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Visual acuity time in range: a novel concept to describe consistency in treatment response in diabetic macular oedema.
Kozak, I, Pearce, I, Cheung, CMG, Machewitz, T, Lambrou, GN, Molina, D, Suleiman, L, Youssef, H, Bressler, NM
Eye (London, England). 2023;(16):3367-3375
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Abstract
OBJECTIVE To assess 'time in range' as a novel measure of treatment response in diabetic macular oedema (DMO). METHODS This post hoc analysis of the Protocol T randomised clinical trial included 660 individuals with centre-involved DMO and best-corrected visual acuity (BCVA) letter score ≤78-≥24 (approximate Snellen equivalent 20/32-20/320). Study participants received intravitreal aflibercept 2.0 mg, repackaged (compounded) bevacizumab 1.25 mg, or ranibizumab 0.3 mg given up to every 4 weeks using defined retreatment criteria. Mean time in range was calculated using a BCVA letter score threshold of ≥69 (20/40 or better; minimum driving requirement in many regions), with sensitivity analyses using BCVA thresholds from 100 to 0 (20/10 to 20/800) in 1-letter increments. RESULTS Time in range was defined as either the absolute or relative duration above a predefined BCVA threshold, measured in weeks or as a percentage of time, respectively. Using a BCVA letter score threshold of ≥69 (20/40 or better), the least squares mean time in range (adjusted for baseline BCVA) in Year 1 was 41.2 weeks with intravitreal aflibercept, 4.0 weeks longer (95% CI: 1.7, 6.3; p = 0.002) than bevacizumab and 3.6 weeks longer (1.3, 5.9; p = 0.004) than ranibizumab. Overall, mean time in range was numerically longer for intravitreal aflibercept for all BCVA letter score thresholds between 92 and 30 (20/20 to 20/250). In the Day 365-728 analysis, time in range was 3.9 (1.3, 6.5) and 2.4 (0.0, 4.9) weeks longer with intravitreal aflibercept vs bevacizumab and vs ranibizumab (p = 0.011 and 0.106), respectively. CONCLUSION BCVA time in range may represent another way to describe visual outcomes and potential impact on vision-related functions over time for patients with DMO and provide a better understanding, for physicians and patients, of the consistency of treatment efficacy.
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COVID-19-Related Retinal Micro-vasculopathy - A Review of Current Evidence.
Teo, KY, Invernizzi, A, Staurenghi, G, Cheung, CMG
American journal of ophthalmology. 2022;:98-110
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Abstract
PURPOSE To evaluate the occurrence of retinal microvasculopathy in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and who developed coronavirus disease (COVID-19). DESIGN Systematic review and meta-analysis. METHODS The Pubmed and Embase databases were comprehensively searched to identify studies that reported retina vascular changes in eyes with COVID-19. Two independent reviewers selected papers and extracted data for analysis. Data of interest were extracted and analyzed in RevMan Web versions 3.3. Quality of evidence was assessed using the National Institute of Health quality assessment tool for a case-control study. RESULTS Thirty-one studies reporting on 1373 subjects (972 COVID-19 and 401 controls) were included. Only case-control studies were included in the pooled analysis. There was a significantly higher likelihood of retinal microvasculopathy in subjects with COVID-19 compared to controls (odds ratio [95% confidence interval], 8.86 [2.54-27.53], P < .01). Optical coherence tomography angiography (OCTA) revealed reduced vessel density and enlarged foveal avascular zone in subjects with COVID-19 compared to controls. CONCLUSIONS The results suggested that COVID-19-related retinal microvasculopathy is a significant ocular manifestation of COVID-19 and may herald future retinal complications. These microvascular impairments might have occurred antecedent to clinically visible changes and could be detected earlier by OCTA. These findings are significant, due to the large numbers with COVID-19, and need to be recognized by ophthalmologists as a potential long-term sequalae of the disease.
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Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial.
Silva, R, Arias, L, Nunes, S, Farinha, C, Coimbra, R, Marques, JP, Cachulo, ML, Figueira, J, Barreto, P, Madeira, MH, et al
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2022;(1):80-90
Abstract
IMPORTANCE Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. METHODS A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). RESULTS Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. TRIAL REGISTRATION The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.
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Outer Retinal Layer Thickening Predicts the Onset of Exudative Neovascular Age-Related Macular Degeneration.
Invernizzi, A, Parrulli, S, Monteduro, D, Cereda, MG, Nguyen, V, Staurenghi, G, Cheung, CMG, Gillies, M, Teo, KYC
American journal of ophthalmology. 2021;:19-27
Abstract
PURPOSE To assess changes in outer retinal layer (ORL) thickness before the development of exudative macular neovascularization (MNV) in eyes with age-related macular degeneration. DESIGN Retrospective observational case series. METHODS Eyes with age-related macular degeneration that eventually developed exudative MNV followed with sequential optical coherence tomography for ≥2 years before the exudation occurred were enrolled. The ORL thickness was automatically calculated by the optical coherence tomography software for each sector of the early treatment diabetic retinopathy study map at each follow-up visit. The ORL thickness change from baseline to the day when the exudative MNV developed was compared between sectors that eventually developed exudative MNV and those that did not. RESULTS Forty-seven eyes (47 patients) were included. At baseline (24 ± 3 months before exudative MNV), mean (standard deviation) ORL thickness of sectors that eventually developed exudative MNV was similar to that of sectors that did not (85.2 [8.2] µm vs 86.8 [5.7] µm, P = .08). ORL thickness significantly increased in sectors that developed exudative MNV compared with those that did not (+5.8 [10.4] µm vs -2.8 [3.6] µm, P < .01). The regression model based on these data predicted an increase in ORL thickness from baseline of +4.2% 55 days and +11.1% 30 days before exudative MNV was detected. The ORL thickness of areas that did not develop exudative MNV did not change. CONCLUSION Thickening of the ORL begins in the area where exudative MNV will develop long before the exudation, accelerating significantly in the last 2 months. The occurrence of exudative MNV could be predicted by 2 months using this simple analysis.
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Gene-Based Therapeutics for Acquired Retinal Disease: Opportunities and Progress.
Tan, TE, Fenner, BJ, Barathi, VA, Tun, SBB, Wey, YS, Tsai, ASH, Su, X, Lee, SY, Cheung, CMG, Wong, TY, et al
Frontiers in genetics. 2021;:795010
Abstract
Acquired retinal diseases such as age-related macular degeneration and diabetic retinopathy rank among the leading causes of blindness and visual loss worldwide. Effective treatments for these conditions are available, but often have a high treatment burden, and poor compliance can lead to disappointing real-world outcomes. Development of new treatment strategies that provide more durable treatment effects could help to address some of these unmet needs. Gene-based therapeutics, pioneered for the treatment of monogenic inherited retinal disease, are being actively investigated as new treatments for acquired retinal disease. There are significant advantages to the application of gene-based therapeutics in acquired retinal disease, including the presence of established therapeutic targets and common pathophysiologic pathways between diseases, the lack of genotype-specificity required, and the larger potential treatment population per therapy. Different gene-based therapeutic strategies have been attempted, including gene augmentation therapy to induce in vivo expression of therapeutic molecules, and gene editing to knock down genes encoding specific mediators in disease pathways. We highlight the opportunities and unmet clinical needs in acquired retinal disease, review the progress made thus far with current therapeutic strategies and surgical delivery techniques, and discuss limitations and future directions in the field.
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Patterns and Characteristics of a Clinical Implementation of a Self-Monitoring Program for Retina Diseases during the COVID-19 Pandemic.
Teo, KYC, Bachmann, LM, Sim, D, Lee, SY, Tan, A, Wong, TY, Cheung, CMG, Wei Tan, GS
Ophthalmology. Retina. 2021;(12):1245-1253
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Abstract
PURPOSE We describe the large-scale self-initiated recruitment of patients to a self-monitoring initiative for macular pathologic features during the coronavirus disease 2019 (COVID-19) pandemic. DESIGN Observational study with retrospective analysis. PARTICIPANTS A total of 2272 patients from the Singapore National Eye Centre (SNEC) whose visits were rescheduled over lockdown (April 13-June 1, 2020) were offered participation in a self-monitoring initiative administered by SNEC with the Alleye application (Switzerland) as the testing instrument. METHODS This was an observational study with retrospective analysis. Demographics and characteristics were compared between those who signed up and those who did not. Similar comparisons were made between patients who complied with the initiative versus those who did not. Outcomes were tracked for 6 months starting from the commencement of lockdown. MAIN OUTCOME MEASURES Participation and compliance rates and characteristics of patients who were more likely to participate and comply with the initiative. RESULTS Seven hundred thirty-two patients (32%) participated in this self-monitoring initiative. Those who participated were younger (62 years of age vs. 68 years of age; P < 0.001), men, and living with family. Patients not receiving treatment and those with poorer vision in the worse-seeing eye were more likely to participate. When grouped according to diagnosis, the proportion who participated was highest for diabetic macular edema (52%), nonneovascular age-related macular degeneration (AMD; 42%), diabetic retinopathy (35%), retinal vein occlusions (18%), and neovascular AMD (15%; P < 0.001). Testing compliance rate was 43% (315/732). Patients who complied with the initiative were older, were receiving treatment, and had poorer vision in the worse-seeing eye. Trigger events occurred in 33 patients, with 5 patients having clinically verified disease progression (1.6%). CONCLUSIONS We provide clinical data on characteristics of patients with stable retinal diseases who were offered, participated in, and complied with a self-monitoring program. The lower participation rate compared with standardized clinical studies reflects the difficulties in implementation for such initiatives in clinical settings. Despite this, self-monitoring continues to show promise in relieving clinic resources, suggesting the feasibility of scaling such programs beyond the COVID-19 pandemic.
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Looking Ahead: Visual and Anatomical Endpoints in Future Trials of Diabetic Macular Ischemia.
Cheung, CMG, Pearce, E, Fenner, B, Sen, P, Chong, V, Sivaprasad, S
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2021;(5):451-464
Abstract
Diabetic macular ischemia (DMI) is a common complication of diabetic retinopathy that can lead to progressive and irreversible visual loss. Despite substantial clinical burden, there are no treatments for DMI, no validated clinical trial endpoints, and few clinical trials focusing on DMI. Therefore, generating consensus on validated endpoints that can be used in DMI for the development of effective interventions is vital. In this review, we discuss potential endpoints appropriate for use in clinical trials of DMI, and consider the data required to establish acceptable and meaningful endpoints. A combination of anatomical, functional, and patient-reported outcome measures will provide the most complete picture of changes that occur during the progression of DMI. Potential endpoint measures include change in size of the foveal avascular zone measured by optical coherence tomography angiography and change over time in best-corrected visual acuity. However, these endpoints must be supported by further research. We also recommend studies to investigate the natural history and progression of DMI. In addition to improving understanding of how patient demographics and comorbidities such as diabetic macular edema affect clinical trial endpoints, these studies would help to build the consensus definition of DMI that is currently missing from clinical practice and research.
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High-Density Lipoprotein Cholesterol in Age-Related Ocular Diseases.
Betzler, BK, Rim, TH, Sabanayagam, C, Cheung, CMG, Cheng, CY
Biomolecules. 2020;(4)
Abstract
There is limited understanding of the specific role of high-density lipoprotein cholesterol (HDL-C) in the development of various age-related ocular diseases, despite it being a common measurable biomarker in lipid profiles. This literature review summarizes current knowledge of the role of HDL-C, if any, in pathogenesis and progression of four age-related ocular diseases, namely age-related macular degeneration (AMD), age-related cataract, glaucoma, and diabetic retinopathy (DR), and will primarily discuss epidemiological and genetic evidence.
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Incidence and progression of diabetic retinopathy: a systematic review.
Sabanayagam, C, Banu, R, Chee, ML, Lee, R, Wang, YX, Tan, G, Jonas, JB, Lamoureux, EL, Cheng, CY, Klein, BEK, et al
The lancet. Diabetes & endocrinology. 2019;(2):140-149
Abstract
Diabetic retinopathy is a leading cause of vision impairment and blindness. We systematically reviewed studies published from Jan 1, 1980, to Jan 7, 2018, assessed the methodological quality, and described variations in incidence of diabetic retinopathy by region with a focus on population-based studies that were conducted after 2000 (n=8, including two unpublished studies). Of these eight studies, five were from Asia, and one each from the North America, Caribbean, and sub-Saharan Africa. The annual incidence of diabetic retinopathy ranged from 2·2% to 12·7% and progression from 3·4% to 12·3%. Progression to proliferative diabetic retinopathy was higher in individuals with mild disease compared with those with no disease at baseline. Our Review suggests that more high-quality population-based studies capturing data on the incidence and progression of diabetic retinopathy with stratification by age and sex are needed to consolidate the evidence base. Our data is useful for conceptualisation and development of major public health strategies such as screening programmes for diabetic retinopathy.
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Optical Coherence Tomographic Angiography in Type 2 Diabetes and Diabetic Retinopathy.
Ting, DSW, Tan, GSW, Agrawal, R, Yanagi, Y, Sie, NM, Wong, CW, San Yeo, IY, Lee, SY, Cheung, CMG, Wong, TY
JAMA ophthalmology. 2017;(4):306-312
Abstract
IMPORTANCE Optical coherence tomographic angiography (OCT-A) is able to visualize retinal microvasculature without the need for injection of fluorescein contrast dye. Nevertheless, it is only able to capture a limited view of macula and does not show leakage. OBJECTIVES To evaluate the retinal microvasculature using OCT-A in patients with type 2 diabetes as well as the association of OCT-A characteristics with diabetic retinopathy (DR) and systemic risk factors. DESIGN, SETTING, AND PARTICIPANTS A prospective, observational study was conducted from January 1 to June 30, 2016, at medical retina clinics at the Singapore National Eye Center among 50 patients with type 2 diabetes with and without DR (n = 100 eyes). We examined the retinal microvasculature with swept-source OCT-A and a semiautomated software to measure the capillary density index (CDI) and fractal dimension (FD) at the superficial vascular plexus (SVP) and deep retinal vascular plexus (DVP). We collected data on histories of patients' glycated hemoglobin A1c, hypertension, hyperlipidemia, smoking, and renal impairment. MAIN OUTCOMES AND MEASURES The CDI and FD at the SVP and DVP for each severity level of DR and the association of systemic risk factors vs the CDI and FD. RESULTS The mean (SD) glycated hemoglobin A1c of the 50 patients (26 men and 24 women; 35 Chinese; mean [SD] age, 59.5 [8.9] years) was 7.9% (1.7%). The mean (SD) CDI at the SVP decreased from 0.358 (0.017) in patients with no DR to 0.338 (0.012) in patients with proliferative DR (P < .001) and at the DVP decreased in patients with no DR from 0.361 (0.019) to 0.345 (0.020) in patients with proliferative DR (P = .04). The mean (SD) FD at the SVP increased from 1.53 (0.05) in patients with no DR to 1.60 (0.05) in patients with proliferative DR (P < .01) and at the DVP increased from 1.55 (0.06) in patients with no DR to 1.61 (0.05) in patients with proliferative DR (P = .02). For systemic risk factors, hyperlipidemia (odds ratio [OR], 9.82; 95% CI, 6.92-11.23; P < .001), smoking (OR, 10.90; 95% CI, 8.23-12.34; P < .001), and renal impairment (OR, 3.72; 95% CI, 1.80-4.81; P = .05) were associated with reduced CDI, while increased glycated hemoglobin A1c (≥8%) (OR, 8.77; 95% CI, 5.23-10.81; P < .01) and renal impairment (OR, 10.30; 95% CI, 8.21-11.91; P < .001) were associated with increased FD. CONCLUSIONS AND RELEVANCE Optical coherence tomographic angiography is a novel imaging modality to quantify the retinal capillary microvasculature in patients with diabetes. It can be potentially used in interventional trials to study the effect of systemic risk factors on the microvasculature that was previously not accessible in a noninvasive manner. The relevance of these findings relative to visual acuity, however, remains largely unknown at this time.