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

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.

Plain Language Summary

Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90-day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital 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. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries.

Keywords:

• COVID-19
• ischemic stroke
• myocardial infarction
• thromboembolism
• venous thromboembolism

Abbreviations

ATE, arterial thromboembolism; CI, confidence interval; CNODES, Canadian Network for Observational Drug Effects Studies; CPRD, Clinical Practice Research Datalink; DVT, deep venous thrombosis; EMA, European Medicines Agency; EMR, electronic medical record; FDA, Food and Drug Administration; GP, general practitioner; ICD-9-CA, International Classification of Diseases, Ninth Revision, Canadian Modification; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CA, International Classification of Diseases, Tenth Revision, Canadian Modification; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; IPCI, Integrated Primary Care Information; PE, pulmonary embolism; SIDIAP, Information System for Research in Primary Care; SNOMED, Systematized Nomenclature of Medicine; US, United States; VTE, venous thromboembolism.

Data Sharing Statement

The data generated in this study are not publicly available. In accordance with current European and national law, the data used in this study are only available for the researchers participating in this study. Thus, we are not permitted to distribute or make publicly available the data to other parties. Additionally, Sentinel uses a distributed data approach in which Data Partners maintain physical and operational control of their own electronic health data after transforming it into a common data model. Sentinel does not save, maintain, or post individual-level datasets in order to preserve patient privacy. However, researchers can request data from the various data sources utilized if they comply with the requirements established by that data source.

Ethics Approval and Informed Consent

In Canada, the research protocol was reviewed and approved by Health Canada and by the data custodian and/or research ethics board at each participating CNODES provincial data center. In Europe, the protocol for this research was reviewed by the European Medicines Agencies and approved by database-specific ethics or data access committees. In the US, this Sentinel project was a public health surveillance activity conducted under US Food and Drug Administration authority and was not subject to Institutional Review Board oversight.

Acknowledgments

VLR and NMC are joint first authors. JMP and DPA are joint senior authors. This study was made possible through data sharing agreements between the participating CNODES member research centers and the respective provincial governments of British Columbia, Ontario, and Manitoba.

The views expressed in this publication are those of the authors and do not necessarily reflect the official policy of the European Medicines Agencies, Health Canada, or United States Food and Drug Administration. No endorsement by the US Food and Drug Administration, Health Canada, the European Medicines Agency, collaborating organizations, funders or data providers is intended or should be inferred.

Disclosure

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.

Additional information

Funding

The Canadian Network for Observational Drug Effect Studies (CNODES) is a core network partner of CoLab and funded by CADTH (grant number C222 360). At the time of this study, CNODES was a collaborating center of the Drug Safety and Effectiveness Network (DSEN) and funded by the Canadian Institutes of Health Research (CIHR, grant numbers DSE-11856 and DSE-146021). Health Canada had no role in data collection, management, or analysis. This project was also supported by Task Order 75F40119F19001 under Master Agreement 75F40119D10037 from the US Food and Drug Administration (FDA). The FDA approved the study protocol, including statistical analysis plan, and reviewed and approved this manuscript. Coauthors from the FDA participated in the result interpretation and in the preparation and decision to submit the manuscript for publication. The FDA had no role in data collection, management, or analysis. The European portion of this project was supported by the European Medicines Agency (EMA) as a specific contract with Erasmus Medical Center, Rotterdam, the Netherlands, under the framework contract number EMA/2018/21/PE, Lot 3. The EMA approved the EU study protocol and reviewed and approved this manuscript. The EMA had no role in data collection, management, or analysis. Additional support was provided by the UK NIHR Oxford Biomedical Research Centre.