Therapeutic-dose anticoagulation may improve COVID-19 outcomes for noncritical inpatients
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NEW ORLEANS — A therapeutic vs. prophylactic dose of anticoagulation therapy did not significantly improve outcomes for noncritically ill patients hospitalized with COVID-19, though fewer therapeutic dose-treated patients died at 30 days.
The FREEDOM COVID trial ultimately did not meet its primary endpoint — a 30-day composite of all-cause mortality, ICU admission, systemic thromboembolism or ischemic stroke, Valentin Fuster, MD, PhD, director of Mount Sinai Heart, physician in chief of The Mount Sinai Hospital, said during a late-breaking clinical trials presentation at the American College of Cardiology Scientific Session. However, evolving circumstances of the COVID-19 pandemic, including new variants and treatment protocols, likely had an impact on whether therapeutic anticoagulation could reduce the combined endpoint.
“Microvascular and macrovascular thrombosis are common in COVID-19; however, whether a therapeutic dose of anticoagulation improves the prognosis is actually uncertain,” Fuster said during the presentation. “Previous data with more than 2,000 patients with COVID-19 not requiring critical care or organ support indicated that a therapeutic dose of anticoagulation suggested superiority over usual care of thromboprophylaxis, with the primary outcome being days free from organ support.”
Signal for mortality, intubation benefit
Fuster and colleagues analyzed data from 3,398 patients hospitalized with COVID-19 who did not require ICU treatment between August 2020 and September 2022 in 76 centers across 10 countries. Researchers randomly assigned patients to one of three groups: prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (Eliquis, Bristol Myers Squibb/Pfizer; n = 1,121). The primary outcome was the 30-day composite of all-cause mortality, ICU admission, systemic thromboembolism or ischemic stroke. Outcomes were assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group.
The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups, for an HR of 0.85 that did not reach statistical significance (95% CI, 0.69-1.04; P = .11).
However, all-cause mortality occurred in 7% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR = 0.7; 95% CI 0.52-0.93; P = .01), and intubation was required in 8.4% of the prophylactic-dose group and 6.4% of the therapeutic-dose group (HR = 0.75; 95% CI, 0.58-0.98; P = 03).
“When you look at mortality, and also intubation, the results are pretty striking,” Fuster said during a discussion after the presentation.
Results were similar in the two therapeutic-dose groups. There was no major bleeding observed across the three groups.
Challenges impacted findings
As with other trials assessing treatments for inpatients with COVID-19, researchers encountered several challenges which may have ultimately affected the findings, Fuster said during a discussion after the presentation. Event rates fell as the study progressed, treatment protocols changed and new COVID-19 variants emerged, which ultimately led to the trial being underpowered, Fuster said.
“We believe that part of the reason the outcomes of this study are more limited is because of the variants of COVID,” Fuster said. “I think, if we would have started this study 6 months [earlier], the results in terms of the primary endpoint would be different. Theoretically speaking, this is what I think.”
Additionally, patients with COVID-19 enrolled from sites in India were not as ill when hospitalized as patients enrolled in the United States, Fuster said, adding that the results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies.
“[Results] depend very much on what patients are admitted into the hospitals,” Fuster said. “We found that outcomes in India were very low, and this really diluted the study. This is the reality.”
Fuster said additional analyses are needed to examine whether the use of adjunctive therapies such as steroids, remdesivir and antiplatelet agents modulate the results.
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These data give us a verification of the 2021 study in The New England Journal of Medicine (The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. N Engl J Med. 2021;doi:10.1056/NEJMoa2105911), when researchers assessed a therapeutic dose of heparin in noncritically ill patients with COVID-19. Still, there was an uncertainty — we could not have only one study demonstrating the effects of anticoagulation treatment.
With the FREEDOM COVID findings, I feel confident that I can give a full-dose anticoagulation treatment to my patients with COVID-19, and they will be equally protected from major thromboembolic events with enoxaparin and apixaban.
Our of our main questions, because we were working in the unknown, was significant bleeding. Now, for the first time, we see no bleeding concerns with these patients.
There was no significant difference observed in adverse outcomes at 30 days. However, we did see a significant reduction in intubation and death.
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Fuster V, et al. Late-Breaking Clinical Trials V. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
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