High-Dose PA, TA Do Not Improve Mortality in Hypoxemic COVID-19 Pneumonia

In patients with hypoxemic COVID-19 pneumonia, high-dose prophylactic anticoagulation (HD-PA) and therapeutic anticoagulation (TA) did not improve mortality and time to clinical improvement compared with standard-dose prophylactic anticoagulation (SD-PA) investigators reported in JAMA Internal Medicine.

Investigators for the Anticoagulation COVID-19 (ANTICOVID) trial (ClinicalTrials.gov Identifier: NCT04808882) sought to identify the most effective and safe anticoagulation therapy for patients with hypoxemic COVID-19 pneumonia, who have a high risk of thrombosis and bleeding related to anti-coagulation. The ANTICOVID trial therefore compared the mortality and disease duration outcomes of TA, HD-PA, and SD-PA.

The open-label, randomized trial involved 334 adult patients with hypoxic COVID-19 pneumonia requiring supplemental oxygen from 23 health centers in France from April 14 to December 13, 2021. No participants had pre-existing macrovascular thrombosis and 90% were in the intensive care unit. Participants (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men) were randomly assigned to receive SD-PA (n=114), HD-PA (n=110), or TA (n=110) using low-molecular weight heparin, either for 14 days or until hospital discharge or 48 hours after weaning from supplemental oxygen, whichever came first.

The primary efficacy outcomes assessed at day 28 were all-cause mortality and time to clinical improvement. Another outcome of interest was a composite of thrombosis, bleeding, and death (termed the “net clinical outcome”). The data analyses were conducted from April 13, 2022, to January 3, 2023.

Through day 28, the ranked composite primary outcome was not significantly different among the treatment groups. The HD-PA group and the SD-PA group had a similar probability of having a more favorable outcome, which also occurred for the TA group vs the SD-PA group, and for the TA group vs the HD-PA group. The probability of a more favorable primary outcome for HD-PA vs SD-PA resulted in an effect size of 47.3% (95% CI, 39.9-54.8), compared with 50.9% (95% CI, 43.4-58.3) for TA vs SD-PA and 53.5% (95% CI, 45.8-60.9) for TA vs HD-PA. Results of the individual components of the primary outcome were consistent with the primary analysis.

The net clinical outcome was significantly decreased in the HD-PA group vs the SD-PA group, and no significant difference was observed between the TA and SD-PA groups or between the HD-PA and the TA groups. The net clinical outcome was an absolute difference of -13.5 (95% CI, -2.6 to -24.3) for HD-PA vs SD-PA, compared with -9.8 (95% CI, 1.4 to -21.1) for TA vs SD-PA, and 3.6 (95% CI, 13.8 to -6.5) for TA vs HD-PA.

Chest computed tomography with pulmonary angiogram (CTPA) screening for pulmonary artery thrombosis, which was conducted in all participants upon study enrollment, was again conducted at day 28 in 69 patients (21%). Within this group, researchers found the rate of positive CTPA to be significantly higher for the SD-PA group vs the HD-PA and TA groups. Major bleeding occurred in 3 (2.2%) patients in the SD-PA group, 4 (3.6%) in the HD-PA group, and 4 (3.6%) in the TA group, and included 3 fatal bleedings (1 spinal bleeding in the HD-PA group and 1 hemoptysis and 1 gastrointestinal bleeding in the SD-PA group).

Trial limitations include the open-label anticoagulation assignment and the relatively small number of patients. Also, the rate of pulmonary artery thrombosis detected on prerandomization CTPA was lower than expected, and microvascular thrombosis on CTPA was not quantified.

“The findings of this randomized clinical trial support the routine empirical use of HD-PA in patients with severe hypoxemic COVID-19 pneumonia,” stated the researchers.

Disclosure: This trial was an investigator-initiated study with financial support from LEO Pharma. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.