Study Reveals Connections Between Scarring and Anti-VEGF Treatments

A 43-center, prospective cohort study designed to identify and describe risk factors for fibrotic scar formation and fibrotic scar changes in age-related macular degeneration (AMD) patients has determined that there is an increased risk of developing fibrotic scars in the first 2 years of anti-vascular endothelial growth factor (anti-VEGF) treatment, but that risk of scar development decreased after 2 years.

These findings shed light on the long-term outcomes of patients treated with anti-VEGF therapy in a real-world setting beyond clinical trials, said study lead author Ebenezer Daniel, MBBS, PhD, with the Scheie Eye Institute, University of Pennsylvania.

In addition to recording the development of and changes to fibroid scarring over a five-year period in AMD patients, the study also determined several baseline factors associated with increased risk of fibrotic scarring during anti-VEGF treatment for AMD.

Data on the 1185 AMD patients with untreated active choroidal neovascularization (CNV) associated with AMD were gathered from a five-year follow up study of patients enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).

The CATT took place between February 2008 and December 2009, and according to Daniel was designed to “assess the differences between ranibizumab and bevacizumab, as well as differences between monthly and pro re nata dosing."

Patients enrolled in the CATT had been diagnosed with CNV associated with AMD and those patients with non-foveal scars on less than half of CNV lesions were included in the original trial. During the CATT study patients were randomly assigned to anti-VEGF treatment at 3 dosing regimens for either ranibizumab or bevacizumab.

Throughout the CATT researchers collected patient data via color fundus photographs (CFPs), fluorescein angiogram (FA), and optical coherence tomography (OCT) imaging. Daniel and colleagues report that 647 of the 914 patients still living opted to participate in the study which used CFP, FA, and OCT to assess disease progression, morphology, and measure changes in scarring during the CATT and five-year follow up. Demographic and health data was also collected to determine any additional candidate risk factors for scar formation.

Daniel and colleagues reported that there were several baseline characteristics that were associated with the development of fibroid scarring during the 5 year study. Classic CNV, Daniel noted, was associated with a 4.5-fold risk (aHR [adjusted hazard ratio], 4.49; 95% CI, 3.34-6.04; P< 0.001) compared with occult CNV.

Other factors, such as good baseline visual acuity (VA) in the fellow eye (≥20/20) was positively associated with increased risk (aHR 1.34; 95% CI, 1.0-1.74; P = 0.04) of scar development in the study eye, whereas a baseline VA of between 20/25 and 20-40 saw a slightly decreased risk (aHR 0.97; 95% CI, 0.74-1.28; P = 0.04) of scar development in the study eye. The study also found that eyes with large hemorrhages (>1 disk area) at baseline had nearly double the risk of scarring (aHR, 2.28; 95% CI, 1.49-3.47; P < 0.001) in comparison to eyes with no hemorrhages associated with the CNV.

Photographic images, according to Daniel, were available for 474 subjects at all 3 (1-, 2-, and 5-year) follow up visits. Those images revealed, according to the study data, that 14.3% (n = 68) developed fibrotic scarring in the first year of the study. Those scars, Daniel and colleagues report, changed slowly between year 1 and 5, but by the end of 5 years 54% (n = 37) with baseline scarring saw expansion of that scarring which affected VA.

Overall, Daniel noted that approximately one-third of the CATT eyes developed retinal scar during the first year of treatment, and an additional 10% developed scar during the second year of treatment. In the three-year follow up period, only 10% more patients developed scar, indicating that in eyes with neovascular AMD (nAMD) treated with anti-VEGF therapy, the majority of scars occur within the first year of treatment.

Risk of scar development, according to Daniel, increased from three-fold at 2 years to 4.5-fold at 5 years, possibly as a result of "treated quiescent classic lesions that relapsed over time." Daniels pointed out that there has been a suggested link between anti-VEGF treatments and formation/development of fibroid scarring.

Although further study is needed to determine an exact link between scarring and anti-VEGF treatment, the study data on increased risk factors for development of scars in AMD patients, could help researchers determine factors affecting the evolution of AMD in individual patients and better assess individual risk.

The study, “Development and Course of Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials” was published online in Ophthalmolgy.