Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression.

Methods: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method.

Results: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78).

Conclusions: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

Keywords: COVID-19; SARS-CoV-2; infection; pneumonia; rivaroxaban.

Figure 1.

Participant flow diagram. COVID-19, coronavirus 2019; IP, investigational product/study drug; ITT, intention to treat; mITT, modified intention to treat; PP, per protocol.

Figure 2.

Proportion of participants within each Gates Medical Research Institute scale at days 1, 8, 14, 21, and 28 (modified intention-to-treat [mITT] population). Gates MRI ordinal scale: 1 = asymptomatic/symptoms similar to pre-coronavirus disease 2019 (COVID-19) status, 2 = mild, 3 = moderate or severe, 4 = critically ill, 5 = critically ill with invasive mechanical ventilation or extrapulmonary complication, 6 = critically ill with extracorporeal membrane oxygenation, and 7 = death. NA = Participants in mITT population who had no available Gates MRI scale value at post-baseline assessments.

Figure 3.

Proportion of participants within each WHO scale at days 1, 8, 14, 21, and 28 (modified intention-to-treat [mITT] population). WHO ordinal scale: 0 = uninfected; 1 = asymptomatic, viral RNA detected; 2 = symptomatic, independent; 3 = symptomatic, assistance needed; 4 = hospitalized, no oxygen therapy; 5 = hospitalized, oxygen by mask or nasal prongs; 6 = hospitalized, oxygen by NIV or high flow; 7 = intubation and mechanical ventilation, pO₂/FiO₂ ≥150 or SpO₂/FiO₂ ≥200; 8 = mechanical ventilation pO₂/FiO₂ <150 (SpO₂/FiO₂ <200) or vasopressors; 9 = mechanical ventilation pO₂/FiO₂ <150 and vasopressors, dialysis, or extracorporeal membrane oxygenation; and 10 = death. NA, participants in mITT Population who have no available WHO scale value at post-baseline assessments; NIV, noninvasive ventilation; WHO, World Health Organization.