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1.
Baseline Factors Associated with Diabetic Retinopathy Improvement in RIDE/RISE.
Dhoot, DS, Hill, LF, Ghanekar, A, Tarnowski, KW, Ali, FS
Ophthalmology. Retina. 2021;(1):101-103
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Ranibizumab in Diabetic Retinopathy with or without Diabetic Macular Edema.
Antoszyk, AN, Tarnowski, KW, Basu, K, Ehrlich, JS, Haskova, Z
Ophthalmology. Retina. 2020;(10):1034-1036
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Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.
Mehta, H, Hennings, C, Gillies, MC, Nguyen, V, Campain, A, Fraser-Bell, S
The Cochrane database of systematic reviews. 2018;(4):CD011599
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Abstract
BACKGROUND The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. OBJECTIVES To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. SELECTION CRITERIA We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. DATA COLLECTION AND ANALYSIS We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. MAIN RESULTS There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. AUTHORS' CONCLUSIONS Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO. There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.
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The Clinical Effectiveness of Ranibizumab Treat and Extend Regimen in nAMD: Systematic Review and Network Meta-Analysis.
Danyliv, A, Glanville, J, McCool, R, Ferreira, A, Skelly, A, Jacob, RP
Advances in therapy. 2017;(3):611-619
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Abstract
INTRODUCTION Neovascular age-related macular degeneration (nAMD) is a chronic eye condition that causes severe deterioration of vision and ultimately blindness. Two vascular endothelial growth factor inhibitors are approved for nAMD treatment in Europe: ranibizumab and aflibercept. The European license for ranibizumab was updated with an individualized "treat and extend" (T&E) regimen, which involves more proactive treatment based on changes in best corrected visual acuity (BCVA) and/or anatomical outcomes. The aim of this publication is to compare the efficacy of the ranibizumab T&E regimen with other approved dosing regimens for nAMD on the basis of outcomes identified from a systematic review and subsequent NMA. METHODS Following a systematic search of publications, to identify relevant studies, a repeated-measures network meta-analysis (NMA) was performed to estimate the relative effectiveness of ranibizumab T&E versus approved dosing regimens of ranibizumab and aflibercept. The analysis focused on licensed treatment regimens for nAMD. We examined mean change from baseline in BCVA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. RESULTS The systematic literature review identified 22,949 records, of which 23 studies were included in the NMA. At 12 months, the ranibizumab T&E dosing regimen vs ranibizumab pro re nata (PRN) was associated with small differences in change in BCVA, between 1.86 letter gain at 12 months and 2.35 letter gain at 24 months. A similar difference was observed in the aflibercept dosing regimen versus ranibizumab T&E ; 1.94 letter gain at 12 months and 3.31 letter gain at 24 months. All doses of ranibizumab and aflibercept showed similar effectiveness, and the differences between treatment options were not significant. CONCLUSION This study used novel repeated-measures NMA to synthesize efficacy results when treatment effects were reported at multiple follow-up times. This repeated-measures NMA suggests that treating patients with the ranibizumab T&E regimen yields similar effectiveness compared to other approved ranibizumab and aflibercept dosing regimens for nAMD treatment. FUNDING Novartis Pharmaceuticals UK Ltd, Surrey, UK.
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Intravitreal Ranibizumab in Diabetic Macular Edema: Long-Term Outcomes.
Zucchiatti, I, Bandello, F
Developments in ophthalmology. 2017;:63-70
Abstract
Intravitreal ranibizumab (RBZ) has been shown in multiple randomized clinical trials to be a valuable treatment for diabetic macular edema (DME), promoting a significant improvement in best-corrected visual acuity (BCVA) and in anatomic outcomes. Compared to sham (RISE and RIDE studies), RBZ rapidly and sustainably improved BCVA and decreased macular edema at 2 years, reducing the risk of further vision loss, with low rates of local or systemic side effects. Compared to macular laser photocoagulation (READ-2 study), RBZ provided a greater improvement in BCVA and regression in foveal thickness, but required a higher number of injections compared to patients treated with both RBZ and laser. In RESTORE trial, RBZ alone or combined with macular laser turned out to be superior to laser alone, without significant differences between the 2 RBZ groups. Compared to combined treatment (RBZ or triamcinolone associated with macular laser) or photocoagulation laser alone (Diabetic Retinopathy Clinical Research Network trial), RBZ with prompt or deferred laser was more effective than laser alone at 1-year follow-up. At 3 years, prompt laser was not better than deferring laser for 24 weeks or more. At 5 years, subjects treated with RBZ achieved better long-term visual outcomes than patients managed with triamcinolone or laser followed by very deferred RBZ. In conclusion, randomized clinical trials showed that RBZ was superior to laser in DME treatment, providing excellent long-term visual outcomes. Frequent injections were necessary in most of the patients to properly control DME and maximize the visual benefits.
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The Efficacy and Safety of Current Treatments in Diabetic Macular Edema: A Systematic Review and Network Meta-Analysis.
Zhang, L, Wang, W, Gao, Y, Lan, J, Xie, L
PloS one. 2016;(7):e0159553
Abstract
PURPOSE To compare the efficacy and safety of current treatments in diabetic macular edema (DME). METHODS PubMed, Embase and CENTRAL were systematically reviewed for randomized controlled trials of current treatments in DME through August 2015. Data on the mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were extracted, and adverse events (AEs) were collected. RESULTS A total of 21 trials were included in our network meta-analysis. Intravitreal ranibizumab improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 6 months and intravitreal aflibercept (+8.19 (5.07 to 11.96)) in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly (-111.34 (-254.61 to 37.93)) in 6 months and intravitreal aflibercept (-110.83 (-190.25 to -35.27)) in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved. CONCLUSIONS Our analysis confirms that intravitreal aflibercept is most favorable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection. More high-quality randomized controlled trials will be necessary.
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Ranibizumab for the treatment of wet AMD: a summary of real-world studies.
Chong, V
Eye (London, England). 2016;(2):270-86
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Abstract
Data from real-world studies of ranibizumab in neovascular (wet) age-related macular degeneration suggest that outcomes in clinical practice fail to match those seen in clinical trials. These real-world studies follow treatment regimens that differ from the fixed dosing used in the pivotal clinical trial programme. To better understand the effectiveness of ranibizumab in clinical practice, we conducted a comprehensive evaluation of 12-month outcomes reported in peer-reviewed 'real-world' publications. Key measures included in our analysis were mean change in visual acuity (VA) and the proportion of patients gaining ≥15 letters or losing ≤15 letters. Twenty studies were eligible for inclusion in our study, with 18 358 eyes having sufficient data for analysis of 12-month outcomes. Mean baseline VA ranged from 48.8 to 61.6 Early Treatment Diabetic Retinopathy Study letters. Mean change in VA was between -2.0 and +5.5 letters, with a grand mean of +2.9±3.2, and a weighted mean (adjusted for the number of eyes in the study) of +1.95. Eleven studies reported that 19±7.5 (mean value) of patients gained ≥15 letters, while in 12 studies the mean percentage of patient losing ≤15 letters was 89±6.5%. Our comprehensive analysis of real-world ranibizumab study data confirm that patient outcomes are considerably poorer than those reported in randomised control trials of both fixed and pro re nata regimens.
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Nurse-administered intravitreal injections: a systematic review.
Li, E, Greenberg, PB, Krzystolik, MG
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2015;(9):1619-21
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Ranibizumab for macular edema secondary to retinal vein occlusion: a meta-analysis of dose effects and comparison with no anti-VEGF treatment.
Song, WT, Xia, XB
BMC ophthalmology. 2015;:31
Abstract
BACKGROUND To compare the efficacy and tolerability of intravitreal ranibizumab (IVR) 0.5 mg or 0.3 mg with non-anti-vascular endothelial growth factor (VEGF), and to compare the efficacy of IVR 0.5 mg with IVR 0.3 mg in the treatment of macular edema secondary to retinal vein occlusion. METHODS Relevant studies were selected after an extensive search using the PubMed, EMBASE, Web of Science, and Cochrane Library databases. Outcomes of interest included visual outcomes, anatomic variables, and adverse events. RESULTS Four randomized controlled trials (RCTs) met our inclusion criteria. IVR 0.5 mg produced a significantly higher improvement in visual acuity at six months, with pooled weighted mean differences (WMDs) of 12.30 early treatment diabetic retinopathy study (ETDRS) letters (95% CI:10.03, 14.58) (P < 0.001),and led to a higher proportion of patients gaining ≥ 15 letters (RR, 2.36; 95%CI: 1.86, 2.99; P < 0.001) at the follow-up endpoint, compared with non-anti-VEGF. A more obvious reduction in central foveal thickness (CFT) was observed in the IVR 0.5 mg group than the non-anti-VEGF group, and the mean difference in CFT was statistically significant (WMD, -216.86 μm; 95%CI: -279.01, -154.71; P < 0.001). A similar efficacy was found between the IVR 0.3 mg group and the non-anti-VEGF group. No significant differences were found between IVR 0.5 mg and 0.3 mg. The incidence of iris neovascularization in the non-anti-VEGF group was significantly higher than that of the IVR group. CONCLUSIONS IVR 0.5 mg or 0.3 mg was more effective than sham injection and laser treatment. IVR 0.3 mg is as effective as IVR 0.5 mg in the treatment of macular edema secondary to retinal vein occlusion.
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New Therapeutic Approaches in Diabetic Retinopathy.
Vaziri, K, Schwartz, SG, Relhan, N, Kishor, KS, Flynn, HW
The review of diabetic studies : RDS. 2015;(1-2):196-210
Abstract
Diabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in center-involved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikrein-kinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy.