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COVID-19 and VTE/Anticoagulation: Frequently Asked Questions

(Version 3.0; last updated May 18, 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 is not well established. Reports have ranged between 1.1% in non-ICU hospital wards to 69% in ICU patients screened with lower extremity ultrasound. Small sample sizes, 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. VTE rate in outpatients has not been reported.

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.

Despite the lack of quality published evidence, many institutional protocols have adopted an intermediate-intensity (i.e., administering the usual daily LMWH dose twice daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis based on local experience. We recommend participation in well-designed clinical trials and/or epidemiologic studies when they become available.

Should seriously ill COVID-19 patients receive therapeutic-intensity anticoagulation empirically (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 to date have been limited but they do show large vessel and microvascular thrombosis, pulmonary hemorrhage and high prevalence of VTE. Although retrospective cohort studies of patients treated or not treated with anticoagulation have been published, such observational data should not be used to support changes in practice due to the survivor bias, confounding by indication, and lack of adjustment for important patient comorbidities and other treatments. Whether critically ill COVID-19 patients should receive therapeutic-intensity anticoagulation in the absence of confirmed or suspected VTE is currently unknown. Multiple randomized controlled trials are investigating the effects of different doses of heparin on patient outcomes. We encourage participation in clinical trials rather than empiric use of therapeutic-dose heparin in COVID-19 patients with no other indication for therapeutic dose anticoagulation..

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. This finding should apply to COVID-19 patients, though data on incidence are not yet available. Therefore, it is reasonable to consider extended thromboprophylaxis after discharge using a regulatory-approved regimen (e.g., betrixaban 160 mg on day 1, followed by 80 mg once daily for 35-42 days; or rivaroxaban 10 mg daily for 31-39 days)1,2, 3. Inclusion criteria for the trials studying these regimens included combinations of age, co-morbidities such as active cancer, and elevated D-dimer >2 times the upper normal limit. Any decision to use post-discharge thromboprophylaxis should consider the individual patient’s VTE risk factors, including reduced mobility and bleeding risk as well as feasibility. “Home hospital” approaches for COVID-19 patients involving early discharge have been suggested to free up inpatient beds. Status at discharge should be considered in any decision to use VTE prophylaxis in these unique patients. Aspirin has been studied for VTE prophylaxis in low-risk patients after orthopedic surgery and could be considered for COVID-19 VTE prophylaxis if criteria for post-discharge thromboprophylaxis are met4. Patients should be educated on the signs and symptoms of VTE at hospital discharge.

If a patient with COVID-19 requires therapeutic anticoagulation for VTE or AFIB stroke prevention, are there any special considerations?

Multiple Multiple medications are under investigation for COVID-19. Sarilumab (KEVZARA) and tocilizumab (ACTEMRA) can increase cytochrome P450 enzyme activity. Apixaban (Eliquis®) and rivaroxaban (Xarelto®) should not be used with sarilumab or tocilizumab and increased doses of warfarin may be 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 at covid19-druginteractions.org. Use LMWH or UFH in hospitalized critically ill patients 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. Patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or pregnancy or lactation should generally continue treatment with warfarin therapy..

References

  1. Cohen et al, Extended thromboprophylaxis with betrixaban in acutely ill medical patients. NEJM, 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa1601747
  2. Weitz et al, Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials, Thrombosis and Haemostasis, 2020, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0039-1701009
  3. Spyropoulos AC. Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1705137
  4. Anderson et al, Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty, NEJM, 2018, https://www.nejm.org/doi/full/10.1056/NEJMoa1712746

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