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CHICAGO -- For outpatient COVID-19, prophylactic anticoagulation with rivaroxaban (Xarelto) did not improve outcomes in elevated thrombotic risk patients, the PREVENT trial showed.

Compared with placebo, giving the direct-acting oral anticoagulant (DOAC) for 35 days in non-hospitalized patients with symptomatic COVID-19 who had at least one risk factor for thrombosis didn't reduce thromboembolic events or all-cause hospitalization or death in the primary intent-to-treat analysis.

The rate was 3.4% with rivaroxaban versus 3.0% with placebo, based on 22 and 19 events, respectively, among the more than 1,200 trial participants (HR 1.16, 95% CI 0.63-2.15), Gregory Piazza, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, reported at the American Heart Association meeting in Chicago.

"With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in non-hospitalized patients with symptomatic COVID-19," he told attendees, noting that the trial was stopped early at about one-third of planned enrollment due to waning pandemic numbers and severity.

That's a message that squares with other anticoagulant trials in outpatient care for COVID-19, noted Renato Lopes MD, PhD, of Duke Clinical Research Institute in Durham, North Carolina, who served as study discussant at the late-breaking clinical trial session.

Meta-analysis with the almost universally negative trials that have emerged thus far suggested no benefit (OR 0.93, 95% CI 0.70-1.23) for the primary endpoint, albeit diverse across trials, or for mortality (OR 0.64, 95% CI 0.25-1.61).

"The results of this trial, in the light of the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19," Lopes said.

PREVENT randomized 1,284 symptomatic patients with a positive laboratory antigen or PCR test for SARS-CoV-2 recruited through integrated health networks in the U.S. to once daily rivaroxaban (10 mg) or placebo, stratified by number of days from positive test to randomization. Participants were followed for outcomes without any lab or office visits, utilizing electronic case report forms and electronic medical records collected only through telehealth or home visits.

Patients were not enrolled if the initial care plan included hospitalization. Enrollment criteria also selected for a higher thrombotic risk group by requiring at least one of the following risk factors:

• Age ≥ 60 years
• Prior history of venous thromboembolism (VTE), thrombophilia, coronary or peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes requiring medication, or heart failure
• BMI ≥35 kg/m²
• Elevated D-dimer

The most common risk factors were older age, obesity, and diabetes. About a quarter of participants had at least two risk factors. Mean age was 56 years; nearly 30% of participants were non-white and about 60% were female.

The primary efficacy endpoint was first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

For that endpoint, the modified intended-to-treat analysis yielded a shift in directionality compared with the intent-to-treat analysis, albeit not statistically significant, with a rate of 2.0% with rivaroxaban versus 2.7% with placebo (HR 0.75, 95% CI 0.35-1.58). Piazza chalked that up to more hospitalizations before receiving study drug in the rivaroxaban group, while Lopes suggested the difference deserves further investigation.

The first major secondary outcome of the composite of symptomatic VTE, arterial thrombotic events, and all-cause mortality likewise showed no significant difference. A post hoc exploratory analysis suggested fewer combined symptomatic VTE and arterial thrombotic events, particularly ischemic stroke, but Lopes urged caution with such non-prespecified analyses.

In terms of safety, there were no fatal or critical site bleeds in the trial and a "significant but modest" increase in nonmajor clinically relevant bleeds with rivaroxaban versus placebo.

"We've seen explosion of observational data in the beginning of pandemic suggesting that patients with COVID-19 might benefit from a more intense form of anticoagulation; however, we also learned to be cautious about observational data when discussing treatment effects," Lopes noted.

That the findings were the opposite of what might have been guessed initially in the pandemic, he said, was "illustrating one more time why we need randomized trials, since they are the only reliable way to guide medical decisions in clinical practice."

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