Ophthalmology. 2019 Aug 27. pii: S0161-6420(19)31954-2.
Macular atrophy in neovascular age-related macular degeneration: A randomized clinical trial comparing ranibizumab and aflibercept (RIVAL Study).
Gillies MC, Hunyor AP, Arnold JJ, Guymer RH, Wolf S, Pecheur FL, Munk MR, McAllister IL.
Purpose: To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD).
Design: A phase 4 randomized, partially masked, multicenter study.
Participants: Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more.
Methods: Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections.
Main Outcome Measures: The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24.
Results: Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups.
Conclusions: No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.
PMID: 31619357 DOI: 10.1016/j.ophtha.2019.08.023
BMC Ophthalmol. 2019 Oct 16;19(1):206.
Real-world data in retinal diseases treated with anti-vascular endothelial growth factor (anti-VEGF) therapy - a systematic approach to identify and characterize data sources.
Daien V, Eldem BM, Talks JS, Korobelnik JF, Mitchell P, Finger R, Sakamoto T, Wong TY, Evuarherhe O, Carter G, Carrasco J.
Background: Real-world data (RWD) has been a valuable addition to the scientific literature regarding treatment pathways, clinical outcomes and characteristics of patients with retinal diseases in recent years. Registries, observational studies and patient databases are often used for real-world research. However, there is limited information for each data source on the design, consistency, data captured, limitations and usability for assessing research questions. Using a systematic approach, we identified RWD sources for patients with retinal diseases and assessed them for completeness of data relating to different outcomes.
Methods: A systematic literature review was carried out to identify RWD sources for patients with retinal disease. Potentially relevant articles published between 2006 and 2016 were screened following electronic searches in Embase and MEDLINE. Congress and supplementary searches were undertaken to identify RWD sources that may not be referenced in full publications. For each data source, availability and quantity of data on baseline status, clinical outcomes, treatment and management, safety, and patient-reported and economic burden were assessed using a bespoke completeness assessment tool based on International Consortium for Health Outcomes Measurement guidelines for macular degeneration. Completeness of data for each area of interest in each data source was assessed and rated using a 'good-moderate-poor' rating system based on availability and quantity of available data. Each data source was then given an overall score based on its score for each of the 7 areas of interest.
Results: A total of 128 RWD sources from 32 countries were identified. Of the identified sources, 64 sources from 16 countries of interest were analyzed. Most of these sources provided information on baseline status and clinical outcomes and treatment, but few collected data on economic and patient-reported burden. Of the RWD sources analyzed, 10 scored highly in the overall completeness assessment, collecting data on most or all of the areas of interest; these sources are considered to be robust data sources for performing ophthalmology real-world studies.
Conclusions: The study provides a comprehensive list of RWD sources for patients with retinal disease, many of which will be useful for conducting real-world studies in the field of ophthalmology.
PMID: 31619195 DOI: 10.1186/s12886-019-1208-9
Retina. 2019 Oct 14.
Smoking status and treatment outcomes of vascular endothelial growth factor inhibitors for neovascular age-related macular degeneration.
Vittorio AF, Nguyen V, Barthelmes D, Arnold JJ, Cheung CMG, Murray N, Gillies MC; Fight Retinal Blindness! Study Group.
Purpose: To assess whether smoking status affects 1-year visual outcomes in eyes treated with vascular endothelial growth factor inhibitors for neovascular age-related macular degeneration.
Methods: Retrospective analysis of data from a prospectively designed, multicenter, observational database. Nine hundred and eighty seven treatment-naive eyes of patients with neovascular age-related macular degeneration were tracked by the Fight Retinal Blindness! outcome registry in Australia, New Zealand, Singapore, and Switzerland who had documented smoking status at baseline and commenced vascular endothelial growth factor inhibitor therapy from January 2006 to December 2016. Generalized additive models were used to display visual acuity results.
Results: There was a significant difference in mean improvement in visual acuity at 12 months between nonsmokers, ex-smokers, and current smokers (7.7 vs. 6.1 vs. 3.5 letters of change; P = 0.046) among patients who completed 12 months of treatment when adjusted for age, baseline visual acuity, and choroidal neovascular membrane lesion type and nested for practice. There was no significant difference in the median number of injections over 12 months of treatment by smoking status. Current smokers were a mean of 6.2 years younger than nonsmokers when they started treatment (P < 0.001).
Conclusion: This study found inferior 12-month visual outcomes in patients who continued to smoke while receiving vascular endothelial growth factor inhibitor therapy for neovascular age-related macular degeneration.
PMID: 31613840 DOI: 10.1097/IAE.0000000000002679
Br J Ophthalmol. 2019 Oct 15. pii: bjophthalmol-2019-314625.
Predictors of treatment response to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for choroidal neovascularisation secondary to chronic central serous chorioretinopathy.
Romdhane K, Zola M, Matet A, Daruich A, Elalouf M, Behar-Cohen F, Mantel I.
Purpose: The aim of this study was to evaluate the effect of anti-vascular endothelial growth factor (VEGF) therapy on choroidal neovascularisation (CNV) complicating central serous chorioretinopathy (CSC) using multimodal imaging, and to identify possible predictive factors of the treatment response.
Design: Retrospective study.
Methods: Data of 27 eyes with CNV complicating CSC treated with anti-VEGF therapy (either ranibizumab or aflibercept) were reviewed. Response to anti-VEGF treatment was evaluated by change in visual acuity, intra/subretinal fluid modifications and CNV changes on optical coherence tomography angiography (OCTA). Univariate and multivariate analyses were performed to identify predictive factors for central retinal thickness (CRT) change and for the relative degree of treatment response (complete, incomplete or absent fluid reduction).
Results: CRT was significantly reduced at 32±15 days after 2.8±1.3 injections (p=0.0004) as was the subretinal fluid (p=0002). Complete fluid resorption was observed in 45% of cases. Best corrected visual acuity did not significantly improve (p=0.18). CNV area (p=0.09) and CNV flow area (p=0.07) did not significantly decrease. No changes in CNV pattern were noted. Univariate analysis identified greater CRT at baseline (p<0.0001), greater amount of subretinal fluid (p<0.0001), a shorter period of retinal fluid (p=0.04) and female gender (p=0.04) as predictors for CRT reduction. After multivariate analysis the factor of greater CRT at baseline (p<0.0001) proved independent. The degree of treatment response was dependent on the size of CNV surface (p=0.05) and flow area (p=0.05) on OCTA in the univariate analysis, and the latter independent after multivariate analysis. In addition, a shorter time period of retinal fluid appeared to play a role (p=0.01 multivariate, p=0.19 univariate).
Conclusion: The anti-VEGF response was highly variable and often incomplete, suggesting that CNV was not solely responsible for the fluid accumulation. Predictive factors may guide indication for anti-VEGF in CNV associated with CSC.
PMID: 31615761 DOI: 10.1136/bjophthalmol-2019-314625
Eye (Lond). 2019 Oct 16.
Translating evidence into practice: recommendations by a UK expert panel on the use of aflibercept in diabetic macular oedema.
Pearce I, Bailey C, Fletcher E, Ghanchi F, Rennie C, Santiago C, Napier J, Yang Y.
Objectives: This paper describes recommendations from a panel of UK retina experts on aflibercept in diabetic macular oedema (DMO).
Methods: A roundtable meeting was held in London, UK in March 2018. The meeting was sponsored by Bayer.
Results: Recommendations are based on clinical experience and level 1 evidence. Clinical experience supports the evidence base, reinforcing that aflibercept should be initiated with intensive proactive dosing at 2 mg every 4 weeks. Most panel members use six initial 4-weekly doses as in Protocol T, rather than five initial monthly doses as recommended in the Summary of product characteristics (SmPC). After intensive proactive dosing, patients with a good response (meet Protocol T 'improvement' criteria ≥5-letter improvement in visual acuity [VA] and/or ≥10% improvement in central subfield thickness [CST] from baseline) but who are not yet stable should continue with 4-weekly aflibercept until stability is reached. Patients with a good response and stability should initiate monitor-and-extend (not in line with SmPC). Those with a sub-optimal response (meet 'improvement' criteria but with additional concerns e.g. fluid worsening on macular volume map) should continue with 4-weekly aflibercept but additional treatments should be considered (aflibercept is not licensed for combination treatment). For patients with no response (no change, or meeting Protocol T 'worsening' criteria [≥5-letter decrease in VA and/or ≥ 10% increase in CST] from baseline), switching to a non-anti-vascular endothelial growth factor treatment should be considered.
Conclusions: Clinical experience reinforces that, when using aflibercept in DMO, the licensed posology or Protocol T regimens achieve the best outcomes.
PMID: 31619777 DOI: 10.1038/s41433-019-0615-8
Br J Ophthalmol. 2019 Oct 14. pii: bjophthalmol-2019-314446.
Moorfields AMD database report 2: fellow eye involvement with neovascular age-related macular degeneration.
Fasler K, Fu DJ, Moraes G, Wagner S, Gokhale E, Kortuem K, Chopra R, Faes L, Preston G, Pontikos N, Patel PJ, Tufail A, Lee AY, Balaskas K, Keane PA.
Background/Aims: Neovascular age-related macular degeneration (nAMD) is frequently bilateral, and previous reports on 'fellow eyes' have assumed sequential treatment after a period of treatment of the first eye only. The aim of our study was to analyse baseline characteristics and visual acuity (VA) outcomes of fellow eye involvement with nAMD, specifically differentiating between sequential and non-sequential (due to macular scarring in the first eye) antivascular endothelial growth factor treatment and timelines for fellow eye involvement.
Methods: Retrospective, electronic medical record database study of the Moorfields AMD database of 6265 patients/120 286 single entries with data extracted between 21 October 2008 and 9 August 2018. The data set for analysis consisted of 1180 sequential, 807 non-sequential and 3410 unilateral eyes.
Results: Mean VA (ETDRS letters±SD) of sequentially treated fellow eyes at baseline was significantly higher (63±13), VA gain over 2 years lower (0.37±14) and proportion of eyes with good VA (≥70 letters) higher (46%) than the respective first eyes (baseline VA 54±16, VA gain at 2 years 5.6±15, percentage of eyes with good VA 39%). Non-sequential fellow eyes showed baseline characteristics and VA outcomes similar to first eyes. Fellow eye involvement rate was 32% at 2 years, and median time interval to fellow eye involvement was 71 (IQR: 27-147) weeks.
Conclusion: This report shows that sequentially treated nAMD fellow eyes have better baseline and final VA than non-sequentially treated eyes after 2 years of treatment. Sequentially treated eyes also had a greater proportion with good VA after 2 years.
PMID: 31611234 DOI: 10.1136/bjophthalmol-2019-314446
Eur J Ophthalmol. 2019 Oct 17:1120672119882333.
Structural and optical coherence tomography angiography in myopic choroidal neovascularization: Agreement with conventional fluorescein angiography.
Iacono P, Giorno P, Varano M, Parravano M.
Purpose: To evaluate the agreement between fluorescein angiography and structural optical coherence tomography in diagnosing and monitoring the activity of myopic choroidal neovascularization and to provide a comparative analysis with optical coherence tomography angiography.
Methods: Thirteen patients with active myopic choroidal neovascularization were prospectively enrolled. At the baseline, 2-month, and 6-month visits, each patient underwent a complete ophthalmological examination, including best-corrected visual acuity assessment, fundus examination, fluorescein angiography, and optical coherence tomography with structural and angiographic assessment. Sensitivity and specificity for all optical coherence tomography parameters were evaluated taking fluorescein angiography as the reference examination.
Results: At the baseline, fluorescein angiography confirmed myopic choroidal neovascularization leakage in all patients. Structural optical coherence tomography demonstrated intraretinal or subretinal fluid in 61% of cases, fuzzy borders and absence of external limiting membrane visibility in 84% of cases, and subretinal hyperreflective exudation in 53% of cases. Sensitivity to the presence of retinal fluid and subretinal hyperreflective exudation was lower than sensitivity to fuzzy borders and external limiting membrane visibility, which reached 84%. During ranibizumab therapy, external limiting membrane visibility showed a higher sensitivity (100%) compared with fuzzy borders and subretinal hyperreflective exudation (66.6%) while displaying an equal specificity of 100%. At baseline and final visit, sensitivity increased to 100% when all structural optical coherence tomography parameters were pooled. Optical coherence tomography angiography detected myopic choroidal neovascularization at baseline, 2-month, and 6-month visits in 92%, 76%, and 76% of cases, respectively.
Conclusion: The study confirms that the new indicators of myopic choroidal neovascularization activity are more reliable than the presence or absence of retinal fluid. Optical coherence tomography angiography identified myopic choroidal neovascularization in most patients in the diagnostic phase and during treatment monitoring and could be considered as an alternative to fluorescein angiography in selected patients.
PMID: 31619075 DOI: 10.1177/1120672119882333
Int J Mol Sci. 2019 Oct 11;20(20). pii: E5049.
Therapeutic effect of garcinia cambogia extract and hydroxycitric acid inhibiting hypoxia-inducible factor in a murine model of age-related macular degeneration.
Ibuki M, Shoda C, Miwa Y, Ishida A, Tsubota K, Kurihara T.
Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD.
Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation.
Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA.
Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model.
PMID: 31614647 DOI: 10.3390/ijms20205049
Retina. 2019 Oct 14.
Serous macular detachment in Best disease: A masquerade syndrome.
Zatreanu L, Freund KB, Leong BCS, Yu HG, Teke MY, Yzer S, Sadda SR, Sarraf D.
Purpose: To describe the clinical and multimodal imaging findings of a series of cases of serous macular detachment (SMD) caused by Best disease (BD) masquerading as neovascular age-related macular degeneration or central serous chorioretinopathy that were inappropriately treated with intravitreal anti-vascular endothelial growth factor or laser therapy. This study will also present data to support age-related progressive choroidal thickening in BD patients, which may play a role in the development of SMD in this population.
Methods: Clinical examination and multimodal imaging findings, including color fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and optical coherence tomography-angiography, were reviewed and analyzed. Subfoveal choroidal thickness was also formally measured, and an age-related choroidal thickness analysis was performed and compared with a normal population.
Results: Twenty-six eyes of 13 patients (5 women) were included. Median age was 44 years. Nine patients presented with a history of SMD and subretinal fluid recalcitrant to various therapies, including intravitreal anti-vascular endothelial growth factor injections and photodynamic therapy. Best disease was subsequently diagnosed genetically in six patients and by detailed family history in seven. Mean logarithm of the minimum angle of resolution best-corrected visual acuity for all 26 eyes at last follow-up was +0.36 (Snellen equivalent of 20/46). Subfoveal choroidal thickness positively correlated with age for our cohort, increasing linearly at a rate of 25.6 µm per decade (R = 0.64; P < 0.001). Choroidal neovascularization was identified in four eyes on optical coherence tomography angiography, but these eyes did not respond to anti-vascular endothelial growth factor treatment.
Conclusion: The diagnosis of BD should be considered in patients presenting with SMD and recalcitrant subretinal fluid masquerading as neovascular age-related macular degeneration or chronic central serous chorioretinopathy to avoid unnecessary treatment procedures. The positive correlation of subfoveal choroidal thickness with age in BD patients may be a factor in the pathogenesis and development of SMD in this population. Recognizing the multimodal imaging features of SMD associated with BD, described in detail in this study, will guide practitioners to the accurate diagnosis of BD and reduce the risk of unnecessary intraocular procedures with potential complications.
PMID: 31613838 DOI: 10.1097/IAE.0000000000002659