Introduction

Respiratory failure is the leading cause of mortality associated with coronavirus disease 2019 (COVID-19) infection.^1,2 Despite the development of different therapeutic interventions, including highly effective vaccines, the mortality rate associated with COVID-19 pneumonia is in the range of 25-50%.^1-3 Among different mechanisms, an intrinsic COVID-19 vasculopathy is postulated as a driver of the severe respiratory manifestations of the infection,^4,5 and the role of therapeutic anticoagulation as a treatment target remains an area of interest.

FREEDOM COVID Trial

The FREEDOM COVID (FREEDOM COVID-19 Anticoagulation Strategy) trial randomized patients with COVID-19 who were not critically ill into three open-label intervention arms: prophylactic enoxaparin, therapeutic enoxaparin, and apixaban.⁶ The primary effectiveness endpoint was a 30-day composite of all-cause mortality, intensive care unit admission, or systemic thromboembolism. A total of 3,452 patients were randomized at 76 centers in 10 countries, and the study was terminated early because of slow recruitment. The primary endpoint developed in 13.2% of patients receiving prophylactic anticoagulation and in 11.3% of patients receiving therapeutic anticoagulation (either enoxaparin or apixaban) (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p = 0.11). There were more deaths in the prophylactic anticoagulation group (7% vs. 4.9%; p = 0.01), as well as a higher need for mechanical ventilation (8.4% vs. 6.4%; p = 0.03), but no differences in the rate of pulmonary embolism, deep vein thrombosis, or other systemic thrombosis than in the therapeutic anticoagulation group. The rate of major bleeding was overall low and similar between groups.

Subgroup analyses were performed in prespecified subgroups. Older patients (≥53 years of age) had higher rates of the 30-day primary outcome and were more likely to benefit from therapeutic anticoagulation (primary outcome 19.6% vs. 15.4%; HR, 0.77; 95% CI, 0.61-0.97). The 30-day mortality rate was higher in patients with acute respiratory distress syndrome (ARDS), which was reduced with therapeutic anticoagulation (12.3% vs. 7.9%; HR, 0.63; 95% CI, 0.45-0.89). There were striking differences in event rates per country. In India, the primary endpoint occurred in 0.7% of patients compared with 21.5% of patients in other countries in the same arm (17.5% in the United States). In general, patients in India were younger, had fewer comorbidities, and were less likely to have ARDS than patients from other countries.

DISCUSSION

Significant progress has been made on the treatment of COVID-19, including the development of effective primary immunization.^7,8 Yet, the associated mortality rate remains in the range of 25-50%.^1-3 The results of the FREEDOM COVID trial provide some answers about the role of therapeutic anticoagulation in patients with COVID-19, which has been investigated in several trials such as the RAPID COVID COAG (Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care), HEP-COVID (Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients), ACTION (AntiCoagulaTIon cOroNavirus), and INSPIRATION (Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19) trials.^9-12 Whereas the primary endpoint was numerically lower (but not reaching statistical significance) in the combined therapeutic anticoagulation arm, therapeutic anticoagulation was associated with a lower rate of mortality and a lower need for mechanical ventilation. The mechanisms behind this therapeutic effect need to be further elucidated because the incidence of venous thromboembolic events did not differ between groups; perhaps there is a role for anticoagulation for microscopic/in situ pulmonary thrombosis.^13,14 The authors are congratulated for conducting such a challenging trial, addressing an important study question.

References

1. COVID-ICU Group on Behalf of the REVA Network and the COVID-ICU Investigators. Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Med 2021;47:60-73.
2. Anesi GL, Jablonski J, Harhay MO, et al. Characteristics, outcomes, and trends of patients with COVID-19-related critical illness at a learning health system in the United States. Ann Intern Med 2021;174:613-21.
3. Carbonell R, Urgelés S, Rodríguez A, et al.; COVID-19 SEMICYUC Working Group. Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU: a multicentre retrospective cohort study. Lancet Reg Health Eur 2021;Nov 4:[ePub ahead of print].
4. Bikdeli B, Madhavan MV, Jimenez D, et al.; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:2950-73.
5. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020;135:2033-40.
6. Stone GW, Farkouh ME, Lala A,  et al. Randomized trial of anticoagulation strategies for noncritically ill patients hospitalized with COVID-19. J Am Coll Cardiol 2023;81:1747-62.
7. Yuan Y, Jiao B, Qu L, Yang D, Liu R. The development of COVID-19 treatment. Front Immunol 2023;Jan 26:[ePub ahead of print].
8. Rashedi R, Samieefar N, Masoumi N, Mohseni S, Rezaei N. COVID-19 vaccines mix-and-match: the concept, the efficacy and the doubts. J Med Virol 2022;94:1294-9.
9. Sholzberg M, Tang GH, Rahhal H, et al.; RAPID Trial Investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021;375:n2400.
10. Spyropoulos AC, Goldin M, Giannis D, et al.; HEP-COVID Investigators. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med 2021;181:1612-20.
11. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al.; 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. Lancet 2021;397:2253-63.
12. Sadeghipour P, Talasaz AH, Rashidi F, et al.; INSPIRATION Investigators. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 2021;325:1620-30.
13. Mandal AKJ, Kho J, Ioannou A, Van den Abbeele K, Missouris CG. Covid-19 and in situ pulmonary artery thrombosis. Respir Med 2021;Oct 2:[ePub ahead of print].
14. Poor HD. Pulmonary thrombosis and thromboembolism in COVID-19. Chest 2021;160:1471-80.

Clinical Topics: Anticoagulation Management, COVID-19 Hub, Dyslipidemia, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Nonstatins, Novel Agents, Statins

Keywords: Enoxaparin, Heparin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Respiration, Artificial, COVID-19, SARS-CoV-2, Venous Thrombosis, Venous Thromboembolism, Hemorrhage, Anticoagulants, Respiratory Distress Syndrome, Intensive Care Units, Immunization, Embolism, ACC Annual Scientific Session, ACC23

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