Impact of Cataract Surgery on Low Luminance Visual Acuity Deficit Measurements.

Purpose: The impact of cataract surgery on low luminance visual acuity deficit (LLVAD) measurements was investigated by measuring the LLVAD before and after cataract surgery. Design: Prospective, longitudinal study. Participants: Patients undergoing cataract surgery. Methods: Photopic luminance (PL)-best-corrected visual acuity (BCVA) and low luminance (LL)-BCVA were obtained using the ETDRS chart. Low luminance visual acuity deficit scores were calculated by subtracting the LL-BCVA letter score from the PL-BCVA letter score. To demonstrate the reproducibility of these visual acuity measurements, we used data from drusen-only eyes previously published in the Complement Inhibition with Eculizumab for the Treatment of Nonexudative Age-Related Macular Degeneration (COMPLETE) study. The PL-BCVA, LL-BCVA, and LLVAD measurements obtained at an interval of 3 months in this cohort were used for comparison. In the current study, the impact of cataract surgery on LLVAD measurements was analyzed by comparing the PL-BCVA, LL-BCVA, and LLVAD measurements before and after cataract surgery. Main Outcome Measures: The reproducibility of the visual acuity measurements and the changes in LLVAD measurement after cataract surgery. Results: In the COMPLETE study, no clinically significant differences were found in the PL-BCVA, LL-BCVA, or LLVAD measurements between baseline and the 3-month follow-up visits with a change of -1.1 letters, -1.3 letters, and 0.1 letters, respectively (P = 0.02, P = 0.11, and P = 0.88, respectively). In the current study, significant increases were found in the PL-BCVA and LL-BCVA measurements, with a change of 7.3 letters and 10.2 letters after cataract surgery (P < 0.001 for both), and a statistically significant decrease in LLVAD measurements was found, with a change of -3.0 letters after cataract surgery (P = 0.002). Conclusions: Because of the variable effect of cataracts on LL-BCVA measurements and the significant change in LLVAD measurements after cataract surgery, investigators should be aware that cataract surgery during a trial will have an unpredictable impact on LLVAD measurements, and pseudophakic and phakic patients should be analyzed separately.

Cardiovascular Adverse Events With Intravitreal Anti-Vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

IMPORTANCE: Systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary. OBJECTIVE: To evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments in patients with ocular diseases. DATA SOURCES: Electronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020. STUDY SELECTION: Randomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs. DATA EXTRACTION AND SYNTHESIS: Studies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated. MAIN OUTCOMES AND MEASURES: Main outcomes were major cardiovascular events (MACEs) and total mortality. Secondary outcomes included nonocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious SAEs, and all SAEs. RESULTS: A total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14 190 patients with age-related macular degeneration (AMD), 24 (32%) included 5424 patients with diabetic retinopathy (diabetic macular edema or proliferative diabetic retinopathy), 17 trials (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Anti-VEGF drug administration did not increase MACEs compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). There was an interaction (subgroup difference, P = .04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P = .04) in the risk of death in patients with diabetic retinopathy; however, no increase was observed in patients with AMD or retinal vein occlusion. Administration of anti-VEGF drugs increased the risk of nonocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD. CONCLUSIONS AND RELEVANCE: Intravitreal anti-VEGF was not associated with an increase in MACEs in the trials examined herein. Increased mortality in patients with diabetes and nonocular hemorrhages, especially in those with AMD, could represent a safety signal, but the evidence was not strong. However, continued surveillance of SAEs remains warranted.

Correlations Between Choriocapillaris and Choroidal Measurements and the Growth of Geographic Atrophy Using Swept Source OCT Imaging.

PURPOSE: Correlations among enlargement rates (ERs) of geographic atrophy (GA) and choriocapillaris (CC) flow deficits (FDs), mean choroidal thickness (MCT), and choroidal vascularity index (CVI) were investigated using swept source-optical coherence tomography (SS-OCT) in age-related macular degeneration (AMD). DESIGN: A retrospective review of prospective, observational case series. METHODS: Eyes with GA from AMD were imaged with SS-OCT using 6 × 6-mm scan pattern. GA lesions were identified and measured using customized en face structural images, and annual square root ERs of GA were calculated. At baseline, choriocapillaris FDs from different regions outside the GA were measured, and MCT and CVI from the entire scan area were measured. All measurements were performed using previously published and validated algorithms. RESULTS: A total of 38 eyes from 27 patients were included. The CC FDs within each region around GA lesions were highly correlated with ERs of GA (all P < .005). CVI inside the GA region was correlated with the ERs (P = .03), whereas other choroidal measurements had no significant correlation with the ERs of GA (P > .06). CONCLUSIONS: Statistically significant correlations were found between the ERs of GA and CC percentage of FD (FD%) from the entire scan region outside the GA and not just the region immediately adjacent to the GA. These results suggest that abnormal CC perfusion throughout the macula contributes to disease progression in eyes with GA. CVI inside the GA region could also be a potential indicator for the growth of GA.

Two-Year Risk of Exudation in Eyes with Nonexudative Age-Related Macular Degeneration and Subclinical Neovascularization Detected with Swept Source Optical Coherence Tomography Angiography.

PURPOSE: Swept source optical coherence tomography angiography (SS-OCTA) was used to study the prevalence, incidence, and natural history of subclinical macular neovascularization (MNV) in eyes with unilateral nonexudative age-related macular degeneration. DESIGN: Prospective cohort study. METHODS: Patients were imaged using 3- × 3-mm and 6- × 6-mm SS-OCTA scan patterns. MNV was detected using the outer retina to choriocapillaris en face slab. Prevalence and incidence of subclinical MNV, Kaplan-Meier cumulative estimates for the overall risk of exudation, and the association between neovascular lesion size and the risk of exudation were assessed through 2 years. RESULTS: From August 2014 through March 2018, 227 patients (154 intermediate and 73 late age-related macular degeneration eyes) underwent SS-OCTA imaging. Thirty eyes (13.2%) had subclinical MNV at first imaging and 12 eyes (8.9%) developed subclinical MNV during follow-up. Of the 191 eyes with >1 visit, 19 developed exudation. Fourteen of these eyes had pre-existing subclinical MNV. The incidence of exudation from the time of first detection of any subclinical MNV was 34.5%. The relative risk of exudation after detection of subclinical MNV was 13.6 times greater (95% confidence interval 4.9-37.7) than in the absence of subclinical MNV (P < .001). There was no significant risk of exudation based on lesion size alone (P = .91). CONCLUSIONS: By 24 months, the risk of exudation was 13.6 times greater for eyes with subclinical MNV detected by SS-OCTA compared with eyes without subclinical MNV. For eyes with subclinical MNV in the absence of symptomatic exudation, we recommend close follow-up without treatment.

Correlations between Choriocapillaris Flow Deficits around Geographic Atrophy and Enlargement Rates Based on Swept-Source OCT Imaging.

PURPOSE: To determine the possible correlation between the annual enlargement rates (ERs) of geographic atrophy (GA) with the percentage and size of the choriocapillaris (CC) flow deficits (FDs) surrounding GA, measured with swept-source OCT angiography (SS-OCTA) images. DESIGN: Prospective, observational case series. PARTICIPANTS: Patients with GA secondary to nonexudative AMD. METHODS: Patients were imaged with a 100-kHz SS-OCTA instrument (PLEX Elite 9000, Carl Zeiss Meditec, Dublin, CA) using a 6×6-mm field of view scan pattern. The GA area measurements were obtained from en face SS-OCT sub-retinal pigment epithelium (RPE) slab images. Visualization of the CC and quantification of FDs were performed using a previously published validated algorithm based on a 20-µm thickness slab with the inner boundary located beneath Bruch's membrane. The percentage of CC FDs (FD%) and the average FD area measurements were calculated in different regions around the GA. MAIN OUTCOME MEASURES: The correlation between the CC FDs and the ERs of GA. RESULTS: Twenty-two eyes from 15 patients were eligible for the analysis. The annual square root ERs for GA ranged from 0.07 to 0.75 mm/year. The CC FD% and average FD area measurements were highly correlated with each other (P < 0.001), with the highest FD values found in the region closest to the margin of GA. The ERs correlated best with the average CC FD area measurements in the total scan area minus the area of GA (Pearson r = 0.747; P < 0.001) than those in the regions immediately surrounding the GA (r = 0.544; P = 0.009). CONCLUSIONS: Contrary to expectations, the global CC FD measurements had a better correlation with the ERs of GA than those in the regions immediately around the GA. The most likely explanation for this outcome is that normal age-related increases in FDs within the central macula confound the correlations between the ERs of GA and FDs, whereas the regions furthest away from the margins of GA are less affected by normal age-related changes and reflect FD alterations related to AMD severity.

Predictive Value of the OCT Double-Layer Sign for Identifying Subclinical Neovascularization in Age-Related Macular Degeneration.

PURPOSE: Structural OCT images from eyes with nonexudative age-related macular degeneration (AMD) were graded for the presence of a double-layer sign to determine if the double-layer sign predicted subclinical macular neovascularization (MNV). DESIGN: Prospective, observational study. PARTICIPANTS: Nonexudative AMD patients with and without subclinical MNV identified by swept-source (SS) OCT angiography (OCTA). METHODS: Participants were enrolled prospectively into an SS OCTA imaging study. A set of test scans with and without subclinical MNV was compiled to assess the ability of trained graders to identify nonexudative type 1 MNV. The graders evaluated only the structural OCT B-scans of those eyes. The presence of a double-layer sign was used as a predictive sign for subclinical type 1 MNV. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) from 2 separate gradings were calculated and compared. MAIN OUTCOME MEASURES: The association between the presence of a double-layer sign and subclinical type 1 MNV. RESULTS: One hundred eyes with nonexudative AMD from 94 patients were used for this study. The test set contained 64 eyes with intermediate AMD, which included 20 eyes with subclinical MNV, and 36 eyes with late AMD, which included 13 eyes with subclinical MNV. Two junior graders read the scans separately then reached a consensus grading. They detected a double-layer sign in 24 of 33 eyes with subclinical MNV and did not detect a double-layer sign in 56 of 67 eyes without MNV. Their sensitivity, specificity, PPV, and NPV were 73%, 84%, 69%, and 86%, respectively. The senior grader detected a double-layer sign in 29 of 33 eyes with subclinical MNV and did not detect a double-layer sign in 58 of 67 eyes without MNV, achieving a sensitivity, specificity, PPV, and NPV of 88%, 87%, 76%, and 94%, respectively. For all graders, there were statistically significant associations between type 1 MNV and presence of the double-layer sign (P < 0.001). CONCLUSIONS: Presence of the double-layer sign on structural OCT B-scans was associated with subclinical type 1 MNV and can be used to identify these lesions with good predictive values in eyes with nonexudative AMD.

En Face Imaging of Geographic Atrophy Using Different Swept-Source OCT Scan Patterns.

PURPOSE: Different swept-source (SS) OCT scan patterns were used to image geographic atrophy (GA) to determine if they provided similar area and enlargement measurements in eyes with age-related macular degeneration (AMD). DESIGN: Prospective, observational case series. PARTICIPANTS: Patients with GA secondary to nonexudative AMD. METHODS: Patients were imaged using SS OCT (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, CA), with follow-up imaging performed after 6 months and 1 year. Both the 6×6 mm and 12×12 mm scan patterns were obtained at each visit. Area measurements of GA were obtained from the en face images generated from a slab with boundaries extending 64 to 400 µm beneath Bruch's membrane. MAIN OUTCOME MEASURES: Comparison of area measurements and enlargement rates (ERs) measurements between the 6×6 mm and 12×12 mm scan patterns. RESULTS: Thirty-two eyes of 25 patients with GA secondary to nonexudative AMD were enrolled. The mean lesion area measurements at baseline were 3.81 mm2 for the 6×6 mm scan and 3.75 mm2 for the 12×12 mm scan. At baseline and over 1 year, the lesion area measurements between the 6×6 mm and the 12×12 mm scan patterns were comparable for all eyes (0.04 mm2; P < 0.001, analysis of variance). The annual ER measurements from the 6×6 mm and 12×12 mm scan patterns were similar (Pearson r = 0.99), with an average ER using the square root transformation strategy of 0.3 mm/year. CONCLUSIONS: Both the 6×6 mm and the 12×12 mm scan patterns resulted in similar area and ER measurements for GA when visualized using the en face images. With the 12×12 mm scan pattern, which represents a 40° field of view (FOV), the measurement of GA using OCT en face imaging is no longer limited by the 6×6 mm FOV. Since macular GA can extend beyond the 6×6 mm FOV, the 12×12 mm FOV can now image all macular GA. With a FOV now similar to autofluorescence and color fundus imaging, SS OCT imaging can be used as the sole imaging method for the detection, measurement, and ER assessment of all GA associated with AMD in clinical practice and in clinical trials.

Overview of Systematic Reviews and Meta-analyses on Systemic Adverse Events Associated With Intravitreal Anti-Vascular Endothelial Growth Factor Medication Use.

Importance: The systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications is still a matter of debate. Objective: This overview of systematic reviews evaluates systemic adverse events associated with intravitreal anti-VEGF treatments in patients with neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. Design, Evidence, and Reporting: This systematic search of PubMed and the Cochrane Central Register of Controlled Trials database includes meta-analyses and systematic reviews. We describe the summary measures of association between anti-VEGF treatments and outcomes reported in each systematic review. Main Outcomes and Measures: The quality of the systematic reviews was assessed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist, version 1. Findings: We retrieved 21 systematic reviews published between January 1, 2011, and June 30, 2016. Of these, 11 analyzed systemic adverse events as the primary outcome. The median (interquartile range) PRISMA and AMSTAR scores were 23 of 27 (15-27) and 8 of 11 (5-11), respectively, but 5 reviews (25%) scored below 20 and 7, respectively. All reviews used an objective scale to assess methodological risk of bias in their included studies, the Cochrane Risk of Bias Tool being the most commonly used (16 reviews [76%]). Anti-VEGF treatments did not increase the risk of systemic adverse events when compared with control regimens; similarly, there was no increase in systematic adverse events when treatment was given on a monthly schedule vs an as-needed regimen. Compared with ranibizumab, bevacizumab did not appear to be associated with an increase in the risk of systemic adverse events in the most recent and exhaustive reviews. Compared with control treatments, ranibizumab may be associated with an increase in the risk of nonocular hemorrhage in patients with age-related macular degeneration. Conclusions and Relevance: This overview of reviews and meta-analyses suggest that anti-VEGF treatments do not increase the risk of systemic adverse events, but that caution might be advisable in older patients with age-related macular degeneration who may be at higher risk of hemorrhagic events when receiving ranibizumab.

Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis.

IMPORTANCE: Few data exist regarding the systemic safety of intravitreal antivascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb). OBJECTIVE: To conduct a systematic review and meta-analysis to evaluate the risk of major cardiovascular and nonocular hemorrhagic events in patients with neovascular age-related macular degeneration (AMD), diabetes mellitus-associated macular edema (DME), or retinal vein occlusions (RVOs) who receive intravitreal anti-VEGF mAbs. DATA SOURCES: The MEDLINE and Cochrane Central databases were searched for potentially eligible studies. STUDY SELECTION: Randomized clinical trials comparing ranibizumab or bevacizumab with no anti-VEGF treatment, as well as those comparing ranibizumab with bevacizumab in patients with AMD, DME, or RVOs. DATA EXTRACTION AND SYNTHESIS: We used a fixed-effects model and report the results as odds ratios (ORs) and 95% CIs. MAIN OUTCOMES AND MEASURES: Primary end points were major cardiovascular and nonocular hemorrhagic events. Secondary end points were all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, venous thromboembolic events (VTEs), and hypertension. RESULTS: Twenty-one trials that evaluated 9557 patients were retrieved. Anti-VEGF mAbs did not significantly increase the risk of major cardiovascular events (OR, 1.18; 95% CI, 0.81-1.71) or nonocular hemorrhagic events (OR, 1.42; 95% CI, 0.95-2.13) in treatment groups compared with control populations. Bevacizumab did not increase the risk of major cardiovascular events (OR, 0.94; 95% CI, 0.59-1.52) or nonocular hemorrhagic events (OR, 2.56; 95% CI, 0.78-8.38) compared with ranibizumab, but significantly increased VTEs (OR, 3.45; 95% CI, 1.25-9.54). Subgroup analysis showed a significant increase of nonocular hemorrhagic events in patients with AMD in ranibizumab vs control trials (OR, 1.57; 95% CI, 1.01-2.44). Anti-VEGF mAbs did not significantly increase overall mortality, cardiovascular mortality, stroke, myocardial infarction, VTEs, or hypertension. CONCLUSIONS AND RELEVANCE: We showed that intravitreal anti-VEGF-mAbs were not associated with significant increases in major cardiovascular or nonocular hemorrhagic events, but studies and meta-analyses were not powered enough to correctly assess these risks. Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD with ranibizumab should be cautiously interpreted because more safety data are needed.