Fixed Versus Weight-Based Enoxaparin Dosing in Thoracic Surgery Patients

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.

Study Overview

• Status: Completed
• Conditions: Surgery; Venous Thromboembolism; Deep Venous Thrombosis
• Intervention / Treatment: Drug: Fixed Dose Enoxaparin; Drug: Variable Dose Enoxaparin

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.

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• receiving Video-Assisted Thoracoscopic Surgery
• able to have Enoxaparin initiated within 8 hours after procedure

Exclusion Criteria:

• Contraindication to use of enoxaparin
• Intracranial bleeding/stroke
• Hematoma or bleeding disorder
• Heparin-induced thrombocytopenia positive
• Creatinine clearance less than or equal to 30 mL/min
• Serum creatinine greater than 1.6 mg/dL
• Epidural catheter

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fixed Dose Enoxaparin; 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.	Drug: Fixed Dose Enoxaparin; 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.
Experimental: Variable Dose Enoxaparin; 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.	Drug: Variable Dose Enoxaparin; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With in Range Initial Peak Xa Level	Number of patients with in range initial peak Xa level	36 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Venous Thromboembolism Events or Death	Any symptomatic venous thromboembolism events, including deep venous thrombosis or pulmonary embolus occurring within 90 days of surgery	90 days
Number of Participants With Bleeding Events	Bleeding events requiring alteration in the course of care within 90 days of surgery	90 days

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: University of Michigan
• Investigators: Principal Investigator: Christopher Puccini, MD, University of Utah

Publications and helpful links

General Publications

• Pannucci CJ, Fleming KI, Bertolaccini C, Moulton L, Stringham J, Barnett S, Lin J, Varghese TK Jr. Fixed or Weight-Tiered Enoxaparin After Thoracic Surgery for Venous Thromboembolism Prevention. Ann Thorac Surg. 2020 Jun;109(6):1713-1721. doi: 10.1016/j.athoracsur.2019.12.058. Epub 2020 Feb 8.

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2017
• Primary Completion (Actual): March 27, 2019
• Study Completion (Actual): July 27, 2019

Study Registration Dates

• First Submitted: August 14, 2017
• First Submitted That Met QC Criteria: August 14, 2017
• First Posted (Actual): August 16, 2017

Study Record Updates

• Last Update Posted (Actual): July 8, 2020
• Last Update Submitted That Met QC Criteria: July 7, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: 100484

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes