To date, the anti-VEGF injection has become the first-line therapy for center-involved DME in most clinical practices [10]. Nevertheless, due to difficulties in access to healthcare services, higher frequency of comorbidities, and/or poor adherence to the treatment by older patients, individualized treatment regimens vary substantially in a real-world setting, mainly resulting in fewer injections and fewer clinic visits than those imposed by strictly monitored clinical trials [11, 12]. This current study of Turkey showed that anti-VEGF injections for DME were associated with functional and anatomic improvement in a real-life setting, which was in line with results observed in clinical trials and other real-world studies. The greater improvements in VA were achieved in patients who had a lower baseline VA over three years. It was also observed that the patients who received loading doses showed better VA gains over the 36 months of follow-up. However, in the present study, anti-VEGF injections for DME were administered less frequently and less effective than those in clinical trials.
Overall, the visual improvements observed in this study are consistent with real-life studies from other countries, though 12-month BCVA gain (+ 8.2 letters) in the 12-month cohort of our study were better than what has been reported in real-world data [11–16]. In the LUMINOUS study, a prospective multicountry analysis of 1063 DME eyes, the country-specific visual gains were between − 0.3 and 6.9 letters with an average of 2.2-6.0 injections over one year [13]. In the OCEAN prospective study, which included 1226 eyes in Germany, the mean VA outcome during 12 months was + 4 letters, achieved with a mean of 4.4 injections [12]. In a 1-year Moorfield’s retrospective study of 102 treatment naïve eyes, a mean improvement of 9.9 letters with a mean of 6.9 injections was observed [17]. Our functional results at 12 months were also similar with a slightly fewer number of 4.6 injections. The visual gain was maintained over the second and third year of follow-up in the 24- and 36- month cohorts with mean 7.1 and 8.0 intravitreal injections, respectively (+ 5.3 letters in the 24-months cohort and + 4.4 letters in the 36-month cohort). Consistent with our results, a retrospective study of 3-year outcomes from Thailand showed improvement of 6.8, 4.1, and 3.0 letters with a mean of 6, 8, and 9 injections at 12, 24, and 36 months, respectively [11]. In another real-world BOREAL-DME study conducted at France, Massin et al. reported similar VA gains of 7.4 letters at month 12 and 4.1 letters at month 36 [16].
The real-world DME study outcomes are notably worse than those from RCTs. RCTs have the intensive treatment and follow-up protocol and narrow inclusion and exclusion criteria, leading to better outcomes. In the VISTA&VIVID study, the reported mean gain in BCVA from baseline to 3-year was between + 10.3 and + 11.7 ETDRS letters with 18.1–32 injections [4]. Similar VA improvements were also observed at 36 months in other RCTs, including RESTORE (+ 8 letters) and RISE&RIDE (+ 11 and + 11.4 letters) [6, 18]. The present study suggests a potential role of undertreatment to account for inferior visual outcomes of our DME population. Recent studies have shown that higher visual gains were obtained with more frequent injections in clinical trials than real-world reports [2, 19]. In line with this finding, a retrospective real-world study in the USA has reported that mean VA improvement had a linear relationship with a mean number of anti-VEGF injections at one year, suggesting that intensive treatment strategy in the first year is essential [20]. Another possible explanation for the differences in visual outcomes is varying population characteristics. Chronic DME and previous laser treatment-related structural damage may limit the potential for visual recovery that may account for the differences in long-term results between the studies [3]. Therefore, considering that 42% of our patients had received previous ocular treatments, the chronicity and severity of DME in some of our patients and thus the relative delay in starting anti-VEGF are important factors further contributing to the inferior outcomes.
As mentioned before, the mean number of injections observed in this study and other real-life studies was relatively lower than that observed in other RCTs. In the landmark trials, the patients have received 7–12 injections in the first year, with over 20 injections at two years [4, 18]. In the present study, the patients received 4.6 injections in the first year, 7.1 and 8.0 injections over 24 and 36 months, reflecting general undertreatment. Similarly, in a recently published real-life study with a 4-year duration, Epstein and Amren have reported 4.7, 1.4, 0.7, and 0.9 injections during years 1–4, respectively [21]. A possible explanation for the low number of anti-VEGF injections in our study may be a high burden of health care visits for patients with DME, and it is likely that missed visits or treatments contributed to reduced injection frequency. The patients had on average 7.4, 13.2, and 18.7 visits at 12, 24, and 36 months, which is notably lower than strictly monitored controlled trials [4, 19]. The poor adherence to the treatment in the current study could be attributed to the need for bilateral treatment, lack of education regarding the need for intensive therapy over a period, interference with work schedules, or other associated patient comorbidities that often contribute to a burden of hospital visits.
Despite undertreatment, substantial and continuous visual and anatomic improvement were observed through 36 months. Patients with low baseline VA (< 70 letters) and those receiving loading doses showed the highest VA gains during the observation period of our study. In contrast, the patients with baseline VA of ≥ 70 ETDRS letters gained less but maintained higher vision than those with lower baseline VA. Considering similar VA outcomes, recently published Protocol V showed that the eyes with very good baseline VA (≥ 80 ETDRS letters) could be managed by observation only instead of starting intravitreal anti-VEGF treatment. Close monitoring rather than proactive treatment may help decrease the burden of clinics and the initial cost of the treatment [22, 23]. Furthermore, results from our study highlight that patients who had a loading dose gained better VA gains than those who did not. Similarly, in a real-world study from Thailand, the authors revealed that the more remarkable mean VA improvement at 12 months was observed in eyes receiving three initial monthly loading injections compared to eyes with non-loading injections [11]. These findings confirm the benefits of receiving loading treatment in a real-life setting.
The incidence of ocular AEs (4.1%) observed in this study was lower than that observed in the RCTs, possibly because of under-reporting in this retrospective observational setting. There was only 1 case of endophthalmitis reported in the study. There were no retinal tears or retinal detachments during the study period. Overall, the safety results observed in this study were consistent with the known safety profile of anti-VEGF agents demonstrated in clinical trials of anti-VEGF therapy in patients with DME [4, 24, 25].
The strength of this current study is that this is the first largest population-based real-world study of anti-VEGF use for DME in Turkey. The study enrolled patients with a variety of demographics and baseline characteristics, including comorbidities which may have excluded patients from RCTs. Therefore, our study could provide additional information to guide management in patients more representative to a typical real-life population. Besides, the multicenter nature of the current study could help to obtain more generalizable data. Additionally, the results of this study depend on the sample that consists of 3 mutually exclusive cohorts, each of which differs in terms of both the number of patients and their characteristics. This could allow us to control for any potential impact of the loss to follow-up on visual and anatomic outcomes in this real-life study.
This study has several potential drawbacks, typically associated with its retrospective nature, such as missing data and patients lost to follow-up. Lack of defined treatment criteria and non-standardized VA assessment among study centers could partially account for shortcomings of our real-world data. Furthermore, we did not have information on the course of DME in the individual eyes before the inclusion of the study, which might have also influenced the outcome results. Lastly, the results for the three different anti-VEGF agents without considering anti-VEGF switching in the treatment were taken together as a whole. In some studies, such as protocol T, some differences in visual outcomes were found between the three drugs, which might influence or explain some of the data in the present study [2].
In conclusion, anti-VEGF therapy for DME over a three-year period was associated with improved functional and anatomic outcomes despite generally low injection numbers in real-life conditions. Baseline VA scores and a loading regimen for anti-VEGF injections seem to be essential factors in achieving better VA outcomes through 3-year follow-up.