Maximal Extension Interval and Visual Outcomes in a Treat-and-Extend Protocol: A Post Hoc Analysis of the CANTREAT Randomized Trial.

INTRODUCTION: The Canadian Treat-and-Extend Analysis Trial with Ranibizumab (CANTREAT) was a 2-year, multicentred, randomized clinical trial to evaluate treat-and-extend (T&E) relative to monthly administration of ranibizumab in neovascular age-related macular degeneration (nAMD). This post hoc analysis of the CANTREAT trial explores the relationship between the maximal extension interval tolerated by patients receiving T&E ranibizumab and visual acuity outcomes. METHODS: Treatment-naïve patients with nAMD were randomized to receive either a once-monthly dosing or T&E regimen of ranibizumab across 27 treatment centres in Canada and were followed for 24 months. For this post hoc analysis, patients in the T&E cohort were subdivided into the following groups based on maximum extension interval: 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks. The primary outcome was the change in ETDRS best-corrected visual acuity (BCVA) from baseline to month 24 while secondary outcomes included change in central retinal thickness (CRT). All results were reported using descriptive statistics. RESULTS: A total of 285 participants undergoing T&E were enrolled in this post hoc analysis. At month 24, the change in BCVA from baseline was +8.5 ± 9.3, +7.7 ± 13.8, +4.4 ± 9.6, +4.4 ± 18.5, and +7.8 ± 14.8 letters in the 4-, 6-, 8-, 10-, and 12-week cohorts, respectively. The change in CRT at month 24 was -79.2 ± 95.0, -143.9 ± 128.9, -97.7 ± 101.1, -120.9 ± 105.3, and -133.2 ± 108.8 µm in the 4-, 6-, 8-, 10-, and 12-week cohorts, respectively. CONCLUSION: The capacity to extend does not necessarily associate with improved visual acuity outcomes, with the poorest change in BCVA seen in those extended 8-10 weeks. The highest change in BCVA and lowest decrease in CRT was in the group maximally extended for 4 weeks. There was a correlation between change in BCVA and change in CRT for other extension groups. Future studies should establish the predictive factors for successful extension in patients undergoing T&E in nAMD.

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.

Long-Term Efficacy of a Treat-and-Extend Regimen with Ranibizumab in Patients with Neovascular Age-Related Macular Disease: An Open-Label 12-Month Extension to the CANTREAT Study.

INTRODUCTION: The objective of this study is to assess the long-term effectiveness of a treat-and-extend (T&E) anti-vascular endothelial growth factor regimen in patients with neovascular age-related macular degeneration who remain on T&E and those switched from once-monthly (OM) dosing to T&E (OM-T&E). METHODS: In this 12-month extension of the 2-year CANTREAT study, patients received intravitreal ranibizumab 0.5 mg in a T&E regimen. Main outcome measures included mean change in best-corrected visual acuity (BCVA) from baseline and from month 24 to month 36; percentages of patients who gained ≥5, ≥10, or ≥15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters or lost ≥5, ≥10, or ≥15 letters from baseline and from month 24 to month 36; and number of injections administered from baseline and from month 24 to month 36 for both groups. RESULTS: Of the 139 patients (73 T&E, 66 OM-T&E) in the extension, 121 (68 T&E, 53 OM-T&E) completed 36 months. Mean (standard deviation [SD]) BCVA changes from baseline to the extension last visit (month 33-36) were +6.6 (11.4) letters in the T&E group and +4.8 (14.3) letters in the OM-T&E group, representing maintenance of 24-month gains. The mean (SD) numbers of injections during the extension were 7.3 (2.7) for T&E and 7.1 (2.8) for OM-T&E. DISCUSSION/CONCLUSION: These findings suggest that after 36 months of treatment, the mean BCVA improvement achieved at 24 months is maintained for both the patients exclusively treated with the T&E regimen and those that switched to T&E after 24 months in the OM regimen.

Canadian Treat-and-Extend Analysis Trial with Ranibizumab in Patients with Neovascular Age-Related Macular Disease: One-Year Results of the Randomized Canadian Treat-and-Extend Analysis Trial with Ranibizumab Study.

PURPOSE: To compare the efficacy of ranibizumab using a treat-and-extend (T&E) regimen with monthly dosing in treatment-naive patients with neovascular age-related macular degeneration (nAMD). DESIGN: Prospective, randomized, open-label, multicenter, noninferiority, postauthorization study. PARTICIPANTS: Treatment-naive patients with choroidal neovascularization secondary to AMD. METHODS: Patients with nAMD were randomized 1:1 to receive intravitreal ranibizumab at a dose of 0.5 mg in either a T&E or monthly dosing regimen. The noninferiority of T&E compared with the monthly dosing regimen was to be shown using a margin of 5 letters in best-corrected visual acuity (BCVA) improvement. MAIN OUTCOME MEASURES: Mean change in BCVA in Early Treatment Diabetic Retinopathy Study letters from baseline to month 12. RESULTS: Baseline and 12-month visual acuity data are available for 526 patients (T&E, n = 268; monthly, n = 258). At baseline, mean age was 78.8 years (standard deviation [SD], 7.8 years), 60.3% were women, and 94.3% were white. No significant between-group baseline differences were observed. The primary outcome of noninferiority regarding visual acuity was met with mean BCVA improvement of 8.4 letters (SD, 11.9 letters) and 6.0 letters (SD, 11.9 letters; P = 0.017) in the T&E and monthly regimens, respectively, with a between-group mean difference of 2.38 letters (95% confidence interval, 0.32-4.45 letters). Per protocol, a secondary analysis was performed to test for superiority of number of injections received up to month 12. This analysis demonstrated significantly fewer injections with T&E versus monthly dosing (9.4 and 11.8 injections, respectively), with a mean difference of -2.46 injections (95% confidence interval, -2.68 to -2.23 injections). CONCLUSIONS: The 12-month results of this 2-year study demonstrated that regarding visual outcomes, the T&E regimen was noninferior to a monthly dosing regimen. Similar visual outcomes in the T&E group as in the monthly dosing group were achieved with significantly fewer injections.

RETROSPECTIVE REVIEW OF LUCENTIS "TREAT AND EXTEND" PATTERNS AND OUTCOMES IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess patterns and outcomes of a "Treat and Extend" dosing regimen of ranibizumab in patients with age-related macular degeneration. METHODS: Three hundred and thirty two treatment-naive age-related macular degeneration patients starting therapy with ranibizumab between January 1, 2011, and June 30, 2012, at the Ivey Eye Institute were reviewed, and 79 met inclusion criteria. Patients on Treat and Extend dosing regimen underwent an induction phase with monthly injections and then moved onto an extension phase. Change in visual acuity and central retinal thickness during the induction and extension phases were recorded. RESULTS: During the induction phase, patients had a significant gain in vision and decrease in central retinal thickness (+8.4 letters, P < 0.001 and -81.3 µm, P < 0.001). During the extension phase, patients did not have significant change in vision (-0.5 letters, P = 0.81) and did not have significant change in central retinal thickness (-11.5 µm, P = 0.17). The average extension interval between treatments was 47.7 days, with patients receiving an average of 8.6 injections per year. Cost analysis showed it cost US $16,659 to treat 1 patient in the first year on Treat and Extend dosing regimen compared with US $20,614 on monthly dosing. CONCLUSION: Treat and Extend dosing regimen allows similar visual outcomes to monthly dosing, while reducing the total number of injections, visits, and overall cost.

LONG-TERM OUTCOMES FOR OPTIC DISK PIT MACULOPATHY AFTER VITRECTOMY.

PURPOSE: To evaluate the efficacy of pars plana vitrectomy for congenital optic disk pit maculopathy with various adjuvant techniques, including gas tamponade, internal limiting membrane peel, and temporal optic disk endolaser in a multicenter study with long-term follow-up. METHODS: A retrospective chart review was performed to identify eyes that underwent surgical repair for congenital optic disk pits and serous macular detachment with or without macular retinoschisis from four retinal centers across Canada from 2003 to 2013. Data collected included surgeries performed, preoperative and postoperative vision, central retinal thickness, and presence or absence of subretinal fluid. Optical coherence tomography was used to define anatomical success (i.e., foveal reattachment). RESULTS: Thirty-two eyes of 32 patients with optic disk pits and serous macular detachments were identified that had undergone surgical repair. All eyes underwent pars plana vitrectomy and induction of posterior vitreous detachment if one was not present. Additional procedures performed on occasion included internal limiting membrane peel (n = 8), temporal optic disk pits endolaser (n = 7), and gas tamponade (air, C3F8 or SF6; n = 31). After vitrectomy surgery, foveal attachment was achieved in 26 of 32 eyes (81.3%). The average number of surgeries required was 1.4 ± 0.6, with a maximum of 3 vitrectomies (n = 2). Mean change in best-corrected visual acuity was -0.47 ± 0.54 logMAR units, which corresponds to approximately 5 lines of visual improvement (P < 0.001). Median time to reattachment was 416 days. Preoperative vision, preoperative symptom days, and age were not associated with postoperative reattachment. Similarly, internal limiting membrane peel and temporal endolaser were not associated with postoperative reattachment, nor was there a difference between air and SF6 and C3F8 gas tamponade. Elevated preoperative central retinal thickness was associated with a lower chance of postoperative reattachment (P = 0.007) and was also the best prognostic indicator of success (P = 0.039). CONCLUSION: Vitrectomy for macular detachment due to optic disk pit has good long-term success and results in an improvement in visual acuity. However, adjuvant techniques such as internal limiting membrane peel and temporal endolaser may not improve outcomes, nor does there seem to be a difference between short- and long-acting gases. Patients should be made aware that it can take more than a year and multiple surgeries to achieve foveal reattachment and that increased baseline central retinal thickness is a poor prognostic sign.

Quality of Life after Pars Plana Vitrectomy, Scleral Buckle, or Pneumatic Retinopexy for Rhegmatogenous Retinal Detachment: A Meta-Analysis.

PURPOSE: Comparisons of the surgical and anatomic results of rhegmatogenous retinal detachment surgery have been investigated previously. A systematic evaluation of the available evidence comparing quality of life outcomes of either pars plana vitrectomy, scleral buckling, or pneumatic retinopexy has not been evaluated to date. This article analyzes whether pars plana vitrectomy, scleral buckling, or pneumatic retinopexy for the treatment of rhegmatogenous retinal detachment results in differing quality of life outcomes. METHODS: In February of 2022, a comprehensive search of MEDLINE, EMBASE, CINHAL, and Cochrane Library was conducted for studies on patients treated surgically for rhegmatogenous retinal detachment and included follow-up measurements of quality of life outcomes. Meta-analysis was completed using STATA v. 14.0. The main outcomes of interest were the mean vision-related quality of life score (VRQOL) and SD of VRQOL of each type of surgical procedure. RESULTS: In this systematic review of 13 distinct trials including follow-up of patient quality of life after rhegmatogenous retinal detachment surgery (n = 1063), a better correlation was found between higher quality of life outcomes with scleral buckling than with pars plana vitrectomy (SMD = 0.62, CI: [0.31, 0.93]). There was also no signficant difference in quality of life outcomes between pneumatic retinopexy and pars plana vitrectomy (SMD = 0.08, CI: [-0.07, 0.22]). CONCLUSIONS: Scleral buckling results in better quality of life outcomes for patients when compared to pars plana vitrectomy. Pneumatic retinopexy did not show a difference in quality of life outcomes compared to pars plana vitrectomy.

Patterns of anti-vascular endothelial growth factor discontinuation in neovascular age-related macular degeneration.

OBJECTIVE: To report on anti-vascular endothelial growth factor (anti-VEGF) discontinuation in neovascular age-related macular degeneration (nAMD). DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naive nAMD patients initiating anti-VEGF injections between 2015 and 2021. METHODS: Demographics, treatment start and end dates, number of injections, treatment length, reason for discontinuation, and baseline and final data (i.e., age, best-corrected visual acuity, and central subfield thickness) were recorded. Statistical analyses using STATA 17.0 assessed differences between baseline and final values and between treatment-discontinuation subgroups. RESULTS: A total of 619 eyes of 502 treatment-naive patients (9015 injections) were included (age, 81.6 ± 8.4 years; 64.0% female). Discontinuation rate was 58.3% (361 of 619), with 310 patients discontinuing because of the lack of visual benefit (n = 152), severe comorbidity or death (n = 82), transferred (n = 33), stable off active treatment (n = 19), lack of benefit plus stable off treatment (n = 14), patient decision (n = 6), and ocular comorbidity (n = 4). Among the 309 remaining patients, 51 (16.5%) were lost to follow-up. Discontinuation occurred within the first year in 49.3% (n = 178). Visual acuity was at least maintained in all groups and improved in the following groups: severe comorbidity or death (p < 0.0001), lost to follow-up (p = 0.0003), transferred (p = 0.0004), and stable off treatment (p = 0.0053). The lack of visual benefit group had no improvement in vision regardless of treatment length. Compared with other subgroups, those stable off treatment group was younger (p = 0.0055), had better baseline vision (p = 0.0018), received more injections (p = 0.0437) over a longer time (p = 0.0034), and achieved better final vision (p < 0.0001). CONCLUSION: While there was a high discontinuation rate over 7.5 years, most were attributable to disease or treatment factors and nonmodifiable patient factors. Discontinuation frequently occurred within the first year.

WAS IT LEUCONOSTOC SPECIES? A CASE OF DELAYED-ONSET ENDOPHTHALMITIS PRESENTING 14 YEARS AFTER CATARACT SURGERY.

PURPOSE: To report a case of delayed-onset endophthalmitis presenting 14 years after an uncomplicated cataract surgery. METHODS: Case report. RESULTS: An 89-year-old pseudophakic man complained of redness and reduced visual acuity in his right eye. He had no history of trauma or systemic infection, and his only surgery on the right eye was an uncomplicated cataract surgery 14 years before. On physical examination, he was found to have keratic precipitates and a white posterior capsular plaque in the right eye. He was treated with a right pars plana vitrectomy and intraocular lens removal. Microbiological classification of the samples revealed the presence of a Leuconostoc species within the vitreous humor and coagulase-negative staphylococci on the lens. Two months after placement of the intraocular lens, he achieved a best-corrected visual acuity of 20/200 in his right eye. CONCLUSION: To the best of our knowledge, this is the first reported case of delayed-onset endophthalmitis occurring more than 10 years after an uncomplicated cataract surgery. This case highlights a highly unusual presentation of delayed-onset endophthalmitis and reports a potential novel microbiological cause of plaque formation.

Treatment discontinuation patterns of anti VEGF in retinal vein occlusion.

OBJECTIVE: The purpose of this research is to report on real-world anti-vascular endothelial growth factor (anti-VEGF) treatment patterns in retinal vein occlusions (RVO). DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naive RVO patients initiating anti-VEGF injections between 2015 and 2021. METHODS: Medical records available until June 2022 were reviewed. Demographics, diagnosis, number of injections, treatment length, reason for discontinuation, and baseline and final data (e.g., date, age, best-corrected visual acuity [BCVA], and central subfield thickness) were recorded. Statistical analyses performed with STATA 17.0 assessed differences between baseline and final values, branch (BRVO) and central retinal vein occlusion (CRVO), and treatment-discontinuation subgroups. RESULTS: A total of 219 treatment-naive eyes were included (70.3 ± 13.2 years of age, 52.5% female), with 99 BRVOs and 120 CRVOs (2482 injections). The discontinuation rate was 76.7% (168 of 219), with 72.7% of patients (77 of 99) with BRVOs and 75.8% of patients (91 of 120) with CRVOs discontinuing injections. Reasons for discontinuation included stable off active therapy (98 eyes), severe comorbidity or death (17 eyes), switched to intraocular steroid (implant or injection) (12 eyes), lack of visual benefit (10 eyes), ocular comorbidity (5 eyes), patient decision (5 eyes), and patient transfer (5 eyes). Among the remaining 67 eyes, 16 (24%) were lost to follow-up. Reasons for discontinuation differed between BRVO and CRVO patients (p = 0.002). Eyes with CRVO presented with worse BCVA (p < 0.0001) and achieved worse final BCVA (p < 0.0001), but both groups experienced improvements (p < 0.0001). Younger age, better baseline BCVA, and a diagnosis of BRVO were independent predictors of better final visual acuity. CONCLUSION: Over 7.5 years, treatment was discontinued for three-quarters of RVOs. Stable disease was the most common reason for discontinuation, with nearly half (45%) of all RVOs in the cohort stable off active therapy. Better visual outcomes were achieved in BRVO than in CRVO, although both groups benefited from treatment.

Diagnostic accuracy of current machine learning classifiers for age-related macular degeneration: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The objective of this study was to systematically review and meta-analyze the diagnostic accuracy of current machine learning classifiers for age-related macular degeneration (AMD). Artificial intelligence diagnostic algorithms can automatically detect and diagnose AMD through training data from large sets of fundus or OCT images. The use of AI algorithms is a powerful tool, and it is a method of obtaining a cost-effective, simple, and fast diagnosis of AMD. METHODS: MEDLINE, EMBASE, CINAHL, and ProQuest Dissertations and Theses were searched systematically and thoroughly. Conferences held through Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, and Canadian Society of Ophthalmology were searched. Studies were screened using Covidence software and data on sensitivity, specificity and area under curve were extracted from the included studies. STATA 15.0 was used to conduct the meta-analysis. RESULTS: Our search strategy identified 307 records from online databases and 174 records from gray literature. Total of 13 records, 64,798 subjects (and 612,429 images), were used for the quantitative analysis. The pooled estimate for sensitivity was 0.918 [95% CI: 0.678, 0.98] and specificity was 0.888 [95% CI: 0.578, 0.98] for AMD screening using machine learning classifiers. The relative odds of a positive screen test in AMD cases were 89.74 [95% CI: 3.05-2641.59] times more likely than a negative screen test in non-AMD cases. The positive likelihood ratio was 8.22 [95% CI: 1.52-44.48] and the negative likelihood ratio was 0.09 [95% CI: 0.02-0.52]. CONCLUSION: The included studies show promising results for the diagnostic accuracy of the machine learning classifiers for AMD and its implementation in clinical settings.

The effectiveness of ocriplasmin versus surgery for the treatment of macular holes: A systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review looking at the effects of ocriplasmin compared to pars plana vitrectomy on macular holes to assess the effectiveness of the treatment options. METHODS: Literature was searched through MEDLINE, EMBASE, CINAHL, Clinical Trials.gov, and ProQuest Dissertations and Theses until June 12, 2018. Conferences held through Association for Research in Vision and Ophthalmology, Canadian Society of Ophthalmology, and American Academy of Ophthalmology were searched until June 18, 2018. A total of 208 records were screened leaving 26. One author independently reviewed them for quality and extracted data. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. The adverse events, MH closure rate, change in MH size, and the extent to which the patients' visual acuity is restored by each treatment option; ocriplasmin and vitrectomy. RESULTS: Twenty-six articles were included for qualitative and quantitative analysis. Meta-analysis results showed a 34% closure of macular holes after ocriplasmin treatment compared to 92% after vitrectomy. A significant improvement in visual acuity was seen after vitrectomy (SMD = -1.42; CI: [-1.98, -0.86]) as well as the ocriplasmin treatment (SMD = -0.73; CI: [-0.98, -0.48]). CONCLUSIONS: Results suggested 92% macular hole closure after vitrectomy compared to 34% after ocriplasmin. A significant improvement in visual acuity of patients was seen after both treatments. More good quality randomized controlled trials are required to make strong conclusions.

Identifying gaps in patient access to diabetic screening eye examinations in Ontario: a provincially representative cross-sectional study.

OBJECTIVE: Diabetes is the leading cause of acquired blindness in Canadians under the age of 50 years, and diabetic retinopathy affects an estimated 500 000 Canadians. Early identification of retinopathy with screening eye examinations allows for secondary prevention. To understand the need for resource allotment in diabetic screening, we undertook a cross-sectional study of key demographics and geographics of screened and unscreened patients in Ontario. METHODS: Ontario Health Insurance Plan (OHIP) records were derived from physician and optometry billing, matched with patients aged >19 years with prevalent diabetes between 2011 and 2013. Data were cross-correlated with demographic covariates, including age, sex, income quintile, immigrant status, as well as geographic covariates such as rurality and patient Local Health Integration Network (LHIN). RESULTS: Of almost 1 146 000 patients included in the analysis, approximately 406 000 were unscreened. Of note, this included 234 000 adults aged 40-64 years. Approximately 818 000 patients with diabetes lived in large cities, and 301 000 (37%) were unscreened. When the City of Toronto was analyzed as an urban area with the highest density of unscreened prevalence, autocorrelation between the percentage of eye examinations among patients with diabetes aged >40 years and low-income revealed that large areas of Toronto Central correlated for low examination rates and low income. The majority (13/22) of Community Health Centres are present in these areas. CONCLUSIONS: Large cross-sectional population statistics for diabetes prevalence and ophthalmic examinations provides a geographic and socioeconomic profile for populations of middle-aged adults in large urban areas at risk for developing diabetic retinopathy and who might benefit from interventions to improve the rates of screening eye examinations.

Acupuncture resulting in eye penetration and proliferative vitreoretinopathy - Surgical and medical management with intraocular methotrexate.

PURPOSE: To highlight the surgical and medical management used in an extensive globe penetrating injury caused by an acupuncture needle. OBSERVATIONS: We report on a case of acupuncture treatment error resulting in needle penetration of the eye, retinal detachment, and progressive post-traumatic proliferative vitreoretinopathy (PVR). This patient required aggressive surgical management with multiple vitrectomies along with adjunctive intravitreal methotrexate to control ongoing PVR. At last follow-up, 15 months after presentation, the patient's BCVA was 20/40 and the periphery was flat with fibrosis stable. CONCLUSIONS AND IMPORTANCE: Open globe injuries are a subtype of ocular trauma which can cause irreparable vision loss. This case highlights the extensive potential complications which can occur following traumatic injury to the retina and choroid, as well as the role of both surgical and medical management of retinal detachment and PVR. In addition, this is the first report of the use of off-label adjunctive intravitreal methotrexate to control post-traumatic PVR. Further research into this treatment approach could reveal a role of adjunctive methotrexate in the management of such injuries.

Efficacy of a Treat-and-Extend Regimen With Ranibizumab in Patients With Neovascular Age-Related Macular Disease: A Randomized Clinical Trial.

Importance: Although the Canadian Treat-and-Extend Analysis Trial With Ranibizumab in Patients With Neovascular Age-Related Macular Disease (CANTREAT) reported herein and the Treat and Extend study provided data to show noninferiority of treat-and-extend (T&E) at 12 months, to date there are few data on 24-month T&E trials compared with monthly dosing. Objective: To compare the efficacy of ranibizumab using a T&E regimen to monthly dosing in treatment-naive patients with neovascular age-related macular degeneration (nAMD) after 24 months. Design, Setting, and Participants: A randomized, open-label, multicenter, noninferiority intention-to-treat trial with a margin of -5 letters in best-corrected visual acuity (BCVA) from baseline to 12 months between groups was conducted at 27 treatment centers in Canada. Participants included 580 patients with treatment-naive choroidal neovascularization secondary to AMD. The study was conducted from May 8, 2013, to August 28, 2018, and data analysis was performed between August 29 and September 12, 2018. Interventions: Patients with nAMD were randomized 1:1 to receive intravitreal ranibizumab, 0.5 mg, in either a T&E or monthly dosing regimen. Main Outcomes and Measures: Mean change in BCVA in Early Treatment of Diabetic Retinopathy Study letters from baseline to month 24. Results: Of the 580 randomized patients, 350 were women (60.3%) and 547 were white (94.3%). Mean (SD) age was 78.8 (7.8) years. By the end of month 24, 466 of the 580 randomized patients (80.3%) had completed the study and participants in the T&E arm received a mean of 17.6 injections compared with 23.5 injections for the monthly arm, for a difference of 5.9 injections and visits over 2 years (95% CI, 5.4-6.5; P < .001). The mean (SD) BCVA improvement was not worse with the T&E arm, 6.8 (14.1) letters vs 6.0 (12.6) letters, compared with the monthly arm (difference, 0.9; 95% CI, -1.6 to 3.3; P = .21). There was a gain of 15 or more letters in 25.5% of the T&E group and 23.1% of the monthly treatment group (difference, 2.4%; 95% CI, -6.8% to 11.6%; P = .59) and a loss of 15 or more letters in 6.5% of the T&E group and 5.8% of the monthly treatment group (difference, -0.7%; 95% CI, -9.9% to 8.5%; P = .85). Conclusions and Relevance: These findings suggest that change in vision from baseline is not worse with a T&E compared with a monthly regimen of ranibizumab for nAMD through 24 months, achieving clinically meaningful improvements in BCVA despite fewer injections and visits. Trial Registration: ClinicalTrials.gov identifier: NCT02103738.

Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study.

PURPOSE: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study. PATIENTS AND METHODS: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients. RESULTS: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported. CONCLUSIONS: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice.

Two-year analysis of changes in the optic nerve and retina following anti-VEGF treatments in diabetic macular edema patients.

Purpose: To evaluate long-term structural and functional changes that happen to the optic nerve and retina following ranibizumab (Lucentis) injections in diabetic macular edema (DME) patients. Methods: Patients with clinically significant DME requiring anti-VEGF injections underwent pre-injection baseline, 6, 12, and 24 month follow-up tests. The tests performed were optical coherence tomography (OCT), best-corrected visual acuity (BCVA), and visual field (VF). Wide-field fluorescein angiogram (IVFA) was performed to monitor the progression of diabetic ischemia. Results: A total of 30 patients requiring anti-VEGF injections and 21 control patients not requiring anti-VEGF injections were enrolled in the study. From baseline, the average macular thickness significantly decreased (p<0.0002) over the 24-month time period. Mean perfused ratio significantly increased (p<0.0005) at 6, 12, and 24 months. Cup volume and vertical cup-to-disk ratio significantly increased (p<0.0014) over the study period. This was verified by masked independent grading of patient optic nerve stereo-photographs by glaucoma specialists. BCVA significantly (p<0.0006) improved over the study period. VFs showed a non-significant trend of deteriorating peripheral vision at 12 and 24 months. Conclusion: Clinically, anti-VEGF therapy appears to affect the optic nerve by increasing cup volume and increasing vertical cup/disk ratio over time. The results provide a cautionary note to monitor both the retina and optic nerve status in patients undergoing frequent injections.

Safety of anti-VEGF treatments in a diabetic rat model and retinal cell culture.

PURPOSE: To analyze the safety of different concentrations of anti-VEGF on retinal cells. METHODS: Non-diabetic and streptozotocin (STZ)-induced diabetic rats received intravitreal rat anti-VEGF injections that had final vitreous concentrations of 0, 0.0625, 0.125 (clinical dose), and 0.25 mg/mL. Rats were also injected with the clinical dose of ranibizumab. TUNEL assay was performed on sectioned eyes to evaluate apoptotic cells. In vitro, rat retinal cell cultures were exposed to 0, 0.0625, 0.125 (clinical dose), and 0.25 mg/mL of ranibizumab for 48 and 72 hrs. Cellular metabolic activity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, necrosis by lactate dehydrogenase (LDH), and apoptosis by cell death enzyme-linked immunosorbent assay (ELISA). RESULTS: Diabetic rats had a significant increase (p<0.03) in apoptotic cell death at half the clinical dose, at the clinical dose, and at double the clinical dose. In vitro, MTT showed a significant decrease (p<0.04) in cellular metabolic activity at the clinical dose and double the clinical dose compared to control at 48 and 72 hrs. LDH showed a significant increase (p<0.04) in necrosis at the clinical dose and double the clinical dose compared to control at 48 and 72 hrs. ELISA showed a significant increase (p<0.04) in apoptosis at half the clinical dose, at the clinical dose, and double the clinical dose, compared to control at 48 and 72 hrs. CONCLUSIONS: Anti-VEGF treatment may be potentially detrimental to the retina by decreasing cellular metabolic activity and increasing cytotoxicity of retinal cells. The results provide a cautionary note to monitor both the retina and optic nerve status in patients undergoing frequent injections.

Evaluation of the side effects and image quality during fluorescein angiography comparing 2 mL and 5 mL sodium fluorescein.

BACKGROUND: Although intravenous fluorescein angiography (IVFA) is a relatively safe procedure, side effects have been shown to occur. The designed purpose of this study was to demonstrate a reduction in the frequency and severity of side effects during digital IVFA using 2 mL compared with 5 mL of 10% sodium fluorescein (NaFl). The secondary hypothesis was to show that no loss of image quality occurred with a reduction in the NaFl dose utilizing digital fluorescein angiography. METHODS: A prospective study was initiated in which 1200 patients were randomized to 2 mL or 5 mL of 10% NaFl to allow for the evaluation of adverse events. Standard IVFA technique utilizing modern high-resolution digital photography was employed. Photographers evaluated the difficulty of image capture. A masked observer recorded all adverse events. Masked ophthalmologists evaluated image quality subjectively with a 4-point rating scale. Secondary to concerns regarding image quality, a masked interim analysis was carried out after 140 patients had been randomized. RESULTS: A statistically significant reduction in the quality of angiograms (p = 0.0025) and ease of photography (p = 0.0012) was associated with 2 mL of NaFl, necessitating the termination of the study. Patients randomized to the 5 mL NaFl group experienced all 3 of the minor adverse events in the study. No statistically relevant conclusions could be obtained from this limited group. INTERPRETATION: Two millilitres of NaFl for IVFA produces inferior quality digital images compared with 5 mL of NaFl. The potential reduction in adverse events associated with 2 mL of NaFl becomes unimportant in light of this significant finding regarding image quality.

Triamcinolone acetonide as adjunctive treatment to verteporfin in neovascular age-related macular degeneration: a prospective randomized trial.

PURPOSE: To examine the use of intravitreal triamcinolone acetonide (IVTA) as adjunctive therapy to photodynamic therapy (PDT) in the treatment of occult and minimally classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Single-center prospective randomized pilot clinical trial. PARTICIPANTS: Thirty eyes of 30 patients with occult or minimally classic CNV secondary to AMD. METHODS: Patients were randomized prospectively to receive either PDT alone or combined PDT plus IVTA treatment for CNV secondary to AMD. Standard verteporfin PDT was performed in all patients. In the PDT plus IVTA group, a 12-mg intravitreal injection of triamcinolone acetonide was given 30 minutes after PDT. Active lesions were retreated every 3 months for 1 year. MAIN OUTCOME MEASURES: Change in visual acuity and retreatment rate. RESULTS: Mean visual acuity remained stable in the PDT plus IVTA group (-1.9 Early Treatment Diabetic Retinopathy Study [ETDRS] letters; P = 0.58), but declined significantly in the PDT alone group (-13.3 ETDRS letters; P = 0.02). The treatment rate was 1.13 in the PDT plus IVTA group and 3.6 in the PDT alone group (P<0.0001). Mean contrast sensitivity increased by 3.6 letters (P = 0.09) in the PDT plus IVTA group and decreased by -1.84 letters (P = 0.07) in the PDT alone group. Cataract progression was noted in 4 of 7 phakic eyes in the PDT plus IVTA group. Six patients (40%) in the combined PDT plus IVTA group required topical glaucoma therapy for control of elevated intraocular pressure. CONCLUSIONS: This pilot study demonstrated effective stabilization of visual acuity and reduced treatment frequency at 12 months with combination PDT plus IVTA therapy versus PDT alone. Larger randomized trials are ongoing to determine the efficacy and risks of PDT with IVTA.