2. What antithrombotic strategy should be given to patients hospitalized for COVID-19 who do not require ICU-level care with organ support?

There have been two published trials evaluating different anticoagulant regimens in this population. The ACTION trial compared treatment-dose rivaroxaban 20 mg daily to prophylactic-dose enoxaparin 40 mg daily in hospitalized patients with COVID-19 and elevated D-dimer.¹ The majority of these patients did not require intensive care unit (ICU)-level care organ support. There was no difference in the rate of death, duration of hospitalization, or duration of supplemental oxygenation between the two treatment groups.

In the multi-platform randomized controlled trial (ATTACC, ACTIV-4a, REMAP-CAP), patients with moderate illness from COVID-19 (hospitalized, but not requiring ICU-level care or organ support) were randomized to receive treatment-dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) or standard prophylactic dose UFH or LMWH heparin.² This trial, which enrolled patients during the first waves of the COVID-19 pandemic (April 2020-January 2021) included an older population (mean age ~60 years) than is currently being hospitalized with the delta variant. The population was stratified by D-dimer level based on initial data suggesting a strong association with thromboembolic risk and outcomes. Importantly, the inclusion criteria were limited to patients hospitalized for COVID-19 infection with an expected length of stay of >48-72 hours and without the need for dual antiplatelet therapy or ongoing anticoagulant therapy. Patients requiring ICU-level organ support were not included in this analysis.

The main findings of the multi-platform trial are that the patients randomized to treatment-dose UFH or LMWH had more days without organ support than those randomized to prophylactic-dose UFH or LMWH (80.2% vs. 76.4%). However, there was no statistically significant difference in overall survival until discharge (adjusted risk difference, 1.3%; 95% CI, 1.1%-3.2%). Major thromboembolic events were slightly lower (1.1% vs. 2.1%) while major bleeding was higher (1.9% vs. 0.9%) in the treatment-dose group. Of note, in-hospital mortality was much more common (7.3%-8.2%) than major thrombotic event (1.1-2.1%).

A few points should be considered when applying the results to clinical practice. In this open-label trial, treating physicians were aware of treatment allocation which could lead to ascertainment bias (i.e., threshold for investigation of thrombosis and bleeding events) and/or differential use of other treatments (i.e., supportive treatments). It is unclear why the rates of thrombotic events (in both groups) were much lower than those reported in numerous previous observational studies.³ It is also unclear what proportion of thrombotic events were proximal vs. distal (e.g., below-the-knee deep vein thrombosis [DVT], subsegmental pulmonary embolism) a distinction which may be prognostically important. Finally, as this study was conducted early in the COVID-19 pandemic, it is possible that some patients were unable to get full imaging to diagnose thrombotic events due to concerns for patients and/or staff safety.

Based on current evidence, treatment-dose UFH or LMWH should be considered a therapy that reduces the need for ICU-level care but has not been shown to conclusively reduce thrombotic events among moderately ill hospitalized COVID-19 patients. In particular, treatment-dose UFH or LMWH may be most helpful for patients deemed at risk of disease progression or organ failure but at relatively low risk for bleeding complications. This approach may be particularly helpful in settings where the volume of patients with COVID-19 is great enough to overwhelm available ICU resources. Furthermore, no currently available biomarker is available to discern which patients are most likely to benefit from treatment-dose heparin therapy. Based on the results of the ACTION trial, the use of treatment-dose rivaroxaban cannot be recommended as a thromboprophylaxis strategy in hospitalized patients with COVID-19. Other ongoing and recently completed randomized trials may further define the role of treatment-dose UFH or LMWH for patients hospitalized with COVID-19.

3. What antithrombotic strategy should be given to patients hospitalized for COVID-19 who require ICU-level care or organ support?

Hospitalized patients with COVID-19 treated in the critical care setting have the highest risk of thromboembolic complications compared with those who are hospitalized but not requiring the ICU.^4,5 While intermediate- or therapeutic-LMWH dosing was proposed for prophylaxis in this population early in the pandemic, some guidelines, such as from the American College of Chest Physicians (ACCP), suggested standard-dose LWMH based on the absence of randomized clinical trial data and concerns about an increased risk of bleeding with therapeutic dosing.⁶ In contrast, guidance from the International Society on Thrombosis and Haemostasis (ISTH) suggested that intermediate therapeutic-dose LMWH (1 mg/kg once daily) be considered for prophylaxis in high-risk patients with COVID-19.⁷ Part of the rationale for augmented dosing of thromboprophylaxis was that critically ill patients with COVID-19 may have in situ small vessel thrombosis, such as in the pulmonary vasculature, contributing to respiratory compromise.^8,9

Early in 2021, several clinical trials were designed to provide clarity on the optimal dosing of thromboprophylaxis in patients with COVID-19 in the critical care setting. The INSPIRATION trial of 600 patients admitted to the ICU with COVID-19 showed that intermediate-dose prophylactic anticoagulation (enoxaparin 1 mg/kg daily), compared with standard-dose prophylactic anticoagulation (enoxaparin 40 mg daily), did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days.¹⁰ Results from the multi-platform randomized clinical trial (REMAP-CAP, ACTIV-4a, ATTACC) demonstrated that therapeutic anticoagulation did not offer significant benefit over standard prophylactic dose anticoagulation for the primary outcome of organ support-free days.¹¹ Furthermore, there was an increase in the rate of major bleeding among patients who were randomized to treatment-dose anticoagulation (3.8% vs. 2.3%). While thrombosis may be a key contributor to adverse outcomes in the ICU, other competing risks, such as infection and respiratory failure, are likely to play key roles such that therapeutic-dose antithrombotic therapy does not provide a net clinical benefit.

4. How should antithrombotic therapy be managed when patients transfer between the floor and ICU?

Early in the COVID-19 pandemic, intermediate- and treatment-dose anticoagulation was being utilized in many patients admitted to the ICU. However, since this time, multiple clinical trials have failed to prove benefit with these higher intensity anticoagulation regimens among these patients. Therefore, when patients are admitted to the ICU, standard thromboprophylaxis is generally recommended. Furthermore, the benefit of treatment-dose anticoagulation from the multi-platform randomized trials was largely for the prevention of ICU-level organ support.² Additionally, when a patient's condition improves enough to no longer require ICU-level organ support, they are unlikely to realize benefit from treatment-dose anticoagulation. Therefore, most patients who transfer between the floor and the ICU can be treated with standard thromboprophylaxis. More data have become available that has failed to demonstrate benefit of these regimens compared to standard prophylaxis dosing. Should therapeutic dose or intermediate dose pharmacologic prophylaxis be utilized in COVID-19 patients admitted to the ICU, the doses should be modified to standard doses once the patients is transferred to the floor.

5. Should patients who are hospitalized with COVID-19 be given post-hospital antithrombotic therapy?

Current evidence from retrospective observational studies suggests that the risk of VTE after hospitalization for COVID-19 is low (0.14%-1.55%), which is similar with patients hospitalized for other acute medical illnesses.^11-14 There are currently no validated risk prediction models to identify patients with COVID-19 who may be at higher risk of VTE after hospitalization and prospective studies are ongoing.

Post-discharge prophylactic dose anticoagulation reduces the risk of VTE after hospitalization for acute medical illness, but this is counterbalanced by a 2-fold increase in the risk of major bleeding. Based on current knowledge, the net clinical benefit of thromboprophylaxis after hospitalization for COVID-19 is not well established and its routine use is not recommended.

The eligibility criteria of recent trials evaluating thromboprophylaxis after hospitalization for acute medical illness (e.g., MARINER, MAGELLAN^15,16) can be used to guide decisions regarding the use of thromboprophylaxis for select patients at low risk of bleeding, as recommended in current guidelines from the American Society of Hematology.¹⁷

6. In patients who develop VTE during a hospitalization for COVID-19, how long should anticoagulation be given?

Hospitalization is a well-known risk factor for the development of VTE. At the same time, most patients recover from their hospitalization and there is little ongoing risk of recurrent VTE beyond ~3 months following discharge. Therefore, most patients can be treated with a short course of anticoagulation when they develop a hospital-associated VTE event, even in the setting of COVID-19. This practice aligns with the most recent guideline recommendations from the American Society of Hematology.¹⁸

All patients with COVID-19 who develop hospital-associated VTE should receive therapeutic anticoagulation for a minimum of 3 months unless they are at prohibitively high bleeding risk. Direct oral anticoagulants are recommended as first-line therapy once the patient has been medically stabilized and should be started before hospital discharge. Warfarin can be considered as an alternative strategy in select patients (e.g., severe renal dysfunction, prohibitive cost, drug interactions). Most patients who develop hospital-associated VTE do not require ongoing secondary prevention for VTE following the initial 3-month period. However, in the presence of persistent risk factors (e.g., long-term immobility), longer courses of anticoagulation may be considered.

7. What does standard VTE prophylaxis mean for patients across the weight spectrum?

All patients hospitalized with COVID-19 should receive pharmacologic prophylaxis for VTE unless contraindicated (e.g., active bleeding) Current guidelines recommend standard prophylactic dosing of LMWH or UFH in most patients (those with creatinine clearance >30 mL/min and BMI <40 kg/m²) admitted with COVID-19-related illness in the absence of suspected or confirmed VTE using standard prophylactic dosing (e.g., enoxaparin 40 mg subcutaneously once daily, UFH 5000 units every 8 hours or every 12 hours).¹⁷ In the setting of heparin-induced thrombocytopenia, fondaparinux at a dose of 2.5 mg subcutaneously once daily may be used. The choice of agent will likely be determined by institutional guidelines and formularies.

Obese patients (BMI >40 kg/m²) may benefit from higher doses for VTE prophylaxis. The recommendation in this patient population is to consider increasing the dose of enoxaparin to 40 mg subcutaneously twice daily, provided renal function is normal.

A list of available drugs and doses for VTE prophylaxis is available in the American Society of Hematology (ASH) Guidelines.¹⁷

References

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2. ATTACC Investigators, ACTIV-41 Investigators, REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med 2021;385:790-802.
3. Jimenez D, Garcia-Sanchez A, Rali P, et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: A systematic review and meta-analysis. Chest 2021;159:1182-96.
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10. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: The INSPIRATION randomized clinical trial. JAMA 2021;325:1620-30.
11. Roberts LN, Whyte MB, Georgiou L, et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood 2020;136:1347-50.
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15. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513-23.
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17. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv 2021;5:872-88.
18. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4:4693-738.

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