Is Treat-and-Extend Truly Effective for Diabetic Macular Edema?

Anti-vascular endothelial growth factor (anti-VEGF) medications have a proven track record in treating diabetic macular edema (DME). However, researchers continue to investigate whether these medications can be made more efficient and cost-effective. One means of potentially achieving these goals is through treat-and-extend dosing, in which anti-VEGF dosing is titrated and tailored to an individual patient's clinical response.

Both the RETAIN^[1] and REACT^[2] studies showed that treat-and-extend regimens for ranibizumab were efficacious for DME. Further support was provided by the TREX-DME study, the first prospective, randomized controlled trial to evaluate ranibizumab 0.3 mg using a unique treat-and-extend algorithm. At 1-year follow-up, there was a significant decrease in the number of administered injections in patients with DME who received treat-and-extend dosing with and without concomitant laser therapy.^[3]

In a recently published update of the TREX-DME study,^[4] investigators evaluated the long-term (2-year) visual outcomes resulting from this approach. Eyes were included if they had central DME and best corrected visual activity (BCVA) between 79 and 24 letters (20/25 to 20/320 Snellen equivalent), and were excluded if they had received anti-VEGF or steroid injections in the prior 12 weeks or underwent prior macular laser photocoagulation.

Patients were randomly assigned to receive ranibizumab in three separate arms: on a monthly basis; or in treat-and-extend dosing established by a fixed algorithm either with navigated focal laser (GILA cohort) or without navigated focal laser (TREX cohort). All study eyes received 0.3 mg ranibizumab monthly, although at week 12, eyes in TREX and GILA could enter a treat-and-extend protocol if and when central retinal thickness (CRT) was ≤ 325 µm. Eyes in the GILA cohort received angiography-guided macular laser photocoagulation at week 4 and every 3 months subsequently if microaneurysm leakage was evident.

The primary outcome assessed was the mean change in BCVA from baseline. Secondary outcomes included mean change in CRT, total number of anti-VEGF injections, incidence of adverse events, and proportion of patients gaining or losing 10 or 15 letters at month 24.

At 2-year follow-up, there were improvements over baseline in mean BCVA of 7.5, 9.6, and 9.0 letters and in mean CRT of 139, 140, and 175 µm for the monthly, TREX, and GILA cohorts, respectively. A similar number of eyes gained one, two, and three lines of vision in each of the three cohorts. There was a significant reduction in the average number of administered injections in both the TREX and GILA cohorts, in comparison to the monthly cohort. No significant difference was evident between the TREX and GILA cohorts in terms of the average treatment interval or percentage of eyes that had treatment extended to 12 weeks.

Taking a Longer-term View on Treat-and-Extend

These latest results from the TREX-DME study indicate that a treat-and-extend protocol for DME with ranibizumab 0.3 mg resulted in significantly better visual acuity improvement and fewer injections than monthly dosing at 2 years. Laser supplementation in addition to the ranibizumab therapy had no extra value per any measured primary or secondary outcomes.

Although this study further confirms the results of similar trials (REACT^[2] and EVADE^[5]) in finding that a treat-and-extend approach is reasonable for DME, it is important to note that this approach was not evaluated against as-needed treatment of DME. It is likely that as-needed treatment would have an even lower mean injection number and would prevent unnecessary treatment in stable patients. The treat-and-extend regimen plan certainly has its advantages, including better long-term maintenance of visual outcomes and disease stability, but it would be helpful to measure the study outcomes against an as-needed treatment cohort.

The clinically insignificant impact of focal laser in the GILA cohort compared with the TREX cohort is interesting, given that the study investigators specifically aimed to standardize laser treatments between patients. The authors do acknowledge the possible impact on their results by other factors, such as photocoagulant effect, spot density, and depth of coagulation. Given that other trials evaluating the role of supplemental laser therapy for DME have had mixed results, additional studies are needed on this topic as well as on the role of the aforementioned possibly confounding factors.

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