MD Research News – Issue 424 – 7 June 2019

Drug treatment

Graefes Arch Clin Exp Ophthalmol. 2019 May 29.

Intravitreal ranibizumab versus aflibercept following treat and extend protocol for neovascular age-related macular degeneration.

Abdin AD, Suffo S, Asi F, Langenbucher A, Seitz B.

Purpose: To assess the morphological and functional outcome and stability of the "treat and extend" protocol using aflibercept compared to ranibizumab for the treatment of eyes with neovascular age-related macular degeneration.

Patients and Methods: This retrospective study included 100 eyes of 94 patients with primary onset neovascular age-related macular degeneration followed up for 12 months. We studied two groups of eyes: group 1, 50 eyes treated with 0.5 mg/0.05 mL ranibizumab and group 2, 50 eyes treated with 2.0 mg/0.05 mL aflibercept. During the first year, all eyes received 3 aflibercept or ranibizumab injections monthly as upload phase. Then, eyes were treated with a treat and extend algorithm. Main outcome measures included: best corrected visual acuity (BCVA), central macular thickness (CMT), and the number of injections. In addition, we compared recurrence rates between the two groups.

Results: BCVA (log MAR) in group 1 vs group 2 was 0.54 ± 0.31 vs 0.49 ± 0.30 (p = 0.38) before treatment and 0.49 ± 0.33 vs 0.47 ± 0.32 (p = 0.85) after treatment. The visual improvement (decimal) was 0.05 ± 0.13 vs 0.04 ± 0.12 (p = 0.91). CMT in group 1 vs group 2 was 375.6 ± 98.3 μm vs 369.6 ± 103.7 μm (p = 0.73) before treatment and 306.3 ± 71.8 μm vs 294.8 ± 96 μm (p = 0.54) after treatment. The decrease in CMT was 69.3 ± 93 μm vs 74.8 ± 96 μm (p = 0.77). The number of injections/eye after upload phase in group 1 vs group 2 was 5.88 ± 1.4 vs 6.16 ± 1.3 (p = 0.25). Finally, major recurrence rates were statistically significantly different between the two groups (2% vs 6%, p = 0.04).

Conclusions: Significant differences regarding BCVA, central macular thickness, and the number of injections were not found between aflibercept and ranibizumab during the first year following the treat and extend protocol. However, the significantly higher major recurrence rates in the aflibercept group after extending the treatment interval to 10 weeks might suggest that aflibercept should better not to be used in longer than 8 weeks intervals during the first year of treatment.

PMID: 31144055 DOI: 10.1007/s00417-019-04360-9

 

Retina. 2019 May 27.

Pharmacokinetic study of intravitreal aflibercept in humans with neovascular age-related macular degeneration.

Do DV, Rhoades W, Nguyen QD.

Purpose: To investigate the half-life of aflibercept in aqueous humor after a single intravitreal injection in patients with neovascular age-related macular degeneration.

Methods: Prospective, noncomparative, interventional case series of five eyes with neovascular age-related macular degeneration naive to anti-vascular endothelial growth factor therapy were enrolled and treated with intravitreal aflibercept. At baseline, best-corrected visual acuity, optical coherence tomography imaging, and aqueous humor (treatment eye) and blood/plasma samples were taken. Patients underwent best-corrected visual acuity, optical coherence tomography imaging, and sampling of aqueous humor from the eye and blood/plasma at six additional post-treatment time points of 4 hours and Days 1, 3, 7, 14, and 28. Concentrations of aflibercept were quantified using an enzyme-linked immunosorbent assay.

Results: Median peak concentration (Cmax) of free aflibercept in the aqueous was 122 mg/L. The median half-life of free aflibercept was 11 days in the eye. In plasma, the concentrations of free aflibercept were low and transient, reaching undetectable levels during the first week after injection, and undetectable in all patients at time points beyond 7 days.

Conclusion: The pharmacokinetic profile in the aqueous humor described here together with the previously reported affinity of aflibercept for vascular endothelial growth factor is consistent with and adds to our understanding for the duration of its clinical efficacy.

PMID: 31145389 DOI: 10.1097/IAE.0000000000002566

 

J Ophthalmol. 2019 Apr 16;2019:2648267.

A systematic review and meta-analysis of clinical outcomes of intravitreal anti-VEGF agent treatment immediately after cataract surgery for patients with diabetic retinopathy.

Zhao LQ, Cheng JW.

Aims: To examine possible benefits of intravitreal anti-vascular endothelial growth factor (VEGF) agent treatment immediately after cataract surgery for patients with diabetic retinopathy (DR).

Methods: A comprehensive literature search was performed using the Cochrane collaboration methodology to identify randomized controlled trials (RCTs) and comparative studies of cataract surgery with or without anti-VEGF agent treatment for any diabetic retinopathy. Meta-analyses were performed for clinical outcome parameters including changes in macular thickness (MT), best-corrected visual acuity (BCVA), incidence of diabetic retinopathy and maculopathy progression, laser treatment rate, and other complications.

Results: Nine RCTs and 3 nonrandomized comparative studies were identified and used for comparing cataract surgery with intravitreal bevacizumab (IVB) or intravitreal ranibizumab (IVR) treatment (338 eyes, intervention group) to cataract surgery alone (329 eyes, control group). Analysis of all data showed that the mean BCVA at 1 week postoperatively had no statistically significant difference in the two groups, but at 1, 3, and 6 months postoperatively, the mean BCVA was statistically significantly better in the anti-VEGF treatment group than that in cataract surgery alone group. Analysis of all data showed that the mean MT was statistically significantly less in the anti-VEGF treatment group at 1 week and 1, 3, and 6 months postoperatively (P=0.05, P=0.006, P=0.0001, and P=0.0001, respectively); but postoperative clinical outcomes were differentiated from the type of anti-VEGF agents, IVB or IVR, and the existing macular edema preoperatively. Intravitreal anti-VEGF agent treatment statistically significantly reduced the incidence of diabetic retinopathy progression and maculopathy progression compared to the control group (P=0.0003, P < 0.00001, respectively).

Conclusion: IVB or IVR treatment immediately after cataract surgery may represent a safe and effective strategy to prevent postoperative macular thickening or reduce macular edema and result in greater mean improvements in visual acuity for diabetic patients.

PMID: 31143469 PMCID: PMC6501156 DOI: 10.1155/2019/2648267

 

BMJ Open. 2019 May 28;9(5):e022031.

Anti-vascular endothelial growth factor treatment for retinal conditions: a systematic review and meta-analysis.

Pham B, Thomas SM, Lillie E, Lee T, Hamid J, Richter T, Janoudi G, Agarwal A, Sharpe JP, Scott

A, Warren R, Brahmbhatt R, Macdonald E, Straus SE, Tricco AC.

Objectives: To evaluate the comparative effectiveness and safety of intravitreal bevacizumab, ranibizumab and aflibercept for patients with choroidal neovascular age-related macular degeneration (cn-AMD), diabetic macular oedema (DMO), macular oedema due to retinal vein occlusion (RVO-MO) and myopic choroidal neovascularisation (m-CNV).

Design: Systematic review and random-effects meta-analysis.

Methods: Multiple databases were searched from inception to 17 August 2017. Eligible head-to-head randomised controlled trials (RCTs) comparing the (anti-VEGF) drugs in adult patients aged ≥18 years with the retinal conditions of interest. Two reviewers independently screened studies, extracted data and assessed risk of bias.

Results: 19 RCTs involving 7459 patients with cn-AMD (n=12), DMO (n=3), RVO-MO (n=2) and m-CNV (n=2) were included. Vision gain was not significantly different in patients with cn-AMD, DMO, RVO-MO and m-CNV treated with bevacizumab versus ranibizumab. Similarly, vision gain was not significantly different between cn-AMD patients treated with aflibercept versus ranibizumab. Patients with DMO treated with aflibercept experienced significantly higher vision gain at 12 months than patients receiving ranibizumab or bevacizumab; however, this difference was not significant at 24 months. Rates of systemic serious harms were similar across anti-VEGF agents. Posthoc analyses revealed that an as-needed treatment regimen (6-9 injections per year) was associated with a mortality increase of 1.8% (risk ratio: 2.0 [1.2 to 3.5], 2 RCTs, 1795 patients) compared with monthly treatment in cn-AMD patients.

Conclusions: Intravitreal bevacizumab was a reasonable alternative to ranibizumab and aflibercept in patients with cn-AMD, DMO, RVO-MO and m-CNV. The only exception was for patients with DME and low visual acuity (<69 early treatment diabetic retinopathy study [ETDRS] letters), where treatment with aflibercept was associated with significantly higher vision gain (≥15 ETDRS letters) than bevacizumab or ranibizumab at 12 months; but the significant effects were not maintained at 24 months. The choice of anti-VEGF drugs may depend on the specific retinal condition, baseline visual acuity and treatment regimen.

PMID: 31142516 DOI: 10.1136/bmjopen-2018-022031

 

J Inflamm (Lond). 2019 May 22;16:9.

Anti-vascular endothelial growth factor agent reduces inflammation in macular edema with central retinal vein occlusion.

Mashima A, Noma H, Yasuda K, Goto H, Shimura M.

Background: Correlations among the aqueous flare value (an indicator of inflammation), functional-morphologic parameters, and aqueous humor levels of growth factors/receptors and inflammatory factors/cytokines were investigated in patients with central retinal vein occlusion (CRVO) and macular edema who received intravitreal ranibizumab injection (IRI) and were followed for 6 months.

Methods: Aqueous humor levels of 11 cytokines or growth inflammatory/factors were measured in 20 CRVO patients with macular edema receiving IRI. Patients with recurrent macular edema were administered further IRI as needed. Aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR), and other cytokines/inflammatory factors were measured by the suspension array method. Aqueous flare values were measured with a laser flare meter and macular edema was examined by optical coherence tomography.

Results: Compared with before treatment (baseline), the aqueous flare value showed a significant decrease at both 1 month and 6 months after IRI therapy. There were significant correlations between the aqueous flare value and the aqueous levels of sVEGFR-1, placental growth factor, monocyte chemoattractant protein 1, soluble intercellular adhesion molecule-1, interleukin (IL)-6, and IL-8. In addition, a significant correlation was noted between the change of the aqueous flare value and improvement of central macular thickness at 6 months after IRI, as well as a significant correlation between the change of the aqueous flare value and improvement of best-corrected visual acuity at 6 months.

Conclusions: These findings suggest that IRI reduces inflammation and that the aqueous flare value is influenced by inflammatory factors/cytokines. In addition, the change of the aqueous flare value may be an indicator of the long-term prognosis in CRVO patients receiving IRI therapy for macular edema.

PMID: 31139023 PMCID: PMC6530041 DOI: 10.1186/s12950-019-0214-2

 

Graefes Arch Clin Exp Ophthalmol. 2019 May 24.

Aflibercept with adjuvant micropulsed yellow laser versus aflibercept monotherapy in diabetic macular edema.

Khattab AM, Hagras SM, AbdElhamid A, Torky MA, Awad EA, Abdelhameed AG.

Purpose: To assess the impact of micropulsed laser (MPL) on modifying the number of aflibercept injections when used as an adjuvant therapy in diabetic macular edema (DME).

Methods: A prospective randomized interventional clinical study included patients with DME attending Al Hadi Clinic, Kuwait, during the period from May 2017 to December 2018. Patients were allocated in two groups; group A received aflibercept injections alone and group B received combined aflibercept injections followed by MPL within a week. The primary outcome was the number of Aflibercept injections in each group guided by the change in central macular thickness (CMT). All the patients were followed for 18 months. Secondary outcome measures included best corrected visual acuity (BCVA), contrast sensitivity (CS), and any recorded complications.

Results: Fifty-four eyes of 51 patients were included (27 in each group). There was no statistically significant difference between the two groups in baseline characteristics except for the age that was statistically higher in group B (p = 0.001). The number of injections were significantly lower in group B (4.1 ± 1.1) than group A (7.3 ± 1.1) (p < 0.005). At 18th month, there was significant reduction in CMT in both groups (p < 0.005) with no statistical difference between the two groups (p = 0.989). Final BCVA in both groups showed statistically significant improvement (p < 0.005) without statistically significant difference between the two groups (p = 0.082). In both groups, the CS showed significant improvement from baseline (p < 0.005). No ocular or systemic adverse effects were observed in either group.

Conclusion: Supplemental MPL in eyes with DME may decrease the burden of the aflibercept injection frequency while resulting in comparable anatomical and visual outcomes.

PMID: 31127381 DOI: 10.1007/s00417-019-04355-6

 

Imaging

Semin Ophthalmol. 2019 May 26:1-7.

For Mass Eye and Ear Special Issue: Optical Coherence Tomography Angiography: Review of Current Technical Aspects and Applications in Chorioretinal Disease.

Wang JC, Miller JB.

Abstract: Optical coherence tomography angiography (OCT-A) has enabled fast, non-invasive, high-resolution visualization of vasculature within the eye. In the past few years, it has become increasingly utilized for a range of disorders including age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, and uveitis among others. This article reviews technical aspects of OCT-A, its applications in chorioretinal disease, and known limitations of the technology.

PMID: 31131663 DOI: 10.1080/08820538.2019.1620797

 

Prognosis

Graefes Arch Clin Exp Ophthalmol. 2019 May 29.

Focal retinal pigment epithelium atrophy at the location of type 3 neovascularization lesion: a morphologic feature associated with low reactivation rate and favorable prognosis.

Kim JH, Kim JW, Kim CG, Lee DW.

Purpose: To investigate the clinical significance of focal retinal pigment epithelium (RPE) atrophy in the eyes with type 3 neovascularization.

Methods: This retrospective study included 184 eyes those were diagnosed with type 3 neovascularization and were treated with antivascular endothelial growth factor (VEGF) therapy. Focal RPE atrophy was defined as a localized RPE atrophy found at the same location as the type 3 lesion. The incidence of reactivation after 3 loading injections and the visual outcomes was compared between a focal RPE atrophy group and a nonfocal RPE atrophy group. In the focal RPE atrophy group, the number of injections was compared between before and after the development of RPE atrophy.

Results: The mean follow-up period was 37.6 ± 18.8 months; focal RPE atrophy developed in 24 eyes (13.0%). Reactivation of the lesion after 3 loading injections was significantly less frequent in the focal RPE atrophy group (58.3%) than that in the nonfocal RPE atrophy group (85.0%) (P = 0.004). In the focal RPE atrophy group, the mean best-corrected visual acuity (BCVA) was 0.68 ± 0.28 (Snellen equivalent = 20/95) at diagnosis and 0.70 ± 0.48 (20/100) at the final follow-up. In the nonfocal RPE atrophy group, the values were 0.75 ± 0.34 (20/112) and 1.12 ± 0.68 (20/263), respectively. The BCVA at the final follow-up was significantly better in the focal RPE atrophy group (P < 0.001). The mean number of injections per year was 4.9 ± 1.8 and 1.3 ± 1.6 before and after the development of focal RPE atrophy, respectively (P < 0.001).

Conclusions: Development of focal RPE atrophy was associated with a low incidence of reactivation of type 3 neovascularization and was therefore predictive of a favorable visual prognosis.

PMID: 31144056 DOI: 10.1007/s00417-019-04373-4

 

Epidemiology

Retina. 2019 May 27.

Lamellar macular holes in the presence of age-related macular degeneration.

Francone A, Yun L, Kothari N, Cheng I, Farajzadeh M, Govetto A, Hubschman JP.

Purpose: To investigate whether age-related macular degeneration (AMD) has an influence on the prevalence and anatomical characteristics of lamellar macular holes (LMHs).

Methods: Clinical records and spectral-domain optical coherence tomography images of 756 eyes of 423 consecutive patients diagnosed with AMD were reviewed and analyzed. Spectral-domain optical coherence tomography was used to identify degenerative or tractional LMH subtypes and assess their morphology. The clinical and optical coherence tomography findings of AMD eyes with LMH were compared with those of a control group of eyes with LMH without AMD from a previously published report.

Results: Lamellar macular holes were identified in 25 eyes of 23 patients (3.3%; 25 of 756). Seventeen of 25 eyes (68%) presented with degenerative LMH and underlying late neovascular AMD. Mean best-corrected visual acuity was worse in eyes with AMD and LMH eyes than in those with AMD and no LMH (20/230 vs. 20/98; P = 0.02). The mean outer diameter was greater in the group with degenerative LMH with concomitant AMD than in the control group of degenerative LMH without AMD (1,323.9 ± 999.1 µm vs. 905.9 ± 356.8 µm, respectively; P = 0.01).

Conclusion: The incidence of degenerative LMH increased in advanced forms of AMD, whereas the presence of tractional LMH subtype may be unrelated to AMD evolution.

PMID: 31145390 DOI: 10.1097/IAE.0000000000002532

 

Genetics

Hum Genet. 2019 May 27.

Insights into the loss of the Y chromosome with age in control individuals and in patients with age-related macular degeneration using genotyping microarray data.

Grassmann F; International AMD Genomics Consortium (IAMDGC), Weber BHF, Veitia RA.

Abstract: The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.

PMID: 31134332 DOI: 10.1007/s00439-019-02029-1

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