Volume 14, Number 5
WELCOME to Review
of Ophthalmology's Retina Online 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.
Estimating Medicare & Patient Savings from Use of Bevacizumab for Exudative AMD Treatment
Researchers estimated Medicare cost savings from the use of bevacizumab in the United States for the treatment of exudative age-related macular degeneration by replacing the use of bevacizumab with ranibizumab and aflibercept, as part of a retrospective trend study.
Main outcome measures were spending by Medicare as tracked by Current Procedural Terminology codes for intravitreal injections (67028) and treatment-specific J-codes (J0178, J2778, J9035, J3490 and J3590) for inhibitors of vascular endothelial growth factor. These claims were identified from the Medicare Provider Utilization and Payment Data from the Centers for Medicare and Medicaid Services among fee-for-service Medicare beneficiaries from 2012 to 2015. The 2008 claims were acquired from the 100-percent FFS Part B Medicare Claims File.
The use of bevacizumab from 2008 to 2015 resulted in an estimated savings of $17.3 billion, which corresponded to a $13.8 billion savings to Medicare and a $3.5 billion savings to individuals receiving treatments. This amount underestimated the actual cost savings to Medicare providers since approximately 30 percent of Medicare-eligible recipients received care within Medicare Advantage plans and were not included in this analysis.
Researchers estimated the cost savings from the use of bevacizumab from 2008 to 2015 for Medicare FFS beneficiaries undergoing treatment for exudative AMD at $17.3 billion. They added that additional savings over the $17.3 billion would have accrued from the use of bevacizumab if diagnostic categories such as diabetic macular edema and retinal vein occlusion were included in this study.
Rosenfeld PJ, Windsor MA, Feuer WJ, et al. Estimating Medicare and patient savings from the use of bevacizumab for the treatment of exudative age-related macular degeneration. Am J Ophthalmol 2018; Apr 12. [Epub ahead of print].
Emixustat Hydrochloride for GA Secondary to AMD
Researchers determined whether emixustat hydrochloride reduced the rate of geographic atrophy enlargement compared with placebos in subjects with age-related macular degeneration, and evaluated the safety and tolerability of emixustat over 24 months of treatment.
The multicenter, randomized, double-masked, placebo-controlled, Phase IIb/III clinical trial included individuals with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2. Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months one, two, three, six, nine, 12, 15, 18, 21, 24 and 25.
The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence images. The change from baseline in normal luminance best-corrected visual acuity was a secondary efficacy end point.
Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; p≥0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low-luminance deficit at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55 percent), chromatopsia (18 percent), visual impairment (15 percent) and erythropsia (15 percent).
Researchers wrote that emixustat didn’t reduce the growth rate of GA in AMD. They noted that the most common adverse events were ocular in nature and likely related to the drug’s mechanism of action. Researchers added that data gained from this study over a two-year period added to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.
SOURCE: Rosenfeld PJ, Dugel PU, Holz FG, et al. Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration. Ophthalmology 2018; April 28. [Epub ahead of print].
Efficacy of Anti-amyloid β Monoclonal Antibody in GA Secondary to AMD
Investigators assessed the efficacy of intravenous GSK933776—a humanized monoclonal antibody directed against the N-terminal amino acids of amyloid β—for the treatment of geographic atrophy in age-related macular degeneration. The prospective, randomized, placebo-controlled, double-masked, multicenter Phase II clinical trial included individuals with GA secondary to AMD, a visual acuity score of at least 35 letters and GA with a total area of 1.9 to 17 mm2.
Participants were monitored monthly for four months during an observation period to determine the rate of GA enlargement in the study eye, after which subjects were randomized into one of four treatment arms (GSK933776 at three and six months, 15 mg/kg/month or placebo). At each monthly visit beyond 18 months, participants underwent visual acuity testing under normal- and low-luminance conditions. Ocular imaging included color fundus photography, fundus autofluorescence, fluorescein angiography and spectral-domain OCT. The main outcome measure was enlargement in GA area measured from color fundus photographs, with reference to fundus autofluorescence images.
A total of 191 participants were randomized into the study, with 139 (73 percent) fulfilling the efficacy population criteria. Over 18 months, GSK933776 didn’t reduce the rate of GA enlargement compared to the placebo. Overall, investigators recorded no consistent meaningful differences relative to the placebo in any of the visual function measures. They did find a correlation between a low-luminance VA deficit at baseline and the rate of GA enlargement, although genetic variations in the complement factor I gene didn’t correlate with GA progression. Investigators identified no serious ocular adverse events related to the GSK933776 treatment, and reported a similar number of serious non-ocular adverse events across all treatment groups.
Investigators wrote that intravenous amyloid β inhibition with GSK933776 didn’t slow the rate of GA enlargement compared to placebo, and that no clinically meaningful differences relative to the placebo were observed in visual function testing over 18 months. They added that a low-luminance VA deficit was associated with faster GA enlargement; however, no correlation was shown between genetic variations in the CFI gene and the rate of GA enlargement.
SOURCE: Rosenfeld PJ, Berger B, Reichel E, et al. A randomized phase II study of an anti-amyloid β monoclonal antibody in geographic atrophy secondary to age-related macular degeneration. Ophthalmology Retina 2018; Apr 17. [Epub ahead of print].
Bioengineered RPE Monolayer for Advanced Dry AMD
Researchers wrote that retinal pigment epithelium dysfunction and loss are hallmarks of non-neovascular age-related macular degeneration. Without proper RPE function and structure, a majority of overlying photoreceptors degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies might delay disease progression or restore vision.
As such, a prospective, interventional, FDA-cleared, Phase I/IIa study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The implant, known as the California Project to Cure Blindness-Retinal Pigment Epithelium 1, consists of a polarized monolayer of human embryonic stem cell-derived RPE on an ultra-thin, synthetic parylene substrate designed to mimic Bruch's membrane.
Researchers reported an interim analysis of the Phase I cohort consisting of five subjects. Four of five individuals enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation.
Researchers concluded that the concurrent structural and functional findings suggested that CPCB-RPE1 might improve visual function, at least in the short term, in some individuals with severe vision loss from advanced NNAMD.
SOURCE: Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.
Sci Transl Med 2018 Apr 4;10:435.
Baseline SD-OCT Characteristics of AMD: Amish Eye Study
Investigators described spectral-domain optical coherence tomography findings in an Amish cohort to assess markers for early age-related macular degeneration.
They performed a family-based, prospective cohort study of 1,146 elderly Amish subjects (2,292 eyes) (ages, 50 to 99 years) with a family history of at least one individual with AMD. All subjects underwent complete ophthalmic exams, SD-OCT using Cirrus and Spectralis instruments (20 × 20-degree scan area), fundus autofluorescence, infrared imaging and color fundus photography. Investigators analyzed SD-OCT characteristics in subjects with AMD (with and without subretinal drusenoid deposits) and normal healthy cohorts.
Participants' mean age was 65.2 years (SD ±11). Color fundus photographic findings in 596 subjects (53 percent) were consistent with AMD; the remaining 478 subjects (43 percent) showed no signs of AMD. The choroid was significantly thinner on OCT in those with AMD (242 ±76 µm, p< 0.001) compared with those without AMD (263 ±63 µm). Subretinal drusenoid deposits were found in 143 eyes (7 percent), and 11 of 143 eyes (8 percent) had no other manifestations of AMD. Drusen volume (p<0.001) and area of geographic atrophy were significantly greater (p<0.001), and choroid was significantly thinner (p<0.001) in subjects with subretinal drusenoid deposits than those without deposits.
Investigators reported that subretinal drusenoid deposits, though relatively uncommon in this population, could be found in the absence of other AMD features, and that eyes with these deposits had thinner choroids.
SOURCE: Nittala MG, Song YE, Sardell R, et al. Amish eye study: Baseline spectral domain optical coherence tomography characteristics of age-related macular degeneration. Retina 2018; May 9. [Epub ahead of print].
Topographic Correspondence of Macular Atrophy with CNV in Ranibizumab-treated Eyes
Researchers quantified the extent of topographic correspondence between baseline choroidal neovascularization and macular atrophy at follow-up in eyes with NVAMD, as part of a post hoc analysis of randomized, controlled clinical trial (TREX-AMD) data.
They followed 60 treatment-naïve neovascular age-related macular degeneration subjects from the TREX-AMD trial for 18 months. At month 18, they graded regions of macular atrophy on fundus autofluorescence aided by spectral-domain optical coherence tomography. They manually graded CNV lesions on fluorescein angiography, with lesion components (including classic and occult CNV) delineated. FAF and FA images were registered to quantify the area and location of overlap between CNV and MA. Findings included the following:
• Twenty-six eyes had MA at month 18 and CNV at baseline.
• A total of 84.6 percent of eyes showed evidence of MA and CNV overlap.
• By month 18, MA appeared in regions corresponding with: baseline classic CNV in 36.4 percent of eyes, occult CNV in 40.9 percent and both regions in 22.7 percent, with more MA area in regions of occult rather than classic CNV.
• Baseline MA position corresponded with: baseline classic CNV in 76.9 percent of eyes, occult CNV in 61.5 percent of eyes and both regions in 15.4 percent, with more MA area in regions of occult rather than classic CNV.
• Among eyes with MA and CNV at baseline but no overlap, 50 percent progressed to involve regions with baseline CNV. Six eyes had no baseline MA but developed MA at month 18 within regions of baseline CNV.
Researchers determined that more MA lesions developed within the region of baseline CNV (type I, CNV-based MA) than outside (type II, CNV-independent MA) in ranibizumab-treated eyes with NVAMD. They found that baseline MA also tended to be located within regions of CNV in the pre-treatment phase.
SOURCE: Abdelfattah NS, Hariri A, Al-Sheikh M, et al. Topographic correspondence of macular atrophy with choroidal neovascularization in ranibizumab treated eyes of the TREX-AMD Trial. Am J Ophthalmol 2018; May 12. [Epub ahead of print].
Association of Single-Nucleotide Polymorphisms with Pseudodrusen in AMD
Investigators evaluated the association of SNPs in complement factor H, age-related maculopathy susceptibility 2, HtrA serine peptidase 1, complement C2, complement C3, lipase C and complement factor B genes, with the presence of pseudodrusen and pseudodrusen subtypes (i.e., dot, reticular and confluent).
In this post hoc analysis of cross-sectional data from U.S. participants in the Comparison of AMD Treatments Trials, genotyping was performed in 835 participants with TaqMan assays for the SNPs:
• rs1061170 (Y402H variant in CFH);
• rs800292 (I62V variant in CFH);
• rs10490924 (A69S variant in ARMS2);
• rs11200638 (HTRA1);
• rs547154 (C2);
• rs2230199 (R102G variant in C3);
• rs10468017 (LIPC); and
• rs4151667 (L9H variant in CFB).
The main outcomes included presence and subtype of baseline pseudodrusen in either eye, determined using color fundus photography, red-free images and fluorescein angiograms.
Among 835 participants enrolled for genotyping, 755 (90.4 percent) were evaluated for pseudodrusen. Of these:
• 471 (62.4 percent) were female and 750 (99.3 percent) were white; the mean (SD) age was 78.3 (7.5) years;
• 213 of 755 participants (28.2 percent) had pseudodrusen, 107 (14.2 percent) had dot pseudodrusen, 180 (23.8 percent) had reticular pseudodrusen, and 102 (13.5 percent) had confluent pseudodrusen.
After adjusting for age, sex and smoking status:
• ARMS2 risk allele T was associated with higher risk of pseudodrusen (OR, 1.93; CI, 1.19 to 3.12) for TT vs. GG (p=0.04), with a similar association found with HTRA1 (OR, 2.04; CI, 1.26 to 3.31) for AA vs. GG (p=0.03);
• CFH Y402H risk allele C was associated with lower risk of pseudodrusen (OR, 0.61; CI, 0.38 to 0.97) for CC vs. TT but was not statistically significant after correcting for multiple comparison (p=0.20); and
• CFH Y402H, ARMS2, HTRA1 and C3 were significantly associated with reticular pseudodrusen.
Investigators wrote that, among individuals with neovascular AMD, risk alleles ARMS2 and HTRA1 were associated with an increased risk of pseudodrusen, and risk allele CFH Y402H was associated with a lower risk of pseudodrusen, supporting findings from previous studies. They added that understanding the role of these SNPs in the development of pseudodrusen might improve the field’s understanding of the pathogenesis of AMD and help develop future therapies.
Lin LY, Zhou Q; Hagstrom S, et al, et al. Association of single-nucleotide polymorphisms in age-related macular degeneration with pseudodrusen. JAMA Ophthalmol 2018; May 3. [Epub ahead of print].
Ranibizumab in Eyes with DME & Macular Nonperfusion in RIDE and RISE
Researchers looked for characteristics that distinguish individuals with diabetic macular edema with coexisting macular nonperfusion (MNP) at baseline, and assessed the potential of individuals with DME to achieve favorable visual acuity, anatomic and diabetic retinopathy outcomes over 24 months, as part of a post hoc analysis of the RIDE/RISE Phase III, randomized, double-masked trials.
Participants included study eyes with best-corrected VA/fluorescein angiogram data at baseline. To measure MNP, researchers overlaid the Early Treatment Diabetic Retinopathy Study grid on FAs of the macula. They calculated the MNP area by estimating the percentage of capillary loss in the central, inner and outer subfields, and converting the data into disc areas using a software algorithm.
Main outcome measures included:
• baseline characteristics, MNP area, BCVA and central subfield thickness at months 12 and 24; and
• incidence of study eyes with ≥2-step DR improvement at months three, six, 12, 18 and 24.
Baseline MNP was detected in 28.2 percent in the ranibizumab 0.3-mg group (n=213), 25.8 percent in the ranibizumab 0.5-mg group (n=225) and 26.3 percent in the sham arm (n=228). Findings included:
• at baseline, individuals with MNP were younger and had shorter diabetes duration, worse vision, increased CST and worse DR severity than those without MNP (p<0.01);
• in the ranibizumab 0.3-mg group, eyes with baseline MNP had lower mean baseline BCVA (53.4 ETDRS letters) than those without baseline MNP (57.2 ETDRS letters)(p=0.05), but comparable mean BCVA gain at month 24 (+15.6 ETDRS letters) than those without baseline MNP (13.4 ETDRS letters)(p=0.2);
• eyes with baseline MNP had increased CST at baseline, but a greater decrease in CST by month 24; and
• the proportion of eyes with ≥2-step DR improvements was greater for eyes with MNP than without baseline MNP in each ranibizumab arm.
Researchers found that eyes with concurrent DME and baseline MNP entering RIDE/RISE studies experienced robust VA and anatomic improvement with ranibizumab, despite having worse vision and increased CST compared with eyes without baseline MNP. As such, they recommended that these cases should not be excluded from therapy consideration.
SOURCE: Reddy RK, Pieramici DJ, Gune S, et al. Efficacy of ranibizumab in eyes with diabetic macular edema and macular nonperfusion in RIDE and RISE. Ophthalmology 2018; May 8. [Epub ahead of print].
Dex Implant for DME in Naive vs. Refractory Eyes: IRGREL-DEX Study
Researchers investigated the efficacy and safety of repeated dexamethasone implants over 24 months in treatment-naive diabetic macular edema eyes compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. This multicenter, retrospective study assessed best-corrected visual acuity and central subfield thickness (CST). Safety data (intraocular pressure rise and need for cataract surgery) were recorded.
A total of 130 eyes from 125 individuals were included. Baseline best-corrected visual acuity and CST were similar for naive (n=71) and refractory eyes (n=59). Vision in both groups improved significantly after 24 months (p<0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (11.3 ±10 vs. 7.3 ±2.7 letters, p=0.01) and were more likely to gain ≥10 letters (OR 3.31, CI 1.19 to 9.24, p=0.02). At six, 12 and 24 months, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was greater in refractory eyes than in naive eyes (313 ±125 vs. 279 ±61 μm, p=0.10).
Over a follow-up period of 24 months, vision improved in DME eyes after treatment with dexamethasone implants—in treatment-naive eyes as well as in eyes refractory to anti-VEGF treatment. Improvement was greater in naive eyes, however.
SOURCE: Iglicki Matias, Busch C, Zur D, et al. Dexamethasone implant for diabetic macular edema in naive compared with refractory eyes: The International Retina Group real-life 24-month multicenter study. The IRGREL-DEX Study. Retina 2018; April 24. [Epub ahead of print].
Somatotype, Risk of Hydroxychloroquine Retinopathy and Safe Daily Dosing Guidelines
The aim of this study was to determine whether somatotype influenced the risk of hydroxychloroquine retinopathy, and if dosing by real body weight, ideal body weight or the lesser of these better predicted risk of HCR.
Investigators enrolled 565 people taking HC, and recorded height and weight, and used sensitive ancillary testing, which included:
• 10-2 visual fields;
• spectral-domain optical coherence tomography;
• fundus autofluorescence imaging; and
• multifocal electroretinography.
Investigators compared body mass index for individuals without and with HCR, along with logistic regression models of:
• cumulative dose; and
• daily dosing based on RBW, IBW or the lesser of these.
Area under the curve of receiver operating characteristic plots aided researchers in evaluating the diagnostic accuracy of RBW, IBW and the lesser of these guidelines for safe dosing. Researchers compared probability plots for the risk of retinopathy and BMI for the different recommended guidelines on safe dosing.
A total of 41 individuals had HCR. The median BMI was 27.6 (interquartile range (IQR 24.3, 32.6) for those without HCR and 24 (IQR 21, 31.6) for those with HCR (p=0.0102). AUC for univariate ROC plots of retinopathy vs. dosing by RBW was 0.71, by IBW was 0.72 and by lesser of these was 0.76. AUC for multivariate ROC plots of retinopathy vs. models incorporating gender, age, cumulative dose and BMI, and customizing dosing by RBW was 0.82, by IBW was 0.82 and by lesser of these was 0.83. For all of the multivariate logistic models, the risk of retinopathy was higher for lower BMIs.
Investigators concluded that short, asthenic women were at higher risk for HCR. They wrote that the 2011 American Academy of Ophthalmology guidelines were safer for short, obese women, but that 2016 AAO guidelines were safer for short, asthenic individuals. They suggested that selecting daily dosing based on the lesser of the RBW and IBW guidelines would be safest for all individuals.
SOURCE: Browning DJ, Lee C. Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines. Clin Ophthalmol 2018;12:811-18.
Systemic & Ocular Determinants of Peripapillary RNFL Thickness
Scientists analyzed systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in a European population, as part of a cross-sectional meta-analysis.
They included 16,084 European adults from eight cohort studies (mean age range, 56.9 ±12.3 to 82.1±4.2 years) of the European Eye Epidemiology consortium. Scientists examined associations with pRNFLT measured by spectral-domain OCT using multivariable linear regression and pooled results from random effects meta-analyses. Main outcome measures included determinants of pRNFLT.
Mean pRNFLT ranged from 86.8 ±21.4 μm in the Rotterdam Study I to 104.7 ±12.5 μm in the Rotterdam Study III. Scientists found the following factors to be associated with reduced pRNFLT:
• older age (β=-0.38 μm/year; CI, -0.57 to -0.18);
• higher intraocular pressure (β=-0.36 μm/mmHg; CI, -0.56 to -0.15);
• visual impairment (β=-5.50 μm; CI, -9.37 to -1.64);
• history of systemic hypertension (β=-0.54 μm; CI, -1.01 to -0.07); and stroke (β=-1.94 μm; CI, -3.17 to -0.72).
• A suggestive, non-significant association was observed for dementia (β=-3.11 μm; CI, -6.22 to 0.01).
• Higher pRNFLT was associated with more hyperopic spherical equivalent (β=1.39 μm/diopter; CI, 1.19 to 1.59) and smoking (β=1.53 μm; CI, 1 to 2.06) for current smokers compared with never-smokers.
In addition to previously described determinants such as age and refraction, researchers found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. They wrote that these factors might be of clinical relevance, especially in monitoring glaucoma with newly occurring vascular comorbidities.
SOURCE: Mauschitz MM, Bonnemaijer PWM, Diers K, et al. Systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness measurements in the European Eye Epidemiology (E3) population. Ophthalmology 2018; Apr 28. [Epub ahead of print].