Rivaroxaban Linked to Increased Bleeding Among Hospitalized COVID-19 Patients

Renato Lopes, MD, PhD

Findings from the ACTION study presented this weekend at the American College of Cardiology (ACC) Annual Scientific Session indicated that rivaroxaban added to in-hospital anticoagulation therapy may not improve clinical outcomes among hospitalized COVID-19 patients with elevated D-dimer levels.

In fact, the investigators noted an increase in bleeding compared with in-hospital prophylactic anticoagulation.

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Led by Renato Lopes, MD, PhD, of Duke University School of Medicine, the investigators conducted a pragmatic, multicenter, open-label phase IV trial to assess the efficacy and safety of rivaroxaban 20 mg as compared with standard prophylactic anticoagulation.

In explaining the motivation behind their study, they noted that “prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation.”

As such, they enrolled and randomized a total of 615 hospitalized patients. All patients were ≥18 years of age and presented with elevated D-dimer levels upon admission. Any patients with an indication for therapeutic anticoagulation at screening, platelets <50,000/mm³, and very high risk of bleeding were excluded from the study.

The enrolled population was then randomized 1:1 to either in-hospital rivaroxaban 20 mg daily or standard of care with in-hospital prophylactic dose anticoagulation through 30 days. Unstable patients in the rivaroxaban cohort first received enoxaparin 1 mg/kg twice daily followed by rivaroxaban through 30 days.

Lopes and team then performed a hierarchical analysis of mortality, duration of hospitalization, and duration of oxygen use through the treatment period. They calculated win ratios by dividing total number of wins by total number of losses.

The primary safety outcomes were major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria.

Results

Of the rivaroxaban population (n = 311), the mean age was the 56.7, with majority (61.7%) being male. Further, 26.7% had diabetes, 48.6% hypertension, and 2.6% heart failure—compared with 22.0%, 49.7% and 1.6%, respectively, in the prophylactic cohort (n = 304). 

Only 7.4% in the rivaroxaban group was considered unstable, defined as having a COVID-related critical illness, suffering from a life-threatening condition, requiring mechanical ventilation, and/or unable to take oral medication.

Overall, rivaroxaban was considered inferior to prophylactic anticoagulation in terms of the primary outcome (Win ratio [WR], 0.86; CI, 0.59-1.22). This trend held up for each component of the primary, showing greater wins for the prophylactic cohort.

Furthermore, the rivaroxaban group had generally greater mortality over the prophylactic group (RR, 1.49; 95% CI, 0.90-2.46).

More patient who received rivaroxaban (8.4%) experienced ISTH major bleeding or clinically relevant non-major bleeding than those who received prophylactic anticoagulation (2.3% [RR, 3.64; 95% CI, 1.61-8.27])

Similarly, a higher proportion of rivaroxaban patients (11.6%) demonstrated any bleeding versus prophylactic patients (3.0% [RR, 3.92; 95% CI, 1.92-8.00]).

“In patients hospitalized with COVID-19 with elevated D-dimer levels, initial in-hospital therapeutic anticoagulation with rivaroxaban 20 mg once daily for stable patients or enoxaparin for unstable patients followed by rivaroxaban through 30 days did not improve clinical outcomes and increased bleeding compared with in-hospital prophylactic anticoagulation,” the team concluded.

The study, “Randomized Clinical Trial To Evaluate A Routine Full Anticoagulation Strategy In Patients With Coronavirus Infection (SARS-CoV-2) Admitted To Hospital: The Coalition ACTION Trial,” was presented at ACC 2021.