Anti-VEGF Efficacy in DME: Early Response Is Not Always Predictive of Long-term Destiny

Saumya M. Shah, BS; Sophie J. Bakri, MD


January 23, 2019

Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T

Bressler NM, Beaulieu WT, Maguire MG, et al; Diabetic Retinopathy Clinical Research Network
Am J Ophthalmol. 2018;195:93-100

Study Summary

Previous studies have shown that eyes with diabetic macular edema (DME) with extensive early improvements in visual acuity (VA) after anti-vascular endothelial growth factor (VEGF) therapy have better long-term visual quality.

The Diabetic Retinopathy Clinical Research Network conducted a post-hoc analysis of the data from Protocol T to study the association between VA at 12 weeks after anti-VEGF treatment for DME, optical coherence tomography central subfield thickness (CST), and 2-year follow-up VA.

There were 616 patients who met inclusion criteria for having central-involved DME with a best corrected VA score of 78 through 24 (approximate Snellen equivalent 20/32 to 20/320) and a CST of at least 250 µm. Patients were randomly assigned to receive one of the three anti-VEGF injections (bevacizumab, ranibizumab, or aflibercept) at baseline and every 4 weeks for the first 20 weeks. However, injection was deferred if the VA letter score was 84 or better (Snellen equivalent 20/20) after two consecutive injections, or the CST was less than sex- and instrument-specific cutoffs (Heidelberg Spectralis ≥ 320 µm for men and ≥ 305 µm for women, Zeiss Cirrus ≥ 305 µm for men and ≥ 290 µm for women, Zeiss Stratus ≥ 250 µm for both sexes). Reinjection was conducted at 24 weeks or restarted at a later time if there was worsening of VA (≥ 5 letters) or CST (change by ≥ 10%). Focal/grid laser were performed at or after 24 weeks if DME persisted, there was lack of improvement in VA or CST with two consecutive injections, or there were lesions amenable to laser.

Overall, VA response to anti-VEGF at 12 weeks was correlated with 2-year response in VA and VA letter score for each drug (P < .001), although with significant individual variability (multivariable R2 of 0.38, 0.29, and 0.26 for 2-year change with aflibercept, bevacizumab, and ranibizumab, respectively). Eyes that gained < 5 letters at 12 weeks on average had less VA improvement from baseline to 2 years in comparison with eyes that gained ≥ 10 letters at 12 weeks. However, the previously mentioned individual variability was on display when 42%, 31%, and 47% of eyes with < 5-letter gain at 12 weeks had ≥ 10 letter gain at 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively.

Median VA at 2 years in the < 5-letter-gain group versus ≥ 10-letter-gain group at 12 weeks was 20/32 versus 20/25 for aflibercept, 20/32 versus 20/25 for bevacizumab, and 20/25 versus 20/32 for ranibizumab. In eyes with an initial gain of < 5 letters versus ≥ 10 letters at 12 weeks, the percentage of eyes with ≥ 10-letter gain from 12 weeks to 2 years was 38% versus 18% with aflibercept (P = .01), 38% versus 11% with bevacizumab (P < .001) and 42% versus 14% with ranibizumab (P < .001). Baseline or 12-week changes in CST were not found to be significantly associated with VA or VA letter score change at 2 years.


This detailed study assessed the course of vision gain or loss with anti-VEGF therapy and the extent to which early VA response is predictive of later vision gain in eyes with DME.

Researchers found that mean change in VA from baseline to 12 weeks was associated with long-term outcomes when treating DME with any of the three anti-VEGF agents. Evidently, eyes with low visual letter score gain at 12 weeks had lower visual letter score at 2 years. However, there was a significant amount of individual variability in the course of long-term vision gain in these low-early-response cases. Although mean change in VA at 12 weeks was found to correlate with later visual outcomes, baseline and 12-week CST response to anti-VEGF had far less association with long-term VA outcomes. Hence, predictions for long-term visual response to anti-VEGF (regardless of the particular drug) based on 12-week VA are difficult for any patient with DME.

A major question not assessed in the current study was whether there is a role for switching to alternative therapies in eyes with persistent DME and an initial < 5-letter gain. Even though the median absolute VA at 2 years was extremely good in the current study for these eyes (ranging from 20/25 to 20/32), discussion on when to incorporate additional therapies like steroid implants is warranted in the future.

It is also unclear how visual outcomes would trend beyond 2 years and what the rate of recurrence is for patients who had evident resolution of disease with good VA initially.

Additionally, it is vital to remember that the preset categories of improvement in this study (< 5 letters and ≥ 10 letters) are not the only measurements of improvement in VA. Individual patients could also exhibit improvements on a more gradual scale, or there could be inherent variability in measurement of VA.

In summary, 12-week response in VA to anti-VEGF treatment seems to be positively associated with 2-year visual outcomes. However, more important, a less than ideal response at 12 weeks did not impede substantial visual gain at 2 years for a large number of eyes. Also, the majority of eyes with < 5-letter gain at 12 weeks usually had very good VA at 2 years.


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