Randomized trials of therapeutic heparin for COVID-19: A meta-analysis

Michelle Sholzberg; Bruno R da Costa; Grace H Tang; Hassan Rahhal; Musaad AlHamzah; Lisa Baumann Kreuziger; Fionnuala Ní Áinle; Mozah Obaid Almarshoodi; Paula D James; David Lillicrap; Marc Carrier; Andrew Beckett; Michael Fralick; Saskia Middeldorp; Agnes Y Y Lee; Kevin E Thorpe; Elnara Márcia Negri; Mary Cushman; Peter Jüni; RAPID Trial Investigators

doi:10.1002/rth2.12638

Randomized trials of therapeutic heparin for COVID-19: A meta-analysis

Res Pract Thromb Haemost. 2021 Dec 17;5(8):e12638. doi: 10.1002/rth2.12638. eCollection 2021 Dec.

Authors

Michelle Sholzberg^{1

2}, Bruno R da Costa^{3

4}, Grace H Tang⁵, Hassan Rahhal⁶, Musaad AlHamzah^{7

8}, Lisa Baumann Kreuziger⁹, Fionnuala Ní Áinle^{10

11

12}, Mozah Obaid Almarshoodi¹³, Paula D James¹⁴, David Lillicrap¹⁵, Marc Carrier¹⁶, Andrew Beckett^{17

18}, Michael Fralick¹⁹, Saskia Middeldorp²⁰, Agnes Y Y Lee²¹, Kevin E Thorpe²², Elnara Márcia Negri²³, Mary Cushman²⁴, Peter Jüni²⁵; RAPID Trial Investigators

Affiliations

¹ Department of Medicine St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.
² Department of Laboratory Medicine and Pathobiology St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.
³ Applied Health Research Centre (AHRC) St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.
⁴ Institute of Primary Health Care (BIHAM) University of Bern Bern Switzerland.
⁵ Hematology-Oncology Clinical Research Group St. Michael's Hospital University of Toronto Toronto ON Canada.
⁶ Disciplina de Emergencias Clinicas Departamento de Clinica Medica Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de Sao Paulo Sao Paulo Brazil.
⁷ Department of Surgery College of Medicine King Saud University Riyadh Saudi Arabia.
⁸ Division of Vascular Surgery King Saud University Medical City Riyadh Saudi Arabia.
⁹ Versiti Medical College of Wisconsin Milwaukee Wisconsin USA.
¹⁰ Mater Misericordiae University Hospital Dublin Ireland.
¹¹ School of Medicine University College Dublin Dublin Ireland.
¹² Irish Network for Venous Thromboembolism Research Dublin Ireland.
¹³ Tawam Hospital SEHA AlAin United Arab Emirates.
¹⁴ Department of Medicine Queen's University Kingston ON Canada.
¹⁵ Department of Pathology and Molecular Medicine Queen's University Kingston ON Canada.
¹⁶ Department of Medicine The Ottawa Hospital Research Institute at the University of Ottawa Ottawa ON Canada.
¹⁷ St. Michael's Hospital University of Toronto Toronto ON Canada.
¹⁸ Canadian Forces Health Services Ottawa ON Canada.
¹⁹ General Internal Medicine Sinai Health University of Toronto Toronto ON Canada.
²⁰ Department of Internal Medicine Radboud Institute of Health Sciences (RIHS) Radboud University Medical Center Nijmegen The Netherlands.
²¹ Vancouver Coastal Health Research Institute University of British Columbia Vancouver BC Canada.
²² Dalla Lana School of Public Health Applied Health Research Centre St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.
²³ Laboratorio de Investigaçao Medica LIM-59 Biologia Celular Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil.
²⁴ Department of Medicine Larner College of Medicine at the University of Vermont University of Vermont Medical Center Burlington Vermont USA.
²⁵ Department of Medicine Institute of Health Policy, Management and Evaluation Applied Health Research Centre St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.

Abstract

Background: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19.

Methods: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs).

Results and conclusions: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.

Keywords: COVID‐19; anticoagulation; clinical trials; heparin; meta‐analysis.