ACTION: Rivaroxaban-based anticoagulation strategy fails to improve outcomes in COVID-19
A rivaroxaban-based anticoagulation strategy did not improve outcomes and increased bleeding in patients hospitalized with COVID-19 compared with standard hospital prophylaxis, according to data from the ACTION trial.
Renato D. Lopes, MD, MHS, PhD, professor of medicine at Duke University School of Medicine and member of the Duke Clinical Research Institute, and colleagues conducted the ACTION trial to determine whether a therapeutic anticoagulation strategy based on rivaroxaban (Xarelto, Janssen/Bayer) improved outcomes in patients with elevated D-dimer levels hospitalized with COVID-19 compared with a prophylactic anticoagulation strategy. The findings were presented at the American College of Cardiology Scientific Session.
“Venous and arterial thrombotic events have been reported in patients with COVID-19,” Lopes said during the presentation. “We also know that elevated biomarkers of thrombosis, such as D-dimer, are associated with disease progression and higher mortality. Recent data have suggested that anticoagulation might improve clinical outcomes in COVID-19, but the optimal strategy, including which patients, type of anticoagulant, dose and duration remains unknown.”
The patient population was hospitalized with a confirmed diagnosis of COVID-19, had elevated D-dimer levels and had symptoms related to hospitalization for 14 days or less. Patients who had an indication for therapeutic anticoagulation at screening and those at very high risk for bleeding were among those excluded, Lopes said during the presentation.
The study included 615 patients. In the therapeutic group, mean age was 57 years, 62% were men, 2.3% had chronic lung disease, 26.7% had diabetes and 18% were current or former smokers. In the prophylactic group, mean age was 57 years, 58% were men, 3.9% had chronic lung disease, 22% had diabetes and 20.7% were current or former smokers. More than 80% of patients in both groups had moderate COVID-19.
Patients assigned therapeutic anticoagulation were treated based on whether or not they were stable, Lopes said. During hospital stay, those who were stable were given rivaroxaban 20 mg daily and those who were unstable were given enoxaparin 1 mg/kg twice daily. For both, that was followed by rivaroxaban treatment for 30 days, regardless of duration of hospitalization. Patients assigned prophylactic anticoagulation received standard of care in-hospital prophylactic-dose anticoagulation.
The primary outcome was a hierarchical analysis of mortality, duration of hospitalization and duration of oxygen use at 30 days, expressed as a win ratio. There was no difference between the groups in the primary outcome (wins in therapeutic group, 34.8%; wins in prophylactic group, 41.3%; ties, 23.9%; win ratio = 0.86; 95% CI, 0.59-1.22), and the win percentages for the individual components were numerically lower in the therapeutic group, Lopes said.
He said there was also no difference between the groups at 30 days in the composite thromboembolic outcome, defined as venous thromboembolism, MI, stroke, systemic embolism and major events of the extremities (RR = 0.75; 95% CI, 0.45-1.26), MI (RR = 0.91; 95% CI, 0.44-1.91), VTE (RR = 0.6; 95% CI, 0.29-1.25), deep vein thrombosis (RR = 0.98; 95% CI, 0.29-3.35), pulmonary embolism (RR = 0.53; 95% CI, 0.21-1.31), all-cause death (RR = 1.49; 95% CI, 0.9-2.46) and the composite thromboembolic plus all-cause death (RR = 1.03; 95% CI, 0.7-1.5).
However, Lopes said, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant nonmajor bleeding was higher in the therapeutic group at 30 days (RR = 3.64; 95% CI, 1.61-8.27), driven primarily by clinically relevant nonmajor bleeding (RR = 5.23; 95% CI, 1.54-17.77). There was no difference in net clinical benefit, defined as the composite thromboembolic outcome, all-cause death and ISTH major or clinically relevant nonmajor bleeding (RR = 1.17; 95% CI, 0.82-1.66).
Perspective
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This was a fascinating study. We know that patients with COVID-19 have thromboembolic complications, including DVT and PE; however, we also know that they have bleeding complications as well.
This study analyzed therapeutic anticoagulation therapy vs. standard of care prophylactic anticoagulation among hospitalized patients with COVID-19 and elevated D-dimer levels without established thrombotic complication to determine if therapeutic anticoagulation could safely prevent thrombotic events. Stable and unstable patients were randomly assigned to therapeutic anticoagulation in house (rivaroxaban for stable patients and enoxaparin for unstable patients) followed by rivaroxaban for 30 days in the therapeutic anticoagulation arm and standard of care in hospital prophylaxis in the other arm.
Considering thrombotic complications alone, these were less common in the therapeutic anticoagulation arm than in the prophylactic anticoagulation arm, most notably with the reduction of PE. However, all-cause mortality was higher in the therapeutic anticoagulation arm, with significantly higher rates of bleeding.
As with any conversation in cardiology surrounding the prevention of thrombosis, we cannot ignore the risk for increased bleeding and associated morbidity as a consequence of our interventions. When we look at both components, the increase in bleeding does not justify the use of therapeutic anticoagulation for COVID-19 patients with elevated D-dimer levels who have not demonstrated thrombotic complications.
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Lopes RD, et al. Featured Clinical Research II. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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