Minimization of Bleeding Related Adverse Drug Events in Plastic & Reconstructive Surgery Patients Randomized to Different Postoperative Anticoagulant Regimens
Phase: PHASE2
Conditions: Venous Thromboembolism, Deep Venous Thrombosis, Pulmonary Embolus, Reconstructive Surgery
Sponsor: University of Utah

Title: Minimization of Bleeding Related Adverse Drug Events in Plastic & Reconstructive Surgery 
 
NCT03212365 
 
Document date: 8.6.2020 
 
 
 

Study Protocol 
Patients 
Eligible patients were 18 years of age or older, had a planned definitive plastic and 
reconstructive surgery operation under a general anesthetic, and had planned post-operative 
admission of at least two overnights.  All patients had sequential compression devices placed in 
the OR and continued during inpatient admission.  Patients were ineligible if they had any one of 
the following: contraindication to use of enoxaparin, intracranial bleeding or stroke, hematologic 
or bleeding disorder, known heparin-induced thrombocytopenia, creatinine clearance 
≤30mL/min, serum creatinine >1.6mg/dL, epidural anesthesia, or patient/surgeon desire to be 
provided with non-enoxaparin chemical prophylaxis after surgery.  Patients who received peri-
operative aspirin were eligible for the study.  Patients whose gross weight was >150kg were 
excluded.  There was no minimum study weight.  All patients provided written informed consent 
prior to their planned definitive operation.   
 
Study Procedures 
Patients were randomized immediately after their planned definitive operation, following 
a direct conversation between the Principal Investigator (CJP), primary plastic surgeon, and 
consultant surgeons or physicians.  Primary surgeons had the discretion to decline study 
participation based on intra-operative events, such as procedure less invasive than planned or 
concern for intra-operative bleeding.  Eligible patients were randomized to enoxaparin 40mg 
twice daily or enoxaparin 0.5mg/kg twice daily.  
Investigational Pharmacy randomized patients and then provided study drug in identical 
syringes containing clear liquid; all doses were diluted to 1.0cc volume.  Patients received the 

first dose of study drug as a subcutaneous injection between 7 and 8 hours after the procedure 
ended, and every 12 hours thereafter until discharge from the hospital.   
Patients had peak and steady state aFXa levels drawn after the third enoxaparin dose, at 
steady state.  Goal peak steady state aFXa was 0.2-0.4 IU/mL.  Investigational Pharmacy 
identified patients with out-of-range peak aFXa levels and performed real time enoxaparin dose 
adjustment.  Dose adjustment was performed because initial low aFXa levels have significantly 
increased risk of VTE and high aFXa levels have been associated with bleeding.  Therefore, not 
providing real time dose adjustment in response to documented aFXa levels would have been 
ethically marginal.  Patients whose level was in-range continued on their initial enoxaparin dose 
until discharge.  Patients who received real time dose adjustment underwent dose optimization 
until in-range peak aFXa level was achieved, and then received that dose until discharge.   
Patients did not routinely receive post-discharge enoxaparin prophylaxis; this was 
provided only at attending physician discretion.  When applicable, the resident physician 
received unblinded dose information, allowing the attending physician to remain blinded and 
objectively identify secondary outcome events while providing patients with a 
pharmacokinetically optimized dose.   
The primary outcome (aFXa level in response to initial enoxaparin dose) occurred 36 
hours after surgery, and could not be confounded by dose adjustment or receipt of post-discharge 
enoxaparin. 
Patients received standard post-operative care from the primary surgeon.  The study team 
contacted all randomized patients at 90 days to identify secondary outcomes. 
 
Study Outcomes 

Study outcomes were defined prior to enrollment of Patient #1, and definitions were 
published previously (Pannucci et al, “Double-Blind Randomized Clinical Trial to Examine the 
Pharmacokinetic and Clinical Imapacts of Fixed Dose versus Weight-based Enoxaparin 
Prophylaxis: A Methodologic Description of the FIxed or Variable Enoxaparin (FIVE) Trial”, 
PubMed ID 31321183). 
Both primary outcomes were pharmacokinetic outcomes derived from the initial peak 
steady state aFXa level, drawn at 36 hours after conclusion of the operation.  The initial peak 
steady state level was in response to the initial enoxaparin dose; when dose adjustment was 
required, this level was not considered in the primary outcome.  The primary effectiveness 
outcome was avoidance of under-anticoagulation (peak aFXa <0.20 IU/mL). The primary safety 
outcome was avoidance of over-anticoagulation (peak aFXa >0.40 IU/mL). Post dose-adjustment 
aFXa levels, if drawn, were not considered in the primary outcomes.  Both secondary outcomes 
were obtained at 90 days after surgery.  The secondary effectiveness outcome was 90-day 
symptomatic VTE, and the secondary safety outcome was 90-day clinically relevant bleeding.   
Symptomatic VTE was defined as 1) any imaging-confirmed deep venous thrombosis 
(DVT) event, including upper limb, lower limb, or central, 2) any imaging-confirmed pulmonary 
embolus event, 3) any autopsy-proven VTE, and/or 4) 90-day mortality in which VTE could not 
be excluded (eg PEA arrest without autopsy).  Patients were not screened for VTE events unless 
symptoms were present.   
Major bleeding was defined using the published consensus definition of major bleeding 
for randomized controlled trials that examine anti-hemostatic drugs from the International 
Society of Thrombosis and Hemostasis.  Major bleeding included any of the following events: 
bleeding requiring two or more units of blood transfusion, bleeding requiring bedside hematoma 

evacuation or interventional radiology procedure, bleeding requiring unplanned return to the 
operating room, bleeding into a critical anatomic space, or fatal bleeding.  In addition, we 
tracked clinically relevant bleeding, which was defined more broadly to include bleeding which 
required enoxaparin cessation in addition to all major bleeding factors. 
90-day bleeding and VTE were compared between groups using a survival analysis log-
rank test.  
 
Outcome events were blindly adjudicated. 
 
Statistical Analysis 
The FIVE trial’s sample size calculations and justifications were previously published 
(Pannucci et al, “Double-Blind Randomized Clinical Trial to Examine the Pharmacokinetic and 
Clinical Imapacts of Fixed Dose versus Weight-based Enoxaparin Prophylaxis: A Methodologic 
Description of the FIxed or Variable Enoxaparin (FIVE) Trial”, PubMed ID 31321183). 
Statistical analyses were performed using Stata15 (StataCorp; College Station, Texas). 
 
We compared patient-level variables (Tables 1 and 2) between groups using student’s t-
test for continuous variables, chi-square or Fisher’s exact test for dichotomous variables, and 
Wilcoxon rank-sum test for ordinal variables. 
 
The primary effectiveness outcome was avoidance of under-anticoagulation (peak aFXa 
<0.20 IU/mL).  Initial sample size estimates for under-anticoagulation avoidance were obtained 

from a prior clinical trial, which established that 90.4% of patients who received enoxaparin 
40mg twice daily were not under-anticoagulated.  We assumed the rate of not being under-
anticoagulated was 90.4% in the weight-based group.  The primary effectiveness analysis was a 
noninferiority analysis with a two-sided test at the 0.05 level.  The noninferiority margin was set 
at -12%.  To achieve 90% power using a two-sided comparison with alpha of 0.05, using a two-
sided 95% confidence interval around the difference in proportions, 127 patients per group were 
needed.  The noninferiority hypothesis was tested by a Poisson regression model for binary 
outcomes with robust standard errors.  After the Poisson model was fit, marginal estimation was 
used to calculate the 95% confidence interval around the difference in proportions.  This method 
took the two estimated proportions used in the risk ratio, subtracted then, and computed the 
confidence interval for non-inferiority testing.  To obtain a two-sided noninferiority test p-value, 
we used a Wald post-test to compare the difference in proportions to the noninferiority margin 
constant -0.12.   
 
The primary safety outcome was avoidance of over-anticoagulation (peak aFXa >0.40 
IU/mL).  Initial sample size estimates for over-anticoagulation were obtained from a prior 
clinical trial, which showed that 72.2% of patients who received enoxaparin 40mg twice daily 
were not over-anticoagulated.  We assumed that weight-based dosing would increase the 
proportion of patients not over-anticoagulated to 90%.  To detect this difference with 90% power 
using a two-sided comparison with alpha of 0.05, 100 patients per group were needed.  For this 
outcome, a Poisson regression model for binary outcomes with robust standard errors was fitted.   
 

The Data Safety and Monitoring Board reviewed unblinded 90-day VTE and bleeding 
data every six months.  To avoid an increased risk for type I error, no interim analyses were 
performed on primary outcomes. 
 
After 254 patients were randomized, the study statistician reviewed unblinded data to 
determine the number of patients who did not produce primary outcome data.  No interim 
statistical analysis was performed at this phase, to avoid an increased risk for type I error.  The 
planned sample size was adjusted upward to 295, to include at least 127 patients in each group 
who produced primary outcomes data.