COVID-19 and VTE/Anticoagulation: Frequently Asked Questions
(Version 12.0; last updated November 2, 2021)
Input from Drs. Lisa Baumann Kreuziger, MD; Agnes Y. Y. Lee, MD, MSc; David Garcia, MD; Maria DeSancho, MD; and Jean M. Connors, MD.
Note: Please review ASH's disclaimer regarding the use of the following information.
ASH has convened a multidisciplinary, international panel to develop guidelines on the use of anticoagulation in patients with COVID-19. These guidelines are “living” in that the updates are made as data become available. In collaboration with experts on the guideline panel, the team conducts urgent systematic reviews of available evidence to make evidence-based recommendations. When available, ASH recommendations will be included in this FAQ.
We all note that several authors of this FAQ have participated as investigators in clinical trials relevant to our recommendations, and thus may have intellectual conflict-of-interests.
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. In a meta-analysis of 66 observational studies through August 2020, the overall prevalence of VTE in hospitalized patients was 9.5 percent without screening ultrasound (US), and 40 percent with screening US; and higher in intensive-care-unit (ICU) patients at 18.7 percent without, and 45.6 percent with US. As with other medical patients, those with more severe disease, especially in the setting of additional risk factors (e.g., age, being male, obesity, cancer, history of VTE, comorbid diseases, ICU care), have a higher risk of VTE than those with mild or asymptomatic disease.
Should ambulatory or posthospital discharge patients with COVID-19 receive anticoagulation for prophylaxis?
We advise not starting anticoagulation for acutely ill COVID-19–positive outpatients. Patients diagnosed with mild-to-moderate COVID-19 not requiring hospitalization do not benefit from starting anticoagulation, either as thromboprophylaxis or to prevent progression of COVID-19, based on a very low event rate in stable outpatients, and based on the ACTIV-4b randomized controlled trial (RCT) comparing placebo, aspirin, or two different doses of apixaban in ambulatory patients older than 40 years.
The risk of VTE following hospital discharge appears low and similar to risks following hospital discharge for other medical conditions, based on observational studies. The ASH Clinical Practice Guidelines do not recommend VTE prophylaxis in this post-discharge population. Two RCTs evaluating post discharge VTE prophylaxis have been subsequently reported. The ACTION trial published that use of therapeutic dose rivaroxaban 20 mg daily during hospitalization followed by continued post-discharge use for 30 days resulted in no benefit compared to in-hospital prophylactic dose low-molecular-weight heparin (LMWH). The efficacy of inpatient versus post-discharge anticoagulation cannot be determined because outcomes were only reported at 30 days after discharge. The MICHELLE trial, presented but not yet published, showed a significant reduction in post-discharge thrombotic events (including screen-detected deep-vein thrombosis and PE at day 35) and death after 35 days of treatment with rivaroxaban 10 mg per day compared to placebo in a population of patients selected for increased VTE risk based on the IMPROVE-DD score.
We advise no routine anticoagulation for post discharge patients. However, an assessment can be performed to determine risk for VTE, using scores such as IMPROVE-DD, to determine whether an individual patient may merit post-discharge prophylaxis, also considering bleeding risk and feasibility. For example, COVID-19 patients who are discharged early to free up inpatient beds (“home hospital” approach) might still have significantly reduced mobility and merit continued thromboprophylaxis. All COVID-19 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.
What dose of anticoagulation should be empirically used in hospitalized COVID-19 patients in the absence of confirmed or suspected VTE?
All hospitalized adults with COVID-19 should at a minimum receive pharmacologic thromboprophylaxis, unless the risk of bleeding even on prophylactic dosing outweigh the risk of thrombosis. LMWH is preferred over unfractionated heparin (UFH). In the setting of heparin-induced thrombocytopenia, fondaparinux is recommended. In patients for whom anticoagulants are contraindicated or unavailable, mechanical thromboprophylaxis (e.g., pneumatic compression devices) can be used. Combined pharmacologic and mechanical prophylaxis is not generally recommended. ASH guidelines currently recommend use of standard VTE prophylaxis-dose anticoagulants in all hospitalized patients.
Optimal anticoagulant dosing to reduce thrombotic complications has been actively investigated. Multiple RCTs have been initiated and some have reported results. For the purposes of these trials, critically ill patients are usually defined as those requiring ICU level care such as hemodynamic support, ventilatory support, and/or renal replacement therapy; and moderately ill as those admitted to hospital but not requiring ICU-level care, however definitions can vary between trials. Outcome endpoints have differed between trials, and need to be kept in mind when reviewing results.
The largest RCT for hospitalized patients, a multiplatform adaptive-design trial (MPT), incorporated three multicenter studies/networks (REMAP-CAP, ATTACC, and ACTIV-4A) to address the question of whether therapeutic anticoagulation is indicated in critically ill or moderately ill patients. 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, extracorporeal membrane oxygenation (ECMO) support together with in-hospital mortality. Thrombosis, bleeding and overall mortality were secondary outcomes. Patients who required therapeutic anticoagulation for other indications were excluded. The INSPIRATION trial compared intermediate dose versus standard prophylactic dose LMWH in critically ill patients. The HEP-COVID trial compared therapeutic with prophylactic/intermediate dose LMWH anticoagulation in hospitalized patients with D-dimer level >4× the upper limit of normal (ULN) or sepsis-induced coagulopathy score of >4. The ]trial compared therapeutic with prophylactic doses of heparin in moderately ill hospitalized patients with elevated D-dimer level. Additional RCTs have been reported at meetings or on pre-print servers or are ongoing.
For patients requiring ICU or ICU level of care:
The MPT initially assessed therapeutic dose versus institutional prophylaxis regimens (including both standard prophylactic and intermediate doses of heparin) in 1098 critically ill patients. The trial was stopped early per pre-specified criteria for futility, with no benefit for therapeutic anticoagulation in reducing need for organ support or death at 21 days. There was also no difference in survival to discharge. It should be noted that approximately 50 percent of patients in the standard of care arm received intermediate dose heparin and 22.4 percent of patients in the therapeutic dose arm did not receive this dose. Major bleeding was seen in 3.8 percent of those assigned to therapeutic dose heparin and 2.3 percent of those assigned to standard of care. For thrombotic events the rate was 6.4 percent in the therapeutic dose arm and 10.6 percent in the standard prophylaxis arm, however thrombosis alone was not a predefined secondary outcome.
The INSPIRATION trial examined intermediate dose LMWH compared with standard prophylactic dose in ICU patients with a primary composite endpoint of venous or arterial thrombosis, ECMO, or mortality within 30 days. The results of this RCT found no benefit with intermediate dose compared to standard prophylactic dose, with major bleeding 2.5 percent in the intermediate dose arm and 1.4 percent in the standard prophylactic dose arm.
Based on these data, we advise that critically ill patients receive standard prophylactic doses of anticoagulants, since increased doses of heparin do not confer a benefit for preventing progression of COVID-19 or death. The ASH guideline panel currently 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).
For hospitalized patients not requiring ICU level of care:
In 2219 hospitalized moderately ill COVID-19 patients, the MPT was stopped early for superiority, finding benefit for the use of therapeutic dose anticoagulation compared to institutional standard thromboprophylaxis in prevention of disease progression, based on the same primary composite outcome used for the critically ill cohort. 28.2 percent assigned to the standard care arm received higher than prophylactic dose heparin and 20.3 percent assigned to therapeutic dose heparin received a lower dose, complicating interpretation. There was a 4 percent benefit of freedom from organ support or death at 21 days for those receiving therapeutic dose anticoagulation. There was no difference in survival to discharge. Major bleeding occurred in 1.9 percent of those assigned to therapeutic anticoagulation compared to 0.9 percent in those assigned to standard care dosing. Major thrombotic events occurred in 1.1 percent of patients in the therapeutic dose arm and 2.1 percent in the standard care arm. Therapeutic heparin/LMWH is the standard of care in hospitalized patients not requiring ICU level of care for additional comparisons in the ACTIV-4a trial.
The RAPID trial randomized 465 non-ICU hospitalized patients with elevated D-dimer to therapeutic dose or prophylactic dose heparin; intermediate dosing was not allowed. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or ICU admission, and was not statistically significantly different between the two arms (OR, 0.69; 95% CI, 0.43 to 1.10; p=0.12), although the odds of death at 28 days was decreased in the therapeutic dose arm (OR, 0.22; 95%-CI, 0.07 to 0.65; p=0.006). There was a numeric decrease in the number of VTE with two events in the therapeutic dose arm and 7 events in the standard prophylactic dose arm. There was no difference in bleeding.
The HEP-COVID trial randomized 253 hospitalized patients deemed to be at increased risk based on an elevated D-dimer > 4× ULN or an elevated sepsis-induced coagulopathy score to therapeutic versus prophylactic dose LMWH and found a significant 13.2 percent absolute risk reduction (28.7% vs 41.9%) in the composite of arterial and venous thrombosis and all-cause mortality in the therapeutic dose arm, driven by decreased thrombotic events, as there was no difference in deaths between the two groups. This benefit was found in the non-ICU/moderately ill patients only (67.2% of the trial population), and not those that required ICU level of care (32.8%). Overall, there were 6 major bleeds in the therapeutic dose arm (2 in non-ICU stratum and 4 in ICU stratum) and 2 major bleeds in the standard of care (non-ICU stratum).
As in the post-discharge anticoagulation discussion above, the ACTION trial comparing therapeutic dose rivaroxaban for moderately ill inpatients followed by 30 days post discharge did not decrease events or mortality at 30 days compared to inpatient prophylactic dose of LMWH only.
Based on these still evolving data we advise that moderately ill patients be carefully considered for therapeutic dose anticoagulation with a determination of individual net clinical benefit in the absence of objectively confirmed VTE. There was no difference in survival to discharge in the MPT trial enrolling the largest number of patients, and the absolute risk difference for progression to organ support or death at 21 days was only 4 percent, with a 1 percent major bleeding rate. This benefit may or may not be considered compelling for an individual patient. However, identifying which patients would benefit is challenging, as the studies within the MPT had different inclusion criteria regarding time from hospital admission to enrollment. There appears to be a signal for decreased VTE in these trials for moderately ill patients given full dose anticoagulation, however VTE was not a stand-alone pre-specified outcome in most trials. Individual patient benefit-risk assessment is appropriate at this time until further analyses are available to identify those patient factors associated with benefit from therapeutic dose anticoagulation. The HEP-COVID and RAPID trial results suggest D-dimer might be such a factor, although in the MPT, D-dimer did not predict a differential treatment effect of therapeutic dose anticoagulation. Even within the group of experts contributing to this FAQ, there were disagreements on whether hospitalized patients merit therapeutic dose anticoagulation, and if so, which ones.
Meta-analysis of RCT findings of differences in anticoagulation intensity in hospitalized patients
A meta-analysis pooled the results of 7 RCT evaluating the effect of therapeutic dose versus prophylactic dose anticoagulation in hospitalized patients. Therapeutic and intermediate dose anticoagulation data were combined and termed the escalated dose group which was compared to standard prophylactic dose; this approach differs from that of the mpRCT in which those treated with intermediate dose anticoagulation were combined with standard prophylactic dose anticoagulation. The results found no difference in mortality for escalated dose versus standard dose anticoagulation in all hospitalized patients. Major bleeding was increased in the escalated dose group but was low at 2.4 percent. In subgroup analyses, there was also no difference in mortality for those treated in the ICU or for non-ICU hospitalized patients. A difference was found favoring escalated dose anticoagulation for the prevention of VTE, but not for MI or stroke. The findings of this meta-analysis should be evaluated with the caveats regarding different classifications of therapeutic dose, intermediate dose, and prophylactic dose, as well as the choice to include studies using both heparin and rivaroxaban, despite differences in mechanism of action. Other meta-analyses are in progress.
The ASH guideline panel currently 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). However, the panel acknowledged that higher intensity anticoagulation may be preferred for patients judged to be at high thrombotic/low bleeding risk.
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.
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. Remdesivir is believed to have no clinical effect on metabolic pathways. Monoclonal antibodies also should not affect DOAC or warfarin metabolism. 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