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2-year study results on anti-VEGF treatments for DME patients indicate relative equivalency and some superiority

Results from a 2-year follow-up study comparing anti-VEGF agents for center-involved DME (using a standardized follow-up and retreatment regimen) have shown that ranibizumab, aflibercept and bevacizumab all demonstrated VA improvement from baseline to 2 years with a decreased number of injections in year 2. According to the published study results, eyes with a worse baseline VA, had superior 2-year VA outcomes with aflibercept compared to bevacizumab, however, the previously reported superiority of aflibercept over ranibizumab at 1 year, was no longer evident at a 24-month time-point. The study also noted that higher anti-platelet event rates with ranibizumab over 2 years warranted continuing evaluation of such events in future trials. Commenting on the study, lead author Dr. Jack Wells, MD, stated that, “In patients with relatively good vision [20/32 or 20/40] at baseline, there was equivalent improvement in vision with the three therapies at 1 and 2 years.” However, Dr. Wells also stated that, “if you look at the totality over the course of the study, aflibercept is better most of the way. I would treat patients with aflibercept because they will have better vision more quickly than if treated with ranibizumab”.


The study, conducted by the Diabetic Retinopathy Clinical Research Network (, involved 89 clinical sites and enrolled 660 patients which were randomised 1:1:1 to intravitreous injections of aflibercept (2.0mg), bevacizumab (1.25mg, re-packaged compounded), or ranibizumab (0.3mg). Injections were performed using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted while clinical visits occurred every 4 weeks during year 1, extending up to every 4 months thereafter when VA and macular thickness became stable. The main results showed that for participants completing the 2-year visit, the median numbers of intravitreous injections during the study were 15 (interquartile range [IQR], 11-17), 16 (IQR, 12-20), and 15 (IQR, 11-19) injections in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P=0.08), with 5 (IQR, 2=7), 6 (IQR, 2-9), and 6 (IQR, 2-9) injections, respectively, between the 1 and 2-year visits (global P=0.32. Focal/grid laser photocoagulation was administered in 41%, 64%, and 52% in the aflibercept, bevacizumab, and ranibizumab groups, respectively (aflibercept vs. bevacizumab, P<0.001; aflibercept vs. ranibizumab, P=0.04; bevacizumab vs. ranibizumab, P=0.01), indicating that eyes in the aflibercept group were less likely to experience persistent edema and therefore less likely to require laser photocoagualtion. At 2 years, the reported mean VA had improved by 12.8 letters with aflibercept, 10.0 letters with bevacizumab, and 12.3 letters with ranibizumab. At the 2-year visit time-point, the central subfield thickness had decreased on average by 171±141μm with aflibercept, 126±143 μm with bevacizumab, and 149±141 μm with ranibizumab (aflibercept vs. bevacizumab, -48.5 μm [95% CI, -70.0 to -27.0μm; P<0.001]; aflibercept vs. ranibizumab, -15.5μm [95% CI, -33.0 to .2.0μm; P=0.08]; and ranibizumab vs. bevacizumab, -33.0μm [95% CI, -53.4 to -12.6μm; P<0.001].


In summary, all three regimens produced substantial VA improvements throughout the 2-year timeframe. Among participants with a better baseline VA, there were no meaningful differences identified in mean VA while in eyes with a baseline VA of 20/50 or worse, the advantage of aflibercept over ranibizumab, noted at the 1 year time-point, had decreased and was no longer statistically significant at 2 years. In respect of safety, the study reported that systemic APTC rates (Anti-platelet Trialists’ Collaboration Definition for an event) were higher in the ranibizumab group, with a greater number of non-fatal strokes and vascular deaths in the ranibizumab group. However, the study authors commented that such a result may not be consistent with previously reported clinical trials, in addition to which, a meta-analysis across multiple retinal diseases did not identify an increased risk of major cardiovascular or hemorrhagic events with ranibizumab compared with control. As a result, the study concluded that, “the implications of the increased rate of APTC events with ranibizumab found in the current study is uncertain because of inconsistency with prior trials”.