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Randomized Safety and Feasibility Trial of Ultra-Rapid Cooling Anesthesia for Intravitreal Injections.
Besirli, CG, Smith, SJ, Zacks, DN, Gardner, TW, Pipe, KP, Musch, DC, Shah, AR
Ophthalmology. Retina. 2020;(10):979-986
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Abstract
PURPOSE To test the safety and preliminary efficacy of rapid, nonpharmacologic anesthesia via cooling for intravitreal injections. DESIGN Single-center, randomized phase 1 dose-ranging safety study (ClinicalTrials.gov identifier, NCT02872012). PARTICIPANTS Adults 18 years of age or older with a diagnosis of exudative macular degeneration or diabetic macular edema requiring bilateral anti-vascular endothelial growth factor therapy were included. METHODS A handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye before intravitreal treatment (IVT). In 22 patients undergoing bilateral IVT, 1 eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at 1 of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS; range, 1-10) at 2 time points: (1) immediately after IVT and (2) 4 hours after IVT. Treated eyes were assessed for ocular safety 24 hours after IVT. MAIN OUTCOME MEASURES We determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately after IVT and 4 hours after IVT in eyes receiving cooling anesthesia were compared with eyes receiving SOC. RESULTS A total of 44 eyes were treated, 22 with cooling anesthesia and 22 with SOC. No dose-related toxicity was found with cooling anesthesia. Mild, transient adverse events were recorded in 32% of patients treated with cooling anesthesia versus 44% of patients receiving SOC. The mean±standard error of the mean (SEM) VAS pain scores immediately after intravitreal injection were 2.3 ± 0.4 for patients receiving SOC and 2.2 ± 0.6 in patients receiving -10° C cooling anesthesia (P = 0.8). Mean±SEM pain scores 4 hours after injection were 1.6 ± 0.4 for SOC and 1.2 ± 0.5 in the combined -10° C arms (P = 0.56). Total mean±SEM procedure time was 124 ± 5 seconds for patients treated with cooling anesthesia versus 395 ± 40 seconds for SOC (P < 0.0001). CONCLUSIONS Ultra-rapid cooling of the eye for anesthesia was well tolerated, with -10° C treatment resulting in comparable levels of anesthesia to SOC with a reduction in procedure time.
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Evaluation of ranibizumab and aflibercept for the treatment of diabetic macular edema in daily clinical practice.
Plaza-Ramos, P, Borque, E, García-Layana, A
PloS one. 2019;(10):e0223793
Abstract
PURPOSE To evaluate the efficacy and safety of ranibizumab and aflibercept in the treatment of diabetic macular edema in a real world study, and to compare the two treatments with each other. METHODS Retrospective observational study of 213 eyes from 141 patients with diabetic macular edema was completed between June 2014 and June 2016. 122 were treated with ranibizumab intravitreal injection and 91 with aflibercept intravitreal injection, with a loading phase of 3 injections and a Pro Re Nata protocol. The drug was selected by the physician and fluorescein angiography was performed by physician`s criteria. Re-treatment was performed when a decline in BCVA, an increase of central macular thickness or an increase or persistence of intraretinal fluid in OCT was observed. The primary outcome was the mean change in best corrected visual acuity at 1 year, while central macular thickness, central macular volume, the number of injections and visits were evaluated as secondary outcomes. The correlation between BCVA at 4th month visit and BCVA at 12th month visit was also evaluated. RESULTS The mean baseline best corrected visual acuity for the eyes treated with ranibizumab was 0.55 (+/- 0.35) logMAR, and with aflibercept it was 0.48 (+/- 0.29) (P = 0.109). Best corrected visual acuity improved in both groups, and at the end of the follow-up was 0.40 (+/- 0.35) in the ranibizumab group and 0.40 (+/- 0.29) in the aflibercept group (P = 0.864). Best corrected visual acuity at 4th month visit is correlated at a high value (R = 0.789) with the one at the end of the study. No differences were found in central macular thickness, central macular volume and glycosylated hemoglobin when adjusting with baseline values. The overall number of injections was 5.77 (+/- 2.01), being 5.56 (+/- 2.0) in the ranibizumab group and 6.07 (+/- 1.99) in the aflibercept group (P = 0.069). The main outcome determining final best corrected visual acuity was the baseline best corrected visual acuity (P<0.001). CONCLUSION There are no differences in efficacy between ranibizumab and aflibercept in diabetic macular edema treatment in this real world study.
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Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial.
Sahni, J, Patel, SS, Dugel, PU, Khanani, AM, Jhaveri, CD, Wykoff, CC, Hershberger, VS, Pauly-Evers, M, Sadikhov, S, Szczesny, P, et al
Ophthalmology. 2019;(8):1155-1170
Abstract
PURPOSE The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). DESIGN The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. PARTICIPANTS The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 μm or more. METHODS Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. MAIN OUTCOME MEASURES The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. RESULTS The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. CONCLUSIONS The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.
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The effects and safety of intravitreal triamcinolone injections in the treatment of diabetic macular edema.
Zając-Pytrus, HM, Kaczmarek, R, Strońska-Lipowicz, D, Pomorska, M, Misiuk-Hojło, M
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2017;(1):45-49
Abstract
BACKGROUND Diabetic macular edema (DME) is responsible for three-quarters of vision-loss cases in diabetic eye disease. In most cases, early treatment by laser photocoagulation can only stabilize vision. Glucocorticoids have been used as a local pharmacological treatment in DME when the inflammation seems to have a pathological background. OBJECTIVES The aim of the study was to establish the effectiveness and safety of intravitreal triamcinolone injections in the treatment of DME. MATERIAL AND METHODS Twenty mg intravitreal injections of triamcinole acetonide (IVTA) were applied to 110 DME patients after ineffective laserphotocoagulation or as an initial treatment. Best corrected visual acuity (BCVA) for distant and near vision, central retinal thickness and intraocular pressure (IOP) were analyzed before and after the treatment at intervals of 1 week, 1 month, 3 months and 6 months. The measurements were continued in cases of repeated IVTA. RESULTS Statistically significant improvements were observed in BCVA in near and distant vision, as well as a decrease in central retinal thickness after all time-intervals following IVTA. BCVA in distant vision was not significantly improved after repeated IVTA. IOP increases were observed 1 week, 1 and 3 months after IVTA, but not at 6 months after IVTA. No sight-threatening side effects of IVTA were observed. CONCLUSIONS IVTA is useful in stabilizing DME progression, although its therapeutic effect may be timelimited.
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Association of Bone Metabolic Markers With Diabetic Retinopathy and Diabetic Macular Edema in Elderly Chinese Individuals With Type 2 Diabetes Mellitus.
Zhang, X, Yang, J, Zhong, Y, Xu, L, Wang, O, Huang, P, Li, C, Qu, B, Wang, J, Zheng, C, et al
The American journal of the medical sciences. 2017;(4):355-361
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BACKGROUND Diabetic retinopathy (DR) is a common and specific microvascular complication of diabetes. The association of bone metabolic markers with the risk of DR and diabetic macular edema (DME) is unclear. MATERIALS AND METHODS We investigated the association between bone turnover markers commonly examined in a clinical setting and DR and DME risk in elderly Chinese patients with type 2 diabetes mellitus (T2DM). A total of 408 patients aged 55-70 years with T2DM were included. We first performed univariable logistic regression followed by multivariable logistic regression that included variables selected using purposeful selection. RESULTS Fasting blood glucose (P = 0.007) and duration of diabetes (P < 0.0001) were significantly associated with DME in multivariable logistic regression; however, the association of beta C-terminal telopeptide of collagen type I (β-CTx) with DME risk was not statistically significant (P = 0.053). Sex-stratified analysis showed that β-CTx was significantly associated with DME only in female subjects (P = 0.011). CONCLUSIONS β-CTx had no significant association with DR. It was significantly associated with DME in female patients with T2DM, but not in male patients with T2DM. More prospective studies with larger sample sizes are warranted to validate our findings.
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Long-term outcomes of phakic patients with diabetic macular oedema treated with intravitreal fluocinolone acetonide (FAc) implants.
Yang, Y, Bailey, C, Holz, FG, Eter, N, Weber, M, Baker, C, Kiss, S, Menchini, U, Ruiz Moreno, JM, Dugel, P, et al
Eye (London, England). 2015;(9):1173-80
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PURPOSE Diabetic macular oedema (DMO) is a leading cause of blindness in working-age adults. Slow-release, nonbioerodible fluocinolone acetonide (FAc) implants have shown efficacy in the treatment of DMO; however, the National Institute for Health and Care Excellence recommends that FAc should be used in patients with chronic DMO considered insufficiently responsive to other available therapies only if the eye to be treated is pseudophakic. The goal of this analysis was to examine treatment outcomes in phakic patients who received 0.2 μg/day FAc implant. METHODS This analysis of the phase 3 FAME (Fluocinolone Acetonide in Diabetic Macular Edema) data examines the safety and efficacy of FAc implants in patients who underwent cataract extraction before (cataract before implant (CBI) group) or after (cataract after implant (CAI) group) receiving the implant. The data were further examined by DMO duration. RESULTS Best corrected visual acuity (BCVA) after 36 months was comparable in the CAI and CBI groups. Both the percentage of patients gaining ≥ 3 lines of vision and mean change in BCVA letter score were numerically greater in the CAI group. In addition, most patients who underwent cataract surgery experienced a net gain in BCVA from presurgery baseline as well as from original study baseline. CONCLUSIONS These data support the use of 0.2 μg/day FAc implants in phakic as well as in pseudophakic patients. These findings will serve as a pilot for design of future studies to evaluate the potential protective effect of FAc implants before cataract surgery in patients with DMO and cataract.
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Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema.
Boyer, DS, Yoon, YH, Belfort, R, Bandello, F, Maturi, RK, Augustin, AJ, Li, XY, Cui, H, Hashad, Y, Whitcup, SM, et al
Ophthalmology. 2014;(10):1904-14
Abstract
PURPOSE To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME). DESIGN Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis. PARTICIPANTS Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography. METHODS Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months. MAIN OUTCOME MEASURES The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP). RESULTS Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (-111.6 μm) and DEX implant 0.35 mg (-107.9 μm) than sham (-41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy. CONCLUSIONS The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.
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Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study.
Massin, P, Bandello, F, Garweg, JG, Hansen, LL, Harding, SP, Larsen, M, Mitchell, P, Sharp, D, Wolf-Schnurrbusch, UE, Gekkieva, M, et al
Diabetes care. 2010;(11):2399-405
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OBJECTIVE The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection). RESULTS At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.
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Diabetic macular oedema and visual loss: relationship to location, severity and duration.
Gardner, TW, Larsen, M, Girach, A, Zhi, X, ,
Acta ophthalmologica. 2009;(7):709-13
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PURPOSE To assess the relationship between visual acuity (VA) and diabetic macular oedema (DMO) in relation to the location of retinal thickening and the severity and duration of central macular thickening. METHODS Data from 584 eyes in 340 placebo-treated patients in the 3-years-long Protein Kinase C Diabetic Retinopathy Study (PKC-DRS2) trial were used to investigate the relationship between VA and DMO. Eligible eyes had moderately severe to very severe non-proliferative diabetic retinopathy and VA of at least 45 letters on Early Treatment Diabetic Retinopathy Study (ETDRS) charts (Snellen equivalent = 20/125). Diabetic retinopathy and DMO status were assessed using stereo photographs. RESULTS Nearly one third of study eyes had foveal centre-involving DMO at the start of the trial. Sustained moderate visual loss was found in 36 eyes, most commonly associated with DMO at the centre of the fovea in 73% of eyes. There was a strong relationship (p < 0.001) between foveal centre involvement with DMO and mean VA. Mean VA decreased with increasing retinal thickness at the centre (p < 0.001) and increasing duration of centre-involving DMO (p < 0.001). CONCLUSION This study documents the relationship between duration of DMO and progressive vision loss, and the key role of central foveal involvement in patients with diabetic retinopathy. These data will help to develop future strategies to prevent vision loss.
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Subthreshold micropulse diode laser treatment in diabetic macular oedema.
Laursen, ML, Moeller, F, Sander, B, Sjoelie, AK
The British journal of ophthalmology. 2004;(9):1173-9
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BACKGROUND/AIM: Enlargement of laser scars after retinal argon laser photocoagulation can give rise to deterioration in visual acuity. Subthreshold micropulse diode laser may decrease this risk. The aim of this study was to compare the effectiveness of subthreshold micropulse diode laser (810 nm) and conventional argon laser (514 nm) photocoagulation for the treatment of clinically significant macular oedema in diabetic patients. METHODS 23 eyes of 16 patients were randomised to either treatment. Follow up was conducted for a minimum of 5 months. Changes in visual acuity and macular oedema measured by optical coherence tomography were examined. RESULTS Visual acuity remained stable in all treatment groups throughout the observation period. Changes in retinal thickness were small both foveally and perifoveally. In patients with focal macular oedema a significant reduction in retinal thickness (9% approximately -26 microm, p = 0.02) was seen foveally 3 months after diode laser photocoagulation. CONCLUSION Subthreshold micropulse diode laser and conventional argon laser treatment showed an equally good effect on visual acuity. Subthreshold micropulse diode laser showed a stabilising or even improving effect on macular oedema. The combination of primary diode laser and supplementary argon laser might be particularly favourable in reducing diabetic macular oedema.