Randomized Controlled Trial

. 2021 Oct 14:375:n2400.

doi: 10.1136/bmj.n2400.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

Michelle Sholzberg¹, Grace H Tang², Hassan Rahhal³, Musaad AlHamzah^{4

5}, Lisa Baumann Kreuziger⁶, Fionnuala Ní Áinle^{7

8

9}, Faris Alomran¹⁰, Khalid Alayed¹¹, Mohammed Alsheef¹², Fahad AlSumait¹², Carlos Eduardo Pompilio³, Catherine Sperlich¹³, Sabrena Tangri¹⁴, Terence Tang¹⁵, Peter Jaksa¹⁶, Deepa Suryanarayan¹⁷, Mozah Almarshoodi¹⁸, Lana A Castellucci¹⁹, Paula D James²⁰, David Lillicrap²¹, Marc Carrier¹⁹, Andrew Beckett^{22

23}, Christos Colovos^{24

25}, Jai Jayakar²⁶, Marie-Pier Arsenault²⁷, Cynthia Wu²⁸, Karine Doyon²⁹, E Roseann Andreou³⁰, Vera Dounaevskaia³¹, Eric K Tseng²², Gloria Lim²², Michael Fralick³², Saskia Middeldorp³³, Agnes Y Y Lee³⁴, Fei Zuo³⁵, Bruno R da Costa^{35

36}, Kevin E Thorpe^{35

37}, Elnara Márcia Negri³⁸, Mary Cushman³⁹, Peter Jüni^{35

40}; RAPID trial investigators

Collaborators, Affiliations

Collaborators

RAPID trial investigators:
Andreas Laupacis, Yulia Lin, Andrew Day, Bram Rochwerg, Jameel Abdulrehman, Mansour Gergi, Rodrigo Hidd Kondo, Bruna Mamprim Piloto, Guilherme de Abreu Pereira, Fernando Salvetti Valente, Ariel Fernando Villarroel Agreda, Pablo Andres Munoz Torres, Maíra Oliveira Moraes, Claudia de Lucena Moreira, Fernando Galassi Stocco Neto, Fabíola Vieira Duarte Baptista, Joanne Alves Moreira, Augusto Séttemo Ferreira, Paula Frudit, Gabriel Martinez, Heraldo Possolo Souza, Rodrigo Antônio Brandão Neto, Elbio Antonio d'Amico, Eduardo Messias Hirano Padrão, Fernando Sarin da Mota E Albuquerque, Giovanna Villela Zangrossi, Alberto Kendy Kanasiro, Alissom Vitti Cincoto, Hugo de Souza Reis, Vitor Miyashiro Arias da Silva, Arthur Petrillo Bellintani, Vivian Dos Santos Pereira, Yohan Washington de Oliveira, Bárbara Justo Carvalho, Mariana de Souza Novaes, Henrique Brito Silveira, Gabriel César Alves de Avelar, Lara Bonanni Mota, Karina Caciola, Matheus de Arêa Leão Freire Marim, Tales Cabral Monsalvarga, Alexandre Salgado Blanco Santos, Ahmed Haydar, Gabriella Seixas Sampaio Saraiva, Sabrina Correa da Costa Ribeiro, Julio Flavio Meirelles Marchini, Julio Cesar Garcia de Alencar, Ana Catharina de Seixas Santos, Caroline Millette, Mathieu Lebeau, Céline Devaux, Mélina Boutin, Trung Nghia Nguyen, Line Srour, Flavia de Angelis, Mariane Fugulin, Alexandra Binnie, Shayna A D Bejaimal, Andrew Binding, Rosa M Marticorena, Galo Ginocchio, Eric Kaplovitch, Klaudia Rymaszewski, Afsaneh Raissi, Marcelo Falappa, Blair Ernst, Amna Ali, Martin Romano, Mobina Khurram, Christie Kim, Ajay Kapur, Michelle Edwards, Vidushi Swarup, Bruna Camilotti, Jiten Jani, Jeff Carter, Mark R Gillrie, Davinder Sidhu, Traci Robinson, Krystina Stutely, Irene Watpool, Rebecca Porteous, Kevin Jao, Jean-Samuel Boudreault-Pedneault, Christopher Kandel, Maureen T Taylor, Wei En Enoch Choo, Laura Parsons, Ann Dowbenka, Gitana Ramonas, Sergey Nikitin, Jeffery Patterson, Mark Hnatiuk, Anca Tapardel, Sarah Takach Lapner, Thirza Carpenter, Lori Rackel, Rebecca Cairns, Jessica Pinder, Peter Anglin, Catherine McPherson, Liselle Chiverton, David Barbosa, Shany Loukiantchenko, Yana Shamiss, Danaë Tassy, Sudeep Shivakumar, Mary-Margaret Keating, Sue Pleasance, Barry Kevane, Sarah Cullivan, Nick Power, Peter Doran, Kelly Leamy, Aoife Kelly, Conor Moran, Mairead O'Connor, Aoife McDonnell, Roseanne Boyce, Faiza Sefroun, Rabia Hussain, Patrick Murray, Anna Malara, Brenda Molloy, Meadbh O'Halloran, Emer Cunningham, Jack Lambert, Aoife Cotter, Brian Marsh, Gerard Sheehan, Eavan Muldoon, James Woo, Sean Gaine, Deirdre Morley, Farjah H AlGahtani, Ibrahim Almaghlouth, Sondus Ata, Fai Alkhathlan, Najma Khalil, Israa Mohamed Hussein, Mohammed Bashir, Ahmed S BaHammam, Abdulrahman Alsultan, Hadeel Alkofide, Tariq M Alhawassi, Abdulhadi M Alqahtani, Emad K Zayed, Ammar AlSughayir, Yacoub Abuzied, Hazzaa AlZahrani, Jawaher Al-Otaibi, Haya Alothaimeen, Noura Alzannan, Amer Al Homssi, Haisam Abid, Stephanie Jones, Shannon Broaddrick, Neha Jain, Roz King, Mohit Jindal, Kristen Sanfilippo, Patty Nieters, Muhammad Hammad, Aleeswa Francis Benny, Tariq A Hamdan, Suhaib Kamal Ahmed Elobaid, Ibrahim Khafagi, Saima Saeed Ahmed, AbduleRehman AlEssaie, Shamma AlAlawi, Khloud Bashir, Aysha Abdulla Salem Al Suwaidi, Hiba Ibrahim Khogali Ahmed, Mohamed Milad Ismail, El Mutasim Ahmed El Faki, Mercy Charles, Alice Dang, Gurpreet Lakhanpal, Dominic Lee, Prachi Ray, Maria Naydenova, Kosma Wysocki, Aziz Jiwajee, Greg Wendling, Rebekah Boyle, Elaine Cornell, Debora Kamin Mukaz

Affiliations

¹ Departments of Medicine, and Laboratory Medicine and Pathobiology, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
² Haematology-Oncology Clinical Research Group, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
³ Internal Medicine Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), University of São Paulo, São Paulo, Brazil.
⁴ Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁵ Division of Vascular Surgery, King Saud University Medical City, Riyadh, Saudi Arabia.
⁶ Versiti, Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Mater Misericordiae University Hospital, Dublin, Ireland.
⁸ School of Medicine, University College Dublin, Dublin, Ireland.
⁹ Irish Network for Venous Thromboembolism Research, Dublin, Ireland.
¹⁰ Department of Vascular Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
¹¹ Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹² Medical Specialties Department, King Fahad Medical City, Riyadh, Saudi Arabia.
¹³ Charles-Lemoyne Hospital, CISSS of Montérégie-Centre, University of Sherbrooke, Greenfield Park, QC, Canada.
¹⁴ Department of Medicine, William Osler Health System, Brampton, ON, Canada.
¹⁵ Institute for Better Health, Trillium Health Partners, Department of Medicine, University of Toronto, ON, Canada.
¹⁶ St Joseph's Health Centre, Unity Health Toronto, Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada.
¹⁸ Tawam Hospital, SEHA, AlAin, United Arab Emirates.
¹⁹ Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON, Canada.
²⁰ Department of Medicine, Queen's University, Kingston, ON, Canada.
²¹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
²² St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²³ Canadian Forces Health Services, Ottawa, Ontario, Canada.
²⁴ Division of Acute Care Surgery, Department of Surgery, University of Vermont Medical Center, VT, USA.
²⁵ University of Vermont Larner College of Medicine, Burlington, VT, USA.
²⁶ Southlake Regional Health Centre, University of Toronto, Newmarket, ON, Canada.
²⁷ Maisonneuve-Rosemont Hospital, University of Montréal, Montréal, QC, Canada.
²⁸ Division of Haematology, University of Alberta Hospital, University of Alberta, Edmonton, AB, Canada.
²⁹ Hospital of the Sacred Heart of Montreal, University of Montréal, Montréal, QC, Canada.
³⁰ Michael Garron Hospital, University of Toronto, Toronto, ON, Canada.
³¹ Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
³² General Internal Medicine, Sinai Health, University of Toronto, Toronto, ON, Canada.
³³ Department of Internal Medicine and Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, Netherlands.
³⁴ Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
³⁵ Applied Health Research Centre, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
³⁶ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
³⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
³⁸ Laboratory of Medical Investigation (LIM-59), Cellular Biology, Department of Pathology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
³⁹ Departments of Medicine and Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, University of Vermont Medical Center, Burlington, VT, USA.
⁴⁰ Departments of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

PMID: 34649864
PMCID: PMC8515466
DOI: 10.1136/bmj.n2400

Randomized Controlled Trial

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

Michelle Sholzberg et al. BMJ. 2021.

. 2021 Oct 14:375:n2400.

doi: 10.1136/bmj.n2400.

Authors

Collaborators

RAPID trial investigators:
Andreas Laupacis, Yulia Lin, Andrew Day, Bram Rochwerg, Jameel Abdulrehman, Mansour Gergi, Rodrigo Hidd Kondo, Bruna Mamprim Piloto, Guilherme de Abreu Pereira, Fernando Salvetti Valente, Ariel Fernando Villarroel Agreda, Pablo Andres Munoz Torres, Maíra Oliveira Moraes, Claudia de Lucena Moreira, Fernando Galassi Stocco Neto, Fabíola Vieira Duarte Baptista, Joanne Alves Moreira, Augusto Séttemo Ferreira, Paula Frudit, Gabriel Martinez, Heraldo Possolo Souza, Rodrigo Antônio Brandão Neto, Elbio Antonio d'Amico, Eduardo Messias Hirano Padrão, Fernando Sarin da Mota E Albuquerque, Giovanna Villela Zangrossi, Alberto Kendy Kanasiro, Alissom Vitti Cincoto, Hugo de Souza Reis, Vitor Miyashiro Arias da Silva, Arthur Petrillo Bellintani, Vivian Dos Santos Pereira, Yohan Washington de Oliveira, Bárbara Justo Carvalho, Mariana de Souza Novaes, Henrique Brito Silveira, Gabriel César Alves de Avelar, Lara Bonanni Mota, Karina Caciola, Matheus de Arêa Leão Freire Marim, Tales Cabral Monsalvarga, Alexandre Salgado Blanco Santos, Ahmed Haydar, Gabriella Seixas Sampaio Saraiva, Sabrina Correa da Costa Ribeiro, Julio Flavio Meirelles Marchini, Julio Cesar Garcia de Alencar, Ana Catharina de Seixas Santos, Caroline Millette, Mathieu Lebeau, Céline Devaux, Mélina Boutin, Trung Nghia Nguyen, Line Srour, Flavia de Angelis, Mariane Fugulin, Alexandra Binnie, Shayna A D Bejaimal, Andrew Binding, Rosa M Marticorena, Galo Ginocchio, Eric Kaplovitch, Klaudia Rymaszewski, Afsaneh Raissi, Marcelo Falappa, Blair Ernst, Amna Ali, Martin Romano, Mobina Khurram, Christie Kim, Ajay Kapur, Michelle Edwards, Vidushi Swarup, Bruna Camilotti, Jiten Jani, Jeff Carter, Mark R Gillrie, Davinder Sidhu, Traci Robinson, Krystina Stutely, Irene Watpool, Rebecca Porteous, Kevin Jao, Jean-Samuel Boudreault-Pedneault, Christopher Kandel, Maureen T Taylor, Wei En Enoch Choo, Laura Parsons, Ann Dowbenka, Gitana Ramonas, Sergey Nikitin, Jeffery Patterson, Mark Hnatiuk, Anca Tapardel, Sarah Takach Lapner, Thirza Carpenter, Lori Rackel, Rebecca Cairns, Jessica Pinder, Peter Anglin, Catherine McPherson, Liselle Chiverton, David Barbosa, Shany Loukiantchenko, Yana Shamiss, Danaë Tassy, Sudeep Shivakumar, Mary-Margaret Keating, Sue Pleasance, Barry Kevane, Sarah Cullivan, Nick Power, Peter Doran, Kelly Leamy, Aoife Kelly, Conor Moran, Mairead O'Connor, Aoife McDonnell, Roseanne Boyce, Faiza Sefroun, Rabia Hussain, Patrick Murray, Anna Malara, Brenda Molloy, Meadbh O'Halloran, Emer Cunningham, Jack Lambert, Aoife Cotter, Brian Marsh, Gerard Sheehan, Eavan Muldoon, James Woo, Sean Gaine, Deirdre Morley, Farjah H AlGahtani, Ibrahim Almaghlouth, Sondus Ata, Fai Alkhathlan, Najma Khalil, Israa Mohamed Hussein, Mohammed Bashir, Ahmed S BaHammam, Abdulrahman Alsultan, Hadeel Alkofide, Tariq M Alhawassi, Abdulhadi M Alqahtani, Emad K Zayed, Ammar AlSughayir, Yacoub Abuzied, Hazzaa AlZahrani, Jawaher Al-Otaibi, Haya Alothaimeen, Noura Alzannan, Amer Al Homssi, Haisam Abid, Stephanie Jones, Shannon Broaddrick, Neha Jain, Roz King, Mohit Jindal, Kristen Sanfilippo, Patty Nieters, Muhammad Hammad, Aleeswa Francis Benny, Tariq A Hamdan, Suhaib Kamal Ahmed Elobaid, Ibrahim Khafagi, Saima Saeed Ahmed, AbduleRehman AlEssaie, Shamma AlAlawi, Khloud Bashir, Aysha Abdulla Salem Al Suwaidi, Hiba Ibrahim Khogali Ahmed, Mohamed Milad Ismail, El Mutasim Ahmed El Faki, Mercy Charles, Alice Dang, Gurpreet Lakhanpal, Dominic Lee, Prachi Ray, Maria Naydenova, Kosma Wysocki, Aziz Jiwajee, Greg Wendling, Rebekah Boyle, Elaine Cornell, Debora Kamin Mukaz

Affiliations

¹ Departments of Medicine, and Laboratory Medicine and Pathobiology, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
² Haematology-Oncology Clinical Research Group, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
³ Internal Medicine Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), University of São Paulo, São Paulo, Brazil.
⁴ Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁵ Division of Vascular Surgery, King Saud University Medical City, Riyadh, Saudi Arabia.
⁶ Versiti, Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Mater Misericordiae University Hospital, Dublin, Ireland.
⁸ School of Medicine, University College Dublin, Dublin, Ireland.
⁹ Irish Network for Venous Thromboembolism Research, Dublin, Ireland.
¹⁰ Department of Vascular Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
¹¹ Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹² Medical Specialties Department, King Fahad Medical City, Riyadh, Saudi Arabia.
¹³ Charles-Lemoyne Hospital, CISSS of Montérégie-Centre, University of Sherbrooke, Greenfield Park, QC, Canada.
¹⁴ Department of Medicine, William Osler Health System, Brampton, ON, Canada.
¹⁵ Institute for Better Health, Trillium Health Partners, Department of Medicine, University of Toronto, ON, Canada.
¹⁶ St Joseph's Health Centre, Unity Health Toronto, Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada.
¹⁸ Tawam Hospital, SEHA, AlAin, United Arab Emirates.
¹⁹ Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON, Canada.
²⁰ Department of Medicine, Queen's University, Kingston, ON, Canada.
²¹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
²² St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²³ Canadian Forces Health Services, Ottawa, Ontario, Canada.
²⁴ Division of Acute Care Surgery, Department of Surgery, University of Vermont Medical Center, VT, USA.
²⁵ University of Vermont Larner College of Medicine, Burlington, VT, USA.
²⁶ Southlake Regional Health Centre, University of Toronto, Newmarket, ON, Canada.
²⁷ Maisonneuve-Rosemont Hospital, University of Montréal, Montréal, QC, Canada.
²⁸ Division of Haematology, University of Alberta Hospital, University of Alberta, Edmonton, AB, Canada.
²⁹ Hospital of the Sacred Heart of Montreal, University of Montréal, Montréal, QC, Canada.
³⁰ Michael Garron Hospital, University of Toronto, Toronto, ON, Canada.
³¹ Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
³² General Internal Medicine, Sinai Health, University of Toronto, Toronto, ON, Canada.
³³ Department of Internal Medicine and Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, Netherlands.
³⁴ Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
³⁵ Applied Health Research Centre, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
³⁶ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
³⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
³⁸ Laboratory of Medical Investigation (LIM-59), Cellular Biology, Department of Pathology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
³⁹ Departments of Medicine and Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, University of Vermont Medical Center, Burlington, VT, USA.
⁴⁰ Departments of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

PMID: 34649864
PMCID: PMC8515466
DOI: 10.1136/bmj.n2400

Abstract

Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.

Design: Randomised controlled, adaptive, open label clinical trial.

Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.

Participants: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237).

Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.

Main outcome measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.

Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m². At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69).

Conclusions: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial.

Trial registration: ClinicalTrials.gov NCT04362085.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: MS reports receiving funding from Task 54, Defense Research Development Canada, Department of National Defense, Ottawa, Canada (to institution), St Michael’s Hospital Foundation, Toronto, Canada (to institution), St Joseph’s Health Centre Foundation, Toronto, Canada (to institution), International Network of Venous Thromboembolism Clinical Research Networks (INVENT) Kickstarter Award (to institution) during the conduct of this study. LBK reports receiving funding from the INVENT Kickstarter Award during the conduct of the study. FNA reports receiving Science Foundation Ireland, Enterprise Ireland, IDA Ireland COVID-19 Rapid Response Funding Call 20/COV/0157 (to Institution; University College Dublin) during the conduct of this study; and grants or contracts from Sanofi, Daiichi-Sankyo, Irish Health Research Board (a state agency under the Department of Health, supporting and funding health and social care research), and Bayer; and reports patent submitted (European Application No 20166826.6) outside of the submitted work. LAC reports receiving honorariums for lectures and presentations for Bristol Meyers Squibb, Pfizer, Bayer, Boehringer Ingelheim, Leo Pharma, Sanofi, The Academy for Continued Advancement in Healthcare Education outside of the submitted work. PDJ reports receiving research grant funding from Bayer, Takeda, CSL Behring outside of the submitted work and reports receiving funding from SEAMO (South-eastern Ontario Academic Medical Organization) COIVD-19 Innovation Fund during the conduct of this study. DL reports receiving research support from Bayer, Biomarin, CSL-Behring, Octapharma, Sanofi; and serving on Data Safety Monitoring and Advisory Boards for Biomarin, CSL Behring, Takeda, Sanofi, and Spark outside of the submitted work. MCa reports grant or contracts from Bristol Meyers Squibb, Leo Pharma, Pfizer (to institution); consulting fees from Bayer, Pfizer, Bristol Meyers Squibb, Sanofi, Servier, Leo Pharma (to institution) outside of the submitted work. CC reports stock options from BioCogniv, Burlington, Vermont, USA outside of the submitted work. CW reports receiving payment or honorariums for speaking engagements from Leo Pharma, Pfizer, Bristol Meyers Squibb-Pfizer, and Servier and serving on advisory board meetings for LEO Pharma, Pfizer, Bristol Meyers Squibb-Pfizer, Servier outside of the submitted work. KD reports receiving honorariums from LEO Pharma and Pfizer outside of the submitted work. ERA reports receiving funding from 2020 TD Community Health Solutions Fund COVID-19 research grant (to institution) during the conduct of this study; honorariums from Pfizer and Bayer; support for attending meetings and/or travel from Pfizer, and participation in advisory board for Tavalisse outside of the submitted work. MF reports consulting fees from Pine Trees Health outside of the submitted work. SM reports grants and personal fees from Daiichy Sankyo, grants and personal fees from Bayer, Pfizer, and Boehringer-Ingelheim, personal fees from Portola, Abbvie, Bristol Meyers Squibb-Pfizer, and Sanofi, outside the submitted work. AYYL reports receiving consulting fees from LEO Pharma; payment or honorariums for speaking engagements and/or consulting from LEO Pharma and Pfizer, and serving on a data safety monitoring board or advisory board for CONNECTS program (COVID-19 clinical trials involving anticoagulation) outside of the submitted work. MC reports receiving an honorarium from the International Society on Thrombosis and Haemostasis outside of the submitted work. PJü reports receiving funding from Task 54, Defense Research Development Canada, Department of National Defense, Ottawa, Canada (to institution), St Michael’s Hospital Foundation, Toronto, Canada (to institution), St Joseph’s Health Centre Foundation, Toronto, Canada (to institution), International Network of Venous Thromboembolism Clinical Research Networks (INVENT) Kickstarter Award (to institution) during the conduct of this study; receiving a grant from Appili Therapeutics (to the institution); payment for participation in advisory boards and/or consulting for Amgen and Fresenius (to the institution); honorariums and travel reimbursement from Amgen, Ava, and Fresenius (to the institution); participation in advisory boards and/or consulting for Amgen and Fresenius; and serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Terumo, and Abbott Vascular outside of the submitted work.

Figures

**Fig 1**
Screening, enrolment, randomisation, and inclusion in analysis. *Six patients in the therapeutic heparin group and five in the prophylactic heparin group had negative D-dimer values at the time of randomisation due to a delay in protocol harmonisation with Brazil. †Did not receive allocated intervention within the first 48 hours post-randomisation without clear clinical indication

**Fig 2**
Subgroup analysis of the primary outcome (a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit). Subgroup specific odds ratios derived from logistic regression. Circles represent point estimates and whiskers represent 95% confidence intervals. Odds ratio <1.0 favours therapeutic heparin. BMI=body mass index; ULN=upper limit of normal

See this image and copyright information in PMC

Update of

Heparin for Moderately Ill Patients with Covid-19.
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Ní Áinle F, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci L, James PD, Lillicrap D, Carrier M, Beckett A, Colovos C, Jayakar J, Arsenault MP, Wu C, Doyon K, Andreou ER, Dounaevskaia V, Tseng EK, Lim G, Fralick M, Middeldorp S, Lee AYY, Zuo F, da Costa BR, Thorpe KE, Negri EM, Cushman M, Jüni P; RAPID Trial investigators. Sholzberg M, et al. medRxiv [Preprint]. 2021 Jul 12:2021.07.08.21259351. doi: 10.1101/2021.07.08.21259351. medRxiv. 2021. Update in: BMJ. 2021 Oct 14;375:n2400. doi: 10.1136/bmj.n2400. PMID: 34268513 Free PMC article. Updated. Preprint.

Comment in

In patients hospitalized with COVID-19, therapeutic- vs. prophylactic-dose heparin did not reduce a composite outcome at 28 d.
Bikdeli B, Garcia DA. Bikdeli B, et al. Ann Intern Med. 2022 Feb;175(2):JC16. doi: 10.7326/J21-0020. Epub 2022 Feb 1. Ann Intern Med. 2022. PMID: 35099997

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Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

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Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

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Conflict of interest statement

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