Therapeutic vs Prophylactic Anticoagulation for Hospitalized COVID-19

Anticoagulant drug for blood, for prevention or prophylaxis of vascular diseases of heart or brain. Packing of pills with inscription “Anticoagulant Medication” on table
Investigators report findings from the ACTION trial assessing outcomes of therapeutic vs prophylactic oral anticoagulant use among hospitalized adult patients with COVID-19 and elevated D-dimer concentration.

Compared with prophylactic anticoagulation, in-hospital therapeutic anticoagulation with enoxaparin or rivaroxaban followed by rivaroxaban to day 30 did not improve outcomes and increased bleeding in patients with COVID-19 and elevated D-dimer concentration, according to study findings published in The Lancet. Therefore, in the absence of strong indications for oral anticoagulation, the use of direct oral anticoagulants like rivaroxaban should be avoided in this patient population.

According to researchers, compared with other respiratory infections, COVID-19 has been associated with a higher incidence and greater magnitude of thrombotic complications, leading to worse outcomes. Investigators of observational studies have suggested that, compared with no anticoagulation treatment, both prophylactic and therapeutic anticoagulation may be associated with lower rates of in-hospital mortality and less frequent intubation. Therefore, based on low-quality evidence, therapeutic anticoagulation has been considered as a COVID-19 treatment option.

The pragmatic, open-label (with blinded adjudication), multicenter, AntiCoagulaTIon cOroNavirus (ACTION) trial ( Identifier: NCT04394377), conducted at 31 sites in Brazil, is the first randomized clinical trial assessing clinical outcomes of therapeutic oral anticoagulant use vs prophylactic anticoagulation use for adult patients hospitalized with COVID-19 and elevated D-dimer concentration.

Patients hospitalized with COVID-19 and elevated D-dimer concentration who had experienced COVID symptoms for up to 14 days prior to hospitalization were randomly assigned 1:1 to either therapeutic or prophylactic anticoagulation treatment. For stable patients, therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) until day 30. For clinically unstable patients, therapeutic anticoagulation was initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0.3-0.7 IU/mL anti-Xa concentration) until they became stable, after which they were transitioned to the oral rivaroxaban therapy described above until day 30.

Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical composite of time to death, length of hospitalization, or duration of supplemental oxygen use, reported according to the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group), considering treatment as a fixed effect stratified by clinical condition (stable or unstable) truncated at 30 days. The primary safety outcome was 30-day major or clinically relevant nonmajor bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria.

Six hundred and fifteen patients were randomly assigned to either the therapeutic anticoagulation group (n=311) or the prophylactic anticoagulation group (n=304). Of the total participants, 576 (94%) were clinically stable, and 39 (6%) were clinically unstable. One participant in the therapeutic group was not included in the primary analysis as they were lost to follow-up due to withdrawal of consent. There was no significant difference in the primary efficacy outcome between the groups. The number of wins in the therapeutic group was 28,899 (34.8%) compared with 34,288 (41.3%) in the prophylactic group (win ratio 0.86; 95% CI, 0.59-1.22; P =.40). The total number of ties was 19,837 (23.9%).

Results were consistent between clinically stable and unstable participants. Major bleeding or clinically relevant nonmajor bleeding occurred in 26 participants (8%) in the therapeutic anticoagulation group and 7 participants (2%) in the prophylactic anticoagulation group (relative risk [RR] 3.64; 95% CI, 1.61-8.27; P =.0010). Two participants (1%) in the therapeutic anticoagulation group experienced an allergic reaction to the study medication compared with 3 participants (1%) in the prophylactic anticoagulation group.

The study was limited by the risk for bias inherent in the open-label design and by the fact that medication adherence at the conclusion of the study was assessed by obtaining pill counts via telephone calls to patients. Nevertheless, the study investigators concluded, “in patients [hospitalized] with COVID-19 with elevated D-dimer concentration, initial in-hospital therapeutic anticoagulation with rivaroxaban for stable patients or enoxaparin for unstable patients followed by rivaroxaban through 30 days did not improve clinical outcomes and increased bleeding compared with in-hospital prophylactic anticoagulation. Thus, the use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in [hospitalized] patients with COVID-19 who do not have an evidence-based indication for oral anticoagulation. Ongoing clinical trials will address the efficacy and safety of other antithrombotic regimens in patients with COVID-19.”

Disclosure: This clinical trial was supported by Bayer SA. Please see the original reference for a full list of authors’ disclosures.


Lopes RD, de Barros E Silva PGM, Furtado RHM, et al; on behalf of the ACTION Coalition COVID-19 Brazil IV Investigators. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Published online June 12, 2021. Lancet. doi:10.1016/S0140-6736(21)01203-4