Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial

Abstract

Background: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation.

Design: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria.

Summary: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.

Trial registration: ClinicalTrials.gov NCT04394377.

Figure 1

Characteristics of COVID-19 associated coagulopathy. Legend: The pathogenesis of COVID-19- associated coagulopathy (CAC) is multifactorial and continues to be determined. CAC with suppressed fibrinolysis and activated coagulation resembles sepsis-induced coagulopathy and disseminated intravascular coagulation. The prothrombotic state due to cytokine storm and proinflammatory cytokines have some aspects of hemophagocytic syndrome and hemophagocytic lymphohistiocytosis. The activation of complement system and von Willebrand factor partially overlap with antiphospholipid syndrome, and thrombotic microangiopathy but CAC has unique features that may be defined as a new category of coagulopathy.

Figure 2

Design of the ACTION trial (study flowchart). Legend: A) 8-point ordinal COVID-19 outcome: death; invasive mechanical ventilation and support for another organ dysfunction; invasive mechanical ventilation alone; noninvasive ventilation/high-flow oxygen; hospitalized on supplemental oxygen; hospitalized not requiring supplemental oxygen; not hospitalized, limitation on activities and/or requiring home oxygen; not hospitalized, no limitations on activities. B) Disease progression: Mild defined as cases without criteria to be classified within the “moderate” or “severe” groups; Moderate: Oxygen saturation <94% or pulmonary infiltrates> 50% or ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300; Severe: Respiratory failure or hemodynamic instability or multiple organ dysfunction.