Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration

Tobias Tritschler; Marie-Eve Mathieu; Leslie Skeith; Marc Rodger; Saskia Middeldorp; Timothy Brighton; Per Morten Sandset; Susan R Kahn; Derek C Angus; Marc Blondon; Marc J Bonten; Marco Cattaneo; Mary Cushman; Lennie P G Derde; Maria T DeSancho; Jean-Luc Diehl; Ewan Goligher; Bernd Jilma; Peter Jüni; Patrick R Lawler; Marco Marietta; John C Marshall; Colin McArthur; Carlos Henrique Miranda; Tristan Mirault; Nuccia Morici; Usha Perepu; Christian Schörgenhofer; Michelle Sholzberg; Alex C Spyropoulos; Steve A Webb; Ryan Zarychanski; Stéphane Zuily; Grégoire Le Gal; International Network of VENous Thromboembolism Clinical Research Networks INVENT-VTE

doi:10.1111/jth.15094

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration

J Thromb Haemost. 2020 Nov;18(11):2958-2967. doi: 10.1111/jth.15094. Epub 2020 Oct 1.

Authors

Tobias Tritschler^{1

2}, Marie-Eve Mathieu¹, Leslie Skeith³, Marc Rodger⁴, Saskia Middeldorp⁵, Timothy Brighton⁶, Per Morten Sandset⁷, Susan R Kahn^{4

8}, Derek C Angus⁹, Marc Blondon¹⁰, Marc J Bonten¹¹, Marco Cattaneo¹², Mary Cushman¹³, Lennie P G Derde^{11

14}, Maria T DeSancho¹⁵, Jean-Luc Diehl^{16

17}, Ewan Goligher^{18

19}, Bernd Jilma²⁰, Peter Jüni^{21

22}, Patrick R Lawler^{23

24

25}, Marco Marietta²⁶, John C Marshall²⁷, Colin McArthur²⁸, Carlos Henrique Miranda²⁹, Tristan Mirault^{17

30

31}, Nuccia Morici³², Usha Perepu³³, Christian Schörgenhofer²⁰, Michelle Sholzberg³⁴, Alex C Spyropoulos³⁵, Steve A Webb³⁶, Ryan Zarychanski^{37

38}, Stéphane Zuily³⁹, Grégoire Le Gal¹; International Network of VENous Thromboembolism Clinical Research Networks INVENT-VTE

Affiliations

¹ Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
² Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
³ Department of Medicine, University of Calgary, Calgary, AB, Canada.
⁴ Department of Medicine, McGill University, Montreal, QC, Canada.
⁵ Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Haematology, New South Wales Health Pathology Randwick, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷ Department of Haematology, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁸ Divisions of Internal Medicine and Clinical Epidemiology, Jewish General Hospital/Lady Davis Institute, Montreal, QC, Canada.
⁹ University of Pittsburgh and UPMC Health System, Pittsburgh, PA, USA.
¹⁰ Division of Angiology and Haemostasis, Faculty of Medicine and Geneva University Hospitals, Geneva, Switzerland.
¹¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹² Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.
¹³ Departments of Medicine and Pathology & Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA.
¹⁴ Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁵ Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA.
¹⁶ Service de Médecine Intensive - Réanimation, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France.
¹⁷ Innovative Therapies in Haemostasis, INSERM UMR-S1140, Paris University, Paris, France.
¹⁸ Interdivisional Department of Critical Care, University of Toronto, Toronto, ON, Canada.
¹⁹ Division of Respirology, Department of Medicine, University Health Network, Toronto, ON, Canada.
²⁰ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
²¹ Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada.
²² Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
²³ Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
²⁴ Ted Rogers Centre for Heart Research, Toronto, ON, Canada.
²⁵ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
²⁶ Dipartimento Oncologia ed Ematologia, Azienda Ospedaliero-Universitaria di Modena, Ospedale Policlinico, Modena, Italy.
²⁷ Department of Critical Care Medicine, St Michael's Hospital, Toronto, ON, Canada.
²⁸ Auckland City Hospital, Intensive Care, Auckland, New Zealand.
²⁹ Division of Emergency Medicine, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University, Ribeirão Preto, Brazil.
³⁰ PARCC, INSERM U970, Paris, France.
³¹ Hôpital Européen Georges-Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France.
³² Intensive Cardiac Care Unit and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
³³ Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
³⁴ St. Michael's Hospital and Departments of Medicine, and Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
³⁵ Feinstein Institutes for Medical Research and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA.
³⁶ School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
³⁷ Department of Internal Medicine, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
³⁸ Cancer Care Manitoba, Research Institute of Oncology and Haematology, Winnipeg, MB, Canada.
³⁹ Vascular Medicine Division and Regional Competence Center for Marfan Syndrome, Inserm, DCAC and CHRU-Nancy, Université de Lorraine, Nancy, France.

Abstract

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed.

Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate.

Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials.

Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.

Keywords: COVID-19; anticoagulant; pulmonary embolism; research networks; thrombosis.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Anticoagulants / administration & dosage*
Anticoagulants / adverse effects
COVID-19 / blood
COVID-19 / diagnosis
COVID-19 / mortality
COVID-19 Drug Treatment*
Cooperative Behavior
Hospitalization*
Humans
International Cooperation*
Multicenter Studies as Topic
Patient Selection
Randomized Controlled Trials as Topic
Risk Assessment
Risk Factors
Thrombosis / blood
Thrombosis / diagnosis
Thrombosis / mortality
Thrombosis / prevention & control*
Treatment Outcome
Venous Thromboembolism / blood
Venous Thromboembolism / diagnosis
Venous Thromboembolism / mortality
Venous Thromboembolism / prevention & control*

Substances

Anticoagulants

Grants and funding

Canadian Venous Thromboembolism Research Network/International