Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 1;183(6):520-531.
doi: 10.1001/jamainternmed.2023.0456.

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial

Vincent Labbé  1   2   3 , Damien Contou  4 , Nicholas Heming  5   6 , Bruno Megarbane  7   8 , Keyvan Razazi  3   9 , Florence Boissier  10   11 , Hafid Ait-Oufella  12 , Matthieu Turpin  1 , Serge Carreira  13 , Alexandre Robert  14   15 , Mehran Monchi  16 , Bertrand Souweine  17 , Sebastien Preau  18   19 , Denis Doyen  20   21 , Emmanuel Vivier  22 , Noémie Zucman  23   24 , Martin Dres  25 , Mohamed Fejjal  26 , Elise Noel-Savina  27 , Marwa Bachir  28 , Karim Jaffal  29 , Jean-François Timsit  30   31 , Santiago Alberto Picos  32 , Eric Mariotte  33 , Nihal Martis  34 , William Juguet  35 , Giovanna Melica  36 , Paul Rondeau  37 , Etienne Audureau  38   39 , Armand Mekontso Dessap  3   9   40 ; ANTICOVID Investigators
Collaborators, Affiliations

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial

Vincent Labbé et al. JAMA Intern Med. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Labbé reported grants from LEO Pharma during the conduct of the study, and personal fees from AOP Health outside the submitted work. Dr Souweine reported personal fees from Sanofi and Gilead outside the submitted work. Dr Dres reported personal fees from Lungpacer outside the submitted work. Dr Timsit reported grants from Pfizer, Merck Sharp & Dohme, MSD, and Thermo Fisher, and personal fees from Shionogi, Aspen, Gilead, and Mundipharma, all outside the submitted work. Dr Audureau reported personal fees from Global Blood Therapeutics and Innovhem outside the submitted work. Dr Mekontso Dessap reported grants and personal fees from LEO Pharma during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Sample Flowchart
aDefined as spending less than 75% of time on assigned treatment from randomization to day 14 (or until reaching thrombosis, major bleeding, hospital discharge, or weaning of supplemental oxygen for 48 h consecutively, whichever was first). bTo convert creatinine clearance to mL/s/m2, multiply by 0.0167. CTPA refers computed tomography with pulmonary angiogram; ICU, intensive care unit; and WHO, World Health Organization.
Figure 2.
Figure 2.. Net Clinical Outcome of SD-PA, HD-PA, and TA Through day 28 Among the 3 Study Groups
A, Cumulative net clinical outcome curves, including any composite thrombotic event, major bleeding, and all-cause death. B, Cumulative mortality curves. C, Cumulative thrombosis curves. D, Cumulative major bleeding curves. P-values shown in the graphs are for global comparison of cumulative incidence curves using Gray test. HD-PA refers to high-dose prophylactic anticoagulation; SD-PA, standard-dose prophylactic anticoagulation; and TA therapeutic anticoagulation. aP = .01 for comparison of HD-PA vs SD-PA. bP < .001 for comparison of HD-PA vs SD-PA. cP < .001 for comparison of TA vs SD-PA.
See this image and copyright information in PMC

Comment in

References

    1. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040. doi:10.1182/blood.2020006000 - DOI - PMC - PubMed
    1. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. . COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500. doi:10.1182/blood.2020006520 - DOI - PMC - PubMed
    1. Roncon L, Zuin M, Barco S, et al. . Incidence of acute pulmonary embolism in COVID-19 patients: systematic review and meta-analysis. Eur J Intern Med. 2020;82:29-37. doi:10.1016/j.ejim.2020.09.006 - DOI - PMC - PubMed
    1. Suh YJ, Hong H, Ohana M, et al. . Pulmonary embolism and deep vein thrombosis in COVID-19: a systematic review and meta-analysis. Radiology. 2021;298(2):E70-E80. doi:10.1148/radiol.2020203557 - DOI - PMC - PubMed
    1. Bikdeli B, Madhavan MV, Jimenez D, et al. ; Global COVID-19 Thrombosis Collaborative Group . COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973. doi:10.1016/j.jacc.2020.04.031 - DOI - PMC - PubMed

Publication types

Associated data