diabetic retinopathy is a major cause of visual loss worldwide , with vision - threatening diabetic retinopathy being present in 10% of people with diabetes . diabetic macular edema ( dme ) is the main cause of visual impairment in diabetic retinopathy , and there is ample evidence for the role of vascular endothelial growth factor ( vegf ) in the pathogenesis of dme.16 several large clinical trials have established the important role of the anti - vegf agents , ranibizumab and bevacizumab , in the treatment of dme.712 aflibercept is a novel anti - vegf agent composed of the vegf - binding portions of the extracellular domains of human vegf receptors 1 and 2 fused to the fc portion of human immunoglobulin g1 . the da vinci , vista , and vivid studies have established that treatment with aflibercept yields greater visual gains than macular laser treatment , and the drug has since received us food and drug administration approval for this indication.1315 a recent trial has also demonstrated that aflibercept is superior to ranibizumab or bevacizumab for eyes with dme and poorer presenting acuity . currently , many patients who have received ranibizumab or bevacizumab for the treatment of dme and who have failed to respond to these drugs are being switched to aflibercept . differences in the pharmacodynamics of aflibercept compared with ranibizumab or bevacizumab have been the basis of this strategy . unlike ranibizumab , aflibercept binds vegf with much greater affinity and also binds placental growth factor . some patients may also be switched to aflibercept due to its reportedly longer duration of action . retrospective data from subjects receiving this treatment for age - related macular degeneration have suggested that anatomical improvement with less significant visual improvement can be expected . the aim of this study was to evaluate the short - term outcomes following conversion from ranibizumab or bevacizumab therapy to aflibercept for the treatment of refractory dme . this was a retrospective series of patients treated at two tertiary eye care centers , ie , singapore national eye centre and massachusetts eye and ear infirmary . subjects were identified from electronic medical records using the appropriate international classification of diseases and billing codes . subjects were included if they had been treated for dme with ranibizumab and/or bevacizumab and were subsequently converted to aflibercept between september 2012 and september 2014 . exclusion criteria included other visually significant ocular pathology and complications of diabetic retinopathy ( eg , tractional retinal detachment , vitreous hemorrhage ) , loss to follow - up , fewer than three ranibizumab and/or bevacizumab injections prior to conversion to aflibercept , and incomplete imaging or clinical data . patient demographics , systemic comorbidities , and patients diabetes control ( hba1c levels ) were recorded . the main outcomes of note were the best - corrected visual acuity , which was recorded as snellen visual acuity and converted to logmar equivalents for analysis , and the anatomical changes as documented on optical coherence tomography . spectral - domain optical coherence tomography was performed using the cirrus ( carl zeiss meditec , dublin , ca , usa ) or spectralis ( heidelberg engineering , heidelberg , germany ) platforms . the main optical coherence tomography measures of note were central foveal thickness ( cft ) as well as the presence of intraretinal or subretinal fluid on the tomogram . the cft values were automatically generated by the imaging software and used in the analyses after the tomograms had been reviewed for segmentation errors . in cases where segmentation errors were seen , intraretinal or subretinal fluid was classified dichotomously as either present or absent , with cases in which only trace fluid was seen ( very fine intraretinal cysts or very thin slivers of subretinal fluid ) being classified as absent . the study complied with the health insurance portability and accountability act of 1996 and was performed in accordance with the tenets of the declaration of helsinki as revised in 1989 . this was an observational , retrospective , noninterventional study , and approval and waiver of consent were obtained from the institutional review boards of both institutions . the median number of ranibizumab or bevacizumab injections before switching to aflibercept was six , and the median number of aflibercept injections after switching was three . the mean interval between bevacizumab / ranibizumab injections prior to the switch was 2.42.2 months and the interval between aflibercept injections was 2.42.2 months ( p=0.92 ) . the mean cft at presentation was 385.65115.16 and 431.18147.79 m immediately prior to the switch ( p=0.17 ) . the mean cft after the first aflibercept injection reduced significantly to 362.5792.82 mm ( wilcoxon signed - rank test ; p<0.001 ) . at the end of follow - up , the mean visual acuity was 0.420.23 logmar just prior to the switch , 0.390.31 logmar after one aflibercept injection , and 0.370.22 logmar at the end of follow - up ( figure 2 ) . the final visual acuity was significantly better compared with the visual acuity before the switch ( p=0.04 ) . three of the 21 eyes ( 14% ) had complete resolution of intraretinal cysts at the end of follow - up . a representative case is shown in figure 3 . a 78-year - old woman had long - standing diabetes with a recent hba1c of 7.5% . after four bevacizumab injections , the right eye had persistent center - involving dme with a cft of 516 mm and large cystoid spaces ( figure 3a ) . after six aflibercept injections , the cft was 357 mm and the cystoid spaces had resolved , although a hyperreflective clump of hard exudates was still seen with disruption of the ellipsoid zone ( figure 3c ) . in the course of dme treatment , physicians may choose to switch between anti - vegf agents for various reasons . clinical reasons include the theoretically greater affinity of aflibercept for vegf as well as the fact that it also binds to and neutralizes placental growth factor . these pharmacodynamic differences may be particularly useful in situations unresponsive to ranibizumab or bevacizumab . in addition , physicians may choose to switch a patient to aflibercept to take advantage of its reportedly longer duration of action . anti - vegf treatment with bevacizumab or ranibizumab has been clearly shown to be effective and superior to laser for the treatment of dme involving the foveal center . pegaptanib was the first anti - vegf agent shown to be effective in the management of dme.16 several large trials , including the read-2 study,7 resolve,8 and the diabetic retinopathy clinical research ( drcr ) network group studies,9,10 have shown anti - vegf treatment with bevacizumab or ranibizumab to be superior to laser alone . despite these encouraging results with anti - vegf agents , some cases either do not respond at all to ranibizumab or bevacizumab , or demonstrate an initial response to treatment followed by subsequent nonresponse to further treatment or during disease reactivation . pharmacodynamic mechanisms include increased vegf expression from inflammatory cells and upregulation of vegf receptors , while pharmacokinetic tolerance represents an immune response to the anti - vegf antibodies injected leading to rapid clearance . in these cases , for example , an intravitreal dexamethasone implant ( ozurdex ) has been shown to be effective in eyes unresponsive to treatment with bevacizumab or ranibizumab.17 more recently , aflibercept has likewise been shown to be effective in the treatment of center - involving dme , producing results comparable with those for ranibizumab and bevacizumab . the da vinci trial evaluated different doses and dosing regimens of aflibercept with laser photocoagulation in eyes with dme.13,14 patients with center - involving dme were assigned to either laser treatment or one of four aflibercept dosing groups . at 24 weeks , all the aflibercept groups had greater visual gains than the laser group , with mean improvements in acuity ranging from 8.5 to 11.4 letters for the aflibercept groups compared with 2.5 letters for the laser group . the differences were even more distinct at 52 weeks , with letter mean gains of 9.712.0 in the aflibercept groups versus a mean letter loss of 1.3 in the laser group . all the aflibercept groups also demonstrated significantly greater reductions in cft compared with the laser group . the vista and vivid trials have shown similar results , with aflibercept being superior to laser.18 the drcr network has recently published the results of a seminal trial comparing the three anti - vegf agents for dme.19 over 1 year , eyes with presenting visual acuity worse than approximately 20/50 experienced greater visual improvement on treatment with aflibercept compared with bevacizumab or ranibizumab , with mean letter gains of 18.9 with aflibercept , 11.8 with bevacizumab , and 14.2 with ranibizumab . these studies suggest that cases unresponsive to ranibizumab and bevacizumab may respond instead to aflibercept . to our knowledge , there are limited data on the results of switching to aflibercept after treatment with ranibizumab or bevacizumab for dme . our study is limited by its small sample size and the inherent limitations of a retrospective report . different optical coherence tomography platforms were also used , although each patient was always imaged with the same platform for follow - up scans . nevertheless , significant visual and anatomical improvement with cft reduction were seen after just one injection and at the end of follow - up . our findings are consistent with those of the drcr network study,19 and support the notion that aflibercept may be more effective than ranibizumab or bevacizumab for more resistant cases . however , complete elimination of chronic cystoid spaces is difficult , and longer follow - up is needed to determine the effects of these lesions on vision . patients with center - involving dme who are unresponsive to ranibizumab or bevacizumab demonstrate anatomical and visual improvements after conversion to aflibercept . while aflibercept injections are much more costly than bevacizumab , the improvement that can be anticipated in these challenging cases suggests that making the switch is justifiable .
backgroundthe purpose of this study was to determine if eyes with diabetic macular edema ( dme ) unresponsive to ranibizumab or bevacizumab would benefit from conversion to aflibercept.methodsthis study was conducted as a retrospective chart review of subjects with dme unresponsive to ranibizumab and/or bevacizumab and subsequently converted to aflibercept.resultsin total , 21 eyes from 19 subjects of mean age 6215 years were included . 
 the majority of subjects were male ( 63% ) . 
 the median number of ranibizumab or bevacizumab injections before switching to aflibercept was six , and the median number of aflibercept injections after switching was three . 
 median follow - up was 5 months after the switch . 
 mean central foveal thickness ( cft ) was 453.52143.39 mm immediately prior to the switch . 
 morphologically , intraretinal cysts were present in all cases . 
 mean cft after the first injection decreased significantly to 362.5792.82 mm ( wilcoxon signed - rank test ; p<0.001 ) . at the end of follow - up , 
 the mean cft was 324.1798.76 mm ( p<0.001 ) . mean visual acuity was 0.420.23 logmar just prior to the switch , 0.390.31 logmar after one aflibercept injection , and 0.370.22 log - mar at the end of follow - up . 
 the final visual acuity was significantly better than visual acuity before the switch ( p=0.04).conclusioneyes with dme unresponsive to multiple ranibizumab / bevacizumab injections demonstrate anatomical and visual improvement on conversion to aflibercept .