Volume 13, Number 8 |
August 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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Serum VEGF Levels in the IVAN Trial: Relationship with Drug, Dosing & AEs
Investigators described serum vascular endothelial growth factor in individuals with neovascular age-related macular degeneration receiving anti-VEGF agents and associations between sVEGF and systemic serious adverse events.
The exploratory analysis involved a randomized controlled trial that enrolled 610 participants with nAMD and compared two anti-VEGF antibodies, ranibizumab and bevacizumab, and two treatment regimens—monthly vs. discontinuous—with two years' follow-up.
Participants included adults ages 50-plus years old with treatment-naïve nAMD and a visual acuity of ≥25 letters (Snellen equivalent 20/320) in the affected eye receiving intravitreal injection of anti-VEGF antibodies.
The main outcome measures included sVEGF and occurrence of SSAE, with particular interest in arteriothromboembolic events and immunologically mediated events.
On average, sVEGF (measured at baseline, one, 11, 12, 23 and 24) decreased from a geometric mean of 168 pg/mL at baseline to 64 pg/mL at month 24. The decrease was greater with bevacizumab than with ranibizumab and was dependent on time since last treatment. At month 24, sVEGF was 11 percent lower with bevacizumab if treated ≥3 months previously; 51 percent lower if treated two months previously; and 76 percent lower if treated the previous month, compared with ranibizumab. The risk of experiencing an ATE increased with age (hazard ratio=2.01; CI, 1.32 to 3.05; p=0.001) and higher sVEGF (HR=1.16; CI, 1.03 to 1.30 per 100 unit rise in sVEGF; p=0.013). Investigators found no association between sVEGF and the risk of an IME (HR=1.01; CI, 0.76 to 1.33; p=0.942); however, the risk of an IME was significantly increased by treatment with bevacizumab compared with ranibizumab (HR=3.53; CI, 1.35 to 9.22; p=0.010). The risk of an “other SSAE” (not categorized as ATE or IME) increased with age (HR 1.51, CI 1.14 to 2.01, p=0.005) and decreased if an injection had been administered within the previous month (HR=0.68; CI, 0.45 to 1.03; p=0.069).
Investigators wrote that the decrease in sVEGF was greater with bevacizumab than with ranibizumab, but the difference was eliminated when treatment was withheld for three months. They added that higher sVEGF increased the risk of an ATE, and bevacizumab increased the risk of an IME compared with ranibizumab.
SOURCE: Rogers CA, Scott LJ, Reeves BC, et al. Serum vascular endothelial growth factor levels in the IVAN trial; Relationships with drug, dosing, and systemic serious adverse events. Ophthalmology Retina 2017; Aug. 18. [Epub ahead of print].
ARMS2 A69S Effect on Number of Ranibizumab Injections for Exudative AMD
Researchers considered whether single-nucleotide polymorphisms known to be strongly associated with the development of age-related macular degeneration have an influence on recurrence rate of choroidal neovascularization activity during four-year ranibizumab treatment for exudative AMD.
This prospective study included 103 treatment-naïve cases (103 eyes) initially receiving a loading dose of three monthly ranibizumab injections, followed by an as-needed regimen for four years. Researchers examined baseline values, visual outcomes and recurrence rates. They detected CFH Y402H and ARMS2 A69S polymorphisms, and analyzed associations with lesion recurrence and visual outcome using a one-way analysis of variance with post hoc comparison tested by Fisher’s LSD method. Multivariate linear regression analysis helped identify factors associated with recurrence rate.
The cumulative total mean number of ranibizumab injections at the end of each year of follow-up was 5.3 ±1.8, 9.2 ±2.9, 12.6 ±4.6 and 15.7 ±6.1. The study revealed great inter-subject variability. Nineteen eyes (18.5 percent) didn’t experience recurrences during the first year, and five (4.8 percent) displayed inactive CNV after four years of follow-up. No significant association was found between the number of injections and mean best-corrected visual acuity change or final BCVA at the end of the study period. Genotypes had no influence on baseline characteristics or visual outcomes, but a significant association was found between the A69S polymorphism and the number of injections needed by individuals. Individuals who were homozygous for the T-risk allele required more retreatments over the 48-month follow-up.
The ARMS2 A69S polymorphism was associated with the CNV recurrence rate, so researchers suggested that predicting greater recurrence risk could help clinicians create more appropriate follow-up treatment plans for individuals with neovascular AMD.
Source: Valverde-Megías A, Veganzones-de-Castro S, Donate-López J, et al. ARMS2 A69S polymorphism is associated with the number of ranibizumab injections needed for exudative age-related macular degeneration in a pro re nata regimen during 4 years of follow-up. Graefes Arch Clin Exp Ophthalmol 2017; July 25. [Epub ahead of print].
Using Ultrasound to Assess Vitreous Changes With Intravitreal Anti-VEGF Injections for AMD
Researchers assessed by ultrasound the impact of repeated intravitreal injections of anti-vascular endothelial growth factor on vitreous findings in individuals with age-related macular degeneration.
They retrospectively collected data from 41 individuals (41 age-related macular degeneration eyes, 41 control eyes) on age, sex, number of injections and type of anti-VEGF (ranibizumab and aflibercept). Ocular ultrasound was performed with open eyelids under topical anesthesia and using carbomers as ultrasonographic gel. Topographic, quantitative and kinetic ultrasonography was performed in all eye quadrants using a 10-MHz posterior pole probe, and vitreous reflectivity was assessed.
The mean age of individuals was 79 (range: 59 to 94) years, with a mean of five intravitreal anti-VEGF injections (range: one to 13). No significant ultrasound differences were noted in conjunction with the incidence of partial or complete posterior vitreous detachment. Vitreous hyperechogenicity increased in treated eyes (p<0.001), and vitreous reflectivity ranges increased with the number of injections (p=0.041, R2=0.214). However, the type of anti-VEGF used and the time elapsed since the last intravitreal injection weren’t significant (p>0.05).
Researchers reported that their preliminary results indicated a proportional increase in reflectivity of vitreous gel on ultrasound with the number of injections.
Source: Mato-Gondelle T, Bande MF, Paniagua L, et al. Ultrasonographic findings in the vitreous of patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor injections. Retina 2017; Aug 16. [Epub ahead of print].
Treatment Patterns & Outcomes With Bevacizumab in DME
Researchers assessed health-care utilization and vision outcomes over two years in individuals receiving bevacizumab treatment in clinical practice for diabetic macular edema.
They identified individuals with newly diagnosed DME who received an intravitreal bevacizumab injection within 12 months of diagnosis from 350,000 Kaiser Permanente cases of diabetes mellitus treated between 2008 and 2013. Researchers wrote that this was the largest U.S. clinical practice-based study of bevacizumab use in DME. Snellen best-corrected visual acuity, number of intravitreal injections and case characteristics were abstracted from the electronic record. The main outcome measure was change in BCVA.
A total of 309 individuals met the inclusion criteria and had two years of follow-up after an initial bevacizumab injection. These individuals had a mean of 3.1 injections (range: one to 17) during follow-up. Mean BCVA improvement was 5.4 letters at 12 months and 5.3 letters at 24 months. Only 29.8 percent of individuals demonstrated ≥3 lines of vision improvement from baseline, while 12.3 percent had ≥3 lines of vision loss from baseline at 24 months.
Researchers wrote that, consistent with national studies, the frequency of injections in individuals receiving bevacizumab treatment in clinical practice for DME was low. They found that average BCVA improvement was lower than in anti-vascular endothelial growth factor trials, but noted significant BCVA improvement in approximately 30 percent of individuals with newly diagnosed DME.
SOURCE: Fong DS, Luong TQ, Contreras R, et al. Treatment patterns and 2-year vision outcomes with bevacizumab in diabetic macular edema: An analysis from a large U.S. integrated health care system. Retina 2017; Aug 8. [Epub ahead of print].
Sustained Benefits of Ranibizumab With or Without Laser in BRVO
Investigators evaluated the efficacy and safety of ranibizumab 0.5 mg (Lucentis, Genentech/Novartis) administered pro re nata with or without a laser, using individualized visual acuity stabilization criteria in individuals with visual impairment due to macular edema secondary to branch retinal vein occlusion, as part of a Phase IIIb, open-label, randomized, active-controlled, three-arm, multicenter study funded by Novartis.
A total of 455 people participated in the study. Individuals were randomized (2:2:1) to ranibizumab 0.5 mg (n=183), ranibizumab 0.5 mg with laser (n=180) or laser (with optional ranibizumab 0.5 mg after month six; n=92). After three monthly injections, individuals in the ranibizumab-with-or-without-laser arms received criteria-driven VA stabilization PRN treatment. Those in the laser arms received lasers at the investigator's discretion.
The main outcome measures included mean (and mean average) change in best-corrected VA and central subfield thickness from baseline to month 24, and safety over 24 months.
A total of 380 individuals (83.5 percent) completed the study. Ranibizumab with or without a laser led to superior BCVA outcomes vs. laser (monotherapy and combined with ranibizumab from month six; 17.3/15.5 vs. 11.6 letters; p<0.0001). Ranibizumab plus a laser treatment was noninferior to ranibizumab monotherapy (mean average BCVA change: 15.4 vs. 15 letters; p<0.0001). However, adding the laser did not reduce the number of ranibizumab injections (mean injections: 11.4 vs. 11.3; p=0.4259). A greater reduction in CSFT was seen with ranibizumab with or without a laser vs. laser monotherapy over 24 months from baseline (ranibizumab monotherapy: -224.7 μm; ranibizumab with laser: -248.9 μm; laser [monotherapy and combined with ranibizumab from month six]: -197.5 μm). Presence of macular ischemia didn’t affect the BCVA outcome or treatment frequency. No reports of neovascular glaucoma or iris neovascularization, and no new safety signals were identified.
Investigators concluded that their results confirmed the long-term efficacy and safety profile of PRN dosing driven by individualized VA stabilization criteria using ranibizumab 0.5 mg in individuals with BRVO. They added that the addition of a laser did not lead to better functional outcomes or lower treatment need, and that the safety results were consistent with ranibizumab’s well-established safety profile.
SOURCE: Tadayoni, MD, Waldstein SM, Boscia F, et al. Sustained benefits of ranibizumab with or without laser in branch retinal vein occlusion: 24-month results of the BRIGHTER study. Ophthalmology 2017; Aug. 11. [Epub ahead of print].
BEVORDEX Trial of Bevacizumab vs. Dexamethasone Implants for DME
Scientists sought to determine whether early vision gains predicted long-term visual outcomes in the BEVORDEX randomized clinical trial of bevacizumab or dexamethasone implants for diabetic macular edema. Some of the study’s funding came in the form of unrestricted educational grants from Allergan and Alimera.
They conducted a post hoc analysis of 68 study eyes (77 percent) from the BEVORDEX multicenter, randomized clinical trial in Australia. Study eyes from both groups were combined and stratified by visual acuity change in the first 12 weeks into three groups: suboptimal gain: <5 letters (including VA loss); moderate gain: five to nine letters; and pronounced gain: ≥10 letters. This was correlated with VA outcome at 104 weeks, and accounted for treatment allocation and baseline lens status.
The change in VA in the first 12 weeks was significantly correlated with VA change at 104 weeks (p<0.001). This was independent of treatment allocation (p=0.353) and lens status at baseline (p=0.593). The change in central macular thickness at 12 weeks didn’t correlate with VA gain at 104 weeks (p=0.847).
Scientists determined that short-term visual gain at 12 weeks was strongly correlated with long-term vision improvement, independent of treatment allocation or baseline lens status. Furthermore, they found that early improvement in central macular thickness was not predictive of long-term visual outcomes.
SOURCE: Mehta H, Fraser-Bell S, Nguyen V, et al. Short-term vision gains at 12 weeks correlate with long-term vision gains at 2 years: Results from the BEVORDEX randomised clinical trial of bevacizumab versus dexamethasone implants for diabetic macular oedema. Br J Ophthalmol 2017; Aug 4. [Epub ahead of print].
Early Visual Cortical Structural Changes in Diabetics Without DR
Researchers wrote that individuals with diabetes are commonly known to have changes in cortical morphometry compared with controls, but clarification is needed on whether the visual cortex is a disease target, even when diabetes complications such as retinopathy are absent. They compared individuals with type 2 diabetes without diabetic retinopathy with controls using magnetic resonance imaging to assess visual cortical changes when retinal damage was not yet present.
Researchers performed T1-weighted imaging in 24 type 2 diabetics without DR and 27 age- and gender-matched controls to compare gray matter changes in the occipital cortex between groups using voxel-based morphometry.
Individuals without DR showed reduced gray matter volume in the occipital lobe when compared with controls. Researchers found reduced gray matter volume in the occipital cortex in diabetics without retinal damage. They suggested that cortical early visual processing regions might be affected in diabetic individuals even before retinal damage occurs.
Source: Ferreira FS, Pereira JMS, Reis A, et al. Early visual cortical structural changes in diabetic patients without diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2017; Aug 4. [Epub ahead of print].
Intravitreal Aflibercept vs. Bevacizumab for ME Secondary to CRVO
Scientists compared the safety, efficacy and frequency of intravitreal injection of aflibercept and bevacizumab for treatment of macular edema secondary to central retinal vein occlusion, as part of a prospective, comparative, randomized, interventional study.
Scientists randomized eyes with ME secondary to CRVO between two groups according to the intravitreal injection used. Group A included eyes treated with intravitreal aflibercept, and group B included eyes treated with intravitreal bevacizumab injections. The inclusion criteria were ME secondary to CRVO and follow-up duration of at least 12 months after the first injection. Exclusion criteria were macular ischemia, associated diabetes, hypertensive or renal retinopathy, other retinal disease and previous anti-vascular endothelial growth factor injections. The main outcome measures were central foveal thickness, best-corrected visual acuity, time intervals between injections, improved retinal nonperfusion and any reported complications.
Group A included 39 individuals with a mean age of 57.4 ±8.2 years. Group B included 40 eyes with a mean age of 56.5 ±9.1 years. Twelve months after the first injection, central foveal thickness significantly improved from 475.45 ±71.05 µm to 259.11 ±20.67 µm in group A and from 460.22 ±89.38 µm to 264.29 ±32.05 µm in group A; BCVA significantly improved from 0.81 ±0.16 logarithm of the minimum angle of resolution (20/125) to 0.34 ±0.14 logMAR (20/40) in group A and from 0.73 ±0.15 logMAR (20/100) to 0.33 ±0.17 logMAR (20/40) in group B; the mean number of injections was 3.72 ±2.93 in group A and 5.44 ±2.85 in group B (p<0.05); and the mean interval between injections was 54.23 ±8.47 days in group A and 35.12 ±7.76 days in group B (p<0.05). Retinal nonperfusion improved in nine of 12 eyes in group A and in three of eight eyes in group B (p<0.05).
Scientists wrote that aflibercept and bevacizumab were comparably effective for treatment of macular edema secondary to CRVO without significant complications. However, they added that the burden of frequent intravitreal injections could be significantly reduced when using aflibercept.
SOURCE: Lotfy A, Solaiman KAM, Abdelrahman A, et al. Efficacy and frequency of intravitreal aflibercept versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina 2017; Aug 1. [Epub ahead of print].
PCT & SFCT After Panretinal Photocoagulation in Type 2 Diabetes
Researchers evaluated changes in peripapillary choroidal thickness and subfoveal choroidal thickness after panretinal photocoagulation for diabetic retinopathy, as part of a retrospective, interventional study including 59 treatment-naive eyes of 33 individuals who underwent PRP and completed ≥12 months of follow-up. They measured peripapillary choroidal thickness and SFCT at baseline and one, three, six and 12 months post-PRP. They determined differences between baseline and 12 months (∆SFCT and ∆PCT) and percentage changes (∆SFCT or ∆PCT/baseline x 100 percent).
Mean SFCT was 287.7 ±76.7 µm (139 to 469 µm) at baseline and 225.8 ±62 µm (102.5 to 379.5 µm) 12 months post-PRP (p<0.001). Mean PCT was 161.2 ±16.5 µm (75.3 to 308.1 µm) at baseline and 128.4 ±41.8 µm (73 to 212.9 µm) 12 months post-PRP (p<0.001). ∆SFCT was -61.3 ±28.7 µm (-139.5 to -17 µm), and %SFCT was 21.2 ±7.2 percent (6.8 percent to 36.1 percent). ∆PCT was -36.4 ±23.2 µm (-149.1 to 5.4 µm), and %PCT was 22.4 ±12 percent (2.5 percent to 62.6 percent). Diabetic retinopathy severity was the only factor significantly correlated with %SFCT (β=0.500, p=0.004) and percent of PCT (β=0.152, p=0.024).
Researchers found that both PCT and SFCT were reduced significantly after PRP. They also reported that diabetic retinopathy severity was significantly correlated with post-PRP changes of PCT and SFCT.
SOURCE: Kang HM, Lee NE, Choi JH, et al. Significant reduction of both peripapillary and subfoveal choroidal thickness after panretinal photocoagulation in patients with type 2 diabetes. Retina 2017; Aug 8. [Epub ahead of print]
Concentration of Acute-phase Factors in Vitreous Fluid in DME
Researchers wrote that diabetic retinal maculopathy was associated with acute and chronic local inflammation. They measured the concentrations of acute-phase factors in the vitreous fluid of individuals with diabetic macular edema, and examined the relationship to visual acuity and central retinal thickness before and after vitrectomy, as part of a retrospective study.
Vitreous fluid was collected during vitreoretinal surgery from 19 individuals with DME, and 12 control subjects with epiretinal membrane. Researchers measured concentrations of acute-phase factors (α2-macroglobulin, haptoglobin, C-reactive protein, serum amyloid P and A, procalcitonin, ferritin, tissue plasminogen activator, fibrinogen) and vascular endothelial growth factor with multiplex assays. And they measured the CRT of macular edema using optical coherence tomography.
Levels of serum amyloid P, procalcitonin, ferritin and fibrinogen in vitreous fluid increased in DME subjects compared with controls. Levels of procalcitonin and fibrinogen in individuals with DME inversely correlated with VA before and three months after vitrectomy, but not six months post-surgery. The concentrations of the four acute-phase factors were not correlated with CRT or VEGF vitreous levels in individuals with DME.
Researchers concluded that acute-phase factors could contribute to local inflammation in DME and might, therefore, influence disease progression.
Source: Kimura K, Orita T, Kobayashi Y, et al. Concentration of acute-phase factors in vitreous fluid in diabetic macular edema. Jpn J Ophthalmol 2017; Jul 28. [Epub ahead of print].
Serum & Aqueous Humor Concentrations of IL-27 in DR
Investigators wrote that interleukin-27 reportedly possesses anti- and proinflammatory properties in several immune related-disorders, but its role in diabetic retinopathy is still elusive. They aimed to evaluate IL-27 concentrations in serum and aqueous humor of diabetics with or without retinopathy and test whether IL-27 was correlated with risk factors of diabetic retinopathy.
The study included 60 diabetic individuals with and without retinopathy and 20 healthy controls. Investigators assessed serum and aqueous humor concentrations of IL-27 using ELISA.
The mean of IL-27 concentration in aqueous humor in individuals with diabetic retinopathy (6.7 ±2.7 ng/L) was significantly elevated compared with diabetics without retinopathy (4.6 ±0.5 ng/L) and healthy controls (4.1 ±0.8 ng/L). IL-27 concentration in aqueous humor was positively correlated with serum glucose, the lipid profile and glycated hemoglobin (HbA1c).
Investigators found that IL-27 was implicated in the pathogenesis of diabetic retinopathy and positively correlated with the disorder’s progression.
SOURCE: Houssen ME, El-Hussiny MAB, El-Kannishy A, et al. Serum and aqueous humor concentrations of interleukin-27 in diabetic retinopathy patients. Int Ophthalmol 2017; Jul 24. [Epub ahead of print].
Retinal Nonperfusion in Posterior Pole Heightens Risk of CRVO Neovascularization
Investigators reviewed the definition of ischemic central retinal vein occlusion and stratifed the risk of neovascular complication based on wider areas of visible retinal nonperfusion, as part of a retrospective, consecutive case series and image analysis study at Moorfields Eye Hospital (London). They included a total of 42 consecutive-treatment naïve eyes with CRVO imaged with ultra-widefield angiography with a minimum of 12 months follow-up.
Investigators determined the spatial location and total area of retinal nonperfusion (measured in disc areas) using the validated concentric rings method, and corrected the area for projection distortion. Two retinal physicians graded the images using average measurements. The main outcome measure was development of neovascular complications.
The percentage of eyes developing new vessels increased from: none in eyes with less than 10 DA of nonperfusion to 14.3 percent in eyes with 10 to 30 DA; 20 percent for 30 to 75 DA; and 80-percent risk with 75 to 150 DA of nonperfusion. Of 13 eyes (31 percent) with a perfused posterior pole (five-disc-diameter with radius centered at the fovea) and more than 10 DA of nonperfusion isolated in the periphery (beyond the posterior pole), only one eye (7.7 percent) developed new vessels, OR 0.12 [CI: 0.01,1.03]. In comparison, for 13 eyes (31 percent) with more than 10 DA of nonperfusion in the posterior pole, 11 (84.6 percent) developed new vessels, OR 74.25 [CI: 9.26, 595.30], p<0.001.
Using ultra-widefield angiography, investigators ascertained that posterior pole nonperfusion of more than 10 DA remains a key risk factor for new vessel development compared to areas of nonperfusion confined to the periphery.
SOURCE: Nicholson L, Vazquez-Alfageme C, Patrao NV, et al. Retinal non-perfusion in the posterior pole is associated with increased risk of neovascularization in central retinal vein occlusion. Am J Ophthalmol 2017; Jul 21. [Epub ahead of print].
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