Therapeutic- vs. Prophylactic-Dose Anticoagulation Reduces Mortality in Patients Hospitalized For COVID-19
Therapeutic- compared with prophylactic-dose anticoagulation was associated with reduced 28-day mortality in patients hospitalized for COVID-19, according to a prospective meta-analysis from the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group published Dec. 24 in the Annals of Internal Medicine.
The REACT Working Group synthesized results of 20 eligible randomized trials identified in the WHO's International Clinical Trials Registry Platform and ClinicalTrials.gov from August 2020 to September 2024, with patients from 21 countries. Most trials compared two anticoagulation doses using heparin. The primary outcome was 28-day all-cause mortality.
Trial interventions were grouped into three exposure comparisons with the following results:
Therapeutic- vs. prophylactic-dose anticoagulation comparison: Of 6,297 patients from 11 trials, data were available on the primary outcome for 3,189 patients (252 deaths) in the therapeutic-dose arm and 3,108 patients (304 deaths) in the prophylactic-dose arm, revealing a summary odds ratio [OR] of 0.77 (95% CI, 0.64-0.93). The absolute mortality risk was 8% and 10% in the two arms respectively. Of note, the summary OR was 0.77 among the 5,447 patients required low or no oxygenation at randomization, 0.71 for the 714 patients receiving noninvasive ventilation (NIV) or high-flow nasal oxygen (HFNO) and 1.15 for the 123 patients receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).
Therapeutic- vs. intermediate-dose anticoagulation comparison: Of 1,798 patients from six trials, 991 (55%) and 363 (20%) were receiving NIV and IMV at randomization, respectively. Primary outcome data on 888 patients (204 deaths) in the therapeutic-dose arm and 915 patients (194 deaths) in the intermediate-dose showed a summary OR of 1.21 (95% CI, 0.93-1.58), with an absolute mortality risk of 27% and assumed 24% respectively. Among 322 patients receiving no or low oxygenation at randomization, the summary OR was 2.24; of 1,063 receiving NIV or HFNO it was 1.18 and of 341 patients receiving IMV or ECMO it was 1.13.
Intermediate- vs. prophylactic-dose anticoagulation comparison: Of 3,897 patients from 10 trials, primary outcome data from 1,939 patients (205 deaths) and 1,958 patients (215 deaths) from the two arms, respectively, demonstrated a summary OR of 0.95 (95% CI, 0.76-1.19). For the intermediate arm, there was little change in the absolute mortality risk and an assumed 10% risk for the prophylactic arm.
In patients hospitalized with COVID-19, 28-day all-cause mortality was reduced with a therapeutic rather than a prophylactic dose of anticoagulation, write the authors. Further, they note that mortality was higher for therapeutic vs. intermediate-dose anticoagulation but that the comparison was not estimated precisely, and mortality was similar for intermediate-dose and prophylactic-dose anticoagulation.
The authors acknowledge that "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."
In an accompanying editorial comment, Claire N. Shapell, MD, MPH, and George L. Anesi, MD, write that while the central conclusion of the meta-analysis is positive, the "full results are more nuanced." Benefit was not seen with the higher dose in the other two comparisons and differences in effect estimates between exposure groups are not what would be expected in a causal dose-dependent relationship. Furthermore they note there were differences among the patients between comparisons.
Clinical Topics: Anticoagulation Management, COVID-19 Hub
Keywords: COVID-19, Anticoagulants, World Health Organization