M, et al. Intravitreal VEGF levels in uveitis patients and treatment of uveitic macular oedema with intravitreal bevacizumab. Eye (Lond). 2009 Sep;23(9):1812-8. Epub 2009 Jan 23.

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        162. di Lauro R, De Ruggiero P, di Lauro MT et al. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248(6):785-91.

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        Codes:
        (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

        CPT*
          67028

        HCPCS
          C9257
          J0178
          J0179
          J2503
          J2778
          J9035

        * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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