Visudyne may be considered medically necessary as a Food and Drug Administration (FDA) off-label indication for:
- Neovascular (wet) age-related macular degeneration (ARMD or AMD); or
- Choroidal neo- revascularization (CNV) secondary to pathologic myopia and presumed ocular histoplasmosis.
Visudyne is considered experimental, investigational and unproven for all other indications.
Pegaptanib sodium injection (Macugen®)
Macugen may be considered medically necessary as an FDA labeled indication for the treatment of neovascular (wet) ARMD.
Macugen may be considered medically necessary as an FDA off-label indication for the treatment of diabetic macular edema and diabetic retinopathy.
Macugen is considered experimental, investigational and unproven for all other indications.
Ranibizumab injection (Lucentis™)
Lucentis may be considered medically necessary as an FDA labeled indication for the treatment of:
- Neovascular (wet) ARMD;
- Macular retinal edema due to retinal vein occlusion;
- Diabetic macular edema.
Lucentis is considered experimental, investigational and unproven as a treatment for all other indications.
Aflibercept injection (Eylea™)
Eylea may be considered medically necessary for treatment of the following FDA labeled indications:
- “Wet” age-related macular degeneration (ARMD),
- Macular edema following central retinal vein occlusion (CRVO)
Eylea is considered experimental, investigational and unproven for all other ophthalmologic indications.
Avastin may be considered medically necessary as an FDA off-label indication for the treatment of:
- Age related macular degeneration (ARMD);
- Diabetic macular edema;
- Diabetic retinopathy;
- Choroidal (subretinal) neovascularization (i.e., secondary to neovascular (wet) age-related macular degeneration, myopic degeneration, angioid streaks, idiopathic, secondary to toxoplasmosis, trauma, etc.);
- Retinal neovascularization (i.e., secondary to diabetes, secondary to central retinal vein occlusion (CRVO), etc.);
- Macular retinal edema due to diabetes mellitus, central retinal vein occlusion (CRVO) and/or branch retinal vein occlusion (BRVO);
- Other neovascular conditions of the eye (e.g., rubeosis iridis, trabecular angle neovascularization, etc.).
Avastin is considered experimental, investigational and unproven for all other ophthalmologic indications.
Conjunctival incision with posterior juxtascleral placement of Anecortave Acetate (Retaane™) is considered experimental, investigational and unproven as a treatment of neovascular (wet) ARMD or AMD.
Delivery of pharmacologic agents into the suprachoroidal space of the eye by injection or microcannulation is considered experimental, investigational and unproven.
Verteporfin photodynamic therapy received FDA approval in 2000 for the treatment of “predominantly classic subfoveal choroidal neovascularization associated with ARMD.” Therefore, the labeled indications for Visudyne and Macugen overlap, although Macugen includes a broader range of patients with ARMD.
While there is no direct comparison with Visudyne therapy, the randomized studies used for both Visudyne and Macugen therapy incorporated the same primary outcome. After one year of follow-up in the randomized study of Visudyne, 61 percent of the treated patients lost less than 15 letters of acuity, versus 46 percent in the placebo group. After two years, 53 percent of the treatment group versus 38 percent of the placebo group lost fewer than 15 letters.
It is not clear how providers may choose to offer either Macugen or Visudyne. One major difference between the two is that Macugen requires intravitreal injections while Visudyne requires intravenous injection followed by laser therapy. In the randomized trials, Macugen was administered every six weeks, in contrast to Visudyne which is administered once, with follow-up every three months, with additional treatment if neovascularization recurs. Many ophthalmologists are now familiar with administering Visudyne therapy, and given the apparently equivalent results of the two drugs, many may continue to preferentially offer Visudyne. Patient preference will also play a role. In the randomized studies of Macugen, patients were allowed to undergo concomitant Visudyne therapy, so it is likely that some patients will continue to receive both therapies.
FDA approval of Macugen was based in part on the results of two similarly designed randomized trials. The results of these studies were published in the New England Journal of Medicine in 2004. Patients were randomized to receive control (placebo treatment) or one of three different doses of Macugen administered as intravitreous injections every six weeks for 48 weeks. Patients were re-randomized between treatment and no-treatment groups during the second year of the trial. The primary outcome was the proportion of patients losing less than 15 letters of visual acuity, from baseline up to 54 week assessment. After the first year in one study, 73 percent of patients in the treatment group lost less than 15 letters of acuity versus 60 percent sham, and 67 percent versus 53 percent in the second randomized trial, both statistically significant results. Macugen was less effective during the second year of the trial, with 57 percent of the treatment group losing less than 15 letters of vision, compared to 56 percent in the sham group in one trial, and 61 percent versus 34 percent in the second trial.
The study entry criteria for Macugen trials were quite broad including patients whose vision ranged from 20/40 to 20/320. While 20/40 vision is required for such routine activities as reading or driving, 20/320 vision represents legal blindness. Therefore, the functional impact of preservation of visual acuity will be quite different at different ends of the spectrum. For example, preservation of vision to a level of 20/100 suggests that with optical assistance, a patient could perform reasonably well. However, preservation of 20/400 vision would provide only very limited function. While patients with greater vision impairment at initiation of therapy also appeared to benefit from Macugen therapy (in terms of visual acuity as measured by number of letters lost), there was no discussion of functional outcomes.
Macugen is a selective RNA aptamer that inhibits vascular endothelial growth factor (VEGF) 165, the VEGF isoform primarily responsible for pathologic ocular neovascularization and vascular permeability, while sparing the physiological isoform VEGF 121. After more than 10 years in development and preclinical study, pegaptanib was shown in clinical trials to be effective in treating CNV associated with ARMD. Its excellent ocular and systemic safety profile has also been confirmed in patients receiving up to three years of therapy. Early, well-controlled studies further suggest that pegaptanib may provide therapeutic benefit for patients with DME, proliferative DR and retinal vein occlusion. Notably, pegaptanib was the first available aptamer approved for therapeutic use in humans and the first VEGF inhibitor for the treatment of ocular vascular diseases.
Administration of intravitreal pegaptanib (Cunningham et al.) led to an improvement in visual acuity and a reduction in central retinal thickness in some patients with early stage DME in a randomized, double-blind, dose-finding, phase II trial. Pegaptanib-treated patients received an average of five injections, with 49% (83/172) receiving the maximum of six injections. Of the patients receiving the active study regimen, the patients allocated to the 0.3 mg dose had greater improvement in vision acuity, greater decrease in retinal thickness, and lesser need for focal or grid laser intervention.
FDA approval of Lucentis for ARMD was based on three, double-masked sham or active-controlled clinical trials in patients with neovascular AMD (combined n=1323). In the first study, patients with minimally classic or occult CNV lesions received monthly intravitreal injections of Lucentis (0.3mg or 0.5mg) or monthly sham injections over a 24-month period. In a second study, patients with predominantly classic CNV lesions received one of the following:
- Monthly intravitreal injections of Lucentis (0.3mg) and sham photodynamic therapy (PDT),
- Monthly intravitreal injections of Lucentis (0.5mg) and sham PDT,
- Sham intravitreal injections and active verteporfin PDT over a twelve month period.
The primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all Lucentis-treated patients (approximately 95%) maintained their visual acuity. Thirty-four percent to 40% of Lucentis-treated patients experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. In the third study (n=184), patients with neovascular AMD (with or without a classic CNV component) received Lucentis 0.3mg (n=60) or 0.5 mg (n=61) intravitreal injections or sham (n=63) injections once a month for three consecutive doses, followed by a dose administered every 12 months. The primary efficacy endpoint was mean change in visual acuity (following monthly dosing), on average, patients dosed once every three months with Lucentis lost visual acuity, returning to baseline at month 12. Ninety percent of Lucentis-treated patients maintained their visual acuity at month 12.
On June 22, 2010 the FDA approved Lucentis® for the treatment of macular edema following retinal vein occlusion (RVO). RVO is the second most common retinal vascular disease after diabetic retinopathy. RVO affects as many as 180,000 people in the United States and macular edema leads to vision loss in many patients with either central or branch retinal vein occlusion (CRVO or BRVO). Accounting for approximately 80% of RVO, BRVO is the more common of the two presentations.
Two phase III clinical trials (BRAVO and CRUISE) studied the effects of intravitreal Lucentis measured over a period of six months. In the BRAVO study 61% of the patients in the Lucentis study arm gained 15 or more letters in BCVA from baseline at six months compared with only 29% in the sham injection arm. In the CRUISE study 48% of the patients in the Lucentis study arm gained 15 or more letters in BCVA from baseline at six months compared to only 17% in the sham injection arm. These results demonstrated that in macular edema due to RVO, patients who were treated with Lucentis made significant improvement in best-corrected visual acuity (BCVA).
On August 10, 2012 the Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection) for the treatment of diabetic macular edema (DME), a sight-threatening eye disease that occurs in people with diabetes.
The safety and efficacy of Lucentis were assessed in two randomized, double-masked, 3-year studies in patients with DME. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (Lucentis 0.3 mg, 250 patients; Lucentis 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36. In Studies DME-1 and DME-2, patients received monthly Lucentis 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly Lucentis 0.5 mg and patients originally randomized to monthly Lucentis 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with Lucentis 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with Lucentis 0.3 mg and 30 of 257 (12%) patients treated with sham. Compared to monthly Lucentis 0.3 mg, no additional benefit was observed with monthly treatment with Lucentis 0.5 mg.
Visual acuity (VA) outcomes observed at Month 24 in patients treated with Lucentis 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received Lucentis 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with Lucentis at the beginning of the studies.
On November 18, 2011, the Food and Drug Administration (FDA) approved Eylea™ (aflibercept) previously called VEGF Trap-Eye for the treatment of “wet” (neovascular) age-related macular degeneration (ARMD, AMD), a leading cause of vision loss and blindness in Americans ages 60 and older. The safety and effectiveness of Eylea was evaluated in two clinical trials involving 2,412 adult patients. Patients in the study received either Eylea or Lucentis (ranibizumab injection). The primary endpoint in each study was a patient’s clearness of vision (visual acuity) after one year of treatment.
A total of 2,457 patients were randomized in the two clinical trials of Eylea, with more than 90% completing the year-long study. Maintenance of visual acuity was similar between aflibercept and ranibizumab in the multicenter, randomized, double-masked, active-controlled VIEW1 and VIEW2 studies for the treatment of neovascular (wet) age-related macular degeneration (n=2412; mean age, 76 years; range, 49 to 99 years). Patients were randomized to receive intravitreal injections of aflibercept 2 mg every eight weeks following three initial monthly doses (n=301), 2 mg every four weeks (n=304), 0.5 mg every four weeks, or ranibizumab 0.5 mg every four weeks (n=304) in VIEW1 and VIEW2 (n=306, n=309, and n=291, respectively). Data from the aflibercept 0.5 mg every four weeks treatment arm was not reported. Of evaluable patients in VIEW1 at 52 weeks, the proportion of patients who maintained visual acuity (less than 15 letter loss of best corrected visual acuity (BCVA) from baseline; primary outcome) was 94%, 95%, and 94% in the aflibercept eight-week arm, four-week arm, and ranibizumab four-week arm, respectively. In VIEW1, the treatment difference at 52 weeks between aflibercept every eight weeks and ranibizumab was 0.6 letters (95.1% confidence interval (CI), -3.2 to 4.4 letters), and the difference between aflibercept every four weeks and ranibizumab was 1.3 letters (95%.1 CI, -2.4 to 5 letters). Similarly, in VIEW2 at 52 weeks, the proportion of patients who maintained visual acuity was 95% among all treatment arms. In VIEW2, the treatment difference at 52 weeks between aflibercept every eight weeks and ranibizumab was 0.6 (95.1% CI, -2.9 to 4 letters), and the difference between aflibercept every four weeks and ranibizumab was -0.3 (95.1% CI, -4 to 3.3 letters). The proportion of patients who gained at least 15 letters of vision from baseline was similar for aflibercept eight-week and four-week arms and ranibizumab in VIEW1 (31%, 38%, and 31%, respectively) and in VIEW2 (31%, 29%, and 34%, respectively). The mean change in BCVA (Early Treatment Diabetic Retinopathy Study) was also similar among all arms in VIEW1 and VIEW2.
Ophthalmologists are using Avastin off-label to treat AMD and similar conditions since research indicates that VEGF is one of the causes for the growth of the abnormal vessels that cause these conditions. Some patients treated with Avastin had less fluid and more normal-appearing maculas, and their vision improved. Avastin is also used to treat macular edema or swelling of the macula.
Intravitreal use of Avastin involves both an off-label application of the drug and an alternative route of drug delivery. Positive presentations at retinal meetings and the two published case reports of visual acuity improvement and decreased retinal thickness have led the retinal community to embrace this new treatment. As a result, the use of intravitreal Avastin has increased exponentially. The main force driving intravitreal Avastin usage is the high percentage of patients who experience symptomatic relief from active subfoveal CNV.
Because Avastin was not created to be given as an intraocular injection, there have been no published animal or human safety data on retinal toxicity. The intraocular safety profile of Avastin is unknown in contrast to that of Macugen or even Lucentis. Avastin is also a full-sized antibody, unlike the Lucentis fragment, which means there is more potential for inflammation and immune reactions to this larger molecule over time. The longer half-life (up to 20 days) of Avastin is useful for systemic cancer but may cause safety concerns in the eye. (In contrast, the half-life of Lucentis was targeted for four hours.) Whether systemic absorption is more likely with a longer half-life drug is unknown. Although an intravitreal injection uses minute fractions of the drug and the systemic absorption is unlikely to be significant, measurement of systemic levels after intravitreal injection has not been done. The clearance of Avastin is 100-fold slower than Lucentis, and the affinity of Avastin for VEGF is less than that of Lucentis. Reasons to use Avastin center on fast onset of improved retinal morphology and visual acuity. The anecdotal report showed dramatic improvement in optical coherence tomography appearance and corresponding improvement in visual acuity. Other reasons to use it include its low cost and wide availability, with no unexpected toxicity shown to date. Applications of its use include:
- Salvage therapy (after lack of efficacy of FDA approved drugs);
- Lesions that fall outside the indications for approved drugs;
- Patient refusal to use other drugs; and
- Lower cost in uninsured patients.
For patients who have failed therapy with approved drugs and have not yet evolved to disciform scars, off-label Avastin could be recommended as a salvage therapy. Of all of these reasons, the overwhelming reason to use it is, of course, efficacy.
Considerations surrounding the use of anti-VEGF agents for neovascular glaucoma include safety, the most effective dose, the best route of administration, and utility as adjuvant therapy to panretinal photocoagulation (PRP), surgical filtration, or cyclodestructive procedures. Studies suggest that the risk of endophthalmitis is extremely small; reported rates include 0.1% and 0.019%. The preferred route of administration currently is intravitreal, and the recommended dose of Avastin for neovascular glaucoma is 1.25 mg.
The Retaane clinical study was a blinded, randomized controlled trial, with an enrollment of 128 patients with subfoveal CNV at 18 clinical sites, followed up patients for two years, and was completed in June 2003. The study eye was randomized to 30 mg, 15 mg, 3 mg, or placebo from a central coordinating center. Retaane or placebo was administered at baseline; retreatment at the six month visit occurred at the discretion of an unmasked ophthalmologist based on perceived benefit. Compared to placebo, 15 mg (the most efficacious dose) was accompanied by a 25.5% absolute risk benefit for losing fewer than 15 letters of visual acuity. No serious clinically relevant-treatment-related safety issues were reported from either the study medication Retaane or the procedure for administration. Adverse ocular events seen in excess in patients treated with Retaane versus placebo were 15.3% excess of vision abnormalities and 7.1% excess of ocular foreign body sensation. Cataracts were found in 27% and 30% and decreased visual acuity was noted in 25% and 30% in the treatment and placebo groups, respectively. These occurrences included only study eyes, untreated eyes, or both eyes and are commonly experienced in patients with AMD. Other adverse events that were reported as mild and transient included ptosis, ocular pain, visual abnormalities (e.g. hazy vision, black spots, light flashes), subconjunctival hemorrhage, and ocular pruritus.
A phase III randomized control trial compared the one-year safety and efficacy of Retaane 15 mg with photodynamic therapy (PDT) with Visudyne in 530 patients with predominantly classic CNV. Retaane 15 mg was comparable to PDT for maintaining vision, with no statistical difference in the responder rates between the two groups. Percent responders, defined as patients losing less than three lines of vision at month 12, in the Retaane 15 mg and PDT groups were 45% and 49% respectively. The month 12 outcome of Retaane was improved in patients for whom reflux was controlled and who were treated within the six month window. The most frequently reported adverse event in both treatment groups was decreased visual acuity, defined as a loss of vision of plus or minus four lines from the previous visit, occurring at an incidence of 31.9% and 30.3%, respectively.
Traditional methods of ocular drug delivery include topical application, intraocular injection and systemic administration however these methods have difficulty effectively delivering drugs to the back (posterior portion) of the eye. Current animal studies show promise of a drug delivery system using the suprachoroidal space of the eye that may avoid the complications associated with intraocular injection and systemic administration.
Clinical trials are currently investigating the potential use of suprachoroidal drug delivery to the posterior pole (macula and optic nerve) using an advanced microcannula system and demonstrated relative safety by studying the choroidal and retinal blood flow with high-speed confocal Scanning Laser Ophthalmoscope (cSLO) video angiography, fundus exam by cSLO imaging and wide-field fundus photography, and short- and long-term histopathology in the pig model. These data have been used to justify the safety of this methodology for use in humans. Clinical trials are currently investigating the potential use of this technology for treatment of macular disease.
A study by Einmahl et al. investigated the feasibility and tolerance of suprachoroidal delivery of poly ortho ester (POE), a bioerodible and biocompatible polymer, as a biomaterial potentially useful for development of sustained drug delivery systems. The authors concluded that POE suprachoroidal injections, an easy, controllable, and reproducible procedure, were well tolerated in the rabbit eye. POE appears to be a promising biomaterial to deliver drugs focally to the choroid and the retina.
Another study by Olsen et al. in 2006 evaluated the pharmacokinetics of a posterior drug delivery system (PDS) by means of microcannulation of the suprachoroidal space in both the primate and pig animal model. Cannulation was performed in 93 of 94 animals. Complications included: endophthalmitis (1/94), choroidal tear (1/94), choroidal blood flow irregularities (4/94), postoperative inflammation (6/94), scleral ectasia (4/94), wound abscess (1/94), and others. Histopathology demonstrated normal anatomy in uncomplicated cases. Triamcinolone remains in the local ocular tissue for at least 120 days, and measurable at very low levels in the systemic circulation. The authors concluded accessing the suprachoroidal space by the microcannulation system can be performed in a safe and reproducible manner by using careful surgical technique. Forceful PDS tip impact into connective tissues in the macular and optic nerve regions should be avoided. Triamcinolone pharmacokinetics is unique and suggests long-term local tissue levels with low systemic levels. PDS access to the suprachoroidal space represents a novel drug delivery method; applicable to a wide variety of pharmacotherapy’s to the macula, optic nerve, and posterior pole.
The published literature to date does not permit scientific conclusions concerning the effects of suprachoroidal delivery of pharmacologic agents on health outcomes in humans.
On September 21, 2012, the FDA granted approval of Aflibercept injection (Eylea®) for the treatment of macular edema following central retinal vein occlusion (CRVO).
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.