Retrospective Analysis of Direct-Acting Oral Anticoagulants (DOACs) Initiation Timing and Outcomes After Thrombolysis in High- and Intermediate-Risk Pulmonary Embolism

Abstract

Direct-acting oral anticoagulants (DOACs) are prescribed in the treatment of venous thromboembolism, including pulmonary embolism (PE). Evidence is limited regarding the outcomes and optimal timing of DOACs in patients with intermediate- or high-risk PE treated with thrombolysis. We conducted a retrospective analysis of outcomes among patients with intermediate- and high-risk PE who received thrombolysis, by choice of long-term anticoagulant agent. Outcomes of interest included hospital length of stay (LOS), intensive care unit LOS, bleeding, stroke, readmission, and mortality. Descriptive statistics were used to examine characteristics and outcomes among patients, by anticoagulation group. Patients receiving a DOAC (n = 53) had shorter hospital LOS compared to those in warfarin (n = 39) and enoxaparin (n = 10) groups (mean LOS 3.6, 6.3 and 4.5 days, respectively; P < .0001). This single institution retrospective study suggests DOAC initiation <48 h from thrombolysis may result in shorter hospital LOS compared to DOAC initiation ≥48 h (P < .0001). Further larger studies with more robust research methodology are needed to address this important clinical question.

Keywords

pulmonary embolism thrombolytic anticoagulation,DOAC

Introduction

Acute pulmonary embolism (PE) is a common disease and has the potential to cause death or serious disability.¹ Risk stratification is essential to determine appropriate initial therapy. Anticoagulation remains the cornerstone of the treatment strategy, while thrombolysis is indicated in massive and selected cases of submassive PE at risk for decompensation.² Acute PE with hypotension is considered high risk or massive. Acute PE with evidence of right ventricle (RV) dysfunction or evidence of myocardial injury related to PE (elevated troponin), not meeting criteria for massive, is considered intermediate risk or submassive.³ Low-risk PE is defined as a hemodynamically stable patient not meeting massive or submissive criteria.

Long-term anticoagulation includes direct-acting oral anticoagulants (DOACs), vitamin K antagonist, or low-molecular-weight heparin. DOACs offer many advantages including no required monitoring, predictable pharmacokinetics, fixed dosing, and rapid onset of action.⁴ In the most recent American College of Chest Physicians guidelines for venous thromboembolism (VTE), DOACs were recommended over warfarin except when associated with antiphospholipid antibody syndrome.² Some patients with high- and intermediate-risk PE benefit from systemic thrombolysis (ST) or catheter-directed thrombolysis (CDT).^5,6 Choosing subsequent long-term anticoagulation in these patients and the timing of initiation of those agents can be more challenging for clinicians.

In many landmark studies showing the benefit of DOACs in the treatment of VTE, patients who received thrombolysis were excluded leaving an evidence gap in clinical guidance.^7–9 Small studies have shown improved safety and reduced length of stay (LOS) with DOAC use after CDT in intermediate-risk PE.^10,11 However, optimal timing on starting DOAC in the absence of immediate bleeding is not known and results in significant practice variation. The objective of this study was to analyze practice patterns at our institution and describe outcomes for patients by anticoagulation group and to examine outcomes by the timing of onset of DOAC initiation. Given sample size and use of retrospective data, these results are intended to generate a new research hypothesis targeting clinical question on outcomes associated with choice and timing of long-term oral anticoagulation in high- and intermediate-risk PE treated with thrombolysis (ST or CDT).

Methods

Study Design and Population

This was a retrospective analysis of patients ≥18 years treated with ST or CDT at a 630-bed tertiary care center between the years 2012 to 2019 for intermediate- or high-risk PE. After thrombolysis, all patients received standard-dose unfractionated heparin (UFH) to maintain anticoagulation. All patients were treated and monitored in an intensive care unit (ICU) for at least 24 h after ST dose or until catheter removal in patients who received CDT. Patients who died or had a bleeding event prior to long-term anticoagulation agent initiation, with low-risk PE, were pregnant, or who objected to the use of their medical data for health research were excluded. Data were abstracted from electronic medical records. This study was approved by the Allina Health Institutional Review Board (IRB#1048921-24).

Study Measures

Patients were categorized based on long-term anticoagulant (DOAC, warfarin, or enoxaparin). To examine the timing of DOAC initiation with outcomes, patients receiving a DOAC were categorized as having initiation <48, 48-72, and >72 h from thrombolysis. The primary outcome was hospital LOS (days). Secondary outcomes included ICU LOS, hospital LOS after oral anticoagulation initiation, in-hospital bleeding events, 30-day readmission, 90-day major and minor bleeding,¹² VTE/stroke, and mortality. Clinical and demographic measures included age, sex, semi-quantitative RV size on echocardiogram, simplified pulmonary embolism severity index, and continuous measures of serum creatinine, troponin, brain natriuretic protein (BNP), weight, heart rate, systolic blood pressure, and respiratory rate.

Statistical Analysis

Descriptive statistics were used to examine the distribution of characteristics among all participants. One-way ANOVA, Kruskal-Wallis, χ², and Fisher exact tests, as appropriate, were used to examine differences in the distribution of baseline demographic and clinical characteristics, as well as outcomes, by anticoagulation group. Similarly, a subanalysis of only patients receiving DOAC for long-term anticoagulation was conducted using the aforementioned statistical testing to examine differences in patient characteristics and outcomes by the timing of DOAC initiation. Ad hoc pairwise comparisons using Bonferroni corrections were conducted. All statistical analyses were conducted using R software version 3.6.1 (The R Foundation for Statistical Computing.) For all analyses, P < .05 was considered statistically significant. Due to the exploratory nature of this study, a sample size/power calculation was not conducted.

Results

One-hundred and two patients met criteria for study inclusion. Average patient age was 58.8 years, and 58.8% patients were male (Table 1). The DOAC group (n = 53) included those receiving apixaban (n = 24) and rivaroxaban (n = 29). The warfarin group (n = 39) had warfarin with bridging anticoagulant agent (n = 29) and warfarin monotherapy (n = 10). The enoxaparin group (n = 10) included patients who received and discharged on enoxaparin monotherapy only. Patient characteristics were similar among groups with no significant difference in most admission vital signs, BNP, or peak troponin. However, patients receiving a DOAC had greater measures for admission creatinine, weight, and systolic blood pressure when compared to those in the warfarin and enoxaparin groups and were least likely to have severely enlarged RV size (P < .05) (Table 1).

Table 1.

Patient Characteristics Stratified by Medication Type (n = 102).

	Total	DOAC	Warfarin	Enoxaparin	P value
	(n = 102)	(n = 53)	(n = 39)	(n = 10)	P value
Age, in years, mean (SD)	58.8 (15.7)	58.5 (14.5)	58.6 (18.3)	61.0 (11.7)	.9715
Median (Q1, Q3)	59 (52, 70)	59 (54, 69)	59 (49, 73)	64 (52, 64)
Min-max	18-87	18-84	20-87	44-87
Sex, male, n (%)	60 (58.8)	34 (64.2)	23 (59.0)	3 (30.0)	.1467
Serum Cr (at initiation of oral coagulation), mean (SD)	0.90 (0.19)	0.92 (0.19)	0.90 (0.20)	0.76 (0.15)	.0492
Median (Q1, Q3)	0.85 (0.77, 1.03)	0.87 (0.79, 1.03)	0.84 (0.77, 1.04)	0.75 (0.63, 0.79)
Min-max	0.55-1.41	0.61-1.34	0.55-1.41	0.58-1.08
Max troponin, mean (SD)	0.45 (0.56)	0.42 (0.63)	0.49 (0.45)	0.47 (0.55)	.2015
Median (Q1, Q3)	0.29 (0.14, 0.58)	0.24 (0.13, 0.48)	0.4 (0.16, 0.69)	0.31 (0.21, 0.39)
Min-max	0.01-3.37	0.01-3.37	0.03-2.42	0.02-1.9
BNP on admission, mean (SD)	320.29 (374.6)	250.4 (313.01)	436.19 (454.61)	283.22 (308.1)	.2273
Median (Q1, Q3)	205.5 (75, 381.5)	172 (75, 251)	313 (89, 570)	91 (35, 471)
Min-max	10-1870	14-1695	10-1870	18-900
Weight, kg, mean (SD)	108.9 (28)	113.2 (27.3)	107.4 (29.7)	91.8 (18.6)	.0385
Median (Q1, Q3)	102.1 (87.2, 127.5)	107.3 (94.7, 128.4)	98.3 (87, 127.5)	84.4 (81.5, 107.9)
Min-max	64.6-212.3	69.2-184	64.6-212.3	67.5-119.7
Heart rate^a, mean (SD)	105.5 (17.6)	103.2 (17.9)	106.5 (17.7)	113.4 (14.4)	.2515
Median (Q1, Q3)	105 (95, 117)	105 (93, 117)	104 (96, 113)	116.5 (103, 124)
Min-max	56-150	56-140	64-150	89-133
Systolic BP^a, mean (SD)	131.5 (23)	137.5 (21.5)	124.7 (21.7)	126.3 (28.8)	.0355
Median (Q1, Q3)	132 (116, 144)	140 (120, 149)	124 (114, 139)	117 (106, 141)
Min-max	62-187	85-182	62-171	96-187
Respiratory rate^a, mean (SD)	21.18 (4.97)	21 (4.5)	21.5 (5.5)	20.8 (5.4)	.9405
Median (Q1, Q3)	20 (17, 24)	20 (17, 24)	20 (18, 24)	19 (16, 24)
Min-max	14-37	16-37	14-36	14-30
Average RV size over hospital stay^b	1.7 (0.8)	1.6 (0.8)	1.7 (0.8)	1.9 (1)	.5229
Median (Q1, Q3)	1.7 (1, 2)	1.6 (1, 2)	2 (1, 2.3)	1.6 (1.5, 3)
Min-max	0-3	0-3	0-3	0-3
sPESI ≥ 1, n (%)	82 (91.1)	42 (89.4)	31 (91.2)	9 (100.0)	.8761

Abbreviations: BNP, brain natriuretic protein; DOAC, direct-acting oral anticoagulant; RV, right ventricle; SD, standard deviation; sPESI, simplified pulmonary embolism severity index.

First value after admission.

Averaged numerically using 0, 1, 2, and 3.

The primary endpoint, in-hospital LOS, was significantly shorter among the DOAC group compared to the warfarin or enoxaparin groups (mean LOS 3.6, 6.3, and 4.5 days, respectively; P < .0001; Table 2). Length of stay after initiation of oral anticoagulation was shorter for the DOAC group compared with the warfarin group (0.88 days vs 3.4 days, P < .0001). No significant differences were noted among groups regarding ICU LOS, in-hospital bleeding, major or minor bleeding, 90-day rate of stroke or VTE, 30-day readmission rates, or 90-day mortality.

Table 2.

Distribution of Patient Outcomes, Stratified by Long-Term Anticoagulation Choice.

	Total(n = 102)	DOAC(n = 53)	Warfarin(n = 39)	Enoxaparin(n = 10)	P value
In-hospital length of stay, days					<.0001
Mean (SD)	4.69 (3.3)	3.56 (1.35)	6.27 (4.6)	4.5 (1.84)
Median (Q1, Q3)	3.84 (2.99, 5.27)	3.12 (2.83, 3.9)	5.06 (3.55, 6.97)	4.05 (3.82, 4.79)
Min-max	1.78-21.98	1.78-8.55	2.02-21.98	2.12-9.02
ICU length of stay, days					.5250
Mean (SD)	2.05 (2.67)	1.63 (0.89)	2.63 (3.96)	1.73 (0.82)
Median (Q1, Q3)	1.52 (1.06, 2.06)	1.42 (1.05, 1.95)	1.69 (1.1, 2.15)	1.81 (0.96, 1.83)
Min-max	0.61-19.43	0.61-5.74	0.62-19.43	0.79-3.15
Length of stay after oral anticoagulation (days)					<.0001
Mean (SD)	1.95 (2.06)	0.88 (0.96)	3.4 (2.26)	NA
Median (Q1, Q3)	1.01 (0.7, 2.87)	0.76 (0.19, 0.97)	2.88 (1.82, 4.68)	NA
Min-max	0.01-10.77	0.01-4.29	0.16-10.77	NA
In-hospital bleeding after anticoagulation initiation, n (%)	2 (1.96)	2 (3.77)	0	0	.5987
30-day readmission rate, n (%)					.1684
Yes	12 (12.0)	5 (9.6)	4 (10.5)	3 (30.0)
No	88 (88.0)	47 (90.4)	34 (89.5)	7 (70.0)
Died within 30 days	1	1	0	0
Unknown^a	1	0	1	0
30-day Readmission rate due to bleeding, n (%)
Yes	2 (2.0)	1 (1.9)	1 (2.7)	0 (0)	>.99
No	97 (98.0)	51 (98.1)	36 (97.3)	10 (100)
Died within 30 days	3	1	0	0
Unknown^a	2	0	2	0
Major bleed within 90 days, n (%)
Yes	3 (3.1)	1 (1.9)	2 (5.6)	0 (0)	.6762
No	94 (96.9)	51 (98.1)	34 (94.4)	9 (100)
Died within 90 days	3	1	1	1
Unknown^a	2	0	2	0
Minor bleed within 90 days, n (%)
Yes	11 (11.5)	6 (11.5)	5 (14.3)	0 (0)	.6363
No	85 (88.5)	46 (88.5)	30 (85.7)	9 (100)
Died within 90 days	4	1	2	1
Unknown^a	2	0	2	0
VTE or ischemic stroke within 90 days, n (%)
Yes	0 (0)	0 (0)	0 (0)	0 (0)	NA
No	96 (100)	52 (100)	35 (100)	9 (100)
Died within 90 days	4	1	2	1
Unknown^a	2	0	2	0
90-day mortality, n (%)	4	1 (1.9)	2 (5.1)	1 (10.0)	.3043

Abbreviations: DOAC, direct-acting oral anticoagulant; ICU, intensive care unit; SD, standard deviation; VTE, venous thromboembolism.

No records post-admission.

Among those receiving DOACs, patient characteristics were similar in different time of initiation DOACs groups (Table 3). Hospital LOS was significantly shorter for those with DOAC initiation <48 h (n = 20) from thrombolysis compared to those who started 48-72 h (n = 23), or greater than 72 h (n = 10) after thrombolysis (mean LOS 2.91, 3.67, and 4.61, respectively; P = .0003; Table 4). There were no significant differences in patient baseline characteristics or other outcomes (ICU LOS, LOS after oral anticoagulation, bleeding, stroke or VTE, 30-day readmission, or 90-day mortality rates) among DOAC timing groups.

Table 3.

Patient Characteristics for Patients Given DOAC, Stratified by Timing of DOAC From tPA Start Time (n = 53).

Timing of DOAC from tPA start time	Total	<48 h post tPA	48-72 h post tPA	>72 h post tPA	P value
Timing of DOAC from tPA start time	(n = 53)	(n = 20)	(n = 23)	(n = 10)	P value
Age, in years, mean (SD)	58.5 (14.5)	58.2 (13.8)	60.4 (12.7)	54.5 (19.8)	.9680
Median (Q1, Q3)	59 (54, 69)	60 (53.5, 69)	58 (54, 71)	60 (39, 65)
Min-max	18-84	26-80	33-83	18-84
Sex, male, n (%)	34 (64.2)	11 (55.0)	17 (73.9)	6 (60.0)	.3949
Serum Cr (at initiation of oral coagulation), mean (SD)	0.92 (0.19)	0.93 (0.16)	0.9 (0.19)	0.95 (0.23)	.9743
Median (Q1, Q3)	0.87 (0.79, 1.03)	0.91 (0.84, 1.02)	0.82 (0.77, 1.05)	0.91 (0.79, 1.1)
Min-max	0.61-1.34	0.61-1.27	0.64-1.34	0.65-1.31
Max troponin, mean (SD)	0.42 (0.63)	0.3 (0.29)	0.31 (0.31)	0.85 (1.18)	.4636
Median (Q1, Q3)	0.24 (0.13, 0.48)	0.23 (0.06, 0.38)	0.19 (0.13, 0.42)	0.34 (0.14, 0.6)
Min-max	0.01-3.37	0.01-0.95	0.04-1.41	0.05-3.37
BNP on admission, mean (SD)	250.4 (313.01)	281.43 (437.51)	191 (153.15)	314.33 (325.41)	.5900
Median (Q1, Q3)	172 (75, 251)	135 (53, 250)	204 (76, 241)	204 (167, 383)
Min-max	14-1695	25-1695	14-631	20-1123
Weight, kg, mean (SD)	113.2 (27.3)	112.9 (24.9)	108.6 (28)	124.2 (29.8)	.1874
Median (Q1, Q3)	107.3 (94.7, 128.4)	113.8 (97.3, 128.3)	102.1 (88.6, 121.3)	131.3 (102.2, 152)
Min-max	69.2-184	70-155	69.2-184	70.4-156.6
Heart rate^a, mean (SD)	103.2 (17.9)	105.2 (20.1)	101.4 (16)	103.3 (18.9)	.6572
Median (Q1, Q3)	105 (93, 117)	106 (92, 119)	99 (91, 110)	105.5 (98, 111)
Min-max	56-140	67-140	78-133	56-124
Systolic BP^a, mean (SD)	137.5 (21.5)	137 (18.6)	135.4 (25.6)	143.1 (17.6)	.4152
Median (Q1, Q3)	140 (120, 149)	140 (120, 144)	136 (115, 149)	144.5 (123, 154)
Min-max	85-182	101-181	85-182	121-173
Respiratory rate^a, mean (SD)	21 (4.5)	20.2 (4)	21 (5.2)	22.7 (3.8)	.2685
Median (Q1, Q3)	20 (17, 24)	20 (16, 24)	19 (16, 24)	23 (22, 25)
Min-max	16-37	16-28	16-37	16-28
Average RV size over hospital stay^b	1.6 (0.8)	1.7 (0.9)	1.5 (0.7)	1.5 (0.9)	.7421
Median (Q1, Q3)	1.6 (1, 2)	2 (1, 2.3)	1.5 (1, 2)	1.5 (1.3, 2)
Min-max	0-3	0-3	0-3	0-3
Time from TPA start to DOAC start, in hours					NA
Mean (SD)	58.2 (25.54)	39.3 (9)	58.1 (7.3)	96.4 (32.4)
Median (Q1, Q3)	50.93 (45.05, 66.05)	42.1 (37.3, 45.7)	56.8 (50.8, 65)	82.1 (80.8, 90.5)
Min-max	16.55-182.05	16.6-47.9	48.6-69.9	77.6-182.1
sPESI ≥ 1, n (%)	42 (89.4)	15 (88.2)	19 (95.0)	8 (80.0)	.3365

Abbreviations: BNP, brain natriuretic protein; DOAC, direct-acting oral anticoagulant; RV, right ventricle; SD, standard deviation; sPESI, simplified pulmonary embolism severity index.

First value after admission.

Averaged numerically using 0, 1, 2, and 3.

Table 4.

Patient Outcomes for Patients Given DOAC, Stratified by DOAC Start Time (n = 53).

	Total(n = 53)	<48 h post tPA(n = 20)	48-72 h post tPA(n = 23)	>72 h post tPA(n = 10)	P value
In-hospital length of stay, days
Mean (SD)	3.56 (1.35)	2.91 (1.06)	3.67 (1.22)	4.61 (1.54)	.0003
Median (Q1, Q3)	3.12 (2.83, 3.9)	2.67 (2.05, 3.51)	3.12 (2.98, 3.57)	3.89 (3.61, 5)
Min-max	1.78-8.55	1.78-5.27	2.82-6.99	3.57-8.55
ICU length of stay, days
Mean (SD)	1.63 (0.89)	1.43 (0.57)	1.66 (1.11)	1.96 (0.87)	.2675
Median (Q1, Q3)	1.42 (1.05, 1.95)	1.4 (1.04, 1.66)	1.18 (0.99, 2.04)	1.85 (1.33, 2.62)
Min-max	0.61-5.74	0.61-2.78	0.77-5.74	0.74-3.34
Length of stay after oral anticoagulation (days)
Mean (SD)	0.88 (0.96)	0.96 (0.79)	0.97 (1.17)	0.49 (0.65)	.1123
Median (Q1, Q3)	0.76 (0.19, 0.97)	0.83 (0.25, 1.2)	0.76 (0.17, 0.89)	0.21 (0.09, 0.73)
Min-max	0.01-4.29	0.03-3.22	0.03-4.29	0.01-2.02
In-hospital bleeding, n (%)	2 (3.77)	1 (5.0)	1 (4.3)	0 (0)	> .99
30-day readmission rate, n (%)
Yes	5 (9.6)	3 (15.0)	2 (8.7)	0 (0)	.5814
No	47 (90.4)	17 (85.0)	21 (91.3)	9 (100)
Died within 30 days	1	0	0	1
30-day readmission rate due to bleeding, n (%)
Yes	1 (1.9)	1 (5.0)	0 (0)	0 (0)	NA
No	51 (98.1)	19 (95.0)	23 (100)	9 (100)
Died within 30 days	1	0	0	1
Major bleed within 90 days, n (%)
Yes	1 (1.9)	1 (5.0)	0 (0)	0 (0)	NA
No	51 (98.1)	19 (95.0)	23 (100)	9 (100)
Died within 90 days	1	0	0	1
Minor bleed within 90 days, n (%)
Yes	6 (11.5)	3 (15.0)	2 (8.7)	0 (0)	.5814
No	46 (88.5)	17 (85.0)	21 (91.3)	9 (100)
Died within 90 days	1	0	0	1
VTE or ischemic stroke within 90 days, n (%)
Yes	0 (0)	0 (0)	0 (0)	0 (0)
No	52 (100)	20 (100)	23 (100)	9 (100)
Died within 90 days	1	0	0	1	NA
90-day mortality, n (%)	1 (1.9)	0 (0)	0 (0)	1 (10.0)	NA

Abbreviations: DOAC, direct-acting oral anticoagulant; ICU, intensive care unit; SD, standard deviation; VTE, venous thromboembolism.

Discussion

Our findings suggest shorter hospital LOS with the use of a DOAC over warfarin and enoxaparin in patients who receive ST or CDT for high- or intermediate-risk PE. Additionally, our study suggests in the absence of bleeding complications, initiating DOAC within 48 h after thrombolysis reduces hospital LOS without adverse outcomes.

Evidence gaps have led to significant practice variation in the acute and long-term management of PE. Many hospitals have started PE response teams to facilitate rapid multidisciplinary care and improve standardization.¹³ National and international PE response team collaborations have helped standardize and consolidate expert opinions on this subgroup of patients with PE.¹⁴ However, high-level evidence and standardization of treatment recommendations for this patient population continue to evolve.

Currently, UFH use is a widely accepted choice of anticoagulant in the peri-thrombolytic period. DOACs are increasingly being used as the chronic anticoagulant of choice as they have been shown to be equally effective in treating/preventing VTE and have less bleeding complications.¹⁵ Despite the use of both warfarin and DOACs in long-term anticoagulation of high- and intermediate-risk PE after thrombolysis, studies comparing outcomes, and the optimal timing of initiation of DOAC after thrombolysis are scarce.

Overall hospital LOS for this patient population is often influenced significantly by the duration of a patient's post-thrombolytic hospitalization monitoring period. Thus, our results showing the reduction in overall hospital LOS, as well as post-anticoagulant initiation LOS among DOAC patients highlights an additional benefit of DOAC therapy.

Current clinician uncertainty around safe timing of post-thrombolytic long-term anticoagulation often results in a cautious/delayed initiation, increasing LOS and practice variation. Our subgroup analysis demonstrated that in absence of bleeding complications post thrombolytic early (<48 h) compared to delayed (>48 h) initiation of a DOAC resulted in reduced hospital LOS without increasing adverse outcomes.

Limitations

This was a retrospective analysis, with a small sample size at single institution. As such, we were unable to conduct more comprehensive statistical modeling to account for potential confounding with respect to our associations of interest. Given sample size, we observed low frequencies of adverse outcomes among our population. As this is not a prospective randomized study, decisions on which patients were given thrombolytics or timing of initiation of long-term anticoagulation agent likely had some impact of selection bias. Future studies should continue to examine these outcomes in larger sample sizes with more robust research design. Further studies should assess if a similar safe reduction in LOS is seen with early DOAC initiation among patients with intermediate- and high-risk PE treated with thrombolysis.

Conclusion

This retrospective study suggests further research is warranted to test this hypothesis that early initiation of DOAC (<48 h) after thrombolytic therapy could be beneficial without major adverse outcomes in high- and intermediate-risk PE in absence of early post-thrombolytic complications.

Footnotes

Acknowledgments

The authors wish to thank Natalie Ha and Abbey Sidebottom for contributions to the preparation of the manuscript.

Authors’ Note

The data that support the findings of this study may be available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. All research described in this manuscript underwent review and was approved by the Allina Health Institutional Review Board.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

David M Tierney

Roman Melamed

Claire Smith

Love Patel

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