Intermediate Versus Standard Dose Enoxaparin to Prevent Venous Thromboembolism in Severe Trauma Patients: a Multicenter Double Blind Randomised Controlled Trial

Обзор

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.

Вмешательства

• Препарат Enoxaparin standard dose
  In 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.
• Препарат Enoxaparin intermediate dose
  In the experimental group, patients will receive 2 injections of enoxaparin 4000 IU until day 14 or hospital discharge.

Первичные конечные точки

• Composite of symptomatic deep vein thrombosis (DVT), proximal DVT, pulmonary embolism (PE). [Срок оценки: Within 14 days following randomisation after severe trauma]

Вторичные конечные точки (6)

• 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 [Срок оценки: Within 14 days following randomisation]
• 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 [Срок оценки: 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 [Срок оценки: 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) [Срок оценки: Within 14 days following randomisation (or until hospital discharge)]
• To evaluate the effect of intermediate versus standard dose LMWH on the incidence of major VTE and major bleeding at day 30 following randomisation after a severe trauma [Срок оценки: At day 30 following randomisation]
• To evaluate the effect of intermediate versus standard dose LMWH on the incidence of deaths at day 30 following randomisation [Срок оценки: At day 30 following randomisation]

Критерии участия

Критерии включения

• 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)

Критерии исключения

• 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)
• Body weight >100 kg or <45 kg
• Indication for therapeutic anticoagulation
• Major known thrombophilia (e.g. antiphospholipid syndrome, antithrombin deficiency)
• Constitutional bleeding disorder (haemophilia, von Willebrand disease, coagulation factor deficiency, platelet disorder).
• Thrombocytopenia inferior to 50 G.L-1
• History of heparin-induced thrombocytopenia
• Study drug hypersensitivity
• Limitation of life support, life expectancy ≤7 days or palliative care
• Contraindication to the administration of anticoagulant according to the SPC (Active clinically significant bleeding or a condition associated with a high risk of bleeding, such as a recent haemorrhagic stroke, gastrointestinal ulcer, the presence of a malignant tumour at high risk of bleeding, recent brain, spinal or ophthalmological surgery, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intrarachid or intracerebral vascular anomalies.)
• pregnant or breastfeeding woman
• Inclusion in another experimental trial
• Protected person (art. L1121-5 to L1121-8 of the CSP or art. 31 to 35 of European regulation 536/2014)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Профилактика

Центры проведения

Франция · 17 центров

• CHU Angers — Angers
• CHU Clermont Ferrand — Clermont-Ferrand
• Hôpital Beaujon AP-HP — Clichy
• CHU Grenoble Alpes — Grenoble
• AP-HP Bicêtre — Le Kremlin-Bicêtre
• CHRU Lille — Lille
• Hôpital Edouard Herriot HCL — Lyon
• HCL Lyon Sud — Lyon
• … и ещё 9 центров

Публикации

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• Grange L, Chapelle C, Ollier E, Zufferey PJ, Douillet D, Killian M, Mismett P, Laporte S. Adjusted versus fixed doses of LMWHs in trauma patients: A systematic review and meta-analysis. Anaesth Crit Care Pain Med. 2022 Dec;41(6):101155. doi: 10.1016/j.accpm.2022.101155. Epub 2022 Sep 7. PMID 36087698
• Harrington D, D'Agostino RB Sr, Gatsonis C, Hogan JW, Hunter DJ, Normand ST, Drazen JM, Hamel MB. New Guidelines for Statistical Reporting in the Journal. N Engl J Med. 2019 Jul 18;381(3):285-286. doi: 10.1056/NEJMe1906559. No abstract available. PMID 31314974
• Klok FA, Ageno W, Barco S, Binder H, Brenner B, Duerschmied D, Empen K, Faggiano P, Ficker JH, Galie N, Ghuysen A, Held M, Heydenreich N, Huisman MV, Jimenez D, Kozak M, Lang IM, Lankeit M, Munzel T, Petris A, Pruszczyk P, Quitzau K, Schellong S, Schmidt KH, Stefanovic BS, Verschuren F, Wolf-Puetz A, Meyer G, Konstantinides SV; PEITHO-2 Investigators. Dabigatran after Short Heparin Anticoagulation PMID 29212130
• Mantz J, Samama CM, Tubach F, Devereaux PJ, Collet JP, Albaladejo P, Cholley B, Nizard R, Barre J, Piriou V, Poirier N, Mignon A, Schlumberger S, Longrois D, Aubrun F, Farese ME, Ravaud P, Steg PG; Stratagem Study Group. Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-c PMID 21873632
• Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ni Ainle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in co PMID 31504429
• Bouzat P, Bosson JL, David JS, Riou B, Duranteau J, Payen JF; PROCOAG study group. Four-factor prothrombin complex concentrate to reduce allogenic blood product transfusion in patients with major trauma, the PROCOAG trial: study protocol for a randomized multicenter double-blind superiority study. Trials. 2021 Sep 16;22(1):634. doi: 10.1186/s13063-021-05524-x. PMID 34530886
• Gauss T, Bouzat P, Geeraerts T. Epidemiology of trauma: From medico-administrative database to large prospective registry. Anaesth Crit Care Pain Med. 2019 Oct;38(5):439-440. doi: 10.1016/j.accpm.2019.08.001. No abstract available. PMID 31585763

Идентификаторы

NCT: NCT07506473 · 38RC23.0261 · 2025-522832-16-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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