Clinical trial NCT03251963
Conditions: Venous Thromboembolism Deep Venous Thrombosis Surgery
Sponsor: University of Utah
Start date: 2017-09-15; Completion date: 2019-07-27
Enrollment: 131 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this research is to better understand how patient-level factors can be used to predict the appropriate enoxaparin dose to maximize venous thromboembolism (VTE) risk reduction and minimize bleeding.

Detailed description:
VTE encompasses deep venous thrombosis and pulmonary embolus and is the proximate cause of death in over 100,000 hospitalized patients per year 4,5. To put this in better context, VTE kills more people each year than the annual morbidity from motor vehicle crashes and breast cancer combined-and one third of these deaths are known to occur after surgical procedures 34. "Breakthrough" VTE events occur in patients despite the receipt of guideline-compliant chemical prophylaxis. These events can be frustrating for surgeons, can represent a resource and financial burden for hospital systems, and most importantly, can be life or limb threatening for patients.

Existing data from our group and others suggests that inadequate enoxaparin dosing, quantified by aFXa levels, represents a plausible explanatory mechanism for "breakthrough" VTE events that occur among thoracic surgery patients. This project will examine the pharmacodynamics of fixed dose enoxaparin (40mg/day) after VATS-this dose and frequency were the most commonly prescribed VTE chemical prophylaxis strategy in a recent survey of thoracic surgeons 35. If inadequate aFXa levels are observed with fixed enoxaparin dosing, the study will design, implement and test a weight-based dosing approach to optimize aFXa levels. The study will also examine how alteration of enoxaparin dose magnitude affects peak aFXa levels and risk for VTE and major bleeding events.

Aim 1: To evaluate peak steady-state aFXa levels in response to a fixed dose of enoxaparin prophylaxis (40mg once daily) in VATS patients.

Rationale: Over 12% of thoracic surgery patients have "breakthrough" VTE events despite receipt of fixed dose chemical prophylaxis 29. Fixed dose enoxaparin prophylaxis has been shown to be inadequate for the majority of patients in other surgical subspecialties.

Hypothesis: Peak steady state aFXa levels will be within the accepted range (0.3-0.5 IU/mL) in 40% of patients after VATS.

Aim 2: To compare the effect of fixed (40mg once daily) and weight-based (0.5mg/kg once daily) enoxaparin prophylaxis on peak steady state aFXa levels after VATS.

Rationale: Our preliminary data shows a potential association between body weight and aFXa levels in response to fixed dosing; this will be confirmed using a multi-center approach in Aim #1. Body weight may be an important predictor of appropriate enoxaparin dose.

Hypothesis: Weight-based enoxaparin prophylaxis, when compared to fixed dose prophylaxis, will increase the proportion of patients with in-range peak aFXa levels from 40% to 80%.

Aim 3: To examine rates of 90-day VTE and clinically relevant bleeding events in VATS patients who receive fixed dose vs. weight-based enoxaparin prophylaxis.

Rationale: This observational Aim will allow us to better understand VTE and bleeding rates after VATS. Since these are rare events it is impossible to power the study to detect increases or decreases in risk between the dose groups. This study does provide a way to demonstrate an unexpected, very large difference in risk.

Hypothesis: Rates of post-operative VTE and clinically relevant bleeding will be less than 2% in each group.

Arms: arm 1: Eligible patients will be administered 40 mg enoxaparin daily and will have steady state peak and trough anti-Xa levels drawn after the third enoxaparin dose. arm 2: Eligible patients will be administered 0.5 mg/kg enoxaparin daily and will have steady state peak and trough anti-Xa levels drawn after the third enoxaparin dose.
Interventions: intervention 1: Fixed Dose Enoxaparin intervention 2: Variable Dose Enoxaparin
Intervention descriptions: intervention 1: Eligible patients will be administered 40 mg enoxaparin daily and will have steady state peak and trough anti-Xa levels drawn after the third enoxaparin dose. For patients in-range (levels 0.3-0.5IUmL), 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. intervention 2: Eligible patients will be administered 0.5 mg/kg enoxaparin daily and will have steady state peak and trough anti-Xa levels drawn after the third enoxaparin dose. For patients in-range (levels 0.3-0.5IUmL), 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.

Protocol documents:
Prot_SAP_001.pdf: 
Study Protocol and Analysis Plan 
Fixed Versus Weight-Based Enoxaparin Dosing in Thoracic Surgery Patients 
NCT03251963 
June 19, 2020 
 
 


Study Design 
Inclusion criteria were thoracic surgery patients, surgery under general anesthesia, and prophylactic 
enoxaparin initiation within 24 hours.  Exclusion criteria were creatinine >1.6mg/dL, planned 
postoperative admission <3 days, epidural catheter, history of heparin induced thrombocytopenia, known 
bleeding issue, weight >150kg, or recent stroke or intracranial bleeding event.  Most open thoracic 
surgery patients at both sites receive concomitant epidural anesthesia; this biased our sample toward the 
video-assisted thorascopic surgery (VATS) population.  Patients provided written informed consent.  
 
The study was designed prospectively as a pre/post trial to examine the impact of a change in practice (a 
switch from fixed dose to weight tiered enoxaparin).  Cohort 1 accrued between September 21, 2017 and 
May 8, 2018, and all patients received fixed dose enoxaparin prophylaxis at 40mg once daily.  Cohort 2 
was planned as weight based at 0.5mg/kg, and recruitment began on May 9, 2018.  Both sites encountered 
insurmountable issues with pharmacist dose rounding.  Nine patients in the 0.5mg/kg group who received 
rounded doses were dropped.  Cohort 2 was revised to weight-tiered, daily enoxaparin 15.  Patients <70kg 
received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg.  Cohort 2 
accrued between August 9, 2018 and March 25, 2019.  Figure 1 describes patient enrollment, exclusion, 
allocation, and followup.   
 
We examined enoxaparin pharmacokinetics using steady state peak and trough aFXa levels, drawn at 4 
and 12 hours after the third dose.  Goal peak aFXa (0.3-0.5 IU/mL) was chosen to maximize VTE risk 
reduction while minimizing bleeding 12,19.  All patients with identified out-of-range levels received dose 
adjustment and repeat aFXa levels per Figure 2.  The algorithm targeted peak aFXa levels because low 
peak aFXa has been associated with symptomatic 90-day VTE 9, because aFXa-driven dose adjustment is 


impactful 8, and because a recent review showed that ~80% of studies targeted peak aFXa 19,20.  Dose 
adjustment was performed until an in-range peak level was achieved, or until time of discharge.   
 
Patients received enoxaparin prophylaxis for the duration of inpatient stay.  Post-discharge enoxaparin 
prophylaxis was not routinely provided; when given, patients were discharged on a pharmacokinetically 
optimized dose.   
 
Study Outcomes 
The primary effectiveness outcome was adequate peak aFXa (≥0.3 IU/mL), chosen because patients 
receiving enoxaparin 40mg once daily with initial peak aFXa <0.3 IU/mL are at elevated risk for 90-day 
symptomatic VTE 9.  The primary safety outcome was avoidance of over-anticoagulation (peak aFXa 
≥0.5 IU/mL), which could increase risk for bleeding.   
 
Secondary outcomes included 1) achievement of adequate trough aFXa level (aFXa ≥0.1 IU/mL), because 
low aFXa trough increases asymptomatic DVT risk 11, 2) 90-day symptomatic VTE, and 3) 90-day 
clinically relevant bleeding.  Symptomatic VTE was defined as any symptomatic deep vein thrombosis or 
pulmonary embolus with imaging confirmation.  Screening duplex ultrasound was not performed, as 
suggested by current American College of Chest Physicians guidelines 2.  Clinically relevant bleeding 
was defined as any bleeding that changed the course of care 21; this included bleeding requiring 
enoxaparin cessation, unexpected transfusion, or procedural (interventional radiology or operating room) 
intervention.  Chart review and mandatory phone calls at 90 days identified events that occurred at other 
facilities; when identified, records were obtained for confirmation.   
 
Analysis plan 
Study data were uploaded to a secure, online Research Electronic Data Capture platform.   


 
Descriptive statistics compared patient level factors including individual VTE risk using the 2005 Caprini 
score 22 and surgical details, by group.   
 
The proportion of patients who achieved the primary effectiveness and primary safety outcomes were 
compared, by group, using the chi-squared or Fishers exact test.      
 
The survival analysis log-rank test compared 90-day VTE and 90-day bleeding, by group.  No patient was 
lost to followup and the censoring rate of this survival analysis was zero.   
 
Sample size calculation 
Historical data showed that the two institutions admitted 14 eligible patients monthly.   Similar studies 
showed that high proportions (~99%) of patients consented and 70% of these would produce primary 
outcome data 8,9,14.  We estimated that 116 patients (58 per group) could be consented within the planned 
12 month study period.   
 
We assumed 32.6% of thoracic surgery patients receiving enoxaparin 40mg once daily would have 
adequate anticoagulation (peak aFXa level ≥0.3 IU/mL) 8, and that 82% of patients would have adequate 
anticoagulation in response to once daily weight-tiered enoxaparin dosing, based on data from women 
having caesarean section 15.  Using alpha of 0.05 and beta of 0.9, at least 23 patients per group would be 
required.  Thus, anticipated recruitment exceeded the minimum number of required patients.    
 
Based on existing trials data from thoracic surgery patients receiving enoxaparin 40mg once daily 8, low 
(~1%) rates of 90-day VTE and bleeding were anticipated.  Thus, it was impossible to adequately power 
the study for a clinical endpoint.