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Preoperative Statin Administration Does Not Protect Against Early Postoperative Acute Respiratory Distress Syndrome: A Retrospective Cohort Study

Yadav, Hemang MBBS*; Lingineni, Ravi K. MPH; Slivinski, Ericka J. RN; Stockler, Katie A. RN; Subramanian, Arun MBBS; Oderich, Gustavo S. MD§; Wigle, Dennis A. MD, PhD; Carter, Rickey E. PhD; Kor, Daryl J. MD

doi: 10.1213/ANE.0000000000000387
Critical Care, Trauma, and Resuscitation: Research Report

BACKGROUND: Statins have been shown to possess antiinflammatory and immunomodulatory effects. In this study, we sought to determine if preoperative statin therapy is associated with a reduced frequency of postoperative acute respiratory distress syndrome (ARDS) in surgical populations at increased risk of developing ARDS.

METHODS: We performed a retrospective cohort evaluation of the association between preoperative statin therapy and early postoperative ARDS in patients undergoing elective high-risk thoracic and aortic vascular surgery. The association between preoperative statin therapy and postoperative ARDS was assessed using propensity-adjusted analyses to control for indication bias and confounding factors.

RESULTS: Of 1845 patients, 722 were receiving preoperative statin therapy. One hundred twenty patients developed postoperative ARDS. Frequencies of ARDS among those receiving statin therapy versus those who were not was 7.2% and 6.1%, respectively (OR = 1.20; 95% CI, 0.83–1.75; P = 0.330). Neither the stratified propensity score analysis (pooled OR 0.93; 95% CI, 0.60–1.43) nor matched analysis (OR = 0.78; 95% CI, 0.48–1.27) identified a statistically significant association between preoperative statin administration and postoperative ARDS. When compared to matched controls, patients who developed postoperative ARDS did not differ in mortality (7.7% vs 8.8%, P = 0.51), hospital length of stay (21 days vs 15 days, P = 0.21), or ventilator-free days (24 days vs 25 days, P = 0.62).

CONCLUSIONS: In patients undergoing high-risk surgery, preoperative statin therapy was not associated with a statistically significant reduction in postoperative ARDS. These results do not support the use of statins as prophylaxis against ARDS in patients undergoing high-risk surgery.

Published ahead of print July 29, 2014.Supplemental Digital Content is available in the text.

From the *Departments of Pulmonary and Critical Care Medicine, Health Sciences Research, Anesthesiology, §Division of Vascular Surgery, Department of Surgery, and Division of Thoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota.

Accepted for publication June 6, 2014.

Published ahead of print July 29, 2014.

Funding: This research was supported by Grant Number 1 KL2 TR000136 from the National Center for Advancing Translational Science (NCATS) as well as the Foundation for Anesthesia Education and Research. Support for data capture and management was received from the Mayo Clinic Center for Translational Science Activities—grant number UL1 TR000135.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the European Respiratory Society Annual Congress, 2013, which was the subject of an article in the ATS Morning Minute, ARDSnet bulletin, MedPage Today.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Daryl J. Kor, MD, Department of Anesthesiology and Division of Critical Care Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. Address e-mail to kor.daryl@mayo.edu.

Acute respiratory distress syndrome (ARDS) is a clinically devastating pulmonary syndrome of acute hypoxemic respiratory failure.1 In surgical populations, ARDS is a common cause of postoperative respiratory failure,2 and high-risk surgery is increasingly recognized as a primary risk factor for the development of ARDS.3,4 Although ARDS-associated mortality has decreased from nearly 100% to below 40% over the past 20 years,5 the impact of postsurgical ARDS on patient-important outcomes remains substantial.6 With the exception of supportive therapies such as lung-protective mechanical ventilation,7,8 neuromuscular blockade,9 and conservative fluid management,10 there are no effective strategies to prevent or treat perioperative ARDS.

Although the pathogenesis of ARDS is unclear, current hypotheses include endothelial activation and injury within the pulmonary microcirculation, lung inflammation and epithelial injury, altered coagulation and platelet function, and oxidative stress.11–14 HMG-CoA reductase inhibitors (statins) are well established for decreasing lipids and preventing cardiovascular disease.5,15 More recent investigations suggest nonlipid-decreasing effects of statin therapy, including the potential to reduce vascular permeability and inflammatory cytokines, increase levels of antiinflammatory cytokines, promote repair of damaged endothelium by accelerating re-endothelialization, mobilize endothelial progenitor cells, and increase endothelial cell proliferation.16–21 These processes are concordant with the hypothesized pathophysiology of ARDS, resulting in a plausible role for statins in the treatment and prevention of ARDS.

Some evidence suggests a potential protective effect of statin therapy in patients at risk of ARDS.22–25 However, there is evidence to the contrary and clinical equipoise remains.15,26,27 Importantly, data specifically evaluating the impact of statin therapy on the development of ARDS in the postsurgical population are limited.27

We evaluated the association between preoperative statin therapy and development of postoperative ARDS in a cohort of patients undergoing surgery that places them at increased risk of developing postoperative ARDS. We hypothesized that the odds of postoperative ARDS after aortic vascular and high-risk thoracic surgery (lung resection, esophagectomy) would be lower in those receiving preoperative statin therapy than in those who did not.

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METHODS

In this investigation, we used a retrospective observational cohort study design. The study was approved by the Mayo Clinic IRB (Rochester, Minnesota) before its initiation. The requirement for written informed consent was waived by the IRB. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used in the conduct of this study as well as in the reporting of our results.28

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Study Population

The study population was identified using 2 institutional surgical databases that contain a comprehensive list of all patients undergoing elective thoracic and aortic vascular surgery at a single tertiary care academic medical center. The study evaluated patients who underwent a procedure of interest between January 1, 2005, and November 11, 2010. Participants included in the study were older than 18 years and undergoing high-risk aortic vascular or thoracic surgery (lung resection or esophagectomy for cancer). Patients who refused the use of their medical record for research; had a preoperative diagnosis of acute lung injury (ALI) or ARDS, trauma, sepsis, shock, pancreatitis, acute congestive heart failure, pneumonia, or witnessed aspiration within 30 days of the procedure of interest; had preoperative mechanical ventilation, high-risk surgery within 30 days of the procedure of interest, cardiac transplantation, extracorporeal membrane oxygenation, ventricular-assist device placement, or history of obstructive sleep apnea or neuromuscular disease requiring home noninvasive ventilatory support were excluded. All patients meeting the inclusion criteria, lacking all exclusion criteria, and whose surgical procedure was performed during the defined interval were evaluated for the development of postoperative ARDS (Fig. 1).

Figure 1

Figure 1

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Outcome Variables

The primary outcome measure was the presence of ARDS. The study was performed before publication of the 2011 Berlin ARDS criteria. Consequently, our definition of postoperative ARDS is based on the 1994 American–European Consensus Conference that distinguishes between ALI and ARDS. In this study, ALI was defined as hypoxemic respiratory insufficiency with acute onset (within 5 days of the index surgical procedure), arterial oxygen tension/fraction of inspired oxygen <300 mm Hg, the presence of new bilateral pulmonary infiltrates on chest radiograph, and no evidence for left atrial hypertension. ARDS was defined as hypoxemic respiratory insufficiency with acute onset (within 5 days of the index surgical procedure), arterial oxygen tension/fraction of inspired oxygen <200 mm Hg, the presence of new bilateral pulmonary infiltrates on chest radiograph, and no evidence of left atrial hypertension. For clarity and in closer accordance with the 2011 Berlin criteria, ALI and ARDS will be considered as a single entity in this study and referred to as ARDS.

The presence of ARDS was first identified by cross-referencing the database containing patients who had undergone a procedure of interest with a second comprehensive database containing all patients who had screened positive for possible ARDS via a validated electronic syndrome surveillance tool known as the “ARDS sniffer.” This automated system has been validated in previous studies29 as having an excellent negative predictive value for identifying ARDS. The details of this algorithm are outlined in Appendix 1, Supplemental Digital Content 1, http://links.lww.com/AA/A941. Each screen-positive patient was independently reviewed by 2 study investigators blinded to the individual’s predictor variables (interobserver κ = 0.63; 95% CI, 0.54–0.71). Investigators underwent a structured ARDS tutorial before reviewing the electronic medical record (EMR). All disagreements were referred to a third investigator with substantial experience in ARDS adjudication.

Secondary outcome measures in patients who developed postoperative ARDS included in-hospital mortality, hospital and intensive care unit (ICU) length of stay, and ventilator-free days (VFD). VFD were defined as the number of days between successful weaning from mechanical ventilation and day 28 after study enrollment.30 Those who died before day 28 were determined to have had 0 VFD. Those who were discharged from the hospital before day 28 were assumed to have had no additional days of mechanical ventilation after hospital discharge.

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Predictor Variables

The primary exposure of interest was the presence of preoperative statin therapy. Exposure ascertainment proceeded with the assistance of a validated automated electronic search strategy that used an institutional database query tool (database discovery and query builder) to perform a search of the EMR for the variable(s) of interest. This automated search tool has been validated against manual data extraction31 and interrogates the medication section of all clinical notes within the EMR for the presence of a statin medication during the specified interval. In addition to the primary risk factor of interest, additional baseline demographics, clinical characteristics, intraoperative data, and postoperative data were extracted as well. The majority of these variables were obtained using the validated search strategies described above. For variables lacking validated web-based extraction techniques, manual chart review was performed. Data definitions and standard operating procedures were created and reviewed by the study team before initiating the data extraction.

To control for procedure-specific risk for ARDS, low-, intermediate-, and high-risk procedural categories were developed based on the frequency of ARDS for the specific surgical procedure.3 Low-risk procedures included wedge and segmental lung resections. Intermediate-risk procedures included lung resection surgery, such as lobectomy and pneumonectomy, lung decortication surgery, esophageal resection surgery, and first-time abdominal aortic surgery. High-risk procedures included thoracoabdominal aortic surgery and revision abdominal aortic surgery.

Data were captured, maintained, and managed using the web-based REDCap data management application. During the initial review, 10 charts were independently reviewed by all abstractors to provide a measure of interobserver and intraobserver variability to identify and correct problems in data collection, interpretation of definitions, and application of study criteria. Subsequently, an extensive series of checks for consistency, proper sequences of dates, and evaluation of missing or incomplete data was performed. If necessary, medical records were reviewed again, and questions resolved with the primary investigator. Charts were reviewed in order, starting with the most recent.

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Descriptive Analysis

Dichotomous variables are presented as counts with percentages. Continuous data are presented as median with 25% to 75% interquartile ranges (IQ range). To assess the degree of imbalance between the statin and no statin groups, univariate logistic regression analysis was performed (unadjusted analyses). The standardized group differences31 were used to quantify the magnitude of group differences before and after propensity score adjustment.

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Propensity Score Analysis

The selection of variables included in the propensity score estimation model was guided by recent studies highlighting the importance of including not only variables relating to the exposure of interest (i.e., statins) but also those relating to the outcome of interest (i.e., ARDS).32,33 Including this more comprehensive list of variables increases the precision of the estimated exposure effect without increasing bias.34 For this investigation, we specifically sought to determine the exposure effect of statin therapy in the most precise manner possible by including a comprehensive set of potentially confounding variables, including those relating to both exposure and outcome. As a sensitivity analysis to evaluate the impact of error in including variables not known preoperatively,35 we also estimated the propensity score using only presurgery variables. For clarity, we have fully outlined these 2 propensity score models in Appendix 2, Supplemental Digital Content 2, http://links.lww.com/AA/A942. The following paragraphs detail the necessary data preparation and analytical steps used.

Missing data were observed in several putative confounding variables. To avoid elimination of these variables and/or case-wise deletion of records with at least 1 missing value, multiple imputation was used to produce 10 different datasets with imputed values for the missing covariates. Logistic regression analysis was used to calculate propensity scores for each dataset with all hypothesized confounding variables in the model (variables included in the propensity score estimation are included in Table 1). The mean of the 10 propensity scores estimated through multiple imputation was used for matching and stratification in the propensity score-adjusted analysis. The estimated propensity scores were stratified, without regard to the statin exposure group, into deciles. A conditional logistic regression analysis using the deciles as strata was performed on each covariate to check for an association between statins and covariates. Strata-specific and common (or pooled) odds ratios were calculated to test the hypothesis. Furthermore, a 1:1 matching analysis using the propensity score logit (logit is the log-odds, ln(p/[1 − p]), where p is the estimated propensity score) was performed using a caliper of 0.3 (0.25 times the standard deviation of propensity score). Standardized mean differences after propensity score adjustment and P values from conditional logistic regression analysis using matched pairs as strata were obtained for each covariate to assess the effectiveness of the propensity score to control for confounding of the observed variables. As with the stratified analysis, conditional logistic regression was used to estimate the odds of ARDS for patients with preprocedure exposure to statins. In all final analyses, statistical significance was considered present when the hypothesis test P value was <0.05. All the statistical analyses were performed using SAS version 9.3 (Cary, NC).

Table 1

Table 1

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RESULTS

A total of 1845 patients met the inclusion criteria, had no exclusion criteria, and were included in this study. Of these, 722 were receiving preoperative statin therapy. The baseline demographics, clinical characteristics, intraoperative data, and early postoperative data for these patients are presented in Table 1. Of 722 patients receiving preoperative statin therapy, 482 (67%) had statin therapy restarted in the immediate postoperative period (within 5 days).

A number of ARDS risk factors and risk modifiers differed in the statin versus nonstatin cohorts. Specifically, the statin cohort was older, included a higher proportion of male study participants, included a larger proportion of past smokers, and had a higher prevalence of hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, and chronic obstructive pulmonary disease. The statin cohort was also more likely to be receiving preoperative angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, inhaled corticosteroids, amiodarone, and antiplatelet therapy. In contrast, the nonstatin cohort had a higher prevalence of recent chemotherapy and was more likely to have never smoked. The statin group had a higher proportion of patients with an ASA score of 3 or more and more frequently underwent procedures with an intermediate or high risk for ARDS. The procedures of statin cohorts were longer and were associated with a greater positive fluid balance, higher median tidal volumes and peak airway pressures, and more frequent need for intraoperative blood product transfusion. The nonstatin cohort more frequently underwent procedures with a low risk for ARDS. While unadjusted group comparisons demonstrated numerous between-group differences, propensity score matching greatly reduced the confounding between the statin exposure groups (Table 1). Propensity matching was effective in balancing baseline covariate imbalances (Fig. 2).

Figure 2

Figure 2

One hundred twenty patients developed postoperative ARDS. The frequency of ARDS among those who received preoperative statin therapy versus those who did not was 7.2% vs 6.1% (OR = 1.20; 95% CI, 0.83–1.75; P = 0.330). Stratified and 1:1 matching propensity score-adjusted analysis evaluating the association between the statins and ARDS is shown in Figures 3 and 4. Conditional logistic regression analysis on deciles of propensity scores showed no association (OR = 0.93; 95% CI, 0.60–1.43) between preoperative statin use and ARDS. These results were consistent with the results from the 1:1 matched analysis (OR = 0.78; 95% CI, 0.8–1.27).

Figure 3

Figure 3

Figure 4

Figure 4

In patients who developed ARDS, secondary outcomes did not differ between those who received preoperative statins and those who did not (Table 2). Specifically, there were no significant differences in mortality (7.7% vs 8.8%, P = 0.51), VFD (24 days [15.5–28] vs 25 days [18–27], P = 0.62), ICU length of stay (8.3 days [4.4–15.5] vs 7.1 days [4.1–13.3], P = 0.44), and hospital length of stay (21 days [14–34.3] vs 15 days [11–33], P = 0.21).

Table 2

Table 2

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Propensity Score—Sensitivity Analysis

The primary propensity score included 5 variables that were measured during the intraoperative period. Because such variables are not known preoperatively, they have the potential to introduce error into the logistic regression. To assess the influence of these variables on the overall study results, a new propensity score was estimated without these variables ([Appendix 2, Supplemental Digital Content 2, http://links.lww.com/AA/A942] estimated equations). The estimated odds ratios for ARDS were 0.93 (95% CI, 0.60–1.43) and 0.87 (95% CI, 0.56–1.34) using the stratified and 1:1 matched analyses, respectively. These results are similar to the primary findings.

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DISCUSSION

In this study, we aimed to better define the association between preoperative statin therapy and postoperative ARDS in patients undergoing high-risk thoracic and aortic vascular surgery. The primary finding was the lack of a protective association between preoperative statin therapy and postoperative ARDS. Notably, this lack of an association appeared robust and was evident in both the unadjusted and propensity-adjusted analyses. In patients who developed postoperative ARDS, patient-important outcomes were not different between those receiving preoperative statins and those who had not.

ARDS has been identified as the most common cause of postoperative respiratory failure and an important cause of perioperative morbidity and mortality.2 Previously identified risk factors for postoperative ARDS have included high-risk surgical procedures (particularly cardiac, aortic vascular, and thoracic), alcohol abuse, chronic obstructive pulmonary disease, diabetes mellitus, and gastroesophageal reflux disease.4 Given the lack of effective therapeutic options for ARDS, interest in exploring preventative therapies in these high-risk groups is high.

The concordance between ARDS pathophysiology and the nonlipid effects of statin therapy make statins a promising potential option for the prevention and/or treatment of ARDS. In animal models of lung injury, simvastatin has been shown to reduce endothelial permeability and lung inflammation across a variety of lung injury mechanisms.18,36–38 In a randomized trial of previously healthy human subjects with lipopolysaccharide-induced lung injury, pretreatment with simvastatin was associated with lower levels of intraalveolar tumor necrosis factor α, as well as a reduction in alveolar neutrophil and protease concentrations.22 However, large-scale randomized clinical trials of statin therapy for the treatment of ARDS have failed to show any measureable benefit of statin therapy in the treatment of established ARDS.24,39 The recently published SAILS study randomized 745 patients to rosuvastatin or placebo within 48 hours of developing sepsis-associated ARDS. The trial was terminated early due to futility after showing no benefit of statin therapy on mortality or other clinical outcomes. Notably, the rosuvastatin group was associated with a greater incidence of renal and hepatic failure.39

Given the discouraging results for statin therapy in the treatment of established ARDS, there is ongoing focus on statins for ARDS prevention. Observational studies evaluating statin therapy have shown mixed results. The results of O’Neal et al.25 suggest that patients taking statins may have reduced risk of developing ARDS. However, this study did not show any effect on patient-centered outcomes such as mortality, ICU length of stay, or VFD. Other observational studies have shown no measureable effects of statins on either ARDS incidence or patient-centered outcomes.15,26 A recently published single-center randomized controlled trial of a small cohort of patients undergoing esophagectomy showed no significant effects in the incidence of ARDS or other patient-important outcomes in patients pretreated with simvastatin.27

Our study has several strengths that deserve mention. It is the first observational study to specifically evaluate whether preexisting statin therapy has any protective effect in the development of ARDS after high-risk surgery. Because the mechanisms underlying ARDS are likely to depend, at least to an extent, on the clinical context surrounding the ARDS episode (e.g., surgery versus sepsis versus aspiration), it is possible that statins may exert differential effects depending on the clinical setting.40 In addition, surgical populations are unique in that the timing of the precipitating factor(s) for ARDS is known in advance. This predictability may facilitate future trials evaluating promising ARDS prevention strategies. To this end, an improved understanding of the potential role of statins in the specific clinical setting of high-risk surgery may provide a template for future clinical trials on statin therapy as an ARDS prevention strategy. This study also used rigorous methods for ARDS adjudication and risk factor ascertainment when compared to prior studies. Our study is the second largest in terms of total patients enrolled and the largest in terms of number of patients taking statins before enrollment. Finally, conclusions drawn from observational studies are inherently limited by measured and unmeasured confounding, bias, as well as missing clinical data. Our study included robust propensity-adjusted analyses that meaningfully addressed baseline imbalances noted in important covariates and allowed an estimation of the error introduced by use of variables not known preoperatively (Table 1). To address missing data, we used sophisticated multiple imputation techniques. In using these strategies, we believe we have substantially enhanced the validity of the study findings.

Importantly, there are also several limitations. As mentioned above, the observational nature of this study creates potential for confounding and bias. While extensive efforts were made to control for bias with a robust propensity-adjusted analysis, potential for residual confounding from variables other than those incorporated in the model remains. The observational study design also precluded the standardization of other important care processes, which could confound the association of interest. A second limitation relates to the determination of the presence of statin therapy. Specifically, due to the retrospective observational nature of this study, formal assessments of medication administration with actual patient interviews were not performed. Rather, we relied on documentation of the medications of interest in the EMR when determining the presence or absence of statin therapy before surgery. It is possible that some patients may have been receiving statin therapy that was not documented in the EMR. Furthermore, it is also possible that some patients with a statin medication listed in the EMR were not actually receiving such therapy before the surgical procedure. In the early postoperative period, 67% of statin takers were restarted on statin therapy. Although stopping statins postoperatively could potentially have masked any protective effect of statin therapy, prior studies have shown no clear consequences of statin cessation in critical illness.41,42 Moreover, any protective effect of statins would most plausibly depend on drug concentrations at the time of the inciting event (i.e., the immediate perioperative period) and consequently not be affected by postoperative statin administration. A third significant limitation is our restriction to patients undergoing high-risk thoracic and aortic vascular surgery. We elected to focus on these specific surgical cohorts due to their known risk for early postoperative ARDS.3,4 As a result of our emphasis on these specific surgical populations, our findings may not generalize to other surgical populations or to medical populations at risk for ARDS. Finally, the study population for this investigation was from a single-center academic medical center. This limited the overall sample size, the number of ARDS events, and consequently the overall precision of the results. This additionally raises concern for referral and institution-specific bias as well as overall generalizability.

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CONCLUSIONS

In patients undergoing high-risk surgical procedures, preoperative statin therapy was neither associated with a statistically significant reduction in the incidence of postoperative ARDS nor improvements in patient-important outcomes in those who developed ARDS. These results do not support the use of statins as an ARDS preventative measure in patients undergoing high-risk surgery.

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DISCLOSURES

Name: Hemang Yadav, MBBS.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Hemang Yadav has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Ravi K. Lingineni, MPH.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Ravi K. Lingineni has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ericka J. Slivinski, RN.

Contribution: This author helped conduct the study.

Attestation: Ericka J. Slivinski has seen the original study data and approved the final manuscript.

Name: Katie A. Stockler, RN.

Contribution: This author helped conduct the study.

Attestation: Katie A. Stockler approved the final manuscript.

Name: Arun Subramanian, MBBS.

Contribution: This author helped design the study and conduct the study.

Attestation: Arun Subramanian approved the final manuscript.

Name: Gustavo S. Oderich, MD.

Contribution: This author helped design the study and conduct the study.

Attestation: Gustavo S. Oderich approved the final manuscript.

Name: Dennis A. Wigle, MD, PhD.

Contribution: This author helped design the study and conduct the study.

Attestation: Dennis A. Wigle approved the final manuscript.

Name: Rickey E. Carter, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Rickey E. Carter has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Daryl J. Kor, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Daryl J. Kor has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Avery Tung, MD.

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