Therapeutic-dose heparin combined with antiplatelets in noncritically ill patients with COVID-19: a secondary analysis of a multiplatform randomized controlled trial

Sylvain A Lother; Wen Teng; Olawale Ayilara; Brett L Houston; Barret Rush; Srinivas Murthy; Jose C Nicolau; Lindsay Bond; Alexis F Turgeon; John C Marshall; Jonathan Paul; Judith S Hochman; Matthew D Neal; Michael E Farkouh; Joel Nkosi; Donald S Houston; Charlotte A Bradbury; Asher A Mendelson; Ewan C Goligher; Allan Garland; Robert Balshaw; Souradet Y Shaw; Patrick R Lawler; Yoav Keynan; Ryan Zarychanski

doi:10.1016/j.rpth.2025.102893

Therapeutic-dose heparin combined with antiplatelets in noncritically ill patients with COVID-19: a secondary analysis of a multiplatform randomized controlled trial

Res Pract Thromb Haemost. 2025 May 21;9(4):102893. doi: 10.1016/j.rpth.2025.102893. eCollection 2025 May.

Authors

Sylvain A Lother^{1

2}, Wen Teng³, Olawale Ayilara⁴, Brett L Houston^{1

5}, Barret Rush¹, Srinivas Murthy⁶, Jose C Nicolau⁷, Lindsay Bond⁸, Alexis F Turgeon^{9

10}, John C Marshall¹¹, Jonathan Paul¹², Judith S Hochman¹³, Matthew D Neal¹⁴, Michael E Farkouh¹⁵, Joel Nkosi¹, Donald S Houston^{1

5}, Charlotte A Bradbury¹⁶, Asher A Mendelson¹, Ewan C Goligher¹⁷, Allan Garland¹, Robert Balshaw¹⁸, Souradet Y Shaw⁴, Patrick R Lawler^{19

20}, Yoav Keynan^{1

2

4}, Ryan Zarychanski^{1

4

5}

Affiliations

¹ Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
² Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
³ Division of Biostatistics, Child Health and Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Department of Community Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
⁵ Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.
⁶ Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
⁷ Departmento Cardio-pneumology, Instituto do Coracao, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
⁸ Ozmosis Research, Toronto, Ontario, Canada.
⁹ Department of Anesthesiology and Critical Care, Université Laval, Quebec City, Quebec, Canada.
¹⁰ Population Health and Optimal Health Practices Research Unit, Departments of Traumatology, Emergency Medicine, and Critical Care Medicine, Université Laval Research Center, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec City, Quebec, Canada.
¹¹ Departments of Surgery and Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Medicine, University of Chicago Medical Center, Chicago, Illinois, USA.
¹³ Division of Cardiology, Department of Medicine, Cardiovascular Clinical Research Center, NYU Grossman School of Medicine, New York, New York, USA.
¹⁴ Department of Surgery, Pittsburgh Trauma Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
¹⁵ Departments of Academic Affairs and Cardiology, Cedars-Sinai Health System, Los Angeles, California, USA.
¹⁶ Department of Hematology, Faculty of Health Sciences, University of Bristol, Bristol, UK.
¹⁷ Interdepartmental Division of Critical Care Medicine, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁸ George and Fay Yee Centre for Healthcare Innovation and Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁹ Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
²⁰ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

Background: Therapeutic-dose heparin improves outcomes in noncritically ill patients hospitalized for COVID-19. The effect of antiplatelet exposure in addition to therapeutic-dose heparin is unknown.

Objectives: To evaluate the effect of antiplatelet exposure in addition to therapeutic-dose heparin on survival without organ support.

Methods: We conducted an observational secondary analysis of a multiplatform randomized controlled trial, analyzing noncritically ill patients hospitalized for COVID-19 who received an antiplatelet agent (acetylsalicylic acid or P2Y12 inhibitor) and therapeutic-dose heparin (combination) compared with therapeutic-dose heparin alone (control). We used a 3-level ordinal primary outcome: (1) survival without organ support, (2) survival with organ support, and (3) mortality by day 21. Propensity scores were estimated using logistic regression. Balanced analytic groups were established using stabilized inverse probability of treatment weighting. A proportional odds model was used to estimate the effect of antiplatelet exposure.

Results: Among 1021 patients, 194 (19.0%) were exposed to an antiplatelet (95.4% acetylsalicylic acid) and therapeutic-dose heparin. All patients were used to calculate the propensity scores and stabilized weights. After applying inverse probability of treatment weighting, the effective sample size was 60 in the combination group and 652 in the control group. Means and prevalences of continuous and dichotomous variables were similar between groups, with no evidence of misclassification. Exposure to an antiplatelet was not associated with improved survival without organ support (76.3% vs 80.5%; odds ratio, 1.07; 95% CI, 0.71-1.64).

Conclusion: In noncritically ill patients hospitalized for COVID-19 receiving therapeutic-dose heparin, exposure to an antiplatelet agent was not associated with improved survival without organ support.

Keywords: COVID-19; SARS-CoV-2; aspirin; clopidogrel; heparin.