COVID-19 and VTE/Anticoagulation: Frequently Asked Questions
(Version 11.0; last updated July 15, 2021)
Input from Drs. Lisa Baumann Kreuziger, MD; Agnes Y. Y. Lee, MD, MSc; David Garcia, MD; Mary Cushman, MD; Maria DeSancho, MD; and Jean M. Connors, MD.
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–intensive care unit (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 thresholds, criteria for diagnostic imaging, and the diversity of 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 based on observational studies and similar to other patients following a medical admission. VTE rate in those who do not require hospitalization has not been reported. Enrollment in a placebo-controlled randomized controlled trial (RCT) was halted due to low event rates in this population (NCT 04498273).
Should therapeutic- or intermediate-dose anticoagulation be empirically used in COVID-19 patients in the absence of confirmed or suspected VTE?
All hospitalized adults with COVID-19 should receive pharmacologic thromboprophylaxis unless the risk of bleeding outweighs the risk of thrombosis; low-molecular-weight heparin (LMWH) is recommended over unfractionated heparin (UFH) to reduce contact. In the setting of heparin-induced thrombocytopenia, fondaparinux is recommended. Dose adjustment for obesity and renal function may be used per institutional guidance. In patients for whom anticoagulants are contraindicated or unavailable, use mechanical thromboprophylaxis (e.g., pneumatic compression devices). Combined pharmacologic and mechanical prophylaxis is not generally recommended.
Therapeutic- and intermediate-dose anticoagulation are being investigated to reduce various measures of mortality and/or the severity of COVID-19 in multiple randomized controlled trials (RCT) (see Table for details of trial design, endpoints, treatments and results reported to date); thrombosis, bleeding and all-cause mortality are secondary outcomes in these trials. A large National Institutes of Health (NIH) multiplatform, adaptive-design trial (mpRCT) that incorporated three global studies/networks (REMAP-CAP, ATTACC, and ACTIV-4A) was designed to determine if full dose therapeutic anticoagulation can reduce mortality or need for organ support in critically ill or moderately ill patients. Patients were randomized to receive therapeutic or usual care (intermediate or prophylactic) doses of LMWH/UFH. In contrast, the INSPIRATION trial compared intermediate (enoxaparin 1 mg/kg daily) with prophylactic dosing of LMWH in hospitalized patients categorized as severely ill with COVID-19. The ACTION trial compared inpatient and post-discharge therapeutic anticoagulation (using rivaroxaban 20 mg daily in stable patients or enoxaparin 1 mg/kg twice daily in unstable patients) with only in-hospital prophylactic anticoagulation with enoxaparin; 93% of the patients were deemed stable or the equivalent of moderately ill. Finally, the RAPID trial also compared therapeutic with prophylactic LMWH/UFH anticoagulation in hospitalized patients not needing ICU level of care.
Given the variable interventions, primary outcomes measures, and different methods of analyses for these RCTs, and that results from the mpRCT and RAPID trials are not yet published, it remains uncertain if higher intensity anticoagulation offers net benefit over standard thromboprophylaxis in patients hospitalized for COVID-19, particularly in the moderately ill patients. The ASH guideline panel is monitoring available evidence and updates its recommendations periodically. The current recommendations are summarized below.
For patients requiring ICU or critical level of care:
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 (conditional recommendation based on very low certainty in the evidence about effects).
Given the lack of benefit in patients admitted to the ICU observed in mpRCT, INSPIRATION and observational data, we discourage the empiric use of full dose heparin or LMWH in this subgroup of COVID-19 patients without other indications for therapeutic anticoagulation, outside of a clinical trial.
For hospitalized patients not requiring ICU level of care at enrollment:
The ASH guideline panel suggests using prophylactic-intensity over intermediate-intensity or therapeutic-intensity anticoagulation in patients with COVID-19–related acute illness who do not have suspected or confirmed VTE (conditional recommendation based on very low certainty in the evidence about effects). This recommendation has not yet been updated since the release of data from ACTION and RAPID trials.
However, the guideline panel suggested that an individualized assessment of the patient’s risk of thrombosis and bleeding is important when deciding on anticoagulation intensity. Risk assessment models to estimate thrombotic and bleeding risk in hospitalized patients are available, but they have not been validated in patients with COVID-19. The panel acknowledges that higher-intensity anticoagulation may be preferred in this subgroup of patients judged to be at high thrombotic and low bleeding risks.
We encourage participation in ongoing clinical trials and epidemiologic studies, and will update this FAQ as more data become available..
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 any acute medical illness are at increased risk for VTE for up to 90 days after discharge, and to date there is little evidence the rate is higher in COVID-19 patients. Whether post-discharge thromboprophylaxis is indicated in COVID-19 patients without other indications for this intervention has been the subject of several observational or retrospective studies. The ACTION trial found that for stable hospitalized patients, rivaroxaban 20 mg once daily for 30 days post-discharge confers no additional benefit when compared to in-hospital prophylactic dose LMWH/UFH. The ASH guidelines panel recently updated recommendations to suggest patients should not receive thromboprophylaxis after hospital discharge for COVID-19 in the absence of other indications. 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. 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, 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