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Because diabetes is a growing epidemic, retina specialists can expect to treat more patients for diabetic macular edema (DME) in the future. Pharmacotherapy with anti-VEGF agents or a corticosteroid can be effective, but it helpful to have some criteria for defining treatment failure to guide decisions on changing therapy.
Recognizing the potential for lack of correspondence between structural and functional measures and how multiple factors can affect visual acuity, assessing failure of treatment for DME is best judged by persistence of macular edema identified with optical coherence tomography (OCT), said Patricia Udaondo, MD.
“The pathophysiology of DME is a very complex and involves VEGF and many inflammatory factors. Therefore, it may not respond to monotherapy,” explained Dr. Udaondo, Hospital Universitario y PolitÃ©cnico La Fe Aiken, Valencia Spain. “Stabilizing and/or improving visual acuity is the main objective of any treatment in ophthalmology, including for DME. However, visual acuity can be an imprecise endpoint for evaluating treatment response because it can be influenced by confounding factors. Unlike visual acuity, change in the OCT is objective and independent of other factors.”
A ceiling effect in patients who have good baseline visual acuity (> 69 letters) is one reason why lack of improvement in visual acuity may not necessarily represent treatment failure. Alternatively, DME may improve in some patients without a corresponding improvement in visual acuity if there is permanent structural damage or, in the case of corticosteroid treatment in a phakic patient, because of treatment-induced cataractous changes.
Another situation to consider is the patient whose visual acuity improves to 20/20, but who still has residual edema on the OCT. “Is that patient a treatment responder because the visual acuity is good?,” Dr. Udaondo added.
A review of the literature shows that various studies have used different criteria to define response to treatment for DME.
Investigators in DRCR.net Protocol I performed a subanalysis to identify factors that predicted success or failure after 4 monthly injections of intravitreal ranibizumab (Lucentis, Genentech) [Bressler SB, et al. Arch Ophthalmol. 2012;130(9):1153-1161.] The OCT images were analyzed to identify whether there was a ≥ 20% reduction from baseline in central subfield thickness (CST) at weeks 16, 32, and 52, and the investigators classified eyes into 4 categories according to whether they met the outcome criterion at all, some, or none of the visits.
Early and consistent responders, who accounted for about 50% of the cohort, had improvement on OCT at week 16 that was maintained at weeks 32 and 52. Early, but inconsistent, responders demonstrated improvement on OCT at week 16 and at either week 32 or 52.
Slow and variable responders did not achieve the pre-specified anatomic outcome until week 32 or 52, and non-responders, accounting for about 25% of patients, did not show a ≥ 20% reduction from baseline in CST at weeks 16, 32, or 52.
Findings of a post-hoc, multivariable analysis of data from the DRCR.net Protocol I are of interest because they showed a significant association between best corrected visual acuity (BCVA) improvement after 3 injections and outcomes at 1 and 3 years. [Gonzalez VH, et al. Am J Ophthalmol. 2016;172:72-79]
“In this analysis, eyes with a < 5 letter improvement in BCVA after 3 ranibizumab injections achieved limited additional improvement at 3 years,” Dr. Udaondo said. “So, perhaps a patient whose response is not what is expected at 3 months might be defined as a non-responder or treatment failure.”
Other criteria for defining treatment failure with anti-VEGF injections for DME include presence of central macular thickness >325 µm or BCVA loss of ≥5 letters after 3 consecutive monthly treatments. In the DRCR.net Protocol T, which compared the 3 commercially available anti-VEGF agents, patients were treated with rescue laser photocoagulation if the visual acuity and OCT were stable for 2 consecutive injections and there was persistent edema or vision loss.
For patients treated with the intravitreal dexamethasone implant (Ozurdex, Allergan), OCT-based criteria for treatment failure might look for a <20% reduction of edema at 6 to 8 weeks post-implantation, which represents the expected time to observe the maximum effect.
Patricia Udaondo, MD
Dr. Udaondo has no relevant financial interests to disclose.