Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia
Authors: Labbé Vincent , Contou Damien , Heming Nicholas , Megarbane Bruno , Razazi Keyvan , Boissier Florence , Ait-Oufella Hafid , Turpin Matthieu , Carreira Serge , Robert Alexandre , Monchi Mehran , Souweine Bertrand , Preau Sebastien , Doyen Denis , Vivier Emmanuel , Zucman Noémie , Dres Martin , Fejjal Mohamed , Noel-Savina Elise , Bachir Marwa , Jaffal Karim , Timsit Jean-François , Picos Santiago Alberto , Mariotte Eric , Martis Nihal , Juguet William , Melica Giovanna , Rondeau Paul , Audureau Etienne , Mekontso Dessap Armand ,   ANTICOVID Investigators, Plantefevre Gaetan , Annane Djillali , Dinh Aurélien , Abdeladim Lilia , Bounab Rania , Moine Pierre , Maxime Virginie , Tessa Hayette , Carlos Miguel , Kuperminc Emmanuelle , Voicu Sebastian , Malissin Isabelle , Deye Nicolas , M'Rad Aymen , Lacoste-Palasset Thomas , Lefevre Thomas , Haudebourg Luc , Ekhérian Jean-Michel , Bagate François , de Prost Nicolas , carteaux Guillaume , Bendib Inès , Tuffet Samuel , Lopinto Julien , Labedade Pascale , Michaud Gaêl , Benelli Brice , Haudebourg Anne Fleur , Gendreau Ségolène , Berti Enora , Bertier Astrid , Arrestier Romain , Masi Paul , Dufranc Etienne , Coudroy Remi , Thille Arnaud W , Veinstein Anne , Chatellier Delphine , Frat Jean-Pierre , Rodriguez Maeva , Reynaud Faustine , De Roubin Victor , Arrive François , Gabarre Paul , Bollens Diane , Ingiliz Patrick , Lefebvre Benedicte , Ouazene Zineb , Chiarabini Thibault , Valin Nadia , Urbina Tomas , Bonny Vincent , Bige Naike , Lacombe Karine , Fartoukh Muriel , Desnos Cyrielle , Voiriot Guillaume , Djibré Michel , Blayau Clarisse , Gibelin Aude , Dessajan Julien , Lassel Ludovic , Bertrand Pierre-Marie , Chambon Raphael , Clément Nicolas , Sy Oumar , Jochmans Sebastien , Dupuis Claire , Calvet Laure , Thouy François , Grapin Kevin , Laurichesse Guillaume , Kinda Frederic , Couhault Pierre , Dopeux Loïc , Goutay Julien , Ledoux Geoffrey , Tortuyaux Romain , Gaudet Alexandre , Rouze Anahita , Moreau Anne-Sophie , Girardi Patrick , Jourdain Mercedes , Poissy Julien , Favory Raphael , Nseir Saadala , Buscot Matthieu , Dellamonica Jean , Saccheri Clément , Demonchy Elisa , Chirio David , Risso Karine , Martis Nihal , Taurel Marina , Bourdin Gaël , Donze Pierre , Pommier Christian , Rosselli Sylvène , Simonin Marine , Ricard Jean-Damien , Thiry Ingrid , Freita ramos Santiago , Verney Charles , Uhel Fabrice , Priour Isabelle , Roux Damien , Beurton Alexandra , Bureau Côme , Déléris Robin , Mayaux Julien , Le Marec Julien , Nemlaghi Safaa , Clerc Sébastien , Demoule Aleandre , Morawiec Elise , Picard Benjamin , Pichon Jérémie , Chafiotte Pierre , Menat Sophie , Pontier Sandrine , Legenne Frédérique , Bouadma Lila , Abdel-Nabey Moustafa , Girard Tiphaine , Jaquet Pierre , Patrier Juliette , Presente Simona , Leroy Julien , Mechai Frederic , Cordel Hugues , Hassold-Rugolino Nolan , Emery Malo 
Published: March 2023

Importance

Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative.

Objectives

To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies.

Design, Settings, and Participants

The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis—114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023.

Interventions

Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days.

Main Outcomes and Measures

A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death).

Results

Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95% CI, 39.9% to 54.8%] vs 52.7% [95% CI, 45.2% to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95% CI, 43.4% to 58.3%] vs 49.1% [95% CI, 41.7% to 56.6%]; P = .82) and TA compared with HD-PA (53.5% [95% CI 45.8% to 60.9%] vs 46.5% [95% CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2% thrombosis, 2.6% bleeding, 14.0% death), 16.4% receiving HD-PA (5.5% thrombosis, 3.6% bleeding, 11.8% death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7% death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, −14.7 [95% CI −6.2 to −23.2] and −14.7 [95% CI −6.2 to −23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, −13.5; 95% CI −2.6 to −24.3).

Conclusions and Relevance

This randomized clinical trial found that compared with SD-PA, neither HD-PA nor TA use improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemic COVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis.

Trial Registration

ClinicalTrials.gov Identifier: NCT04808882