Randomized Controlled Trial

. 2023 Feb;2(2):EVIDoa2200293.

doi: 10.1056/EVIDoa2200293. Epub 2022 Dec 10.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19

Zoe K McQuilten^{1

2}, Balasubramanian Venkatesh^{3

4

5

6

7}, Vivekanand Jha^{5

8}, Jason Roberts^{3

9}, Susan C Morpeth¹⁰, James A Totterdell¹¹, Grace M McPhee¹², John Abraham¹³, Niraj Bam¹⁴, Methma Bandara¹², Ashpak K Bangi¹⁵, Lauren A Barina¹², Bhupendra K Basnet¹⁶, Hasan Bhally¹⁷, Khema R Bhusal¹⁸, Umesh Bogati¹⁶, Asha C Bowen^{19

20}, Andrew J Burke^{3

21}, Devasahayam J Christopher²², Sanjeev D Chunilal^{1

23}, Belinda Cochrane^{24

25}, Jennifer L Curnow^{11

26}, Santa Kumar Das¹⁸, Ashesh Dhungana¹⁶, Gian Luca Di Tanna⁴, Ravindra Dotel²⁷, Hyjel DSouza⁵, Jack Dummer^{28

29}, Sourabh Dutta³⁰, Hong Foo³¹, Timothy L Gilbey³², Michelle L Giles^{1

12}, Kasiram Goli³³, Adrienne Gordon^{11

34}, Pradip Gyanwali^{14

18}, Dipak Haksar³⁵, Bernard J Hudson³⁶, Manoj K Jani³⁷, Purnima R Jevaji⁵, Sachin Jhawar³⁷, Aikaj Jindal³⁸, M Joseph John¹³, Mary John¹³, Flavita B John²², Oommen John^{5

39}, Mark Jones¹¹, Rajesh D Joshi⁵, Prashanthi Kamath⁵, Gagandeep Kang²², Achyut R Karki¹⁶, Abhishek M Karmalkar⁴⁰, Baldeep Kaur⁴, Kalyan Chakravarthy Koganti⁴¹, Jency M Koshy⁴², Mathew S Krishnamurthy⁴², Jillian S Lau^{43

44}, Sharon R Lewin^{2

12}, Lyn-Li Lim¹, Ian C Marschner¹¹, Julie A Marsh¹⁹, Michael J Maze²⁸, James M McGree⁴⁵, James H McMahon⁴⁴, Robert L Medcalf¹, Eileen G Merriman¹⁷, Amol P Misal⁴⁶, Jocelyn M Mora¹², Vijaybabu K Mudaliar⁵, Vi Nguyen¹², Matthew V O'Sullivan^{11

26

31}, Suman Pant¹⁸, Pankaj Pant¹⁴, David L Paterson⁴⁷, David J Price^{12

48}, Megan A Rees⁴⁹, James O Robinson^{50

51}, Benjamin A Rogers^{1

2}, Sandhya Samuel¹³, Joe Sasadeusz^{12

52}, Deepak Sharma⁵³, Prabhat K Sharma⁵³, Roshan Shrestha¹⁸, Sailesh K Shrestha¹⁶, Prajowl Shrestha¹⁶, Urvi Shukla⁵⁴, Omar Shum^{55

56}, Christine Sommerville¹², Tim Spelman^{57

58}, Richard P Sullivan^{59

60}, Umashankar Thatavarthi⁴¹, Huyen A Tran^{1

44}, Nanette Trask⁶¹, Clare L Whitehead⁶², Robert K Mahar^{48

63}, Naomi E Hammond^{4

36}, James D McFadyen^{44

64}, Thomas L Snelling^{11

19}, Joshua S Davis^{60

65}, Justin T Denholm^{12

52}, Steven Y C Tong^{12

52}

Affiliations

¹ Monash University, Melbourne, Australia.
² Monash Health, Melbourne, Australia.
³ University of Queensland, Brisbane, Australia.
⁴ The George Institute for Global Health, Sydney, Australia.
⁵ The George Institute for Global Health, Delhi, Delhi, India.
⁶ The Wesley Hospital, Brisbane, Queensland, Australia.
⁷ University of New South Wales, Sydney, New South Wales, Australia.
⁸ Imperial College, London, England, United Kingdom.
⁹ Metro North Health, Brisbane, Queensland, Australia.
¹⁰ Middlemore Hospital, Auckland, North Island, New Zealand.
¹¹ Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹² Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹³ Christian Medical College, Ludhiana, Punjab, India.
¹⁴ Institute of Medicine, Maharajgunj Medical Campus, Kathmandu, Bagmati, Nepal.
¹⁵ Jivanrekha Multispeciality Hospital, Pune, Maharashtra, India.
¹⁶ National Academy of Medical Sciences, Bir Hospital, Kathmandu, Bagmati, Nepal.
¹⁷ North Shore Hospital, Auckland, North Island, New Zealand.
¹⁸ Institute of Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Bagmati, Nepal.
¹⁹ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
²⁰ Perth Children's Hospital, Perth, Western Australia, Australia.
²¹ The Prince Charles Hospital, Brisbane, Queensland, Australia.
²² Christian Medical College, Vellore, Tamil Nadu, India.
²³ Monash Medical Centre, Melbourne, Victoria, Australia.
²⁴ Campbelltown Hospital, Campbelltown, New South Wales, Australia.
²⁵ Western Sydney University, Sydney, New South Wales, Australia.
²⁶ Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Blacktown Hospital, Sydney, New South Wales, Australia.
²⁸ University of Otago, Dunedin, Otago, New Zealand.
²⁹ Dunedin Hospital, Dunedin, Otago, New Zealand.
³⁰ Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India.
³¹ NSW Health Pathology, Sydney, New South Wales, Australia.
³² Wagga Wagga Base Hospital, Wagga Wagga, New South Wales, Australia.
³³ Aditya Multi-speciality Hospital, Guntur, Andhra Pradesh, India.
³⁴ Royal Prince Alfred Hospital, Newborn Care, Melbourne, Victoria, Australia.
³⁵ ITC Hotels, Gurugram, Haryana, India.
³⁶ Royal North Shore Hospital, Sydney, New South Wales, Australia.
³⁷ Apex Hospitals, Jaipur, Rajasthan, India.
³⁸ Satguru Partap Singh Hospitals, Ludhiana, Punjab, India.
³⁹ Manipal Academy of Higher Education, Udupi, Karnataka, India.
⁴⁰ Sterling Multispeciality Hospital, Pune, Maharashtra, India.
⁴¹ Samishta Hospital & Research Institute, Guntur, Andhra Pradesh, India.
⁴² Believers Church Medical College Hospital, Thiruvalla, Kerala, India.
⁴³ Eastern Health, Melbourne, Victoria, Australia.
⁴⁴ The Alfred Hospital, Melbourne, Victoria, Australia.
⁴⁵ Queensland University of Technology, Brisbane, Queensland, Australia.
⁴⁶ Core Hospital, Chakan, Maharashtra, India.
⁴⁷ National Institute of Singapore, Singapore, Singapore, Singapore.
⁴⁸ Melbourne School of Population & Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁴⁹ Respiratory and Sleep Medicine, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁵⁰ College of Science, Health, Engineering and Education, Discipline of Health, Murdoch University, Perth, Western Australia, Australia.
⁵¹ PathWest Laboratory Medicine, Perth, Western Australia, Australia.
⁵² Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁵³ Maharaja Agrasen Superspeciality Hospital, Delhi, Delhi, India.
⁵⁴ Symbiosis University Hospital & Research Centre, Pune, Maharashtra, India.
⁵⁵ The Wollongong Hospital, Wollongong, New South Wales, Australia.
⁵⁶ University of Wollongong, Wollongong, New South Wales, Australia.
⁵⁷ Karolinska Institute, Solna, Stockholm, Sweden.
⁵⁸ Burnet Institute, Melbourne, Victoria, Australia.
⁵⁹ St. George Hospital, School of Clinical Medicine, UNSW Medicine & Health, Sydney, New South Wales, Australia.
⁶⁰ Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
⁶¹ Chartered Accountants Australia and New Zealand, Perth, Western Australia, Australia.
⁶² The Royal Women's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁶³ Murdoch Children's Research Institute, Perth, Western Australia, Australia.
⁶⁴ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁶⁵ University of Newcastle, Newcastle, New South Wales, Australia.

PMID: 38320033
DOI: 10.1056/EVIDoa2200293

Randomized Controlled Trial

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19

Zoe K McQuilten et al. NEJM Evid. 2023 Feb.

. 2023 Feb;2(2):EVIDoa2200293.

doi: 10.1056/EVIDoa2200293. Epub 2022 Dec 10.

Authors

Affiliations

¹ Monash University, Melbourne, Australia.
² Monash Health, Melbourne, Australia.
³ University of Queensland, Brisbane, Australia.
⁴ The George Institute for Global Health, Sydney, Australia.
⁵ The George Institute for Global Health, Delhi, Delhi, India.
⁶ The Wesley Hospital, Brisbane, Queensland, Australia.
⁷ University of New South Wales, Sydney, New South Wales, Australia.
⁸ Imperial College, London, England, United Kingdom.
⁹ Metro North Health, Brisbane, Queensland, Australia.
¹⁰ Middlemore Hospital, Auckland, North Island, New Zealand.
¹¹ Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹² Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹³ Christian Medical College, Ludhiana, Punjab, India.
¹⁴ Institute of Medicine, Maharajgunj Medical Campus, Kathmandu, Bagmati, Nepal.
¹⁵ Jivanrekha Multispeciality Hospital, Pune, Maharashtra, India.
¹⁶ National Academy of Medical Sciences, Bir Hospital, Kathmandu, Bagmati, Nepal.
¹⁷ North Shore Hospital, Auckland, North Island, New Zealand.
¹⁸ Institute of Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Bagmati, Nepal.
¹⁹ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
²⁰ Perth Children's Hospital, Perth, Western Australia, Australia.
²¹ The Prince Charles Hospital, Brisbane, Queensland, Australia.
²² Christian Medical College, Vellore, Tamil Nadu, India.
²³ Monash Medical Centre, Melbourne, Victoria, Australia.
²⁴ Campbelltown Hospital, Campbelltown, New South Wales, Australia.
²⁵ Western Sydney University, Sydney, New South Wales, Australia.
²⁶ Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Blacktown Hospital, Sydney, New South Wales, Australia.
²⁸ University of Otago, Dunedin, Otago, New Zealand.
²⁹ Dunedin Hospital, Dunedin, Otago, New Zealand.
³⁰ Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India.
³¹ NSW Health Pathology, Sydney, New South Wales, Australia.
³² Wagga Wagga Base Hospital, Wagga Wagga, New South Wales, Australia.
³³ Aditya Multi-speciality Hospital, Guntur, Andhra Pradesh, India.
³⁴ Royal Prince Alfred Hospital, Newborn Care, Melbourne, Victoria, Australia.
³⁵ ITC Hotels, Gurugram, Haryana, India.
³⁶ Royal North Shore Hospital, Sydney, New South Wales, Australia.
³⁷ Apex Hospitals, Jaipur, Rajasthan, India.
³⁸ Satguru Partap Singh Hospitals, Ludhiana, Punjab, India.
³⁹ Manipal Academy of Higher Education, Udupi, Karnataka, India.
⁴⁰ Sterling Multispeciality Hospital, Pune, Maharashtra, India.
⁴¹ Samishta Hospital & Research Institute, Guntur, Andhra Pradesh, India.
⁴² Believers Church Medical College Hospital, Thiruvalla, Kerala, India.
⁴³ Eastern Health, Melbourne, Victoria, Australia.
⁴⁴ The Alfred Hospital, Melbourne, Victoria, Australia.
⁴⁵ Queensland University of Technology, Brisbane, Queensland, Australia.
⁴⁶ Core Hospital, Chakan, Maharashtra, India.
⁴⁷ National Institute of Singapore, Singapore, Singapore, Singapore.
⁴⁸ Melbourne School of Population & Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁴⁹ Respiratory and Sleep Medicine, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁵⁰ College of Science, Health, Engineering and Education, Discipline of Health, Murdoch University, Perth, Western Australia, Australia.
⁵¹ PathWest Laboratory Medicine, Perth, Western Australia, Australia.
⁵² Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁵³ Maharaja Agrasen Superspeciality Hospital, Delhi, Delhi, India.
⁵⁴ Symbiosis University Hospital & Research Centre, Pune, Maharashtra, India.
⁵⁵ The Wollongong Hospital, Wollongong, New South Wales, Australia.
⁵⁶ University of Wollongong, Wollongong, New South Wales, Australia.
⁵⁷ Karolinska Institute, Solna, Stockholm, Sweden.
⁵⁸ Burnet Institute, Melbourne, Victoria, Australia.
⁵⁹ St. George Hospital, School of Clinical Medicine, UNSW Medicine & Health, Sydney, New South Wales, Australia.
⁶⁰ Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
⁶¹ Chartered Accountants Australia and New Zealand, Perth, Western Australia, Australia.
⁶² The Royal Women's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁶³ Murdoch Children's Research Institute, Perth, Western Australia, Australia.
⁶⁴ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁶⁵ University of Newcastle, Newcastle, New South Wales, Australia.

PMID: 38320033
DOI: 10.1056/EVIDoa2200293

Abstract

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non–critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

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Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19

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Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19

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