Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Vincent Lo Re Iii^#^{1

2}, Noelle M Cocoros^#^{3

4}, Rebecca A Hubbard², Sarah K Dutcher⁵, Craig W Newcomb², John G Connolly^{3

4}, Silvia Perez-Vilar⁵, Dean M Carbonari², Maria E Kempner^{3

4}, José J Hernández-Muñoz⁵, Andrew B Petrone^{3

4}, Allyson M Pishko⁶, Meighan E Rogers Driscoll^{3

4}, James T Brash⁷, Sean Burnett^{8

9}, Catherine Cohet¹⁰, Matthew Dahl^{8

11}, Terese A DeFor¹², Antonella Delmestri¹³, Djeneba Audrey Djibo¹⁴, Talita Duarte-Salles^{15

16}, Laura B Harrington¹⁷, Melissa Kampman¹⁸, Jennifer L Kuntz¹⁹, Xavier Kurz¹⁰, Núria Mercadé-Besora¹⁵, Pamala A Pawloski¹², Peter R Rijnbeek¹⁶, Sarah Seager⁷, Claudia A Steiner^{20

21}, Katia Verhamme¹⁶, Fangyun Wu^{8

22}, Yunping Zhou²³, Edward Burn¹³, J Michael Paterson^#^{8

22}, Daniel Prieto-Alhambra^#^{13

16}

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Population Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Harvard Pilgrim Healthcare Institute, Boston, MA, USA.
⁵ Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁶ Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ IQVIA, Real World Solutions, Brighton, UK.
⁸ Canadian Network for Observational Drug Effect Studies (CNODES), Toronto, Ontario, Canada.
⁹ Therapeutics Initiative, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Data Analytics and Methods Task Force, European Medicines Agency, Amsterdam, Netherlands.
¹¹ Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² HealthPartners Institute, Bloomington, MN, USA.
¹³ Pharmaco- and Device Epidemiology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
¹⁴ CVS Health, Blue Bell, PA, USA.
¹⁵ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
¹⁶ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
¹⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁸ Health Canada, Ottawa, Ontario, Canada.
¹⁹ Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA.
²⁰ Kaiser Permanente Colorado Institute for Health Research, Aurora, CO, USA.
²¹ Colorado Permanente Medical Group, Denver, CO, USA.
²² ICES, Toronto, Ontario, Canada.
²³ Humana Healthcare Research, Inc., Louisville, KY, USA.

^# Contributed equally.

PMID: 38357585
PMCID: PMC10865892
DOI: 10.2147/CLEP.S448980

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Vincent Lo Re Iii et al. Clin Epidemiol. 2024.

. 2024 Feb 10:16:71-89.

doi: 10.2147/CLEP.S448980. eCollection 2024.

Authors

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Population Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Harvard Pilgrim Healthcare Institute, Boston, MA, USA.
⁵ Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁶ Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ IQVIA, Real World Solutions, Brighton, UK.
⁸ Canadian Network for Observational Drug Effect Studies (CNODES), Toronto, Ontario, Canada.
⁹ Therapeutics Initiative, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Data Analytics and Methods Task Force, European Medicines Agency, Amsterdam, Netherlands.
¹¹ Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² HealthPartners Institute, Bloomington, MN, USA.
¹³ Pharmaco- and Device Epidemiology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
¹⁴ CVS Health, Blue Bell, PA, USA.
¹⁵ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
¹⁶ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
¹⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁸ Health Canada, Ottawa, Ontario, Canada.
¹⁹ Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA.
²⁰ Kaiser Permanente Colorado Institute for Health Research, Aurora, CO, USA.
²¹ Colorado Permanente Medical Group, Denver, CO, USA.
²² ICES, Toronto, Ontario, Canada.
²³ Humana Healthcare Research, Inc., Louisville, KY, USA.

^# Contributed equally.

PMID: 38357585
PMCID: PMC10865892
DOI: 10.2147/CLEP.S448980

Abstract

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability.

Patients and methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE.

Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09-0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99-1.04%) in the US.

Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.

Keywords: COVID-19; ischemic stroke; myocardial infarction; thromboembolism; venous thromboembolism.

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Conflict of interest statement

VLR III reports research grants to his institution from the US Food and Drug Administration (FDA) and the National Institutes of Health (NIH); consulting fees from Entasis, Takeda, and Urovant Sciences; and participation on the FDA Drug Safety and Risk Management Advisory Committee. NMC reports research funding from FDA via a Department of Health and Human Services (HHS) contract during the conduct of the study and funding from HPHCI (a non-profit organization that conducts work for government and private organizations, including pharmaceutical companies) outside the submitted work. RAH reports grants from FDA, NIH, and Merck. AMP reports royalties from UpToDate (including for an article on anticoagulation), consulting fees via advisory board from BioMarin LLC outside the submitted work, and speaker honorarium from the American Society of Hematology. DAD reports stock options in CVS Health. JLK reports unrelated research grants to her institution from Vir Biotechnology, Pfizer, Novartis, and the Centers for Disease Control and Prevention. PRR reports unrelated research grants to his institution from Chiesi, UCB, Amgen, Johnson & Johnson, Innovative Medicines Initiative, and the European Medicines Agency. KV reports unrelated research grants to her institution from Chiesi, UCB, Amgen, Johnson & Johnson, and the European Medicines Agency. DPA reports research grants to his institution from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma as well as consulting fees from Astra Zeneca and UCB Biopharma. The authors report no other conflicts of interest in this work.

Figures

**Figure 1**
Country-level estimates (95% confidence intervals) of 90-day absolute risk of arterial (red) and venous (blue) thromboembolism events among patients initially diagnosed with COVID-19 in the ambulatory (ie, outpatient, emergency department, or institutional) setting, by month of diagnosis across the pre- and post-vaccine availability periods.

See this image and copyright information in PMC

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Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Affiliations

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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