Could Extended Anticoagulation Help After COVID-19?

After hospitalization for medical illness, an extended course of low-dose anticoagulation reduced arterial and venous thromboembolic events combined, secondary analysis of a randomized trial suggested — a finding with implications for post-COVID care.

Taking 10-mg rivaroxaban (Xarelto) for 45 days post-discharge reduced fatal and major events by a relative 28% in patients with additional risk factors for venous thromboembolism (VTE) in a prespecified secondary analysis of the MARINER trial.

Symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, or cardiovascular death occurred in 1.28% of rivaroxaban-treated patients versus 1.77% on placebo (hazard ratio 0.72, 95% CI 0.52-1.00), reported Alex Spyropoulos, MD, of the Feinstein Institute for Medical Research and Northwell Health at Lenox Hill Hospital in New York City, in the Journal of the American College of Cardiology.

While these findings have to be considered exploratory due to MARINER having failed in its primary endpoint of lowering risk of symptomatic VTE and death due to VTE compared with placebo, the researchers noted that the carefully selected patient population appeared to gain net clinical benefit when considering bleeding risk.

Major bleeding occurred in 0.27% versus 0.18% of patients given rivaroxaban and placebo, respectively (HR 1.44, P=0.398) — a 0.09% absolute increase compared with the 0.49% absolute risk reduction for the efficacy endpoint.

“This is very relevant in the COVID era, where we’re seeing increased risk of arterial as well as venous thromboembolic events,” Spyropoulos told MedPage Today.

“The data that were just published, in my view, really bring home the fact that COVID-19 patients are high risk almost by definition from a thrombotic point of view,” he added. “In our institution at Northwell, all COVID patients that meet high-risk criteria, which are the vast majority — they’re over 60 and they have high D-dimers — all of them would get extended prophylaxis.”

A consensus group of the International Society on Thrombosis and Haemostasis and other professional societies recommended risk stratifying for VTE prophylaxis in all hospitalized COVID-19 patients, and advocated up to 45 days of prophylaxis with low-molecular weight heparin or direct oral anticoagulants (DOACs) as reasonable after discharge, with individualized risk stratification for thrombotic and hemorrhagic risk.

Rivaroxaban was approved for post-discharge VTE prophylaxis for up to 39 days in acute medical illness in 2019, based on MARINER and the more favorable MAGELLAN trial, which showed rivaroxaban to be on par with enoxaparin (Lovenox) for combined asymptomatic, symptomatic, or fatal VTE at 10 days and superior to it by 35 days, although with more bleeding.

However, uptake for medical patients overall has been poor, whereas “the surgical community rapidly adopted extended-duration VTE prophylaxis as the norm, not the exception” based on trial evidence, noted Samuel Z. Goldhaber, MD, of Brigham and Women’s Hospital in Boston, in an accompanying editorial.

Rivaroxaban — and even more so the other, less popular DOAC approved for post-discharge prophylaxis, betrixaban (Bevyxxa) — faces an uphill battle, he wrote, citing three factors:

• “FDA checklist of major bleeding exclusions is too complicated to deal with”
• “1% absolute VTE reduction is not enough to spawn ‘local champions’ at U.S. hospitals”
• “Hospital budgets strained post-COVID-19”

Even so, the risk of clotting seen with COVID-19 has led a number of centers to change their practice in favor of post-discharge prophylaxis for selected patients.

“At this point, every one agrees COVID-19 is a prothrombotic state. What we don’t know yet is what is the optimal way to mitigate risk in the in-patient setting and post-discharge,” said Behnood Bikdeli, MD, of NewYork-Presbyterian Hospital/Columbia University Irving Medical Center in New York City, who was an author on the consensus guidance.

There are several trials underway to answer questions of dosing and the best type of antithrombotic to use in COVID-19 patients, he noted in an interview. However, the pandemic and its response moved so quickly that it may be months before sufficient patients are enrolled to provide the answer, he said. “Investigators were quick to design trials, but the disease epidemiology curve got ahead of us.”