Trial Suggests Anticoagulation 'Sweet Spot' for COVID in the ICU

No anticoagulation strategy came out a clear winner for hard outcomes in a hypoxic and largely critically ill COVID-19 patient population, although higher-dose prophylaxis did decrease risk of developing thrombosis, a French trial showed.

Therapeutic anticoagulation, and high-dose prophylactic anticoagulation (HD-PA) came out on par with standard-dose prophylactic anticoagulation for the hierarchical primary endpoint of mortality and clinical improvement at 28 days, Vincent Labbé, MD, of the Hôpital Universitaire de Bruxelles, Belgium, and colleagues reported in JAMA Internal Medicine.

The probability that a random intervention group patient would have a more favorable outcome on that composite endpoint than an individual randomly selected from the comparator group was similar for all the comparisons:

• HD-PA and standard-dose prophylaxis groups: 47.3% vs 52.7% (P=0.48)
• Therapeutic dose anticoagulation and standard-dose prophylaxis: 50.9% vs 49.1% (P=0.82)
• Therapeutic dose anticoagulation and HD-PA: 53.5% vs 46.5% (P=0.37)

However, HD-PA did improve a net clinical outcome measure, "driven by a 4-fold reduction in de novo thrombosis rate" compared with standard-dose thromboprophylaxis (5.5% vs 20.2%; absolute difference -14.7, 95% CI -6.2 to -23.2) in the face of no increase in major bleeding. "This benefit was not observed with therapeutic-dose anticoagulation," the researchers noted.

Their conclusion: "The findings of this randomized clinical trial support the routine empirical use of HD-PA in patients with severe hypoxemic COVID-19 pneumonia."

The findings generally align with a number of other studies showing that increasing intensity of anticoagulation reduces the heightened risk of venous thromboembolism in COVID-19 patients who are hypoxemic and require hospitalization, although with somewhat different findings between general wards and intensive care unit (ICU).

Randomized controlled trials (RCTs) like REMAP-CAP, ACTIV4, ATTACC, and COVID-PACT "offer a level of consistency and clinical guidance" for COVID-19 patients, in that therapeutic-level anticoagulation has reduced risk of progression and cut days on organ support in non-ICU admissions but reduced venous thromboembolism at the price of more nonfatal bleeding in the ICU, noted an editorial accompanying Labbé's ANTICOVID trial.

"Could high-dose prophylactic anticoagulation represent the sweet spot for efficacy and safety?" posited editorialists Richard C. Becker, MD, of the University of Cincinnati Heart, Lung, and Vascular Institute, and Thomas L. Ortel, MD, PhD, of Duke University Medical Center in Durham, North Carolina.

They concluded that "for treating patients hospitalized with hypoxemic COVID-19 pneumonia: a higher dose of prophylactic [low molecular-weight heparin] (twice the standard dose) is necessary and sufficient to prevent thrombotic complications without increasing the rate of major bleeding."

Why heparin-based anticoagulant therapy at any intensity has not proven to lower mortality despite tackling a common pathobiological underpinning for poor outcomes -- COVID-19 coagulopathy and endotheliopathy -- is a lingering question, Becker and Ortel noted.

"Our study results together with those of previous RCTs support the premise that the role of microvascular thrombosis in worsening organ dysfunction may be narrower than estimated," Labbé and colleagues wrote.

Their ANTICOVID trial included 334 patients (mean age 58.3 years, 32.3% women) with hypoxemic COVID-19 pneumonia requiring supplemental oxygen admitted within 72 hours of enrollment at 23 health centers in France from April 14 to Dec. 13, 2021, a time during which most patients had the Delta variant. Enrolled patients couldn't have any initial thrombosis detected on chest CT with pulmonary angiogram and were selected as a low bleeding risk population.

They were randomly assigned 1:1:1 to immediately start open-label treatment with standard-dose prophylactic anticoagulation, a dose two times higher (HD-PA), or therapeutic dose anticoagulation using low-molecular-weight or unfractionated heparin for 14 days or until hospital discharge or weaning off of supplemental oxygen for 48 consecutive hours, whichever came first.

Nearly all of the patients (89.5%) were in the ICU at enrollment, and most (60.8%) were on high-flow nasal oxygen.

Limitations of the study included the open-label design, raising potential risk for biases. "Performance bias cannot be denied because time to clinical improvement can be subjective," the researchers acknowledged. "Likewise, detection bias cannot be denied because potential events (especially incidental thromboses) were less likely to be investigated in patients treated with [the higher anticoagulant doses]."

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