Intravitreal aflibercept injection vs sham as prophylaxis against conversion to exudative age-related macular degeneration in high-risk eyes: a randomized clinical trial

Data from the Age-related Eye Disease Study (AREDS) suggest a 10% conversion rate in at least one eye in individuals with bilateral drusen (without advanced AMD); high-dose vitamins/antioxidants (per AREDS) seem provide a modest reduction in risk of conversion (25%) over the course of 5 years. While previously conducted research has provided some insight into potential risk factors and conversion rates for progression from intermediate dry age-related macular degeneration (AMD) to exudative AMD, there remains an unmet need in the realm of conversion prophylaxis. The authors here had hoped to answer an important question in the treatment of AMD: do intravitreal anti-VEGF injections help to reduce the risk of developing wet AMD?

The Prophylaxis Against Conversion to Neovascular Age-Related Macular Degeneration was a prospective, single-masked randomized clinical trial comparing a 2-mg intravitreal aflibercept injection (IAI) vs sham injection as prophylaxis against conversion to exudative (AMD) in high-risk eyes. Conducted across 4 centers, the study initially included 128 individuals randomized 1:1 to receive either quarterly IAI or sham injection for 24 months. Enrollment was stratified to balance both groups for patients diagnosed with exudative AMD in their fellow eye no longer than 2 years prior, vs those diagnosed greater than 2 years prior to enrollment.

Study eyes had to carry a diagnosis of nonexudative AMD characterized by the presence of multiple intermediate drusen, 1 or more large drusen, and/or hyperpigmentary changes. Presence of geographic atrophy was not exclusionary. The fellow (nonstudy) eye had to have active exudative AMD (as evidenced by leakage on FA, and/or subretinal, intraretinal, or sub-RPE fluid on OCT), or a documented history of exudative AMD (a known history of treatment, or imaging confirming the diagnosis). Study assessments were carried out quarterly, and included manifest refraction (ETDRS), slit-lamp and dilated fundus exam, SD-OCT, OCT angiography (OCTA), and fluorescein angiography.

The primary outcome measure was proportion of patients with conversion to exudative AMD at 24 months. Secondary outcomes included time to conversion to exudative AMD, rate of conversion based on duration of exudative AMD in fellow eye (less than or equal to 2 years, or greater than 2 years), rate of conversion based on presence of nonexudative CNVM (as seen on OCTA, without evidence of leakage/exudation on SD-OCT or FA).

Of the 128 patients initially enrolled, one patient in the IAI group was found to have exudative AMD at the time of enrollment (subsequent to the initial treatment) and was excluded from analyses. Both groups were balanced in terms of demographics and baseline characteristics (age, gender distribution, duration of exudative AMD in fellow eye, presence of nonexudatve CNVM, BCVA, and proportion of patients with GA).

By month 24, 6 patients (9.5%) in the IAI group, and 7 patients in the sham group (10.9%) had developed exudative AMD. Interestingly, patients carrying a diagnosis of exudative AMD in the fellow eye for longer than 2 years showed a lower rate of conversion than those with exudative AMD in the fellow eye for less than or equal to 2 years. The number of eyes with nonexudative CNVM was found to have increased from 4 eyes in the IAI group (6.3%) and 6 in the sham group (9.4%), to 11 (IAI; 17.5%) and 13 (sham; 20.3%) during the study period. Among these, 3/11 eyes in the IAI group and 4/13 in the sham group, eventually went on to develop exudative AMD during the study period.

The authors offered multiple suggestions for the lack of prophylactic effect seen in this study: (1) inadequate dosing frequency, (2) failure to target the “trigger” that leads to the development of exudative AMD (which may not be related to upregulation of VEGF), (3) imbalanced estimated exudative AMD conversion rates due to higher number of “dropouts” from the study in the sham group than in the IAI group. And while the study benefitted from standardized protocol assessments and imaging, a lower-than-expected rate of conversion may have led to an underpowering of the study to detect a difference in conversion rates between the two groups.

Ultimately, the authors assert, fellow eyes in individuals with exudative AMD in one eye should be monitored closely for at least the first 1 to 2 years following diagnosis. Future treatment modalities may be able to target “triggers” for exudative AMD conversion; the authors also have hopes that novel anti-VEGF agents with increased durability, or agents with different therapeutic targets altogether may provide a solution to reducing the likelihood of conversion to exudative AMD.