Association of Intravitreal Anti–Vascular Endothelial Growth Factor Therapy With Risk of Stroke, Myocardial Infarction, and Death in Patients With Exudative Age-Related Macular Degeneration | Acute Coronary Syndromes | JAMA Ophthalmology | JAMA Network
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Figure 1.  Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Stroke in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD
Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Stroke in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD

No difference was found in the 5-year risk of stroke in patients with exudative AMD compared with controls with exudative AMD (9.0%, P = .23), controls with dry AMD (7.2% vs 3.0%, P = .01), and controls without AMD (7.0%, P = .99).

Figure 2.  Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Myocardial Infarction (MI) in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD
Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Myocardial Infarction (MI) in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD

No difference was found in the 5-year risk of MI in patients with exudative AMD compared with controls with exudative AMD (6.1% vs 11.4%, P = .01), controls with dry AMD (6.2%, P = .71), and controls without AMD (7.2%, P = .96).

Figure 3.  Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Death (All-Cause Mortality) in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD
Kaplan-Meier Analysis Examining the 5-Year Cumulative Risk of Death (All-Cause Mortality) in Patients With Exudative Age-Related Macular Degeneration (AMD) Compared With Controls With Exudative AMD in the Era Before Anti–Vascular Endothelial Growth Factor, Controls With Dry AMD, and Controls Without AMD

No difference was found in the 5-year risk of mortality in patients with exudative AMD compared with controls with AMD (26.8%, P = .36), controls with dry AMD (26.7%, P = .24), and controls without exudative AMD (23.0%, P = .03) on univariate analysis. On multivariate analysis, there was an increased risk of mortality in patients with exudative AMD compared with controls with exudative AMD (P < .001).

Table 1.  Baseline Characteristics, Medical History, Medication Use Data, and Cardiac Events for the Study Participantsa
Baseline Characteristics, Medical History, Medication Use Data, and Cardiac Events for the Study Participantsa
Table 2.  Comparison of Patients With Exudative AMD With Controls With Exudative AMD in the Era Before Anti-VEGF, Controls With Dry AMD, and Controls Without AMD
Comparison of Patients With Exudative AMD With Controls With Exudative AMD in the Era Before Anti-VEGF, Controls With Dry AMD, and Controls Without AMD
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Original Investigation
January 31, 2019

Association of Intravitreal Anti–Vascular Endothelial Growth Factor Therapy With Risk of Stroke, Myocardial Infarction, and Death in Patients With Exudative Age-Related Macular Degeneration

Author Affiliations
  • 1Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
  • 2Mayo Clinic School of Medicine, Rochester, Minnesota
  • 3Department of Health Sciences Research/Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida
  • 4Department of Neurology, Mayo Clinic, Rochester, Minnesota
JAMA Ophthalmol. 2019;137(5):483-490. doi:10.1001/jamaophthalmol.2018.6891
Key Points

Question  Do patients receiving intravitreal anti–vascular endothelial growth factor injections for neovascular age-related macular degeneration have an increased incidence of cardiovascular events, such as myocardial infarction, stroke, and death compared with individuals not receiving the injections?

Findings  In this cohort study of 504 patients from Olmsted County, Minnesota, no consistent associations were found in the 5-year risk of stroke, myocardial infarction, or death among patients with age-related macular degeneration receiving intravitreal anti–vascular endothelial growth factor injections compared with control groups with and without age-related macular degeneration.

Meaning  This study suggests that intravitreal anti–vascular endothelial growth factor therapy for neovascular age-related macular degeneration is not associated with increased risk of stroke, myocardial infarction, or death.

Abstract

Importance  Current studies assessing the risk of stroke, myocardial infarction (MI), and death in patients undergoing intravitreal anti–vascular endothelial growth factor (VEGF) therapy are inconclusive. To our knowledge, no population-based studies have been performed to examine these potential risks.

Objective  To examine whether patients with exudative age-related macular degeneration (AMD) receiving intravitreal anti-VEGF injections have a higher incidence of MI, stroke, or death compared with control populations.

Design, Setting, and Participants  This population-based, retrospective cohort study included 504 patients from Olmsted County, Minnesota, identified through the Rochester Epidemiology Project (REP) database as receiving at least 1 intravitreal anti-VEGF injection for exudative AMD from January 1, 2004, to December 31, 2013. Three age- and sex-matched control groups of individuals who did not receive anti-VEGF treatment and were derived from the REP database were also studied: control individuals with exudative AMD in the era before anti-VEGF (January 1, 1990, to December 31, 2003), controls with dry AMD, and controls without AMD. Data analysis was performed from September 1, 2016, to September 1, 2017.

Main Outcomes and Measures  Five-year risk of stroke, MI, and death were assessed in patients compared with controls using Kaplan-Meier and multivariate analysis with Cox proportional hazards regression models.

Results  The study included 504 patients (321 female [63.7%]; mean [SD] age, 76.5 [10.0] years) who received at least 1 intravitreal anti-VEGF injection for exudative AMD during the study period. Kaplan-Meier analysis revealed a 5-year risk of 7.2% for stroke, 6.1% for MI, and 30.0% for death. Patients who received anti-VEGF had no increased risk of stroke or MI compared with controls with dry AMD (n = 504), controls with exudative AMD (n = 473), or controls without AMD (n = 504). There was an increased risk of mortality compared with controls with exudative AMD in the era prior to anti-VEGF therapy but not the other control groups on multivariate analysis (hazard ratio, 1.63; 95% CI, 1.30-2.04; P < .001).

Conclusions and Relevance  This population-based study revealed that intravitreal anti-VEGF therapy for exudative AMD was not associated with consistent increases in the risk of stroke, MI, or death compared with no therapy in patients with or without AMD. It appears to be likely the cardiac events these patients experience are not attributable to their anti-VEGF therapy.

Introduction

Intravitreal anti–vascular endothelial growth factor (VEGF) therapy is now a mainstay in the treatment of exudative age-related macular degeneration (AMD).1-3 Currently, 3 drugs account for most intravitreal anti-VEGF therapy.4,5 Ranibizumab and aflibercept have been approved by the US Food and Drug Administration (FDA) for use in exudative AMD. Bevacizumab, an anti-VEGF agent that is FDA approved for use in the treatment of several cancers, is an appealing alternative to these agents given its cost-effectiveness despite its lack of FDA approval for intravitreal use and need for repackaging with a compounding pharmacy.6-8

Given the importance and frequency of use of these agents in the treatment of exudative AMD, it is incumbent on ophthalmologists to adequately counsel patients regarding the potential risks of their use. When administered systemically in doses used for chemotherapy, bevacizumab is associated with an increased risk of stroke.9 Although the doses of these agents administered intravitreally are smaller, some studies10-12 have described an increased incidence of thromboembolic events and death in patients treated with intravitreal anti-VEGF therapy. Other studies,13-16 however, suggest that these agents are safe and without increased risk of cardiovascular events. A study17 that examined pegaptanib suggested that use could be associated with higher mortality but not myocardial infarction (MI) or stroke.

Despite numerous studies,17-23 the risk of stroke, MI, and death in patients undergoing anti-VEGF therapy is not well understood. Although the data indicate a minimally increased risk of cardiovascular events with the use of anti-VEGF agents17 in intravitreal doses, definitive conclusions about the safety of these agents cannot be made.18,19 Many available studies3,7 have event rates too low to be able to determine confidently whether there is an increased risk of cardiovascular events associated with intravitreal anti-VEGF injections, and other studies20,21 have relied on medical billing codes to identify treatment groups and/or cardiovascular events. Moreover, some studies22,23 may be confounded by ocular disease associations with systemic cardiovascular risks in patients who require anti-VEGF therapy.

The purpose of this article is to present a population-based study of the risk of stroke, MI, and all-cause mortality in patients with exudative AMD receiving intravitreal anti-VEGF therapy compared with control individuals with and without AMD not receiving anti-VEGF therapy in Olmsted County, Minnesota.

Methods

This retrospective cohort study used the Rochester Epidemiology Project (REP) medical records linkage system, which consists only of residents of Olmsted County, Minnesota, who have provided written informed consent for research. Although medical care of this population is provided primarily by Mayo Clinic and Olmsted Medical Center, small independent clinics also participate in the REP, capturing nearly all Olmsted County residents.24,25 Unlike tertiary referral center research, this database is not biased toward patients with health conditions that require more frequent monitoring, and the database has excellent concordance for date of last contact, patient status at last contact, and date of death compared with manual record abstraction.26-28 The REP database was used when possible for these elements of the medical record review. An additional subanalysis that examined only patients who received at least 3 intravitreal anti-VEGF injections in the year before a stroke, MI, or death was performed. We included all patients with at least 3 injections during the year before an event or at least 3 injections in the final year of follow-up. All other patients were excluded from this cohort. This case cohort was compared with the 3 control cohorts in a similar manner as the overall analysis. This study adhered to the Health Insurance Portability and Accountability Act, received Mayo institutional review board approval, and adhered to the tenets of the Declaration of Helsinki.29 All data were deidentified.

This study included a cohort with exudative AMD who received anti-VEGF injection (hereafter referred to as the injection cohort) and 3 control groups described below. All data were manually collected and checked for accuracy by 2 study team members (L.A.D. and M.R.S.). The number of patients with 5-year follow-up was large enough to allow for 5-year Kaplan-Meier data to be reported. The number of at-risk patients decreased significantly after 5 years; thus, that time point was the most practical end point for this study.

Injection Cohort

We identified all patients who received 1 or more intravitreal anti-VEGF injections from January 1, 2004, to December 31, 2013, allowing for a postinjection follow-up period of at least 24 months. Records were reviewed through December 31, 2015, when available. Data analysis was performed from September 1, 2016, to September 1, 2017. Records of deceased patients were reviewed up to the time of death, and the date of last contact with the health care system was recorded for all patients. All patients who received an intravitreal anti-VEGF injection for the indication of exudative AMD were enrolled, including those who had received pegaptanib. Patients who received anti-VEGF injections for other indications were excluded from this analysis. All patients were treated by a retinal specialist and typically underwent fluorescein angiography and optical coherence tomography at the time of initiating therapy with anti-VEGF and interval optical coherence tomography at the treating physician’s discretion. We did not differentiate between patients who received injections in both eyes and those who converted to the contralateral eye during the study. Injection frequency was recorded for both eyes, and in the case of an event, the date of the last injection in either eye was recorded.

All records were manually reviewed for total number and frequency of anti-VEGF injections; specific anti-VEGF agent used; patient birth date and race/ethnicity; smoking status; body mass index; and family history of heart disease, stroke, and macular degeneration. Pertinent medical history and systemic medications are listed in Table 1. When applicable, dates of stroke and MI were recorded, and the total number of these events was logged.

Control Individuals

Because event risk can be associated with the indicating diagnosis for anti-VEGF therapy, we attempted to control for this by collecting an age- and sex-matched control group of patients with exudative AMD who did not receive anti-VEGF treatment; this group consisted of patients with baseline characteristics and underlying diagnoses similar to those of the injection cohort. All matching was on a per patient basis, with match criteria, including exact sex match and age within 5 years of injection cohort patient’s age between the start of injections and index date of disease diagnosis. These patients were seen from January 1, 1990, through December 31, 2003, before the anti-VEGF era but were deemed to be likely anti-VEGF treatment candidates had they been seen today. These patients were taken from the REP database, and similar data were collected through manual medical record review. Patients who later received intravitreal anti-VEGF treatment were excluded from this control group.

Controls With Dry AMD

To control for overall stroke, MI, and death rates having potentially changed from the era before anti-VEGF to the present day, we also collected age- and sex-matched controls with concurrent dry AMD. This group allowed for the closest approximation of similar baseline patient characteristics in a group without exposure to anti-VEGF. Again, similar data were collected through manual medical record review, and all patients who were exposed to anti-VEGF treatment were excluded.

Controls Without AMD

To explore the possibility that AMD could be associated with increased risk of stroke, MI, and death, we identified a second age- and sex-matched concurrent control group of patients who had documented eye examinations with no AMD diagnosis noted in the medical record. Similar data were also collected on these patients through manual medical record review.

Statistical Analysis

The study used χ2 analysis to assess differences in baseline characteristics among the groups. Kaplan-Meier analysis was used to assess 5-year event risks, and multivariate analyses were fit with Cox proportional hazards regression models. Time zero for Kaplan-Meier analysis was defined as the date of first injection for the injection cohort and the corresponding index date for the age-matched control cohorts. Multivariate analysis for stroke accounted for differences in atrial fibrillation, cancer, carotid stenosis, coronary artery disease, and diabetes; multivariate analysis for myocardial infarction accounted for cardiomyopathy, congestive heart failure, and hypertension; and multivariate analysis for death (all-cause mortality) adjusted for age, body mass index, cancer, congestive heart failure, coronary artery disease, diabetes, high cholesterol level, hypertension, pulmonary embolism, and sleep apnea. These factors were chosen based on the American Heart Association’s known risk factors for cardiovascular events.30 The number of factors that could be statistically accounted for in multivariate analysis depended on the total number of events (fewer myocardial infarction and stroke events than death events). Only patients with complete data were included in the models with missing variables. Statistical analysis was performed using SAS, version 9.4 (SAS Institute Inc). A Bonferroni correction was made, and only 2-tailed P < .001 was considered to be statistically significant.

Results

We identified a total of 504 patients (321 female [63.7%]; mean [SD] age, 76.5 [10.0] years) who received at least 1 intravitreal anti-VEGF injection from January 1, 2004, to December 31, 2013, for exudative AMD. Patients received a mean (SD) of 24 (21) injections for a mean (SD) of 33 (30) months, and most patients were treated primarily with bevacizumab. Patients were treated predominantly with pegaptanib (n = 10), bevacizumab (n = 377), ranibizumab (n = 72), or aflibercept (n = 45). A total of 7 patients received pegaptanib only, without exposure to other anti-VEGF agents. The group of controls with exudative AMD in the era before anti-VEGF consisted of 473 patients (314 female [66.4%]). This cohort was smaller (n = 504 in the other groups) than the other groups because matches could not be found for 31 patients. The concurrent dry AMD cohort and the cohort without AMD each consisted of 504 patients (321 female [63.7%]) matched for an index date from January 1, 2004, to December 31, 2013. None of the controls received anti-VEGF therapy.

Baseline characteristics were examined for all 1985 patients and controls, and results were compared among the groups (Table 1). In brief, significant differences between cohorts included greater prevalence of high cholesterol levels in the injection cohort (389 [77.2%]) compared with the controls with exudative AMD in the era before anti-VEGF (255 [53.9%], P < .001) and controls without AMD (327 [64.9%], P < .001) and less congestive heart failure in the injection cohort (136 [27.0%]) compared with controls with exudative AMD in the era before anti-VEGF (198 [41.9%], P < .001).

Rate of Stroke, MI, and Death

Kaplan-Meier analysis revealed a 7.2% five-year cumulative risk of stroke, 6.1% risk of MI, and 30.0% risk of death (all-cause mortality) in the injection cohort; a 3.0% risk of stroke, 6.1% risk of MI, and 27.7% risk of death in patients with dry AMD; a 9.0% risk of stroke, 11.4% risk of MI, and 26.8% risk of death in patients with exudative AMD in the era before anti-VEGF; and a 7.0% risk of stroke, 7.2% risk of MI, and 23.0% risk of death in patients with no AMD (Figure 1, Figure 2, and Figure 3). There was no increase in the 5-year risk of stroke or MI in any of the cohorts (Table 2). Univariate analysis found no difference in 5-year mortality, but there was a significantly increased risk of death in the injection group compared with the cohort with exudative AMD before the anti-VEGF era on multivariate analysis (univariate analysis: 26.8%; hazard ratio, 1.10; 95% CI, 0.90-1.35; P = .36; multivariate analysis: hazard ratio, 1.63; 95% CI, 1.30-2.04; P < .001).

Risk of Stroke, MI, and Death in Patients With 3 or More Anti-VEGF Injections in the Year Before the Event

A total of 292 patients received at least 3 intravitreal injections in the final year of follow-up or in the year before having a cardiac event. Kaplan-Meier analysis revealed a 6.5% five-year cumulative risk of stroke, 6.8% risk of MI, and 30.8% risk of death in this cohort. No significant differences were found in stroke risk, MI risk, or mortality risk in this group compared with controls (Table 2).

Discussion

The results of this study suggest that intravitreal anti-VEGF therapy for patients with exudative AMD is safe, but they must be interpreted with caution. After performing multivariate analysis, the risk of MI or stroke in patients treated with anti-VEGF was not significantly different from that in any of the control groups. However, there was an increased risk of death in patients who received anti-VEGF treatment compared with patients with past exudative AMD who did not receive anti-VEGF treatment on multivariate analysis. We suspect that the increased risk of death associated with AMD in the injection cohort compared with controls with past exudative AMD was influenced by the inability to completely match the 2 cohorts. This finding is challenging to interpret and could be attributable to chance alone. Compared with other cohorts and when examined by patients receiving at least 3 injections within 1 year of death, no significant differences in mortality were found. However, another study31 found increased mortality associated with intravitreal anti-VEGF injections, which would support this finding.

The incidences of stroke, MI, and death in the cohort with past exudative AMD were similar to those in the injection cohort. A decrease in event incidence in the injection cohort would be expected with health care advances. The fact that event rates were similar might indicate that anti-VEGF therapy was associated with increased risk of stroke, MI, and death. However, there were also no differences in event risk between the past exudative AMD cohort and the concurrent dry AMD cohort, making this unlikely. When examining the systemic comorbidities that pose the greatest risk for cardiac events in patients actively receiving intravitreal injections, no significant differences were found, further validating the evidence that these agents may be associated with increased risk of MI, stroke, or death.

Overall, however, the findings suggest that intravitreal anti-VEGF agents are safe, with no consistent evidence of increased event risk in the comparisons among different cohorts. These conclusions are supported by the prior Vascular Events in Noncardiac Surgery Patients Cohort Evaluation Study (VISION) trials with pegaptanib that found no increased risk of thromboembolic events or death.32,33 Similarly with ranibizumab, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA), Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR), and Safety Assessment of Intravitreal Lucentis for AMD (SAILOR) trials did not find statistically increased risks of nonfatal stroke, MI, or vascular-related death.33-37 These results contrast, however, with a meta-analysis by Ueta et al38 in which significantly increased risk of stroke, transient ischemic attacks, and cerebral ischemic incidents were found in ranibizumab-treated patients compared with sham-treated patients (2.2% vs 0.7%; P = .04); no difference in MI risk was found in that meta-analysis. Given that our study did not include transient ischemic attacks as an end point, lumping those events with stroke may account for the difference between our findings and those of Ueta et al.38 A meta-analysis by Thulliez et al20 found no significantly increased risk of stroke, MI, cardiovascular-related death, or all-cause mortality in patients treated with ranibizumab or bevacizumab.

Strengths and Limitations

Compared with prior studies,3,7,20,21 our study had the advantage of being specifically designed to examine the risk of stroke, MI, and death within multiple population-based control groups; this allowed us to account for changes in event rates over time and examine different risks associated with anti-VEGF therapy. Records were manually reviewed, with diagnoses individually adjudicated based on subspecialist diagnosis (ie, neurologist documentation for stroke, cardiologist for MI) rather than relying on medical coding to confirm diagnoses and events. Consequently, we were able to collect information regarding risk factors for stroke, MI, and death as well as systemic medications taken by these patients. This study also had the advantage of examining patients in whom dose interval was based on real-world clinical practice patterns rather than patients who received injections at intervals dictated by a clinical trial. In addition, long-term follow-up data were readily available for this population-based cohort.

This study has limitations given its retrospective nature. Despite efforts to match patients for baseline characteristics, there are still elements that could confound our results. The cohort with dry AMD excluded patients who received anti-VEGF therapy, which potentially excluded patients developing more severe retinal disease and at increased risk of developing systemic disease; this criterion could have led to selective inclusion of patients less likely to have systemic disease progression. We performed multivariate analysis to limit the effects of unequal baseline patient characteristics as much as possible. Results must also be interpreted with caution given that the study examined a single, predominantly white population in Olmsted County, Minnesota. Although population-based data from Olmsted County are similar to other US communities,39 results might not accurately reflect those in other racial/ethnic populations. We also included patients with other retinal comorbidities, such as diabetic retinopathy, if AMD was the anti-VEGF–indicating diagnosis; despite medical record review to confirm that anti-VEGF was used to treat AMD, these inclusion criteria could have confounded study results. We did not perform any analyses based on individual agents because of the significant number of patients who switched agents throughout the study. Each agent could have risk factors independent of the other drugs and, therefore, could confound the results. In addition, smoking status was unavailable for a significant percentage of patients across all cohorts and is a known risk factor for death, stroke, and MI that could have affected the results. Also, as evidenced in the Kaplan-Meier curves, after 3 years of follow-up across the 3 curves, the AMD cohort had fewer patients at risk, possibly because of the very events this study was screening for, which could limit the results.

Conclusions

The findings suggest that intravitreal anti-VEGF agents are safe for patients with exudative AMD. However, this topic continues to warrant further study. Additional studies will be required to characterize the risk of stroke, MI, and death in patients receiving anti-VEGF therapy for nonexudative AMD diagnoses and to determine whether there are differences in the association of risk with therapy among anti-VEGF agents. In our study, we found no consistent evidence that intravitreal anti-VEGF therapy was associated with increased risk of stroke, MI, or death.

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Article Information

Accepted for Publication: November 16, 2018.

Corresponding Author: Raymond Iezzi, MD, MS, Department of Ophthalmology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (iezzi.raymond@mayo.edu).

Published Online: January 31, 2019. doi:10.1001/jamaophthalmol.2018.6891

Author Contributions: Drs Bakri and Iezzi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Dalvin, Starr, Abou Chehade, Bakri.

Study concept and design: Iezzi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Dalvin, Starr, Garcia, Shah, Iezzi.

Critical revision of the manuscript for important intellectual content: Starr, Abou Chehade, Damento, Hodge, Meissner, Bakri, Iezzi.

Statistical analysis: Starr, Abou Chehade, Shah, Hodge, Iezzi.

Obtained funding: Dalvin, Iezzi.

Administrative, technical, or material support: Starr, Garcia, Iezzi.

Study supervision: Meissner, Bakri, Iezzi.

Conflict of Interest Disclosures: Dr Bakri reported receiving personal fees from Genentech, Allergan, Zeiss, Eyepoint, and Novartis and grants from Ophthotech, Lowy Medical Foundation, and Apellis outside the submitted work. Dr Dalvin reported receiving nonfinancial support from Research to Prevent Blindness and grants from VitreoRetinal Surgery Foundation and Heed Ophthalmic Foundation during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported in part by an unrestricted grant from Research to Prevent Blindness Inc, the Mayo Foundation for Medical Research, and the VitreoRetinal Surgery Foundation (Dr Dalvin).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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