scholarly journals Contextualising Single-Arm Ophthalmology Trials With Real-World Data: An Emulated Target Trial Comparing The Efficacy Of Interventions For Neovascular Age-Related Macular Degeneration

2020 ◽  
Author(s):  
Darren S Thomas ◽  
Aaron Y. Lee ◽  
Philipp L. Muller ◽  
Roy Schwartz ◽  
Abraham Olvera-Barrios ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Real World ◽  
Age Related Macular Degeneration ◽  
Target Trial ◽  
Real World Data ◽  
World Data ◽  
Off Label ◽  
Age Related ◽  
Randomised Controlled

Methods of causal inference have shown promise in replicating randomised trials using real-world data recorded by Electronic Health Records (EHRs). We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week-54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n 65) was taken from the ABC randomised controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from EHRs and synthetic control arms were created by emulating randomisation conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of ≥ 15, ≥ 10, and ≤ -15 Early Treatment Diabetic Retinopathy Letters (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of ≥ 15, ≥ 10, and ≤ -15 ETDRS letters by week 54. Our findings suggest off-label bevacizumab to be neither non-inferior nor superior to licensed aflibercept. While being no substitute for randomised controlled trials, emulated target trials could aid the interpretation of single-armed trials.

scholarly journals The ‘Real World’ Clinic Measured Visual Acuity Versus the Best Correct Visual Acuity Measurement in Patients Treated for Neovascular Age-Related Macular Degeneration

2021 ◽  
Author(s):  
Obaid Kousha ◽  
Amritpal Chaggar ◽  
Sergio Pagliarini
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Real World ◽  
Age Related Macular Degeneration ◽  
P Value ◽  
The Real ◽  
Age Related ◽  
Clinical Session ◽  
Bland Altman Method ◽  
The Uk

Abstract BACKGROUNDIn ophthalmology clinics, the visual acuity (VA) is usually measured by non-refracting healthcare professionals (HCPs). We compared the ‘real world’ or clinic measured VA versus the best-corrected visual acuity measurement in patients with neovascular age-related macular degeneration (nAMD).METHODSDuring the same clinical session using Early Treatment of Diabetic Retinopathy Study (ETDRS) vision chart, monocular distance VA was measured by non-refracting HCPs in nAMD patients and compared to the monocular distance VA measured by an optometrist with subjective refractive correction (BCVA). The study was powered to detect a difference of >5 ETDRS letters between the groups and for HCP measured VA to detect a BCVA between 6/12 and 6/96 (National Institute of Health and Care Excellence condition of approval of nAMD treatment with licensed drugs in the UK).RESULTSData from 167 patients (324 eyes) were analysed. Absolute mean difference in BCVA versus HCP measured VA was 5.71 (95% confidence interval (CI) 5.10-6.41) ETDRS letters (p-value<0.001). Using Bland-Altman method, limits of agreement between the two groups was found to be between 18.39 and -14.66 ETDRS letters. The prevalence of BCVA between 6/12 and 6/96 was 53.40% (95% CI 47.96-58.83%). In detecting this BCVA bracket, the non-refracting HCP measured VA had a sensitivity of 91.91% (95% CI 87.84-95.97%) and a specificity of 84.77% (95% CI 79.04-90.50%). CONCLUSIONSThe ‘real world’ HCP measured VA was found to have considerable inaccuracy and imprecision when compared to BCVA in nAMD patients. Unreliable VA measurement can have important implications in assessing and treating eye conditions, including nAMD.

scholarly journals Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration

2019 ◽  
Vol 4 (1) ◽  
pp. e000273
Author(s):  
Irina Balikova ◽  
Laurence Postelmans ◽  
Brigitte Pasteels ◽  
Pascale Coquelet ◽  
Janet Catherine ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Treatment Response ◽  
Multiple Testing ◽  
Age Related Macular Degeneration ◽  
Patient Specific ◽  
Multiple Testing Correction ◽  
Anti Vegf ◽  
Age Related ◽  
Vegf Pathway

ObjectiveAge-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.Methods and analysisA retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.ResultsAssociation with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.ConclusionIdentifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

scholarly journals Comparative efficacy and safety of different regimens of ranibizumab for neovascular age-related macular degeneration: a network meta-analysis of randomised controlled trials

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e040906
Author(s):  
Xinyu Zhao ◽  
Lihui Meng ◽  
Youxin Chen
Keyword(s):  
Adverse Events ◽  
Macular Degeneration ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Age Related Macular Degeneration ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Efficacy And Safety ◽  
Age Related ◽  
Randomised Controlled

ObjectiveTo give a comprehensive efficacy and safety ranking of different therapeutic regimens of ranibizumab for neovascular age-related macular degeneration (nAMD).DesignA systematic review and network meta-analysis.MethodsThe PubMed, Embase, Cochrane Central Register of Controlled Trials, and other clinical trial registries were searched up to 1 October 2019 to identify related randomised controlled trials (RCT) of different regimens of ranibizumab for nAMD. The primary efficacy outcome was the changes of best-corrected visual acuity (BCVA) at 1 year, the primary safety outcome was the incidence of severe ocular adverse events. Secondary outcomes such as changes of central retinal thickness (CRT) were evaluated. We estimated the standardised mean difference (SMD), ORs, 95% CIs, the surface under the cumulative ranking curves and the mean ranks for each outcome using network meta-analyses with random effects by Stata 14.0.ResultsWe identified 26 RCTs involving 10 821 patients with nAMD randomly assigned to 21 different therapeutic regimens of ranibizumab or sham treatment. Ranibizumab 0.5 mg (treat and extend, T&E) is most effective in terms of changes of BCVA (letters, SMD=21.41, 95% CI 19.86 to 22.95) and three or more lines of BCVA improvement (OR=2.83, 95% CI 1.27 to 4.38). However, it could not significantly reduce retreatment times compared with monthly injection (SMD=−0.94, 95% CI −2.26 to 0.39). Ranibizumab 0.5 mg (3+pro re nata)+non-steroidal anti-inflammatory drugs (NSAIDs) is most effective in reducing CRT and port delivery system of ranibizumab (100 mg/mL) could reduce the number of retreatment most significantly. All regimes have no more risk of severe ocular complications (including vitreous haemorrhage, rhegmatogenous retinal detachment, endophthalmitis, retinal tear and retinal pigment epithelium tear) or cardiocerebral vascular complications.ConclusionsRanibizumab 0.5 mg (T&E) is most effective in improving the visual outcome. The administration of topical NSAIDs could achieve additional efficacy in CRT reduction and visual improvement. Both interventions had acceptable risks of adverse events.

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