Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial.

Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden. Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD. Design, Setting, and Participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021. Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 µL) or 2 mg (50 µL) of aflibercept followed by doses at weeks 20 and 32. Main Outcomes and Measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety. Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, -1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, -6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was -159.4 (16.4) vs -137.2 (22.8) µm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, -9.5 [95% CI, -51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, -1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed. Conclusions and Relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema. Trial Registration: ClinicalTrials.gov Identifier: NCT04126317.

Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.

COMBINED PARS PLANA VITRECTOMY AND SCLERAL FIXATION OF AN INTRAOCULAR LENS USING GORE-TEX SUTURE: One-Year Outcomes.

PURPOSE: To report the 1-year clinical outcomes of combined pars plana vitrectomy and ab externo scleral fixation of an intraocular lens using Gore-Tex suture. METHODS: Retrospective, interventional case series. Outcome measures were change in visual acuity and occurrence of intraoperative and postoperative complications with minimum follow-up of 1 year. RESULTS: Eighty-four eyes of 83 patients were identified. The mean best available visual acuity improved from 20/782 preoperatively to 20/65 postoperatively (P < 0.001). The mean follow-up was 598 ± 183 days (median 533 days, range 365-1,323 days). There were no intraoperative complications noted. A Bausch & Lomb Akreos AO60 intraocular lens was implanted in 77 eyes and an Alcon CZ70BD in 7 eyes. Postoperative complications included transient vitreous hemorrhage in six eyes (7.1%), cystoid macular edema in four eyes (4.8%), ocular hypertension in three eyes (3.6%), hyphema in two eyes (2.4%), and transient corneal edema in two eyes (2.4%). There were no cases of postoperative endophthalmitis, suture erosion/breakage, hypotony, retinal detachment, suprachoroidal hemorrhage, choroidal detachment, uveitis-glaucoma-hyphema syndrome, or persistent postoperative inflammation during the follow-up period. CONCLUSION: Combined pars plana vitrectomy and ab externo scleral fixation of an intraocular lens with Gore-Tex suture was well tolerated at a minimum of 1-year follow-up. No suture-related complications were encountered.

Primary bilateral uveal melanoma: a population-based study and systematic review.

IMPORTANCE: Primary bilateral uveal melanoma (UM) is a rare and incompletely described entity. It is not known how these patients compare to those with unilateral UM. BACKGROUND: We sought to comprehensively characterize and compare patients with primary bilateral and unilateral UM. DESIGN: Retrospective, population-based and systematic review. PARTICIPANTS: Patients with bilateral (n = 52) and unilateral UM (n = 8915). METHODS: We analysed cases of primary bilateral UM from three data sources: (i) the University Hospitals Cleveland Medical Center pathology database from 1996 to 2016 (n = 1); (ii) the Surveillance, Epidemiology and End-Results (SEER)-18 database from 1973 to 2013 (n = 5) and (iii) a systematic review of the English language literature (n = 46). Cases of unilateral UM were obtained from the SEER-18 database from 1973 to 2013 for comparison (n = 8915). MAIN OUTCOME MEASURES: Demographics, clinicopathological characteristics, treatments and survival. RESULTS: There were no differences in sex, race, mean age at diagnosis, site of uveal involvement, metastases at diagnosis, or treatment among patients with bilateral as compared to unilateral UM. Additionally, there were no clinicopathological differences between the two UMs in each patient with bilateral disease. Overall survival did not differ between unilateral and bilateral UM patients, or between bilateral UM patients who presented with, or subsequently developed, bilateral disease. CONCLUSIONS AND RELEVANCE: Bilateral and unilateral UM patients share similar demographics, clinicopathological characteristics, treatments and prognoses. Moreover, the development of bilateral disease does not portend a poorer prognosis and patients should be treated similarly to those with unilateral disease.

Effect of topical aqueous suppression on intraocular gas duration after pure perfluoropropane injection in nonvitrectomized eyes with retinal detachment.

PURPOSE: To determine whether topical aqueous suppressants affect the duration of pure expansile intraocular gas in nonvitrectomized eyes. METHODS: A prospective randomized controlled trial was performed on nonvitrectomized patients undergoing retinal detachment repair with scleral buckle or pneumatic retinopexy using 0.3 mL of 100% perfluoropropane (C3F8) gas tamponade. Eyes were randomly assigned to receive topical dorzolamide 2% and timolol 0.5% twice daily postoperatively until gas dissolution or to observation. RESULTS: Twenty-one patients met all inclusion and exclusion criteria. Twelve were randomized to the control group and nine to the dorzolamide-timolol group. In the dorzolamide-timolol group, mean intraocular pressure was 17.4 on postoperative Day 1 and 12.5 on postoperative Week 1 (P = 0.03). In the control group, mean intraocular pressure was 14.5 on postoperative Day 1 and 15.1 on postoperative Week 1 (P = 0.73). The mean duration of C3F8 was 37.8 days in the dorzolamide-timolol group and 40.4 days in the control group (P = 0.70). CONCLUSION: Topical aqueous suppression does not seem to have a significant effect on the duration of pure expansile intraocular C3F8 in nonvitrectomized eyes after pneumatic retinopexy or scleral buckling.

Conjunctival flora antibiotic resistance patterns after serial intravitreal injections without postinjection topical antibiotics.

PURPOSE: To report conjunctival bacterial flora antibiotic resistance patterns after serial intravitreal injections performed using a povidone-iodine preparation without the use of preinjection or postinjection topical antibiotics. DESIGN: Prospective, interventional case series. SETTING: Single-center clinical practice in Pennsylvania. STUDY POPULATION: Thirteen eyes of 13 treatment-naïve patients undergoing serial intravitreal anti-vascular endothelial growth factor (VEGF) injections for exudative age-related macular degeneration or macular edema attributable to retinal vein occlusion. INTERVENTION: Conjunctival cultures from the treatment eye were performed prior to each injection preparation. A minimum of 3 monthly conjunctival cultures were obtained per eye over the course of the study. Ocular surface preparation consisted of topical anesthetic and povidone-iodine 5% without the use of preinjection or postinjection topical antibiotics. MAIN OUTCOME MEASURES: Conjunctival flora growth patterns and antibiotic resistance patterns to several common antibiotics tested over the course of the study. RESULTS: A total of 48 cultures were performed with a 77% culture positivity rate. Over the course of the serial conjunctival cultures in each patient, there was no evidence for emergence of resistant bacteria to any of the tested antibiotics (including fluoroquinolones and azithromycin) or significant alteration from baseline conjunctival flora. Of the 47 bacterial isolates, the most commonly isolated organism was coagulase-negative Staphylococcus both at baseline (73%) and following serial intravitreal injections (78%, P = .73). CONCLUSIONS: Ocular surface preparation for intravitreal injection using povidone-iodine 5% alone in the absence of postinjection topical antibiotics does not appear to promote bacterial resistance or a discernible change in conjunctival flora.

Electroretinographic effects of omega-3 Fatty Acid supplementation on dry age-related macular degeneration.

OBJECTIVES: To evaluate the effects of high-dose oral omega-3 fatty acid supplementation on electroretinography and omega-3 index in patients with dry age-related macular degeneration. DESIGN: Single institution, prospective, nonrandomized, noncomparative interventional case series comprising 34 eyes of 17 patients older than 50 years of age with early to intermediate age-related macular degeneration. Patients received oral supplementation with 4 g of omega-3 fatty acids daily (840 mg eicosapentaenoic acid/2520 mg docosahexaenoic acid) for 6 months. The main outcome measures included Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, change in N1 and P1 peak amplitudes on multifocal electroretinographic testing, and change in serum omega-3 index. RESULTS: Mean baseline Early Treatment Diabetic Retinopathy Study best-corrected visual acuity letter score was 77 letters (Snellen equivalent of 20/32). There were no statistically significant changes in visual acuity (P = .12) or retinal function by multifocal electroretinographic testing. Serum omega-3 index increased by an average of 7.6% during the course of the study (P < .001). Study limitations included the relatively short duration of the study and small number of participants. CONCLUSIONS: Short-term supplementation with high doses of omega-3 fatty acids does not result in any measurable changes in visual acuity or retinal function by multifocal electroretinographic testing. Dietary supplementation with 4 g of omega-3 fatty acids results in a significant increase in serum omega-3 index in patients with dry age-related macular degeneration and may provide a useful clinical measure for future studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01258335.

Preferred therapies for neovascular age-related macular degeneration.

PURPOSE OF REVIEW: This report reviews the current treatment strategies and the most recent clinical trials in the treatment of neovascular age-related macular degeneration. RECENT FINDINGS: The functional and anatomic outcomes achieved in the pivotal ranibizumab trials with monthly injections set the standard for comparison. Since then, various modified dosing regimens with the aim of lessening the treatment burden associated with monthly injections have been investigated. Additionally, level I evidence now exists for the noninferiority of bevacizumab, as compared to ranibizumab, in the treatment of neovascular age-related macular degeneration (AMD) through 1 year of follow-up. Aflibercept has emerged as a new anti- vascular endothelial growth factor (VEGF) therapy showing encouraging treatment results at 1 year. Novel treatments combined with anti-VEGF agents such as localized radiation are currently being investigated. SUMMARY: Anti-VEGF monotherapy remains the preferred therapy for the management of neovascular AMD at the present time. Aflibercept is a new, FDA-approved, effective, anti-VEGF agent available for clinical use. Ongoing clinical trials will help determine the optimal dosing regimens for all of these agents, as well as the long-term efficacy and safety of combination therapy modalities.

Unilateral keratitis following death of a twin as the presenting sign of herpetic infection in a neonate.

Neonatal herpes simplex virus (HSV) manifests as a disease limited to skin, eyes, and/or mucous membranes, central nervous system disease with/without skin involvement, or disseminated infection. Given the high morbidity and mortality of untreated neonatal HSV, early recognition and prompt treatment are important. We report two cases of unilateral HSV keratitis, after Cesarean section, in neonates whose twin had died. Both mothers denied history of HSV. Ophthalmic diagnosis led to full systemic workup and appropriate treatment.

Punctate inner choroidopathy: a survey analysis of 77 persons.

PURPOSE: To evaluate the demographic and clinical features of punctate inner choroidopathy (PIC). DESIGN: Noncomparative survey. PARTICIPANTS: Persons with PIC who were in contact with the PIC Society. METHODS: A survey was designed and posted on the Web site of the PIC Society, and persons diagnosed with PIC were invited to participate. Seventy-seven persons with PIC completed the survey. MAIN OUTCOME MEASURES: Demographics, presenting symptoms, disease manifestations, treatment regimens, and ocular complications. RESULTS: Of the 77 participants who completed the survey, 90% were women, 97% Caucasian, and 85% myopic. The median age of participants was 30 years (range, 15-55). The median duration of disease at the time of survey completion was 3 years (range, <1-14). Reported presenting symptoms of PIC included scotomata (91%), blurred vision (86%), photopsias (73%), floaters (69%), photophobia (69%), metamorphopsia (65%), and loss of peripheral vision (26%). Eighty-five percent reported unilateral scotomata initially. Thirty-two percent of participants reported waxing and waning symptoms before treatment. The majority of participants (86%) had received treatment, most commonly with systemic (60%) and/or intraocular corticosteroids (22%). Fourteen percent of participants reported treatment with at least one immunosuppressive agent at some time during their disease. Sixty-nine percent had been diagnosed with choroidal neovascularization and 56% with subretinal fibrosis in at least one eye. In 75% of respondents, the onset of choroidal neovascularization occurred less than 1 year after the presenting symptoms of PIC, and in 79%, the onset of subretinal fibrosis occurred less than 1 year after the presenting symptoms. CONCLUSIONS: In this survey of 77 persons with PIC, the majority of respondents were young, myopic, Caucasian women, who experienced unilateral scotoma and blurred vision as initial symptoms. The ocular complications choroidal neovascularization and subretinal fibrosis were present in the majority of participants in at least one eye and typically occurred within the first year of initial symptoms.