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Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. 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. Lancet. 2021 Jun 12;397(10291):2253-2263. doi: 10.1016/S0140-6736(21)01203-4. Epub 2021 Jun 4. (Original study)

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.

METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged =18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or 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) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.

FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.

INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Discipline Area Score
Intensivist/Critical Care 7 / 7
Hemostasis and Thrombosis 7 / 7
Infectious Disease 7 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Comments from MORE raters

Hemostasis and Thrombosis rater

Important RCT of therapeutic vs prophylactic AC for patients admitted with COVID. Most notably, 95% of the study population was considered clinically stable (not critically ill, no vent/pressor) and were randomized to treatment-dose DOAC vs prophalactic-dose LMWH/UFH. No benefit and increased bleeding noted. Limited by open-label design. These results need to be reconciled with final report from the linked RCTs, which preliminarily found a benefit from treatment-dose LMWH in a similar population.

Hospital Doctor/Hospitalists rater

My concern with this trial is its generalizability. My impression was that the trial participants were less ill than those I cared for with COVID-19. Therefore the lack of benefit they found might be due to a lack of power. Only 6% of patients in this trial were "clinically unstable", whereas the majority of COVID-19 patients I cared for, none of whom were in the ICU, were on high flow NC or PPV. It is unclear whether these patients would be considered "clinically stable" or "unstable in this trial. Additionally, the DDimer threshold for inclusion seemed to be low-only greater than the ULN for each lab, again suggesting that this population may have been less ill than those I cared for. It would have been helpful to have seen actual DDimer levels for each group, type of oxygen support, duration of hospitalization etc.

Hospital Doctor/Hospitalists rater

This is an interesting study showing that therapeutic anticoagulation with rivaroxaban and enoxaparin did not lead to better outcomes. Another important point is that this study is suggesting that the type of anticoagulation and route of administration influence the clinical outcomes.

Intensivist/Critical Care rater

Waiting impatiently for final report of several studies.

Internal Medicine rater

A well done trial with important results. Difficult to integrate with ACTIV-4/REMAP/ATTAC results.
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