Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

PURPOSE: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. RESULTS: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. CONCLUSION: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.

Efficacy, safety, and treatment burden of treat-and-extend versus alternative anti-VEGF regimens for nAMD: a systematic review and meta-analysis.

This study aimed to compare efficacy and treatment burden of treat-and-extend (T&E) anti-VEGF against fixed and pro re nata (PRN) regimens for neovascular age-related macular degeneration (nAMD). MEDLINE, CENTRAL, and EMBASE were searched. Randomized-controlled trials and observational studies comparing T&E to PRN or fixed dosing for treatment-naïve AMD patients were included. Mean difference (MD) for visual acuity (VA) and number of injections are presented. Risk of bias was assessed according to Cochrane guidelines. Methodology was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). VA improvement was similar with T&E and fixed dosing at one (MD -0.08 letters, p = 0.95) and two years (MD 0.58 letters, p = 0.62). In contrast, VA improvements were significantly greater for T&E when compared against a PRN regimen at one (MD 3.95 letters, p < 0.0001) and two years (MD 4.08 letters, p < 0.001). Significantly fewer ranibizumab injections were administered in the T&E arm at one (MD -2.42 injections, p < 0.0001) and two years (MD -6.06 injections, p < 0.00001) relative to fixed dosing. Fewer aflibercept injections were likewise administered to patients on a T&E regimen versus fixed dosing at one year (MD -0.78 injections, p < 0.0001). Low-certainty evidence from the present synthesis implies that T&E preserves VA similar to fixed schedules with significantly fewer injections at one and two years. Also, patients with T&E dosing achieved better VA outcomes than those on PRN regimen but T&E dosing was associated with more injections.

Role of Positioning after Full-Thickness Macular Hole Surgery: A Systematic Review and Meta-Analysis.

TOPIC: The importance of postoperative face-down positioning (FDP) to achieve anatomic and functional success after full-thickness macular hole (FTMH) surgery is explored in this meta-analysis of randomized controlled trials (RCTs). CLINICAL RELEVANCE: There is considerable variability in clinical practices regarding the need and length of FDP recommended to patients after FTMH surgery. There is also a lack of robust clinical guidelines on the topic. As such, an updated estimate of the effect size of FDP on clinically important outcomes is critical to inform practice. METHODS: Ovid MEDLINE, EMBASE, CENTRAL, and SCOPUS databases were searched from inception to October 3, 2021, for RCTs evaluating FDP versus non-FDP (nFDP). Data were collected for 7 clinically important outcomes after macular hole surgery: closure rate, visual acuity (VA) improvement, recurrence of FTMH, visual function, quality of life, patient satisfaction, and complication rates. We used the Cochrane risk-of-bias tool for randomized trials (RoB 2) to assess the risk of bias and followed the Grade of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the certainty in the evidence across outcomes. We conducted meta-analyses using random-effects modeling. Subgroup analyses were carried out based on hole size, type of gas, and duration of FDP. RESULTS: Eight RCTs of 709 eyes were included. The relative risk (RR) of FTMH closure rate comparing FDP versus nFDP was RR 1.05 (95% confidence interval [CI]: 0.99, 1.12, P = 0.09, I2 = 44%, GRADE rating: LOW). The mean difference (MD) regarding VA improvement comparing FDP and nFDP was MD -0.07 (95% CI: -0.12 to 0.01, P = 0.03, I2 = 16%, GRADE rating: LOW). CONCLUSION: The current review did not demonstrate a difference between FDP and nFDP with respect to FTMH closure, although the CIs were wide. There was a visual benefit to FDP; however, the CIs included values of trivial clinical significance. Subgroup analyses demonstrated that the VA benefit observed was driven by large holes. Limited data precluded analysis regarding the rate of FTMH recurrence, measures of visual function, quality of life measures, and patient satisfaction metrics. Further prospective trials are required to assess the gaps in the literature and improve the certainty of evidence for the outcomes examined.

Role of anti-vascular endothelial growth factor in the management of non-proliferative diabetic retinopathy without centre-involving diabetic macular oedema: a meta-analysis of trials.

This systematic review and meta-analysis investigated the impact of anti-vascular endothelial growth factor (VEGF) treatment in management of eyes with non-proliferative diabetic retinopathy (NPDR) without centre involving diabetic macular oedema (CI-DMO). We searched multiple databases for all randomised clinical trials (RCTs) that evaluated anti-VEGF treatment versus observation in eyes with NPDR without CI-DMO. Data was collected for six outcomes (best corrected visual acuity (BCVA) improvement, diabetic retinopathy severity score (DRSS), central subfield thickness, progression to vision threatening complications (VTCs), ocular adverse events and quality of life measures). Risk of bias was assessed using Cochrane risk-of-bias tool for randomised trials (RoB 2) and certainty of evidence was assessed using Grade of Recommendations, Assessment, Development and Evaluation (GRADE). We identified a total of 2 unique RCTs that compared aflibercept and sham to treat a total of 811 eyes. For BCVA change, there was a small, clinically insignificant benefit for aflibercept treatment at year 2 (MD 0.70, 95% CI 0.02-1.38, GRADE rating: MODERATE). DRSS demonstrated a statistically significant improvement with aflibercept use at year 2 (RR 3.76, 95% CI 2.75-5.13, GRADE rating: MODERATE). VTCs were significantly less in aflibercept arm at year 2 (RR 0.30, 95% CI 0.23-0.40, GRADE rating: MODERATE). In conclusion, aflibercept treatment versus observation in eyes with NPDR without CI-DMO can result in reduced risk of development of VTCs and regression of DRSS score over 2 years. Future trials are needed to increase the precision of the treatment effect and to provide data on quality-of-life metrics.PROSPERO Registration: CRD42021288608.

Treat-and-extend versus alternate dosing strategies with anti-vascular endothelial growth factor agents to treat center involving diabetic macular edema: A systematic review and meta-analysis of 2,346 eyes.

Anti-vascular endothelial growth factor (Anti-VEGF) agents are the standard of care for diabetic macular edema (CI-DME) with vision loss. They are commonly administered using several treatment protocols, including fixed, pro re nata (PRN) and treat-and-extend (T&E) regimens. Because of the lack of evidence defining an ideal treatment paradigm, we systematically compared T&E with fixed or PRN regimens. Visual acuity improvement was similar when comparing T&E to fixed or PRN dosing at 12 and 24 months. Regarding anatomic outcomes, no significant difference was found between T&E and fixed regimens for central retinal thickness or central subfoveal thickness at 12 and 24 months. Similarly, no significant difference was found for central retinal thickness at 12 months for T&E versus PRN regimen. Regarding total number of injections, no significant difference existed between T&E versus fixed regimens at 12 months. PRN regimens delivered fewer injections compared to T&E regimens at 12 months. The results of this analysis support that visual acuity and anatomic outcomes at 12 and 24 months are similar between T&E with either fixed or PRN regimens. More head-to-head trials comparing T&E versus fixed and PRN dosing are needed to provide visual and functional outcome data beyond year 2. PROSPERO Registration: CRD42021249362.

The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis.

TOPIC: To investigate the effect of anti-vascular endothelial growth factor (VEGF) therapy on intraocular pressure (IOP) 12 and 24 months after initiation. CLINICAL RELEVANCE: It is unclear whether serial anti-VEGF injections result in sustained IOP increases. METHODS: Randomized controlled trials (RCTs) comparing anti-VEGF agents with each other or with controls for the treatment of neovascular age-related macular degeneration, retinal vein occlusions, or diabetic macular edema were included. Pairwise meta-analysis and Bayesian network meta-analysis examined the proportion of patients whose IOP (1) increased 5 mmHg or more from baseline on consecutive visits, (2) increased 10 mmHg or more from baseline at any visit, (3) was 21 mmHg or more on consecutive visits, (4) was 25 mmHg or more at any visit, (5) was 30 mmHg or more at any visit, (6) prompted initiation of IOP-lowering medications, or (7) increased as per the clinicians' discretion. Grading of Recommendations Assessments, Development, and Evaluations methodology informed the certainty of evidence. RESULTS: Twenty-six RCTs of 12 522 eyes were included. Aflibercept, bevacizumab, ranibizumab (0.3 mg and 0.5 mg), and noninjection controls were analyzed. Eighty-three of 84 network estimates for comparisons between anti-VEGF agents demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates than bevacizumab of IOP measurements of 30 mmHg or more at 12 months (low certainty of evidence). Fifty-three of 56 network estimates for comparisons between anti-VEGF agents and controls demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates of consecutive IOP increases of 5 mmHg or more at 24 months (low certainty of evidence) and higher rates of IOP increases as per the clinicians' discretion at 12 and 24 months (low and very low certainty of evidence, respectively). The 95% credible intervals in comparisons without statistically significant effects did not rule out important clinical effects. The certainty of evidence in these comparisons is limited by imprecision. CONCLUSION: This network meta-analysis does not show any clear difference in IOP increases 12 and 24 months after treatment initiation between anti-VEGF agents and controls. Imprecision precludes definitive conclusions.

Treat-and-extend regimens of anti-vascular endothelial growth factor therapy for retinal vein occlusions: a systematic review and meta-analysis.

OBJECTIVE: To investigate treat-and-extend (T&E) regimens of anti-vascular endothelial growth factor (anti-VEGF) therapy for the treatment of macular oedema secondary to retinal vein occlusions (RVOs). METHODS: Ovid MEDLINE, Ovid EMBASE and CENTRAL were searched on 25 February 2021. Randomized controlled trials, cohort studies, case-control studies and case series were included. The primary outcome was the change in Early Treatment Diabetic Retinopathy Score (ETDRS) letters from baseline. Conversions from Snellen to ETDRS letters were performed utilizing a published protocol. Secondary outcomes included improvement in retinal thickness from baseline, number of anti-VEGF injections and frequency of adverse events. Outcomes were examined at 12 and 24 months. Certainty of evidence was assessed utilizing GRADE (Grading of Recommendations Assessments, Development and Evaluations) guidelines. RESULTS: Seven hundred eighty-six eyes from 16 studies were included. Meta-analysis demonstrated a mean improvement of 15.7 (95% CI: 13.3-18.0) ETDRS letters at 12 months. Central retinal thickness improved 269.7 µm (95% CI: 233.64-305.90) at 12 months. Injections were performed 8.1 (95% CI: 7.4-8.7) and 13.1 (95% CI: 9.4-16.8) times at 12 and 24 months respectively. Adverse events were infrequent across all studies. Grading of Recommendations Assessments, Development and Evaluations (GRADE) certainty of evidence was very low across all outcomes. CONCLUSIONS: The results support the viability of T&E regimens for the treatment of macular oedema secondary to RVOs.

Quantifying Physical Resilience in Ageing Using Measurement Instruments: A Scoping Review.

Purpose: The capacity to recover motor function with pathology or age-related decline is termed physical resilience. It is unknown what outcome domains are captured with existing measurement instruments. Thus, this scoping review aimed to identify measurement instruments for physical resilience, identify research gaps, and make recommendations for future research. Methods: Articles were included from the search when their subject matter included the term resilience in relation to the physical health of older adults. Data on physical resilience measurement instruments were extracted using the outcome domains: body function or structure, activity and participation, and societal impact. Results: The majority of the 33 included articles involved older adults with fractures, cardiac conditions, and cancer. Many measurement instruments quantified body function or structure, and some instruments captured activity and participation, and societal impact of physical resilience. Measurement instruments were pooled into 4 categories: psychological, physiological, motor function, and psychosocial scales. No studies combined all areas of measurement. Conclusions: A potential gap of a measurement instrument capturing social aspects of physical resilience was identified. Comprehensive measurement could identify which outcome domains could be targeted to foster resilience. This knowledge might be useful across many health disciplines and contribute to therapeutic decision-making and rehabilitation strategies.

Objectif : la résilience physique désigne la capacité de recouvrer sa fonction motrice malgré le déclin lié à une pathologie ou à l'âge. On ne sait pas quels domaines de résultats cliniques les instruments de mesure actuels saisissent. Ainsi, la présente étude de portée visait à déterminer les instruments pour mesurer la résilience physique, repérer les lacunes de la recherche et faire des recommandations en vue des futures recherches. Méthodologie : les articles de la recherche étaient conservés lorsque leur sujet incluait le terme resilience à l'égard de la santé physique des personnes âgées. Les chercheurs ont extrait les données sur les instruments de mesure de la résilience physique au moyen des domaines de résultats suivants : fonction ou structure corporelle, l'activité et la participation et les répercussions sociétales. Résultats : la majorité des 33 articles inclus portaient sur des personnes âgées ayant des fractures, des affections cardiaques et un cancer. De nombreux instruments de mesure quantifiaient la fonction ou la structure corporelle et certains saisissaient l'activité, la participation et les répercussions sociétales de la résilience physique. Les chercheurs ont regroupé les instruments de mesure en quatre catégories : échelles psychologique, physiologique, de la fonction motrice et psychosociale. Aucune étude ne combinait tous les domaines de mesure. Conclusions : les chercheurs ont repéré une lacune potentielle d'un instrument qui saisit les aspects sociaux de la résilience physique. Une mesure exhaustive pourrait déterminer les domaines de résultat à cibler pour favoriser la résilience. Ces connaissances pourraient être utiles dans de nombreuses disciplines et contribuer aux décisions thérapeutiques et aux stratégies de réadaptation.