Outcomes of Protocol-Driven Venous Thromboembolic Chemo-Prophylaxis in Trauma Patients: A Trauma Quality Improvement Project Analysis

Abstract

Introduction

Low molecular weight heparin (LMWH) is the standard for venous thromboembolic (VTE) chemo-prophylaxis in trauma patients; however, inconsistencies in the use of LMWH exist. The objective of this study was to assess VTE outcomes in response to a chemo-prophylaxis protocol guided by patient physiology (eg, creatinine clearance) and comorbidities.

Methods

ACS TQIP Benchmark Reports at a level 1 trauma center using a patient physiology and comorbidity directed VTE chemo-prophylaxis protocol were analyzed for Spring 2019 to Fall 2021. Patient demographics, VTE rates and pharmacologic VTE prophylaxis type were collected for “All Patients” and “Elderly” (TQIP: age ≥ 55 years) cohorts.

Results

Data was analyzed for 1919183 “All Hospitals” (AH) and 5843 patients single institution (SI) using the physiologic and comorbidity guided VTE chemo-prophylaxis protocol. Elderly subgroup had 701965 (AH) and 2939 (SI) patients. Use of non-LMWH chemo-prophylaxis was significantly higher at SI: All patients = 62.6% SI vs 22.1% (P < .01); Elderly = 68.8% SI vs 28.1% AH (P < .01). VTE, DVT, and PE rates for All Patients and Elderly subgroup were significantly reduced at SI, except Elderly PE which was statistically equivalent.

Conclusions

Protocol-driven VTE chemo-prophylaxis was associated with significantly lower LMWH use accompanied by significant reductions in All VTE, DVT, PE, and Elderly VTE and DVT with no difference in Elderly PE rates. These results may imply that adherence to a physiologic and comorbidity directed chemo-prophylaxis protocol, rather than LMWH, reduces VTE events in trauma patients. Further investigation to elucidate best practice is warranted.

Keywords

venous thromboembolism chemical deep vein thrombosis prophylaxis trauma enoxaparin low molecular weight heparin

Key Takeaways

• When benchmarked compared to other trauma centers, adherence to a clinical- and physiology-driven venothromboembolism (VTE) chemical prophylaxis clinical practice guideline (CPG) resulted in lower overall VTE rates including deep vein thrombosis (DVT) and pulmonary embolism (PE).

• Using this CPG resulted in a similar reduction in VTE and DVT rates for geriatric patients, but there was no statistical reduction in PE rates.

• Adherence to a CPG and time to start VTE chemical prophylaxis may be as important as the agent that is used.

Introduction

Worldwide trauma remains one of the leading causes of both morbidity and mortality for patients of all ages, accounting for approximately 5 million deaths annually.¹ Among trauma patients who survive their initial insult beyond the first 24 hours venous thromboembolism (VTE) is a common and potentially life threatening complication with VTE observed in 6% to 60% of these patients² and pulmonary embolisms observed in 2% to 22%.³ Briefly, trauma patients are at a higher risk of VTE than other surgical patients due to multiple factors. Direct tissue injury disrupts the endothelium leading to activation of the intrinsic clotting pathway after exposure of tissue factor. Depending on the severity of injury, patients also have reduced mobility leading to venous stasis in the absence of normal ambulation and induced venous return. The acute blood loss and blood product transfusion associated with trauma patients further alters the normal homeostatic balance leading to a hypercoagulable state. Current VTE prophylaxis strategies include early application of mechanical compression devices, low dose unfractionated heparin (UF), low molecular weight heparin (LMWH), and oral anticoagulants.

Given that VTE is both a common sequela of trauma, prior studies⁴ have attempted to elucidate the optimal strategy with regards to agent, dosing, timing, and screening protocols. The study published by Geerts et al in 1996 remains a seminal paper demonstrating both the safety of LMWH and relative superiority when compared to UF when prophylaxis was initiated within 36 hours of injury.³ Over the past 27 years, since this study was published, many further studies that have attempted to determine the optimal solution to this challenging clinical issue. A recent Cochrane review from 2013 analyzed 16 studies containing 3005 patients and found that LMWH appears to be more effective at reducing DVT, however they found quality of evidence is low and more adequately powered studies are warranted.⁴ Our hypothesis is that use of a standardized patient driven protocol yields lower rates of VTE compared with benchmarked data from other trauma centers. Furthermore, we hypothesized there would be a similar reduction in VTE event in elderly patients.

Materials and Methods

This study was approved by the MaineHealth Institutional Review Board. Demographics and VTE data were collected from the American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP) benchmark reports at Maine Medical Center (MMC, Portland, Maine), a level I ACS verified trauma center. The biannual reports included Spring/Fall 2019-2021. The MMC Adult VTE clinical practice guideline (CPG) for the Trauma Service is a standard VTE chemo-prophylaxis CPG based on patient physiology and comorbidity. Patient demographics, VTE rates and pharmacologic VTE prophylaxis type were collected for “All Patients” and “Elderly” cohorts. TQIP defines elderly as age ≥ 55 years. These cohorts are reported for the individual institution and benchmarked against all hospitals reporting to TQIP.

Statistical Analysis

Statistical analysis was performed within the R statistical environment (R Core Team, Vienna, Austria). Continuous data are presented as means ± standard deviation. Skewed variables are reported as median with interquartile range. Comparisons of continuous data between 2 groups were performed using the Student’s t-test and between greater than 2 groups using one-way analysis of variance (ANOVA). Overall differences in categorical (binomial) responses were assessed using χ² analysis. Statistical significant was set an alpha equal to or less than .05.

Results

Over the 3 year study period, data was collected and analyzed for 1919183 “All Hospitals” (AH) and 5843 MMC patients using our institution’s DVT (venous thromboembolism) Prophylaxis CPG (Appendix A). Among the Elderly subgroup there were 701965 (36.6%, AH) and 2939 (50.3%, MMC) patients. Patient demographics are seen in Table 1 which shows statistical differences in MMC’s mean age 61.3 ± 20.7 vs 54.4 ± 22.2 AH (P < .01), 64.6% AH were males compared to 59% males in MMC (P < .01), AH survival was 70.9% and 72.6% MMC (P < .01), longer median ICU stay in MMC population 4 vs 3 for AH (P < .01), and 63% of MMC’s mechanism of injury being falls vs 45.5% (P < .01). There was no difference in median Injury Severity Score (ISS) between AH and MMC for All Patients (14 vs 13, P = .82) or the Elderly (13 vs 11, P = .26). VTE, DVT, and PE rates for All Patients were significantly reduced at MMC compared to AH (Table 2). Initiation of VTE prophylaxis was similar in both groups for All Patients. Median (IQR) time to VTE prophylaxis was 2 (2-3) days for AH and 2 (2-3) days for MMC. For all patients, there were 151 (.1%) patients with unknown time to VTE prophylaxis compared to 0 (.0%) patients in the M MC group (P = .45). Use of UFH chemo-prophylaxis was significantly higher at MMC than for All Patients (MMC 62.6% vs AH 22.1%; P < .01).

Table 1.

TQIP Demographic Data for All Patients and Elderly Cohorts.

	AH	MMC	P-value
All patients	n = 1919183	n = 5843
Mean age (years)	54.4 ± 22.2	61.3 ± 20.7	<.01
Male (%)	64.6%	59%	<.01
Survival (%)	70.86	72.57	<.01
Median LOS (IQR, days)	6 (3-10)	6 (3-10)	.74
Median ICU LOS (IQR, days)	3 (2-6)	4 (2-8)	<.01
Fall mechanism (%)	45.5	63.0	<.01
AKI	.8	.9	<.01
CKD	1.7	.8	.22
Elderly patients	n = 701 965	n = 2939
Mean age (years)	78.2 ± 8.6	78.1 ± 8.4	.53
Male (%)	49.3	50.2	.33
Survival (%)	65.73	68.51	<.01
Median LOS (IQR, days)	6 (4-9)	6 (4-9)	.62
Median ICU LOS (IQR, days)	3 (2-6)	4 (2-7)	<.01
Fall mechanism (%)	77.1	83.7	<.01
AKI	.9	1.0	.19
CKD	3.2	1.6	<.01

AH, All hospitals; MMC, Maine Medical Center; IQR, interquartile range; LOS, length of stay; ICU, intensive care unit; AKI, acute kidney injury; CKD, chronic kidney disease.

Table 2.

Comparison of VTE, DVT, PE Rates for All Patients and Elderly Cohorts.

	AH (n = 1919183)	MMC (n = 5843)	P-value
UF utilization (%)	22.1	62.6	<.01
ALL VTE	32908 (1.71%)	59 (1.03%)	<.01
ALL DVT	21713 (1.13%)	31 (.0054%)	<.01
ALL PE	11495 (.58%)	28 (.48%)	<.01
UF utilization (%)	28.1	68.8	<.01
Elderly VTE	9325 (1.32%)	21 (.72%)	<.01
Elderly DVT	6291 (.90%)	10 (.30%)	<.01
Elderly PE	3034 (.43%)	11 (.37%)	.633

UF, unfractionated heparin; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolus; AH, all hospitals; MMC, Maine Medical Center.

Use of unfractionated heparin chemo-prophylaxis was significantly higher at MMC, particularly in the Elderly group (Table 2). Initiation of VTE prophylaxis was also similar for Elderly patients. The median (IQR) time to VTE prophylaxis in this subgroup was 2 (2-3) days for AH and 2 (2-3) days for MMC. There were 50 (.1%) patients with unknown time to VTE prophylaxis compared to 0 (0%) patients in the MMC group (P = .10).

Discussion

LMWH has subsequently become the standard agent for VTE prophylaxis in trauma patients over the past 2 decades. Multiple studies have shown a benefit of chemical VTE prophylaxis with LMWH in trauma victims.^5-7 Despite near universal acceptance of chemical prophylaxis for VTE, Bandle et al. demonstrated a highly varied application of specific agents, frequency, duration, and dosage across different trauma centers with only 50% of centers adhering to a standard guideline.⁸ Balancing the risk of VTE events vs exacerbating bleeding in critically injured patients is a clinical challenge. The dosage of LMWH has been further studied and refined based on anti-Xa levels, thromboelastography, and weight. In order to standardize VTE prophylaxis, our trauma program implemented an institutional CPG (Appendix A). This CPG was developed in collaboration with pharmacy, surgical critical care medicine, trauma surgery, and other surgical subspecialists.

Based on the TQIP data, this study demonstrates a statistically significant reduction in overall VTE, DVT, and PE rates at our hospital compared to other participating TQIP trauma centers despite a significantly higher rate of UF utilization compared to LMWH (Table 2). A similar reduction was noted in overall VTE and DVT rates for our Elderly cohort compared to the national benchmark. Interestingly, in this subgroup, however, there was not a significant reduction in PE rates MMC (.37%) and AH (.43%). Our results are supported by studies from other centers that demonstrate no difference in efficacy of the chemo-prophylaxis agent chosen. Indeed, early initiation (<48 hours from injury) of thromboprophylaxis is the most important factor^9,10 and may supersede the choice of either agent (LMWH or UFH). Moreover, Arnold et al. demonstrated a substantial cost savings with UFH over LMWH.¹⁰

While TQIP data does not allow for drawing a direct correlation, the paradox of increased utilization of UFH and lower rates of VTE events at our trauma center was striking. Time to initiation of VTE therapy in trauma patients is thought to be an important factor in the development of VTE.⁵ Both groups (SI/AH) in our study had similar time to initiation of VTE therapy, in both the elderly and younger subgroups. While our protocol is highly standardized, perhaps there is significant variability between institutions with regards to protocol adherence in the TQIP data accounting for the higher rates of VTE seen.

Reasons for increased UFH utilization are likely related to unique elements of the demographics of trauma patients treated at MMC. The State of Maine has the oldest population in the United States.⁶ Overall, the median age for the MMC cohort (61.3 years) was almost a decade older than AH (54.4 years).¹¹ Falls are the most common injury mechanism reported in TQIP by our trauma center and traumatic brain injury, spine fractures, and rib fractures are common associated injuries. In addition, chronic kidney disease (CKD) is also common in this population. In fact, CKD was one of the patient factors in our CPG which lead to our higher use of UFH. These factors alone in or in combination are outlined as contraindications (eg, CKD) or special populations designated for UFH (eg, traumatic brain injury). For patients receiving continuous epidural catheters for pain control, there has been shown to be a clinically significant anticoagulant effect with LMWH at the time of the catheter removal,¹² leading to the possibility of epidural hematoma formation. Secondary analysis of the Consortium Leaders in the Study of Traumatic Thromboembolism (CLOTT) trial indicated improved VTE events in spinal cord injuries with early use of LMWH.¹³ Applying the results of the CLOTT trial which was primarily comprised of young patients (mean age = 29.0 years) may be challenging at other trauma centers.¹⁴ For example, the traumatic spine surgery practice at MMC with older patient population is oriented toward early UFH use. Furthermore, there is conflicting evidence regarding the choice chemo-prophylaxis agents used for VTE in traumatic brain injury, with our CPG favoring UFH. The risk of intracranial hemorrhage expansion has been demonstrated with both UF and LMWH.^15-17

There are several limitations to this study. The use of large database such as TQIP that facilitate population based investigation of uncommon events such as VTEs but do not allow enough transparency to find the root causes for individual patients. Furthermore, TQIP uses proprietary methodology; only a subset of the patients submitted to National Trauma Database from MMC are selected for inclusion in TQIP. In this regard, there may be a selection bias and some VTE events may not be represented in this dataset. Another consideration is the possibility of reporting centers with a very high rate of VTE events which could skew TQIP results. With regard to the timing of VTE prophylaxis initiation, TQIP records only drug administration based on hospital days. This allows significant variation in timing of drug administration which we would be unable to distinguish with further granularity (medication given at hour-one will appear the same as hour-23). Subclinical VTEs may not have been identified as our institution does not employ surveillance venous duplex ultrasound for detection of DVTs. In addition, anti-Xa levels are not routinely used to adjust DVT prophylaxis dosing of enoxaparin or unfractionated heparin.

In conclusion, protocol-driven VTE chemo-prophylaxis was associated with significantly lower LMWH use accompanied by significant reductions in VTE and DVT rates and no difference in PEs in the elderly. These results imply that adherence to chemo-prophylaxis CPG, rather than exclusive use of LMWH, reduces VTE events in trauma patients. These results warrant further investigation to elucidate best practice.

Footnotes

Authors’ Note

Presented (Oral Presentation) at the 2023 Annual Meeting of the Southeastern Surgical Congress, Savannah, Georgia. February 11-14, 2022.

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.

Appendix

References

World Health Organization

The global burden of disease: 2004 update, Vol. 1. Switzerland: WHO Library and Cataloguing-Data; 2008.

Velmahos

Nigro

Tatevossian

, et al.

Inability of an aggressive policy of thromboprophylaxis to prevent deep venous thrombosis (DVT) in critically injured patients: are current methods of DVT prophylaxis insufficient?

J Am Coll Surg. 1998;187:529-533.

Geerts

Jay

Code

, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335(10):701-707.

Barrera

Perel

Ker

Cirocchi

Farinella

Morales Uribe

. Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev. 2013;28(3):CD008303.

Gaitanidis

Breen

Christensen

, et al. Low-molecular weight heparin is superior to unfractionated heparin for elderly trauma patients. J Surg Res. 2021;268:432-439.

Jacobs

Cain-Nielsen

Jakubus

, et al. Unfractionated heparin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in trauma. J Trauma Acute Care Surg. 2017;83(1):151-158.

Tran

Fernando

Carrier

, et al. Efficacy and safety of low molecular weight heparin vs unfractionated heparin for prevention of venous thromboembolism in trauma patients: a systematic review and meta-analysis. Ann Surg. 2022;275(1):19-28.

Bandle

Shackford

Sise

Knudson

CLOTT Study Group . Variability is the standard: the management of venous thromboembolic disease following trauma. J Trauma Acute Care Surg. 2014;76(1):213-216.

Zeeshan

Khan

O’Keeffe

, et al. Optimal timing of initiation of thromboprophylaxis in spine trauma managed operatively: a nationwide propensity-matched analysis of trauma quality improvement program. J Trauma Acute Care Surg. 2018;85(2):387-392.

10.

Arnold

Dart

Barker

, et al. Gold Medal Forum Winner. Unfractionated heparin three times a day versus enoxaparin in the prevention of deep vein thrombosis in trauma patients. Am Surg. 2010;76(6):563-570.

11.

Annual Estimates of the Resident Population for Selected Age Groups by Sex: April 1, 2020 to July 1, 2021 (SC-EST2021-AGESEX), U.S. Census Bureau, Population Division, Release Date: June 2022. https://www.census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html

12.

Douketis

Kinnon

Crowther

. Anticoagulant effect at the time of epidural catheter removal in patients receiving twice-daily or once-daily low-molecular-weight heparin and continuous epidural analgesia after orthopedic surgery. Thromb Haemost. 2002;88(1):37-40.

13.

Godat

Haut

Moore

Knudson

Costantini

. Venous thromboembolism risk after spinal cord injury: A secondary analysis of the CLOTT study. J Trauma Acute Care Surg. 2023;94(1):23-29.

14.

Knudson

Moore

Kornblith

, et al. Challenging traditional paradigms in posttraumatic pulmonary thromboembolism. JAMA Surg. 2022;157(2):e216356.

15.

Thier

Drake-Lavelle

Prest

, et al. Progression of intracranial hemorrhage after chemical prophylaxis using low-molecular-weight heparin in patients with traumatic brain injury. Am Surg. 2022;88(5):894-900.

16.

Dudley

Aziz

Bonnici

, et al. Early venous thromboembolic event prophylaxis in traumatic brain injury with low-molecular-weight heparin: risks and benefits. J Neurotrauma. 2010;27(12):2165-2172.

17.

Minshall

Eriksson

Leon

Doben

McKinzie

Fakhry

. Safety and efficacy of heparin or enoxaparin prophylaxis in blunt trauma patients with a head abbreviated injury severity score >2. J Trauma. 2011;71(2):396-399.