Lesion characteristics important in assessing therapies for AMD

Four clinical studies show a range of results with treatment of CNV, suggesting differences within similar CNV subtypes.

ByMary Elizabeth Hartnett, MD

Neovascular age-related macular degeneration is a growing concern in eye care. It is important to look closely at data from clinical trials to sort out the complexity of this disease, particularly its stage in development, when interpreting treatment response.

For some therapies, it is important for the clinician to recognize differences in lesion subtypes. However, data from past and current clinical studies reveal differences in baseline lesion characteristics within the same lesion subtypes that may account for differences in the reported outcomes. Because the pathogenesis of AMD is complex, future management will likely involve several treatments geared at different steps in the development of the disease. This article will give some background on choroidal neovascularization lesion subtypes and relate this to clinical data from new and existing treatments for neovascular lesions.

Midframe angiogram shows filling of predominantly classic CNV (a) with late leakage noted in late frame of angiogram (b).

Images: Hartnett ME

Background

Wet AMD is most often caused by an abnormal proliferation of blood vessels, which is called choroidal neovascularization. CNV leaks blood and fluid into and beneath the neurosensory retina of the macula, damaging it and distorting or destroying central vision. CNV is characterized as either classic or occult based on fluorescein angiographic characteristics. Most lesions are characterized by the percentage of classic and occult components. Indocyanine green angiography can also be useful. Both angiographic techniques document the circulation of dye within blood vessels over time.

The high-resolution images in the Z-axis obtained with optical coherence tomography (OCT) provide invaluable information about edema and fluid in the neurosensory and retinal spaces, and limited information as to the actual location of the abnormal retinal or choroidal vascular lesions. As more progress is made in discerning lesion subtypes, OCT and other advanced imaging systems will be essential diagnostic tools.

CNV lesion subtypes

Classic CNV is characterized by well-demarcated hyperfluorescence in the early phase of the fluorescein angiogram with progressive dye leakage into the sub-neurosensory-retinal space (Figure 1a and 1b). Sometimes boundaries are obscured by blood or, in combined classic and occult lesions, detachment of the retinal pigment epithelium (RPE). Occult CNV displays less bright and discrete hyperfluorescence and is characterized by late leakage from an undetermined source or irregular elevation of the RPE, known as fibrovascular pigment epithelial detachment. Late leakage appears as speckled hyperfluorescence in the subretinal space during late-phase angiography.

Retinal vascular lesions can also present and sometimes appear in combination with occult CNV (Figure 2a and 2b). Superficial retinal hemorrhage, first described as an early sign of incipient retinal vascular anomalous complexes (RVACs), was recently reported with occult chorioretinal anastomosis (OCRA). Retinal angiomatous proliferation (RAP) includes RVACs in its steps of pathogenesis. Both RVACs and RAPs may be associated with late leakage within the center, rather than the edge, of a pigment epithelial detachment. Polypoidal choroidal vasculopathy is caused by RPE detachments associated with choroidal polypoidal lesions. Late phases of indocyanine green angiography can be useful in recognizing some of these lesion subtypes; however, there may also be overlap among RVACs, RAPs and OCRAs.

The ability to accurately identify CNV has been thought to be imperative for a proper diagnosis and treatment in several clinical trials, including the Macular Photocoagulation Study (MPS), the Treatment of Age-Related Macular Degeneration with PDT (TAP) study and the Verteporfin in Photodynamic Therapy (VIP) trial. In some trials, lesions have been characterized as predominantly classic (50% or more of the entire lesion contains classic CNV — Figure 1a and 1b), minimally classic (greater than 0% but less than 50% of the entire lesion is classic — Figure 3) or occult.


Retinal vascular anomalous complexes (a, arrows) associated with surrounding late leakage of undetermined origin and speckled hyperfluorescence, ie occult CNV (b, arrow).

Minimally classic CNV. Classic component shown with arrow.

Clinical results and lesion subtypes

At the 2004 American Academy of Ophthalmology meeting, additional results of phase 2/3 clinical trials for Macugen (pegaptanib sodium 0.3 mg, Eyetech/Pfizer) and Retaane (anecortave acetate 15 mg, Alcon) were announced. Data from two randomized, controlled, double-blind studies showed that Macugen, delivered every 6 weeks by intravitreous injection, effectively maintained vision (a loss of less than three lines in ETDRS measured visual acuity) in 45% of patients with all types of CNV lesions over a period of 2 years compared to controls receiving sham injection. In a published study, repeated 0.3 mg injections maintained vision in 70% of patients compared to 55% in sham treated patients at 1 year. Endophthalmitis was reported in 1.3% of cases.

In a study comparing Retaane to Visudyne, after 1 year, Retaane, administered every 6 months by posterior juxtascleral depot, maintained vision (a loss of less than three lines in ETDRS measured visual acuity) in 45% of patients with predominantly classic lesions and Visudyne in 49% of patients. After controlling for drug reflux and treatment interval (data collected prospectively), the efficacy of Retaane was found to be 57%. A study of Retaane monotherapy vs. placebo revealed that 79% of subjects with CNV lesions (80% predominantly classic) had stable or improved vision after 1 year of Retaane, compared to 53% of patients in the placebo group. After 2 years, the benefit of Retaane was 73% vs. 47% in the placebo group.

In reviewing the enrollment data from the TAP, Retaane monotherapy, Retaane vs. Visudyne and Macugen monotherapy studies, there are differences in the number of eyes enrolled with predominantly classic lesions, the average lesion size and the average duration of time from diagnosis of lesion to treatment. Although direct comparison across all four studies is not valid, these observations are important to note when looking at outcomes. Stable vision at 1 year after Visudyne treatment was found in 67% of lesions in the predominantly classic subgroup of the TAP study and 49% in the Retaane vs. Visudyne study, where lesions were smaller and present for a shorter period of time. Stable vision with Retaane was found in 84% of the lesions in the predominantly classic subgroup of the monotherapy study at one year and in 57% in the Retaane vs. Visudyne study, again with smaller lesions of shorter duration. Thus, a closer look at these studies shows that while the inclusion criteria were similar between studies, the actual baseline characteristics were different.

As physicians look to establish therapeutic practices using these treatments for neovascular AMD patients, we need to recognize the differences in enrollment criteria, length of time from diagnosis to treatment, size and possibly stage of pathology of CNV lesions. Still, as clinicians, we will need to make recommendations to patients as to the best treatments. As we move forward, careful classification of CNV may be important in choosing a treatment, and documentation after therapy will be needed to assess treatment effect and help design future interventional studies.

For Your Information:

Mary Elizabeth Hartnett, MD, can be reached at 5109D Bioinformatics Building, CB#7040, 130 Mason Farm Road, Chapel Hill, NC 27599 U.S.A.; +1-504-412-1200; fax: +1-504-412-1315; e-mail: hartnet@med.unc.edu.

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