Anticoagulation strategies in non–critically ill patients with Covid-19
Zoe K McQuilten, Balasubramanian Venkatesh, Vivekanand Jha, Jason Roberts, Susan C Morpeth, James A Totterdell, Grace M McPhee, John Abraham, Niraj Bam, Methma Bandara, Ashpak K Bangi, Lauren A. Barina, Bhupendra K. Basnet, Hasan Bhally, Khema R. Bhusal, Umesh Bogati, Asha C Bowen, Andrew J Burke, Devasahayam J. Christopher, Sanjeev D. Chunilal, Belinda Cochrane, Jennifer L Curnow, Santa Kumar Das, Ashesh Dhungana, Gian Luca Di Tanna, Ravindra Dotel, Hyjel DSouza, Jack Dummer, Sourabh Dutta, Hong Foo, Timothy L Gilbey, Michelle L. Giles, Kasiram Goli, Adrienne Gordon, Pradip Gyanwali, Dipak Haksar, Bernard J Hudson, Manoj K Jani, Purnima R Jevaji, Sachin Jhawar, Aikaj Jindal, M. Joseph John, Mary John, Flavita B John, Oommen John, Mark Jones, Rajesh D Joshi, Prashanthi Kamath, Gagandeep Kang, Achyut R Karki, Abhishek M. Karmalkar, Baldeep Kaur, Kalyan Chakravarthy Koganti, Jency M. Koshy, Mathew S Krishnamurthy, Jillian S Lau, Sharon R Lewin, Lyn-li Lim, Ian C Marschner, Julie A. Marsh, Michael J. Maze, James M. McGree, James H McMahon, Robert L Medcalf, Eileen G Merriman, Amol P Misal, Jocelyn M Mora, Vijaybabu K Mudaliar, Vi Nguyen, Matthew V. O’Sullivan, Suman Pant, Pankaj Pant, David L Paterson, David J Price, Megan A Rees, James O Robinson, Benjamin A Rogers, Sandhya Samuel, Joe Sasadeusz, Deepak Sharma, Prabhat K Sharma, Roshan Shrestha, Sailesh K Shrestha, Prajowl Shrestha, Urvi Shukla, Omar Shum, Christine Sommerville, Tim Spelman, Richard P Sullivan, Umashankar Thatavarthi, Huyen A Tran, Nanette Trask, Clare L Whitehead, Robert K Mahar, Naomi E Hammond, James D McFadyen, Thomas L Snelling, Joshua S Davis, Justin T Denholm, Steven YC Tong
NEJM Evidence, published online 10 December 2022. DOI: https://doi.org/10.1056/EVIDoa2200293
Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain.
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.
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.
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.)