Higher-Dose Anticoagulation Not a Sure Bet for Hospitalized COVID Patients

Trials evaluating anticoagulation in patients hospitalized for COVID-19 did not consistently favor stepping up dosing for short-term survival, according to a systematic review and prospective meta-analysis.

Among 22 studies that mostly evaluated heparins, the risk of all-cause mortality 28 days after randomization was:

• Lower with therapeutic-dose versus prophylactic-dose anticoagulation (OR 0.77, 95% CI 0.64-0.93)
• Not statistically different but numerically higher with therapeutic-dose versus intermediate-dose anticoagulation (OR 1.21, 95% CI 0.93-1.58)
• Not statistically different for intermediate-dose versus prophylactic-dose anticoagulation (OR 0.95, 95% CI 0.76-1.19)

Higher-dose anticoagulation was associated with a greater risk for major bleeding, but fewer thromboembolic events, compared with lower-dose anticoagulation, reported Srinivas Murthy, MD, of the University of British Columbia in Vancouver, and collaborators of the WHO REACT group in the Annals of Internal Medicine.

“Associations between dose of anticoagulation and outcome appeared broadly consistent across all predefined patient subgroups, although some analyses had limited power to detect interactions,” they wrote.

“Interpretation of these results is difficult because of the different doses of anticoagulation compared, and because severity of illness at randomization differed for different dose comparisons,” the authors noted. “The lack of dose-dependency of the treatment effect is possibly explained both by the varied patients recruited and doses assessed within trials, and by the balance between risks and benefits.”

What’s more, the 22 trials included in the meta-analysis had primarily evaluated enoxaparin, tinzaparin (Innohep), dalteparin (Fragmin), or unfractionated heparin — with only one study examining a direct oral anticoagulant.

However, how much better one dose of any anticoagulant is than another may now be a moot point.

“Even if the results provided clear direction about the benefits of higher-dose anticoagulation for a particular patient subgroup, whether the results would be appropriately applied to the patients admitted with COVID-19 today is not assured,” noted Claire Shappell, MD, MPH, of Brigham and Women’s Hospital in Boston, and George Anesi, MD, MSCE, MBE, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

In their accompanying editorial, they nevertheless commended the prospective nature of the meta-analysis design as it allowed for higher-quality data harmonization across a larger sample.

“We should follow the authors’ lead and strive for ever greater emphasis on the prospective harmonization of interventions and outcomes between trials to facilitate comparison and pooling of results,” Shappell and Anesi wrote. “At the same time, we must anticipate the need to analyze trial data in the face of changing pathogens and pandemic dynamics and not assume that interventions shown beneficial under different circumstances remain so when important changes have occurred.”

The meta-analysis included 11,733 hospitalized COVID-19 patients from 21 countries in studies that had been published from 2020 to 2023. Median patient age ranged from around 50 to 74 years, and most patients were men.

The study authors acknowledged some inconsistencies in the reporting of severe adverse events across trials. This left them without sufficient data on the severity of hemorrhages or specific thromboembolic events to perform those analyses.

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