Abstract
Background:
Recent guidelines do not recommend routine use of aspirin for primary cardiovascular prevention (ppASA) and suggest avoidance of ppASA in older individuals due to bleeding risk. However, ppASA is frequently taken without an appropriate indication. Estimates of the incidence of upper gastrointestinal bleeding due to ppASA in the United States are lacking. In this study, we provide national estimates of upper gastrointestinal bleeding incidence, characteristics, and costs in ppASA users from 2016–2020.
Methods:
ppASA users (patients on long-term aspirin therapy without cardiovascular disease) presenting with upper gastrointestinal bleeding were identified in the Nationwide Emergency Department Sample using ICD-10 codes. Trends in upper gastrointestinal bleed incidence, etiology, severity, associated Medicare reimbursements and the impact of ppASA on bleeding outcomes were assessed with regression models.
Results:
From 2016–2020, adjusted incidence of upper gastrointestinal bleeding increased 29.2% among ppASA users, with larger increases for older patients (increase of 41.6% for age 65–74 years and 36.0% for age ≥75 years). The most common etiology among ppASA users was ulcer disease but increases in bleeding incidence due to angiodysplasias were observed. The proportion of hospitalizations with major complications/comorbidities increased 41.5%, and Medicare reimbursements increased 67.6%. Among patients without cardiovascular disease, ppASA was associated with increased odds of hospital admission, red blood cell transfusion, and endoscopic intervention as compared to no ppASA use.
Conclusions:
Considering recent guideline recommendations, the rising incidence, severity, and costs associated with upper gastrointestinal bleeding among patients on ppASA highlights the importance of careful assessment for appropriate ppASA use.
Keywords: aspirin, gastrointestinal hemorrhage, primary prevention, epidemiology
Introduction
Low-dose aspirin for the primary prevention of cardiovascular events (ppASA) in individuals without a history of atherosclerotic cardiovascular disease is commonly prescribed in the United States, with an estimated 29 million ppASA users in 20171. While the benefits of aspirin in secondary prevention of cardiovascular events are well-established2, the benefits of aspirin for primary prevention are controversial. Although older guidelines supported its use, recent multi-society guidelines from the American Heart Association/American College of Cardiology (AHA/ACC) and the United States Preventive Services Task Force (USPSTF) have restricted ppASA use based on three randomized controlled trials that failed to identify a significant benefit of ppASA in the prevention of cardiovascular events3–5. The new AHA/ACC and USPSTF guidelines do not make a recommendation for routine ppASA use and indicate ppASA may be considered in those with increased cardiovascular risk but recommend against initiating ppASA in individuals ≥60–70 years and stopping ppASA around age 75 due to increased bleeding risk6, 7.
There is likely an excess risk of upper gastrointestinal bleeding attributable to ppASA within the United States population. This is supported by the finding that ppASA use is associated with a 56% increase in the risk of gastrointestinal bleeding, particularly upper gastrointestinal bleeding, compared to placebo or no aspirin8, 9 and that multiple studies have demonstrated that ppASA is frequently prescribed inappropriately or taken without physician recommendation1, 10. One recent study using a large, national, quality improvement registry of cardiology clinics found that after the 2019 AHA/ACC guideline change, over half of patients were taking ppASA either inappropriately (<40 or >70 years) or without an appropriate indication (low, borderline, or intermediate cardiovascular risk)11. Considering the narrowing indications for ppASA use, identification of individuals for ppASA deprescription is of paramount importance to reduce the number hospitalizations for upper gastrointestinal bleeding.
To date, national estimates of Emergency Department (ED) visits and hospitalizations for upper gastrointestinal bleeding attributable to ppASA that would contextualize the scope of the problem are lacking. Though the absolute risk of bleeding with ppASA is low, given the large number of users in the United States, the burden of upper gastrointestinal bleeding is likely substantial1, 12, 13. In this study, we sought to provide the first national estimates of this burden by elucidating trends in the incidence of ED visits for upper gastrointestinal bleeding in ppASA users from 2016–2020, estimate costs for those hospitalized, and investigate the impact of ppASA on bleeding severity compared to ppASA non-users.
Methods
Data Source and Variables
The National Emergency Department Sample (NEDS) is the largest all-payer ED database in the United States and is a composite of the Healthcare Cost and Utilization Project (HCUP) State Inpatient Database and the State Emergency Department Database. The NEDS provides information on ED visits that result in hospital admission, together with their associated hospital encounter, as well as ED visits that do not result in hospital admission. Patients ≥45 years old presenting to the ED with a primary diagnosis of upper gastrointestinal bleeding were identified in NEDS from 2016–2020 using International Classification of Disease, Tenth Revision (ICD-10) codes as previously described14. Adults ≥45 years old accounted for approximately 75% of all ED visits for gastrointestinal bleeding in the United States from 2006–2019 and one in three adults over 40 years old in the United States reported use of ppASA in 201910, 14. As such an age cutoff of ≥45 years old was selected to capture as many upper gastrointestinal bleeding events in our cohort as possible while also including patients that were likely to be on primary prevention aspirin. Etiologies of upper gastrointestinal bleeding including peptic ulcer disease, esophageal and gastric varices, Mallory-Weiss tears, angiodysplasias, Dieulafoy lesions, gastritis, duodenitis, esophagitis, and esophageal ulceration were identified by ICD-10 codes as previously described14. Patients were considered to be on ppASA if they had no codes for atherosclerotic cardiovascular disease (94.5% positive predictive value among aspirin users)15, 16 or long-term use of non-steroidal anti-inflammatory drugs, anticoagulants, or antiplatelets use and carried an ICD-10 code for long-term aspirin therapy (Z79.82). While no studies to date have investigated the accuracy of this specific ICD-10 code for identifying patients on long-term aspirin therapy, literature on the use of the Z79 family of ICD-10 codes for coding other classes of long-term medications suggest that they are accurate and likely underestimate the true number of patients on the long-term medication of interest17.
Demographic data collected included sex, age, census location, hospital urban-rural teaching status, ED volume, income quartile, primary insurance payer, and Charlson Comorbidity index.
Outcomes
The outcomes of interest were incidence of upper gastrointestinal bleeding, hospital admission rate, in-hospital red blood cell transfusion, in-hospital endoscopic intervention, hospital costs and severity of hospitalization for upper gastrointestinal bleeding. Age- and sex-specific incidence were calculated to remove the confounding effects of changes in age and sex composition across time as previously described14. Weighted national estimates were used for the purposes of the study. Red blood cell transfusions and endoscopic intervention were identified by using Current Procedure Terminology (CPT) and ICD Procedure Coding System codes. Estimates of hospital costs were calculated based on the average national Medicare reimbursement amount for each Diagnosis Related Group-associated with the hospital encounter multiplied by the weighted national estimates of hospital encounters with the associated Diagnosis Related Group code. The associated Diagnosis Related Group was also used to determine upper gastrointestinal bleeding hospitalization severity as the associated Diagnosis Related Groups reflected gastrointestinal hemorrhage with major complication or comorbidity (377), complication or comorbidity (378), or no complication or comorbidity (379).
Statistical Analysis
Continuous variables were presented as mean and standard deviation and compared using an unpaired Student’s t-test. Categorical variables were analyzed using a Pearson’s chi-square test. Linear regressions were used to analyze trends from 2016–2020 and reported p-values for age- and sex-specific upper gastrointestinal bleeding incidence, Medicare reimbursements for upper gastrointestinal bleeding hospitalizations, and proportions of patients without atherosclerotic cardiovascular disease presenting with upper gastrointestinal bleeding on ppASA and specific Diagnosis Related Group codes. Given the impact of the COVID-19 pandemic on ED visits, we performed a sensitivity analysis for trend from 2016–2019. We performed complete case analysis for all estimates and excluded patients who had missing data for age, sex, hospital region, income quartile, primary payer, and urban, rural, and teaching hospital status. Multivariate regression analysis was performed to explore the impact of ppASA on ED discharge, red blood cell transfusion, and endoscopic hemostatic intervention. Multivariate models were adjusted for gender, geographic region, zip code income quartile, primary insurance payer, year, Charlson Comorbidity Index, and urban/rural or teaching hospital status. All statistical analyses were performed using R version 4.0.2 (R Foundation for Statistical Computing) and STATA v17.0 (StataCorp LLC).
Results
From 2016–2020, there were 535,525 ED visits for upper gastrointestinal bleeding nationwide among patients without atherosclerotic cardiovascular disease, of which 63,862 occurred in patients on ppASA. Baseline characteristics all included patients in the cohort as well as those on ppASA and those not on ppASA are provided in Table 1. Patients without atherosclerotic cardiovascular disease on ppASA were significantly older than those not on ppASA. Notably, while patients ≥65 and ≥75 years old without atherosclerotic cardiovascular disease accounted for 40% and 21% of ED visits for upper gastrointestinal bleeding, respectively, they accounted for 70% and 43% of all upper gastrointestinal bleeds among patients on ppASA. During this time, the age- and sex-specific incidence of upper gastrointestinal bleeding increased 29.2% from 7.5 events/100,000 population to 10.0 events/100,000 (p-value for linear trend = 0.065) (Table 2). The rise in incidence was marked among patients 65–74 and ≥75 years old, increasing 41.6% and 36.0%, respectively, with similar rates between males and females (Figure 1). A significant rise in incidence was also observed in patients 55–64 years old but not among patients 45–54 years old. Among all patients without atherosclerotic cardiovascular disease presenting with upper gastrointestinal bleeding, the proportion of ppASA users increased by 23.8% (p<0.001) between 2016–2020. In addition, the proportion of patients without atherosclerotic cardiovascular disease on ppASA with upper gastrointestinal bleed hospitalizations with major complications/comorbidities increased 41.5% (p<0.001), and Medicare reimbursements for hospitalizations for upper gastrointestinal bleeding on ppASA increased 67.6% from $51.6 million in 2016 to $86.5 million in 2020 (Table 2).
Table 1. Baseline characteristics of patients ≥45 years old without atherosclerotic cardiovascular disease presenting to the Emergency Department with upper gastrointestinal bleeding.
Continuous variables presented as mean and standard deviation. P-value represents comparison between patients on ppASA and those not on ppASA.
| Patients on ppASA (n=63,862) |
Patients not on ppASA (n=471,663) |
p-value | |
|---|---|---|---|
|
| |||
| Age (years) | 71.6 (12.3) | 64.6 (13.0) | <0.001 |
|
| |||
| Female | 50.0% | 47.9% | <0.001 |
|
| |||
| Hospital Type | <0.001 | ||
| Urban Non-Teaching | 23.9% | 25.0% | |
| Urban Teaching | 65.9% | 64.3% | |
| Rural | 10.2% | 10.7% | |
|
| |||
| Income Quartile | <0.001 | ||
| 0–25th percentile | 26.8% | 30.7% | |
| 26th–50th percentile | 24.9% | 25.8% | |
| 51st–75th percentile | 25.3% | 23.0% | |
| >75th percentile | 23.0% | 20.5% | |
|
| |||
| Primary Payer | <0.001 | ||
| Medicare | 68.2% | 50.7% | |
| Medicaid | 8.0% | 16.8% | |
| Private Insurance | 18.6% | 22.4% | |
| Self-Pay | 2.8% | 6.9% | |
| No Charge | 0.2% | 0.5% | |
| Other | 2.2% | 2.7% | |
|
| |||
| Charlson Comorbidity Index | <0.001 | ||
| 0 | 26.8% | 33.1% | |
| 1 | 28.8% | 25.3% | |
| 2 | 16.8% | 12.7% | |
| 3 | 11.1% | 11.7% | |
| 4 | 16.5% | 17.2% | |
Table 2. Trends in age- and sex-specific incidence and hospital costs among patients without atherosclerotic cardiovascular disease on primary prevention aspirin presenting with upper gastrointestinal bleeding, 2016–2020.
ED = emergency department; ppASA = aspirin for primary cardiovascular prevention. P-value is for linear trend.
| Age- and sex-specific incidence of ED visits for upper gastrointestinal bleeding among ppASA users (per 100,000 population) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| 2016 | 2017 | 2018 | 2019 | 2020 | Change (2016–2020) | P value | Change (2016–2019) | P value | |
|
| |||||||||
| All ages | 7.5 | 8.9 | 9.8 | 10.9 | 10.0 | +29.2% | 0.065 | +39.3% | 0.006 |
| Male | 7.9 | 9.5 | 10.0 | 11.4 | 10.6 | ||||
| Female | 7.2 | 8.3 | 9.2 | 9.7 | 8.9 | ||||
| 45–54 years | 2.5 | 2.6 | 2.9 | 3.1 | 2.6 | +4.8% | 0.438 | +27.1% | 0.013 |
| Male | 3.4 | 3.7 | 3.8 | 4.1 | 3.4 | ||||
| Female | 1.6 | 1.5 | 2.0 | 2.2 | 1.9 | ||||
| 55–64 years | 5.0 | 6.1 | 6.9 | 7.4 | 7.1 | +41.2% | 0.039 | +47.2% | 0.014 |
| Male | 6.2 | 7.8 | 8.9 | 9.7 | 9.2 | ||||
| Female | 3.9 | 4.5 | 5.0 | 5.2 | 5.1 | ||||
| 65–74 years | 9.5 | 11.3 | 12.1 | 14.1 | 13.4 | +41.6% | 0.025 | +49.5% | 0.012 |
| Male | 10.4 | 12.3 | 13.7 | 17.4 | 15.7 | ||||
| Female | 8.7 | 10.4 | 10.7 | 11.3 | 11.4 | ||||
| ≥75 years | 20.4 | 25.3 | 28.5 | 31.6 | 27.7 | +36.0% | 0.111 | +55.2% | 0.007 |
| Male | 19.6 | 24.9 | 25.7 | 29.9 | 27.9 | ||||
| Female | 20.9 | 25.7 | 30.4 | 32.8 | 27.6 | ||||
|
| |||||||||
| Proportion of patients without atherosclerotic cardiovascular disease on ppASA presenting with upper gastrointestinal bleeding | |||||||||
|
| |||||||||
| All Ages | 10.1% | 11.4% | 12.4% | 12.9% | 12.5% | +23.8% | <0.001 | +27.7% | <0.001 |
| 45–54 years | 4.2% | 4.4% | 4.9% | 5.1% | 4.6% | ||||
| 55–64 years | 7.6% | 8.5% | 9.4% | 9.4% | 9.5% | ||||
| 65–74 years | 13.0% | 14.3% | 14.7% | 15.5% | 14.9% | ||||
| ≥75 years | 16.2% | 18.2% | 20.1% | 21.3% | 20.5% | ||||
|
| |||||||||
| Proportion of all upper gastrointestinal bleeding hospitalizations for patients on ppASA stratified by Diagnosis-Related Group code* | |||||||||
|
| |||||||||
| DRG Code | |||||||||
| 377 | 18.3% | 21.1% | 19.8% | 23.9% | 25.9% | +41.5% | <0.001 | +30.6% | <0.001 |
| 378 | 69.7% | 69.6% | 69.6% | 67.5% | 67.2% | −3.2% | −3.2% | ||
| 379 | 12.0% | 9.3% | 10.6% | 8.6% | 6.9% | −42.5% | <0.001 | −28.3% | <0.001 |
|
| |||||||||
| Nationwide Medicare reimbursements for upper gastrointestinal bleeding hospitalizations in patients on ppASA (in millions) | |||||||||
|
| |||||||||
| Total Costs | $51.6 | $74.6 | $83.0 | $97.3 | $86.5 | +67.6% | <0.001 | +88.6% | <0.001 |
| 65–74 years | $31.5 | $45.6 | $50.8 | $59.9 | $54.1 | +71.7% | <0.001 | +90.2% | <0.001 |
| ≥75 years | $20.1 | $29.0 | $32.2 | $37.4 | $32.4 | +61.2% | <0.001 | +86.1% | <0.001 |
Diagnosis-Related Group codes correspond to the following: 377 = Gastrointestinal hemorrhage with major complication or comorbidity; 378 = Gastrointestinal hemorrhage with complication or comorbidity; 379 = Gastrointestinal hemorrhage without complication or comorbidity
Figure 1. Trends in incidence of Emergency Department visits for upper gastrointestinal bleeding from 2016–2020, stratified by age and sex.
Incidence (per 100,000 population) and percent change from 2016 to 2020 for upper gastrointestinal bleeding as primary diagnosis for emergency department visits in patients without atherosclerotic cardiovascular disease stratified by sex for patients (A) 45–54 years old; (B) 55–64 years old; (C) 65–74 years old and (D) ≥75 years old. *p<0.05 for linear trend.
We next assessed trends in etiologies of upper gastrointestinal bleeding in patients on ppASA from 2016–2020 (Figure 2). Peptic ulcer disease was the most common etiology for upper gastrointestinal bleeding in this population and rose in incidence from 4.5/100,000 to 5.8/100,000 (p-value for linear trend=0.05). Bleeding from angiodysplasias increased 87.7% between 2016–2020, rising from 0.3/100,000 to 0.5/100,000 (p=0.035). We also observed a significant increase in upper gastrointestinal bleed incidence from gastritis/duodenitis, rising from 0.9/100,000 to 1.5/100,000 (74.2% increase, p=0.007). Incidence of bleeding from varices, Dieulafoy lesions, and upper gastrointestinal bleeding not otherwise specified were relatively stable from 2016–2020.
Figure 2. Trends in etiology of upper gastrointestinal bleeding in patients on primary prevention aspirin from 2016–2020.
Age- and sex-specific incidences (per 100,000 population) and percentage change from 2016 to 2020 of different causes of upper gastrointestinal bleed among patients on primary prevention aspirin. *p<0.05 for linear trend.
To exclude the impact on hospitalizations of the COVID-19 pandemic, we performed a sensitivity analysis of trends for the period 2016–2019 (Table 2). We found qualitatively similar results in this analysis, with more marked numerical increases in upper gastrointestinal bleed incidence trends. In addition, the p-value for linear trend of the overall incidence of upper gastrointestinal bleeding in patients ppASA was statistically significant in this sensitivity analysis (p=0.006).
Next, to explore whether the trends in upper gastrointestinal bleeding in ppASA users were reflected in patients who were not on aspirin therapy, we performed a similar analysis of upper gastrointestinal bleeding incidence in individuals without atherosclerotic cardiovascular disease who were not on long-term aspirin therapy. We found that age- and sex-specific incidence of upper gastrointestinal bleeding only increased 4.2% from 73 events/100,000 population to 76 events/100,000 (p=0.275) (Supplement 1). The rise in incidence was most marked among patients 65–74 (21.4% increase), and only increased minimally among patients ≥75 years (2.7% increase), unlike what we observed for patients on ppASA. (Supplement 1). A sensitivity analysis excluding the year 2020 yielded similar findings. With regards to etiologies of upper gastrointestinal bleeding in this population, we similarly observed a significant increase in bleeding related to angiodysplasias (41.8% increase; p=0.011) and gastritis/duodenitis (26.2% increase; p=0.037) (Supplement 2).
We next performed multivariate regression analysis among patients without atherosclerotic cardiovascular disease presenting with upper gastrointestinal bleeding to determine the impact of ppASA on bleeding outcomes. ppASA users were more likely to be admitted to the hospital (OR=1.45, 95% CI 1.41–1.47), to receive red blood cell transfusions (OR=1.15, 95% CI 1.12–1.18), and endoscopic hemostatic intervention (OR=1.21, 95% CI 1.17–1.25) than patients without atherosclerotic cardiovascular disease who were not on ppASA.
Discussion
Using a large national database of ED visits, we present several key findings. First, the age- and sex-specific incidence rates of ED visits for upper gastrointestinal bleeding in ppASA users has increased by 29% from 2016–2020 with larger increases among patients ≥65 years old. Second, among all patients without atherosclerotic cardiovascular disease, the proportion of ED visits for upper gastrointestinal bleeding occurring in those on ppASA has increased by 24% during the same period. Third, the risk of poor clinical outcomes associated with upper gastrointestinal bleeding is greater among patients without atherosclerotic cardiovascular disease taking ppASA vs. not taking ppASA as demonstrated by higher odds of hospital admission, red blood cell transfusion and endoscopic hemostatic therapy. Fourth, the severity of upper gastrointestinal bleeding in patients on ppASA is rising rapidly with a 42% increase in hospital admissions for upper gastrointestinal bleeding with associated major complications/comorbidities from 2016–2020. Fifth, total costs for upper gastrointestinal bleeding in ppASA users in the United States have risen markedly, presumably due to the increased number and increased complexity of patients on ppASA hospitalized with upper gastrointestinal bleeding.
ppASA use is widespread in the United States and frequently occurs without a clear indication or without a physician’s recommendation1, 11. Our findings have important implications. Despite recent recommendations that narrow the population for its use, we demonstrate that the number of ED visits for upper gastrointestinal bleeding associated with ppASA is rising. It is especially notable that the largest proportion of ppASA users presenting with upper gastrointestinal bleeding were ≥75 years old. Our findings are consistent with a recent study demonstrating that 46% of individuals ≥70 years old reported ppASA use10. The risk of disabling or fatal upper gastrointestinal bleeding has been shown to markedly increase at age ≥75 years old18. Moreover, recent data from the Health and Retirement Study showed that hospitalization for extracranial hemorrhage (the majority of which were upper gastrointestinal bleeds) in elderly patients was associated with significantly decreased independence and function, with many patients never recovering to pre-hemorrhage levels of function19. As such, careful systematic assessment of the indication for aspirin use is critically important and deprescription may serve as an opportunity for prevention of hospitalizations for upper gastrointestinal bleeding.
Importantly, recent studies support the safety of ppASA deprescription by demonstrating that deprescription of ppASA in high-risk patients is not associated with increased cardiovascular events. In a post hoc study of the ASPREE (ASPirin in Reducing Events in the Elderly) trial, in a median follow-up time of 4.9 years, investigators found no significant increase in the risk of all-cause mortality or major adverse cardiovascular events among patients that were on ppASA prior to trial enrollment and stopped as a result of being randomized to placebo or those that continued ppASA20. Additionally, in a retrospective study of 320 patients on ppASA who presented with gastrointestinal bleeding, though deprescription of ppASA after bleeding was rare, cessation was not associated with increased risk of major adverse cardiovascular events compared to those that continued ppASA16. Though additional confirmatory studies are needed, these studies should reassure providers regarding the safety of ppASA deprescription in appropriate populations.
The results from our analysis also provide conservative estimates as to the economic burden of upper gastrointestinal bleeding among older patients (≥65 years old) based on Medicare reimbursements. Notably, the total costs increased steadily from 2016–2019 before falling slightly in 2020, likely explained by the lockdowns and precautions related to the coronavirus pandemic21. In 2014, ED visits and hospitalizations for upper gastrointestinal bleeding resulted in over $2 billion dollars in aggregate charges and the number of ED visits and hospitalizations for upper gastrointestinal bleeding have increased since22. In the context of evolving guidelines, the costs related to upper gastrointestinal bleeding among older patients highlighted in our study represent an opportunity for cost savings to the health care system that may be recouped by thoughtful prescription and deprescription of ppASA.
Our study is the first to estimate the real-world burden of ED visits and hospitalizations related to upper gastrointestinal bleeding in patients on primary prevention aspirin in the United States. The principal strength of our study stems from the use of a national database that allowed us to analyze a large patient sample representative of the national population. However, our study has several limitations that are worth discussion. The use of administrative codes for the identification of ppASA users may lead to misclassification and does not capture all ppASA users. However, this likely means our report underestimates the true burden of upper gastrointestinal bleeding in ppASA users in the United States. In addition, we identified aspirin use through a specific ICD-10 code and therefore could not verify if aspirin was being taken at the time of upper gastrointestinal bleeding. Furthermore, we were unable to assess the appropriateness of ppASA use in these patients as we were unable to calculate atherosclerotic cardiovascular disease risk scores.
In conclusion, the incidence of ED visits due to upper gastrointestinal bleeding in patients on ppASA has increased substantially from 2016–2020 in the United States. Moreover, the rise in incidence is most marked in elderly patients, who stand to incur the most significant harm from continued ppASA use. Over this period, ppASA patients with upper gastrointestinal bleeding were more likely to be admitted to hospital, to receive red blood cell transfusion and endoscopic therapy, and to have major complications or comorbidities associated with their hospital admission. Our findings underscore the importance for health care providers to identify patients that would benefit from ppASA deprescription that ultimately may prevent hospitalizations for upper gastrointestinal bleeding.
Supplementary Material
Clinical Significance.
Incidence of Emergency Department visits for upper GI bleeding in primary prevention aspirin users has significantly increased, particularly for older patients no longer recommended to take primary prevention aspirin.
Severity and costs associated with upper GI bleeding hospitalizations in primary prevention aspirin users have significantly increased.
Among patients without cardiovascular disease with upper GI bleeding, aspirin is associated with increased risk of hospital admission, red-blood-cell transfusion, and endoscopic intervention.
Funding:
D.L.S. was supported by a grant from the National Institutes of Diabetes and Digestive and Kidney Diseases (Grant/Award Number: DK125718).
Footnotes
Declaration of Interest Statement
All authors declare no affiliations with or involvement in any financial or non-financial interest in the subject matter or materials discussed in this manuscript.
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