How are antithrombotics being used in the treatment of COVID-19?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Answer

COVID-19 is a systemic illness that adversely affects various organ systems. A review of COVID-19 hypercoagulopathy aptly describes both microangiopathy and local thrombus formation, and a systemic coagulation defect leading to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism, in critically ill patients. [299]  While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. [300]   

Several retrospective cohort studies have described use of therapeutic and prophylactic anticoagulant doses in critically ill hospitalized patients with COVID-19. No difference in 28-day mortality was observed for 46 patients empirically treated with therapeutic anticoagulant doses compared with 95 patients who received standard DVT prophylaxis doses, including those with D-dimer levels greater than 2 mcg/mL. In this study, day 0 was the day of intubation, therefore, they did not evaluate all patients who received empiric therapeutic anticoagulation at the time of diagnosis to see if progression to intubation was improved. [301]  

In contrast to the above findings, a retrospective cohort study showed a median 21 day survival for patients requiring mechanical ventilation who received therapeutic anticoagulation compared with 9 days for those who received DVT prophylaxis. [302]  

NIH trial

Current guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. As of September 2020, the NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient, inpatient, and convalescent settings. 

The 3 adaptive clinical trials within ACTIV-4 include preventing, treating, and addressing COVID-19-associated coagulopathy (CAC). Additionally, a goal to understand the effects of CAC across patient populations – inpatient, outpatient, and convalescent. 

In December 2020, the ACTIV-4 trial enrolling critically ill patients with COVID-19 requiring intensive care unit supports was paused owing to a potential for harm in this subgroup. Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question.

Purpose and initial drugs included in ACTIV-4 are: 

Outpatient trial 

Investigates whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed patients with COVID-19 who do not require hospital admission. Participants will be randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. 

Inpatient trial 

Investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized patients with COVID-19. Varying doses of unfractionated heparin or LMWH will be evaluated on ability to prevent or reduce blood clot formation.

Convalescent trial

Investigates safety and efficacy anticoagulants and/or antiplatelets administered to patients who have been discharged from the hospital or are convalescing in reducing thrombotic complications (eg, MI, stroke, DVT, PE, death). Patients will be assessed for these complications within 45 days of being hospitalized for moderate and severe COVID-19.

Investigational antithrombotics 

AB201

AB201 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor (TF)/factor VIIa complex and has anticoagulant, anti-inflammatory, and potential antiviral properties. TF plays a central role in inflammatory response to viral infections. Phase 2b/3 clinical trial (ASPEN-COVID-19) started in December 2020 in hospitalized patients with COVID-19 at the University of Colorado. The phase 2b trial randomizes 2 AB201 dosage regimens compared with heparin. The primary endpoint is change in D-dimer level from baseline to Day 8. The phase 3 trial design is contingent upon phase 2b results. [303]  


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