The following are key points to remember from this state-of-the-art review on recent randomized trials of antithrombotic therapy for patients with coronavirus disease 2019 (COVID-19):

1. COVID-19 can potentiate all three components of Virchow’s triad and increase the risk of thrombosis. This includes direct endothelial dysfunction from viral binding and associated inflammatory response, pro-thrombotic changes through inflammatory and anti-phospholipid antibody-related mechanisms, and venous stasis due to fatigue, hypoxemia, and hospitalization.
2. Patients hospitalized with COVID-19 are at increased risk for venous thromboembolism (VTE). In meta-analyses, hospitalized patients have an estimated incidence of 17% (95% confidence interval, 13.4%-20.9%). This is markedly higher in critically ill patients admitted to the intensive care unit (ICU; 28% vs. 7%).
3. As of December 16, 2020, there were 75 randomized clinical trials (RCTs) of antithrombotic therapy for patients with COVID-19 in ClinicalTrials.gov or the World Health Organization registry. Agents used in these studies include antiplatelet agents, heparin, parenteral direct thrombin inhibitors, direct oral anticoagulants (DOACs), fibrinolytic agents, and others.
4. Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) are the most commonly included antithrombotic agents in the ongoing RCTs. Most of these trials include patients in the hospital, both in the ICU and medical floors, and include standard prophylactic dose, intermediate-dose, or therapeutic-dose treatment arms. Many include dose adjustments for obesity and/or abnormal renal function.
5. Most RCTs that are studying DOACs are enrolling ambulatory patients or patients upon hospital discharge. These studies include both low-intensity (prophylactic dose) and therapeutic-dose DOAC treatment strategies.
6. RCTs exploring antiplatelet therapy including either ambulatory or hospitalized patients are primarily testing aspirin, clopidogrel, prasugrel, or combination therapy.
7. There are six studies exploring the use of fibrinolytic therapy for patients with severe COVID-19 admitted to the ICU. This therapy is not being tested in other settings currently.
8. Patients at increased risk for COVID-19 complications were variably included in the identified studies. While only a few studies exclude patients with obesity, nearly all studies exclude pregnant patients and those with liver failure. Patients with advanced kidney disease or end-stage renal disease were variably included/excluded in the studies.
9. The authors note a number of important changes in RCT design in response to the COVID-19 pandemic. Highlights include more multi-specialty collaborations, time-sensitive trial designs with pragmatic design features, and applicability of adaptive platform designs. They also noted an accelerated funding review process and more frequent regulatory and data safety reviews. Finally, they noted that the use of pre-print servers to share early results of studies was far more frequent during the COVID-19 pandemic than previously.
10. The authors outlined remaining important knowledge gaps. These include exploring appropriate antithrombotic preventative regimens in ambulatory and post-discharge populations, the safety of common antithrombotic regimens in vulnerable populations, and the impact of antiplatelet therapy on survival in critically ill patients.

Clinical Topics: Anticoagulation Management, COVID-19 Hub, Geriatric Cardiology, Prevention, Vascular Medicine

Keywords: Anticoagulants, Antithrombins, Aspirin, Coronavirus, COVID-19, Critical Illness, Fatigue, Fibrinolytic Agents, Geriatrics, Heparin, Heparin, Low-Molecular-Weight, Inflammation, Kidney Diseases, Obesity, Platelet Aggregation Inhibitors, Primary Prevention, Thrombolytic Therapy, Thrombosis, Vascular Diseases, Venous Thrombosis, Virus Attachment

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