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No Benefit to Therapeutic Oral Anticoagulation in COVID-19 Hospitalizations

NEW YORK (Reuters Health) – In patients hospitalized with COVID-19 and elevated D-dimer concentrations, therapeutic dosing of oral anticoagulants did not improve outcomes compared with prophylactic anticoagulation, and it also increased bleeding, a large trial found.

“This is the first published randomized trial testing therapeutic oral anticoagulation in COVID-19. So, I do believe it will directly influence clinical practice,” Dr. Renato Lopes of Duke University Medical Center in Durham, North Carolina told Reuters Health by email.

“Based on all prior observational data in this field, we were expecting a therapeutic anticoagulation strategy to work in COVID-19 patients and impact mortality and length of hospital stay,” he said. “However,…our trial showed a very modest and non-significant reduction in thromboembolic events (without any effect in mortality), but a significant and marked increased in bleeding events when compared with the traditional prophylactic anticoagulation strategy.”

“Direct oral anticoagulants like rivaroxaban have been widely used for COVID-19 patients without any good evidence – based on pure ‘guessing and extrapolation of results from non-COVID-19 trials,'” he noted. “Our study provides high-quality evidence in a field where this is desperately needed and cautions about the use of direct oral anticoagulants in therapeutic doses for these patients in the absence of the formal indication for anticoagulation.”

As reported in The Lancet, Dr. Lopes and colleagues conducted a pragmatic, open-label randomized, controlled trial at 31 sites in Brazil.

Six hundred and fifteen patients (mean age, 56; about 60% men) hospitalized with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomization, received either therapeutic or prophylactic anticoagulation. Ninety-four percent were clinically stable.

Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0.3-0.7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30.

Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin.

The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalization, or duration of supplemental oxygen to day 30, analyzed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group).

The primary safety outcome was major or clinically relevant non-major bleeding through 30 days.

No significant between-group differences were seen in the primary efficacy outcome: 34.8% wins in the therapeutic group and 41.3% in the prophylactic group. Results were consistent in stable and unstable patients.

The primary safety outcome occurred in 8% of patients assigned therapeutic anticoagulation and 2% on prophylactic anticoagulation (relative risk. 3.64).

Allergic reactions to the study medication occurred in 1% of patients in both groups.

The authors conclude, “Use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.”

Dr. Lopes said, “We still need to wait for publication of trials testing therapeutic anticoagulation with heparin so we can then evaluate potential differences in results and hypothesize potential reasons for differences in results.”

Dr. Avraham Cooper, a pulmonologist and intensive care physician at The Ohio State University Wexner Medical Center in Columbus, commented on the study in an email to Reuters Health, “These results align with our current practice, even in the intensive care unit. While the effects of empiric therapeutic anticoagulation in the critically ill patient population with COVID-19 are not as well-studied, there is no high-quality evidence that therapeutic anticoagulation is superior to prophylactic doses when blood clots are not present.”

“Therefore,” he said, “we reserve therapeutic anticoagulation for patients with confirmed or highly suspected DVTs or pulmonary emboli.”

That said, he noted, “Most of the patients enrolled in the study were not critically ill or in the intensive care unit. Patients who are critically ill tend to have even higher rates of blood clots forming. This study did not adequately examine that population.”

Separately, Brigham and Women’s Hospital announced on June 21 that the NIH ACTIV-4B COVID-19 outpatient thrombosis prevention trial was terminated early because data collected to date through a randomized, placebo-controlled trial suggested a very low rate of thrombotic complications in the study group. Trial leadership concluded that rates of major cardio-pulmonary complications in the mildly symptomatic group who were sick at home for at least a week did not justify antithrombotic therapy.

The Brazilian study was funded by the Coalition COVID-19 Brazil and Bayer SA. Numerous coauthors have received funds from Bayer.

SOURCE: and The Lancet, online June 4, 2021.

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