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

Abstract

Background SARS-CoV-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 COVID-19 progression. Methods Adults (N=497) symptomatic with mild COVID-19 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 endpoints were safety and progression to moderate or severe disease, per the Gates MRI scale. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. Results The study was terminated after 497 of target 600 participants were enrolled due to a pre-specified interim analysis of the first 200 participants which crossed the futility boundary for the primary efficacy endpoint in the Intent to Treat population. Enrollees were 85% aged < 65 years old, 60% female, 27% Hispanic, Black or other minorities and 69% with ≥2 comorbidities. Rivaroxaban was well-tolerated. Disease progression rates were 46/222 (20.7%) in rivaroxaban vs. 44/222 (19.8%) in placebo groups, with a risk difference of -1.0, 95% CI, -6.4 to 8.4; P = 0.78. Conclusions Our study 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.

Cardiovascular drugs and COVID‐19 clinical outcomes: a systematic review and meta‐analysis of randomized controlled trials

“…Eleven studies 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 55 investigated anticoagulant exposure and included large multicentre or multiplatform trials such as the RAPID COVID COAG trial (465 hospitalized patients), 53 the INSPIRATION trial (562 ICU patients), 44 , 45 the ACTION trial (614 hospitalized patients), 47 the REMAP‐CAP, ACTIV‐4A and ATTACC trials (1098 ICU/critically ill patients 50 and 2231 hospitalized noncritically ill patients 52 ), and the ACTIV‐4B trial (657 outpatients). 48 …”

“…Two of these trials investigated hospitalization and compared to placebo. Rivaroxaban (10 mg once daily for 21 d) 51 or apixaban (2.5 or 5 mg twice daily for 45 d) 48 had no effect on the risk of hospitalization (pooled RR 0.82, 95% CI 0.12 to 5.68, I 2 = 34%, 805 patients, Figure 3 ). The ACTIV‐4B trial 48 also investigated the effect of therapeutic‐dose apixaban (5 mg orally twice daily) vs .…”

“…Disease severity was investigated by 3 trials, 51 , 52 , 53 One of these trials 51 compared rivaroxaban 10 mg once daily for 21 days to a multivitamin supplement provided as the placebo. In this trial and based on the Gates Medical Research Institute scale, 20.7 vs .…”

To Anticoagulate or Not to Anticoagulate in COVID-19: Lessons after 2 Years

“…Use of anticoagulation with DOACs may be useful in patients for a month postdischarge, 69 hospitalization for COVID-19, antiplatelet and antithrombotic therapy has thus far shown no benefit. 54,55 When determining whether or not to initiate anticoagulation in COVID-19 positive patients, it is essential to consider their severity of illness as disease progresses, comorbidities, drug interactions, and any pertinent laboratory values that can help weigh the risks and benefits of whether or not to anticoagulate. However, patients with COVID-19 and a clear indication for anticoagulation (e.g., atrial fibrillation, PE, etc.)…”

“…Because of the very low rate of thrombotic complications in patients not needing hospitalization for COVID-19, antiplatelet and antithrombotic therapy has thus far shown no benefit. 54 55…”