Age-Related Macular Degeneration

Number: 0765

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses age-related macular degeneration.

Medical Necessity

Aetna considers the following interventions medically necessary for management of age-related macular degeneration when criteria are met:
1. Use of any of the following therapies for treatment of neovascular (wet) age-related macular degeneration (ARMD):
  1. Aflibercept (Eylea) injection (CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications)
  2. Bevacizumab (Avastin) injection (CPB 0685 - Bevacizumab for Non-Ocular Indications)
  3. Pegaptanib sodium (Macugen) injection (CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications)
  4. Photodynamic therapy (PDT) with light-activated verteporfin (CPB 0594 - Visudyne (Verteporfin) Photodynamic Therapy)
  5. Ranibizumab (Lucentis) injection (CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications)
  6. Brolucizumab (Beovu) injection (CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications);
2. Implantable miniature telescope (IMT) for monocular implantation in members aged 65 years and older with stable, untreatable, severe-to-profound central vision impairment caused by blind spots (bilateral central scotoma) associated with end-stage ARMD as determined by fluorescein angiography when all of the following are met:
  1. Achieve at least a 5-letter improvement on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart in the eye scheduled for surgery using an external telescope; and
  2. Adequate peripheral vision in the eye not scheduled for surgery, to allow for orientation and mobility; and
  3. Agree to undergo 2 to 4 pre-surgical training sessions with low vision specialist (optometrist or occupational therapist); and
  4. Evidence of a visually significant cataract (grade 2 or higher); and
  5. No active wet ARMD (no sign of active choroidal neovascularization in either eye); and
  6. No sign of eye disease other than well-controlled glaucoma; and
  7. Not been treated for wet ARMD in the previous 6 months; and
  8. Visual acuity poorer than 20/160, but not worse than 20/800 in both eyes; and
  9. Willingness to participate in a post-operative visual rehabilitation program.
Experimental and Investigational

Aetna considers the following interventions experimental and investigational for management of age-related macular degeneration (ARMD) because the effectiveness of these approaches has not been established (not an all-inclusive list):
1. Diagnostic or detection of ARMD
  1. Artificial intelligence (e.g., deep learning convolutional neural networks) for detection of ARMD
  2. Home monitoring with preferential hyperacuity perimetry (ForeseeHome device, Notal Vision Ltd., Tel Aviv, Israel) for detection of ARMD-associated choroidal neovascularization and for all other indications;
  3. Homocysteine testing as a diagnostic marker for ARMD (see CPB 0763 - Homocysteine Testing);
  4. Microperimetry for detection of functional progression in non-neovascular ARMD;
  5. Portable VEP system with dark-adapted visual evoked potentials (DAVEP1) metric for diagnosing/screening ARMD;
2. Interventions or therapies
  1. Anecortave acetate (CPB 0706 - Anecortave acetate (Retaane))
  2. Ciliary neurotrophic factor
  3. Complement factor H (CFH) rs1061170 polymorphism genotyping
  4. Complement inhibitors (e.g., avacincaptad pegol and pegcetacoplan) for treatment of ARMD
  5. Conbercept (for the treatment of ARMD)
  6. Epiretinal radiation therapy (also known as epimacular brachytherapy) (CPB 0756 - Epiretinal Radiation Therapy)
  7. Gene therapy
  8. Heterochromatic flicker photometry for evaluation of ARMD
  9. Injection of bevacizumab, pegaptanib, or ranibizumab for dry/non-neovascular ARMD (CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications)
  10. Interferon alpha (CPB 0404 - Interferons)
  11. Intraocular electrically stimulated devices (e.g., optic nerve, cortical, epiretinal and subretinal)
  12. Intravitreal bevasiranib
  13. Intravitreal injection of autologous stem cells
  14. Intravitreal triamcinolone
  15. Laser photocoagulation of macular drusen (CPB 0609 - Laser Photocoagulation of Drusen)
  16. Macular/foveal translocation (CPB 0409 - Macular/Foveal Translocation)
  17. Metabolomics (metabolic biomarkers) for the management of ARMD
  18. Photobiomodulation for the treatment of non-exudative ARMD
  19. Polymorphism testing as markers of ARMD (e.g., ABCA1 rs1883025, CX3CR1, and TLR3 rs3775291)
  20. Polymorphism testing as a predictor of therapeutic response to anti-vascular endothelial growth factor (VEGF) (e.g., Y402H)
  21. Polymorphism testing of complement factor H (CFH) gene (rs3766405 and rs412852) and one Age Related Maculopathy Sensitivity 2 (ARMS2) variant (372_815del44ins54) (e.g., Vita Risk) in predicting neovascular ARMD risk associated with zinc supplementation
  22. Proton beam radiotherapy (CPB 0270 - Proton Beam and Neutron Beam Radiotherapy)
  23. Simultaneous use of Visudyne PDT in combination with anti-angiogenic agents (for choroidal neovascularization due to ARMD)
  24. Single-nucleotide polymorphism (SNP)-based genotype testing (e.g., Macula Risk PGx, RetnaGene AMD, RetnaGene LR) (see CPB 0140 - Genetic Testing)
  25. Stem cell transplantation (CPB 0606 - Hematopoietic Cell Transplantation for Autoimmune Diseases and Miscellaneous Indications)
  26. Submacular surgery
  27. Sub-threshold retinal laser therapy
  28. Surgical implantation of optic nerve
  29. Transpupillary thermotherapy (CPB 0490 - Transpupillary Thermal Therapy)
  30. Visual cycle modulators (e.g., emixustat and fenretinide) for the treatment of geographic atrophy due to ARMD.
Related Policies

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes covered if selection criteria are met:
67028	Intravitreal injection of a pharmacologic agent (separate procedure)
67221	Destruction of localized lesion of choroid (e.g., choroidal neovascularization); photodynamic therapy (includes intravenous infusion)
+ 67225	photodynamic therapy, second eye, at single session (List separately in addition to code for primary eye treatment)
CPT codes not covered for indications listed in the CPB:
ABCA1 rs1883025, CX3CR1, TLR3 rs3775291 polymorphism testing, Y402H polymorphism testing, single-nucleotide polymorphism (SNP)-based genotype testing, microperimetry, Complement factor H (CFH) rs1061170 polymorphism genotyping, Sub-threshold retinal laser therapy, metabolomics (metabolic biomarkers), photobiomodulation, use of artificial intelligence – no specific code
0378T	Visual field assessment, with concurrent real time data analysis and accessible data storage with patient initiated data transmitted to a remote surveillance center for up to 30 days; review and interpretation with report by a physician or other qualified health care professional [ForeseeHome device]
0379T	Visual field assessment, with concurrent real time data analysis and accessible data storage with patient initiated data transmitted to a remote surveillance center for up to 30 days; technical support and patient instructions, surveillance, analysis and transmission of daily and emergent data reports as prescribed by a physician or other qualified health care professional [ForeseeHome device]
0506T	Macular pigment optical density measurement by heterochromatic flicker photometry, unilateral or bilateral, with interpretation and report.
0205U	Ophthalmology (age-related macular degeneration), analysis of 3 gene variants (2 CFH gene, 1 ARMS2 gene), using PCR and MALDI-TOF, buccal swab, reported as positive or negative for neovascular agerelated macular-degeneration risk associated with zinc supplements
38232	Bone marrow harvesting for transplantation; autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
38242	Allogeneic lymphocyte infusions
77432	Stereotactic radiation treatment management of cranial lesion(s) (complete course of treatment consisting of one session)
77520	Proton treatment delivery; simple, without compensation
77522	simple, with compensation
77523	intermediate
77525	complex
83090	Homocysteine
95930	Visual evoked potential (VEP) checkerboard or flash testing, central nervous system except glaucoma, with interpretation and report [portable VEP system with dark-adapted visual evoked potentials (DAVEP1) metric]
HCPCS codes covered if selection criteria are met:
C9161	Injection, aflibercept hd, 1 mg
C9257	Injections, Bevacizumab, 0.25 mg
J0178	Injection, aflibercept, 1 mg
J0179	Injection, brolucizumab-dbll, 1 mg
J2503	Injection, pegaptanib sodium, 0.3 mg
J2778	Injection, ranibizumab, 0.1 mg
J3396	Injection, verteporfin, 0.1 mg
J9035	Injection, bevacizumab, 10 mg
Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
HCPCS codes not covered for indications listed in the CPB:
Conbercept, visual cycle modulators (e.g., emixustat and fenretinide) - no specific code
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, per 10 mg
J9212	Injection, interferon alfacon-1, recombinant, 1 mcg
J9213	Interferon alfa-2A, recombinant, 3 million units
J9214	Interferon alfa-2B, recombinant, 1 million units
J9215	Interferon alfa-N3, (human leukocyte derived), 250,000 IU
S2140	Cord blood-derivedstem cell transplantions, allogenic
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogenic or autologous, harvesting, transplantation, and related complications; including; pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
S9559	Home injectable therapy; interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
H35.3210 - H35.3293	Exudative age-related macular degeneration
ICD-10 codes not covered for indications listed in the CPB:
H35.051 - H35.059	Retinal neovascularization, unspecified [associated with age-related macular degeneration]
H35.30	Unspecified macular degeneration [age-related]
H35.3110 - H35.3194	Nonexudative age-related macular degeneration
*Implantable Miniature Telescope (IMT)*:
CPT codes covered if selection criteria are met:
0308T	Insertion of ocular telescope prosthesis including removal of crystalline lens or intraocular lens prosthesis
ICD-10 codes covered if selection criteria are met [covered for ages 65 and above only]:
H35.31	Nonexudative age-related macular degeneration
H35.32	Exudative senile macular degeneration
H53.413	Scotoma involving central area, bilateral [associated with end-stage ARMD]

Background

Age-related macular degeneration (ARMD), a progressive degenerative disease of the macula, is the leading cause of blindness in developed countries afflicting about 15 million people in the United States. The risk of ARMD increases with age, and usually affects people 60 years of age and older. Heavy alcohol consumption (more than 3 standard drinks per day) is associated with an increased risk of early ARMD (Chong et al, 2008). Early ARMD is characterized by the presence of a few (less than 20) medium-size drusen or retinal pigmentary abnormalities. Intermediate ARMD is characterized by at least one large druse, numerous medium-size drusen, or geographic atrophy that does not extend to the center of the macula. Late or advanced ARMD can be either neovascular (wet or exudative) or non-neovascular (dry, atrophic, or non-exudative). The neovascular form includes serous or hemorrhagic detachment of retinal pigment epithelium and choroidal neovascularization (CNV), which lead to leakage and scarring. It is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina. These blood vessels leak blood and fluid into the retina, resulting in visual abnormalities. The development of these abnormal blood vessels is due in part to the activity of vascular endothelial growth factor (VEGF), which induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular form of ARMD. The non-neovascular form leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. It does not involve leakage of blood or serum, and is characterized by drusen and geographic atrophy extending to the center of the macula. Patients with non-exudative ARMD can progress to the exudative form of ARMD, in which pathologic CNV membranes develop under the retina, leak fluid and blood, and ultimately cause a blinding disciform scar in a relatively short time. Approximately 10 to 20 % of patients with non-exudative ARMD eventually progress to the exudative form, which is responsible for most of the cases of advanced ARMD in the United States (AAO, 2006; Comer, 2006; Jager et al, 2008).

Various therapeutic approaches have been employed in the treatment of patients with ARMD. High-dose antioxidants are thought to be able to limit the damage caused by oxidative stress in the macula. However, this treatment only slows progression in some patients and does not reverse damage already present. After ARMD becomes exudative, laser photocoagulation, photodynamic therapy (PDT) with verteporfin (Visudyne), and intra-vitreal injections of pegaptanib sodium (Macugen), bevacizumab (Avastin) and ranibizumab (Lucentis) have been used to control CNV. Because of the limitations in current treatment, researchers are presently developing alternative therapies for wet ARMD including alternative types of PDT, irradiation, intra-ocular devices, intra-vitreal administration of bevasiranib (a small interfering RNA agent that inhibits intra-cellular transcription of VEGF), transpupillary thermotherapy, treatment with a variety of growth-factor modulators, and vitreo-retinal surgery (AAO, 2006; Comer, 2006; Jager et al, 2008).

Argon laser photocoagulation therapy was once the most common therapy for wet ARMD. It is now used only occasionally to treat CNV that extends by more than 200 µm from the center of the macula, since this treatment itself can create a large retinal scar associated with permanent visual loss (Jaeger, 2008). In a Cochrane review, Virgili and Bini (2007) examined the effects of laser photocoagulation for wet ARMD. A total of 15 trials were included in the review (2,064 subjects). Three types of photocoagulation were used in the trials:

direct photocoagulation of the entire CNV (11 trials),
peri-foveal photocoagulation (1 trial) and
grid photocoagulation (3 trials).

In 12 trials the control group was observation only. One trial compared photocoagulation to submacular surgery and 2 trials compared different lasers. Data on the progression of visual loss could be extracted from 5 of the 8 trials of direct photocoagulation of the CNV versus observation. The treatment effect was in the direction of harm in all studies at 3 months follow-up (relative risk [RR] 1.41, 95% confidence intervals [CI]: 1.08 to 1.82). After 2 years the treatment effect was in the direction of benefit (RR 0.67, 95 % CI: 0.53 to 0.83). These studies were clinically heterogeneous with participants having CNV lesions in different locations and different baseline visual acuity (VA). There was little evidence of statistical heterogeneity at 3 months but substantial statistical heterogeneity at 2 years. However, all treatment effects in the individual trials were in the direction of benefit. One study comparing perifoveal photocoagulation or observation of subfoveal CNV found benefits that were statistically significant only at 2 years (RR 0.36, 95 % CI: 0.18 to 0.72). Other comparisons did not demonstrate differences. The authors concluded that in the medium to long-term, laser photocoagulation of CNV slows the progression of visual loss in people with wet ARMD. However, it is associated with an increased risk of visual loss immediately after treatment and this period may be longer in people with subfoveal ARMD. With the advent of pharmacotherapies, and concern for the impact of iatrogenic scotoma in subfoveal CNV, laser photocoagulation of subfoveal CNV is not recommended. No studies have compared photocoagulation with modern pharmacological agents for ARMD for non-subfoveal CNV.

In a Cochrane review on laser treatment of drusen to prevent progression to advanced ARMD, Parodi and colleagues (2009) stated that the trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, there is no evidence that this subsequently results in a reduction in the risk of developing CNV, geographic atrophy or visual acuity loss.

In a Cochrane review, Giansanti et al (2009) evaluated the effectiveness of submacular surgery for preserving or improving vision in patients with ARMD. These investigators searched CENTRAL, MEDLINE, EMBASE and LILACS. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 11 February 2009. They included randomized or quasi-randomized controlled trials comparing submacular surgery with any other treatment or observation. Two authors independently extracted the data. The risk ratio of visual loss and visual gain was estimated at 1 year. Two multi-center studies with a similar design were conducted between 1997 and 2003 and compared submacular surgery with observation in people affected by subfoveal neovascular ARMD with (n = 336) or without (n = 454) extensive blood in the macula. At 1 year, there was high quality evidence of no benefit for preventing visual loss (risk ratio: 0.96; 95 % CI: 0.84 to 1.09). No difference could be demonstrated regarding the chance of visual gain (risk ratio: 1.06; 95 % CI: 0.75 to 1.51), although this evidence was of low quality because of imprecision. The risk difference was -2 % (95 % CI: -10 % to 5 %) and 1 % (95 % CI: -4 % to 6 %) for visual loss and visual gain, respectively, thus excluding a large benefit with surgery in terms of absolute risk in this sample. There was high quality evidence that cataract needing surgery (risk ratio: 8.69; 95 % CI: 4.06 to 18.61) and retinal detachment (risk ratio: 6.13; 95 % CI: 2.81 to 13.38) were more common among operated patients, and detachment occurred in 5 % of patients with no extensive blood and in 18 % of those with extensive blood beneath the macula. A pilot study compared submacular surgery with laser photocoagulation in 70 patients. No difference between the 2 treatments could be demonstrated for any outcome measure, but estimates were very imprecise because of small sample size. The authors concluded that there is no benefit with submacular surgery in most people with subfoveal CNV due to ARMD in terms of prevention of visual loss. Furthermore, the risk of developing cataract and retinal detachment increases after surgery.

A systematic evidence review published in BMJ Clinical Evidence (Arnold and Heriot, 2006) also concluded that submacular surgery for ARMD "is likely to be ineffective or harmful."

Ocular PDT entails the use of an intravenously administered, light-sensitive dye, verteporfin, which preferentially concentrates in new blood vessels. Visudyne is activated with the use of a 689-nm laser beam focused over the macula, causing localized choroidal neovascular thrombosis through a non-thermal chemotoxic reaction. Although it generally does not improve vision and its use as monotherapy appears to be less effective than other treatments, PDT does limit visual loss in wet ARMD, and its repeated use over a 5-year period appears to be safe, with minimal, infrequent side effects including dye extravasation at the injection site, back pain, and photosensitivity (Jager et al, 2008).

Kaiser (2007) discussed the rationale for combining anti-angiogenic treatment with Visudyne PDT in the management of CNV due to ARMD and evaluated available evidence for the therapeutic benefits of such approaches. Treatments for CNV due to ARMD can be directed at either the vascular component of CNV or the angiogenic component that leads to the development of the condition. Verteporfin targets the vascular component, whereas anti-angiogenic agents (such as pegaptanib and ranibizumab) target key mediators of the angiogenic cascade. The different mechanisms of action of these approaches offer the potential for additive or synergistic effects with combination therapy. In addition, anti-angiogenic agents might counteract up-regulation of angiogenic factors (including VEGF) that occur after verteporfin PDT. Results from pre-clinical and clinical studies of the combination of ranibizumab or pegaptanib with verteporfin warrant continued investigation. The author concluded that the use of anti-angiogenic agents in combination with verteporfin may have the potential to improve visual outcomes and reduce the number of treatments in eyes with CNV due to ARMD, and requires further evaluation in randomized, controlled clinical trials.

The first intra-vitreal agent approved by the Food and Drug Administration (FDA) for wet ARMD was pegaptanib, a messenger RNA aptamer and VEGF antagonist. Pegaptanib binds to VEGF and inhibits its binding to cellular receptors; its anti-vascular endothelial growth factor (anti-VEGF) activity is expected to inhibit abnormal blood vessel proliferation and thus decrease the vision loss associated with the proliferation of abnormal blood vessels. However, the number of patients whose VA improved with pegaptanib was limited, so the agent is no longer widely used (Jager et al, 2008).

Currently, the most common treatments for wet ARMD are intra-vitreal bevacizumab and ranibizumab. Bevacizumab, a monoclonal antibody to VEGF is being used off-label for wet ARMD. Although data from long-term studies are not yet available, several short-term studies of intra-vitreal bevacizumab have shown improvement in VA that is similar to the improvement with ranibizumab. Intra-vitreal bevacizumab appears to have systemic adverse events similar to those of ranibizumab, which is designed to block new blood vessel growth and leakiness, and is the first treatment which, when given monthly, can maintain the vision of more than 90 % of patients with wet ARMD. In contrast to pegaptanib, ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF. Ranibizumab exhibits high affinity for human VEGF and exerts its neutralizing effects by inhibiting the VEGF-receptor interaction. Unlike the larger whole antibody, ranibizumab can penetrate the internal limiting membrane and reach the subretinal space following intra-vitreal injection (van Wijngaarden et al, 2005).

In an editorial on the use of intra-vitreal bevacizumab as the low cost alternative to ranibizumab published in the American Journal of Ophthalmology, Rosenfeld (2006) stated that "[c]urrently, there appears to be a global consensus that the treatment strategy using intra-vitreal Avastin is logical, the potential risks to our patients are minimal, and the cost-effectiveness is so obvious that the treatment should not be withheld". On March 20, 2006, a survey by the American Society of Retinal Specialists of its membership was completed. It found that 92 % of 289 respondents felt intra-vitreal bevacizumab was "somewhat better" or "much better" than other FDA-approved or covered therapies. Only 4 % of respondents had seen any thromboembolic complications thought to be related to the intra-vitreal bevacizumab, and 96 % thought intra-vitreal bevacizumab was the same or better in terms of overall safety compared to other FDA-approved or covered therapies.

On April 20, 2006, the American Academy of Ophthalmology (AAO) wrote to the Centers for Medicare and Medicaid Services supporting the reimbursement for treating ARMD with intra-vitreal injections of bevacizumab to meet the medical needs of patients who have not responded to Visudyne PDT or intra-vitreal pegaptanib. The AAO's support for reimbursement is limited to "such patients who are deemed by their treating physician to have failed FDA-approved therapies, or in the judgment of their treating physician, based on his/her experience, are likely to have greater benefit from the use of intra-vitreal bevacizumab". On October 5, 2006, the National Institutes of Health's National Eye Institute said it will fund a multi-center clinical trial to compare ranibizumab with bevacizumab in the treatment of ARMD (NIH, 2006).

In a Cochrane review, Vedula and Krzystolik (2008) examined the effects of anti-VEGF modalities for treating neovascular ARMD. These investigators concluded that pegaptanib and ranibizumab reduce the risk of VA loss in patients with neovascular ARMD. Ranibizumab causes gains in VA in many eyes. Other agents blocking VEGF are being tested in ongoing trials.

In a multi-center, randomized controlled trial (RCT), the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group (2012) described

the effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years, and
the impact of switching to as-needed treatment after 1 year of monthly treatment.

Subjects (n = 1,107) were those who were followed-up during year-2 among 1,185 patients with neovascular ARMD who were enrolled in the clinical trial. At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were re-assigned randomly to monthly or as-needed treatment, without changing the drug assignment. Main outcome measure was mean change in VA. Among patients following the same regimen for 2 years, mean gain in VA was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95 % CI: -3.7 to 0.8; p = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95 % CI: -4.8 to -0.1; p = 0.046). The proportion without fluid ranged from 13.9 % in the bevacizumab-as-needed group to 45.5 % in the ranibizumab monthly group (drug, p = 0.0003; regimen, p < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; p = 0.03) and a lower proportion without fluid (-19 %; p < 0.0001). Rates of death and arterio-thrombotic events were similar for both drugs (p > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9 % versus 31.7 %; adjusted risk ratio, 1.30; 95 % CI: 1.07 to 1.57; p = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting VEGF. The authors concluded that ranibizumab and bevacizumab had similar effects on VA over a 2-year period. Treatment as needed resulted in less gain in VA, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arterio-thrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

In a prospective, double-masked, placebo-controlled, randomized clinical study, Lee and colleagues (2007) examined the effect of intra-vitreal injection of high-dose triamcinolone acetonide on minimally classic or occult CNV secondary to ARMD. The treatment group (21 eyes) received intra-vitreal injection (20 to 25 mg) of triamcinolone acetonide and the control group (18 eyes) received intra-vitreal injection (500 mug) of dexamethasone at 6-month intervals. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) score, contrast sensitivity score, and central macular volume were measured at 1 month, 3 months, 6 months, and 12 months. Mean baseline best-corrected VA (BCVA [logarithm of the minimal angle of resolution]) was 0.64 (Snellen equivalent, 20/80) in each group. At 1 month, 3 months, and 6 months after the injection, neither group had a significant change in BCVA. At 12 months, mean BCVA +/- SD significantly decreased to 1.06 +/- 0.34 (Snellen equivalent, 20/200) in the treatment group (paired t-test, p < 0.001), whereas it was 0.78 +/- 0.52 (Snellen equivalent, 20/125) in the control group (p = 0.23). The difference was marginally significant (p = 0.06, Student's t-test). All phakic eyes in the treatment group developed marked cataract progression. The authors concluded that intra-vitreal injection of high-dose triamcinolone had no beneficial effect on eyes with minimally classic or occult CNV secondary to ARMD and was associated with outcomes similar to those associated with intra-vitreal injection of dexamethasone, which was used as placebo.

On November 18, 2011, the FDA approved aflibercept ophthalmic solution (Eylea, Regeneron Pharmaceuticals Inc.) for the treatment of neovascular (wet) ARMD. The FDA's approval of Eylea was based on positive results from the 2 phase III VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials. Both found the drug non-inferior to ranibizumab, which is currently the most potent FDA-approved treatment option for wet ARMD. The most commonly reported adverse events in patients receiving aflibercept included eye pain, conjunctival hemorrhage, vitreous floaters, cataract, and an increase in eye pressure. Aflibercept should not be used in those who have an active eye infection or active ocular inflammation. It has not been studied in pregnant women, so the treatment should be used only in pregnant women if the potential benefits of the treatment outweigh any potential risks. Age-related macular degeneration does not occur in children and aflibercept has not been studied in children. The recommended dose is 2 mg every 4 weeks (monthly) for the first 12 weeks, followed by 2 mg every 8 weeks (2 months).

In a review, Jager and colleagues (2008) discussed several evolving methods in the treatment of neovascular ARMD. Intra-vitreal administration of bevasiranib, a small interfering RNA agent, inhibits intra-cellular transcription of VEGF. This agent appears to inhibit CNV; phase III clinical trials are underway to ascertain its effectiveness in treating ARMD (Chappelow and Kaiser, 2008). The implantation of artificial intra-ocular devices might benefit patients who are refractory to pharmacotherapies. Implantable miniature telescopes might improve the quality of life of patients with severe visual loss from end-stage ARMD. Surgical implantation of optic nerve, cortical (visual cortex), subretinal, and epiretinal electrically stimulated devices have all led to the perception of phosphenes (discrete, reproducible perceptions of light) in humans. These devices may help restore functional vision in the future but are primitive at present.

Artificial lens systems usually consist of a single miniature telescope prosthesis or a combination of individual lenses implanted separately. Implantation is performed under local anesthesia. The natural lens is removed through a small incision at the limbus and the new lens system is inserted. An iridectomy is performed to prevent pupillary block. The exact technique for implantation may vary according to the system being used.

On July 6, 2010, the FDA approved the implantable miniature telescope (IMT) (VisionCare Ophthalmic Technologies, Saratoga, CA) for patients aged 75 years and older with stable, untreatable, severe-to-profound vision impairment (when vision impairment has not changed over time) caused by blind spots (bilateral central scotoma) associated with end-stage ARMD with evidence of a visually significant cataract.

In October 2014, the FDA expanded approval of IMT to patients 65 years of age or older. FDA approval to expand access to those age 65 and older was based on clinical data provided by the pivotal safety and efficacy study, IMT-002, and long-term studies IMT-002-LTM and IMT-002-LTME, which followed patients to 5 and 8 years, respectively.

The IMT device is a compound telescope system that consists of a glass cylinder (4.4 mm in length and 3.6 mm in diameter) housing wide-angle micro-optics. The height of the glass cylinder approximately equals that of 13 stacked intraocular lenses (IOLs). The device is heavier (115 mg in air and 60 mg in aqueous) and the carrier haptics are less flexible than those found on 1-piece polymethylmethacrylate IOLs. The IMT device is surgically implanted in the posterior chamber of the eye after removal of the eye’s lens and is designed to be implanted in 1 eye only; the implanted eye provides central vision, while the non-implanted eye is used for peripheral vision. The IMT protrudes 0.1 to 0.5 mm through the papillary plane, leaving a minimum of 2.0 mm of corneal clearance. When properly implanted in eyes with anterior chamber depths of 2.5 mm or more, the face of the optic should not touch the corneal endothelium. The device provides higher resolution images to the central retina and its telephoto effect also allows more to be seen in the central visual field. The device is used for both near and distance activities, with objects being brought into focus by standard spectacles. Prior to implantation, patients must agree to undergo training with an external telescope with a low vision specialist to determine whether adequate improvement in vision with the external telescope can be obtained and to verify if the patient has adequate peripheral vision in the eye that would not be implanted. Patients must also agree to participate in a post-operative visual training program. The device is available in 2 models: one provides 2.2 x magnification and the other provides 2.7 x magnification.

The IMT-002 clinical trial (Hudson et al, 2006) evaluated the safety and efficacy of VisionCare’s IMT in patients with bilateral, end-stage ARMD in a prospective, open-label, multi-center clinical trial with fellow eye controls. A total of 217 patients (mean age of 76 years) with ARMD and moderate to profound bilateral central VA loss (20/80 to 20/800) resulting from bilateral untreatable geographic atrophy, disciform scars, or both were enrolled; however, 11 eyes did not receive the device because of an aborted procedure. The IMT was implanted monocularly in the capsular bag after lens extraction. Fellow eyes were not implanted to provide peripheral vision and served as controls. Study patients participated in 6 visual rehabilitation visits after surgery. The majority of patients (90 %) met or exceeded the VA end-point defined as an improvement in 2 lines or more in either near or distance BCVA at the 1-year follow-up. Change in VA was not related to lesion type. Mean quality-of-life scores from the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) and the Activities of Daily Life scale, a secondary outcome measure, improved by more than 7 points from baseline on 7 of 8 relevant subscales (e.g., social functioning, mental health, role difficulties, and dependency); at 12 months, 51.8 % (100/193) of patients gained at least 5 points, 25.9 % (50/193) of patients reported no change (i.e., change within +/- 5 points), and 22.3 % of patients (43/193) lost at least 5 points in VFQ-25 composite score from baseline. Mean endothelial cell density (ECD) loss at 3 months was 20 % and 25 % at 12 months. The decrease in ECD was correlated with post-surgical edema, and there was no evidence that endothelial cell loss accelerated by ongoing endothelial trauma after implantation. The authors concluded that the IMT can improve VA and quality of life in patients with moderate-to-profound visual impairment caused by bilateral, end-stage ARMD.

Because the IMT is large and non-foldable, it requires a much larger incision (12 mm) than phacoemlusification with foldable IOL. The risk of corneal endothelial cell loss during implantation is higher than conventional anterior segment procedures, but is comparable with that seen after large-incision cataract extraction (Colby et al, 2007). Significant losses in ECD may lead to corneal edema, corneal decompensation, and the need for corneal transplant. In the IMT-002 trial, 10 eyes had unresolved corneal edema, with 5 resulting in corneal transplants. The device was removed from 8 eyes post-operatively (4 subjects requested removal because they were dissatisfied with the device, 2 were removed due to condensation of the telescope portion, and 2 eyes underwent corneal transplantation as a result of corneal decompensation). The calculated 5-year risk for unresolved corneal edema, corneal decompensation, and corneal transplant are 9.2 %, 6.8 % and 4.1 %, respectively (FDA, 2010). Four device failures were reported during the IMT-002 trial.

According to the manufacturer's website, the IMT is intended for monocular implantation in patients aged 65 years and older with stable, untreatable, severe-to-profound vision impairment caused by blind spots (bilateral central scotoma) associated with end-stage ARMD as determined by fluorescein angiography when all of the following are met:

Achieve at least a 5-letter improvement on the Early Treatment Diabetic Retinopathy Study (ETDRS) VA chart in the eye scheduled for surgery using an external telescope; and
Adequate peripheral vision in the eye not scheduled for surgery; and
Agree to undergo 2 to 4 pre-surgical training sessions with low vision specialist (optometrist or occupational therapist); and
Evidence of a visually significant cataract (grade 2 or higher); and
No active wet ARMD (no sign of active CNV in either eye); and
No sign of eye disease other than well-controlled glaucoma; and
Not been treated for wet ARMD in the previous 6 months; and
Stable, untreatable ARMD disease present in both eyes (end-stage, geographic atrophy or disciform scar) as determined by fluorescein angiography; and
Visual acuity poorer than 20/160, but not worse than 20/800 in both eyes; and
Willingness to participate in a post-operative visual rehabilitation program.

As a condition of FDA approval, the manufacturer must conduct 2 post-approval studies:

VisionCare must continue follow-up on the subjects from its long-term follow-up cohort for an additional 2 years, and
an additional study of 770 newly enrolled subjects will include an evaluation of the ECD and related adverse events for 5 years after implantation.

The IMT is contraindicated in patients with any of the following:

A history of steroid-responsive rise in intra-ocular pressure (IOP), uncontrolled glaucoma, or pre-operative IOP greater than 22 mm Hg while on maximum medication;
Any ophthalmic pathology that compromises the patient’s peripheral vision in the fellow eye;
Evidence of active CNV on fluorescein angiography or treatment for CNV within the past 6 months;
Known sensitivity to post-operative medications;
Previous intra-ocular or corneal surgery of any kind in the operative eye, including any type of surgery for either refractive or therapeutic purposes;
Prior or expected ophthalmic related surgery within 30 days preceding IMT implant surgery;
Significant communication impairments or severe neurological disorders;
Stargardt's macular dystrophy;
The planned operative eye has any of the following:
- A history of retinal detachment
- A narrow angle (i.e., less than Schaffer grade 2)
- An axial length less than 21 mm
- An ocular condition that predisposes the patient to eye rubbing
- Central anterior chamber depth less than 3.0 mm (measured from the posterior surface of the cornea (endothelium) to the anterior surface of the crystalline lens
- Cornea stromal or endothelial dystrophies or disorders, including guttata
- Diabetic retinopathy
- Endothelial cell counts below the following minimum baseline:
  - Aged 65 to 84 years with ECD below 2,000 cells/mm²
  - Aged 85 years or older with ECD below 1,800 cells/mm²
- Hyperopia greater than 4.0 diopters
- Inflammatory ocular disease
- Intraocular tumor
- Myopia greater than 6.0 diopters
- Optic nerve disease
- Retinal vascular disease
- Retinitis pigmentosa
- Untreated retinal tears
- Zonular weakness/instability of crystalline lens, or pseudoexfoliation.

One of the internal components of the IMT implant containing stainless steel has been evaluated for magnetic resonance imaging (MRI) compatibility and determined to be MR-conditional.

The National Institute for Clinical Excellence's (NICE, 2008) guidance on implantable miniature lens systems for the treatment of ARMD stated that: "[e]vidence on the efficacy of implantation of miniature lens systems for advanced age-related macular degeneration (AMD) shows that the procedure can improve both vision and quality of life in the short-term. Short-term safety data are available for limited numbers of patients. There is currently insufficient long-term evidence on both efficacy and safety. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research." The National Institute for Clinical Excellence included a non-randomized study and a case series study as part of the evidence review. In the non-randomized study of 217 patients, 67 % (128/192) and 68 % (130/192) of eyes with an implanted lens system improved by 3 or more lines of best-corrected distance and near VA, respectively, compared with 13 % (24/192) and 33 % (64/192) of non-implanted fellow eyes (p less than 0.0001) at 1-year follow-up. Loss of 2 or more lines of best-corrected distance VA was reported in 2 % of implanted eyes and 9 % of fellow eyes at 1-year follow-up (p = 0.005). Two patients developed corneal decompensation and underwent device removal and corneal transplantation more than 1 year after the initial surgery and 5 % of the procedures were aborted due to complications (e.g., posterior capsule rupture and choroidal effusion/hemorrhage). In a case series study of 35 patients (40 eyes), best-corrected distance VA improved in all patients after a mean of 20 months. Other complications in the non-randomized study and case series study included increased IOP requiring treatment (28 % [57/206]) and corneal edema (25 % [9/36], 7 % [14/206]). Two specialist advisors reported corneal endothelial cell loss as an adverse event. They considered additional theoretical complications to include corneal decomposition and corneal and macular edema. One specialist advisor commented that the procedure has more risks than standard cataract surgery. Furthermore, the Committee noted that there are several different lens systems available and that the technique is still evolving.

An UpToDate review on "Age-related macular degeneration: Treatment and prevention" (Arroyo, 2014) states that "Two procedures have been tried, with limited success, for AMD: submacular surgery and macular translocation surgery. Submacular surgery involves the removal of abnormal subretinal neovascularization and large submacular hemorrhages, if present. Clinical trials have been largely disappointing, showing lack of benefit and high rates of retinal detachment. There may be a role for submacular surgery, however, in patients with large peripapillary membranes. Macular translocation surgery is experimental and involves moving the macula to a less diseased area of the retina in patients with subfoveal choroidal neovascularization. The advent of effective pharmacologic therapy has limited the use of this surgical modality to patients with large submacular hemorrhages. The surgical risks are substantial …. External beam radiation therapy has been studied in patients with AMD. A meta-analysis of randomized, controlled trials concluded that there was no consistent evidence of benefit. The long-term safety of radiation therapy is unknown".

Si and colleagues (2014) compared the safety and effectiveness of combination of ranibizumab with PDT versus ranibizumab monotherapy in the treatment of ARMD. The Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, and Embase were searched. There were no language or data restrictions in the search for trials. Only RCTs were included. Methodological quality of the literatures was evaluated according to the Jadad Score. RevMan 5.2.6 software was used to do the meta-analysis. A total of 7 studies were included in this systematic review, among which 4 of them were included in quantitative analysis. The result showed that the ranibizumab monotherapy group had a better mean BCVA change versus baseline at month 12 compared with that of the combination treatment group, and the statistical difference was significant (weighted mean difference [WMD], -2.61; 95 % CI: -5.08 to -0.13; p = 0.04). However, after the removal of 1 study, the difference between the 2 groups showed no significant difference (WMD, -2.29; 95 % CI: -4.81 to 0.23; p = 0.07). Meanwhile, no significant central retinal thickness (CRT) reduction was found in the combination treatment group and the ranibizumab monotherapy group at 12 months follow-up. Nevertheless, the combination group tended to have a greater reduction in CRT (WMD, -4.13 µm; 95 % CI: -25.88 to 17.63, p = 0.71). The proportion of patients gaining more than 3 lines at month 12 in the ranibizumab group was higher than in the combination group and there was a significant difference (RR, 0.72; 95 % CI: 0.54 to 0.95; p = 0.02). Whereas there was no significant difference for the proportion of patients gaining more than 0 line at month 12 between the 2 groups (RR, 0.93; 95 % CI: 0.76 to 1.15; p = 0.52). The general tendency showed a reduction in ranibizumab re-treatment number in the combination treatment group compared with the ranibizumab monotherapy group. As major adverse events, the differences in the number of eye pain, endophthalmitis, hypertension and arterial thromboembolic events were not significant between the 2 groups, and the incidence of serious adverse events in the 2 groups was very low. The authors concluded that for the maintenance of vision, the comparison of the combination of ranibizumab with PDT versus ranibizumab monotherapy showed no apparent difference. Compared with the combination of ranibizumab and PDT, patients treated with ranibizumab monotherapy may gain more VA improvement. The combination treatment group had a tendency to reduce the number of ranibizumab re-treatment. Both treatment strategies were well-tolerated.

Jiang et al (2014) noted that ranibizumab is used monthly or as-needed (PRN) for the treatment of ARMD. However, which treatment regimen is more effective remains unknown. These investigators compared the effectiveness of monthly versus as-needed quarterly treatment; and the effectiveness of ranibizumab 0.5 mg treatment with:

no anti- VEGF;
ranibizumab 0.3 mg; and
bevacizumab.

This was a systematic meta-analytic review of RCTs of ranibizumab in neovascular AMD. Weighted multiple regression analyses were used to compare the monthly versus PRN/quarterly treatment. A total of 8 RCTs met inclusion criteria. Patients on the monthly ranibizumab treatment had higher VA letter gains (β = 0.441, p < 0.05) compared with patients on as-needed/quarterly treatment. More patients on the monthly treatment gained greater than or equal to 15 letters than as-needed/quarterly treatment (β = 0.582, p < 0.05). Ranibizumab produced significantly higher improvement in VA (d = 1.20, z = 7.14, p < 0.05) and led to a higher proportion of patients gaining greater than or equal to 15 letters (odds ratios [OR]: 6.67; 9 5% CI: 3.16 to 14.06; p < 0.05) when compared with non-anti-VEGF. Ranibizumab did not show any advantage in VA compared with bevacizumab. No significant differences were found between ranibizumab 0.3 mg and 0.5 mg. The authors concluded that this was the first meta-analysis to systematically evaluate the effectiveness of different treatment regimens for anti-VEGF therapy. Ranibizumab 0.3 or 0.5 mg monthly treatment was more effective for neovascular AMD than non-anti-VEGF treatments; but is no better than bevacizumab.

MacLaren et al (2014) examined the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with choroideremia. In a multi-center clinical trial, a total of 6 male patients (aged 35 to 63 years) with choroideremia were administered AAV.REP1 (0.6 to 1.0×10(10) genome particles, subfoveal injection). Visual function tests included BCVA, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. Despite undergoing retinal detachment, which normally reduces vision, 2 patients with advanced choroideremia who had low baseline BCVA gained 21 letters and 11 letters (more than 2 and 4 lines of vision). Four other patients with near normal BCVA at baseline recovered to within 1 to 3 letters. Mean gain in VA overall was 3.8 letters (SE 4.1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23.0 dB (SE 1.1) at baseline to 25.3 dB (1.3) after treatment (increase 2.3 dB [95 % CI: 0.8 to 3.8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1.7 [SE 1.0]) was correlated with the vector dose administered per mm(2) of surviving retina (r = 0.82, p = 0.04). By contrast, small non-significant reductions (p > 0.05) were noted in the control eyes in both maximal sensitivity (-0.8 dB [1.5]) and mean sensitivity (-1.6 dB [0.9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector. The authors concluded that the initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. They stated that these findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as ARMD, for which intervention should ideally be applied before the onset of retinal thinning.

Shin et al (2016) stated that clinical study findings regarding the association between repeated injections of intra-vitreal anti-VEGF and the risk of retinal nerve fiber layer (RNFL) thinning in patients with ARMD have been inconsistent. These researchers investigated this association by using a meta-analysis. In August 2015, these investigators systematically reviewed PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Two independent evaluators identified eligible articles by using pre-determined selection criteria. Average RNFL thickness before and after intra-vitreal anti-VEGF injections was examined by using data obtained at baseline and at the last follow-up visit. A total of 6 studies on 288 eyes were ultimately included. The meta-analysis revealed that average RNFL thickness following repeated anti-VEGF injections was not significantly different from baseline (mean difference [MD] = -0.171, 95 % CI: -0.371 to 0.029, p = 0.093) or control group measurements (MD = -0.091, 95 % CI: -0.517 to 0.335, p = 0.674). However, subgroup analyses by the methodological quality of study revealed a significant RNFL thickness loss in 2 low-biased, controlled experimental studies (MD = -0.534, 95 % CI: -0.783 to -0.286, p = 0.001), but not in 4 observational studies (MD = -0.038, 95 % CI: -0.171 to 0.095, p = 0.576). The authors concluded that there was no association between anti-VEGF injections and RNFL thickness changes when all studies were examined together. However, when 2 low-biased, controlled clinical trials were separately examined, repeated anti-VEGF injection was associated with RNFL loss. They stated that large-scale, prospective studies are needed to determine long-term effects of anti-VEGF treatments on the RNFL in ARMD patients.

Prevention of ARMD

In a meta-analysis, Chuo and colleagues (2007) examined the effect of lipid-lowering agents in the development of ARMD. Case-control and cohort studies presenting relative risks and 95 % CI were identified through a literature review. Inclusion was limited to studies where both the exposure of interest (lipid-lowering agents) and outcome (ARMD) were explicitly defined. Pooled estimates were computed using the random effects model. To quantify heterogeneity, these researchers calculated the proportion of total variance of between study variance using the Ri statistic. The Q statistic for heterogeneity was also calculated. Eight studies were identified. The pooled RR for all studies was 0.74 (95 % CI: 0.55 to 1.00). When only those studies examining the use of statins were pooled (n = 7), the RR was 0.70 (95 % CI: 0.48 to 1.03). Using the Ri statistic, the heterogeneity between studies was found to be 0.85 for all studies and 0.89 for studies examining statins. The authors concluded that lipid-lowering agents, including statins, do not appear to lower the risk of developing ARMD, although clinically significant effects can not be excluded. The use of these agents in the prevention of ARMD can not be recommended until well-designed prospective studies with long-term follow-up have demonstrated a benefit.

Evans and Henshaw (2008) stated that some observational studies have suggested that people who eat a diet rich in antioxidant vitamins (e.g., carotenoids, vitamins C and E) or minerals (e.g., selenium and zinc) may be less likely to develop ARMD. In a Cochrane review, these researchers examined the evidence as to whether or not taking vitamin or mineral supplements prevents the development of ARMD. They included all randomized trials comparing an antioxidant vitamin and/or mineral supplement (alone or in combination) to control; and included only studies where supplementation had been given for at least 1 year. Three RCTs were included in this review (23,099 people randomized). These trials investigated alpha-tocopherol and beta-carotene supplements. There was no evidence that antioxidant vitamin supplementation prevented or delayed the onset of ARMD. The pooled risk ratio for any age-related maculopathy (ARM) was 1.04 (95 % CI: 0.92 to 1.18), for ARMD (late ARM) was 1.03 (95 % CI: 0.74 to 1.43). Similar results were seen when the analyses were restricted to beta-carotene and alpha-tocopherol. The authors concluded that there is no evidence to date that the general population should take antioxidant vitamin and mineral supplements to prevent or delay the onset of ARMD.

Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced ARMD. Observational data suggested that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. The Age-Related Eye Disease Study 2 (AREDS2) RCT examined if adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced ARMD and evaluated the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. The AREDS2 is a multi-center, randomized, double-masked, placebo-controlled phase III study with a 2 × 2 factorial design, conducted in 2006 to 2012 and enrolling 4,203 participants aged 50 to 85 years at risk for progression to advanced ARMD with bilateral large drusen or large drusen in 1 eye and advanced ARMD in the fellow eye. Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both. Main outcome measure was development of advanced ARMD. The unit of analyses used was by eye. Median follow-up was 5 years, with 1,940 study eyes (1,608 participants) progressing to advanced ARMD. Kaplan-Meier probabilities of progression to advanced ARMD by 5 years were 31 % (493 eyes [406 participants]) for placebo, 29 % (468 eyes [399 participants]) for lutein + zeaxanthin, 31 % (507 eyes [416 participants]) for DHA + EPA, and 30 % (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced ARMD (hazard ratio [HR], 0.90 [98.7 % CI: 0.76 to 1.07]; p = 0.12 for lutein + zeaxanthin; 0.97 [98.7 % CI: 0.82 to 1.16]; p = 0.70 for DHA + EPA; 0.89 [98.7 % CI: 0.75 to 1.06]; p = 0.10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced ARMD. More lung cancers were noted in the beta carotene versus no beta carotene group (23 [2.0 %] versus 11 [0.9 %], nominal p = 0.04), mostly in former smokers. The authors concluded that addition of lutein + zeaxanthin (Lutemax 2020), DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced ARMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.

In a multi-center, phase III, RCT, Dugel et al (2013) evaluated the safety and effectiveness of epi-macular brachytherapy (EMBT; also known as epiretinal brachytherapy) for the treatment of neovascular ARMD. A total of 494 participants with treatment-naïve neovascular ARMD were included in this study. Participants with classic, minimally classic, and occult lesions were randomized in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received 2 mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received 3 mandated, monthly loading injections of ranibizumab then quarterly injections. Both arms also received monthly as needed (pro re nata) re-treatment. Main outcome measures included the proportion of participants losing fewer than 15 ETDRS letters from baseline VA and the proportion gaining more than 15 ETDRS letters from baseline VA. At 24 months, 77 % of the EMBT group and 90 % of the control group lost fewer than 15 letters. This difference did not meet the pre-specified 10 % non-inferiority margin. This end-point was non-inferior using a 20 % margin and a 95 % CI for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The EMBT did not meet the superiority end-point for the proportion of participants gaining more than 15 letters (16 % for the EMBT group versus 26 % for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. Mean VA change was -2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least 1 serious adverse event occurred in 54 % of the EMBT arm, most commonly post-vitrectomy cataract, versus 18 % in the control arm. Mild, non-proliferative radiation retinopathy occurred in 3 % of the EMBT participants, but no case was vision threatening. The authors concluded that the 2-year effectiveness data do not support the routine use of EMBT for treatment-naive wet ARMD, despite an acceptable safety profile. They stated that further safety review is needed.

Petrarca et al (2013) reported the optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) results of the MERITAGE (Macular Epiretinal Brachytherapy in Treated Age-Related Macular Degeneration) study. In this prospective, multi-center, interventional, non-controlled clinical trial, a total of 53 eyes of 53 participants with chronic, active neovascular ARMD requiring frequent anti-VEGF re-treatment were enrolled. Participants underwent pars plana vitrectomy with a single 24-gray dose of EMBT, delivered with an intra-ocular, hand-held, cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were re-treated with ranibizumab administered monthly as needed, using pre-defined re-treatment criteria. Patients underwent FFA at baseline, month 1, and month 12. Patients underwent OCT at baseline and then monthly for 12 months. The FFA and OCT images were evaluated by independent, central reading facilities. Main outcome measures included change in OCT center-point thickness and angiographic lesion size 12 months after EMBT. Mean center-point thickness increased by 50 μm, from 186 to 236 μm (p = 0.292), but 70 % of participants had an increase of less than the mean, with a median increase of only 1.8 μm. The FFA total lesion size increased slightly by 0.79 mm(2), from 14.69 to 15.48 mm(2) (p = 0.710). Total CNV area increased by 1.17 mm(2), from 12.94 to 14.12 mm(2) (p = 0.556). The classic CNV area decreased substantially by 3.70 mm(2), from 3.90 to 0.20 mm(2) (p < 0.01). Predominantly classic lesions showed the greatest response, with mean ETDRS VA improving by 1.5 letters (versus -4.0 for all participants combined); mean center-point thickness decreased by 43 μm (p = 0.875). The angiographic and OCT response did not correlate with lesion size at baseline. The authors concluded that in chronic, active, neovascular ARMD, EMBT is associated with non-significant changes in center-point thickness and FFA total lesion size over 12 months. Moreover, they stated that "Although EMBT may be most appropriate for the treatment of classic ARMD, larger studies are needed".

Ciliary Neurotrophic Factor

Zhang and colleagues (2011) stated that there is no treatment available for vision loss associated with advanced dry ARMD or geographic atrophy (GA). In a pilot, proof of concept phase II study, these investigators evaluated ciliary neurotrophic factor (CNTF) delivered via an intra-ocular encapsulated cell technology implant for the treatment of GA. They designed a multi-center, 1-year, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high- or low-dose implant or sham surgery. The primary endpoint was the change in BCVA at 12 months. Ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by VA stabilization (loss of less than 15 letters) in the high-dose group (96.3 %) compared with low-dose (83.3 %) and sham (75 %) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100 % of patients in the high-dose group lost less than 15 letters compared with 55.6 % in the combined low-dose/sham group (p = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (p = 0.0315). Both the implant and the implant procedure were well-tolerated. The authors concluded that these findings suggested that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline. The findings of this phase II clinical study need to be validated by well-designed studies.

ForeseeHome Technology

Chew et al (2013) reported that home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, resulted in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. For this nonmasked randomized controlled trial, 1970 participants 53 to 90 years of age at high risk of CNV development were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 (AREDS2) clinical centers, a clinical trial of nutritional supplements for the prevention of AMD. Participants had either bilateral large drusen (potentially 2 study eyes) or large drusen in 1 eye (study eye) and advanced AMD in the fellow (nonstudy eye) and best-corrected visual acuity (BCVA) of 20/60 or better in the study eye(s). In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. Aids such as Amsler grids could be recommended. In the device arm, in addition to receiving standard care instructions, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and December 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, - 4 letters; interquartile range [IQR], - 11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, - 14.0 to -.0 letters; p = 0.021), resulting in better visual acuity at CNV detection in the device arm.

An editorialist (Han, 2014) commented that, "[d]espite its efficacy in the HOME trial, the effectiveness of the ForeSeeHome device in the ‘real world’ remains uncertain. Notably, the study experienced a 23% screen failure rate. A similar rate of failure in a clinical setting could be a factor in its effectiveness." The editorialist also noted that the HOME study was not intended to compare the ForeSeeHome device with use of the Amsler grid as a stand-alone approach, and that it is possible that mandatory, supervised use of the Amsler grid may have increased the success rate in the control arm.

Guidelines on the management of neovascular age-related macular degeneration (AMD) from the European Society of Retina Specialists (EURETINA) (Schmidt-Erfurth, et al., 2014) state that "patients should be instructed to self-monitor their vision between routine office visits. By contrast with current home monitoring strategies, those with intermediate AMD (large drusen in one or both eyes) could benefit from home monitoring with PHP [preferential hyperacuity perimetry], whenever the device is available."

An American Academy of Ophthalmology preferred practice pattern on age-related macular degeneration (AAO, 2014) states: "Electronic monitoring devices are now available to aid in the detection of neovascularization at an early stage. Such devices use hyperacuity perimetry (or Vernier acuity) to create a quantified central visual map of metamorphosia. Further studies of a variety of such devices are ongoing."

Chew and associates (2014) evaluated the effects of a home-monitoring device with tele-monitoring compared with standard care in detection of progression to CNV associated with ARMD, the leading cause of blindness in the US. The authors noted that the study design appeared to be feasible despite challenges to conducting such a multi-site randomized study for a tele-monitoring device, resulting in the enrollment of greater number of participants than the anticipated sample size in a large number of clinics, with potential for answering an important clinically relevant research question. Limitation of the study includes decreased generalizability of the results for all persons with intermediate ARMD as an anticipated number of participants may not successfully pass the screening for the testing. However, the results may have impact on the management of persons with ARMD, a disease of public health importance.

Chaikitmongkol et al (2015) described clinical and imaging findings in 2 eyes with new onset subtle neovascular ARMD that was detected by the regular use of a home monitoring device based on preferential hyper-acuity visual field testing. The authors concluded that this report demonstrated the potential utility of a home monitoring program in a clinical setting. They stated that although both patients described in this report were participants in a home monitoring program study, and thus, might be better trained and experienced in using the device than a typical patient in a clinic, the cases nevertheless demonstrated the potential value of the device in detecting the earliest manifestation of the CNV.

Chew and colleagues (2016) determined the effectiveness of different monitoring modalities to detect incident neovascularization associated with ARMD. They concluded that tele-monitoring may alter the management of patients with ARMD and improve vision outcomes. They stated that a key limitation of the home monitoring device is the exclusion of persons with ARMD who were not able to use the technology or to establish the crucial reproducible baseline values for future comparisons. Furthermore, the utility of the device is not known for those individuals who are monitored more frequently such as patients receiving monthly intra-vitreal injections of anti-VEGF in their fellow eye. To fully explore the utility for this subset of individuals, further studies are needed.

The American Academy of Ophthalmology (AAO)’s preferred practice pattern on “Age-related macular degeneration” (AAO, 2019) stated that “Patients with early AMD and/or a family history of AMD should be encouraged to assess their own VA using monocular vision testing (i.e., Amsler grid or electronic home monitoring [AREDS2-HOME Study Research Group, 2014 and Chew et al, 2014]) and have scheduled dilated eye examinations for detecting the intermediate stage of AMD.

In a retrospective analysis of electronic health records, Yu et al (2021) examined the real-world utility of the ForeseeHome monitoring device (Notal Vision, Ltd., Tel Aviv, Israel) for the detection of conversion from intermediate age-related macular degeneration (iAMD) to neovascular AMD (nAMD) and compared with results published by the Home Monitoring of the Eye (HOME) study. Participants were eyes prescribed use of the ForeseeHome device across 4 retinal practices in the U.S. Usage information was collected from the online ForeseeHome portal for all eyes prescribed the device. For a pre-determined subset of eyes, additional clinical information was collected via chart review and analyzed for clinical utility. Main outcome measures included frequency and length of use, number of eyes that used the device, number of eyes that established a baseline measurement, number of eyes that converted to nAMD, and number of alerts. A total of 775 eyes of 448 patients were prescribed use of the ForeseeHome device; 649 eyes (83.7 %) used the device at least once; among this population, 478 (73.7 %) established a baseline measurement. Patients who established a baseline measurement were significantly younger than those who did not (p < 0.001). Among eyes that established a baseline measurement, 126 (26.4 %) had an overall inadequate frequency of use (greater than or equal to 2 tests per week), and 250 (52.3 %) did not use the device as frequently as instructed by the manufacturer (greater than or equal to 3 tests per week); 24.7 % of eyes discontinued use within 1 year. Of the 136 eyes that established a baseline measurement among 211 eyes prescribed the device at 1 clinical site, 52 alerts were recorded; 3 (6.8 %) correctly identified conversion to nAMD and 47 (93.2 %) represented false-positive alerts. The authors concluded that compared with the prospective HOME study, the use of the ForeseeHome device in the current analysis of clinical practice application was limited. A meaningful proportion of eyes never used the device or could not establish a baseline measurement. Overall frequency of use was low, and continuous use of the device decreased over time. These researchers stated that these findings underscored a need for further refinement of the technologies used for home monitoring for the conversation of iAMD to nAMD with the goal of optimizing long-term visual outcomes for patients.

The authors stated that drawbacks of this study included that VA and other aspects of the disease state were not evaluated uniformly throughout the study, and the follow-up time for device use was limited per eye because of the retrospective nature of the study. The retrospective nature of the study also made it difficult to evaluate how compliance with device use was encouraged by physicians and staff longitudinally. It was also unknown how thoroughly patients were prescreened before prescription of the device for their ability to use a computer mouse. The cost of the device for each patient also was not assessed, and the influence of cost could not be evaluated. Furthermore, for eyes that were classified as having never used the device, no distinction was made between whether patients had never filled the prescription or whether they had filled the prescription and never used the device. This study also was limited in its follow-up of test score change alerts and its confirmation of dry AMD or nAMD diagnosis. In the HOME study, every alert was followed-up with clinical examination, FA, and SD OCT, whereas this study only followed-up alerts with SD OCT and clinical examination, with FA being performed only if deemed clinically indicated. Finally, this study did not evaluate possible reasons for false-positive alerts such as structural changes in eyes not resulting from CNV development.

Clemons et al (2021) provided a commentary to statements regarding the use and compliance made by Yu et al (2021) on the real-world experience with the ForeseeHome device (Notal Vision Inc., Manassas, VA). In their analysis, Yu et al (2021) failed to consider that on average, 1.7 eyes per patient were tested (775 eyes of 448 patients prescribed). Multiplying the reported 3.44 tests per week per eye by 1.7 eyes per patient resulted in 5.9 tests per week per patient. This number was larger than the 4.4 tests per week per patient reported in the HOME study; thus, the compliance in the real world was better, not worse, than in the randomized clinical trial. It was important to note that the proclaimed finding that the compliance rate was worse in the real world compared with the HOME study was the basis for the overall sentiment and conclusions of the publication regarding possible lack of motivation by the patients and limited utility of the ForeseeHome age-related macular degeneration monitoring program. Both the HOME study and the real-world study enrolled eyes from the same intermediate dry AMD population with visual acuity of 20/60 or better, which explained why less than 2 eyes per patient were tested. Both studies collected data from the same online database of the system. The publication provided limited information regarding performance of the ForeseeHome device during the real-world study in early detection and vision preservation, probably because of the lack of statistical power to examine these important performance characteristics, which further called into question the claim about the stated limited utility of the program.

Ho et al (2021) noted that the real-world performance of a home telemonitoring strategy (ForeseeHome AMD Monitoring System, Notal Vision, Inc., Manassas VA) was examined and compared to the device arm of the AREDS2-HOME study among patients with iAMD who converted to nAMD. All patients with confirmed conversion to nAMD who used the home monitoring system from October 2009 through September 2018 were identified by Notal Vision Diagnostic Clinic's medical records. Selected outcome variables were evaluated, including visual acuity (VA) at baseline and at conversion, and change in VA from baseline to time of conversion. A total of 8,991 patients performed 3,200,999 tests at a frequency of 5.6 ± 3.2 times/week. The 306 eyes that converted from iAMD to nAMD over the study period (a 2.7 % annual rate) were included in the analyses. There was a median (inter-quartile range [IQR]) change of -3.0 (0.0-(-10.0)) letters among converted eyes, 81 % [95 % confidence interval [CI]: 72 % to 88 %)] maintained a VA of greater than or equal to 20/40 at the time of conversion, while 69 % of the conversion detections were triggered by system alerts. The real-world performance of an at-home testing strategy was similar to that reported for the device arm of the AREDS2-HOME study. The home telemonitoring system could markedly increase early detection of conversion to nAMD. The authors concluded that the findings of this study suggested that the consistent long-term use of an at-home monitoring system may provide a significant benefit to patients as a means of increasing early detection of nAMD with good vision, a known strong predictor for long-term preservation of vision. These conclusions differed from those of another recently published real-world data set (Yu et al, 2020) primarily because the reports evaluated 2 different populations of real-world patients. The current study examined a patient population that had a device with a valid baseline up to and including the time of conversion. Yu et al. [34] evaluated all patients who were prescribed the device, and they cited a large number of patients who did not or could not establish or re-establish a baseline, as well as a considerable number of patients who discontinued use of the device.

The authors stated that the main drawback of this study was that it was a retrospective database analysis. The VA was not available at baseline or at conversion for all patients, and some of the VA values were reported over the telephone, which may have introduced some bias. This review only included patients who converted to nAMD after establishing a baseline on the ForeseeHome monitoring system. In trying to evaluate the sensitivity of the findings to possible methodological limitations resulting from the retrospective, real-world study design, these investigators considered a worst-case scenario in which an unbalanced, larger number of events were triggered by routine visits or symptoms that were not identified and therefore not included in the report, and they found the expected VA loss to be 4.5 letters. Another drawback was that these researchers did not collect information about the outcomes of alerts issued by the home monitoring system that did not result in an immediate identification of conversion to nAMD. These may include alerts that led to conversions to nAMD that were identified after some delay, alerts that led to the diagnosis of non-nAMD pathologies, and those that wound up being false alerts. In some instances, the patient re-established a baseline and resumed testing. However, these drawbacks were mitigated by study strengths, which included the length of review (9 years) and the very large number of tests and monitoring years. Furthermore, the same system was used in both the real-world and the AREDS2-HOME study, with the same support and reminders as reflected in the high weekly frequency of use. This allowed these researchers to avoid some of the typical difference between studies and real-world evidence. Other strengths were the uniquely large number of newly diagnosed nAMD events that were detected early after a period of close follow-up with the ForeseeHome system, which differed from how a typical cohort of treatment-naive nAMD eyes were traditionally diagnosed, treated, and reported during an office visit.

Furthermore, an UpToDate review on “Age-related macular degeneration: Treatment and prevention” (Arroyo, 2021) states that “Follow-up -- The type and frequency of follow-up depend on the severity of the AMD and risk of progression. Ophthalmology follow-up utilizes a number of modalities to monitor patients, including self-examination with Amsler grid, vision test with an eye chart, optical coherence tomography, or fundoscopic examination”. This UTD review does not mention the use of ForeseeHome device / electronic home monitoring.

Low-Vision Rehabilitation

Hamade and colleagues (2016) examined the effect of various low-vision rehabilitation strategies on reading speed and depression in patients 55 and older with ARMD. Computer databases including Medline (OVID), Embase (OVID), BIOSIS Previews (Thomson-Reuters), CINAHL (EBSCO), Health Economic Evaluations Database (HEED), ISI Web of Science (Thomson-Reuters) and the Cochrane Library (Wiley) were searched from the year 2000 to January 2015. Included papers were research studies with a sample size of 20 eyes or greater focused on ARMD in adults aged 55 or older with low vision (20/60 or lower). Two independent reviewers screened and extracted relevant data from the included articles. Standardized mean difference (SMD) was chosen as an effect size to perform meta-analysis using STATA. Fixed- and random-effect models were developed based on heterogeneity. Main outcomes were reading speed and depression scores. A total of 9 studies (885 subjects) were included. Overall, a significant improvement in reading speed was found with a SMD of 1.01 [95 % CI: 0.05 to 1.97]. Low-vision rehabilitation strategies including micro-perimetric biofeedback, microscopes teaching program significantly improved reading speed. Eccentric viewing training showed the maximum improvement in reading speed. In addition, a non-significant improvement in depression scores was found with a SMD of -0.44 [95 % CI: -0.96 to 0.09]. The authors concluded that a considerable amount of research is needed in the area of low-vision rehabilitation strategies for patients with ARMD. They stated that based on current research, low-vision rehabilitation aided in improving reading speed; however, they did not have a significant effect on depression scores in those 55 and older with ARMD.

ABCA1 rs1883025 Polymorphism Testing

Wang et al (2016) evaluated the association of the ABCA1 rs1883025 polymorphism and susceptibility to ARMD. They conducted a systematic search of the PubMed, Embase, and ISI web of science databases to identify eligible published studies without language restrictions up to September 2015. Pooled ORs with 95 % CIs were estimated under different genetic models using meta-analytic methods. Stratified analysis and sensitivity analysis were performed to explore potential sources of heterogeneity. A total of 12 articles with 25,445 cases and 36,460 controls were eligible in this meta-analysis. The ABCA1 rs1883025 variant showed significant association with the lower risk of overall ARMD under the allelic model (OR = 0.81, 95 % CI: 0.74 to 0.89). Stratified analysis based on ethnicity demonstrated a strong association between rs1883025 polymorphism and ARMD in the Caucasian population, but not in Asian population. For late ARMD, the ABCA1 rs1883025 variant was observed to have a significant association with the lower risk of this disease (OR = 0.81, 95 % CI: 0.72 to 0.91). In early-stage ARMD, significant associations of the rs1883025 polymorphism with lower risk of early ARMD were observed in different genetic models (OR ranging from 0.45 to 0.65, all p < 0.05). The authors concluded that the present meta-analysis indicated that the T allelic in rs1883025 variant was significantly associated with the risk of developing ARMD, especially at the early stage. They stated that the associations of the ABCA1 locus with ARMD risk in various populations need further exploration.

CX3CR1 Polymorphism Testing

Li and colleagues (2015) noted that studies investigating the associations between CX3CR1 genetic polymorphisms and ARMD have reported controversial results. In a meta-analysis, these investigators examined the effects of CX3CR1 T280M and V249I polymorphisms on ARMD risk. Results from 6 studies were pooled in the meta-analysis. Relevant studies were selected through an extensive search of PubMed, Embase, and the Web of Science databases. Pooled ORs and 95 % CIs were calculated using random-effects model. A total of 6 studies with were included in this systematic review and meta-analysis. There was no significant association between CX3CR1 T280M polymorphism and risk of AMD under all genetic models (TT versus CC/CT: OR = 1.57, 95 % CI: 0.87 to 2.84; CC versus TT/CT: OR = 0.75, 95 % CI: 0.54 to 1.06; TT versus CC: OR = 0.58, 95 % CI: 0.30 to 1.144; CT versus CC: OR = 1.25, 95 % CI: 0.91 to 1.70). The CX3CR1 V249I polymorphism also did not significantly affect the ARMD risk (AA versus GG/AG: OR = 1.23, 95 % CI: 0.98 to 1.55; AG/AA versus GG: OR = 0.56, 95 % CI: 0.29 to 1.07; AA versus GG: OR = 1.43, 95 % CI: 0.97 to 2.09; AG versus GG: OR = 1.07, 95 % CI: 0.85 to 1.36). The authors concluded that the findings of this meta-analysis suggested that CX3CR1 T280M and V249I polymorphisms may not be associated with an increased risk of ARMD based on current published data. They stated that given the limited sample size, the finding on CX3CR1 polymorphisms needs further investigation.

TLR3 rs3775291 Polymorphism Testing

Ma and colleagues (2016) noted that association of a polymorphism rs3775291 in the toll-like receptor 3 (TLR3) gene in patients with ARMD had been investigated intensively, with variable results across studies. These researchers conducted a meta-analysis to verify the effect of rs3775291 on ARMD. They searched for genetic association studies published in PubMed, Embase and Web of Science from start dates to March 10, 2015. A total of 235 reports were retrieved and 9 studies were included for meta-analysis, involving 7,400 cases and 13,579 controls. Summary ORs with 95 % CIs for alleles and genotypes were estimated. TLR3 rs3775291 was associated with both geographic atrophy (GA) and neovascular ARMD (nARMD), with marginally significant pooled-p values. Stratification analysis by ethnicity indicated that rs3775291 was associated with all forms of ARMD, GA and nARMD only in Caucasians (OR = 0.87, 0.78 and 0.77, respectively, for the TT genotype) but not in East Asians. However, the associations could not withstand Bonferroni correction. The authors concluded that the findings of this meta-analysis revealed suggestive evidence for TLR3 rs3775291 as an associated marker for ARMD in Caucasians but not in Asians. They stated that this SNP may have only a small effect on ARMD susceptibility; further studies in larger samples are needed to confirm its role.

Y402H Polymorphism Testing

Hong and associates (2016) examined if the complement factor H (CFH) polymorphism rs1061170/Y402H is associated with responsiveness to anti- VEGF agents in ARMD. These investigators reviewed the English literature to examine the association between the polymorphism rs1061170/Y402H of the CFH gene and responsiveness to treatment with anti-VEGF drugs in ARMD patients. A meta-analysis of eligible studies was also performed. Pooled ORs and 95 % CIs were estimated using Stata V.12.0. Statistical heterogeneity was measured using Q-statistic testing. A total of 14 relevant studies including a total of 2,963 ARMD patients were eligible. In ARMD patients without a treatment history, individuals carrying the rs1061170/Y402H TT genotype were more likely to achieve a better outcome (OR = 1.932, 95 % CI: 1.125 to 3.317, p = 0.017) than those carrying the CC genotype. The authors concluded that polymorphism rs1061170/Y402H might be a genetic predictor of treatment response to anti-VEGF therapy in ARMD patients. They stated that further prospective research including a larger number of patients is needed to validate this finding.

Intravitreal Injection of Autologous Stem Cells

Kuriyan and colleagues (2017) noted that adipose tissue-derived "stem cells" have been increasingly used by "stem-cell clinics" in the U.S. and elsewhere to treat a variety of disorders. These investigators evaluated 3 patients in whom severe bilateral visual loss developed after they received intravitreal injections of autologous adipose tissue-derived "stem cells" at one such clinic in the U.S. In these 3 patients, the last documented VA on the Snellen eye chart before the injection ranged from 20/30 to 20/200. The patients' severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation. After 1 year, the patients' VA ranged from 20/200 to no light perception.

Stem Cell Transplantation

Li et al (2022) noted that stem cell transplantation (SCT) may improve VA in patients with dry AMD. In a systematic review and meta-analysis, these researchers examined the evidence on the risks and benefits of SCT for improving VA, including the risk of AEs in patients with dry AMD. Data were obtained from the PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases, and each database was examined from the date of inception until March 19, 2022. The rates of VA outcomes and AEs associated with SCT were assessed. All statistical analyses were carried out using Review Manager 5.4. The analysis examined 10 studies (102 patients), including 1 and 3, RCT and non-RCTs; and 1 and 5, multi-center prospective and prospective clinical trials, respectively. Meta-analysis showed changes in BCVA in the study eyes following SCT (6 months: RR = 17.00, 95 % CI: 6.08 to 47.56, p < 0.00001; 12 months: RR = 11.00, 95 % CI: 2.36 to 51.36, p = 0.002). Subgroup analysis showed that different stem cell types achieved better BCVA at post-operative 6 months, compared to that observed at baseline; 4 cases of related ocular AEs and no related systemic AEs were observed. The authors concluded that the findings of this meta-analysis suggested that SCT may improve BCVA in dry AMD, based on small sample sizes and fewer RCTs.

The authors stated that this study had several drawbacks. First, because of the un-synthetic reasons, existing clinical data detected by microperimetry, fundus autofluorescence, spectral domain-optical coherence tomography (SD-OCT), and ERG were not applied to the meta-analysis. Second, this meta-analysis did not compare outcomes among SCT types. Third, associated ocular and systemic AE reports were incomplete and the estimates varied, suggesting that further studies are needed to evaluate the safety of SCT. Fourth, long-term outcomes were not examined in this study due to the lack of data. Fifth, this meta-analysis included few studies, which had small sample sizes; thus, increasing the risk of bias.

Microperimetry for Detection of Functional Progression in Non-Neovascular Age-Related Macular Degeneration

Wong and colleagues (2017) reviewed the current literature on the ability of microperimetry to detect non-neovascular ARMD disease progression. The index test was retinal sensitivity measurement assessed by microperimetry and comparators were other functional measures (best-corrected and low-luminance visual acuities, and fixation stability) and structural parameters [retinal thickness, choroidal thickness, and area of GA determined by color fundus photographs, short-wave or near-infrared fundus auto-fluorescence (FAF)]. The reference standard was area of GA. The literature search was conducted in January 2016 and included Medline, Embase, the Cochrane Library, Biosis, Science Citation Index, ProQuest Health and Medicine, CINAHL, and Highwire Press. These researchers included 6 studies that enrolled 41 eyes with intermediate ARMD (from a single study) and 80 eyes with GA secondary to ARMD. Retinal sensitivity measured by microperimetry was the only functional measure that consistently detected progression in each cohort. Insufficient reported data precluded meta-analysis. Various microperimetry parameters were used to assess cohort-level change in retinal sensitivity, but the methods of analysis have yet to mature in complexity in comparison with established glaucoma field progression analysis. The authors concluded that microperimetry-assessed retinal sensitivity measurement may be more sensitive in detecting progression than other functional measures in non-neovascular ARMD; however, the lack of standardized testing protocol and methods of progression analysis hindered comparison. They stated that harmonization of testing protocol and development of more robust methods of analyzing raw microperimetric data will facilitate clinical implementation of this retinal assessment tool.

Cassels and associates (2018) stated that microperimetry is a novel technique for assessing visual function and appears particularly suitable for ARMD. Compared to standard automated perimetry (SAP), microperimetry offers several unique features. It simultaneously images the fundus, incorporates an eye tracking system to correct the stimulus location for fixation loss, and identifies any preferred retinal loci. A systematic review of microperimetry in the assessment of visual function in ARMD identified 680 articles. Of these, 52 met the inclusion criteria. These investigators discussed microperimetry and ARMD in relation to disease severity, structural imaging outcomes, other measures of visual function, and evaluation of the effectiveness of surgical and/ or medical therapies in clinical trials. The evidence for the use of microperimetry in the functional assessment of ARMD is encouraging. Disruptions of the ellipsoid zone band and retinal pigment epithelium (RPE) are clearly associated with reduced differential light sensitivity (DLS) despite the maintenance of good VA. Reduced DLS is also associated with outer segment thinning and RPE thickening in early ARMD and with both a thickening and a thinning of the whole retina in choroidal neovascularization. The authors concluded that microperimetry, however, lacks the robust diffuse and focal loss age-corrected probability analyses associated with SAP, and the technique is currently limited by this omission.

The American Academy of Ophthalmology Preferred Practice Pattern for age-related macular degeration stated that microperimetry is among several other tests that have been used to evaluate patients with AMD; "however, their specific role in clinical practice has yet to be specifically defined."

Optical Coherence Tomography Grading Algorithms for Retinal Biomarkers of Age-Related Macular Degeneration

Schmidt-Erfurth and associates (2017) stated that computer-based advances in image analysis provide complementary imaging tools such as OCT angiography, further novel automated analysis methods as well as feature detection and prediction of prognosis in disease and therapy by machine learning. In early ARMD, pathognomonic features such as drusen, pseudo-drusen, and abnormalities of the RPE can be imaged in a qualitative and quantitative way to identify early signs of disease activity and define the risk of progression. In advanced ARMD, disease activity can be monitored clearly by qualitative and quantified analyses of fluid pooling, such as intra-retinal cystoid fluid, sub-retinal fluid, and pigment epithelial detachment (PED). Moreover, machine learning methods detect a large spectrum of new biomarkers. Evaluation of treatment efficacy and definition of optimal therapeutic regimens are an important aim in managing neovascular ARMD. In atrophic ARMD hallmarked by GA, advanced spectral domain (SD)-OCT imaging largely replaces conventional FAF as it adds insight into the condition of the neurosensory layers and associated alterations at the level of the RPE and choroid. The authors concluded that exploration of imaging features by computerized methods has just begun but has already opened relevant and reliable horizons for the optimal use of OCT imaging for individualized and population-based management of ARMD.

In a systematic review, Wintergerst and colleagues (2017) evaluated the quality of OCT grading algorithms for retinal biomarkers of ARMD. Following a systematic review of the literature data on detection and quantification of ARMD retinal biomarkers by available algorithms were extracted and descriptively synthesized. Algorithm quality was assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies 2 check-list with a focus on accuracy against established reference standards and risk of bias. A total of 35 studies reporting computer-aided diagnosis (CAD) tools for qualitative analysis or algorithms for quantitative analysis were identified. Compared with manual assessment in reference standards correlation coefficients ranged from 0.54 to 0.97 for drusen, 0.80 to 0.98 for GA, and 0.30 to 0.98 for intra- or sub-retinal fluid and PED detection by automated algorithms; CAD tools achieved area under the curve (AUC) values of 0.94 to 0.99, sensitivity of 0.90 to 1.00, and specificity of 0.89 to 0.92. The authors concluded that automated analysis of ARMD biomarkers on OCT is promising; however, most of the algorithm validation was performed in pre-selected patients, exhibiting the targeted biomarker only. In addition, type and quality of reported algorithm validation varied substantially.

Heterochromatic Flicker Photometry

Heterochromatic flicker photometry (HFP) is a test employed to measure macular pigment optical density (MPOD). In the retina, the pigments zeaxanthin, lutein, and the metabolite meso-zeaxanthin shield it from damaging short-wavelength, high-energy, visible, blue light (400 to 495 nm); such damage may lead to the development of AMD. Serial measurement of MPOD can examine if dietary changes and/or anti-oxidant supplementation may diminish the harmful effect of blue light. Heterochromatic flicker photometry is carried out in a dark room on 1 eye (the other eye is occluded). The subject views a small circular stimulus that alternates between a blue wavelength (460 nm) that is absorbed, and a green wavelength (540 nm) that is not absorbed by the macular pigment. The subject sees a flicker at the moment when the macular pigment is saturated by the absorbed blue light and presses a response button on the device; and a MPOD measurement is generated. In some cases, where the subject has pre-existing pathology, a peripheral test is also performed. However, there is currently insufficient evidence to support the use of HFP in the management of AMD.

McCorkle and associates (2015) noted that the reliability of MPOD assessed by customized HFP (cHFP) has not been investigated in children. These researchers examined inter-session reliability of MPOD using modified cHFP. Pre-adolescent children (aged 7 to 10 years; n = 66) underwent cHFP over 2 visits using 11 examiners. Reliability was also assessed in a sub-sample (n = 46) with only 2 examiners. Among all subjects, there was no significant difference between the 2 sessions (p = 0.59-session 1: 0.61 ± 0.28; session 2: 0.62 ± 0.27). There was no significant difference in the MPOD of boys versus girls (p = 0.56). There was a significant correlation between sessions (Y = 0.52x + 0.31; R² = 0.29, p ≤ 0.005), with a reliability of 0.70 (Cronbach's α). Among the sub-sample with 2 examiners, there was a significant correlation between sessions (Y = 0.54x + 0.31; R² = 0.32, p < 0.005), with a reliability of 0.72 (Cronbach's α). The authors concluded that there was moderate reliability for modified cHFP to measure MPOD in pre-adolescents. These findings provided support for future studies aiming to conduct non-invasive assessments of retinal xanthophylls and study their association with cognition during childhood. Moreover, they stated that future studies should limit the number of examiners, as this was found to improve the reliability of the task in children. Further, they noted that researchers would be well-advised to consider variations in the procedure that could further improve the reliability of this technique. This will be a benefit to future studies that investigate how macular pigment (MP) density, a surrogate measure of brain levels of xanthophylls, particularly lutein, relates to other dependent measures in children. The finding that boys and girls had similar MPOD levels suggested that children can be considered collectively without the need for analysis by sex.

The authors stated that a main drawback of this study was that it only examined test-retest reliability. This study did not evaluate the validity of measuring MPOD by HFP in children. Without validation data , these researchers were unable to clarify whether the consistency between the 2 sessions was due to the validity of the HFP technique or a consequence of poor comprehension of task instruction at the 2 sessions.

Akuffo and co-workers (2015) compared MP measurements using cHFP (Macular Metrics Densitometer) and dual-wavelength fundus auto-fluorescence (Heidelberg Spectralis HRA + OCT MultiColor) in subjects with early AMD; MP was measured in 117 subjects with early AMD (aged 44 to 88 years) using the Densitometer and Spectralis, as part of the Central Retinal Enrichment Supplementation Trial (CREST; ISRCTN13894787). Baseline and 6-month study visits data were used for the analyses. Agreement was investigated at 4 different retinal eccentricities, graphically and using indices of agreement, including Pearson correlation coefficient (precision), accuracy coefficient, and concordance correlation coefficient (ccc). Agreement was poor between the Densitometer and Spectralis at all eccentricities, at baseline (e.g., at 0.25° eccentricity, accuracy = 0.63, precision = 0.35, ccc = 0.22) and at 6 months (e.g., at 0.25° eccentricity, accuracy = 0.52, precision = 0.43, ccc = 0.22). Agreement between the 2 devices was significantly greater for males at 0.5° and 1.0° of eccentricity. At all eccentricities, agreement was unaffected by cataract grade. The authors concluded that in subjects with early AMD, MP measurements obtained using the Densitometer and Spectralis were not statistically comparable and should not be used interchangeably in either the clinical or research setting. They stated that despite this lack of agreement, statistically significant increases in MP, following 6 months of supplementation with macular carotenoids, were detected with each device, confirming that these devices were capable of measuring change in MP within subjects over time. The main drawback of this study was that cataract grades were obtained within the 1st year of the study rather than at baseline.

Najjar and colleagues (2016) stated that while several methods have been proposed to evaluate lens transmittance, there is currently no consensual in-vivo approach in clinical practice. These investigators compared ocular lens density and transmittance measurements obtained by an improved psycho-physical scotopic HFP (sHFP) technique to the results obtained by 3 other measures: a psycho-physical threshold technique, a Scheimpflug imaging technique, and a clinical assessment using a validated subjective scale. A total of 43 subjects (18 young, 9 middle-aged, and 16 older) were included in the study. Individual lens densities were measured and transmittance curves were derived from sHFP indexes. Ocular lens densities were compared across methods by using linear regression analysis. The 4 approaches showed a quadratic increase in lens opacification with age. The sHFP technique revealed that transmittance decreased with age over the entire visual spectrum. This decrease was particularly pronounced between young and older participants in the short-wavelength regions of the light spectrum (53.03 % decrease in the 400 to 500 nm range). Lens density derived from sHFP highly correlated with the values obtained with the other approaches. Compared to other objective measures, sHFP also showed the lowest variability and the best fit with a quadratic trend (r2 = 0.71) of lens density increase as a function of age. The authors concluded that these findings suggested that the sHFP technique gave an accurate and objective estimate of lens density and transmittance. The densities obtained with this approach were compatible with those obtained with the Scheimpflug technique, clinical subjective scales, and psycho-physical threshold methods, but with a lower intra- and inter-individual variability, and a more accurate description of the effects of age on lens density. They stated that this approach was practical, cost-effective, and could easily be implemented for use in clinical settings, and photo-reception and non-visual photobiology research.

The authors stated that this study had several drawbacks. First, since the light stimulation used in this study involved the peripheral retina, these researchers believed that sHFP reflected mainly cortical lens density. This was supported by the finding that sHFP values showed a higher correlation with cortical lens opacification measures in the current study. Second, because sHFP relied on visual detection, it could not be used in visually impaired individuals (e.g., patients with altered peripheral visual field due to glaucoma). Third, although participants were likely to have displayed their largest pupils for the psycho-physical measurements (after dark adaptation), and for the Scheimpflug measures (after tropicamide administration), measurements may have occurred at slightly different pupil sizes. Additionally, the Beer-Lambert law resulted in less incident light reaching the deeper parts of the lens, and in turn could influence the assessment of the opacity of the lens nucleus with the imaging technique. Thus, it could not be excluded that part of the differential variability between the imaging and the psycho-physical techniques could be due to the different methodologies.

Furthermore, an UpToDate review on "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis" (Arroyo, 2018) does not mention heterochromatic flicker photometry as a management tool.

Complement Factor H rs1061170 Polymorphism Genotyping

Maugeri and colleagues (2019) noted that the strength of association between complement factor H (CFH) rs1061170 polymorphism and ARMD differs between ARMD subtypes and ethnicities. These investigators provided a systematic review and an updated meta-analysis stratified by stage of disease and ethnicity. They carried out a literature search in the PubMed-Medline, Embase and Web of Science databases to identify epidemiological studies, published before September 2017, that included at least 2 comparison groups (a control group with no signs of ARMD and a case group of ARMD patients). Genotype distribution, phenotype of the cases, ethnicity, mean age and gender ratio were collected; ORs and 95 % CIs were estimated under the allelic, homozygous and heterozygous models. Sensitivity and subgroup analyses, by ARMD subtype and ethnicity, were performed. The meta-analysis included data of 27,418 ARMD patients and 32,843 controls from 76 studies. In Caucasians, the rs1061170 showed a significant association with early ARMD (OR: 1.44; 95 %CI: 1.27 to 1.63), dry AMD (OR: 2.90; 95 % CI: 1.89 to 4.47) and wet AMD (OR: 2.46; 95 % CI: 2.15 to 2.83), under an allelic model. In Asians, the rs1061170 showed a significant association with advanced ARMD (OR: 2.09; 95 % CI: 1.67 to 2.60), especially wet AMD (OR: 2.24; 95 % CI: 1.81 to 2.77). The authors concluded that their work provided a more comprehensive meta-analysis of studies examining the effect of the CFH rs1061170 polymorphism on ARMD risk. These findings not only improved the assessment of disease risk associated with the polymorphism, but also constituted a scientific background to be translated into clinical practice for ARMD prevention. Moreover, these researchers stated that further investigations are needed to better clarify the effect of genetic susceptibility in the development of ARMD and its perspectives for disease prevention.

The authors stated that the principal drawback of this meta‐analysis was the high heterogeneity across studies. To take into account this issue, data of individual studies were combined via a random effects model; consequently, the pooled ORs should be interpreted with caution. Moreover, to examine the source of heterogeneity, a meta‐regression was conducted and the pooled ORs were calculated in more homogeneous subsets of studies through a subgroups analysis. In addition, the possible existence of a publication bias was considered and the symmetry of funnel plots was assessed by the Begg's test and Egger's regression asymmetry test. No publication bias was detected under any genetic model. Finally, ARMD is a complex disorder with sociodemographic, environmental and genetic risk factors. Although potential confounding factors and gene‐environment interactions should be considered, not all included studies provided adjusted ORs. Therefore, this meta‐analysis combined crude ORs from each study and hence the effect of confounders could not be completely excluded. To partially overcome this weakness, these investigators performed a meta‐regression, adjusting for age and gender, and then they stratified their analysis by ethnicity.

Complement Factor H and Age Related Maculopathy Sensitivity 2 Polymorphism Genotyping

Patients with dry AMD are commonly treated with eye vitamins and supplements, such as Age-Related Eye Disease Study 2 (AREDS2) formulation which contains zinc, to prevent advanced disease and vision loss. However, studies have evaluated the relationship between genetics and long-term use of zinc, which is thought to increase disease progression from dry AMD to wet AMD. Thus, there are proponents that suggest genetic testing may be of benefit to identify patients who have an increased risk of progression to wet AMD after chronic exposure to zinc, which could help patients to avoid supplements that increase their risk of vision loss.

Genetic polymorphisms in several genes have been identified that could account for many cases of AMD. Complement activation and inflammation appear to play a role in its etiology. A common polymorphism in the complement factor H (CFH) gene appears to explain about 50 percent of cases of AMD. Two polymorphisms of the CFH and LOC genes have been found to be independently associated with progression of AMD (Arroyo, 2020a). Variants in the CFH gene and LOC387715 loci, also known as ARMS2 (Age-Related Maculopathy Susceptibility 2), have the strongest effect on AMD development and progression; however, variations in other genes may also contribute to the disease (Seddon et al., 2007).

Arctic Medical Laboratories (Grand Rapids, MI) offers Vita Risk, a pharmacogenetic DNA test that measures DNA polymorphisms in two variants of the complement factor H (CFH) gene (rs3766405 and rs412852) and one Age Related Maculopathy Sensitivity 2 (ARMS2) variant (372_815del44ins54), using a buccal swab and PCR with MALDI-TOF, which is reported as positive or negative for neovascular age-related macular-degeneration risk associated with zinc supplementation (CMS/MLN, 2020; Palmetto, 2017).

Vita Risk genetic testing is marketed for use to identify patients who have an increased risk of progression to wet AMD after chronic exposure to zinc, allowing patients to avoid supplements that increase their risk of vision loss (Arctic Medical Laboratories, 2019).

Awh et al. (2013) state that the Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreased progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. The authors conducted a genetic analysis of a randomized, prospective clinical trial to evaluate the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. Caucasian patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the other eye were enrolled in the AREDS with available peripheral blood-derived DNA (995). Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. The primary endpoint was the effect of inherited gene polymorphisms on treatment group-specific rate of progression to advanced AMD. The authors found that over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (p = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (p = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. The authors concluded that individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. The authors state that these recommendations could lead to improved outcomes through genotype-directed therapy.

Awh and colleagues (2015) evaluated the impact of CFH and ARMS2 risk alleles on the observed response to components of the AREDS formulation using genetic and statistical subgroup analysis of a randomized, prospective clinical trial. Participants included white patients (n=989) from the AREDS with category 3 or 4 age-related macular degeneration (AMD) with available DNA. Four genotype groups based on CFH and ARMS2 risk allele number were defined. Progression to advanced AMD was analyzed by genotype and treatment using Cox proportionate hazards estimates and 7-year events. The primary endpoint was the effect of predefined genotype group on treatment-specific progression to advanced AMD. The authors found that patients with 2 CFH risk alleles and no ARMS2 risk alleles progressed more with zinc-containing treatment compared with placebo, with a hazard ratio (HR) of 3.07 (p = 0.0196) for zinc and 2.73 (p = 0.0418) for AREDS formulation (AF). Seven-year treatment-specific progression rates were: placebo, 17.0%; zinc, 43.2% (p = 0.023); and AF, 40.2% (p = 0.039). Patients with 0 or 1 CFH risk alleles and 1 or 2 ARMS2 risk alleles benefited from zinc-containing treatment compared with placebo, with an HR of 0.514 for zinc (p = 0.012) and 0.569 for AF (p = 0.0254). Seven-year treatment-specific AMD progression rates were as follows: placebo, 43.3%; zinc, 25.2% (p = 0.020); and AF, 27.3% (p = 0.011). Zinc and AF treatment each interacted statistically with these 2 genotype groups under a Cox model, with p values of 0.000999 and 0.00366, respectively. For patients with 0 or 1 CFH risk alleles and no ARMS2 risk alleles, neither zinc-containing treatment altered progression compared with placebo, but treatment with antioxidants decreased progression (p = 0.034). Seven-year progression with placebo was 22.6% and with antioxidants was 9.17% (p = 0.033). For patients with 2 CFH risk alleles and 1 or 2 ARMS2 risk alleles, no treatment was better than placebo (48.4%). The authors concluded that the benefit of the AREDS formulation seems to be the result of a favorable response by patients in only 1 genotype group, balanced by neutral or unfavorable responses in 3 genotype groups.

Seddon et al. (2016) evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. Data from AREDS were used in the analysis. Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial were evaluated. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 (ARMS2) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. The authors found that among antioxidant and zinc supplement users compared to the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high risk ARMS2 (TT) carriers (p=0.005). Similar results were seen for the NV subtype but not GA. The authors concluded that the effectiveness of antioxidant and zinc supplementation appears to differ by genotype; however, further study is needed to determine the biological basis for this interaction.

Evans and Lawrenson (2017) state that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Thus, higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of age-related macular degeneration (AMD). The authors conducted a meta-analysis to assess the effects of antioxidant vitamin or mineral supplementation on the progression of AMD in people with AMD. Included in the criteria were randomized controlled trials (RCTs) that compared antioxidant vitamin or mineral supplementation (alone or in combination) to placebo or no intervention, in people with AMD. In addition, most evidence in their systematic review came from the AREDS and AREDS2 studies. The AREDS trial found a statistically significant benefit of antioxidants plus zinc supplementation on progression of early AMD in one eye in patients with wet AMD or vision loss due to dry AMD in the other eye. Subsequently, the AREDS2 trial found that substitution of lutein and zeaxanthin for beta-carotene and using a lower zinc dose did not affect the treatment benefit (Arroyo, 2020b). Five studies compared zinc with placebo. The duration of supplementation and follow-up ranged from 6 months to 7 years. People taking zinc supplements may be less likely to progress to late AMD (OR 0.83, 95% CI 0.70 to 0.98; 3790 participants; 3 RCTs; low-certainty evidence), neovascular AMD (OR 0.76, 95% CI 0.62 to 0.93; 2442 participants; 1 RCT; moderate-certainty evidence), geographic atrophy (OR 0.84, 95% CI 0.64 to 1.10; 2442 participants; 1 RCT; moderate-certainty evidence), or visual loss (OR 0.87, 95% CI 0.75 to 1.00; 3791 participants; 2 RCTs; moderate-certainty evidence). There were no data reported on quality of life. Very low-certainty evidence was available on adverse effects because the included studies were underpowered and adverse effects inconsistently reported. The authors concluded that "people with AMD may experience some delay in progression of the disease with multivitamin antioxidant vitamin and mineral supplementation. This finding was largely drawn from one large trial, conducted in a relatively well-nourished American population. [They] do not know the generalizability of these findings to other populations. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed. Supplements containing lutein and zeaxanthin are heavily marketed for people with age-related macular degeneration, but [their] review shows they may have little or no effect on the progression of AMD".

Vavvas et al. (2020) state that prophylactic high-dose zinc and antioxidant supplements treatments are typically recommended with the assumption of homogeneously distributed benefit and risk of developing neovascular AMD. The authors report that individual variation at complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), genes which predispose persons to AMD, determines the effectiveness of nutritional prophylaxis. Vavvas and colleagues performed a validation analysis from a subset of subjects derived from the AREDS population. Their analyses were restricted to subjects randomized to placebo or to zinc plus antioxidants (the "AREDS formulation") in persons with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation. Subjects who experienced progression events at 2 y or less from study enrollment were not considered in this analysis. To clarify the sample population, the authors eliminated duplicates and all Michigan, Mayo, AREDS, Pennsylvania (MMAP) samples obtained from subjects who were not part of the AREDS. This resulted in 1,626 samples. Of these, 802 were from subjects randomized to treatment with either placebo or the AREDS formulation, which the authors refer to as the "expanded" dataset. Of these 802 subjects, 299 had not been part of the prior published analyses by Awh et al. The authors referred to this subgroup of 299 subjects as the "unique" dataset.

To analyze the common genetic variability of the CFH locus, Vavvas and colleages selected rs3766405 and rs412852 to tag the two major CFH haplotypes. The authors used published genetic grouping for either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Subjects receiving AREDS formulation treatment and those receiving placebo were balanced with respect to the distribution of CFH or ARMS2 risk alleles, smoking, education level, sex, and age, reflecting random AREDS treatment assignment. Progression risk was determined using the Cox proportional hazard model. Genetics–treatment interaction on neovascular AMD (NV) risk was assessed using a multi-iterative bootstrap validation analysis. The authors state that they identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk, and that analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. The authors state that their observations regarding genetic risk, AMD, and treatment with the AREDS formulation were based upon multiple statistical analyses of DNA and data from one of the largest groups of AREDS subjects. They report that bootstrapping analysis confirmed the presence of a genetics–treatment interaction which suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Thus, the authors state its use should be based on patient-specific genotype.

An UpToDate review on "Age-related macular degeneration: Treatment and prevention" (Arroyo, 2020) recommend Age-Related Eye Disease Study 2 (AREDS2) formulation which contains 80 mg of zinc oxide for both dry and wet AMD. "Preliminary findings suggest that certain risk alleles for AMD (CFH and ARMS2) may influence preferential response to zinc or antioxidant vitamins. However, further confirmation will be needed to determine the role for genotyping to guide therapy."

Although AMD has a strong genetic component, various studies have found mixed results in the evidence regarding genetic testing and predicting disease progression from dry to wet AMD. Furthermore, there are several variants of the complement genes which can create different levels of AMD risk, and though researchers are also evaluating ARMS2/HTRA1, the role of these genes in AMD are not fully understood (Mukamal, 2019). Genetic testing holds promise in the management of AMD; however, further confirmation will be needed to determine the role for genotyping to guide therapy. "A statement from the American Academy of Ophthalmology recommends that until tailoring management strategy to genotype results has been shown to provide benefit in published clinical trials, genotyping should be confined to patients participating in research trials" (Arroyo, 2020b). The American Academy of Ophthalmology does not currently recommend genetic testing for AMD (Mukamal, 2019).

Neutrophil-to-Lymphocyte Ratio

Niazi and colleagues (2019) noted that ARMD is etiologically linked to immunological aging and dysfunction. One aspect of this is the altered neutrophil-to-lymphocyte ratio (NLR; defined as the neutrophil count divided by the number of lymphocytes), which in other domains have been associated with inflammation and angiogenesis, was thus examined in patients with ARMD in several papers. In a systematic review and meta-analysis, these investigators summarized the findings in patients with ARMD in relation to NLR, both qualitatively and quantitatively. They searched PubMed/Medline, Embase, Web of Science, and the Cochrane Central and identified 6 studies from where they extracted data on 1,178 individuals (777 patients with ARMD and 401 healthy controls). Patients with ARMD had a higher NLR (WMD: 0.37, 95 % CI: 0.08 to 0.66, p = 0.013) when compared to healthy controls. In subgroup analyses, these researchers did not find a significant difference between patients with dry ARMD and healthy controls (WMD: 0.34, 95 % CI: -0.03 to 0.69, p = 0.068), but did find a strong significant difference between patients with neovascular ARMD and healthy controls (WMD: 0.54, 95 % CI: 0.23 to 0.86, p = 0.00068). The authors concluded that the association between ARMD and elevated NLR may have stronger relevance to the neovascular subtype of ARMD; however, the clinical value of measuring the NLR (blood) remains unclear.

Conbercept

Zhang and colleagues (2018) stated that conbercept is a novel VEGF inhibitor for the treatment of wet ARMD. In a systematic review, these researchers examined the safety and efficacy of conbercept in the treatment of ARMD. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched from their earliest records to June 2017. They included RCTs evaluating the safety and efficacy of conbercept in wet ARMD patients. Outcomes included the mean changes from baseline in BCVA score (primary outcome), CRT, plasma level of VEGF over time, and the incidence of adverse events (AEs). A total of 18 RCTs (1,285 subjects) were included in this systematic review. Conbercept might improve BCVA compared to triamcinolone acetonide (MD = 0.11, 95 % CI: 0.08 to 0.15), and reduce CRT compared to the other 4 therapies (conservative treatment, ranibizumab, transpupillary thermotherapy, and triamcinolone acetonide). The incidence of AEs in patients receiving conbercept was significantly lower than those receiving triamcinolone acetonide (RR = 0.25, 95 % CI: 0.09 to 0.72), but was similar to the other therapies. Conbercept appeared to be more effective than ranibizumab in lowering the plasma level of VEGF (MD = - 15.86, 95 % CI: - 23.17 to - 8.55). The authors concluded that current evidence showed that conbercept is a promising option for the treatment of wet ARMD. Moreover, these researchers stated that further studies are needed to compare the efficacy, long-term safety and cost-effectiveness between conbercept and other anti-VEGF agents in different populations.

Sub-Threshold Retinal Laser Therapy

Eng and colleagues (2019) stated that ARMD is the leading cause of irreversible blindness among the elderly in developed countries. Sub-threshold retinal laser therapy is a new technique that targets drusen – a marker of non-exudative ARMD – without causing incidental retinal damage associated with conventional laser photocoagulation. These researchers summarized published literature on sub-threshold retinal laser therapy as prophylactic treatment of non-exudative ARMD. They carried out a literature search of the PubMed, Medline, and Embase databases from January 1997 to April 2018. Studies were analyzed based upon study design, laser parameters, drusen reduction, changes in VA, and the development of CNV and/or GA. A total of 12 studies involving 2,481 eyes treated with sub-threshold retinal laser therapy were included in this review. Treatment led to increased drusen reduction, and studies with significant VA improvement were associated with significant drusen reduction. There was no significant change in the risk of developing CNV or GA. The authors concluded that sub-threshold retinal laser therapy was effective for reducing drusen and potentially improving vision in patients with non-exudative ARMD. Moreover, these researchers stated that this therapy did not show benefits in reducing development of CNV or GA. Therefore, its long-term efficacy to prevent progression to advanced ARMD could not yet be recommended.

Metabolomics (Metabolic Biomarkers) for the Management of ARMD

Hou and colleagues (2020) noted that ARMD is one of the leading causes of blindness among the elderly, and its exact pathogenesis remains unclear. In a systematic review, these investigators examined potential metabolic biomarkers and pathways of ARMD that might facilitate risk predictions and clinical diagnoses of this condition. They obtained relevant publications of metabolomics studies in humans by searching the Medline (PubMed) database before June 2020. Studies were included if they carried out mass spectrometry-based or nuclear magnetic resonance-based metabolomics approach for humans. Furthermore, ARMD was evaluated from fundus photographs based on standardized protocols. The metabolic pathway analysis was conducted by means of MetaboAnalyst 3.0. A total of 13 studies were included in this review. Repeatedly identified metabolites including phenylalanine, adenosine, hypoxanthine, tyrosine, creatine, citrate, carnitine, proline, and maltose had the possibility of being biomarkers of ARMD; validation of the biomarker panels was observed in 1 study. Dysregulation of metabolic pathways entails lipid metabolism, carbohydrate metabolism, nucleotide metabolism, amino acid metabolism, and translation, which might play important roles in the development and progression of ARMD. The authors concluded that this systematic review summarized the potential metabolic biomarkers and pathways related to ARMD, providing opportunities for the construction of diagnostic or predictive models for ARMD and the discovery of new therapeutic targets.

The authors stated that this review laid the foundation for the discovery of ARMD biomarkers and providing new ideas for the research of ARMD mechanism; however, the summary of available ARMD studies showed few reproductively verified conclusions, limiting the extrapolation of the results. This study also had several drawbacks. First, the existing research sample size was small, the subjects came from different ethnic groups, and the standardized operating procedures are still unavailable to metabolomics of ARMD. Second, the eye is a relatively independent organ of metabolism, and eye tissue is more closely related to ocular lesions. However, because of its fine ocular structure and low tissue availability, the eye tissue is mainly derived from surgical resection or post-mortem sampling, which limited its application in metabolomics research. Third, the approach based on pathway analysis was to combine a series of metabolic feature changes shown by statistical analysis in metabolomics studies with prior biological knowledge to simplify the interpretability of data analysis. In a disease state, the original metabolic state in the body will be changed, cells and biological fluids that provide metabolic support for cells will enter a new metabolic balance state, and abnormal disturbance effects will be reflected in all aspects of the body. Using metabolic pathways to study changes in metabolic states of diseases is to study diseases from a relatively holistic perspective. Thus, in this study, all the different metabolites in different tissues were included in the pathway analysis to obtain as many descriptions of the metabolic state of the disease as possible under the condition of limited research. This has been carried out in many other reviews on other disorders such as the systematic review of pancreatic cancer, ischemic stroke, and diabetes. Still, these researchers acknowledge that the study has a bias because of the uneven distribution of metabolites in tissues (the systemic and local distribution of metabolites remains unclear), but this opened the possibility for a comprehensive description of disease metabolic changes. These investigators stated that in future studies, more attention could be paid to metabolic differences of different biological tissues of the same disease, as well as joint studies of multiple omics, so as to gradually draw a complete blueprint for the disease mechanism of ARMD.

Photobiomodulation for the Treatment of Non-Exudative ARMD

Henein and Steel (2021) stated that ARMD is one of the leading causes of blindness in high-income countries. The majority of cases of ARMD are of the non-exudative type. Experts have proposed photo-biomodulation (PBM) therapy as a non-invasive approach to restore mitochondrial function, up-regulate cytoprotective factors and prevent apoptotic cell death in retinal tissue affected by ARMD. In a Cochrane review, these researchers examined the safety and effectiveness of PBM compared to standard care, no treatment or sham treatment for patients with non-exudative ARMD. They searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 5, 2020), Ovid Medline, Embase, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to May 11, 2020 with no language restrictions. The review included RCTs on subjects receiving any type of PBM therapy for non-exudative ARMD compared to standard care, sham treatment, or no treatment. These investigators used standard methodological procedures expected by Cochrane. They considered the following outcome measures at 12 months: BCVA; contrast sensitivity; near vision; low luminance density score; reading speed; vision-related quality of life (QOL) score; and AEs such as progression of ARMD and conversion to exudative ARMD. They graded the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. These researchers included 2 published RCTs from single centers in the U.K .and Canada, which recruited 60 subjects (60 eyes) and 30 subjects (46 eyes), respectively. Subjects in these trials were individuals with non-exudative ARMD with age-related eye disease study (AREDS) categories 2 to 4. One study compared single wavelength PBM with no treatment. This study was at risk of performance bias because the study was not masked, and there was attrition bias. One study compared multi-wavelength PBM with sham treatment and conflicts of interest were reported by study investigators. These researchers also identified 3 eligible ongoing RCTs from searching the clinical trials database. When comparing PBM with sham treatment or no treatment for non-exudative ARMD, there was no evidence of any meaningful clinical difference in BCVA at 12 months (MD 0.02 logMAR, 95 % CI: -0.02 to 0.05; 2 RCTs, 90 eyes; low-certainty evidence). One study comparing multi-wavelength PBM with sham treatment showed an improvement in contrast sensitivity at Level E (18 cycles/degree) at 12 months (MD 0.29 LogCS, 95 % CI: 0.23 to 0.35; 1 RCT, 46 eyes; low-certainty evidence). Visual function and health-related QOL scores were comparable between single wavelength PBM and no treatment groups at 12 months (VFQ-48 score MD 0.43, 95 % CI: -0.17 to 1.03; p = 0.16; 1 RCT, 47 eyes; low-certainty evidence). When comparing PBM with sham treatment or no treatment for non-exudative ARMD, there was no evidence of any meaningful clinical difference in conversion to exudative ARMD (RR 0.97, 95 % CI: 0.17 to 5.44; 2 RCTs, 96 eyes; very low-certainty evidence) at 12 months. There was inconclusive evidence that single wavelength PBM prevented the progression of ARMD (RR 0.79, 95 % CI: 0.41 to 1.53; p = 0.48; 1 RCT, 50 eyes; low-certainty evidence). Disease progression was defined as the development of advanced ARMD or significant increase in drusen volume. No included study reported near vision, low luminance vision or reading speed outcomes. The authors concluded that currently there remains uncertainty whether PBM treatment is beneficial in slowing progression of non-exudative ARMD. There is a need for further well-designed controlled trials evaluating dosimetry, powered for both safety and effectiveness outcomes. Consideration should be given to the adoption of agreed clinical outcome measures and patient-based outcome measures for ARMD.

Portable VEP System and Dark-Adapted Visual Evoked Potentials (DAVEP1) Metric for Diagnosing/Screening ARMD

Versek and colleagues (2021) noted that delayed dark-adapted vision recovery (DAR) is a biomarker for ARMD; however, its measurement is burdensome for both examiners and patients. In this study, these researchers developed a portable, wireless and user-friendly system that employs a head-set with a smartphone to deliver controlled photo-bleach and monocular pattern reversal stimuli, while using custom electroencephalography (EEG) electrodes and electronics in order to measure dark-adapted visual evoked potentials (DAVEP) objectively and separately at the peripheral and central visual field. This is achieved in 1 comfortable 20-min session, without requiring subject reporting. DAVEP responses following photo-bleach for up to 15 mins were measured concurrently from both eyes in 12 ARMD patients, 1 degenerative myopia patient, and 8 controls who had no diagnosed macular vision loss. Robust positive polarity DAVEP responses were observed at 200 to 500 ms from stimulus onset to scotopic stimuli that have been seldom reported and analyzed previously. The amplitude recovery of the DAVEP response was significantly delayed in ARMD patients as compared to controls. These investigators developed DAVEP1 scores, a simple metric for DAR, which classified 90 % of subject eyes correctly, indicating the presence of ARMD in at least 1 eye of all pre-confirmed subjects with this diagnosis. The authors developed a user-friendly, portable VEP system and DAVEP1 metric that showed a high potential to identify DAR-deficits in ARMD-patients; this novel technology could aid in early diagnosis of ARMD. Moreover, these researchers stated that due to the limited resources of this preliminary study, control subjects were not age-matched to the range of ARMD patients, so diagnostic validity has yet to be confirmed in older populations. These investigators noted that DAVEP1 metric is a new objective biomarker for ARMD that identifies deficits in DAR, which -- given further refinement and validation -- may show promise for future clinical diagnostics and drug-trial monitoring. They stated that further studies are suggested to validate the DAVEP approach in a larger cohort of subjects including age-matched controls, test-retest repeatability trials, fixation compliance monitoring, and the use of more-refined ARMD patient group staging to stratify test results according to disease severity.

Visual Cycle Modulators (e.g., Emixustat and Fenretinide) for the Treatment of Geographic Atrophy due to ARMD

Yeong and colleagues (2020) stated that although insidious in the early stages, advanced ARMD (neovascular and atrophic forms) can cause significant visual disability. The most common form, geographic atrophy, has no effective treatment to-date, whereas neovascular ARMD can be treated with intravitreal anti-VEGF injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to evaluate treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials. In a Cochrane review, these investigators examined the safety and efficacy of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to ARMD. They searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Medline Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to January 11, 2020 with no language restrictions. They also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. These researchers included RCTs and quasi-randomized clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in individuals diagnosed with ARMD (early, intermediate or geographic atrophy). Two authors independently evaluated risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. They resolved discrepancies via discussion; and graded the certainty of the evidence using the GRADE approach.

These investigators included 3 RCTs from the U.S.; 1 of these had clinical sites in Germany; 2 studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6 %). All participants were diagnosed with geographic atrophy due to ARMD based on validated imaging modalities. All 3 studies had high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. These researchers considered only 1 study to be adequately conducted and reported with high-risk of bias in only 1 domain (attrition bias). They considered the other 2 studies to be poorly reported and to have high-risk of attrition bias and reporting bias. Patients with geographic atrophy treated with emixustat may not experience a clinically important change in BCVA between baseline and 24 months compared to patients treated with placebo (MD of 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95 % CI: -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4 % versus 18 %) (RR of 0.91, 95 % CI: 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (MD of 0.09 mm2/year; 95 % CI: -0.26 to 0.44, low-certainty evidence). All 3 studies reported AEs of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main AEs were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5 %; fenretinide: 39.3 %) and chromatopsia (emixustat: 22.6 %; fenretinide: 25.2 %) were the most common AEs reported, and were the most prevalent reasons for study drop-out in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic AEs were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported 6 deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. These researchers planned to examine progression to advanced ARMD (geographic atrophy or neovascular ARMD) in prevention studies, including participants with early or intermediate ARMD; however, they identified no such studies. Two of the included studies reported an additional outcome -- incidence of CNV that was not in the published protocol. Onset of CNV may be reduced in those treated with emixustat but the evidence was uncertain (RR of 0.67; 95 % CI: 0.27 to 1.65, low-certainty evidence), or fenretinide (RR of 0.5; 95 % CI: 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. The authors concluded that there is limited evidence to support the use of visual cycle modulators (e.g., emixustat and fenretinide) for the treatment of established geographic atrophy due to ARMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

Intravitreal Faricimab

Heier et al (2022) noted that faricimab is a bi-specific antibody that acts via dual inhibition of both angiopoietin-2 and VEGF A. These researchers reported primary results of 2 phase-III clinical trials examining intravitreal faricimab with extension up to every 16 weeks for nAMD. TENAYA and LUCERNE were randomized, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2.0 mg every 8 weeks. Randomization was carried out through an interactive voice or web-based response system using a stratified permuted block randomization method. Patients, investigators, those evaluating outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in BCVA from baseline averaged over weeks 40, 44, and 48 (pre-specified non-inferiority margin of 4 letters), in the intention-to-treat (ITT) population. Safety analyses included patients who received at least 1 dose of study treatment. Across the 2 trials, a total of 1,329 patients were randomly assigned between February 19, 2019 and November 19, 2019 (TENAYA n = 334 faricimab and n = 337 aflibercept), and between March 11, 2019 and November 1, 2019 (LUCERNE n = 331 faricimab and n = 327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5.8 letters [95 % CI: 4.6 to 7.1] and 5.1 letters [3.9 to 6.4]; treatment difference 0.7 letters [-1.1 to 2.5]) and LUCERNE (6.6 letters [5.3 to 7.8] and 6.6 letters [5.3 to 7.8]; treatment difference 0.0 letters [-1.7 to 1.8]). Rates of ocular AEs were comparable between faricimab and aflibercept (TENAYA n = 121 [36.3 %] versus n = 128 [38.1 %], and LUCERNE n = 133 [40.2 %] versus n = 118 [36.2 %]). The authors concluded that visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained effectiveness; thus, reducing treatment burden in patients with nAMD.

Complement Inhibitors

Tzoumas et al (2023) stated that AMD is a common eye disease and leading cause of sight loss worldwide. Despite its high prevalence and increasing incidence as populations age, AMD remains incurable and there are no treatments for most patients. Mounting genetic and molecular evidence implicates complement system over-activity as a key driver of AMD development and progression. The past 10 years has witnessed the development of several novel therapeutics targeting complement in the eye for the treatment of AMD. In a Cochrane review, these investigators examined the safety and effectiveness of complement inhibitors in the prevention or treatment of AMD. They searched CENTRAL on the Cochrane Library, Medline, Embase, LILACS, Web of Science, ISRCTN registry, ClinicalTrials.gov, and the WHO ICTRP to June 29, 2022 with no language restrictions. These researchers also contacted companies running clinical trials for unpublished data. They included RCTs with parallel groups and comparator arms that examined complement inhibition for advanced AMD prevention/treatment. Two authors independently evaluated search results and resolved discrepancies via discussion. Outcome measures examined at 1 year included change in BCVA, untransformed and square root-transformed GA lesion size progression, development of macular neo-vascularization (MNV) or exudative AMD, development of endophthalmitis, loss of 15 or more letters of BCVA, change in low luminance VA, and change in QOL. These investigators examined risk of bias and evidence certainty using Cochrane risk of bias and GRADE tools.

A total of 10 RCTs with 4,052 participants and eyes with GA were included; 9 evaluated intra-vitreal (IVT) administrations against sham, and 1 examined an intravenous agent against placebo; 7 studies excluded patients with prior MNV in the non-study eye, whereas the 3 pegcetacoplan studies did not. The risk of bias in the included studies was low overall. These researchers also synthesized results of 2 IVT agents (lampalizumab, pegcetacoplan) at monthly and every-other-month (EOM) dosing intervals. Safety and effectiveness of IVT lampalizumab versus sham for GA For 1,932 participants in 3 studies, lampalizumab did not meaningfully change BCVA given monthly (+1.03 letters, 95 % CI: -0.19 to 2.25) or EOM (+0.22 letters, 95 % CI: -1.00 to 1.44) (high-certainty evidence). For 1,920 subjects, lampalizumab did not meaningfully change GA lesion growth given monthly (+0.07 mm², 95 % CI: -0.09 to 0.23; moderate-certainty due to imprecision) or EOM (+0.07 mm², 95 % CI: -0.05 to 0.19; high-certainty). For 2,000 subjects, lampalizumab may have also increased MNV risk given monthly (RR 1.77, 95 % CI: 0.73 to 4.30) and EOM (RR 1.70, 95 % CI: 0.67 to 4.28), based on low-certainty evidence. The incidence of endophthalmitis in patients treated with monthly and EOM lampalizumab was 4 per 1,000 (0 to 87) and 3 per 1,000 (0 to 62), respectively, based on moderate-certainty evidence. Safety and effectiveness of IVT pegcetacoplan versus sham for GA For 242 participants in 1 study, pegcetacoplan probably did not meaningfully change BCVA given monthly (+1.05 letters, 95 % CI: -2.71 to 4.81) or EOM (-1.42 letters, 95 % CI: -5.25 to 2.41), as supported by moderate-certainty evidence. In contrast, for 1,208 participants across 3 studies, pegcetacoplan meaningfully reduced GA lesion growth when given monthly (-0.38 mm², 95 % CI: -0.57 to -0.19) and EOM (-0.29 mm², 95 % CI -0.44 to -0.13), with high certainty. These reductions correspond to 19.2 % and 14.8 % versus sham, respectively. A post-hoc analysis showed possibly greater benefits in 446 participants with extra-foveal GA given monthly (-0.67 mm², 95 % CI: -0.98 to -0.36) and EOM (-0.60 mm², 95 % CI: -0.91 to -0.30), representing 26.1 % and 23.3 % reductions, respectively. However, these investigators did not have data on sub-foveal GA growth to undertake a formal subgroup analysis. In 1,502 participants, there is low-certainty evidence that pegcetacoplan may have increased MNV risk when given monthly (RR 4.47, 95 % CI: 0.41 to 48.98) or EOM (RR 2.29, 95 % CI: 0.46 to 11.35). The incidence of endophthalmitis in patients treated with monthly and EOM pegcetacoplan was 6 per 1,000 (1 to 53) and 8 per 1,000 (1 to 70), respectively, based on moderate-certainty evidence. Safety and effectiveness of IVT avacincaptad pegol versus sham for GA. In a study of 260 participants with extra-foveal or juxta-foveal GA, monthly avacincaptad pegol probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95 % CI: -5.89 to 8.67) or 4 mg (-0.28 letters, 95 % CI: -8.74 to 8.18), based on moderate-certainty evidence. Despite this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5 % reduction at 2 mg (-0.70 mm², 95 % CI: -1.99 to 0.59) and 25.6 % reduction at 4 mg (-0.71 mm², 95 % CI: -1.92 to 0.51), based on moderate-certainty evidence. Avacincaptad pegol may have also increased the risk of developing MNV (RR 3.13, 95 % CI: 0.93 to 10.55), although this evidence was of low certainty. There were no cases of endophthalmitis reported in this study.

The authors concluded that despite confirmation of the negative findings of intravitreal lampalizumab across all endpoints, local complement inhibition with intravitreal pegcetacoplan meaningfully reduced GA lesion growth relative to sham at 1 year. Inhibition of complement C5 with intravitreal avacincaptad pegol is also an emerging therapy with probable benefits on anatomical endpoints in the extra-foveal or juxta-foveal GA population. However, there is currently no evidence that complement inhibition with any agent improves functional endpoints in advanced AMD; further results from the phase-III clinical trials of pegcetacoplan and avacincaptad pegol are eagerly awaited. Progression to MNV or exudative AMD is a possible emergent AE of complement inhibition, requiring careful consideration should these agents be used clinically. Intravitreal administration of complement inhibitors is probably associated with a small risk of endophthalmitis, which may be higher than that of other intravitreal therapies. These investigators stated that further research is likely to have an important impact on the confidence in the estimates of adverse effects and may change these. The optimal dosing regimens, treatment duration, and cost-effectiveness of such therapies are yet to be established.

Artificial Intelligence (e.g., Deep Learning Convolutional Neural Networks) for Detection of Age-Related Macular Degeneration

In a systematic literature review, Hanson et al (2022) examined the impact of retinal biomarkers identifiable via OCT on disease progression and response to treatment in nAMD and established which biomarkers are currently identifiable by artificial intelligence (AI) models and the use of this technology. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, PubMed was searched for peer-reviewed publications dated between January 2016 and January 2022. Prospective/retrospective cohort studies, RCTs and review articles were selected for analysis. From 228 articles, 130 were reviewed, 50 were removed for falling outside the scope of this review with 10 added from the author's inventory, resulting in the inclusion of 90 articles. From 9 biomarkers identified; intra-retinal fluid (IRF), subretinal fluid, pigment epithelial detachment, subretinal hyperreflective material (SHRM), RPE atrophy, drusen, outer retinal tabulation (ORT), hyperreflective foci (HF) and retinal thickness, 5 are considered pertinent to nAMD disease progression; IRF, SHRM, drusen, ORT and HF. A number of these biomarkers can be classified using current AI models. Significant retinal biomarkers pertinent to disease activity and progression in nAMD are identifiable via OCT; IRF being the most important in terms of the significant impact on visual outcome. The authors concluded that important retinal biomarkers pertinent to disease activity and progression in nAMD can be identified routinely from structural OCT imaging, providing an individualized management tool. However, emerging innovative imaging techniques such as OCT-angiography have the potential to uncover additional biomarkers not yet identifiable with OCT alone. These researchers stated that incorporating AI into ophthalmology practice is a promising advancement towards an automated and reproducible analysis of clinical OCT data. AI has the potential to review retinal images more efficiently, identifying regions of pathology in which clinicians can focus their attention. Research has shown that a number of the most pertinent biomarkers can accurately be classified using the current AI models not only to diagnose disease but also to predict future disease conversion. AI also provides promising improvements for grading retinal fluid which could lead to more tailored treatment on an individual level. This move towards measuring retinal changes quantitatively, in terms of volume or area, may ultimately produce a more accurate diagnostic tool but further clinical testing of this is needed.

In a systematic review and meta-analysis, Leng et al (2023) examined the diagnostic accuracy of deep learning (DL) algorithms to identify AMD and explored factors impacting the results for future model training. Diagnostic accuracy studies published in PubMed, Embase, the Cochrane Library, and ClinicalTrails.gov before August 11, 2022 which employed DL for AMD detection were identified and extracted by 2 independent researchers. Sensitivity analysis, subgroup, and meta-regression were carried out by Review Manager 5.4.1, Meta-disc 1.4, and Stata 16.0. The risk of bias was assessed using QUADAS-2. The pooled sensitivity and specificity in this meta-analysis were 94 % (p = 0, 95 % CI: 0.94 to 0.94, I2 = 99.7 %) and 97 % (p = 0, 95 % CI: 0.97 to 0.97, I2 = 99.6 %), respectively. The pooled positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the AUC value were 21.77 (95 % CI: 15.49 to 30.59), 0.06 (95 % CI: 0.04 to 0.09), 342.41 (95 % CI: 210.31 to 557.49), and 0.9925, respectively. Meta-regression indicated that types of AMD (p = 0.1882, RDOR = 36.03) and layers of the network (p = 0.4878, RDOR = 0.74) contributed to the heterogeneity. The authors stated that convolutional neural networks are mostly adopted DL algorithms in AMD detection. Convolutional neural networks (CNNs), especially ResNets, are effective in detecting AMD with high diagnostic accuracy. Types of AMD and layers of the network are the 2 essential factors that impact the model training process. Proper layers of the network will make the model more reliable. More datasets established by new diagnostic methods will be used to train DL models in the future, which will benefit for fundus application screening, long-range medical treatment, and reducing the workload of physicians. Moreover, these researchers stated that DL is still in the early stages of development in AMD diagnosis; however, in the foreseeable future, widespread use could play a significant role in fundus applications, screening, telemedicine, reducing the workload of physicians, etc.

The authors stated that this meta-analysis and the included studies had several drawbacks. First, some variants of CNN including CapsNet, AlexNet, and DenseNet only existed once, and some studies used self-created CNN architectures; thus, the subgroup analysis of networks was inaccurate. Second, these researchers attempted to establish more subgroups or to find more possible co-variates such as hardware, network, and hyper-parameters; however, these potential factors were not mentioned in many studies. Third, these investigators concentrated more on diagnostic accuracy; however, as DL develops, AMD diagnostics has become more diverse, more plentiful, and more useful in lesion segmentation and efficacy prediction, which will be highly considered for further research. Fourth, the Duke and some self-built datasets had a small number of images for training.

References

The above policy is based on the following references:

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Last Review 02/20/2024

Effective: 10/10/2008

Next Review: 08/22/2024
Review History
Definitions

Age-Related Macular Degeneration

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Experimental and Investigational

Diagnostic or detection of ARMD

Interventions or therapies

Related Policies

CPT Codes / HCPCS Codes / ICD-10 Codes

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

HCPCS codes covered if selection criteria are met:

HCPCS codes not covered for indications listed in the CPB:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Implantable Miniature Telescope (IMT):