Reference - Lancet. 2024 Mar 23;403(10432):1141-1152
Practice Point: Aflibercept 8 mg every 16 weeks seems to be “not worse than” 2 mg every 8 weeks for treating wet age-related macular degeneration.
EBM Pearl: Non-inferiority trials can lead us to cheaper and more convenient medical treatments. It behooves you to understand the basics of this method.
Anti-vascular endothelial growth factor (VEGF) treatments are used to treat a variety of retinal diseases, including both dry and wet age-related macular degeneration and macular degeneration associated with diabetes and premature birth. The proliferation of blood vessels and associated edema with these conditions impairs macular function, and intravitreal injections of these agents, uncomfortable as they are, can often help preserve vision in people suffering from these otherwise disabling conditions. Despite best efforts, each injection carries a significant financial, logistical, and discomfort-related cost. Recently, the PHOTON and PULSAR studies for therapy for diabetic- and age-related retinopathy were published in Lancet looking at whether higher doses of aflibercept (8 mg/0.07 mL, priced at $2,625/vial) injected every 16 weeks would be non-inferior to standard doses (2 mg/0.05 mL, priced at $1957.55/vial) every 8 weeks.
Noninferiority trials, like all double negatives, can be confusing to simple folks like us. While they often get a bad rap for hosting “me too” therapies and being less stringent than superiority trials at times, they can be powerful tools for finding therapies that are safer, less costly, less frequent, at a lower dose, etc. that are “not worse than” an intervention with already-proven efficacy.
Let’s look at the PULSAR noninferiority trial of neovascular age-related macular degeneration (nAMD). In this trial, 1,009 patients with nAMD were all initially given monthly intravitreal injections of 2 mg aflibercept for 3 months, followed by randomization into three groups: 2 mg every 8 weeks (standard dosing), or high-dose extended-interval (HDEI) dosing: 8 mg either every 12 weeks or every 16 weeks. Intervention group participants received scheduled placebo injections when not receiving 8 mg dosing. Monthly vision checks assessed for ability to read a standard Snellen eye chart and retinal imaging assessed presence or absence of worsening changes in vascular proliferation or retinal swelling/edema. The noninferiority margin was set at a 4-letter difference on the Snellen chart, although all patients were expected to be able to read more letters at the end of 48 weeks. Patients who either failed to improve or worsened in the HDEI treatments were brought down to shorter intervals as needed depending on monthly monitoring.
At the end of 48 weeks, intention-to-treat analysis demonstrated noninferiority. Of those in the every 12-week arm, 79% maintained 12-week dosing. For the every 16-week arm, 11% dropped to every 12-week dosing and another 12% dropped to every 8 week dosing. Adverse events were roughly equal. Overall, the folks in standard treatment were able to read a mean of 7 more letters at 48 weeks, compared to approximately 6 letters for both the HDEI groups.
Now, notice that we stated the data were analyzed by intention-to-treat (ITT). This is important, and is a problem for this study’s validity. Unlike with superiority trials, a per-protocol analysis is preferred over ITT for noninferiority trials. The reason has to do with the null hypotheses, which are different for these two types of trials. For noninferiority trials, the null hypothesis (that is trying to be disproved) is that there is a difference between the groups. Because analyzing by ITT preserves prognostic equivalence (which is what we want for superiority trials with a null hypothesis that the two groups are the same), it actually overestimates the sameness in a noninferiority trial. So from an EBM standpoint, this study takes a hit to validity because they did not do a per-protocol analysis.
Despite this downgrade for ITT analysis, the data are convincing enough for us to consider it in clinical practice. It does appear that for some patients with retinopathy, we can decrease the injection burden without sacrificing efficacy. And while “not worse than” isn’t always the same as “as good as,” the potential power of non-inferiority trials to help people receive less burdensome treatments is worth considering in this era of drug-resistant infections, sky-rocketing costs, and of course, a longer-lived population.
For more information, see the topic Age-Related Macular Degeneration (AMD) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.