Faculty Bibliography

Purpose: To evaluate low-voltage X-ray stereotactic radiotherapy (SRT) delivered in conjunction with intravitreal ranibizumab for the treatment of active macular polypoidal choroidal vasculopathy (PCV). Methods: At baseline, all eyes received an intravitreal injection of ranibizumab, followed by 16-Gy X-ray SRT to the macula. Further ranibizumab injections were given pro re nata. The primary outcome measure was regression of the polyps assessed by indocyanine green angiography. Secondary outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness (CFT) changes on optical coherence tomography. Local or systemic adverse events were evaluated as well. Results: We examined 12 eyes of 12 patients with PCV. At month 12, an angiographic regression of the polyps was observed in 10 of the 12 eyes. The mean BCVA improved by 7.6 letters: from 65.08 +/- 11.4 to 72.7 +/- 14.75 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The mean CFT decreased from 372.3 +/- 79.6 to 215.9 +/- 57.9 microm (p < 0.01). No local or systemic adverse events were reported. Conclusions: The preliminary data support the safety of low-voltage X-ray SRT for the treatment of macular PCV and show polyp closure, reduction in CFT and improvement in the mean BCVA. Additional research is warranted to confirm the efficacy and longer-term safety of this therapy in this population. (c) 2014 S. Karger AG, Basel.

PURPOSE: To develop a new diabetic retinopathy severity scoring system and to determine if it can monitor changes from baseline as well as identify precise features that have changed over time. Such a grading system could potentially provide an understanding of the impact of treatments utilizing an algorithmic scoring technique. METHODS: The traditional ETDRS grading system was examined and a flow algorithm based on the grading approach was created. All visual comparative assessment points, relying on identification of features in relation to prior standard photographic images, were evaluated and quantified. A new grading form was created that provided fields that captured all relevant features required for determining the ETDRS grading score. A computer software algorithm was developed that examines all entered fields and calculates the appropriate diabetic severity score. RESULTS: This diabetic retinopathy scoring algorithm system was successful in generating a severity score comparable to traditional methods of grading images. Validation with traditionally graded images was performed, demonstrating that in a majority of cases, the severity scores were comparable. The algorithmic grading system was then used to analyze images obtained in a large clinical study of diabetic macular edema, resulting in data regarding baseline scoring values, as well as detailed features of the microvasculature that drove the severity scoring results, and changes seen during the trial. CONCLUSION: This new algorithmic diabetic severity scoring system provides a means to monitor the progression or regression of retinopathy with therapeutic intervention as well as assess the individual microvascular features that may be modified over the course of treatment.

PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTADME and VIVIDDME. PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained >/=15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining >/=15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 mum (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 mum (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

PURPOSE:: To assess for change in intraocular pressure (IOP) in neovascular age-related macular degeneration patients switched to aflibercept after receiving previous treatments of intravitreal bevacizumab or ranibizumab. METHODS:: This is a retrospective chart review of the first 53 patients (53 eyes) treated with at least 2 injections of 2 mg in 0.05 mL of aflibercept by March 6, 2013, after at least 2 previous injections of 0.5 mg in 0.05 mL of ranibizumab with or without previous injections of 1.25 mg in 0.05 mL of bevacizumab. The analysis was restricted to the first such sequence within each patient. The last previous anti-vascular endothelial growth factor injection before the switch to aflibercept was ranibizumab in all cases included in the study. Each person served as his or her own control. The pre-aflibercept IOP in the before state (treatment with bevacizumab or ranibizumab) was the preinjection IOP measure before dilation at the visit of the first aflibercept injection. Statistical analysis was performed using Microsoft Excel. RESULTS:: There were 41 patients who were first treated with ranibizumab followed by aflibercept and 12 patients treated with ranibizumab and bevacizumab followed by aflibercept. For each of these sequences, IOP in the treated eye during treatment with aflibercept (the after state) was computed in 3 different ways: the first IOP, the last IOP, and the mean IOP for the period when treated with aflibercept. The pooled data showed a mean pre-aflibercept (the before state) IOP of 14.87 that decreased to a mean first IOP of 14.57, mean last IOP of 13.79, and a mean IOP of 14.14 during aflibercept treatment. The inference is based on the pooled analysis. The 95% confidence interval for the differences (after minus before) were -0.30 (-1.12 to 0.52), -1.08 (-1.83 to -0.32), and -0.73 (-1.30 to -0.17) for the first, last, and mean IOPs, respectively. The corresponding P values were 0.46 for the first, 0.006 for the last, 0.01 for the mean IOP during the aflibercept treatment period. CONCLUSION:: Intraocular pressure was found to be significantly lower in patients switched to aflibercept after previous treatments with ranibizumab and/or bevacizumab. Aflibercept may have a more favorable IOP safety profile in patients previously on other anti-vascular endothelial growth factor treatments.

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was down-regulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of 4 common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; p=0.00012; OR=1.5; 95%C.I. [1.2;1.8], and p=0.0014; OR=0.70; 95%C.I. [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (p=0.0002; OR=0.61, 95%CI [0.47-0.79]). We propose that genetically pre-determined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population

PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD). METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts. RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months. CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.

PURPOSE: To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. DESIGN: Two randomized, double-masked, active-controlled, phase 3 trials. PARTICIPANTS: Two thousand four hundred fifty-seven patients with neovascular AMD. METHODS: From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES: Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. RESULTS: Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of -0.64 [95% CI, -0.89 to -0.40] and -0.55 [95% CI, -0.79 to -0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week 96. CONCLUSIONS: All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.