Therapeutic rivaroxaban for stable COVID-19: More risk than benefit

In hospitalized COVID-19 patients with elevated D-dimer levels who were under stable condition, initial in-hospital anticoagulation using a therapeutic dose of rivaroxaban 20 mg did not improve clinical outcomes compared with standard prophylactic anticoagulation, according to the ACTION* trial presented at ACC.21 Meeting. 

Not only that, the therapeutic strategy was also associated with increased bleeding rates compared with prophylactic anticoagulation.

“[For now,] we can say that based on ACTION, that we should not be using rivaroxaban at a dose of 20 mg once daily for thrombotic prophylaxis in stable COVID-19 patients who do not have another indication for anticoagulation such as DVT or PE**,” said presenting author Professor Renato Lopes from Duke University Medical Center, Durham, North Carolina, US.

Noting that COVID-19 has been associated with thromboembolic complications, Lopes pointed out that “recent data suggest that anticoagulation might improve clinical outcomes in COVID-19, but the optimal strategy, including for which patients, type of anticoagulant, dose, and duration remains unknown.”

To help address this, the ACTION trial randomized 615 patients (mean age 57 years) hospitalized with COVID-19 and elevated D-dimer levels to therapeutic anticoagulation or standard-of-care prophylactic anticoagulation, which typically comprised low-dose enoxaparin 40 mg once daily. [ACC.21, session 409-14]

For the therapeutic strategy, patients were given rivaroxaban 20 mg daily for those in stable condition, otherwise they received enoxaparin (1 mg/kg) twice daily for those who were unstable***. All patients were given rivaroxaban 20 mg through to 30 days after discharge from hospital.

“An oral drug would be very attractive in moderately ill patients as there is a hypothesis that the inflammation and prothrombotic state continues after hospital discharge,” Lopes explained.

The primary outcome entailed a hierarchical analysis of mortality, hospitalization length, and duration of oxygen use within 30 days, assessed using the “unmatched win ratio” method.

As Lopes explained, this method compared every patient in one treatment group with each patient in the other group for all individual components of the primary outcome^#. The win ratio is then computed by dividing the number of wins in the treatment group by that in the control group. If the ratio is greater than 1, this indicates that therapeutic treatment is beneficial, and vice versa.

For the composite primary outcome, there were 34.8 percent wins in the therapeutic anticoagulation group compared with 41.3 percent in the prophylactic strategy group. This translates to a win ratio of 0.86 (95 percent confidence interval [CI], 0.59–1.22) — indicating that therapeutic anticoagulation trended towards worse outcomes than the prophylactic strategy.

Similar findings were observed for each component of the composite primary endpoint, in favour of the prophylactic strategy.

The therapeutic anticoagulation was associated with numerically fewer thromboembolic events (relative risk [RR], 0.75, 95 percent CI, 0.45–1.26), but numerically greater mortality rates at 30 days (RR, 1.49, 95 percent CI, 0.90–2.46).

The difference in major or clinically relevant bleeding, however, was significant — occurring more frequently in the therapeutic group than the prophylactic group (8.4 percent vs 2.3 percent; RR, 3.64).

When asked about what the findings showed on strategies for stable and unstable patients, Lopes said the primary objective was to study therapeutic dose of rivaroxaban, but they also wanted to allow the use of heparin for those in unstable condition.

“It turns out that the vast majority of patients were stable, and we really didn’t have enough unstable patients to answer that question,” he stated, noting that >90 percent of the study population was in stable condition. 

“Our trial should be focused primarily on stable patients on an oral drug, and that’s what this trial adds to the field,” he added.

 

 

*ACTION: The AntiCoagulaTIon cOroNavirus trial

** DVT: Deep vein thrombosis; PE: pulmonary embolism

***unstable patients: defined as those with COVID-19-related critical illness, suffered from a life-threatening condition, required mechanical ventilation or vasopressors, and/or were unable to take oral medication