Full-Dose Anticoagulation Again Favored for COVID Admissions

NEW ORLEANS -- Full-dose anticoagulation failed to improve overall hard outcomes for non-intensive care unit (ICU) admissions for COVID-19 in the FREEDOM trial, but there was a signal for benefit among U.S. patients and for mortality overall.

A therapeutic dose of either enoxaparin (Lovenox) or apixaban (Eliquis) reduced composite 30-day risk of all-cause mortality, progression to ICU care, systemic thromboembolism, or ischemic stroke by a relative 15% compared with prophylactic dosing of enoxaparin, which was not statistically significant (11.3% vs 13.2%, HR 0.85, 95% CI 0.69-1.04, P=0.11).

The higher dose, though, reduced all-cause mortality by a relative 30% versus prophylactic dosing (rate 4.9% vs 7.0%, P=0.01) and intubation by a relative 25% at that point (6.4% vs 8.4%, P=0.03), reported Valentin Fuster MD, PhD, of Mount Sinai Medical Center in New York City.

No differences emerged between the two full-dose anticoagulants, Fuster told attendees at the American College of Cardiology annual meeting late-breaking session, where the findings were presented along with publication in the Journal of the American College of Cardiology.

The findings were overall consistent with prior trials supporting use of therapeutic anticoagulation in this setting, noted session panelist Geoffrey Barnes, MD, MSc, of the University of Michigan in Ann Arbor.

"This data supports it, although not perfectly," he told MedPage Today.

Full-dose prophylactic anticoagulation held substantial benefit for moderately ill COVID-19 patients in the ACTIV-4a, ATTACC, and REMAP-CAP platform trials, among others. In critically ill COVID-19 patients, full-dose prophylactic anticoagulation hasn't proven beneficial and actually appeared harmful. Guidelines have followed suit.

The reason FREEDOM didn't fall fully in line were some international patient selection factors, suggested co-author Gregg W. Stone, MD, also of Mount Sinai.

"The event rate was approximately half of what we anticipated," he said at an ACC press conference. "And the real reason for this was that about 40% of the patients were in India. And while the patients in India had confirmed COVID-19, we assessed that by monitoring 100% of all of the charts, they were a substantially lower risk phenotype: They were younger, they were much more likely to have more [abnormal findings on] chest x-rays on admission, their biomarkers were much lower."

Subgroup analysis showed only a 0.7% rate of the primary endpoint with prophylactic-dose enoxaparin in India, "precluding the possibility to demonstrate a benefit of therapeutic-dose anticoagulation," compared with a rate of 21.5% with prophylactic-dose enoxaparin and 18.0% with therapeutic-dose anticoagulation in trial participants in other countries, the researchers said.

For the 13% of patients enrolled from the U.S., the trial would have met its primary endpoint, with a relative 47% reduction in composite events at 30 days (rate 9.5% vs 17.5%, HR 0.53, 95% CI 0.31-0.91).

ACC press conference study discussant Julia Grapsa, MD, PhD, of King's College London, said she found the new results reassuring.

"From now on, I feel more confident when I have a patient with COVID-19 starting a therapeutic dose," she said. "Also because the bleeding events were insignificant, I feel confident that this patient will have a better prognosis."

Across the board, there was "very little bleeding actually," Fuster noted, with Bleeding Academic Research Consortium types 2, 3, and 5 bleeding rates of 0.1% to 0.5% across groups.

The trial enrolled patients at 76 hospitals in 10 countries between Aug. 26, 2020, and Sept. 19, 2022, who had confirmed COVID-19. It included 3,398 patients (average age 53 years, 59% of whom were men) in the modified intent-to-treat population of those who got at least one dose of the study drug, randomly assigned as follows:

• Prophylactic-dose enoxaparin (40 mg subcutaneously once daily or 30 mg for low kidney function)

• Therapeutic-dose enoxaparin (1 mg/kg subcutaneously every 12 hours)

• Therapeutic-dose apixaban (5 mg orally twice a day or 2.5 mg every 12 hours for a combination of two of the three risk factors of age ≥80 years, weight ≤60 kg [132 lb], and serum creatinine ≥1.5 mg/dL)

While Fuster called it of interest that the oral agent, apixaban, came out similar for outcomes compared with injections of therapeutic enoxaparin, Stone suggested that the practical and cost differences would be trivial for a short course in the hospital.

Yet another issue with the trial was that the event rate dropped internationally during the second half of the study period.

"COVID has changed," Barnes said. "COVID from 2020 is nothing like COVID from 2023 ... We're just not seeing as much of that severe illness as we were before. I actually think we're also not seeing as much thrombosis related to COVID as we did before. Whether it's our therapies or the virus or whatever has changed, we're just seeing less and less of that."

Moreover, while the guidelines support therapeutic-level anticoagulation for non-critically ill hospitalized COVID-19 patients, actual implementation remains widely variable, Barnes added.

"We're still sort of making that gestalt decision of who should get it," he said. "I think the question is still unanswered, mostly because by the time we get good quality trial data COVID has evolved where the data was generated from so people aren't sure how to apply it."

One finding Fuster pointed to as interesting in that regard was a bigger relative benefit to full-dose anticoagulation in patients with a chest x-ray suggesting lung abnormalities although not rising to the level of acute respiratory distress.

For such a COVID-19 patient on low-flow oxygen and an abnormal chest computed tomography or x-ray, "these are patients who no question I would treat with therapeutic anticoagulation," Fuster said.

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