Evaluating Effects of Switching Anti–Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration and Diabetic Macular Edema

Question  In studies of effects of switching anti–vascular endothelial growth factor agents after poor initial response, can it be assumed that there will be no future improvement if there is no switching?

Findings  In eyes meeting criteria for switching but maintained on the original agent, improvements in visual acuity and retinal thickness were observed.

Meaning  A control group maintained on the original agent should be included in studies of switching agents to make valid conclusions.

Importance  When a patient with neovascular age-related macular degeneration or diabetic macular edema does not respond to an initial anti–vascular endothelial growth factor agent, usually after several injections, ophthalmologists may switch to another anti–vascular endothelial growth factor agent. Authors of case series have suggested beneficial effects from switching. However, to our knowledge, there are no studies with an appropriate control group to evaluate how such patients would do without switching agents.

Objective  To assess outcomes in patients who have a poor initial response but continue treatment without switching agents.

Design, Setting, and Participants  We obtained data from 2 multicenter clinical trials, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Diabetic Retinopathy Clinical Research Network (DRCR.net). Based on typical clinical reasons for switching agents, we developed “switching rules” at both 3 and 6 months after initiation of treatment. Using these switching rules, we identified a 3-month and a 6-month cohort of “treatment failures” from both CATT and DRCR.net studies.

Interventions  Although the cohorts from each study met criteria for switching, they were treated with the initial agent throughout the study (bevacizumab or ranibizumab in CATT and ranibizumab in DRCR.net).

Main Outcomes and Measures  Primary outcomes were change in visual acuity and change in central retinal thickness on optical coherence tomography from the 3- or 6-month visit at which switching rules were met.

Results  The 126 patients from CATT and the 59 patients from DRCR.net who were selected for the switching analysis were similar in age, sex and race/ethnicity to the overall study populations. Among the participants who met the criteria for switching, the CATT participants were a mean (SD) of 79.7 (7.8) years of age, 65.9% women, and 97.6% white, while the DRCR.net participants were a mean (SD) of 65.5 (9.3) years of age, 44.1% women, and 76.3% white In all 4 cohorts, there was a 3- to 5-letter improvement in mean visual acuity over the 3 months after the switching rules were met, although all patients continued on their originally assigned treatment. Mean central retinal thickness also improved by 40 to 70 μM.

Conclusions and Relevance  These results demonstrate the importance of having a comparison group to evaluate the effect of switching anti–vascular endothelial growth factor agents for treatment of neovascular age-related macular degeneration or diabetic macular edema. Without a comparison group, it is impossible to know whether any improvement observed after switching was related to the new treatment or was related to regression to the mean and time effects as observed in the 4 cohorts presented here. Randomization to switching or not switching drugs would provide a basis for valid conclusions about the effects of switching.