Review of Anticoagulation in Patients With COVID-19: Key Points

Authors:
Farkouh ME, Stone GW, Lala A, et al.
Citation:
Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week. J Am Coll Cardiol 2022;79:917-928.

The following are key points to remember from this review on anticoagulation in patients with coronavirus disease 2019 (COVID-19):

  1. COVID-19 has led to unprecedented morbidity and mortality with >200 million cases and 4 million deaths worldwide. Apart from acute respiratory distress syndrome, COVID-19 is associated with thromboembolic disease.
  2. Viral entry through the endothelium may cause inflammation and vascular injury. Mononuclear cell activation can also trigger cytokine release and cytokine storm. Collectively, these lead to a prothrombotic state for patients with COVID-19. Other mechanisms may also contribute, including complement activation and anti-phospholipid antibodies.
  3. COVID-19 coagulopathy is categorized by laboratory abnormalities including increased levels of fibrinogen and D-dimer, mild prolongation of prothrombin time or activated partial thromboplastin time, and mild thrombocytopenia. Patients admitted with COVID-19 who have elevated D-dimer or troponin levels are associated with worse outcomes, including mortality.
  4. The incidence of venous thromboembolism in patients hospitalized with COVID-19 was 17% in a meta-analysis of 49 studies. The rate was higher in patients with critical illness (27.9%) as compared to those who were not critically ill (7.1%).
  5. Clinicians and researchers have explored the role of antithrombotic therapy to prevent COVID-19–associated thromboembolism. This includes use of standard prophylactic-dose anticoagulation, intermediate-dose anticoagulation, and therapeutic-dose anticoagulation given for prophylactic purposes.
  6. Several large observational studies have suggested that prophylactic-dose enoxaparin was associated with lower rates of intubation and death. However, the role of higher-dose prophylactic anticoagulation in preventing poor outcomes is not clear from observational studies.
  7. Two large trials have explored the use of anticoagulation outside of the hospital setting for patients with COVID-19. The MICHELLE trial compared rivaroxaban 10 mg daily for 35 days after hospital discharge with placebo and found a 67% relative risk reduction in their primary outcome without an increased risk of bleeding. Conversely, the ACTIV-4B study compared apixaban versus placebo in ambulatory patients with mild COVID-19 but was ended early due to a very low rate of thromboembolic events that did not meaningfully differ between treatment arms.
  8. Several trials have compared intermediate- or treatment-dose anticoagulation with standard prophylactic-dose anticoagulation in hospitalized patients with COVID-19. The multiplatform trial included 2,219 patients hospitalized without critical illness and found an increase in the number of organ support-free days with treatment-dose anticoagulation. In a concurrent trial of 1,098 critically ill patients in the multi-platform trial, treatment-dose anticoagulation did not increase the number of organ support-free days as compared to standard prophylaxis.
  9. In the HEP-COVID trial of 257 patients hospitalized with COVID-19 who required oxygen support and other risk factors, therapeutic-dose enoxaparin led to lower rates of thromboembolism and death as compared to standard-dose thromboprophylaxis. Similarly, in the RAPID trial of 465 patients with moderately ill COVID-19 and elevated D-dimer, therapeutic-dose heparin led to numerically (but not statistically) lower rates of death, intensive care unit (ICU) admission, and mechanical ventilation as compared to standard prophylactic-dose heparin.
  10. The authors are conducting a large-scale, prospective, multicenter, open-label randomized clinical trial of patients hospitalized with COVID-19 who will be randomized to receive prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary effectiveness outcome will be a composite of all-cause mortality, requirement for intensive care, systemic thromboembolism, or ischemic stroke within 30 days.

Clinical Topics: Anticoagulation Management, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism

Keywords: Anticoagulants, Brain Ischemia, COVID-19, Critical Illness, Cytokines, Endothelium, Enoxaparin, Fibrinogen, Fibrinolytic Agents, Intubation, Ischemic Stroke, Partial Thromboplastin Time, Prothrombin Time, Respiration, Artificial, Risk Factors, Rivaroxaban, Secondary Prevention, Stroke, Thrombocytopenia, Troponin, Vascular Diseases, Venous Thromboembolism


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