Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial
- PMID: 35779558
- PMCID: PMC9243568
- DOI: 10.1016/S2352-3026(22)00175-2
Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial
Abstract
Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.
Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.
Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.
Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.
Funding: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests SB reports institutional research grants from Concept Medical, Bard, Bentley, Boston Scientific, INARI, Sanofi, and Bayer; and personal fees from Concept Medical, Bayer, Boston Scientific, and INARI. DV, UH, AG, NRS, GC, FM, MR, and TS do not report any conflicts of interest. BG reports non-financial support and funding for an accredited continuing medical education programme from Axonlab, and Thermo Fisher Scientific; personal fees and funding for an accredited continuing medical education programme from Alnylam, Pfizer, and Sanofi; funding for an accredited continuing medical education programme from Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Takeda, Octapharma, SOBI, Janssen, Novo Nordisk, Mitsubishi Pfizer, Tanabe Pharma, outside the submitted work. SVK reports grants or contracts from Bayer AG; consulting fees from Bayer, Daiichi Sankyo, and Boston Scientific; and payment or honoraria from Bayer, INARI Medical, MSD, Pfizer, and Bristol-Myers Squibb. SS reports research grants from Edwards Lifesciences to the institution, research grants from Medtronic to the institution, research grants from Boston Scientific to the institution, research grants from Abbott to the institution, personal fees from Boston Scientific, from Teleflex, from BTG –Boston Scientific outside the submitted work. HRE reports speaker honoraria from Daichi-Sankyo, and Bayer. DS reports employment by Sanofi-Aventis Switzerland. DD reports research support from German Research Foundation, CytoSorbents, Haemonetic; consulting and speaker's fees from Bayer Healthcare, Daiichi Sankyo, LEO Pharma, AstraZeneca, Boston Scientific, and BMS–Pfizer. NK reports institutional research grants from Concept Medical, Bard, Bentley, Boston Scientific, INARI, Sanofi, and Bayer; and personal fees from Concept Medical, Bayer, Boston Scientific, and INARI.
Figures
Comment in
-
Antithrombotic prophylaxis for symptomatic outpatients with COVID-19: less is consistently more.Lancet Haematol. 2022 Aug;9(8):e551-e553. doi: 10.1016/S2352-3026(22)00205-8. Epub 2022 Jun 30. Lancet Haematol. 2022. PMID: 35779559 Free PMC article. No abstract available.
Similar articles
-
Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial.Trials. 2020 Sep 9;21(1):770. doi: 10.1186/s13063-020-04678-4. Trials. 2020. PMID: 32907635 Free PMC article.
-
Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial.Thromb Res. 2023 Jan;221:157-163. doi: 10.1016/j.thromres.2022.10.021. Epub 2022 Nov 12. Thromb Res. 2023. PMID: 36396519 Free PMC article. Clinical Trial.
-
Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial.Lancet Haematol. 2022 Aug;9(8):e594-e604. doi: 10.1016/S2352-3026(22)00173-9. Epub 2022 Jun 30. Lancet Haematol. 2022. PMID: 35779560 Free PMC article. Clinical Trial.
-
Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.Lancet. 2021 Jun 12;397(10291):2253-2263. doi: 10.1016/S0140-6736(21)01203-4. Epub 2021 Jun 4. Lancet. 2021. PMID: 34097856 Free PMC article. Clinical Trial.
-
Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).Trials. 2020 Oct 13;21(1):846. doi: 10.1186/s13063-020-04619-1. Trials. 2020. PMID: 33050924 Free PMC article. Clinical Trial.
Cited by
-
Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19.Thromb Update. 2023 Mar;10:100126. doi: 10.1016/j.tru.2022.100126. Epub 2022 Nov 11. Thromb Update. 2023. PMID: 38620822 Free PMC article. Review.
-
The impacts of prophylactic anticoagulation therapy during hospitalization on long-term cardiovascular outcomes in high-risk COVID-19 patients amid the omicron wave of the pandemic.Int J Cardiol Heart Vasc. 2024 Feb 6;50:101353. doi: 10.1016/j.ijcha.2024.101353. eCollection 2024 Feb. Int J Cardiol Heart Vasc. 2024. PMID: 38347941 Free PMC article.
-
Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis.J Med Virol. 2023 Dec;95(12):e29310. doi: 10.1002/jmv.29310. J Med Virol. 2023. PMID: 38105461
-
Incidence and individual risk prediction of post-COVID-19 cardiovascular disease in the general population: a multivariable prediction model development and validation study.Eur Heart J Open. 2023 Sep 28;3(6):oead101. doi: 10.1093/ehjopen/oead101. eCollection 2023 Nov. Eur Heart J Open. 2023. PMID: 38046622 Free PMC article.
-
A case report of spontaneous pectoral hematoma in a male with background antiplatelet therapy after severe COVID-19 infection.Thromb J. 2023 Sep 7;21(1):93. doi: 10.1186/s12959-023-00539-7. Thromb J. 2023. PMID: 37679755 Free PMC article.
References
-
- Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122:743–752. - PubMed
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Medical