Volume 13, Number 6 |
June 2017 |
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. |
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Brolucizumab vs. Aflibercept in nAMD: A Randomized Trial
Researchers compared the efficacy and safety of brolucizumab with aflibercept to treat neovascular age-related macular degeneration, as part of a prospective, randomized, double-masked, multicenter, two-arm Phase II study. They included 89 treatment-naïve participants ages ≥50 years with active choroidal neovascularization secondary to AMD.
Eligible participants were randomized 1:1 to intravitreal brolucizumab (6 mg/50 μl) or aflibercept (2 mg/50 μl). Both groups received three monthly loading doses and were then treated every eight weeks (q8) with assessments up to week 40. In the brolucizumab group, the final q8 cycle was extended to enable two cycles of treatment every 12 weeks (q12 to week 56); participants on aflibercept continued q8. Unscheduled treatments were allowed at the investigator's discretion.
Primary and secondary hypotheses included noninferiority (margin: five letters at a one-sided alpha level 0.1) in best-corrected visual acuity change from baseline of brolucizumab vs. aflibercept at weeks 12 and 16. Researchers assessed BCVA, central subfield thickness and morphologic features throughout the study.
The mean BCVA change from baseline (letters) at week 12 with brolucizumab (5.75) was noninferior to aflibercept (6.89 [80 percent CI for treatment difference, -4.19 to 1.93]) and week 16 (brolucizumab: 6.04 and aflibercept: 6.62 [-3.72 to 2.56]), with no notable differences up to week 40. Outcomes exploring disease activity during the q8 treatment cycles suggested greater stability of the brolucizumab participants, supported by fewer unscheduled treatments vs. aflibercept (six for brolucizumab vs. 15 for aflibercept) and more stable CSFT reductions. In addition, post hoc analysis revealed a greater proportion of brolucizumab-treated eyes resolved intraretinal and subretinal fluid compared with aflibercept-treated eyes. Approximately half of the brolucizumab-treated eyes had stable BCVA during the q12 cycles. Brolucizumab and aflibercept adverse events were comparable.
Researchers concluded that, during the matched q8 phase, BCVA in brolucizumab-treated eyes appeared comparable to aflibercept-treated eyes, with more stable CSFT reductions, fewer unscheduled treatments and higher rates of fluid resolution. They found that the brolucizumab safety profile was similar to aflibercept over 56 weeks of treatment and suggested that a 12-week treatment cycle for brolucizumab might be viable in a relevant proportion of eyes.
SOURCE: Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab vs. aflibercept in participants with neovascular age-related macular degeneration: A randomized trial. Ophthalmology 2017; May 24. [Epub ahead of print].
Oral Tyrosine Kinase Inhibitor for nAMD: Phase I Dose-Escalation Study
Researchers tested the safety of an oral tyrosine kinase inhibitor (X-82), active against vascular endothelial growth factor and platelet-derived growth factor, administered for the treatment of neovascular age-related macular degeneration. The Phase I, open-label, uncontrolled, dose-escalation study at five U.S. retinal clinics took place between November 2012 and March 2015. Thirty-five participants with nAMD, seven of whom were treatment-naïve, were included.
Participants received oral X-82 for 24 weeks at: 50 mg alternate days (n=3); 50 mg daily (n=8); 100 mg alternate days (n=4); 100 mg daily (n=10); 200 mg daily (n=7); and 300 mg daily (n=3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every four weeks, participants underwent best-corrected visual acuity measurements, fundus exam and spectral-domain optical coherence tomography. The main outcome was adverse events. Other outcomes included VA, central subfield retinal thickness and number of anti-VEGF injections.
Of the 35 participants, the mean age was 76.8 years (16 men and 19 women; 33 Caucasian and two non-white subjects). Of 25 participants (71 percent) who completed the 24 weeks of X-82 treatment, all except one maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60 percent) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness was reduced by -50 [97] μm, with eight participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n=6), nausea (n=5), fatigue (n=5) and transaminase elevation (n=4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but one were asymptomatic. Ten participants withdrew consent or discontinued prematurely—six due to adverse events attributed to X-82, including leg cramps (n=2), elevated alanine aminotransferase (n=2), diarrhea (n=1) and nausea/anorexia (n=1).
Researchers wrote that X-82 could be associated with reversible, elevated liver enzymes, so liver function testing would be needed to identify those unsuited to treatment. Although 17 percent of participants discontinued X-82 owing to adverse effects, those who completed the study had lower than expected anti-VEGF injection rates. Researchers concluded that further studies were justified and noted that a Phase II randomized clinical study was underway.
SOURCE: Jackson TL, Boyer D, Brown DM, et al. Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: A phase 1 dose-escalation study. JAMA Ophthalmol 2017; Jun 1. [Epub ahead of print].
OCT-based Scoring System for AMD Progression
Scientists set out to develop a simple, clinically practical, optical coherence tomography-based scoring system for early age-related macular degeneration, to predict an individual’s risk for progression to late AMD.
They retrospectively reviewed OCT images (512 × 128 macular cube, Cirrus) from 138 individuals diagnosed with early AMD in at least one eye and follow-up of at least 12 months. For those with early AMD in both eyes, only the right eye was chosen as the study eye for longitudinal assessment. Scientists graded scans on four SD-OCT criteria associated with disease progression in previous studies: drusen volume within a central 3-mm circle ≥0.03 mm3; intraretinal hyperreflective foci; hyporeflective foci within a drusenoid lesion; and subretinal drusenoid deposits. Each criterion was assigned one point. For risk assessment of the study eye, scientists considered the baseline status of the fellow eye and analyzed the four features in the fellow eye. They summed up the number of risk factors for both eyes, yielding a total score of 0 to 8 for each individual. A fellow eye with evident choroidal neovascularization or atrophy automatically received four points. Scores were grouped into four categories for comparative analysis: I (TS of 0, 1, 2); II (TS of 3, 4); III (TS of 5, 6); and IV (TS of 7, 8). Scientists evaluated the correlation of baseline category assignment with progression to late AMD (defined as the presence of atrophy or CNV on OCT) by the last follow-up visit, via logistic regression analysis.
The rate of progression to late AMD was 39.9 percent (55/138). Progression rates by category were: I: 0 percent; II: 14.3 percent; III: 47.5 percent; and IV: 73.3 percent. Logistic regression analysis showed risk of progression to late AMD was three times (CI, 1.2 to 7.9) higher for an eye assigned to category IV than for an eye in category III and 16.4 (CI, 4.7 to 58.8) times higher than for an eye in category II.
Scientists found that a simple scoring system relevant to prognosis for early AMD utilizing SD-OCT criteria alone could aid clinicians.
SOURCE: Lei J, Balasubramanian S, Abdelfattah NS, et al. Proposal of a simple optical coherence tomography-based scoring system for progression of age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2017; May 22. [Epub ahead of print].
Structural Changes Associated With Delayed Dark Adaptation in AMD
Researchers examined the relationship between dark adaptation and optical coherence tomography-based macular morphology in age-related macular degeneration, as part of a prospective, cross-sectional study. Participants included individuals with AMD and a comparison group (>50 years) without any vitreoretinal disease. One of the authors is on the scientific advisory board for dark adaptation device maker MacuLogix, but receives no compensation from the company.
They imaged individuals with spectral-domain OCT and color fundus photographs, and staged them for AMD using the Age-related Eye Disease Study system. Both eyes were tested with the AdaptDx (MacuLogix) DA extended protocol (i.e., 20 minutes). Researchers developed a software program to map the DA testing spot (2-degree circle, 5-degree superior to the fovea) to the OCT B-scans. Two independent graders evaluated the B-scans within the testing spot along with the macula, and recorded the presence of several AMD-associated abnormalities. Multilevel mixed-effects models provided analyses.
The primary outcome was rod-intercept time (RIT), defined in minutes, as a continuous variable. For subjects unable to reach RIT within 20 minutes of testing, the value of 20 was assigned.
Researchers included 137 eyes (n=77 subjects), 72.3 percent (n=99 eyes) with AMD and the rest in the comparison group. Multivariable analysis revealed that, after adjusting for age and AMD stage, presence of abnormalities within the DA testing spot (ß=4.8, p<0.001) and in the macula (ß=2.4, p=0.047) were significantly associated with delayed RITs and, therefore, impaired DA. In eyes with no structural changes within the DA testing spot (n=76, 55.5 percent), presence of abnormalities in the macula was associated with delayed RITs (ß=2.00, p=0.046). Presence of subretinal drusenoid deposits and ellipsoid zone disruption were a consistent predictor of RIT, whether located within the DA testing spot (p=0.001 for both) or in the macula (p<0.001 for both). Within the testing spot, the presence of classic drusen or serous pigment epithelium detachment was significantly associated with DA impairments (p≤0.018).
Researchers suggested that these results indicated a significant association between macular morphology evaluated by OCT and time to dark adaptation. They added that subretinal drusenoid deposits and ellipsoid zone changes appeared to be strongly correlated with impaired dark adaptation.
SOURCE: Laíns I, Miller JB, Park DH, et al. Structural changes associated with delayed dark adaptation in age-related macular degeneration. Ophthalmology 2017; May 10. [Epub ahead of print].
Choroidal Thickness and Disease Manifestation in Nonexudative AMD
Investigators assessed the relationship between subfoveal choroidal thickness and disease manifestation in eyes with nonexudative age-related macular degeneration, as part of a retrospective study.
They graded and compared extracellular deposits, drusen and subretinal drusenoid deposits, and a newly recognized form of drusen, pachydrusen, via choroidal thickness on optical coherence tomography. Investigators evaluated demographic and imaging information with descriptive statistics and estimating equations.
A total of 94 eyes of 71 individuals with a mean age of 78.1 years participated. Soft drusen alone were found in 45 eyes (47.9 percent), and subretinal drusenoid deposits— with or without drusen—were found in 38 (40.4 percent). Pachydrusen—which were typically larger than 125 µm, often had an irregular outer contour, showed a scattered distribution over the posterior pole, and occurred in isolation or in groups of a few drusen—were found in 11 individuals (11.7 percent). The mean subfoveal choroidal thickness was 227.9 µm in the soft drusen group, 167.3 µm in the subretinal drusenoid deposit group and 419 µm in the pachydrusen group. The differences between the groups were highly significant.
Investigators found that extracellular deposits, subretinal drusenoid deposits and drusen were common in nonexudative AMD, and a new form of drusen presentation was associated with thicker choroids. They suggested that disease manifestation in nonexudative AMD appeared to be associated with choroidal thickness and that the findings could lead to certain forms of late AMD.
SOURCE: Spaide RF. Disease expression in nonexudative age-related macular degeneration varies with choroidal thickness. Retina 2017; May 11. Epub ahead of print].
CNV Features Associated With Choroidal Nevus on OCTA
Using optical coherence tomography angiography imaging, researchers described the choroidal neovascularization features associated with choroidal nevus, as part of a retrospective, observational case series.
Individuals with CNV secondary to choroidal nevus underwent a full imaging exam including fundus photography, fluorescein angiography, indocyanine green angiography, spectral-domain OCT and OCTA. Researchers analyzed OCTA features and compared them with conventional angiography findings and spectral-domain OCT.
A total of 11 eyes from 11 individuals (six men and five women, mean age 65 ±20.4 years) were included. Fluorescein disclosed CNV in 90 percent of cases, and angiography and indocyanine green angiography disclosed CNV in 83 percent of cases. OCTA displayed a CNV network in 11 eyes (100 percent), a "sea-fan" pattern in eight eyes (73 percent) and "long filamentous linear vessels" in three eyes (27 percent). Distinct from CNV, researchers observed intrinsic vasculature within the nevus in six eyes (55 percent), corresponding to those with chronic retinal pigment epithelium changes.
Researchers wrote that OCTA was a useful imaging technique to disclose CNV associated with choroidal nevus. Despite the presence of intraretinal or subretinal fluid and hemorrhage, OCTA revealed CNV in all cases, with results noninferior to indocyanine green angiography. Researchers added that the imaging modality could be useful for analysis of longstanding nevi with related exudation.
SOURCE: Pellegrini M, Corvi F, Say EAT, et al. Optical coherence tomography angiography features of choroidal neovascularization associated with choroidal nevus. Retina 2017; May 29. [Epub ahead of print].
Using OCTA to Assess Macular Vascular Density, VA & Peripheral Nonperfusion Area in RVO
Investigators studied correlations in individuals with retinal vein occlusion using automatically quantified macular vascular densities in the superficial and deep capillary plexus obtained by optical coherence tomography angiography and data from conventional exams, particularly visual acuity and peripheral retinal nonperfusion with fluorescein angiography.
The retrospective, observational study looked at individuals with RVO who underwent comprehensive ophthalmic exams using FA and the AngioVue OCTA system (Optovue). Investigators measured vascular densities in the superficial capillary plexus and DCP as well as the foveal avascular zone.
The study of 65 eyes of 61 individuals (33 men, mean age: 67 years) showed a significant correlation between peripheral nonperfusion on FA and automatically quantified global vascular density in the plexus (p=0.021 for the DCP) and foveal avascular zone areas (p=0.037). Investigators also found significant correlations between capillary dropout in the plexus and peripheral nonperfusion area (p<0.001 for both), and between VA and vascular densities (p=0.002 for global density in the DCP). Global density less than 46 percent in the DCP was associated with the presence of peripheral nonperfusion area on FA (p=0.003) and enlargement of the superficial foveal avascular zone (p=0.002).
Investigators found a significant correlation between automatically quantified macular vascular density on OCTA and peripheral nonperfusion on FA. They suggested that OCTA could help identify high-risk RVO cases that might benefit from further evaluation using FA.
SOURCE: Seknazi D, Coscas F, Sellam A, et al. Optical coherence tomography angiography in retinal vein occlusion: Correlations between macular vascular density, visual acuity, and peripheral nonperfusion area on fluorescein angiography. Retina 2017; May 31. [Epub ahead of print].
Eyes With Preserved Foveal Depression Post-IRI Injection for ME Secondary to CRVO
Scientists determined the prognosis of eyes with central retinal vein occlusion and preserved foveal depressions at baseline that were treated with intravitreal ranibizumab injections.
They reviewed the medical records of 23 eyes of 23 consecutive treatment-naive individuals who received ranibizumab injections to treat macular edema due to CRVO. They classified eyes by the pre-injection presence or absence of a foveal depression. A foveal depression was defined as a central foveal thickness that was <50 µm thinner than the average thickness at 200 µm temporal and nasal to the central fovea. Scientists compared the characteristics of the two groups.
Seven of 23 eyes had a preserved foveal depression before IRI. The mean number of injections within 12 months after the initial injection was significantly fewer (p<0.001) in eyes with a foveal depression (1.6 ±0.5) than in those without a foveal depression (4.3 ±1.3). The mean best-corrected visual acuity at 12 months after the initial injection was significantly better (p=0.003) in eyes with a foveal depression (0.10 ±0.17 logMAR; 20/25 Snellen) than in eyes without a foveal depression (0.77 ±0.54 logMAR; 20/118 Snellen units).
Scientists wrote that the results indicated that the prognosis was better for eyes with a foveal depression before the treatment.
SOURCE: Kitagawa S, Yasuda S, Ito Y, et al. Better prognosis for eyes with preserved foveal depression after intravitreal ranibizumab injection for macular edema secondary to central retinal vein occlusion. Retina 2017; May 18. [Epub ahead of print].
Risk Factors for Recurrences of CSC
Investigators described recurrence patterns and investigate candidate risk factors for recurrences of central serous chorioretinopathy.
They retrospectively evaluated 46 individuals with acute CSC who had follow-up >12 months after the first episode resolution through a frailty Cox proportional hazard survival model. Covariates included:
• baseline systemic findings: age, gender, corticosteroid use, stress, shift work, sleep disorders, depression, allergy and cardiovascular risk;
• baseline optical coherence tomography findings: subfoveal choroidal thickness, pigment epithelial detachment pattern (regular/bump/irregular), number of subretinal hyperreflective foci at leakage site;
• baseline angiographic findings: fluorescein leakage intensity (intense/moderate/subtle/absent), hyperpermeability pattern on indocyanine-green angiography (focal/multifocal); and
• episode-related findings: duration and treatment of previous episode.
Twenty of 46 subjects (43 percent) presented ≥1 recurrences during a mean follow-up of 29.9 ±9.5 months (range, 15 to 54 months). Follow-up duration didn’t differ between cases with or without recurrences (p=0.3). Worse final visual acuity levels (logMAR) were associated with a higher number of episodes during follow-up (p=0.032, r=0.28). In a univariate analysis, higher subfoveal choroidal thickness (p=0.021); nonintense fluorescein leakage (=moderate/subtle/absent, p=0.033); multiple subretinal hyperreflective foci (p=0.026); and shift work (p<0.0001) were significantly associated with recurrences, with a near-significant influence of irregular pigment epithelial detachment (p=0.093). In a multivariate analysis, higher subfoveal choroidal thickness (p=0.007), nonintense fluorescein leakage (p=0.003) and shift work (p<0.0001) remained significant and independent risk factors for recurrences.
Investigators concluded that multiple factors influenced the risk of CSC recurrence—a finding that could aid in identifying high-risk individuals who could benefit from earlier or more intensive treatment.
SOURCE: Matet A, Daruich A, Zola M, et al. Risk factors for recurrences of central serous chorioretinopathy. Retina 2017; May 29. [Epub ahead of print].
Risk of Progression in Macula-on RRD
Investigators aimed to identify factors that lead to rapid progression of macula-on rhegmatogenous retinal detachment and macular involvement, as part of an observational, prospective, single-center study.
They included individuals referred for surgery due to primary, macula-on RRD, between 2009 and 2013. Factors analyzed included age, time delay until surgery, lens status, myopia, the detachment’s location and configuration, as well as number, size and type of retinal breaks. Eyes underwent optical coherence tomography to detect macular detachment, and investigators performed a multivariate analysis to assess the effect of several factors in retinal detachment progression.
A total of 116 eyes of 116 individuals were included. Mean time delay between admission and surgery was 1.8 ±1.4 days. Investigators observed progression in 19.8 percent of the eyes. Of those, 47.8 percent presented macular detachment. Ten of 11 (90.9 percent) eyes presenting with progression involving the macula also exhibited a bullous configuration—the only parameter significantly correlating with detachment progression in individuals with macular involvement (p=0.0036) and without macular involvement (p=0.0014).
Investigators wrote that, for the first time in a prospective trial, a bullous configuration was found to be a highly significant predictor for progression in macula-on detachments. They added that these results supported prompt surgery in individuals diagnosed with bullous macula-on RRD.
SOURCE: Callizo J, Pfeiffer S, Lahme E, et al. Risk of progression in macula-on rhegmatogenous retinal detachment. Graefes Arch Clin Exp Ophthalmol 2017; May 27 [Epub ahead of print].
Retinal Redetachment After Cataract Surgery in Eyes with Previous Scleral Buckling Surgery
Scientists determined the cumulative risk and outcome of retinal redetachment after cataract surgery in eyes with a history of retinal detachment repair by scleral buckling techniques, as part of a population-based, retrospective cohort study.
They included phakic cases without previous ocular surgery or significant trauma that underwent scleral buckling surgery for rhegmatogenous retinal detachment between January 1, 2001, and December 31, 2010, at Norrlands University Hospital (Sweden) (n=537).
They used ICD-10 diagnosis codes corresponding to rhegmatogenous retinal detachment to identify cases. Scientists reviewed medical charts to confirm the diagnoses, and examined retinal detachment recurrence and visual outcome. They analyzed the frequency of redetachment and the time from cataract surgery to redetachment surgery. Main outcome measures included redetachment surgery after cataract surgery and best-corrected visual acuity.
A total of 301 (56 percent) males and 236 (44 percent) females were identified. During the follow-up period, 145 of 537 individuals (27 percent) had phacoemulsification surgery, with a median time of 3.4 years after the retinal detachment repair. Males had cataract surgery significantly more often (31 percent vs. 22 percent; p=0.036) and at an earlier age than females (65.6 vs. 69.4 years; p=0.013). Retinal detachment recurrence occurred after cataract extraction in three individuals (3/145; 2.1 percent) at 2.4 years (final BCVA: 20/70); at 3.9, years (final BCVA: 20/25); and at 6.9 years (final BCVA: 20/30). The cumulative percentage of redetachment surgery after phacoemulsification was 1 percent—up to 10 years after the scleral buckling surgery, as calculated by a life table analysis. Ten years after cataract surgery, the cumulative percentage of redetachment surgery was 5 percent in eyes with previous scleral buckling surgery.
In individuals with a history of previous scleral buckling surgery, scientists determined that the risk of redetachment after cataract surgery was low. They added that phacoemulsification could be performed safely with no need for extended postoperative attention. However, they emphasized the importance of informing anyone with previous retinal detachment surgery experiencing symptoms of redetachment, even years after cataract surgery, to seek prompt medical care.
SOURCE: Forsell S, Mönestam E, et al. Frequency of retinal redetachment after cataract surgery in eyes with previous scleral buckling surgery. Retina 2017; May 27. [Epub ahead of print].
Intravitreous Injection of AAV2-Sflt01 in Advanced nAMD
Researchers wrote that long-term intraocular injections of vascular endothelial growth factor-neutralizing proteins can preserve central vision in many individuals with neovascular age-related macular degeneration. As such, they tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralizing protein sFLT01 in individuals with advanced nAMD, as part of a Phase I, open-label, dose-escalating study at four U.S.-based outpatient retina clinics.
Individuals were assigned to each cohort in order of enrollment, with the first three being assigned to and completing the first cohort before filling positions in the treatment groups. Individuals 50 years of age or older with nAMD and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort one, 2 × 108 vector genomes; cohort two, 2 × 109 vg; cohort three, 6 × 109 vg; and cohort four, 2 × 1010 vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort five, 2 × 1010 vg, n=7), and followed for up for 52 weeks. The primary objective was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01 through eye-related adverse events.
Nineteen individuals with advanced nAMD were enrolled in the study between May 18, 2010, and July 14, 2014. All completed the 52-week trial period. Two individuals in cohort four (2 × 1010 vg) experienced adverse events—pyrexia and intraocular inflammation—that were possibly study-drug related and that resolved with a topical steroid. Five of ten people who received 2 × 1010 vg had aqueous humor concentrations of sFLT01 that peaked at 32.7-112 ng/mL (mean 73.7 ng/mL, SD 30.5) by week 26 with a slight decrease to a mean of 53•2 ng/mL at week 52 (SD 17.1). At baseline, four of these five individuals were negative for anti-AAV2 serum antibodies, and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 individuals with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One person in cohort five showed a large decrease in vision between weeks 26 and 52 that researchers suspected was not vector-related.
Researchers found that intravitreous injection of AAV2-sFLT01 appeared to be safe and well-tolerated at all doses, but advised that additional studies were needed to identify sources of variability.
Source: Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: A phase 1, open-label trial. Lancet 2017; May 17. [Epub ahead of print].
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