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COVID-19 and VTE/Anticoagulation: Frequently Asked Questions

(Version 9.0; last updated February 25, 2021)

Input from Drs. Lisa Baumann Kreuziger, MD; Agnes Y. Y. Lee, MD, MSc; David Garcia, MD; Adam Cuker, 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 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.

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 with LMWH over unfractionated heparin to reduce contact with health care providers, 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 for whom 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. For instance, a large National Institutes of Health (NIH) multiplatform, adaptive-design trial that incorporates three global studies/networks (REMAP-CAP, ATTACC, and ACTIV-4A) was set up to address the question of whether more intensive anticoagulation is indicated in critically ill or moderately ill patients. ACTIV-4A Inpatient and ATTACC enrolled patients within the first 72 hours of hospitalization, while REMAP-CAP used a 48-hour cutoff for those needing organ support on admission and up to 14 days for those who were moderately ill. Patients were randomized in an adaptive fashion to receive different intensities of anticoagulation and/or antiplatelet agents. The primary outcome was a composite of 21-day “organ support–free” days, defined as number of hospital days not requiring high-flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO) support and in-hospital mortality. Thrombosis, bleeding and overall mortality were secondary outcomes. Patients who required therapeutic anticoagulation for other indications (e.g., mechanical heart valves) were excluded.

ASH convened a multidisciplinary, international panel to develop guidelines on the use of anticoagulation in patients with COVID-19. In collaboration with experts on the guideline panel, the team conducted urgent systematic reviews of available evidence on the baseline risk of thrombosis in patients with COVID-19 and on the use of prophylactic versus higher intensity anticoagulation in patients who are acutely or critically ill. Notably, the outcome examined by the ASH guidelines panel and systemic review was risk of thrombosis. This is subtly different than the primary outcome of the NIH study, where the endpoint was “organ-support-free” days. The initial guidelines were published online in October 2020, and updates are being made as further clinical trial information is made available. The current guidelines panel recommendations are summarized below, along with explanations of recent results released by NIH regarding the multiplatform trials.

For patients requiring ICU or critical level of care:

Patients with COVID-19–related critical illness are defined as those suffering from an immediately life-threatening condition who would typically be admitted to an ICU. Examples include patients requiring hemodynamic support, ventilatory support, and renal replacement therapy.

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).

As of December 21, 2020, enrollment of patients requiring ICU level of care in the NIH multiplatform trials was paused due to an interim pooled analysis demonstrating futility (OR, 0.76; 0.60 – 0.97) of full dose anticoagulation in reducing the need for organ support and mortality, compared with usual care prophylactic dose anticoagulation, in this specific subgroup. Peer-reviewed publication is pending (see Table for preliminary data from NIH ). In addition, given the concern for safety (numerically higher mortality and bleeding; probability of therapeutic dose is harmful is 98.5%), 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).

Acute illness in the guidelines was defined as conditions normally requiring hospitalization but not ICU care, including dyspnea or mild to moderate hypoxia.

On January 22, 2021, NIH announced that full dose anticoagulation appeared superior to usual care prophylactic dose anticoagulation (proportional OR 1.5; 1.1 – 2.2) in reducing the need for organ support and mortality in moderately ill hospitalized COVID-19 patients enrolled in the multiplatform trials. Preliminary, non-adjudicated data on thrombotic and bleeding outcomes have been made public (see Table). Until peer-reviewed data are available, we recommend using clinical judgment, with careful consideration of the risk of bleeding in managing individual patients. The ASH guidelines panel has not changed their recommendation for using of prophylactic-intensity dosing pending availability and review of the finalized multiplatform trial data. However, the 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 patients judged to be at high thrombotic risk and low bleeding risk.

Table: Prepublication, interim, non–peer reviewed data from the Multiplatform Trial

  Moderate State Severe State
  Therapeutic Usual Care  Therapeutic Usual Care
Need for organ support* ~16% ~23% N/A N/A
Mortality 40/699 (5.7%) 54/699 (7.7%) 160/453 (35.3%) 144/442 (32.6%)
Thrombotic events ƚ 16/853 (1.9%) 24/742 (3.2%) 31/460 (6.7%) 53/448 (11.8%)
ISTH major bleeding 14/853 (1.6%) 7/742 (0.9%) 17/460 (3.7%) 8/448 (1.8%)

*a post-hoc analysis
ƚ includes DVT, PE, MI, ischemic stroke, other thrombotic event

Planning for continuing enrollment in these multiplatform trials is in process, while other studies are continuing in evaluation of other dosing regimens and interventions such as intermediate dose anticoagulation or antiplatelet agents. 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 acute medical illness are at increased risk for VTE for up to 90 days after discharge. A symptomatic VTE incidence of between 0-0.6% at 30-42 days post–COVID-19 discharge has been reported in observations studies of 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 may merit thromboprophylaxis 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 discharge for 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. Enrollment in clinical trials to address this question is encouraged.

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.

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