Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

OBJECTIVE: To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. RESULTS: A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 µm increase in central sub-field thickness (CST) are considered, 90% will be eligible for interval extension. CONCLUSION: Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

The Natural History of Retinal Sensitivity Loss in Diabetic Macular Ischemia over One Year Evaluated by Microperimetry.

Background/Objectives: This one-year prospective observational study, conducted at two centers, aimed to report the natural history of retinal sensitivity (RS) loss in diabetic macular ischemia (DMI). Methods: Patients with stable-treated proliferative diabetic retinopathy (PDR) were recruited if there was evidence of DMI on optical coherence tomography angiography, defined as a foveal avascular zone ≥ 0.5 mm2 or parafoveal capillary dropout ≥ 1 quadrant. The minimal visual acuity required for performing microperimetry (MP) was ≥54 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent 20/80). The overall RS (oRS) and pointwise sensitivity (PWS) within the 3 × 3 mm macula were assessed at baseline and twelve months. A value <25 decibels (dB) was defined as impaired RS, and a decrease of 2 and 7 dB was regarded as mild and severe loss, respectively. Results: A total of 88 patients (97 eyes) were included. No statistically significant MP changes were detected at one year. However, 10% of the cohort lost oRS ≥ 2 dB, and 73% lost ≥2 dB PWS in ≥5 loci, whereas 1% lost oRS ≥ 7 dB, and 4% lost ≥7 dB PWS in ≥5 loci. The foveola and temporal parafovea were the most vulnerable to severe RS loss. Compared to their counterpart, eyes with baseline oRS ≥ 25 dB had significantly more RS loss in the macula and superior parafovea (55% versus 32% and 53% versus 28%, both p = 0.01). Conclusions: Rather than oRS loss, ≥2 dB loss in PWS in ≥5 loci is a more feasible outcome measure for clinical trials in DMI.

Subretinal transient hyporeflectivity in neovascular age-related macular degeneration and its response to a loading phase of aflibercept: PRECISE report 4.

PURPOSE: To describe the prevalence of subretinal transient hyporeflectivity (STHR) in exudative neovascular age-related macular degeneration (nAMD) and its response to a loading phase of aflibercept. METHODS: Optical coherence tomography (OCT) scans of treatment-naïve nAMD patients captured at baseline and after a loading phase of aflibercept were graded for presence of STHR, defined as a small, well-defined, round, subretinal, hyporeflective area, delimited between the ellipsoid zone (EZ) and the retinal pigmented epithelium/Bruch membrane complex. OCT parameters recorded were macular neovascularisation (MNV) subtypes, location of retinal fluids (subretinal fluid, SRF and intraretinal fluid, IRF), central retinal and choroidal thickness. Response was defined as absence of IRF and SRF. Factors associated with completely resolved STHR versus persistent STHR post-loading phase were compared. RESULTS: 2039 eyes of 1901 patients were analysed. STHR was observed in 79 eyes of 78 patients, with an estimated prevalence of 3.87% (95% CI 3.08-4.81%). STHR were seen in 44 type 1 MNV (56%), 27 with type 2 (34%), and 8 with type 3 (10%). At baseline, a total of 303 STHR were present, ranging between 1-22 per eye. The total number of STHR reduced significantly after the loading phase to 173 (p = 0.002). Complete disappearance of STHR was seen in 44 eyes (56%) and persistent STHR in the rest (44%). CONCLUSIONS: STHR may represent a marker of low-grade exudation in nAMD eyes with good response to a loading phase of aflibercept. However, its potential role as an independent nAMD activity biomarker is limited as most resolve after the loading phase.

Associations of presenting visual acuity with morphological changes on OCT in neovascular age-related macular degeneration: PRECISE Study Report 2.

PURPOSE: To study associations of optical coherence tomography (OCT) features with presenting visual acuity (VA) in treatment naive neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on aflibercept therapy were recruited from December 2019 to August 2021. Demographic and OCT (Spectralis, Heidelberg Engineering) features associated with good VA (VA ≥ 68 ETDRS letters, Snellen ≥ 6/12) and poor VA (VA < 54 letters, Snellen < 6/18) were analysed using Generalised Estimating Equations to account for inter-eye correlation. RESULTS: Of 2274 eyes of 2128 patients enrolled, 2039 eyes of 1901 patients with complete data were analysed. Mean age was 79.4 (SD 7.8) years, female:male 3:2 and mean VA 58.0 (SD 14.5) letters. On multivariable analysis VA < 54 letters was associated with increased central subfield thickness (CST) (OR 1.40 per 100 µm; P < 0.001), foveal intraretinal fluid (OR 2.14; P < 0.001), polypoidal vasculopathy (PCV) relative to Type 1 macular neovascularisation (MNV) (OR 1.66; P = 0.049), presence of foveal subretinal hyperreflective material (SHRM) (OR 1.73; P = 0.002), foveal fibrosis (OR 3.85; P < 0.001), foveal atrophy (OR 5.54; P < 0.001), loss of integrity of the foveal ellipsoid zone (EZ) or external limiting membrane (ELM) relative to their preservation (OR 3.83; P < 0.001) and absence of subretinal drusenoid deposits (SDD) (presence vs absence; OR 0.75; P = 0.04). These features were associated with reduced odds of VA ≥ 68 letters except MNV subtypes and SDD. CONCLUSION: Presence of baseline fovea-involving atrophy, fibrosis, intraretinal fluid, SHRM, PCV EZ/ELM loss and increased CST determine poor presenting VA. This highlights the need for early detection and treatment prior to structural changes that worsen baseline VA.

Topographic Correlation of Microperimetry With Structural Characteristics in Diabetic Macular Ischemia.

PURPOSE: This study aimed to determine the threshold for defining abnormal retinal sensitivity (RS) that correlates with structural changes in diabetic macular ischemia (DMI) patients with stable treated proliferative diabetic retinopathy (PDR). DESIGN: Prospective cross-sectional study. METHODS: In a single center, we recruited 85 eyes (67 patients) with stable treated PDR with best-corrected visual acuity (BCVA) ≥54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/80) and optical coherence tomography angiography evidence of DMI. The function-function and function-structure correlation were assessed. Two preselected thresholds in overall RS (oRS), 25 decibels (dB) and age-matched normative data (AMND), were tested on their ability to reflect abnormal anatomy in DMI. Finally, a multivariable regression model was established to depict the relationship between the oRS and various parameters. RESULTS: The oRS showed only a modest correlation with BCVA and low-luminance visual acuity (LLVA). The whole-image deep vessel density (wiDVD) was the most reliable vascular metric correlated with RS. For every 1% decline in the wiDVD, the oRS decreased by 0.37 dB (P < .001) after multivariable adjustment. Furthermore, both a reduction of oRS to <25 dB or below AMND could differentiate eyes with FAZ ≥0.5 mm2, whole image superficial vessel density (wiSVD) <37.7%, wiDVD <41.9%, and the presence of disorganization of the retinal inner layers (DRIL) from their counterparts. CONCLUSIONS: The absolute value of 25 dB in oRS is worth considering as a trial endpoint, because it does not require complex calculation and closely reflects the structural abnormalities in DMI.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3.

PURPOSE: To compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold. RESULTS: Of 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4. CONCLUSION: On average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

Quantitative response of macular neovascularisation to loading phase of aflibercept in neovascular age-related macular degeneration.

PURPOSE: To evaluate quantitative morphological changes in macular neovascularisation (MNV) network after aflibercept therapy in neovascular age-related macular degeneration (nAMD) patients. METHODS: Consecutive treatment-naïve patients with optical coherence tomography (OCT) angiography confirmed MNV due to nAMD who completed a loading phase of intravitreal aflibercept injections. A quantitative analysis of the vascular network remodelling was performed using a computational software (Angiotool). RESULTS: A total of 53 eyes of 52 patients were included in the analysis. The total MNV area decreased significantly after three aflibercept injections (p = 0.003). Total vessel area and vessel density decreased respectively of 20% and 12% at V3 (p < 0.001 in both cases). Other parameters that reduced significantly were total vessel length, average vessel length and density of vascular junctions (p = 0.018, p = 0.002, and p = 0.044, respectively). The number of vascular endpoints (p = 0.001) and lacunarity (p = 0.011) increased significantly, whilst the number of vascular junctions did not vary significantly (p = 0.068). Changes in vascular metrics were predominantly driven by MNV type 1 and 2. No clear relationship was observed between any of the vascular metrics and the macular fluid status. CONCLUSION: Although objective quantification of vascular parameters showed a significant remodelling of the MNV post-loading phase of aflibercept in type 1 and 2 MNV subtypes, none of the quantified vascular metrics correlated to the macular fluid response. These findings highlight a dissociation of anti-angiogenic and anti-permeability properties of aflibercept therapy during the loading phase.

A Multi-Modal AI-Driven Cohort Selection Tool to Predict Suboptimal Non-Responders to Aflibercept Loading-Phase for Neovascular Age-Related Macular Degeneration: PRECISE Study Report 1.

Patients diagnosed with exudative neovascular age-related macular degeneration are commonly treated with anti-vascular endothelial growth factor (anti-VEGF) agents. However, response to treatment is heterogeneous, without a clinical explanation. Predicting suboptimal response at baseline will enable more efficient clinical trial designs for novel, future interventions and facilitate individualised therapies. In this multicentre study, we trained a multi-modal artificial intelligence (AI) system to identify suboptimal responders to the loading-phase of the anti-VEGF agent aflibercept from baseline characteristics. We collected clinical features and optical coherence tomography scans from 1720 eyes of 1612 patients between 2019 and 2021. We evaluated our AI system as a patient selection method by emulating hypothetical clinical trials of different sizes based on our test set. Our method detected up to 57.6% more suboptimal responders than random selection, and up to 24.2% more than any alternative selection criteria tested. Applying this method to the entry process of candidates into randomised controlled trials may contribute to the success of such trials and further inform personalised care.

Study protocol on prevalence of non-exudative macular neovascularisation and its contribution to prediction of exudation in fellow eyes with unilateral exudative AMD (EYE-NEON).

PURPOSE: Fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) are at risk of developing macular neovascularisation (MNV). These eyes may first develop subclinical non-exudative MNV (neMNV) before they leak to form exudative MNV (eMNV). The EYE NEON study is a 2-year study aimed at estimating the prevalence and incidence of neMNV and evaluating its role as a predictor for conversion to neovascular AMD. METHODS: EYE NEON is a multicentre study that will run in retinal clinics across 25 National Health Service with the aim to recruit 800 patients with new onset nAMD in the first eye. The fellow-eye with no evidence of nAMD at baseline will be the study eye. All study eyes will have OCT and OCTA done at first and second year following first anti-VEGF treatment to the first eye (non-study eye), with new onset nAMD. We will estimate the prevalence and incidence of neMNV over 2 years, rate of conversion from neMNV to eMNV and numbers initiated on treatment for neovascular AMD in the study eye will be reported. Predictive models of conversion including neMNV with other demographic and imaging parameters will be developed. CONCLUSION: The study design with proposed target sample size is sufficient to evaluate the retinal imaging characteristics of the study eyes with and without neMNV and develop predictive models to inform risk of conversion to nAMD.

Characterization of the Structural and Functional Alteration in Eyes with Diabetic Macular Ischemia.

OBJECTIVE: To investigate the relative effect of disorganization of the retinal inner layers (DRIL) and ellipsoid zone (EZ) loss on visual function in diabetic macular ischemia (DMI). DESIGN: Prospective cross-sectional observational study. PARTICIPANTS: Patients with stable treated proliferative diabetic retinopathy (PDR) without center-involved diabetic macular edema were recruited at the Moorfields Eye Hospital from December 2019 to November 2021. The main inclusion criteria were best-corrected visual acuity (BCVA) of ≥ 40 ETDRS letters (Snellen equivalent 20/160) with OCT angiography (OCTA) evidence of DMI in ≥ 1 eye. METHODS: Each eligible eye of the recruited patients was assessed for BCVA, OCT, and OCTA metrics. The prespecified OCT parameters were DRIL and subfoveal EZ loss. Generalized estimating equations were used. MAIN OUTCOMES MEASURES: The frequency of DRIL and EZ loss, their relative contributions to vision loss, and their associations with microvascular alterations were evaluated. RESULTS: A total of 125 eyes of 86 patients with PDR were enrolled; 104 (83%) eyes had a BCVA of ≥ 70 letters. Disorganization of the retinal inner layers was more prevalent than EZ loss (46% [58 eyes] vs. 19% [24 eyes]). On average, the presence of DRIL had a more pronounced impact on vision, retinal thickness, and microvascular parameters than EZ loss. After multivariable adjustment, the odds of coexisting DRIL increased by 12% with every letter decrease in BCVA; however, there was no statistically significant association of subfoveal EZ loss with BCVA. In eyes with DRIL in the absence of EZ loss, the BCVA declined significantly by 6.67 letters compared with eyes with no DRIL nor EZ loss (95% confidence interval [CI], -9.92 to -3.41; P < 0.001). However, if DRIL and EZ loss coexisted, the resultant BCVA was 13.22 letters less than eyes without these structural abnormalities (95% CI, -18.85 to -7.59; P < 0.001). CONCLUSIONS: In patients with DMI with a Snellen visual acuity of 20/160 or better, eyes with DRIL were associated with more visual function loss and retinal blood circulation alterations than those with subfoveal EZ loss only.

Correlation of Optical Coherence Tomography Angiography Characteristics with Visual Function to Define Vision-Threatening Diabetic Macular Ischemia.

The thresholds of macular microvasculature parameters associated with mild visual impairment in diabetic macular ischemia (DMI) patients are unclear. Therefore, this prospective observational study is aimed at demonstrating the optical coherence tomography angiography parameters that best correlate with mild visual impairment (<70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, Snellen equivalent 20/40) in DMI. The study was completed at the Moorfields Eye Hospital from December 2019 to August 2021. A total of 123 eyes of 87 patients with stable-treated proliferative diabetic retinopathy following panretinal photocoagulation were recruited. DMI was defined as an irregular foveal avascular zone (FAZ) area ≥ 0.5 mm2 or a smaller FAZ area with parafoveal capillary dropout in at least one quadrant. The analysis showed that the whole image deep vascular complex vessel density (DVC VD) in the 3 × 3 mm area had the best discriminatory ability to identify participants with mild visual impairment at 41.9% (area under the curve = 0.77, sensitivity 94%, specificity 54%, likelihood ratio [LR] = 2.04), and the FAZ area had the greatest post-test LR = 4.21 at 0.64 mm2. The 3 × 3 mm whole image DVC VD and FAZ area cutoffs are useful for screening vision-threatening DMI, but DVC VD has low specificity.

RETINAL NONPERFUSION IN THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SEVEN FIELDS COMPARED WITH WIDEFIELD FLUORESCEIN ANGIOGRAPHY: Correlation and Use of Extrapolation Factor.

BACKGROUND: In previous landmark studies on central retinal vein occlusion, retinal nonperfusion assessments were obtained using 7-field (7F) angiography. The widespread current use of widefield imaging allows better visualization of the peripheral retina and more comprehensive estimation of the total area of nonperfusion. The relationship between nonperfusion measurement of 7F and widefield angiography (WFA) in central retinal vein occlusion has not been studied. We aim to identify the correlation of retinal nonperfusion measured within the 7F and on WFA in eyes with central retinal vein occlusion. METHODS: Retinal nonperfusion in participants with central retinal vein occlusion was determined using a 7F Early Treatment Diabetic Retinopathy Study template and the concentric rings method. RESULTS: A total of 153 eyes were included. Pearson correlation test showed a near-perfect positive, linear correlation between the nonperfusion found in the 7F and total retinal nonperfusion on WFA (0.985 95% CI [0.793, 0.999]) The regression line equation for nonperfusion on 7F and WFA was y = 37 + 3.2x. Eyes with 0 disk areas (DA), >0 DA to 10 DA and >10 DA of nonperfusion on 7-fields had on average 23 DA 95% CI (19.20, 27.06), 45 DA 95% CI (35.75, 55.18), and 115 DA 95% CI (88.89, 142.05) on widefield respectively. CONCLUSION: There is a positive and linear relationship between nonperfusion measured by 7F and WFA in central retinal vein occlusion with more than 3-times the amount of nonperfusion identified on WFA. Despite <10 DA no areas of nonperfusion on 7F, there is typically at least 35 DA of nonperfusion on WFA whereas eyes with >10 DA of nonperfusion on 7F had at least 88 DA on WFA.

Barriers in establishing systematic diabetic retinopathy screening through telemedicine in low- and middle-income countries.

Vision-threatening diabetic retinopathy (VTDR) is one of the leading causes of impaired vision in the working-age population. Early identification, timely diagnosis, and prompt treatment of VTDR have to be tackled simultaneously to reduce the rate of blindness due to this condition. Considerable emphasis has been placed globally on establishing diabetic retinopathy screening (DRS) programs to enable early identification and referral of VTDR for treatment. However, there is an urgent need to shift from the common practice of opportunistic screening to a systematic DRS pathway to ensure that individuals with diabetes are screened at regular intervals and treated appropriately. While systematic DRS programs have been successfully established in countries such as the United Kingdom (UK), it continues to be a challenge to initiate and sustain such programs in low- and middle-income countries (LMIC), home to approximately 80% of people with diabetes. Telemedicine is widely recognized as an ideal DRS screening program. Although it has resulted in an upsurge of opportunistic screening, systematic recall of screened patients remains a challenge. In addition, the link between referred patients from the telemedicine programs to treatment centers is often not established or has failed to deliver; so, there is minimal impact of these telemedicine programs on VTDR blindness at present. This review covers the various barriers of establishing and sustaining systematic telemedicine DRS programs, especially in resource-constrained settings, and the challenges in aligning telemedicine to VTDR treatment pathways to ensure patients with VTDR are treated promptly and effectively.