Fixed Versus Weight-Based Enoxaparin Dosing in Thoracic Surgery Patients

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT03251963
• Collaborator: University of Michigan (Other)
• Enrollment: 131
• Location: 1
• Arms: 2
• Actual Duration (Months): 22.3
• Patients Per Site Per Month: 5.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolism; Deep Venous Thrombosis; Surgery	Drug: Fixed Dose Enoxaparin; Drug: Variable Dose Enoxaparin	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 131 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants enrolled in months 1-6 of the study will all receive a fixed dose of enoxaparin. Patients enrolled in months 7-12 of the study will all receive a variable dose of enoxaparin.Participants enrolled in months 1-6 of the study will all receive a fixed dose of enoxaparin. Patients enrolled in months 7-12 of the study will all receive a variable dose of enoxaparin.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Fixed Versus Weight-Based Enoxaparin Dosing in Thoracic Surgery Patients
• Actual Study Start Date: Sep 15, 2017
• Actual Primary Completion Date: Mar 27, 2019
• Actual Study Completion Date: Jul 27, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Number of Patients With in Range Initial Peak Xa Level [36 hours]

   Number of patients with in range initial peak Xa level

Secondary Outcome Measures

1. Number of Participants With Venous Thromboembolism Events or Death [90 days]

   Any symptomatic venous thromboembolism events, including deep venous thrombosis or pulmonary embolus occurring within 90 days of surgery

2. Number of Participants With Bleeding Events [90 days]

   Bleeding events requiring alteration in the course of care within 90 days of surgery

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah
• University of Michigan

Investigators

• Principal Investigator: Christopher Puccini, MD, University of Utah

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 19, 2020

More Information

Publications

None provided.

• Responsible Party: Christopher Pannucci, Assistant Professor, University of Utah
• ClinicalTrials.gov Identifier: NCT03251963
• Other Study ID Numbers: 100484
• First Posted: Aug 16, 2017
• Last Update Posted: Jul 8, 2020
• Last Verified: Jul 1, 2020

• 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
• Additional relevant MeSH terms: Thrombosis; Thromboembolism; Venous Thromboembolism; Venous Thrombosis; Enoxaparin; Enoxaparin sodium

Study Results

Participant Flow

Arm/Group Title	Fixed Dose Enoxaparin	Weight Tiered Enoxaparin
Arm/Group Description	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. 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.	Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.
Period Title: Overall Study
STARTED	65	66
COMPLETED	56	61
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	Fixed Dose Enoxaparin	Weight Tiered Enoxaparin	Total
Arm/Group Description	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. 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.	Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.	Total of all reporting groups
Overall Participants	65	66	131
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	32 49.2%	33 50%	65 49.6%
>=65 years	33 50.8%	33 50%	66 50.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.9 (15.6)	59.0 (16.8)	60.0 (16.2)
Sex: Female, Male (Count of Participants)
Female	37 56.9%	32 48.5%	69 52.7%
Male	28 43.1%	34 51.5%	62 47.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	2 3%	2 1.5%
Black or African American	1 1.5%	0 0%	1 0.8%
White	61 93.8%	63 95.5%	124 94.7%
More than one race	3 4.6%	1 1.5%	4 3.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	65 100%	66 100%	131 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fixed Dose Enoxaparin	Weight Tiered Enoxaparin
Arm/Group Description	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. 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.	Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.
Measure Participants	56	61
Count of Participants [Participants]	27 41.5%	27 40.9%

2. Secondary Outcome

Title	Number of Participants With Venous Thromboembolism Events or Death
Description	Any symptomatic venous thromboembolism events, including deep venous thrombosis or pulmonary embolus occurring within 90 days of surgery
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fixed Dose Enoxaparin	Weight Tiered Enoxaparin
Arm/Group Description	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. 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.	Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.
Measure Participants	65	66
Count of Participants [Participants]	1 1.5%	0 0%

3. Secondary Outcome

Title	Number of Participants With Bleeding Events
Description	Bleeding events requiring alteration in the course of care within 90 days of surgery
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fixed Dose Enoxaparin	Weight Tiered Enoxaparin
Arm/Group Description	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. 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.	Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.
Measure Participants	65	66
Count of Participants [Participants]	1 1.5%	3 4.5%

Adverse Events

Time Frame	90 days
Adverse Event Reporting Description	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. Clinically relevant bleeding was defined as any bleeding that changed the course of care; this included bleeding requiring enoxaparin cessation, unexpected transfusion, or procedural (interventional radiology or operating room) intervention.
Arm/Group Title	Fixed Dose Enoxaparin		Weight Tiered Enoxaparin
Arm/Group Description	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. 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.		Eligible patients will be receive weight tiered daily enoxaparin. Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. Variable Dose Enoxaparin: Patients <70kg received 30mg, patients 70kg to 89.9kg received 40mg, and patients ≥90kg received 50mg. 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.
All Cause Mortality
	Fixed Dose Enoxaparin		Weight Tiered Enoxaparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)		0/66 (0%)
Serious Adverse Events
	Fixed Dose Enoxaparin		Weight Tiered Enoxaparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)		0/66 (0%)
Blood and lymphatic system disorders
90-day Death	1/65 (1.5%)	1	0/66 (0%)	0
Other (Not Including Serious) Adverse Events
	Fixed Dose Enoxaparin		Weight Tiered Enoxaparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)		3/66 (4.5%)
Blood and lymphatic system disorders
DVT/PE	0/65 (0%)		0/66 (0%)
clinically relevant bleeding	1/65 (1.5%)		3/66 (4.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.