Study cautions against use of oral anticoagulants in admitted COVID patients, ACC 2021

Evidence over last one and half year has suggested that COVID-19 is characterized by a prothrombotic state, with perhaps a much higher thrombotic risk compared with other viral infections. This has led to use of higher-than-standard doses of thromboprophylaxis (rivaroxaban and other drugs) in hospitalized patients, although there is still no consensus about the best approach to anticoagulation. Results from ACTION trial presented this week at ACC 2021 have shown that full dose rivaroxaban given as a therapeutic anticoagulant in hospitalised COVID-19 patients causes a marked increase in bleeding which outweighed any potential modest reduction in thrombotic events versus standard prophylaxis.

The goal of the ACTION trial was to evaluate therapeutic anticoagulation compared with prophylactic anticoagulation among patients admitted with COVID-19 infection. 615 hospitalised COVID infected patients with elevated D-dimer levels at admission were randomised to therapeutic-dose or prophylactic-dose anticoagulation.

Therapeutic anticoagulation involved in-hospital rivaroxaban 20 mg daily for stable patients (94% of the cohort) and in-hospital enoxaparin 1 mg/kg twice daily for those deemed unstable; rivaroxaban was continued after discharge through 30 days, regardless of the length of hospitalization. The control group received standard prophylactic anticoagulation in the hospital.

About three-quarters of the patients needed some type of oxygen support, and 83% were treated with systemic corticosteroids. Roughly nine out of 10 were being treated with anticoagulation (mostly standard thromboprophylaxis) before randomization. About one-quarter (27%) had a D-dimer level at least three times above the upper limit of normal.

The primary outcome was a hierarchical analysis of mortality, duration of hospitalization, and duration of oxygen use through 30 days, assessed using the unmatched win ratio method.

In this analysis, full-dose anticoagulation won in 34.8% of comparisons versus 41.3% in the control arm, for a nonsignificant win ratio of 0.86 (95% CI 0.59-1.22). That means therapeutic anticoagulation tended to fare worse, and that was seen for each of the composite outcome's individual components. Findings were consistent across subgroups.

Risk of a secondary composite outcome of thromboembolic events (venous thromboembolism, MI, stroke, systemic embolism, and major adverse events of the extremities) was non significantly lower with full-dose anticoagulation (RR 0.75; 95% CI 0.45-1.26), while all-cause mortality was nonsignificantly higher (RR 1.49; 95% CI 0.90-2.46).

ISTH major bleeding, ISTH clinically relevant non major bleeding, and any bleeding were all increased in the therapeutic-dose group.

Among patients admitted with COVID-19 infection with elevated D-dimer, therapeutic anticoagulation was not superior to prophylactic anticoagulation. Rivaroxaban for stable patients and enoxaparin for unstable patients did not improve clinical outcomes; however, major bleeding was increased.

ACTION was unique in that it tested therapy primarily with a direct oral anticoagulant in the therapeutic-dose arm and extended treatment through the postdischarge period for up to 30 days. Most previous trials, including the multiplatform effort, used heparin and confined treatment to the hospital setting.

"The choice of agent could be important", Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC), explained, "because heparin has been shown to not only have anticoagulant effects but also anti-inflammatory and possibly direct antiviral effects, which may not be the case for an oral factor Xa inhibitor like rivaroxaban".

"Therefore, that gives the answer that routine anticoagulation with this oral agent for 30 days in COVID patients who are hospitalized should not be done, as we are seeing has been done in an off-label fashion by many sites in many countries.", added Lopes.

The best approach for anticoagulating hospitalized COVID-19 patients is still unclear, Lopes said. But the ACTION results indicate that "we clearly should not use DOACs in therapeutic doses. Based on our study, the classic prophylactic heparin should still be used."

• Source: Lopes RD. Anticoagulation in patients hospitalized with COVID-19: the Anticoagulation Coronavirus (ACTION) trial. Presented at: ACC 2021. May 16, 2021.