Clinical trial NCT03339349
Conditions: Venous Thromboembolism Deep Vein Thrombosis Pulmonary Embolus
Sponsor: University of Utah
Start date: 2017-11-15; Completion date: 2019-10-29
Enrollment: 80 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The rates of Venous thromboembolism (VTE) after orthopedic surgery are as high as 40-60% without prophylactic measures. Enoxaparin, a low-molecular-weight heparin, produces an anticoagulant effect by binding antithrombin, thereby accelerating antithrombin's inactivation of coagulation factor Xa (FXa), thus decreasing the likelihood of clot formation. Despite standard dosing enoxaparin prophylaxis, VTE rates in post-operative orthopedic trauma patients remain as high as 12.2%.The investigators will examine enoxaparin pharmacokinetics and test whether a clinical protocol for real-time enoxaparin dose adjustment can favorably alter the proportion of patients with in-range anti-Factor Xa (aFXa) levels. Outcomes will include peak and trough steady-state aFXa levels in response to standard and escalated doses of enoxaparin and the incidence of venous thromboembolism and bleeding events post-surgery. In the trauma and orthopaedic populations, patients with low initial aFXa levels are significantly more likely to develop deep venous thrombosis. Thus, this study has important implications for appropriate enoxaparin dose magnitude and frequency, and may ultimately help to decrease the substantial morbidity and mortality associated with post-operative VTE.

Detailed description:

Arms: arm 1: Eligible patients will have steady state peak and trough anti-Xa levels drawn after the third enoxaparin dose. For patients in-range (levels 0.2-0.4 IU/mL), no intervention will be undertaken. For patients out of range, enoxaparin dose will be adjusted according to an established dose adjustment algorithm. Repeat levels will be checked after the third administration of the new dose.
Interventions: intervention 1: Enoxaparin
Intervention descriptions: intervention 1: Enrolled patients will receive real-time monitoring of peak and trough steady state anti-Xa levels. Out-of-range patients will receive real time dose adjustment of Enoxaparin using a clinical protocol developed with our inpatient pharmacists.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Summary (ERICA) 
 
IRB_00102526 
Page 1 of 8 
 
IRB Approval 8/22/2018 
 
 
Weight-Based Enoxaparin Dosing and Real-time Dose 
Adjustment in Orthopaedic Trauma 
 
Protocol Summary 
 
 
 
IRB Approval Date of Current Version: 8/22/2018 
University of Utah IRB #: IRB_00102526 
Sponsor: ORTHOPEDIC SURGERY 
NCT: 03339349 
Principal Investigator: Christopher Pannucci 
Internal Staff and  Sub-Investigators: 
Graham DeKeyser 
Kory Fleming 
Andrea Gurule 
Daniel Jones 
David Rothberg 
External Sub-Investigators: 
 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 


Protocol Summary (ERICA) 
 
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IRB Approval 8/22/2018 
 
Background and Introduction 
 
Venous thromboembolism, which encompasses both deep vein thrombosis (DVT) and 
pulmonary embolism (PE), is a potentially devastating post-operative complication. VTE results 
in approximately 100,000 deaths per year, a number higher than the annual mortality from breast 
cancer and motor vehicle accidents combined1-3. PE results in 5-10% of hospital deaths, making 
it one of the most common preventable causes of in-hospital death1,4. The rates of VTE after 
orthopaedic surgery are as high as 40-60% without prophylactic measures4. Polytrauma, older 
age, obesity, prolonged operative time, and prolonged bed-rest are some factors that put surgical 
patients at higher risk. Enoxaparin chemoprophylaxis has been shown to result in a four-fold 
reduction in DVT rates in post-operative orthopaedic trauma5. 
The American College of Chest Physicians (ACCP) and American Academy of Orthopedic 
Surgeons (AAOS) have issued guidelines for thromboprophylaxis following total knee 
arthroplasty, total hip arthroplasty, and hip fracture surgery (HFS)6,7. These guides lack specific 
recommendations for other high-risk injuries including pelvic, acetabular, or femur fractures. 
The Orthopaedic Trauma Association (OTA) has published an expert panel consensus on 
prophylaxis in the orthopaedic trauma population, however8. Even with these guides though, the 
optimal strategy to prevent post-operative VTE remains unclear. Drug choice, drug dosing, 
duration of prophylaxis, and the degree of anti-coagulation are all still debated. The 2012 ACCP 
guidelines in HFS, for example, recommend the use of one of several agents including low 
molecular weight heparins, unfractionated heparin, warfarin, or aspirin for 10 to 35 days, leaving 
the surgeon left to decide the exact drug and duration6. The OTA and AAOS favor enoxaparin as 
drug of choice, but are equally non-specific on duration and make no recommendations for 
specific orthopaedic injuries7,8. 
Enoxaparin, a low-molecular-weight heparin (LMWH), produces an anticoagulant effect by 
binding antithrombin, thereby accelerating antithrombin’s inactivation of coagulation factor Xa 
(FXa), thus decreasing the likelihood of clot formation. Current recommended prophylactic 
dosing of enoxaparin is either 30mg twice daily (BID) or 40mg daily (QD). While not currently 
part of the standard of care, steady state peak and trough anti-Factor Xa (aFXa) levels can be 
used to monitor enoxaparin activity9,10. On twice daily dosing, a steady state peak range of 0.2-
0.4 IU/mL and trough of > 0.1 IU/mL have been shown to maximize VTE risk reduction in non-
orthopaedic populations10-13. 
Despite standard dosing enoxaparin prophylaxis, VTE rates in post-operative orthopaedic trauma 
patients remain as high as 12.2%5. It is not known why some patients suffer from breakthrough 
VTE events despite standard prophylaxis. Current prophylaxis guidelines do not adequately 
address these individuals6,7. The use of standardized enoxaparin dosing is has been challenged 
by a data from a prior study by this group as well as several other surgical fields. Body weight 
and the extent of thermal or surgical injury have been shown to correlate with anti-Xa levels in 
thermally injured, critically ill, and obese patients12-16 


Protocol Summary (ERICA) 
 
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Unpublished data from prior study on standard enoxaparin dosing in orthopaedic trauma 
From May 2016 to May 2017, 109 unique post-operative orthopaedic trauma patients were 
enrolled and obtained appropriately timed peak aFXa levels. Fifty eight (53%) had initial peak 
aFXa levels within the goal range of 0.2-0.4 IU/mL while 15 (19%) had initial aFXa trough 
within goal range >0.1 IU/mL. Real-time dose adjustment was successful in achieving goal peak 
aFXa in and additional 14 of 20, resulting in 72 of 109 (66.1%) achieving goal steady-state peak 
aFXa levels. Ninety-eight patients (89.9%) were discharge from the hospital on some duration of 
outpatient enoxaparin, 25 (25.5%) of which were receiving doses that were inadequate based on 
aFXa level (aFXa <0.2 IU/mL). 
  
Eighty-eight patients have reached the 90-day mark post-operatively as of May 15, 2017. Eleven 
patients were lost to follow-up (no clinic visits and unreachable by phone) leaving 90-day follow 
up data available for 77 patients (87.5%). There were no re-operative bleed events and there 
were two minor bleed events while on anticoagulation, including one patient with a heavy 
menses and one with a positive guiac but no identified GI bleed. 
  
Seven VTE events occurred, including 4 DVTs and 3 PEs in 5 patients (n 109, rate 4.6%). One 
DVT occurred in a patient who was within the goal peak aFXa range on initial blood draws (n 
58, 1.7%). The remaining 6 VTE events occurred in 4 patients who had initial peak aFXa levels 
below goal range (n 47, 8.5%). Our data demonstrated that 43% of patients received inadequate 
prophylaxis in response to 30mg BID enoxaparin dosing and that a moderate correlation (R2 = 
0.46) exists between weight and peak aFXa in response to a fixed dose. Four patients were 
considered to be over anticoagulated (>0.4 IU/mL). 
  
This study would examine if a weight based enoxaparin protocol could elevate the number of 
post-operative orthopaedic trauma patients receiving adequate chemoprophylaxsis. It aims to see 
if the orthopaedic trauma service can increase the number of patients that start on adequate 
prophylaxis and increase the number of patients that get discharged on appropriate doses. Two 
VTE events occurred while patients in the prior study were undergoing enoxaparin dose 
adjustment. These may have been avoided if the patients received an initial enoxaparin doses that 
were weight based rather than of standard dosing. Ultimately this study may aid in our 
understanding why breakthrough VTE events occur and hopefully become part of a means to 
reduce breakthrough occurrences.  
 
 
 
Purpose and Objectives 
 


Protocol Summary (ERICA) 
 
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The American College of Chest Physicians and American Academy of Orthopaedic Surgeons 
recommend post-operative venous thromboembolism (VTE) prophylaxis in certain orthopaedic 
trauma patients to lower the risk of DVT and PE. 30mg twice daily (BID) or 40mg once daily 
(QD) of enoxaparin is commonly used as chemoprophylaxis and has shown efficacy in reducing 
VTE rates in post-operative patients. Based on steady state anti-Factor Xa (aFXa), a marker of 
enoxaparin activity, obese, critically ill, and thermally injured patients are often provided 
inadequate prophylaxis on these standard  enoxaparin doses9,10,12,13. In joint replacement and 
trauma populations, inadequate steady-state aFXa levels have been associated with an increase in 
DVT rates10,14,. Despite enoxaparin prophylaxis, VTE rates remain as high as 12.2% in 
orthopaedic trauma. These events can represent a significant financial burden to hospitals and 
can be life or limb threatening for patients. Existing data from our group and others suggest that 
inadequate enoxaparin dosing, quantified by xFXa levels, represents a plausible explanatory 
mechanism for some of these “breakthrough” VTE events. 
  
A previous study by this group examined the association between standard enoxaparin dosing 
(30mg BID) and steady state aFXa levels in orthopaedic trauma and found an association with 
inadequate aFXa levels and VTE events. A correlation was found between patient weight and 
their peak aFXa level. No association was found between aFXa and major bleed events. Based 
on these data, a weight-based protocol was adopted on for enoxaparin prophylaxis on the 
orthopaedic trauma service. The current study aims to examine how a weight-based dosing 
protocol alters the steady state aFXa in orthopaedic trauma patients as well as their risk for VTE 
and major bleed events. 
  
Aim 1: Evaluate peak steady-state aFXa levels in response to weight-based enoxaparin 
prophylaxis (0.4mg/kg twice daily) in orthopaedic trauma patients.  
Rationale: More than 12% of orthopaedic trauma patients experience breakthrough VTE events 
despite standard dose enoxaparin prophylaxis. Fixed dose enoxaparin prophylaxis has been 
shown to be inadequate in orthopaedic trauma surgery and several other surgical subspecialties. 
Prior data from this group showed that 53% of orthopaedic trauma patients were within goal 
peak aFXa range. 
Hypothesis: Initial peak steady-state aFXa levels will be within the accepted range (0.2-0.4 
IU/mL) in 75% of patients on weight-based enoxaparin dosing in orthopaedic trauma patients, up 
from 53% on fixed 30mg BID dosing. 
  
Aim 2: Examine the response of aFXa levels to a real-time dose adjustment protocol. 
Rationale: Literature in several surgical subspecialties shows that dose adjustment can 
significantly increase the number of patients within goal the peak aFXa range. Data from this 
group showed that dose adjustment achieved an increase in the number of patient within range 


Protocol Summary (ERICA) 
 
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from 53% to 66%. 
Hypothesis 2: Protocol-driven enoxaparin dose adjustment in response to aFXa levels will 
increase the proportion of patients with appropriate aFXa peak levels to from 75% to 85%. 
  
Aim 3: Examine rates of 90-day VTE and clinically relevant bleeding events in orthopaedic 
trauma patients on weight-based enoxaparin prophylaxis. 
Rationale: This observational aim will allow us to better understand VTE and bleeding rates after 
orthopaedic trauma surgery. Events have been shown to be rare and we recognize that the 
proposed study is underpowered to rigorously examine alterations in VTE or bleed rates in 
response to the proposed dose adjustment protocol. 
Hypothesis 3: Rates of post-operative VTE and re-operative bleeds will be < 2% in each group. 
  
  
 
 
 
Study Population 
 
Age of Participants: 18+ 
 
Sample Size: 
At Utah: 
137  
All Centers: 
 
 
Inclusion Criteria: 
We will include adult patients who have undergone orthopaedic trauma surgery and can have 
enoxaparin initiated within 36 hours after procedure.  All patients will undergo informed 
consent. 
 
 
Exclusion Criteria: 
We will exclude those with intracranial bleeding/stroke, bleeding disorder, heparin-induced 
thrombocytopenia, creatinine clearance ≤ 30mL/min, epidural catheter, or serum creatinine 
>1.6mg/dL.  
 
 
Design  
 
Prospective Clinical Research 
 


Protocol Summary (ERICA) 
 
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Study Procedures 
 
Recruitment/Participant Identification Process: 
Daily operative schedule will be reviewed for University of Utah orthopaedic trauma surgeons 
to identify post operative trauma patients. Once identified, patients will be approached by Dr. 
Daniel Jones or the study clinical research coordinators (Kory Fleming, Andrea Gurule) to 
undergo the informed consent process. 
 
 
Informed Consent: 
Description of location(s) where consent will be obtained:  
University of Utah Hospital 
 
Description of the consent process(es), including the timing of consent:  
Patients will be identified based on the daily surgery schedule and followed to see if they are 
started on enoxaparin post operatively at the discretion of the surgeon. Patients will undergo 
the informed consent process on post-operative day one or two while admitted to the hospital. 
No waiting period between the consent process and obtaining consent is planned, unless 
requested by the patient. 
 
Procedures: 
Patients will have enoxaparin initiated within 36 hours after the surgical procedure.  The 
starting dose will be 0.4mg/kg. Blood draws will be a procedure performed in this study. After 
the third enoxaparin dose, patients will have peak and trough steady state anti-Factor Xa levels 
drawn.  These will occur at 4 and 12 hours after the third enoxaparin dose, 
respectively.  Patients with "in range" peak anti-Factor Xa levels (0.2-0.4 IU/mL) will have no 
additional lab values drawn and will have no dose adjustment.  Patients with "out of range" 
anti-Factor Xa levels (<0.2 IUmL or >0.4 IU/mL) will have real time enoxaparin dose 
adjustment performed and will have repeat peak and trough steady state anti-Factor Xa levels 
drawn after the third dose. Most patients that require dose adjustment will only need it once. 
We anticipate a very small percentage of patients that will go through two or three rounds of 
dose adjustment. Dose adjustment for those under range will be a 10mg increase in their 
weight-based dose. Those over range will have a 10mg dose increase in their weight-based 
dose. Monitoring of aFXa levels will be discontinued when peak levels are in range, the 
surgeon discontinues enoxaparin prophylaxis, or the patient is discharged from the hospital. 
The enoxaparin doses used in this study are in accordance with the approved usages of 
enoxaparin and therefore do not require an IND. 
All patients will also receive sequential compression devices for the duration of their inpatient 
stay, as per hospital policy. 
Patients will be contacted via telephone or certified latter at 90 days after surgery to identify 
VTE or bleeding complications that were diagnosed or managed at other institutions. 
 


Protocol Summary (ERICA) 
 
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IRB Approval 8/22/2018 
 
 
Procedures performed for research purposes only:  
The surgery is standard of care.  The decision to have surgery or not is part of the standard
care and has nothing to do with the research process. 
Provision of post-operative enoxaparin is standard of care.  The decision (yes/no) to give 
enoxaparin by the surgeon is not part of this study. 
The non standard of care procedures for this study include: 
1. Blood draws for anti-Factor Xa levels after surgery (generally 2-4 blood draws per patie
2. Possible Enoxaparin dose adjustment based on anti-Factor Xa level 
 
 
Statistical Methods, Data Analysis and Interpretation 
 
The proportion of patients with in-range peak aFXa levels using fixed vs. weight-based dosing 
will be compared with the chi-squared test.  The impact of real time enoxaparin dose adjustment 
will be examined by comparing the proportion of patients with in-range aFXa levels before and 
after dose adjustment.  Time series analysis will examine associations between initial in-range 
and out-of-range aFXa levels and downstream VTE and/or major bleeding events. 
Our projected recruitment results in inadequate power to examine VTE prevention or major 
bleeding events in response to enoxaparin dose escalation (one of our aims).  This study will 
provide important preliminary data for weight-based dosing in orthopaedic trauma, which to our 
knowledge has not been done in orthopaedic surgery to date. We will collect data on 90-day 
symptomatic VTE events, 90-day major bleeding events (re-operative hematoma), and time to 
VTE or major bleeding event.  We will contact patients at 90 days via telephone or certified mail 
to identify events that were diagnosed or managed at other institutions.  
  
Sample size calculation:  
Retention from our previous study in orthopaedic trauma was 72%. 151 patients were enrolled, 
22 discharged prior to lab draws, 8 were changed from enoxaparin to an alternative blood thinner 
prior to lab draws, and 12 underwent blood draws but had unusable data as the draws were 
inappropriately timed (<3hrs or >5hrs after 3rd enoxaparin dose for steady-state peak xFXa 
level). Of these remaining 109 patients, 53% had initial peak aFXa levels within our goal range 
of 0.2-0.4IU/mL. Dose adjustment achieved adequate prophylaxis in an additional 13% of 
patients. Our hypothesis is that 75% of patients will be within range with weight-based dosing. 
Using an alpha of 0.05 and beta of 0.9, we would need 107 patients to effectively power a 
similar change for peak aFXa levels in the proposed study. With 28% over enrollment to allow 
for attrition, we would require n = 137.  
  


Protocol Summary (ERICA) 
 
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