Discussion
nAMD
In RAINBOW, treatment-naïve patients with nAMD treated with IVT-AFL in routine clinical practice in France maintained anatomic improvements over 4 years, with a mean change in CRT of − 118 μm at month 48 for the overall FAS. However, the initial mean gain in BCVA of + 5.1 letters at month 12 (baseline, 57.2 letters) was not maintained, with visual acuity returning toward baseline levels (and below baseline levels in patients who received the fewest number of injections, namely, the irregular treatment cohort without the 3 initial injections) by the end of the study because of progressive undertreatment.Although more than 80% of patients received the 3 initial monthly injections of IVT-AFL, the majority of patients were not treated regularly over the full study period. Those patients who did receive the 3 initial monthly injections showed greater persistence with treatment, and those who were treated regularly during the first year experienced better functional outcomes than patients who received irregular treatment without the initial injections. However, the 4-year outcomes were similar for all treatment cohorts, suggesting an association with undertreatment after the first year. Based on the data, we cannot draw any conclusions regarding whether the improved outcomes in patients with regular treatment were due to treatment frequency or whether treatment frequency was higher in these patients because they experienced better outcomes and were, therefore, more likely to adhere to treatment. The mean number of visits was higher than the mean number of IVT-AFL injections received, implying that more patients may have been treated pro re nata instead of by T&E. The overall safety profile of IVT-AFL was consistent with previous studies.The BCVA gains observed in RAINBOW are lower than those observed in the key RCTs of IVT-AFL treatment of nAMD: in the VIEW 1 and 2 studies, patients who received 3 initial monthly injections and treatment every 2 months thereafter had a mean gain of + 7.6 letters (baseline, 53.6 letters) over 96 weeks, after a mean of 11.2 injections [The 12-month BCVA gains in RAINBOW are numerically higher, however, than those observed in earlier real-world studies of anti-VEGF treatment of nAMD in France. In LUMIERE, a mean gain of + 3.2 letters from baseline was observed after 12 months of ranibizumab treatment in 551 patients; < 40% of patients received the recommended initial injections, and patients received a mean of 5.1 injections over 12 months [Other European real-world studies of IVT-AFL treatment further highlight the challenges inherent in longer-term, non-interventional studies with respect to study discontinuations, low treatment persistence, and irregular treatment. In the German PERSEUS study, treatment-naïve patients who received regular IVT-AFL treatment achieved a mean visual acuity gain of + 8.0 letters (baseline, 52.8 letters) compared with + 4.0 letters (baseline, 53.7 letters) among those who received irregular treatment in year 1 [In a retrospective single-center case series analysis of IVT-AFL treatment of nAMD based in the UK, a mean gain of + 5.9 letters at 1 year, + 6.4 letters at 2 years, and + 6.6 letters at 3 years from a baseline of 54.4 letters was reported [To date, the most extensive real-world data on the anti-VEGF treatment of nAMD have been collected by FRB!. The first 10-year outcome report based on FRB! data found that patients in Australia and New Zealand who completed 10 years of continuous treatment lost a mean of only 0.9 letters, whereas those in Switzerland lost a mean of 14.9 letters [Thus, the findings of RAINBOW are consistent with those of prior RWE, emphasizing the importance of 3 initial monthly IVT-AFL injections followed by continuous proactive treatment beyond the first year. In routine clinical practice, the frequency of anti-VEGF treatment of nAMD tends to be less regular, which can lead to poorer visual outcomes compared with RCTs [Besides loss to follow-up, several other limitations inherent to the observational design of RAINBOW may affect interpretation of the findings reported here. A variety of charts were used to assess visual acuity, and this may have introduced bias. Furthermore, the scheduling of patient visits and monitoring was at the discretion of the attending physician, and this led to a large quantity of missing data.