Volume 12, Number 3
WELCOME to Review
of Ophthalmology's Retina
Online e-newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.
Aflibercept, Bevacizumab or Ranibizumab for DME
Scientists sought two-year results comparing anti-vascular endothelial growth factor agents for center-involved diabetic macular edema using a standardized follow-up and retreatment regimen involving a randomized clinical trial of 660 participants with visual acuity impairment from DME.
Randomization to 2.0-mg aflibercept; 1.25-mg repackaged (compounded) bevacizumab; or 0.3-mg ranibizumab intravitreous injections were performed up to monthly, using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after six months if DME persisted. Visits occurred every four weeks during year one and extended to every four months thereafter when VA and macular thickness were stable. Main outcome measures included VA change, adverse events and retreatment frequency.
Median numbers of injections were: five in year two in the aflibercept group; six in year two in the bevacizumab group; and six in year two in the ranibizumab group; and 15 over two years in the aflibercept group; 16 over two years in the bevacizumab group; and 15 over two years in the ranibizumab group (global p=0.08). Focal/grid laser photocoagulation was administered in 41 percent of the aflibercept group; 64 percent of the bevacizumab group; and 52 percent of the ranibizumab group (aflibercept vs. bevacizumab, p<0.001; aflibercept vs. ranibizumab, p=0.04; bevacizumab vs. ranibizumab, p=0.01). At two years, mean VA improved by 12.8 letters in the aflibercept group; 10.0 in the bevacizumab group; and 12.3 letters in the ranibizumab group. Treatment group differences varied by baseline VA (p=0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.3 in the aflibercept group; 13.3 in the bevacizumab group; and 16.1 letters in the ranibizumab group (aflibercept vs. bevacizumab, p=0.02; aflibercept vs. ranibizumab, p=0.18; ranibizumab vs. bevacizumab, p=0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8 in the aflibercept group; 6.8 in the bevacizumab group; and 8.6 letters in the ranibizumab group (p>0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration events occurred in 5 percent with aflibercept; 8 percent with bevacizumab; and 12 percent with ranibizumab (global p=0.047; aflibercept vs. bevacizumab, p=0.34; aflibercept vs. ranibizumab, p=0.047; ranibizumab vs. bevacizumab, p=0.20; global p=0.09 adjusted for potential confounders).
All three anti-VEGF groups showed VA improvement from baseline to two years with a decreased number of injections in year two. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior two-year VA outcomes compared with bevacizumab; however, superiority of aflibercept over ranibizumab, noted at one year, was no longer identified. Scientists proposed that higher APTC event rates with ranibizumab over two years warranted continued evaluation in future trials.
SOURCE: Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. Ophthalmology. 2016; Feb 9 [Epub ahead of print].
IOP in DME Subjects Treated With DEX Implant: Three-year Study
Investigators evaluated the occurrence, management and clinical significance of increases in intraocular pressure in individuals with diabetic macular edema treated with dexamethasone intravitreal implant, as part of a randomized, multicenter, three-year Phase III study.
Those (n=1,048) with diabetic macular edema were randomized to 0.7-mg DEX implant; 0.35-mg DEX implant; or sham procedure with retreatment allowed at ≥six-month intervals (seven injections maximum).
Investigators observed ≥10-mmHg IOP increases from baseline in: 27.7 percent of the 0.7-mg DEX implant group; 24.8 percent of the 0.35-mg DEX implant group; and 3.7 percent of the sham group. Frequency did not increase with repeat injections. IOP-lowering medication was used by 41.5 percent of 0.7-mg DEX implant subjects; 37.6 percent of 0.35-mg DEX implant subjects; and 9.1 percent of sham subjects. Only one individual (0.3 percent) in each DEX implant group had filtering surgery to manage a steroid-induced IOP increase. Among 0.7-mg-treated DEX implant subjects, 21.9 percent (21 of 96) of those with a ≥10-mmHg IOP increase, and 22.4 percent (57 of 255) without a ≥10-mmHg IOP increase achieved ≥15-letter best-corrected visual acuity gain. Mean average change in central retinal thickness from baseline was -127 µm in those with a ≥10-mmHg IOP increase; and -106 µm without a ≥10-mmHg IOP increase.
Investigators found DEX implant demonstrated clear treatment benefits despite IOP increases. Sequential implants had no cumulative effect on IOP.
SOURCE: Maturi, Raj K. MD; Pollack, Ayala MD; Uy, Harvey S. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year mead study. Retina. 2016; Feb 11 [Epub ahead of print].
Anatomic Clinical Trial Endpoints for Nonexudative AMD
Researchers examined the role of anatomic endpoints in clinical trials to study nonexudative age-related macular degeneration emphasizing novel composite endpoints for developing emerging intermediate AMD therapeutics. Unlike clinical trials for exudative AMD, researchers wrote it is impractical to use change in visual acuity as a primary endpoint. By the time VA was lost in nonexudative AMD, proof-of-concept, early-stage clinical trials would be ongoing, and drug development would be a virtually impossible task, researchers explained. As such, they proposed that surrogate endpoints that could easily be measured were needed to reliably predict future vision loss. Anatomic changes correlating with disease progression in nonexudative AMD offered the greatest promise as primary endpoints, researchers wrote further.
In preparation for the review, the PubMed database was searched for research pertaining to anatomic endpoints to study nonexudative AMD. Recent review articles and results from large clinical trials—preferably with outcomes from several years of follow-up—were favored over trials of short duration.
The most commonly used anatomic endpoint for studying late, nonexudative AMD was growth of geographic atrophy, researchers wrote. Advantages of studying GA were said to be: the acknowledgement that GA’s enlargement through the foveal center led to significant vision loss as evidenced by natural history studies; the understanding that prevention of GA growth would preserve future vision; the ability to reliably measure GA using different imaging strategies; and development of statistical tools that reliably predicted GA growth over time. The major disadvantage of using GA was said to be that significant, irreversible disease progression had already occurred. However, use of drusen volume as a predictor of disease progression, and a composite endpoint that incorporated drusen growth, and formation of GA and neovascularization were said to offer an opportunity to study therapies at an earlier stage of AMD with a greater likelihood of preserving vision over a lifetime.
Researchers concluded that anatomic endpoints to study nonexudative AMD were needed to accelerate drug development, and optical coherence tomography algorithms to reliably measuring drusen morphology offered the best opportunity to study iAMD therapies.
SOURCE: Schaal KB, Rosenfeld PJ, Gregori G, et al. Anatomic clinical trial endpoints for nonexudative age-related macular degeneration. Ophthalmology. 2016;Jan 21. [Epub ahead of print].
Visual Function Measures in Early & Intermediate AMD
Investigators set out to evaluate: 1) the feasibility of performing computerized tests of low luminance visual acuity; cone-specific contrast (Cone Contrast Test [CCT]); contrast sensitivity; and microperimetry; and 2) the test-retest repeatability of these outcomes in dry age-related macular degeneration.
This prospective study enrolled 30 participants at a single site (eight controls; eight early AMD subjects; and 12 intermediate AMD subjects). Subjects underwent LLVA; contrast sensitivity; CCT; and microperimetry with eye tracking. Low luminance deficit was defined as best-corrected visual acuity minus LLVA in EDTRS letters. Follow-up testing was administered at approximately one month.
There was high test-retest repeatability at one month for all visual function metrics (intraclass correlations >0.7) except log contrast sensitivity (intraclass correlations 0.6). Compared with controls, individuals with intermediate AMD showed significant deficits on BCVA; LLVA; low luminance deficit; percent-reduced threshold on microperimetry; and red CCT (p<0.05), but not on contrast sensitivity; green; and blue CCT.
Investigators found the pilot study supported the feasibility and reliability of using LLVA; microperimetry; and CCT in early dry AMD. Though data suggested these measures could be used as alternative future clinical trial endpoints, investigators advised that a larger, prospective, natural history study of alternative visual function measures in dry AMD was warranted.
SOURCE: Chandramohan A, Stinnett SS, Petrowski JT, et al. Visual function measures in early and intermediate age-related macular degeneration. Retina. 206; Feb 16 [Epub ahead of print].
Ranibizumab for Wet AMD: Three-year Follow-up
Scientists conducted a retrospective review to determine the effect of ranibizumab on visual acuity following a three-year treatment period for individuals diagnosed with wet age-related macular degeneration, and establish whether baseline VA and injection frequency influence visual outcomes.
They included 70 subjects (76 eyes) treated with 0.5 mg-intravitreal ranibizumab for three consecutive months, and pro re nata thereafter (three plus p.r.n. protocol) over a three-year period.
VA was measured using Early Treatment Diabetic Retinopathy Study charts at baseline, 12, 24 and 36 months. The number of injections administered at the end of years one, two and three was also recorded. Eyes were stratified according to baseline VA, as well as the number of injections administered at the end of year one. Linear regression analysis determined the relationship between VA, and both baseline VA and injection frequency, with p<0.05 considered statistically significant.
At 36 months, VA improved by a mean of 5.3 ETDRS letters (p=0.002), with 29 percent of eyes (n=22) demonstrating a clinically significant improvement in VA (gain of ≥15 ETDRS letters). Improvements in VA from baseline to 36 months were inversely proportional to the baseline VA (r=0.414, p=<0.001). A positive correlation was observed between injection frequency and change in VA from baseline to 36 months (r=0.244, p=0.036).
Scientists concluded that mean improvement in VA was inversely proportional to baseline VA and directly proportional to injection frequency.
SOURCE: Razi F, Haq A, Tonne P, et al. Three-year follow-up of ranibizumab treatment of wet age-related macular degeneration: influence of baseline visual acuity and injection frequency on visual outcomes. Clin Ophthalmol. 2016;10:313-19.
Prevalence of ORT in CNV Eyes
Recent studies have suggested that presence of outer retinal tubulations is indicative of a photoreceptor degeneration process representing a final stage of multiple retinal degenerative pathologies, investigators wrote. In this study, ORTs were observed in three pathologies: neovascular AMD; neovascular angioid streaks; and myopic neovascular membranes. Investigators sought to determine the prevalence of ORTs in eyes with choroidal neovascularization undergoing treatment with anti-angiogenic intravitreous injection with anti-vascular endothelial growth factor at the ophthalmology department of a tertiary hospital in São Paulo, Brazil.
The descriptive study was based on medical charts and spectral-domain optical coherence tomography scans of 142 individuals (158 eyes) treated between 2012 and 2014 with IVI of anti-VEGF for CNV. Data was analyzed according to age; gender; pathology; presence of ORTs; and best-corrected visual acuity. Individuals with and without ORTs were compared by the last BCVA obtained using the chi-square test corrected by the Yates factor.
ORTs were found in 40 of 158 eyes (25.31 percent) with CNV; in 33 out of 119 eyes (27.7 percent) with neovascular AMD; in five of eight eyes (62.5 percent) with neovascular angioid streaks; and in two of 12 eyes (16.67 percent) with myopic neovascular membranes. Most individuals with ORTs had BCVA below 20/200, which was significantly worse than those without ORTs.
Investigators concluded that ORTs had a high prevalence in the population studied, and that their correct identification presents relevant therapeutic implications.
SOURCE: Giachetti Filho RG, Zacharias LC, Thaís Vera Monteiro TV, et al.
Prevalence of outer retinal tubulation in eyes with choroidal neovascularization.
International Journal of Retina and Vitreous. 2016;2:6.
Baseline Optical Intensity on OCT & CRAO Visual Outcome
Researchers examined the relationship between optical coherence tomography characteristics at baseline and visual outcomes in central retinal artery occlusion.
The medical charts and OCT images of individuals with central retinal artery occlusion and follow-up of more than 90 days were reviewed. The optical intensities of inner retinal layers; outer nuclear layers; and photoreceptor/retinal pigment epithelium were measured using Image J software. (Optical intensity ratio was calculated as the optical intensity of inner retinal layers divided by that of photoreceptor/retinal pigment epithelium.) Retinal thickness over the nine Early Treatment Diabetic Retinopathy Study regions was automatically calculated by OCT software. The relationship between best-corrected visual acuity at the last follow-up and OCT characteristics was analyzed using Spearman correlation.
Fifteen eyes of 15 individuals with central retinal artery occlusion were included, with mean follow-up of 327.1 ±184.1 days. The final BCVA was mildly or moderately correlated with retinal thicknesses, and strongly correlated with the optical intensity of photoreceptor/retinal pigment epithelium (r=-0.707, p=0.003) and optical intensity ratio (r=0.825, p<0.001).
Researchers determined that optical intensity ratio on OCT was highly correlated with visual prognosis in central retinal artery occlusion and might be a potential biomarker of retinal ischemia.
SOURCE: Chen H; Xia H, Qiu Z, et al. Correlation of optical intensity on optical coherence tomography and visual outcome in central retinal artery occlusion. Retina. 2016; Mar 10.
Comparison of Retinal Vessel Measurements Using AOSLO & OCT
Investigators compared adaptive optics scanning laser ophthalmoscopy (AOSLO) and optical coherence tomography vessel caliber measurements, using AOSLO videos acquired from 28 volunteers with healthy eyes.
Artery measurements were made 0.5-1 disc diameters away from the optic disc margin. Individual segmented retinal arterial caliber was measured in synchronization with cardiac pulsation and averaged to obtain final horizontal retinal arterial caliber (ACH) and horizontal retinal arterial lumen (ALH). All OCT images were obtained with the Spectralis OCT. Vertical retinal arterial caliber (ACV) and vertical retinal arterial lumen (ALV) were measured on the same artery measured with AOSLO. Measurements made with the two imaging systems were compared.
Average ACH measured with AOSLO was 123.4 ±11.2, and average ALH was 101.8 ±10.2 µm. Average ACV measured with OCT was 125.5 ±11.4, and average ALV was 99.1 ±10.6 µm. Both arterial caliber (r=0.767, p<0.0001) and arterial lumen (r=0.81, p<0.0001) measurements were significantly correlated between imaging modalities. ACH and ACV were not significantly different (p=0.16). However, ALH measurements were significantly higher than ALV measurements (p=0.03).
Investigators determined that vessel measurements made with AOSLO and OCT were well-correlated, although plasma was visible and distinguishable from the retinal vessel wall in AOSLO images but not in OCT images. As such, investigators suggested that AOSLO may measure vessel width more precisely than OCT.
SOURCE: Arichika S, Uji A, Ooto S, et al. Comparison of retinal vessel measurements using adaptive optics scanning laser ophthalmoscopy and optical coherence tomography. Jpn J Ophthalmol. 2016; Feb 23 [Epub ahead of print].
PPV & Internal Limiting Membrane Peeling for Recurrent ME
Scientists evaluated the anatomic/functional outcomes of pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema due to branch retinal vein occlusion after intravitreal injections of antivascular endothelial growth factor agents.
Twenty-four eyes of 24 subjects with treatment-naive ME from BRVO were treated with anti-VEGF agent intravitreal injections. Recurrent ME was treated with PPV combined with internal limiting membrane peeling.
After the surgery, ME was significantly reduced at one month (p=0.031), and the reduction increased with time (p=0.007 at the final visit). With the ME reduction, treated eyes showed a slow improvement in visual acuity. At the final visit, VA improvement was statistically significant compared with baseline (p=0.048). The initial presence of cystoid spaces; serous retinal detachment; subretinal hemorrhage under the fovea; and retinal perfusion status showed no association with VA improvement. However, the presence of epiretinal membrane showed a significant association with visual recovery. Although eyes without epiretinal membrane showed visual improvement (-0.10 ±0.32 in logMAR), eyes with epiretinal membrane showed greater visual improvement (0.38 ±0.12 in logMAR, p=0.012).
Scientists determined that pars plana vitrectomy combined with internal limiting membrane peeling might be a treatment option for recurrent ME due to BRVO after anti-VEGF treatment, particularly when accompanied by epiretinal membrane.
SOURCE: Shirakata Y, Fukuda K, Fujita T, et al. Pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema due to branch retinal vein occlusion after antivascular endothelial growth factor treatments. Clin Ophthalmol. 2016;10:277-83.
Retinotomy, Anterior Flap Retinectomy & Radial Retinotomy in RD Management
Investigators compared outcomes with rhegmatogenous retinal detachment and retinal detachment following penetrating injury after combined 360-degree retinotomy, anterior flap retinectomy and radial retinotomy to manage advanced proliferative vitreoretinopathy.
The retrospective, comparative, interventional case series included 24 eyes (60 percent) of 24 individuals diagnosed with RRD, and 16 eyes (40 percent) of 16 people diagnosed with RD after penetrating injury, and compared 360-degree retinotomy, anterior flap retinectomy and radial retinotomy to manage advanced PVR (grade D). The primary outcome was anatomic surgical success; secondary outcomes were changes in visual acuity and postoperative complications.
The mean number of previous interventions was 1.04 in the RRD group, and 1.31 in the trauma group, (p=.13). After 51.5 (± 52.7) months of mean follow-up, complete retinal reattachment rates for the RRD group was 79 percent (19/24), and for the trauma group was 75 percent (12/16) (p>.99). The final mean VA was 2.2 logMAR (20/2000) in both groups, with improvement in the RRD group (p=.04). The most common postoperative complications were persistent hypotony: in six eyes (25 percent) in the RRD group and in five eyes (31 percent) in the trauma group (p=.73); corneal damage in eight eyes (29 percent) in the RRD group and six eyes (38 percent) in the trauma group (p=.34); and epiretinal membrane in five eyes (20.8 percent) in the RRD group and four eyes (25 percent) in the trauma group (p>.99).
Investigators found that only 25 percent of eyes (10/40) had VA of 20/200 or better, and wrote that the aim of peripheral 360-degree retinotomy, anterior flap retinectomy and radial retinotomy is to obtain retinal reattachment, which is otherwise unachievable.
SOURCE: Hocaoglu M, Karacorlu M, Muslubas IS, et al. Peripheral 360 degree retinotomy, anterior flap retinectomy, and radial retinotomy in the management of complex retinal detachment. Am J Ophthalmol. 2016;163:115–121.e1.
PPV With Silicone Oil Tamponade in Primary Uncomplicated RRD
Researchers assessed anatomical/functional outcomes and possible complications after pars plana vitrectomy with silicone oil (SO) tamponade in primary uncomplicated rhegmatogenous retinal detachments, as part of a prospective, observational study.
Some 62 consecutive individuals who underwent surgical repair by PPV and SO injection for primary uncomplicated RRD between January 01, 2006, and April 30, 2012, were followed. In general, PPV was chosen over scleral buckling when a significant cataract or a vitreous hemorrhage prevented adequate fundus visualization. Silicone oil was chosen over gas tamponade in those living at 1,000 meters (3,280.84 feet) above sea level, while SF6 or C3F8 tamponade could not be performed because of the risk of acute increase of intraocular pressure. One thousand centistokes SO was used in all eyes. At all visits, individuals underwent a detailed ocular history and thorough bilateral evaluation, including: best-corrected visual acuity; anterior segment exam; and IOP measurements by applanation and fundus examination. Outcomes were assessed at one day; one week; one month; three months; six months; and every six months thereafter. Increased IOP was defined as an IOP of more than 21 mmHg.
The main outcome measures were: anatomical success rate; final BCVA; IOP elevation; cataract formation; and other complications. The study included 62 eyes of 62 people (41 men, 21 women) who underwent retinal detachment repair by PPV and SO injection. The age at the time of intervention was 57.6 ±10.5 years (mean ± standard deviation; range, 34-79 years). All individuals were white. Mean follow-up was 24.5 ±17.3 months (range, six to 70 months).
Anatomical success rate (defined as retinal reattachment six months after SO removal) was 93.5 percent. Final BCVA was improved in 55 eyes (88.7 percent), with a mean of four Snellen lines; unchanged in five (8.1 percent); and worse in two eyes (3.2 percent), with a mean of three Snellen lines. Mean duration of SO tamponade was 5.12 ±2.37 months (range, two to 12 months). From the 30 eyes that were still phakic after vitrectomy, 24 eyes (80.0 percent) underwent cataract surgery within a period of 7.37 ±3.00 months (range, two to 13 months). Thirty-five eyes (56.5 percent) had an increase in IOP during follow-up. Thirty-one people had transient ocular hypertension requiring topical treatment during the immediate postoperative period (one month). Only one eye (2.9 percent) required filtrating drainage surgery for IOP control. No eyes developed optic neuropathy secondary to IOP elevation.
Researchers concluded that PPV with SO injection appeared to be a safe and efficient surgical approach in treating primary uncomplicated RRD in people living in high altitude (>1,000 m [3,280.84 feet]). As well in the study series, PPV and SO injection were associated with good anatomical and functional outcomes; reattachment rates were high; proliferative vitreoretinopathy rates were low; and cataract formation and elevated IOP represented frequent but successfully controlled complications.
SOURCE: Antoun J, Azar G, Jabbour E, et al. Witreoretinal surgery with silicone oil tamponade in primary uncomplicated rhegmatogenous retinal detachment: clinical outcomes and complications. Retina 2016;Mar 10. [Epub ahead of print].