Venous thromboembolism is a frequent issue in severe trauma patients. Guidelines for venous thromboembolism prevention include the use of pharmacological thromboprophylaxis, mainly with low-molecular-weight heparin, and/or mechanical thromboprophylaxis. However, a high incidence of venous thromboembolism is observed despite standard dose thromboprophylaxis (such as enoxaparin 40 mg once daily).
An increase of the dose of anticoagulants could improve thromboprophylaxis in trauma patients. To date, two randomised trials have assessed the effect of weight-based low-molecular-weight heparin dosing vs. fixed dose in trauma patients. These pilot studies did not demonstrate a statistical difference between groups although there was a trend in favour of a lower incidence of deep vein thromboses with the increased dose low-molecular-weight heparin prophylaxis. However, both studies included non-severe trauma patients and the second study focused only on deep vein thromboses. Other studies suggested that a superior-than-standard dose of low-molecular-weight heparin, sometimes
guided by the anti-Xa activity, decreases the incidence of venous thromboembolism in severe trauma without increasing bleeding events, but they were observational in nature.
The hypothesis of the HEPTRAUMA trial is that, in severe trauma patients, a thromboprophylaxis with intermediate dose low-molecular-weight heparin (twice the standard dose) decreases the incidence of major venous thromboembolism compared to standard dose.
All adult patients (age ≥18 years) admitted to an intensive care unit following trauma with an expected stay >48 hours and a planned administration of LMWH.
Affiliation to the French social security system or European (CEAM)
Prehospital cardiac arrest
Hospital admission >72 hours
More than one dose of prophylactic anticoagulant already administered since trauma
Renal failure defined by creatinine clearance of 30 mL/min or less (Cockcroft-Gault formula)
Parallel
Enoxaparin standard dose
DrugIn the control group, patients will receive 1 injection of enoxaparin 4000 IU and 1 injection of placebo until day 14 or hospital discharge in the same form as enoxaparin (subcutaneous injection). A placebo injection is administered as needed to maintain blinding and ensure the same number of injections as in the intermediate-dose arm.
Enoxaparin intermediate dose
DrugIn the experimental group, patients will receive 2 injections of enoxaparin 4000 IU until day 14 or hospital discharge.
Composite of symptomatic deep vein thrombosis (DVT), proximal DVT, pulmonary embolism (PE).
Effect of intermediate-dose versus standard-dose enoxaparin on the 14-day risk of major venous thromboembolism (symptomatic proximal DVT or PE) in adult patients with severe trauma eligible for pharmacologic thromboprophylaxis. Analyses will be conducted in the ITT population using a competing-risk approach (death before VTE considered as a competing event).
To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the net clinical benefit combining major venous thromboembolism and major bleeding events
Composite of major venous thromboembolism, as defined in the primary endpoint, and major bleedings, defined by (i) the need for a haemostatic invasive procedure because of bleeding, (ii) the need for interruption of prophylactic enoxaparin for ≥48 hours because of bleeding, or (iii) bleeding in a critical organ within 14 days following randomisation after a severe trauma
To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the individual components of the primary outcomethe incidence of major bleeding and clinically relevant non-major bleeding as per ISTH definition
* Symptomatic DVT of the lower limb within 14 days following randomisation * Proximal DVT within 14 days following randomisation * Pulmonary embolism within 14 days following randomisation
To evaluate the effect of intermediate versus standard dose LMWH on the incidence of major bleeding and clinically relevant non-major bleeding as per ISTH definition
Major or clinically relevant non-major bleeding, as per ISTH definition, occurring during or within 48h of the last dose of study drug
To evaluate the effect of intermediate versus standard dose LMWH on the incidence of red blood cell transfusions within 14 days following randomisation after severe trauma (or until hospital discharge)
Number of red blood cell transfusions within 14 days following randomisation after severe trauma (or until hospital discharge)
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