Current issues in managing AMD

Technology will play an increasing role in determining progression and management of AMD.

By Michael Colucciello, MD

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States: a study published in 2004 indicated that there were nearly 2 million late AMD cases and 8 million intermediate AMD cases (one would predict the prevalence is currently higher).¹

Today’s retina practitioner has several options regarding AMD management. Varied effective management approaches exist; patient care can be individualized. This article will address issues regarding genetic testing and preventive strategies, monitoring and evaluation, wet AMD treatment paradigms, assessment of treatment and adjunctive strategies.

Figure 1. Color image of a case of wet AMD, showing subretinal and sub-retinal pigment epithelial hemorrhage, central macular region (SD-OCT, lower left insert). The foveal external limiting membrane and ellipsoid zone layers are disrupted.

Genetic studies and preventing progression

Patients with intermediate-to-high risk AMD should take nutritional supplements with the Age-Related Eye Disease Study (AREDS) ² formula to, first, prevent progression to advanced disease, and second, to the fellow eye. An AREDS study published in 2003 showed that more than 300,000 people at high risk for advanced AMD would avoid progression over a five-year period if they used the supplement.²

Tobacco exposure is a known strong modifiable dose-responsive risk factor for the development of wet AMD. Conversely, the value of genetic testing to identify subgroups of patients who may benefit more or, be harmed by the AREDS supplements has been controversial.

A subgroup analysis of the AREDS 2 database using a portion of the AREDS 2 patients with available DNA suggested that the composition of the supplements should be changed based on an individual’s CFH and ARMS2 genotypes.³ However, further investigations of the entire cohort and a replication sample confirmed that genetic testing to determine utility of prophylactic AREDS 2 supplementation is not helpful clinically; administration of AREDS 2 supplements in patients with increased risk based on phenotype reduce the rate of AMD progression across all genotype groups.^4,5

For patients with dysphagia and/or symptomatic presbyesophagus, AREDS 2 is available in a powdered form (Viteyes AREDS2 powder).

Patient monitoring at home

Patient home monitoring presents the clinician with an option beyond the standard Amsler grid test. According to AREDS report number 11, approximately 670,000 of the 8 million patients in the United States with intermediate- to high-risk dry AMD could progress to neovascular macular degeneration over a five-year period after treatment is started.² In the AREDS 2-HOME Study Research Group study, patient home monitoring of the disease with both the Amsler Grid and the ForeseeHome AMD Monitor with Preferential Hyperacuity Perimetry (Notal Vision) is more sensitive than the Amsler Grid alone: 87% maintained vision of 20/40 or better at diagnosis of CNV compared with 62% of study eyes evaluated with only the Amsler grid.⁶ Although this involves further patient expense, the addition of testing at home could translate into 100,000 patients maintaining 20/40 vision over five years — a significant potential public health impact.

EVALUATION WITH MULTIMODAL IMAGING

Optical coherence tomography

Spectral domain optical coherence tomography (SD-OCT) is essential in the management of these patients. Evidence for active choroidal neovascularization and VEGF activity can be inferred with use of these sensitive instruments to detect subretinal, intraretinal or subretinal pigment epithelial fluid.

Two important OCT options are before the FDA for its regulatory consideration; namely time-encoded frequency domain OCT (also known as “swept-source OCT”) and OCT angiography. Swept-source OCT has enhanced resolution, deeper penetration and a wider field of view as compared to spectral domain OCT. OCT angiography features sequential OCT cross-sectional scans to detect red blood-cell motion within the vasculature, allowing imaging of native vessels and neovascularization.

FA, fundus photography and ICG

Fluorescein angiography (FA), photography and indocyanine green (ICG) angiography can help detect evidence of active choroidal neovascularization. Many clinicians do not employ FA and photography when conducting routine evaluations of AMD patients; they opt to use serial OCT to manage them. Some practitioners use FA initially and at the extremes of a “treat-and-extend” treatment paradigm (explained below) to determine NV activity.

ICG angiography is especially useful in identifying polyps and branching vascular networks related to pachychoroid anatomy associated with polypoidal choroidal vasculopathy (PCV). Clinicians who use ICG often do so to identify PCV-associated CNV subtypes. These patients may be more resistant to standard anti-VEGF regimens; their identification is important since they may benefit more from adjunctive verteporfin photodynamic therapy (PDT, Visudyne, Valeant Pharmaceuticals) than those with non-PCV associated choroidal neovascularization (discussed below).

Fluorescein angiography shows choroidal vascularization and RPE atrophy, but does not reveal how deeply the RPE is affected. Fundus autofluorescence (FAF) allows evaluation of coexisting retinal pigment epithelial (RPE) damage in AMD cases; this information may be valuable for serial evaluation, for low-vision treatment guidance of patients to determine preferred retinal locus and eccentric viewing strategies, and (hopefully) and for future use to assess the need for stem cell treatment.

ROD-MEDIATED DARK ADAPTATION’S ROLE

Rod-mediated dark adaptometry (DA) measures the recovery of light sensitivity by rod photoreceptors after exposure to a bright light. Patients with early AMD may have good Snellen acuity, but note problems with vision at night or under low light levels that correlate with the extent of delays in DA. Therefore, rod-mediated DA may be a functional biomarker for early AMD. In fact, a recent study showed that in older adults with a normal macular clinical exam, delayed rod-mediated DA is associated with incident early AMD three years later.⁷ In the future, rod-mediated DA may be used as a bioassay of RPE-Bruch membrane health and a functional biomarker for incident AMD risk.

WET AMD WITH ANTI-VEGF AGENTS: COMMON QUESTIONS

Which agent should I use when initiating treatment?

When considering treatment initiation for wet AMD, efficacy and cost are prime issues.The CATT and IVAN studies compared 0.5 mg ranibizumab (Lucentis, Genentech) with 1.25 mg bevacizumab (Avastin, Genentech) for treatment of wet AMD and demonstrated equivalent visual outcomes in patients treated monthly with either agent.^8,9 Similarly, the VIEW 1 and VIEW 2 studies compared ranibizumab and aflibercept (Eylea, Regeneron) and found 2 mg aflibercept (given every other month following three monthly doses) to be noninferior to monthly administered ranibizumab.¹⁰

Figure 2. Multimodal imaging in dry AMD. Enhanced depth mode SD-OCT of dry AMD, with fundus autofluorescence (FAF) insert, upper right, and color photograph, lower center. The OCT shows atrophy of the external limiting membrane and ellipsoid zone layers (indicative of photoreceptor atrophy) in the central macula, associated with sub-foveal debris.

By inferential (not scientific) reasoning, therefore, bevacizumab can be equivalent to aflibercept; all three agents can be thought of as yielding equivalent vision results. Given the large difference in cost to patients per dose: bevacizumab ($50, via compounding pharmacy), 0.5 mg ranibizumab ($1950), and aflibercept ($1850), bevacizumab should be considered for first-line therapy in these patients when evaluating from a cost-efficiency perspective.

What treatment paradigm should be used?

Treatment paradigms include monthly, pro re nata (PRN) and treat and extend (TAE).

The ANCHOR and MARINA trials demonstrated that approximately 90% of eyes treated with monthly intravitreal ranibizumab for wet AMD lost fewer than 15 letters over two years.^11,12 Similar outcomes were seen in patients treated with aflibercept in the VIEW 1 and VIEW 2 studies.³ The VIEW 1 and VIEW 2 studies concluded that outcomes with 2 mg aflibercept dosed every 2 months after three monthly loading doses of 2 mg aflibercept were clinically equivalent to the other dosing regimens.¹⁰

However, the cost and time required for monthly injections can result in a significant burden for patient and physician, and it’s possible that monthly treatment could be associated with increasing geographic atrophy.¹³ Clinical trial data have demonstrated that visual acuity tends to be slightly better with monthly treatment versus PRN treatment: a PRN regimen with close follow-up and treatment when activity is noted could be attempted, but CATT data showed a loss of 2.4 letters in mean visual acuity improvement for patients treated with a PRN regimen compared with a monthly regimen.⁸

TAE, as described by the LUCAS TAE protocol, involves treating the patient monthly until inactive disease is achieved, then gradually extending treatment intervals by two weeks per visit, up to a maximum of 12 weeks. If recurrent disease appears, the treatment interval is decreased by two weeks at a time.¹⁴ LUCAS demonstrated that bevacizumab and ranibizumab, when administered according to the treat-and-extend protocol, show equivalence in visual acuity gains and reduction of central retinal thickness at one year. Also, the visual acuity results in LUCAS are comparable to those achieved with a monthly treatment regimen.¹⁴

When should I consider a switch to a different agent?

A switch to an alternative anti-VEGF agent often occurs if no improvement is seen following three to six consecutive monthly treatments.

A recent study showed benefit for nonresponders (stable or increasing subretinal fluid during a period of three monthly injections) when treatment was changed to a different anti-VEGF drug (bevacizumab or ranibizumab).¹⁵

A similar investigation showed that switching to intravitreal aflibercept after at least six monthly ranibizumab injections without improvement is associated with decreased macular edema and pigment epithelial detachment (PED) height.¹⁶

When should adjunctive treatment with PDT be used?

Routine use of verteporfin photodynamic therapy (PDT) as an adjunct to intravitreal anti-VEGF does not appear to offer an advantage. In the MONT BLANC study, the combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving vision gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatments over 12 months.¹⁷

An advantage in using combination anti-VEGF therapy with verteporfin PDT, however, has been found in patients with PCV-associated choroidal neovascularization (CNV). Although the incidence of PCV is higher in Asia, it is fairly common in the Caucasian population: PCV accounts for about 25% to 50% of cases manifesting as exudative AMD in Asia, and accounts for 10% of cases of wet AMD in the Caucasian population. When accompanied by choroidal neovascularization, PCV is typically associated with type 1 neovascularization (CNV located under the retinal pigment epithelium). These lesions often show resistance to anti-VEGF monotherapy.

Combination therapy using an anti-VEGF agent with verteporfin photodynamic therapy may be a more suitable option for these cases.¹⁸

The EVEREST study was a six-month study including patients with symptomatic macular polypoidal choroidal vasculopathy. The results showed that verteporfin PDT alone or combined with ranibizumab 0.5 mg was superior to 0.5 mg ranibizumab monotherapy in achieving complete regression of polyps.¹⁹

When is it appropriate to stop treatment?

In the MARINA and ANCHOR trials, 30% to 35% of patients treated with monthly ranibizumab showed visual improvement after a year; there was reasonably strong evidence that continued treatment would be superior to intermittent treatment with respect to visual outcome.^11,12

However, treating automatically “according to protocol” for years may become burdensome, costly and, in many cases after some time, unnecessary: the natural history of choroidal neovascularization includes fibrosis at some point.

In practice, in a “treat and extend” protocol, consideration is often given to converting to a “treat and observe” protocol after the treatment interval reaches 12 weeks, often after confirmation of no leakage with intravenous fluorescein angiography.

IMPLANTABLE MINIATURE TELESCOPE

The IMT can be used successfully in these patients: five-year results showed substantial improvement retention in best-corrected distance visual acuity. Persistent corneal edema occurred in approximately 5% of patients; mean endothelial cell loss was 20% at three months, then 3% per year.²⁰

Visual rehabilitation is important in patients with AMD whose vision impairment makes activities of daily (ADL) living a challenge. Consultation with and recommendations from low vision specialists may enhance the patients’ abilities to perform ADL, allowing for more independence, safety and potentially lowering risk for depression. The state Commission for the Blind can offer much support, including home visits to assess home safety, providing aids for ADL assistance, and talking books.

Conclusion

Medical advances have resulted in enhanced longevity; this fortunate circumstance also has allowed more patients to present with intermediate and late AMD. Although some controversy exists in the evaluation and management of these patients, more options are available to save and enhance vision (and thus quality of life).

Extended release preparations, medications with unique mechanisms of action and regenerative therapies promise an even more positive future. OM

REFERENCES

About the Author
	Dr. Colucciello is a member of the Retina Society and the American Society of Retinal Specialists. He is a partner at South Jersey Eye Physicians, Moorestown/Medford/Columbus, NJ and is a clinical associate, University of Pennsylvania School of Medicine. He has no financial relationships with any of the companies mentioned in this article.