The report is a product of the VA/HSR&D Evidence Synthesis Program.
Evidence Brief: Anticoagulation for Hospitalized Adults with COVID-19
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the disease COVID-19, can lead to profound inflammation and a prothrombotic state. Most adults hospitalized in the US receive low-dose anticoagulation as part of standard care to prevent venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). At the beginning of the pandemic, observational data and anecdotal reports on the risk of thrombotic complications in COVID-19 prompted some clinicians, hospitals, and health systems to modify their approaches to prophylactic anticoagulation in the inpatient setting by using higher than standard doses. Whether the benefits of higher anticoagulation dosing, if any, outweigh potential harms such as increased bleeding risk has been an ongoing area of research during the pandemic. Several randomized controlled trials (RCTs) have recently been published, adding to extensive observational data from the first 18 months of the pandemic.
Deep vein thrombosis occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis. One half of blood clots occur during or soon after a hospital stay or surgery.
VA’s Evidence Synthesis Program (ESP) Coordinating Center in Portland, OR, conducted an evidence review to synthesize the available research on the benefits and harms of intermediate-dose and therapeutic-dose anticoagulation compared to standard thromboprophylaxis among hospitalized adults with COVID-19. Investigators searched Ovid MEDLINE and the WHO Global Literature on Coronavirus Disease database through October 12, 2021. From 586 articles that remained after abstract review, they included 2 RCTs and 23 cohort studies of intermediate-dose anticoagulation and 6 RCTs and 22 cohort studies of therapeutic-dose anticoagulation.
Studies were organized according to intervention type (intermediate or therapeutic anticoagulation dosage) and population (moderately ill or severely/critically ill participants). Standard thromboprophylaxis was defined as anticoagulants prescribed according to pre-COVID-19 era guidelines for VTE prevention among adults hospitalized with medical illness. Treatment-dose anticoagulation was defined as anticoagulants prescribed at doses typically used for treatment of diagnosed thrombus or thromboembolic disease, but used empirically in the case of COVID-19 (e.g., without imaging-confirmed thrombotic disease). Intermediate-dose anticoagulation was defined as doses in between standard thromboprophylaxis and typical treatment doses.
Summary of Findings
Compared to standard thromboprophylaxis, intermediate-dose anticoagulation may be associated with a small mortality benefit among hospitalized adults with COVID-19 but was not associated with a significantly lower risk of thrombotic events. In contrast, therapeutic-dose anticoagulation may reduce the risk of thrombotic events but does not appear to reduce mortality when compared to standard thromboprophylaxis. However, confidence in these findings is low, primarily due to study methodological inconsistencies and limitations. In terms of harms, when considered alongside extensive pre-pandemic evidence linking higher anticoagulation doses to increased bleeding risk, available COVID-19-specific evidence is sufficient to conclude that higher doses of anticoagulation are likely associated with a dose-dependent increase in bleeding risk among hospitalized patients with COVID-19 comparable to adults hospitalized with other medical illnesses.
Research in progress
The investigators identified 12 ongoing trials, including two that are complete but do not yet have published results. [See Appendix E in Supplemental Materials.] Both of the completed trials are small (fewer than 200 participants) and compared thrombotic events with intermediate-dose anticoagulation to standard thromboprophylaxis. Among trials that are currently recruiting, two will investigate mortality with intermediate and therapeutic-dose anticoagulation compared to standard thromboprophylaxis.
Research Gaps/Future Research
Important gaps exist in the evidence regarding anticoagulation use among hospitalized adults with COVID-19. No studies have directly compared intermediate and therapeutic-dose anticoagulation among adults with different disease severity. Some trends in the evidence suggest that adults with less severe disease may benefit from higher anticoagulation doses but whether mortality benefits, if any, outweigh potential harms remains unclear. Future research is needed to better understand if, and when higher-dose anticoagulation is beneficial.
Mackey K, Young S, Oakes M, Arastu A, Maldonado E, Anderson J, Parr NJ. Evidence Brief: Anticoagulation for Hospitalized Adults with COVID-19. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-199; 2022.
To view the full report, go to https://www.hsrd.research.va.gov/publications/esp/COVID-Anticoagulation-brief.cfm
ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.
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