Assessment of Anti–Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics | Colorectal Surgery | JAMA Surgery | JAMA Network
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Figure 1.  Clinical Study Protocol Including Real-time Anti–Factor Xa (aFXa) Level Monitoring and Enoxaparin Dose Adjustment
Clinical Study Protocol Including Real-time Anti–Factor Xa (aFXa) Level Monitoring and Enoxaparin Dose Adjustment
Figure 2.  Peak Anti–Factor Xa (aFXa) Stratified by Weight
Peak Anti–Factor Xa (aFXa) Stratified by Weight

The shaded area denotes peak aFXa levels that are considered in range.

Figure 3.  Enoxaparin Dose Grouped by Anti–Factor Xa (aFXa) Level
Enoxaparin Dose Grouped by Anti–Factor Xa (aFXa) Level
Table 1.  Demographics and Operative Indications for 116 Patients
Demographics and Operative Indications for 116 Patients
Table 2.  Frequency of 2005 Caprini Risk Assessment Model Risk Factors Among 116 Patients
Frequency of 2005 Caprini Risk Assessment Model Risk Factors Among 116 Patients
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Lin  H, Faraklas  I, Saffle  J, Cochran  A.  Enoxaparin dose adjustment is associated with low incidence of venous thromboembolic events in acute burn patients.  J Trauma. 2011;71(6):1557-1561.PubMedGoogle Scholar
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    Original Investigation
    May 22, 2019

    Assessment of Anti–Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics

    Author Affiliations
    • 1Division of Plastic Surgery, University of Utah, Salt Lake City
    • 2Division of Health Services Research, University of Utah, Salt Lake City
    • 3Division of Pharmacy, University of Utah, Salt Lake City
    • 4Division of General Surgery, University of Utah, Salt Lake City
    JAMA Surg. 2019;154(8):697-704. doi:10.1001/jamasurg.2019.1165
    Key Points

    Question  Is enoxaparin, 40 mg per day, adequate, based on pharmacokinetics, for venous thromboembolism prophylaxis in patients undergoing colorectal surgery?

    Findings  This nonrandomized clinical trial enrolled 116 patients undergoing colorectal surgery who received enoxaparin, 40 mg per day, for venous thromboembolism prophylaxis at a single institution. The study found that among 106 patients with appropriately timed anti–factor Xa levels, a marker of the extent of anticoagulation and enoxaparin effectiveness, 72 patients (67.9%) received inadequate anticoagulation.

    Meaning  This study demonstrates that two-thirds of patients undergoing colorectal surgery have inadequate anti–factor Xa levels in response to enoxaparin, 40 mg once daily, and that a higher weight is associated with lower anti–factor Xa levels.

    Abstract

    Importance  Between 4% and 12% of patients undergoing colorectal surgery and receiving enoxaparin, 40 mg per day, have a postoperative venous thromboembolism (VTE) event. An improved understanding of why “breakthrough” VTE events occur despite guideline-compliant prophylaxis is an important patient safety question.

    Objective  To determine the proportion of patients undergoing colorectal surgery who received adequate anticoagulation based on peak anti–factor Xa (aFXa) levels while receiving enoxaparin at 40 mg per day.

    Design, Setting, and Participants  This prospective, nonrandomized clinical trial was conducted between February 2017 and July 2018 with 90-day follow-up at a quaternary academic medical center in the Intermountain West and included patients undergoing colorectal surgery who had surgery after receiving general anesthesia, were admitted for at least 3 days, and received enoxaparin, 40 mg once daily.

    Interventions  All patients had aFXa levels measured after receiving enoxaparin 40 mg per day. Patients whose aFXa level was out of range entered the trial’s interventional arm where real-time enoxaparin dose adjustment and repeated aFXa measurement were performed.

    Main Outcomes and Measures  Primary outcome: in-range peak aFXa levels (goal range, 0.3-0.5 IU/mL) with enoxaparin, 40 mg per day. Secondary outcomes: (1) in-range trough aFXa levels (goal range, 0.1-0.2 IU/mL) and (2) the proportion of patients with in-range peak aFXa levels from enoxaparin, 40 mg once daily, vs the real-time enoxaparin dose adjustment protocol.

    Results  Over 16 months, 116 patients undergoing colorectal surgery (65 women [56.0%]; 99 white individuals [85.3%], 13 Hispanic or Latino individuals [11.2%], and 4 Pacific Islander individuals [3.5%]; mean [range] age, 52.1 [18-85] years) were enrolled. Among 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation (aFXa < 0.3 IU/mL) with enoxaparin, 40 mg per day. Weight and peak aFXa levels were inversely correlated (r2 = 0.38). Forty-seven patients (77%) had a trough aFXa level that was not detectable (ie, most patients had no detectable level of anticoagulation for at least 12 hours per day). Real-time enoxaparin dose adjustment was effective. Patients were significantly more likely to achieve an in-range peak aFXa with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001).

    Conclusions and Relevance  This study supports the finding that most patients undergoing colorectal surgery receive inadequate prophylaxis from enoxaparin, 40 mg once daily. These findings may explain the high rate of “breakthrough” VTE observed in many clinical trials.

    Trial Registration  ClinicalTrials.gov identifier: NCT02704052

    Introduction

    Venous thromboembolism (VTE) includes deep venous thrombosis (DVT), central venous thrombosis, and pulmonary embolus (PE) and is a source of morbidity and mortality in patients undergoing colorectal surgery.1-5 Current guidelines from the American Society of Colon and Rectal Surgeons (ASCRS) recognize that patients undergoing colorectal surgery are at elevated risk for postoperative VTE, and provide a grade 1A recommendation for providing chemical VTE prophylaxis for these patients.2 The ASCRS and American College of Chest Physicians recommend clinicians consider postdischarge chemical prophylaxis.2,6 Enoxaparin is a low-molecular-weight heparin commonly provided for postoperative chemical prophylaxis in patients undergoing colorectal surgery. The drug is approved by the US Food and Drug Administration for VTE prophylaxis at a dose of 40 mg once daily based on multicenter randomized clinical trial data demonstrating its effectiveness and safety.7-9

    Despite the administration of guideline-compliant chemical prophylaxis, “breakthrough” VTE events are common in patients undergoing colorectal surgery. Several multicenter randomized clinical trials have demonstrated that the rate of symptomatic plus asymptomatic DVT in patients undergoing abdominal and pelvic surgery who are receiving enoxaparin, 40 mg per day, is between 4.8% and 12.6%.8-10

    Enoxaparin prophylaxis is typically provided as a fixed or “one-size-fits -all” dose, meaning that patients receive an identical dose (40 mg) and regularity (once daily).7 However, emerging data show that, between patients, fixed doses of enoxaparin are metabolized at variable rates. This finding has been demonstrated through an examination of peak and trough steady-state anti–factor Xa (aFXa), a marker of the extent of anticoagulation used to quantify enoxaparin activity.11-13 Based on aFXa levels, more than 50% of patients who have thoracic surgery, plastic and reconstructive surgery, and abdominal surgery receive inadequate anticoagulation when provided with enoxaparin, 40 mg once daily.14-16 This is relevant because patients whose postoperative aFXa levels are inadequate are significantly more likely to develop asymptomatic DVT17-19 or symptomatic VTE.14

    We hypothesize that breakthrough VTE events among the colorectal surgery population occur because of inadequate enoxaparin dosing. To examine this hypothesis, we performed a prospective clinical study to examine the pharmacokinetics of enoxaparin, 40 mg per day, in patients undergoing colorectal surgery and the association of aFXa levels with 90-day VTE and bleeding events.

    Methods

    This study received institutional review board approval from the University of Utah and was registered on ClinicalTrials.gov (NCT02704052) before patients were enrolled. The inclusion criteria were (1) patients undergoing colorectal surgery, (2) surgery by 1 of 2 attending surgeons (T.B.P. or L.C.H.), (3) general anesthesia, and (4) postoperative admission. The exclusion criteria were (1) creatinine levels greater than 1.6 mg per dL (to convert to micromoles per liter, multiply by 76.25), (2) admission less than 3 days, (3) epidural catheter, (4) known bleeding disorder, (5) heparin-induced thrombocytopenia, (6) recent stroke or intracranial bleeding, or (7) received nonenoxaparin chemical prophylaxis per the discretion of the attending physician.

    Patients received enoxaparin, 40 mg per day, for VTE prophylaxis, which was administered the morning after surgery. In addition, all patients had sequential compression devices placed before the induction of anesthesia. Patients continued to have these devices through the postanesthesia care unit and inpatient stays and they were removed at hospital discharge. Patients were encouraged to ambulate as soon as possible after surgery and order sets included a mandatory 4 times per day ambulation starting on postoperative day 1.

    Patients meeting inclusion and exclusion criteria were approached by the study research coordinator on postoperative day 1 to provide written informed consent. All patients had their peak and trough levels checked at a steady state (4 and 12 hours after the third dose of enoxaparin, 40 mg). Patients with out-of-range peak aFXa levels (Figure 1) entered the interventional arm of the study that examined the effect of the real-time enoxaparin dose adjustment. The dose adjustment regimen (Figure 1) was designed by pharmacist collaborators (A.M.P. and C.B.B.) and reflects our institution’s experience using aFXa level monitoring and dose adjustment.16,20-26

    For once-daily enoxaparin, the goal steady-state peak and trough aFXa levels were 0.3 to 0.5 IU/mL and 0.1 to 0.2 IU/mL, respectively; these ranges have been shown to optimize VTE risk reduction and minimize bleeding risk.14,17,27,28 Laboratory draw results occurring within a 1-hour window of the planned laboratory draw time were included.14,16,20 The study design included real-time enoxaparin dose adjustment based on the peak steady-state aFXa level. We used peak aFXa levels, as our recent review showed that 80% of identified articles targeted peak aFXa levels and because insufficient peak aFXa level is associated with symptomatic, instead of all-cause, 90-day VTE.14,27 No masking was performed.

    Using face-to-face interviews and a medical record review, we prospectively identified patient demographics and operative indications and identified VTE-centric risk factors using a 2005 Caprini score.29 After the surgical procedure, the operating surgeon supplemented data on tumor characteristics and operative details. The operating surgeon reported all VTE and bleeding events were reported by the research staff. At 90 days after surgery, all patients’ medical records were retrospectively reviewed to identify bleeding or VTE events that were not reported to study staff by the operating surgeon. In addition, all patients received a 90-day phone call to screen for bleeding or VTE events that occurred outside of the University of Utah health system. When identified, confirmatory medical records were obtained from outside institutions for review.

    Study Outcome Definitions

    The primary study outcomes included low vs in-range or high peak aFXa levels in patients receiving enoxaparin, 40 mg per day. Secondary outcomes included low, in-range, or high trough aFXa levels in patients receiving enoxaparin, 40 mg per day, and the effect of real-time enoxaparin dose adjustment guided by aFXa.

    Additional secondary outcomes included 90-day symptomatic VTE and 90-day clinically relevant bleeding. We defined symptomatic VTE before the study as any symptomatic VTE event with imaging confirmation. This included patients with DVT, central venous thrombosis (such as inferior vena cava or portal vein), and/or pulmonary embolus. We included catheter-associated DVT as a DVT event because existing treatment algorithms30 recommend the same magnitude and duration of anticoagulation for catheter-associated DVT when compared with other DVT events.

    We defined clinically relevant bleeding as any bleeding event that changed the course of care. This intentionally broad definition was used to capture the spectrum of bleeding that encompassed bleeding that required enoxaparin cessation (because a delay to adequate prophylaxis is known to be associated with VTE),31-34 unanticipated blood transfusion, or an unanticipated procedure (either interventional radiology drainage or a return to the operating room).

    Analysis Plan

    Descriptive statistics examined the proportion of patients with in-range and out-of-range peak and trough aFXa levels. We examined the associations between patient-level factors and in-range peak aFXa levels using bivariate statistics, including the t test, χ2 test, Fisher exact test, and the Wilcoxon rank sum test.

    We compared the rates of 90-day VTE and 90-day bleeding in those with low vs in-range/high peak aFXa levels. The comparison was performed using a survival analysis log-rank test, which allowed consideration of whether patients had a 90-day event and when within the 90-day follow-up the event occurred. The analysis strategy allowed the inclusion of patients for whom 90-day follow-up could not be performed (ie, lost to follow-up) but no patients were lost to follow-up. The censoring rate of this analysis was zero.

    We examined the effectiveness of the clinical protocol described in Figure 1 for real-time aFXa level monitoring and dose adjustment on achieving in-range peak aFXa levels. We compared the proportion of patients whose peak aFXa levels were in range before and after dose adjustment. Patients whose level was not in range had their enoxaparin dose adjusted (Figure 1). However, the “after dose adjustment” group denominator included only patients who either had dose adjustment with repeated aFXa levels or patients whose initial aFXa levels were in range. This plan excluded patients who received dose adjustment and had no repeated aFXa levels as confirmation of protocol effectiveness.

    A multivariable linear regression was performed to examine the association of patient-level variables with peak aFXa levels when controlling for identified confounders. Analyses were performed using Stata, version 14 (StataCorp), and statistical significance was set at P < .05.

    Results

    Between February 2, 2017, and July 20, 2018, 202 patients undergoing colorectal surgery met the initial screening criteria. Patients provided informed consent in the preoperative area or on postoperative day 1. Two hundred one patients provided informed consent for participation. Eighty-eight patients (43.8%) who provided consent did not produce data for the primary outcomes (aFXa level). Reasons included that they were discharged before laboratory draw results were obtained (77 [87.5%]), underwent an alternate chemical prophylaxis strategy (4 [4.5%]), resumed therapeutic anticoagulation for atrial fibrillation (2 [2.3%]), had a bleeding event before laboratory draws were conducted (3 [3.4%]), had a postoperative epidural (1 [1.1%]), and requested withdrawal from study (1 [1.1%]). The study recruitment rate was 99.5% and the study retention rate was 57.0%. One hundred thirteen patients (56.2%) generated data for peak and/or trough steady-state aFXa levels while receiving enoxaparin, 40 mg once daily. We also included 3 patients (1.5%) who had a bleeding event before aFXa levels were measured who subsequently stopped taking enoxaparin.

    Patients were representative of the Intermountain West’s population (Table 1). Among 116 patients, 1 (0.9%) died within the 90-day follow-up. We established phone contact with all 115 living patients at 90 days. Table 2 describes the population’s risk factors for VTE, characterized using the 2005 Caprini score.29Table 1 also describes details about the operative procedures performed.

    Peak and Trough aFXa Levels

    Among 113 patients, 6 (5.3%) had inappropriately timed peak aFXa levels and 1 (0.9%) did not have peak aFXa levels drawn. Among 106 patients receiving enoxaparin, 40 mg per day, with adequately timed peak aFXa levels, 72 (67.9%) had a peak aFXa level of less than 0.3 IU/mL, which was indicative of inadequate anticoagulation. Thirty-one (29.3%) received adequate anticoagulation (0.3-0.5 IU/mL) and 3 (2.8%) received overanticoagulation. A scatterplot analysis demonstrated an inverse association between peak aFXa levels and patient weight (r2 = 0.38) (Figure 2).

    Multiple patient-level factors showed an association with low peak aFXa levels on a bivariate screen (eTable 1 in the Supplement). However, a linear regression model that controlled for the effect of identified confounders showed that only patient weight had a significant and independent association with peak aFXa level in patients who received enoxaparin, 40 mg per day, (eTable 2 in the Supplement).

    Sixty-nine patients (65.1%) had trough steady-state aFXa levels drawn while receiving enoxaparin, 40 mg once daily. Eight (7.5%) were excluded for inappropriate timing, leaving 61 patients. Among these patients, 47 (77.1%) had undetectable aFXa activity 12 hours after the third enoxaparin dose. In addition, 13 (21.3%) had an in-range trough level (0.1-0.2 IU/mL) and 1 (1.6%) had a high trough level (eFigure 1 in the Supplement).

    Real-time dose adjustment was effective. Seventy-five patients (70.8%) with out-of-range peak aFXa levels received real-time enoxaparin dose adjustment. Among 17 patients (16.0%) who had at least 1 repeated peak aFXa level drawn, 6 (35.3%) achieved in-range levels after the first round of dose adjustment, 3 (17.6%) achieved in-range levels after the second round, and 1 (5.9%) after the third round. Patients were significantly more likely to achieve in-range peak aFXa levels with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001).

    90-Day VTE and Bleeding

    Among 116 participants with 90-day follow-up or confirmed 90-day death, the rate of symptomatic VTE was 2.6% and the rate of clinically relevant bleeding was 3.4%. Events are described in eTable 3 in the Supplement. One of 3 VTE events occurred during enoxaparin prophylaxis and 2 occurred after enoxaparin cessation. Four of 4 bleeding events occurred during enoxaparin prophylaxis. A Kaplan-Meier analysis examined the association of low vs in-range/high aFXa levels with 90-day VTE events. Three 90-day VTE events occurred and 106 patients with appropriately drawn peak aFXa levels were included in the analysis. There was no significant difference in 90-day VTE when patients with low vs in-range aFXa levels were compared (2.7% vs 2.9%, P = .96) (eFigure 2 in the Supplement). A Kaplan-Meier analysis was not performed for bleeding events because of a paucity of outcome events. Three events occurred before aFXa levels were drawn and 1 occurred after an aFXa level was drawn.

    For 106 patients with adequately timed peak aFXa levels, the fixed enoxaparin, 40 mg per day, dose was considered as a milligram per kilogram dose. Weight-based doses were stratified by low (<0.3 IU/mL), in-range (0.3-0.5 IU/mL), and high (>0.5 IU/mL) peak steady-state aFXa levels (Figure 2). Forty-one patients (38.7%) received a dose that was less than 0.5 mg/kg; among those, 38 (92.7%) had low peak aFXa levels. Weight-based once-daily dosing at 0.5 to 0.8 mg/kg allowed a higher proportion of patients to achieve in-range levels; among 60 patients (56.6%) who received a dose of 0.5 to 0.8 mg/kg, 30 (50%) had low aFXa levels, 27 (45%) had in-range aFXa levels, and 3 (5%) had high aFXa levels (Figure 3).

    Discussion

    This study demonstrates that about 2 in 3 patients (67.9%) undergoing colorectal surgery receive inadequate prophylaxis based on aFXa levels when receiving enoxaparin, 40 mg per day. It also demonstrates that patient weight is independently associated with enoxaparin metabolism after colorectal surgery and that elevated weight can identify patients who are more likely to receive an inadequate dose. Baumgartner et al15 previously examined aFXa levels in 55 patients after abdominal surgery who were provided with enoxaparin, 40 mg per day, showing that about half of the patients (54.4%) had inadequate peak aFXa levels. Our findings and the findings of Baumgartner et al15 are important because studies in other surgical specialties have associated inadequate enoxaparin prophylaxis with downstream asymptomatic DVT17-19 and symptomatic VTE.14 The data presented here challenge the current idea that a “one-size-fits-all” enoxaparin prophylaxis strategy is appropriate for patients undergoing colorectal surgery. These data also support future trials in patients undergoing colorectal surgery to investigate the effect of alterations in enoxaparin dose magnitude to 0.5 to 0.8 mg per kilogram or alterations in dose frequency to twice daily.

    The ASCRS recently published their Clinical Practice Guideline for Prevention of Venous Thromboembolism in Colorectal Surgery Patients.2 These guidelines support a multifaceted approach to VTE risk stratification and prevention in patients undergoing colorectal surgery. Recommendations include individualized VTE risk stratification using the 2005 Caprini score or the Rogers score,29,35 using sequential compression devices, early ambulation, and postoperative chemical prophylaxis.2 In addition, current guidelines advocate for considering postdischarge chemical prophylaxis in patients with colorectal cancer who are deemed at high risk for VTE based on data that show significant decreases in all-cause (symptomatic plus asymptomatic) 30-day DVT.8,36-38

    The ASCRS Clinical Practice Guidelines discuss current data that show the equipoise between low-molecular-weight heparins and unfractionated heparins when used for prophylactic purposes. However, the current guidelines do not consider why patients have “breakthrough” VTE events while receiving guideline-compliant prophylaxis. These “breakthrough” events occur in 4% to 12% of patients who receive fixed-dose anticoagulation regimens as part of large clinical trials.8,36 The data presented here demonstrate that most patients (67.9%) undergoing colorectal surgery receive inadequate prophylaxis based on aFXa levels using a fixed-dose prophylaxis strategy. This finding is important because studies in orthopedics,17 trauma,19 and surgical patients with critical illness18 have shown a significant association between low aFXa levels and asymptomatic DVT. In addition, 1 study in patients undergoing plastic and reconstructive surgery has shown a significant association between low aFXa levels and symptomatic 90-day VTE.14

    Data from this study show that 77.1% of patients have trough levels that are undetectable at 12 hours; for a once-daily enoxaparin dose, this supports that most patients receive anticoagulation for fewer than 12 hours a day. Prior studies have addressed this using enoxaparin, 40 mg twice daily, and studies in bariatric surgery39 and plastic and reconstructive surgery21 have shown low rates of inadequate anticoagulation (21% and 9.6%, respectively).

    Dose-adjusted enoxaparin using a weight-based or weight-tiered approach allows significantly more patients to achieve in-range aFXa levels when compared with fixed-dose prophylaxis; this has been demonstrated in the trauma surgery, gynecologic surgery, and medically ill intensive care unit populations.25,26,40-43 Similarly, enoxaparin dose prediction equations that incorporate patient-centric factors, such as weight and the extent of injury, allow more patients to have in-range aFXa levels.24

    Real-time aFXa level monitoring and enoxaparin dose adjustment is feasible in patients undergoing trauma surgery, plastic surgery, and thoracic surgery14,16,23,42,44 and significantly increases the proportion of patients with in-range levels. Rates of symptomatic VTE are known to be significantly decreased in trauma patients (1.1% vs 7.6%, P = .046)44 and in orthopedic trauma patients (1.7% vs 13.9%, P = .03)45 who receive an aFXa-guided enoxaparin dose adjustment as opposed to an unmonitored fixed-dose prophylaxis regimen. One international society, the Royal College of Obstetrics and Gynecology, formally recommends weight-tiered postoperative enoxaparin dosing.46 Patient-centric enoxaparin dosing allows patients to achieve in-range aFXa levels more rapidly and more frequently than unmonitored, fixed-dose prophylaxis strategies. This is important because a delay to adequate chemical prophylaxis is a risk factor for downstream VTE.31-34

    Limitations

    This study has several limitations. We observed low rates of 90-day VTE and bleeding (2.6% and 3.4%, respectively), which is desirable in this high-risk population. However, the low number of outcome events made rigorous examination of the association of aFXa levels with 90-day outcomes impossible; thus, we cannot definitively associate aFXa levels with VTE or bleeding. This is particularly true for the bleeding outcome, for which many events occurred before a steady state. A larger trial or pooled analysis of multiple trials could further examine this issue. Enoxaparin reaches a steady state after the third dose and our study administered this medication once daily. Thus, all patients who produced data for the primary outcome were admitted at least 3 days after surgery. In this trial, 88 patients (43.8%) who provided informed consent did not produce data for the primary outcome; for 79 patients (90%) who did not produce data, the reason was “discharged prior to laboratory draws.” This is a reminder that our findings are not necessarily generalizable to patients whose inpatient stay is shorter than 3 days, and the effect of enoxaparin on patients discharged before a steady state is reached remains unknown.

    Conclusions

    In this prospective clinical study, two-thirds of patients who underwent colorectal surgery had low aFXa levels when receiving enoxaparin, 40 mg per day. The adequacy of enoxaparin prophylaxis represents a direction for future research, and future studies should examine the effectiveness and safety of weight-based or twice-daily enoxaparin prophylaxis in patients undergoing colorectal surgery.

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    Article Information

    Accepted for Publication: February 15, 2019.

    Corresponding Author: Christopher J. Pannucci, MD, MS, Divisions of Plastic Surgery and Health Services Research, University of Utah, 30 N 1900 E, 3B400, Salt Lake City, UT 84102 (christopher.pannucci@hsc.utah.edu).

    Published Online: May 22, 2019. doi:10.1001/jamasurg.2019.1165

    Author Contributions: Dr Pannucci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Pannucci, Fleming, Bertolaccini, Prazak.

    Acquisition, analysis, or interpretation of data: Pannucci, Bertolaccini, Prazak, Huang, Pickron.

    Drafting of the manuscript: Pannucci, Fleming.

    Critical revision of the manuscript for important intellectual content: Bertolaccini, Prazak, Huang, Pickron.

    Statistical analysis: Pannucci.

    Obtained funding: Pannucci.

    Administrative, technical, or material support: All authors.

    Supervision: Bertolaccini.

    Conflict of Interest Disclosures: Dr Pannucci received grant support from the Association for Academic Surgery's Joel J. Roslyn Award during the conduct of the study. Dr Pickron reported personal fees from Intuitive Surgical outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was funded by an Association for Academic Surgery Joel J. Roslyn Award (Dr Pannucci).

    Role of the Funder/Sponsor: The Association for Academic Surgery 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.

    Meeting Presentation: Preliminary data from this trial were presented at the 2018 Academic Surgical Congress Annual Meeting; January 30, 2018; Jacksonville, Florida.

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