The Use of Fondaparinux in Preventing Thromboembolism in High Risk Trauma Patients

• ClinicalTrials.gov Identifier: NCT00531843
• Recruitment Status: Completed
• First Posted: September 19, 2007
• Results First Posted: December 24, 2013
• Last Update Posted: December 24, 2013
• Sponsor: Mary Knudson, M.D.
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): Mary Knudson, M.D., University of California, San Francisco

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Venous Thromboembolism
• Interventions: Drug: fondaparinux sodium; Device: sequential compression devices
• Enrollment: 105

Participant Flow

Recruitment Details	During a 6-month period, consecutive adults presenting to one Level I urban trauma center were screened for eligibility, enrolled and assigned to a treatment category using previously-developed clinical guidelines.
Pre-assignment Details	Of 105 enrolled participants, 18 were excluded from analysis (13 discharged or transferred prior to second venous ultrasonography; 4 received non-study DVT prophylaxis; 1 had a known protein-C deficiency).

Arm/Group Title	Fondaparinux Sodium	No Fondaparinux
Arm/Group Description	Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg via subcutaneous administration (SubQ) daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.	Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary inferior vena cava (IVC) filter (prn as determined by caregiver).
Period Title: Overall Study
Started	81	6
Completed	81	6
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Fondaparinux Sodium	No Fondaparinux	Total
Arm/Group Description		Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.	Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver).	Total of all reporting groups
Overall Number of Baseline Participants		81	6	87
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	81 participants	6 participants	87 participants
		43.1 (19.3)	56.8 (20.9)	44.3 (19.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	81 participants	6 participants	87 participants
	Female	21 25.9%	1 16.7%	22 25.3%
	Male	60 74.1%	5 83.3%	65 74.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	81 participants	6 participants	87 participants
		81	6	87

Outcome Measures

1. Primary Outcome

Title	Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE)
Description	Color-flow duplex venous ultrasonography examinations of upper and lower extremities were performed within 48 hours of injury, and then weekly until discharge or 3 weeks. DVT was defined as any clot occurring in the subclavian, iliac, femoral, or popliteal location. Patients were examined daily for clinical signs and symptoms of venous thromboembolism (VTE) and PE. Small, nonocclusive clots discovered in other locations were observed for progression on sequential ultrasonography examinations.
Time Frame	within 3 weeks post injury

Outcome Measure Data

Analysis Population Description

Of 11 patients with initial contraindication to anticoagulation, 5 were cleared by the treating physicians to receive fondaparinux within 3 days of injury, and 6 were not.

Arm/Group Title	Fondaparinux Sodium	No Fondaparinux
Arm/Group Description:	Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.	Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver).
Overall Number of Participants Analyzed	81	6
Measure Type: Number; Unit of Measure: participants
DVT	2	2
DVT after fondaparinux	1	NA [1]
PE	0	0

[1]

This arm/group did not receive Fondaparinux.

2. Secondary Outcome

Title	Normal Trough and Peak Fondaparinux Concentration
Description	Serum samples were collected 30 minutes before (trough) and 2 hours after (peak) the third dose of fondaparinux. Normative data plots comparing study participants with healthy volunteers were supplied by the company outsourced to analyze samples.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Serum samples were obtained from 63 representative patients from our study who received Fondaparinux and compared against normative values from normal volunteers supplied by our sponsor.

Arm/Group Title	Fondaparinux Sodium	No Fondaparinux
Arm/Group Description:	Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.	Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver).
Overall Number of Participants Analyzed	63	0
Measure Type: Number; Unit of Measure: Participants
Trough values outside normative range	0
Peak values outside normative range	0

3. Secondary Outcome

Title	Increased Bleeding Attributed to Fondaparinux
Description	Coagulopathic bleeding due to fondaparinux was suspected in patients requiring packed red cell transfusions after initiation of fondaparinux therapy only if the change in hematocrit prompting transfusion was not clinically commensurate with the degree of injuries that the patient had sustained (primarily orthopaedic) and/or the hematocrit did not respond appropriately post-transfusion.
Time Frame	3 weeks post injury

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Sodium	No Fondaparinux
Arm/Group Description:	Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.	Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver).
Overall Number of Participants Analyzed	81	0
Measure Type: Number; Unit of Measure: participants
	0

Adverse Events

Time Frame	3 weeks post-injury
Adverse Event Reporting Description	This study did not record adverse events that were related to the severity of participants' trauma unless assessed for potential attribution to study participation
Arm/Group Title	Fondaparinux Sodium		No Fondaparinux
Arm/Group Description	Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury.		Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver).
All-Cause Mortality
	Fondaparinux Sodium		No Fondaparinux
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Fondaparinux Sodium		No Fondaparinux
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/81 (0.00%)		0/6 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Fondaparinux Sodium		No Fondaparinux
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/81 (16.05%)		2/6 (33.33%)
Blood and lymphatic system disorders
Drop in hematocrit †	13/81 (16.05%)	13	0/6 (0.00%)	0
Vascular disorders
DVT †	2/81 (2.47%)	2	2/6 (33.33%)	2
Superficial nonoccluding clots †	4/81 (4.94%)	4	0/6 (0.00%)	0
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: M. Margaret Knudson, MD
• Organization: UCSF/SF General Hospital
• Phone: 415.205.4623
• EMail: pknudson@sfghsurg.ucsf.edu

Publications of Results:

Lu JP, Knudson MM, Bir N, Kallet R, Atkinson K. Fondaparinux for prevention of venous thromboembolism in high-risk trauma patients: a pilot study. J Am Coll Surg. 2009 Nov;209(5):589-94. doi: 10.1016/j.jamcollsurg.2009.08.001. Epub 2009 Sep 11.

Other Publications:

Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M; PEGASUS investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005 Oct;92(10):1212-20.

Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7.

Velmahos GC. Posttraumatic thromboprophylaxis revisited: an argument against the current methods of DVT and PE prophylaxis after injury. World J Surg. 2006 Apr;30(4):483-7.

Hill AB, Garber B, Dervin G, Howard A. Heparin prophylaxis for deep venous thrombosis in a patient with multiple injuries: an evidence-based approach to a clinical problem. Can J Surg. 2002 Aug;45(4):282-7.

Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):338S-400S. Review.

Turpie AG, Bauer KA, Eriksson BI, Lassen MR; PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet. 2002 May 18;359(9319):1721-6. Erratum in: Lancet 2002 Oct 5;360(9339):1102.

Kudsk KA, Fabian TC, Baum S, Gold RE, Mangiante E, Voeller G. Silent deep vein thrombosis in immobilized multiple trauma patients. Am J Surg. 1989 Dec;158(6):515-9.

Knudson MM, Ikossi DG. Venous thromboembolism after trauma. Curr Opin Crit Care. 2004 Dec;10(6):539-48. Review.

Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, de Greef R. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002;41 Suppl 2:1-9.

Knudson MM, Ikossi DG, Khaw L, Morabito D, Speetzen LS. Thromboembolism after trauma: an analysis of 1602 episodes from the American College of Surgeons National Trauma Data Bank. Ann Surg. 2004 Sep;240(3):490-6; discussion 496-8.

Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001 Nov 1;345(18):1298-304.

Bauer KA, Eriksson BI, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001 Nov 1;345(18):1305-10.

Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994 Dec 15;331(24):1601-6.

Allen TL, Carter JL, Morris BJ, Harker CP, Stevens MH. Retrievable vena cava filters in trauma patients for high-risk prophylaxis and prevention of pulmonary embolism. Am J Surg. 2005 Jun;189(6):656-61.

Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006 Feb 11;332(7537):325-9. Epub 2006 Jan 26.

• Responsible Party: Mary Knudson, M.D., University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00531843
• Other Study ID Numbers: H6693-30799-01
• First Submitted: September 17, 2007
• First Posted: September 19, 2007
• Results First Submitted: June 10, 2013
• Results First Posted: December 24, 2013
• Last Update Posted: December 24, 2013