Background The role of thromboprophylaxis in the post-acute phase of COVID-19 is uncertain due to conflicting results from randomised controlled trials and observational studies. We aimed to determine the effectiveness of post-hospital apixaban in reducing the rate of death and hospital readmission of hospitalised adults with COVID-19. Methods HEAL COVID is an adaptive randomised open label multicentre platform trial recruiting participants from National Health Service Hospitals in the United Kingdom. Here we report the preliminary results of apixaban comparison of HEAL-COVID. Participants with a hospital admission related to confirmed COVID-19 and an expected date of discharge in the subsequent five days were randomised to either apixaban 2.5 mg twice daily or standard care (no anticoagulation) for 14 days. The primary outcome was hospital free survival at 12 months obtained through routine data sources. The trial was prospectively registered with ISRCTN (15851697) and Clincialtrials.gov (NCT04801940). Findings Between 19 May 2021 and 21 November 2022, 402 participants from 109 sites were randomised to apixaban and 399 to standard care. Seven participants withdrew from the apixaban group and one from the standard care group. Analysis was undertaken on an intention-to-treat basis. The apixaban arm was stopped on the recommendation of the oversight committees following an interim analysis due to no indication of benefit. Of the 402 participants randomised to apixaban, 117 experienced death or rehospitalisation during a median follow-up of 344.5 days (IQR 125 to 365), and 123 participants receiving standard care experienced death or rehospitalisation during a median follow-up of 349 days (IQR 124 to 365). There was no statistical difference in the rate of death and rehospitalisation (HR: 0.96 99%CI 0.69-1.34; p=0.75). Three participants in the apixaban arm experienced clinically significant bleeding during treatment. Interpretation Fourteen days of post-hospital anticoagulation with the direct oral anticoagulant apixaban did not reduce the rate of death or rehospitalisation of adults hospitalised with COVID-19. These data do not support the use of prophylactic post-hospital anticoagulation in adults with COVID-19. Funding HEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [ BRC-1215-20014*].

MT has received personal payment for consulting unrelated to the subject of this manuscript for MorphogenIX and Jansen, and support for attending meetings from GlaxoSmithKline and Jansen. He is a member of the Data Safety and Monitoring Committee for ComCov and FluCov vaccine trials. CG has no relevant conflicts to declare. JKB has no relevant conflicts to declare. EB has no relevant conflicts to declare. AB has no relevant conflicts to declare. JB declares that her institution has received research grants from Health and Social Care (Northern Ireland) and National Institute for Health and Social Care (NIHR). Equipment has been donated in kind to support the Clear clinical trial by Pari Medical. MC declares that her institution has received research grants from Health Data Research UK, Innovate UK, Macmillan Cancer Support, GlaxoSmithKline, UCB Pharma, Research England, European Commission and EFPIA, Brain Tumor Charity, Gilead, Janssen, National Institute for Health and Care Research (NIHR) and UK Research and Innovation (UKRI). She has also received consultancy fees from Aparito Limited, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GlaxoSmithKline, PCORI, Genetech, and Vertex. MC has also received lecture fees from the University of Maastricht, and consultancy fees from the PROTEUS Consortium (Genentech and PCORI). She has a family member who hold GlaxoSmithKline stock, and is a co-author of the Symptom Burden Questionnaire for Long COVID. EHD declares receiving funding to support the research contained within the manuscript from National Institute for Health and Care Research (NIHR), that she is the Chair for Metabolic Support UK, and holds stock in Aparito Limited. AMD declares no conflicts of interest relevant to this manuscript. EG declares no conflicts of interest relevant to this manuscript. DH declares no conflicts of interest relevant to this manuscript. TJ declares no conflicts of interest relevant to this manuscript. RGJ declares that his institution has received research grants (unrelated to the subject of this manuscript) from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX, and Pliant. He has received consulting fees from Bristol Myers Squibb, Chiesi, Daewoong, Veracyte, Resolution Therapeutics and Pliant, and honoraria from Boehringer Ingelheim, Chiesi, Roche, PatientMPower, and AstraZeneca. RGJ is a member for a Data Safety Monitoring or Advisory Board for Boehringer Ingelheim, Galapagos, and Vicore. He has a leadership or fiduciary role with NuMedii and is a Trustee of Action Pulmonary Fibrosis. AJ declares no conflicts of interest relevant to this manuscript. ML declares that his institution has received research funding from Medical Research Council, NIHR Oxford Biomedical Research Centre, Merck, Novartis, and Boehringer Ingelheim. Drug supply has also been received for the RECOVERY trial from Roche, Abbvie, Regeneron, GlaxoSmithKline. ML is a member of the European Society of Cardiology Regulator Affairs Committee. Protas (non-profit organisation with which ML is affiliated) have received research grants from Sanofi and Regeneron. JM declares that he has received fees from Bristol Myers Squib and Pfizer. DFM declares that his institution has received research grants from National Institute for Health and Care Research (NIHR), Wellcome Trust, Innovate UK, Medical Research Council, Randox, Novavax, Northern Ireland Health and Social Care R&D Division. His institution holds a patent (USB962032) for a novel treatment for inflammatory disease, and he has received consultancy fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, SOBI, Eli Lilly and speaker fees from GlaxoSmithKline. DFM is a member of Data Safety Monitoring Boards for Vir Biotechnology and Faron Pharmaceuticals. He is the Director of the NIHR Efficacy and Mechanism Evaluation (EME) programme a member of the NIHR EME Strategy Advisory Committee, the NIHR EME Funding Committee. He was previously a Director of Research for the Intensive Care Society and a member of the NIHR HTA General and Commissioning Committees. PO declares that his institution has received research grants from RESCEU EU IMI, UKRI-MRC/DHSC/NIHR, UKRI-BEIS, MRC EMINENT Consortium and National Heart and Lung Institute. He has received consultancy fees from GlaxoSmithKline, Moderna, Janssen, Seqirus, Pfizer and honoraria from Moderna, Medscape and Janssen. He has also received support for attending a meeting from Moderna. DR declares no conflicts of interest relevant to this manuscript. PW declares receiving funding from the NIHR Cambridge Biomedical Research Centre to support the work in this manuscript, and that he has received consultancy fees from AstraZeneca and speaker fees from Aparito Limited. CS declares that her institution has received research funding from the National Institute for Health and Care Research (NIHR), the NIHR Cambridge Biomedical Research Centre, the Wellcome Trust, and UK Innovation and Research (Medical Research Council). Her institution has also received fees for her participation in advisory boards for GlaxoSmithKline, Abbvie, Roche, and AM Pharma, and a speaker fere from Sanofi Pasteur.

NCT04801940

https://www.heal-covid.net/for-staff/staff-page/

HEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [ BRC-1215-20014*

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval for the HEAL-COVID platform clinical trial was granted by the South Central Berkshire Research Ethics Committee (reference 21/HRA/0646).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Deidentified patient data will be available after the primary results have been published. Requests will be reviewed by the Trial Management Group and where at all possible access will be granted.

https://www.heal-covid.net