COVID-19 and VTE/Anticoagulation: Frequently Asked Questions
(Version 5.1; last updated December 24, 2020)
Input from Drs. Lisa Baumann Kreuziger, Agnes Lee, David Garcia, Adam Cuker, Mary Cushman, Maria DeSancho, and Jean M. Connors
Note: Please review ASH's disclaimer regarding the use of the following information.
Is COVID-19 associated with an increased risk for venous thromboembolism (VTE)?
The incidence of VTE in COVID-19 patients varies depending on the patient population. Reports have ranged from 1.1% in non-ICU hospital wards to 69% in ICU patients screened with lower extremity ultrasound. Small sample sizes, retrospective design and differences in patient characteristics, co-morbidities, hospital and ICU admission criteria, criteria for diagnostic imaging, and COVID-19 therapies likely contribute to this wide range of estimates. Like other medical patients, those with more severe disease, especially if they have additional risk factors (e.g. older, male, obesity, cancer, history of VTE, comorbid diseases, ICU care), have a higher risk of VTE than those with mild or asymptomatic disease. The risk of VTE following hospital discharge appears low and similar to other patients following a medical admission. VTE rate in those who do not require hospitalization has not been reported. The benefit of thromboprophylaxis in these patients is being investigated in a placebo-controlled randomized controlled trial.
What is the recommended VTE prophylaxis in patients with COVID-19?
All hospitalized adults with COVID-19 should receive pharmacologic thromboprophylaxis with LMWH over unfractionated heparin to reduce contact, unless the risk of bleeding outweighs the risk of thrombosis. In the setting of heparin-induced thrombocytopenia, fondaparinux is recommended. Dose adjustment for obesity may be used per institutional guidance. In patients where anticoagulants are contraindicated or unavailable, use mechanical thromboprophylaxis (e.g. pneumatic compression devices). Combined pharmacologic and mechanical prophylaxis is not generally recommended.
Optimal anticoagulant dosing to reduce thrombotic complications is being actively investigated. The ASH guideline panel suggests using prophylactic-intensity over intermediate-intensity or therapeutic-intensity anticoagulation in patients with COVID-19 related critical illness who do not have suspected or confirmed VTE. We encourage participation in ongoing clinical trials and epidemiologic studies.
Should therapeutic dose anticoagulation be empirically used in COVID-19 patients requiring ICU level care (i.e., in the absence of confirmed or suspected VTE)?
Microvascular thrombosis is hypothesized to be involved in hypoxemic respiratory failure in some patients with COVID-19. Autopsy studies show large vessel and microvascular thrombosis, pulmonary hemorrhage and high prevalence of VTE. Although retrospective cohort studies of patients treated or not treated with therapeutic anticoagulation have been published, such observational data should not be used to support changes in practice due to survivor bias, confounding by indication, and lack of adjustment for important patient comorbidities and other treatments.
Recently, enrollment of patients requiring ICU level of care in the 3 ongoing multiplatform trials (REMAP-CAP, ATTACC and ACTIV-4A) was paused (as of December 21, 2020) due to an interim pooled analysis demonstrating futility of therapeutic-intensity anticoagulation in reducing the need for organ support over the first 21 days compared with standard-intensity prophylaxis in this specific subgroup. ICU level of care and organ support were defined as requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support. Additional outcomes have not yet been reported. This FAQ will be updated as more information becomes available. Enrollment in these three trials is continuing for patients who require hospitalization but do not require an ICU level of care at time of enrollment. Patients who require therapeutic anticoagulation for other indications are not enrolled in these trials.
Consequently, we discourage the empiric use of therapeutic-intensity heparin or LMWH in COVID-19 patients with no other indication for therapeutic anticoagulation, outside a clinical trial. Patients should be given therapeutic anticoagulation only as otherwise indicated. We recommend participation in ongoing clinical trials and epidemiologic studies.
How should we manage COVID-19 patients who experience recurrent clotting of access devices (e.g., central venous catheters, arterial lines) or extracorporeal circuits (e.g., CRRT, ECMO) despite prophylactic anticoagulation?
Although of unproven benefit, it may be reasonable to increase the intensity of anticoagulation (i.e., from standard-intensity prophylaxis to intermediate-intensity prophylaxis or from intermediate-intensity prophylaxis to therapeutic-intensity) or switch anticoagulants in these settings. Any decision to increase the intensity of anticoagulation should take into account the individual patient’s bleeding risk.
Should COVID-19 patients receive post-discharge thromboprophylaxis?
Patients hospitalized for acute medical illness are at increased risk for VTE for up to 90 days after discharge. A symptomatic VTE incidence between 0-0.6% at 30-42 days post discharge has been reported in patients with COVID-19. Whether post-discharge thromboprophylaxis is warranted is being investigated in clinical trials and enrollment is encouraged. Any decision to use post-discharge thromboprophylaxis should consider the individual patient’s VTE risk factors at the time of discharge, including reduced mobility and bleeding risk, as well as feasibility. For example, COVID-19 patients who are discharged early to free up inpatient beds (“home hospital” approach) might still have significantly reduced mobility. Aspirin has been studied for VTE prophylaxis in low-risk patients after hip or knee arthroplasty and is currently being investigated for COVID-19 post-discharge thromboprophylaxis. Patients should be educated on the signs and symptoms of VTE at hospital discharge and advised to seek urgent medical attention should these develop.
If a patient with COVID-19 requires therapeutic anticoagulation for VTE or AFIB stroke prevention, are there any special considerations?
Multiple medications are being used for COVID-19 treatment. Dexamethasone is an inducer of CYP3A4 and the extent of the drug interaction with direct oral anticoagulants is unknown. Sarilumab (KEVZARA) and tocilizumab (ACTEMRA) can increase cytochrome P450 enzyme activity and so they should not be used together with apixaban (Eliquis®) or rivaroxaban (Xarelto®) and may also increase the doses of warfarin required. Atazanavir and lopinavir/ritonavir will increase drug concentrations of apixaban and rivaroxaban and decrease the active metabolite of clopidogrel and prasugrel. The University of Liverpool has collated a list of drug interactions (Link: http://covid19-druginteractions.org/). LMWH or UFH in hospitalized critically ill patients is preferred because of the shorter half-life and fewer drug-drug interactions compared with direct oral anticoagulants. Regular warfarin users who are unable to get INR monitoring during isolation may be candidates for direct oral anticoagulant therapy (add link), but patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or lactation should continue treatment with warfarin therapy. LMWH or UFH remain the anticoagulants of choice in pregnancy.
For additional information, see:
- 2018 ASH VTE guidelines – prevention in medical patients
- 2018 ASH VTE guidelines – anticoagulation therapy
- COVID-19 drug interactions
- Transitioning to DOAC from Coumadin, British Columbia Ministry of Health, BC Provincial Academic Detailing Service
- Barnes et al. Thromboembolism and Anticoagulant Therapy During the COVID-19 Pandemic: Interim Clinical Guidance from the Anticoagulation Forum
- Antithrombotic therapy in patients with COVID-19
- AC Forum COVID-19 Guidelines
- American College of Cardiology
- CHEST COVID-19 Guidelines
- NIH COVID-19 Guidelines
- ISTH COVID-19 Guidance
- Italian Society on Thrombosis and Haemostasis
- Royal College of Physicians
- World Health Organization