Surgery, Tissue Plasminogen Activator, Antiangiogenic Agents, and Age-Related Macular Degeneration Study: A Randomized Controlled Trial for Submacular Hemorrhage Secondary to Age-Related Macular Degeneration.

PURPOSE: To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm. DESIGN: Randomized, open-label, multicenter superiority study. PARTICIPANTS: Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium. METHODS: Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 µg], and 20% sulfur hexafluoride [SF6] tamponade) or PD (0.05 ml intravitreal tPA [50 µg] and 0.3 ml intravitreal pure SF6). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up. MAIN OUTCOME MEASURES: The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up. RESULTS: Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference ß, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group. CONCLUSIONS: Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

EFFICACY AND SAFETY OF AFLIBERCEPT FOR THE TREATMENT OF IDIOPATHIC CHOROIDAL NEOVASCULARIZATION IN YOUNG PATIENTS: The INTUITION Study.

PURPOSE: To evaluate the mean change in visual acuity at 52 weeks in patients with idiopathic choroidal neovascularization treated with aflibercept. METHODS: We conducted a prospective noncomparative open-label Phase-II trial. The dosage regimen evaluated in this study was structured into two periods: (1) from inclusion to 20 weeks: a treat-and-extend period composed of three mandatory intravitreal injections, and complementary intravitreal injections performed if needed; (2) from 21 weeks to 52 weeks: a pro re nata period composed of intravitreal injections performed only if needed. RESULTS: A total of 19 patients were included, and 16 completed the 52-week study. At baseline, the mean best corrected visual acuity was 66.56 (±20.72) letters (≈20/50 Snellen equivalent), and the mean central retinal thickness was 376.74 µm (±93.77). At 52 weeks, the mean change in the best-corrected visual acuity was +19.50 (±19.36) letters [95% confidence interval = +9.18 to +29.82]. None of the patients included lost ≥15 letters at 24 weeks or 52 weeks. The mean change in central retinal thickness was -96.78 µm (±104.29) at 24 weeks and -86.22 µm (±112.27) at 52 weeks. The mean number of intravitreal injections was 5.4 (±3.0) at 52-weeks. No ocular serious adverse events related to the treatment were reported. CONCLUSION: The present analysis shows clinically significant functional and anatomical treatment effect of aflibercept in case of idiopathic choroidal neovascularization. The treat-and-extend regimen proposed after the first injection seems adequate to treat most neovessels.

Undetectable Macular Neovascularization on OCT Angiography in Age Related Macular Degeneration: Comparison between Different Devices.

Background and Objectives: The aim of this study was to report the characteristics of macular neovascularization (MNV) with undetectable flow on optical coherence tomography angiography (OCTA) in neovascular age related macular degeneration (nAMD), and compare them with the characteristics of detectable MNV. Materials and Methods: Patients with a diagnosis of nAMD who underwent dye imaging and OCTA in the same day were included and divided into two groups: undetectable and detectable flow on OCTA. Three OCTA devices were used, two with spectral-domain technology (AngioVue, RTVue 100xAvanti, Optovue, Freemont, CA, USA and Heidelberg OCT2 Beta Angiography Module, Heidelberg Engineering, Germany) and one swept-source OCTA (PlexElite 9000; Carl Zeiss Meditec, Inc., Dublin, CA, USA). We studied the demographics, neovascularization characteristics, and OCTA device and acquisition characteristics for both groups. Results: A global comparison between Group 1 and Group 2 was made, followed by an analysis of variables associated with (un)detectability for each OCTA device. A total of 108 eyes were included: 90 in the detectable group (Group 1) and 18 in the undetectable group (Group 2), corresponding to a global sensitivity of OCTA for the detection of MNV of 83.49%. There was a statistically significant difference between the two groups regarding MNV type (p = 0.02) and PED height (p = 0.017). For the three devices, detection sensitivity with automatic segmentation was significantly lower than with manual segmentation. For Heidelberg, PED Height and scan quality explained 68.3% of the undetectability. For AngioVue, PED Height and absence of hemorrhage explained 67.9% of undetectability. Conclusions: In this study, we found a global sensitivity of 83.49% for the three OCTA devices combined, with a range from 55.5% to 96.26% depending on the segmentation and OCTA device. This means that undetectable/undetected MNV can represent up to 45% of the examinations, eventually misdiagnosing choroidal neovascularization for 1 out every 2 patients.

AFLIBERCEPT AFTER RANIBIZUMAB INTRAVITREAL INJECTIONS IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION: The ARI2 Study.

PURPOSE: To analyze the efficacy of aflibercept switch treatment for regression of pigment epithelial detachment (PED) in patients previously treated with ranibizumab. METHODS: Multicenter, prospective, nonrandomized clinical trial. One eye of patients presenting neovascular age-related macular degeneration with PED of more than 250 µm in height, with persistent fluid, was included. Patients had to have received at least six ranibizumab intravitreal injections during the 12 months before enrollment. Patients were switched from ranibizumab pro re nata to aflibercept (fixed regimen, 3 monthly intravitreal injections, and then Q6). Main outcome measure was change in PED height from baseline to Week 12 after switch. Secondary outcomes were best-corrected visual acuity and PED volume changes. RESULTS: Eighty four patients were included. Mean delay between last ranibizumab intravitreal injection and switch was 44.7 days. Mean maximal PED height at baseline visit was 347 µm (±109) and reduced to a mean of 266 µm (±114) at Week 12 (P < 0.001) and 288.2 µm at Week 32 (P < 0.001). Mean PED volume was reduced from 1.3 mm to 0.98 mm at Week 12 (P < 0.001). Best-corrected visual acuity improved by 3.3 Early Treatment Diabetic Retinopathy Study letters at Week 32 (P = 0.003). CONCLUSION: Aflibercept switch therapy seems to be effective on large PED in patients previously treated with pro re nata ranibizumab.

Clinical Outcomes and Experiences with Prefilled Syringes Versus Vials for Intravitreal Administration of Anti-VEGF Treatments: A Systematic Review.

INTRODUCTION: Anti-vascular endothelial growth factor (VEGF) agents have been the standard treatment for retinal diseases for almost two decades. These treatments are administered via intravitreal injection using single-use vials or prefilled syringes (PFS). In this systematic review, we evaluate health care resource use and clinical outcomes and experiences with PFS for intravitreal injection of anti-VEGF treatments. METHODS: MEDLINE, EMBASE, and The Cochrane Library were searched from January 1, 2015 to February 8, 2024 to identify literature reporting outcomes regarding procedural efficiency, health care resource use, patient and clinician experiences, and safety for currently approved anti-VEGFs (ranibizumab, aflibercept, brolucizumab) administered using PFS. Comparators were vial-based injections of the same anti-VEGFs. RESULTS: A total of 36 publications met the criteria for inclusion in the systematic literature review; the majority were non-randomized studies, with a small number of reviews, case series, survey studies, and opinion articles. Publications reported that preparation times were significantly shorter for PFS (40.3-57.9 s) versus vials (ranibizumab, 62.8-98.0 s; aflibercept, 71.9-79.5 s), with no differences in product stability between PFS and vials. Clinicians expressed a preference for PFS and thought PFS were faster, easier to use, and had increased safety versus vials. Publications consistently reported significantly lower rates of endophthalmitis per injection with PFS versus vials (ranibizumab PFS, 0-0.02%; aflibercept PFS, 0.01-0.02%; ranibizumab vial, 0.02-0.05%; aflibercept vial, 0.02-0.06%). Four publications reported increased rates of transient vision loss after aflibercept PFS injection versus vial-based injection. No publications reported outcomes regarding health care resource use or patient experiences. CONCLUSION: The available literature supports the increased procedural efficiency of PFS versus vial-based intravitreal injection of anti-VEGFs. PFS are positively perceived by clinicians and have a safety benefit in the form of a decreased risk of endophthalmitis versus vials.

Anti-vascular endothelial growth factor (VEGF) drugs, given by injection into the eye, are commonly used to treat diseases that affect the back of the eye (the retina). Anti-VEGF drugs are provided in small containers (vials) or in syringes that are already filled with the drug (prefilled syringes). When someone is treated with an anti-VEGF drug from a vial, the drug must first be taken from the vial using a needle and syringe, and then injected. When someone is treated with an anti-VEGF drug from a prefilled syringe, the drug is injected directly from the prefilled syringe, i.e., there are fewer steps involved when a prefilled syringe is used. We searched the medical literature to see if there were differences in clinical outcomes and experiences between prefilled syringes and vials when used to inject anti-VEGF drugs. Clinicians spent about 50% less time getting ready for injections when prefilled syringes were used than when vials were used. Clinicians also preferred to use prefilled syringes than vials for injecting anti-VEGF drugs. Clinicians reported that prefilled syringes were easier to use, faster, and safer than vials. Patients who were given injections from prefilled syringes had a lower rate of infection of the inside of the eye (endophthalmitis) than patients who were given injections from vials. These results indicate that using prefilled syringes for injecting drugs into the eye can improve efficiency at ophthalmology clinics and improve safety for patients.

Causes of unsuccessful ranibizumab treatment in exudative age-related macular degeneration in clinical settings.

PURPOSE: To identify the causes of loss of vision after ranibizumab therapy in patients with exudative age-related macular degeneration treated in three clinical settings. METHODS: A retrospective multicentric analysis of 290 consecutive eyes comprising cohorts from 3 clinical settings showed that 21 eyes lost ≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart 1 year after the start of ranibizumab treatment. Fundus images of these eyes were analyzed by two independent readers to investigate the causes of visual loss. The three cohorts were compared. A search was made for factors predisposing to visual loss. A second analysis was performed to compare the baseline characteristics of patients who gained (visual acuity gainers) or lost (visual acuity losers) ≥ 15 letters. RESULTS: Among the 290 eyes included, the proportions from each center experiencing visual loss were not significantly different (mean, 7.24%, P = 0.2631). Mean visual loss of affected eyes was 27 letters. There was no significant difference between these eyes and others as regards age and gender of patients, laterality, type of choroidal neovascularization, number of visits, or initial visual acuity. Visual loss was secondary to the progression of atrophy in eight eyes, fibrosis in five eyes, a combination of fibrosis and atrophy in three eyes, severe subretinal hemorrhage in three eyes, and retinal pigment epithelial tear in two eyes. A significant difference between visual acuity gainers and losers was observed for 2 parameters: age of patients, 80.9 ± 5.3 years in visual acuity losers versus 77.5 ± 7.3 years in visual acuity gainers (P = 0.0473) and visual acuity at diagnosis, respectively, 56.2 ± 11.2 versus 49.0 ± 12.0 (P = 0.0288). CONCLUSION: Although uncommon, visual loss may occur during ranibizumab treatment and is because of the natural course of age-related macular degeneration in most cases.

Two-Year Outcome of Aflibercept Intravitreal Injection in Vitrectomized Eyes with Diabetic Macular Edema.

Purpose: To evaluate the efficacy of intravitreal aflibercept injection (IAI) for vitrectomized eyes with diabetic macular edema (DME) at two years. Methods: This is a prospective, non-comparative, multicenter observational study including diabetic patients with visual acuity between 20/400 to 20/40 due to DME, who have undergone vitrectomy at least 3 months before the first aflibercept injection. Treatment protocol included 5 monthly aflibercept injection followed by a ProReNata regimen during the first year. Participants were managed at clinicians' discretion using Treat and Extend or Observe and Plan regimen during the second year. Visual acuity, OCT findings and number of IAI were assessed at two years. Results: Available data for 28 eyes with DME previously vitrectomized treated with aflibercept intravitreal injection during at least 2 years were collected. Visual gain was +5.4 letters (p = 0.01), and central macular thickness decreased significantly -62µm, p < 0.001) at 2 years. Resolution of macular edema allowing discontinuation of aflibercept was observed in 7 eyes (15%). Mean number of injections was 14.6, and mean interval injection was 6.4 weeks for 2 years. Conclusion: These results suggest that IAI is beneficial in vitrectomized eyes leading to improvement of visual and anatomical outcome which was maintained for 2 years.

One-Year Outcome of Aflibercept Intravitreal Injection in Vitrectomized Eyes with Diabetic Macular Edema.

AIM: To evaluate the efficacy of intravitreal Aflibercept injection (IAI) for vitrectomized eyes with diabetic macular edema (DME) at one year. METHODS: This is a prospective, non-comparative, multicenter observational study including diabetic patients whose HbA1c is < 9%, with visual acuity between 20/400 to 20/40 due to DME, who have undergone vitrectomy since at least 3 months before the first aflibercept injection. Treatment protocol included 5 monthly aflibercept injection followed by a ProReNata regimen during the first year. Visual acuity, OCT findings and number of IAI were assessed at 6 months and one year. RESULTS: Forty-six eyes were included. Indications for vitrectomy were epiretinal membrane (58.7%), intravitreal hemorrhage (26.1%), and vitreomacular traction (8.7%), retinal detachment (4.3%), and other cause (4.3%). Median duration of macular edema was 3 years. Median interval between vitrectomy and first visit was 9 months. Thirty eyes were non-naïve and received previously thermal laser (44.3%), intravitreal injection of triamcinolone (26.7%), of ranibizumab (70%), of dexamethasone implant (36.7%), or bevacizumab (6.7%). Data was available for 35 eyes at 1 year. Visual gain was significant, +6 letters (p <0.001) and central subfield thickness (CST) decreased significantly (-108µm, p < 0.001) at 1 year. Mean number of injections was 9.3 and mean interval injection was 5.8 weeks. CONCLUSION: These results suggest that IAI may be beneficial in vitrectomized eyes with refractory DME which require frequent injections to obtain visual and anatomical improvement. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov, registration Number NCT02874859.

Optical Coherence Tomography Angiography in Retinal Vein Occlusion: Evaluation of Superficial and Deep Capillary Plexa.

PURPOSE: To evaluate the optical coherence tomography angiography (OCT angiography) appearance of the superficial and deep capillary plexa in eyes with retinal vein occlusion (RVO) and to compare these findings with those of fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD OCT). DESIGN: Retrospective observational case series. METHODS: Patients presenting with RVO to Creteil University Eye Clinic were retrospectively evaluated. All patients had undergone a comprehensive ophthalmic examination including FA, SD OCT, and OCT angiography. RESULTS: There were 54 (31 male, 57%) RVO patients with a mean age of 70 years. The perifoveal capillary arcade was visible in 52 of 54 eyes (96%) on OCT angiography and in 45 eyes (83%) on FA; this arcade was disrupted in 48 eyes (92%) and 39 eyes (72%) on OCT angiography and FA, respectively (P = .002). Perifoveal capillary arcade disruption was correlated with peripheral retinal ischemia (P = .025). Intraretinal cystoid spaces were observed in 34 eyes (68%) using FA, in 40 eyes (76%) using SD OCT, and in 49 eyes (90%) using OCT angiography (P = .008 for OCT angiography vs SD OCT and P = .001 for OCT angiography vs FA). Retinal capillary network abnormalities were observed in all patients in both superficial capillary plexus and deep capillary plexus on OCT angiography. Nonperfusion grayish areas were more frequent in the deep capillary plexus (43 eyes, 84%) than in the superficial capillary plexus (30 eyes, 59%, P < .001). CONCLUSION: OCT angiography can simultaneously evaluate both macular perfusion and edema. For the first time, an imaging technique enables the evaluation of the deep capillary plexus, which appears to be more severely affected than the superficial capillary plexus in RVO.

Macular burn after transpupillary thermotherapy for occult choroidal neovascularization.

PURPOSE: To report a case of severe macular burn as a complication of transpupillary thermotherapy treatment for occult choroidal neovascularization. DESIGN: Interventional case report. METHODS: A 65-year-old man developed a severe macular burn following transpupillary thermotherapy treatment. RESULTS: Before treatment, fluorescein angiography and indocyanine green angiography showed a progressive, ill-defined leakage corresponding to the presence of occult choroidal neovascularization. One month after treatment, fundus examination disclosed macular atrophy. The early phases of fluorescein angiography and indocyanine green angiography showed that the macular choroidal filling time had worsened dramatically. At the late phase of indocyanine green angiography, the initial hyperfluorescence of choroidal neovascularization was replaced by a persistent, markedly hypofluorescent area. CONCLUSION: Prolonged choroidal filling may be a risk factor for macular burn and choroidal occlusion after transpupillary thermotherapy. In such cases, we suggest that transpupillary thermotherapy should be considered with caution and, when applied, that its intensity should be reduced.

Choroid thickness measurement with RTVue optical coherence tomography in emmetropic eyes, mildly myopic eyes, and highly myopic eyes.

PURPOSE: To evaluate choroid thickness (CT) with RTVue spectral domain optical coherence tomography (SD-OCT) and the effect of age and myopia in eyes without posterior complications.
 METHODS: In this multicenter cross-sectional study, all enrolled patients were over age 18 and divided them in 3 groups based on refraction: emmetropia (+1 D to -1 D), mild myopia (-1 D to -6 D), and high myopia (-6 D to -20 D) groups. Horizontal scans through the fovea were acquired with RTVue OCT (Optovue Inc., Fremont, California, USA). Choroid thickness was measured at 500 µm intervals up to 1,500 µm temporal and nasal to the fovea by 2 graders. Mean CT was calculated based on the average of the 7 locations. Statistical analysis was performed to evaluate CT at each location, the effects of age and myopia, and grader agreement. 
 RESULTS: A total 85 eyes of 85 subjects (30 emmetropic, 24 myopic, and 31 high myopic) were enrolled. Excellent grader agreement was observed with an intraclass correlation coefficient (ICC) >0.97. The mean CT was 248.2±78.5 (µm) for emmetropia (age = 58±18), 247.0±85.4 (µm) for myopia (age = 45±20), and 131.5±70.9 (µm) for high myopia (age = 54±13). The mean CT was not significantly different between emmetropia and myopia groups, which were significantly thicker than high myopia group. The overall slope of age-related change for the mean CT was -1.95 µm/y and the effect of age differed among the groups. CONCLUSIONS: Choroid thickness can be measured from RTVue OCT images with good reproducibility. Age and high myopia appear to negatively affect CT. The age effect may vary with refraction groups.